Michele G. Sullivan

Major Finding: Children who received at least one antibiotic during the first year of life were 2.6 times more likely to develop inflammatory bowel disease during childhood than were those who did not take an antibiotic during infancy.

Data Source: Case-control study of 393 children.

Disclosures: Mr. Shaw said he had no conflicts of interest. Dr. Bernstein disclosed relationships with Abbott Canada, Shire Pharmaceuticals, and UCB Pharma. Dr. Proctor disclosed relationships with Abbott Laboratories and Genentech.

NEW ORLEANS — Children who receive antibiotics during their first year of life may be at increased risk of developing inflammatory bowel disease before age 10, based on a case-control study presented at the meeting.

The investigators found that children with inflammatory bowel disease were almost three times more likely to have received at least one antibiotic prescription before reaching their first birthday, compared with children in a control group.

The findings are enough to give pediatricians a moment's pause before reaching for the prescription pad, said lead author Dr. Charles Bernstein, head of gastroenterology and director of the University of Manitoba IBD clinical and research center.

“This association may give us cause to think about the overuse of antibiotics in young children, especially in those who may be at risk for developing IBD,” he said in a prepared statement.

His protg, Manitoba University doctoral student Souradet Y. Shaw, presented the data at the meeting. The investigators conducted a case-control study that used information extracted from the University of Manitoba Inflammatory Bowel Disease Epidemiological Database, which contains information on every IBD patient diagnosed in the province since 1984.

The investigators found 36 cases of pediatric inflammatory bowel disease with full prescribing records. The controls were 360 children without IBD who were matched for age, sex, and region of residence.

Most of the pediatric IBD patients had Crohn's disease (79%); the rest had ulcerative colitis. The average age at diagnosis was 8 years.

Antibiotic use was significantly more common among the cases than the controls; 58% of the cases (21 children) had received at least one prescription during their first year of life, compared with 39% (139) of the controls. About half of those prescriptions were for otitis media.

A regression analysis indicated that cases were 2.6 times more likely than were controls to have taken antibiotics during infancy. When the investigators controlled for sex, however, the association remained significant only for boys.

“There does seem to be some link between getting an antibiotic in the first year of life and developing an inflammatory bowel disease in childhood,” Mr. Shaw said. “But this was a small sample size, and shows only an association—not a causative effect.” However, the findings are strong enough to warrant further investigation in larger groups, he said.

He speculated that early transformation of the gut biome could predispose a child to inflammatory bowel disease. “One possible mechanism is that early antibiotics might change the balance between the 'good' flora and the 'bad' flora,” he said. “There may also be some interference with proper immune system exposure to the bacteria in the gut.”

Dr. Mara T. Abreu commented in an interview, “Something is different about the environment in the developed world that leads to an increase in IBD. Therefore, it is reasonable to consider that changes in the gut microbiome may predispose to IBD.

“We also know that innate immune defects are associated with IBD, so it may be that these patients need antibiotics more often. Nevertheless, there are many good reasons to discourage needless antibiotic use in children,” said Dr. Abreu, professor of medicine and chief, division of gastroenterology, University of Miami.

Dr. Bernstein also cautioned against interpreting the findings as indicating a cause of IBD. “It's also possible that children who require antibiotics may, for other reasons, be predisposed to developing IBD,” he said. “However, if the use of antibiotics is associated with triggering IBD, it may be by [affecting] bowel flora at a vulnerable point in development.”

Dr. Deborah Proctor, who moderated the session, agreed. “A baby is born with a sterile GI tract and it gets populated with bacteria in the first 1–2 years of life. The use of antibiotics during this time could change the flora and therefore could change the ratio of bacteria. This is all speculation, since this study did not address a causal association, but if it holds up in review, physicians should think twice about prescribing antibiotics in infants,” said Dr. Proctor, medical director of the inflammatory bowel disease program at Yale University, New Haven, Conn.

Reporting from the AAP NCE 2010

Pediatric News reporters Sherry Boschert (left) and Alicia Ault will be onsite at NCE 2010. They'll be bringing you the specialty-specific news that has made Pediatric News the best-read publication in the field.

Vitals

Major Finding: Children who received at least one antibiotic during the first year of life were 2.6 times more likely to develop inflammatory bowel disease during childhood than were those who did not take an antibiotic during infancy.

Data Source: Case-control study of 393 children.

Disclosures: Mr. Shaw said he had no conflicts of interest. Dr. Bernstein disclosed relationships with Abbott Canada, Shire Pharmaceuticals, and UCB Pharma. Dr. Proctor disclosed relationships with Abbott Laboratories and Genentech.

NEW ORLEANS — Children who receive antibiotics during their first year of life may be at increased risk of developing inflammatory bowel disease before age 10, based on a case-control study presented at the meeting.

The investigators found that children with inflammatory bowel disease were almost three times more likely to have received at least one antibiotic prescription before reaching their first birthday, compared with children in a control group.

The findings are enough to give pediatricians a moment's pause before reaching for the prescription pad, said lead author Dr. Charles Bernstein, head of gastroenterology and director of the University of Manitoba IBD clinical and research center.

“This association may give us cause to think about the overuse of antibiotics in young children, especially in those who may be at risk for developing IBD,” he said in a prepared statement.

His protg, Manitoba University doctoral student Souradet Y. Shaw, presented the data at the meeting. The investigators conducted a case-control study that used information extracted from the University of Manitoba Inflammatory Bowel Disease Epidemiological Database, which contains information on every IBD patient diagnosed in the province since 1984.

The investigators found 36 cases of pediatric inflammatory bowel disease with full prescribing records. The controls were 360 children without IBD who were matched for age, sex, and region of residence.

Most of the pediatric IBD patients had Crohn's disease (79%); the rest had ulcerative colitis. The average age at diagnosis was 8 years.

Antibiotic use was significantly more common among the cases than the controls; 58% of the cases (21 children) had received at least one prescription during their first year of life, compared with 39% (139) of the controls. About half of those prescriptions were for otitis media.

A regression analysis indicated that cases were 2.6 times more likely than were controls to have taken antibiotics during infancy. When the investigators controlled for sex, however, the association remained significant only for boys.

“There does seem to be some link between getting an antibiotic in the first year of life and developing an inflammatory bowel disease in childhood,” Mr. Shaw said. “But this was a small sample size, and shows only an association—not a causative effect.” However, the findings are strong enough to warrant further investigation in larger groups, he said.

He speculated that early transformation of the gut biome could predispose a child to inflammatory bowel disease. “One possible mechanism is that early antibiotics might change the balance between the 'good' flora and the 'bad' flora,” he said. “There may also be some interference with proper immune system exposure to the bacteria in the gut.”

Dr. Mara T. Abreu commented in an interview, “Something is different about the environment in the developed world that leads to an increase in IBD. Therefore, it is reasonable to consider that changes in the gut microbiome may predispose to IBD.

“We also know that innate immune defects are associated with IBD, so it may be that these patients need antibiotics more often. Nevertheless, there are many good reasons to discourage needless antibiotic use in children,” said Dr. Abreu, professor of medicine and chief, division of gastroenterology, University of Miami.

Dr. Bernstein also cautioned against interpreting the findings as indicating a cause of IBD. “It's also possible that children who require antibiotics may, for other reasons, be predisposed to developing IBD,” he said. “However, if the use of antibiotics is associated with triggering IBD, it may be by [affecting] bowel flora at a vulnerable point in development.”

Dr. Deborah Proctor, who moderated the session, agreed. “A baby is born with a sterile GI tract and it gets populated with bacteria in the first 1–2 years of life. The use of antibiotics during this time could change the flora and therefore could change the ratio of bacteria. This is all speculation, since this study did not address a causal association, but if it holds up in review, physicians should think twice about prescribing antibiotics in infants,” said Dr. Proctor, medical director of the inflammatory bowel disease program at Yale University, New Haven, Conn.

Reporting from the AAP NCE 2010

Pediatric News reporters Sherry Boschert (left) and Alicia Ault will be onsite at NCE 2010. They'll be bringing you the specialty-specific news that has made Pediatric News the best-read publication in the field.

Vitals

Major Finding: Children who received at least one antibiotic during the first year of life were 2.6 times more likely to develop inflammatory bowel disease during childhood than were those who did not take an antibiotic during infancy.

Data Source: Case-control study of 393 children.

Disclosures: Mr. Shaw said he had no conflicts of interest. Dr. Bernstein disclosed relationships with Abbott Canada, Shire Pharmaceuticals, and UCB Pharma. Dr. Proctor disclosed relationships with Abbott Laboratories and Genentech.

NEW ORLEANS — Children who receive antibiotics during their first year of life may be at increased risk of developing inflammatory bowel disease before age 10, based on a case-control study presented at the meeting.

The investigators found that children with inflammatory bowel disease were almost three times more likely to have received at least one antibiotic prescription before reaching their first birthday, compared with children in a control group.

The findings are enough to give pediatricians a moment's pause before reaching for the prescription pad, said lead author Dr. Charles Bernstein, head of gastroenterology and director of the University of Manitoba IBD clinical and research center.

“This association may give us cause to think about the overuse of antibiotics in young children, especially in those who may be at risk for developing IBD,” he said in a prepared statement.

His protg, Manitoba University doctoral student Souradet Y. Shaw, presented the data at the meeting. The investigators conducted a case-control study that used information extracted from the University of Manitoba Inflammatory Bowel Disease Epidemiological Database, which contains information on every IBD patient diagnosed in the province since 1984.

The investigators found 36 cases of pediatric inflammatory bowel disease with full prescribing records. The controls were 360 children without IBD who were matched for age, sex, and region of residence.

Most of the pediatric IBD patients had Crohn's disease (79%); the rest had ulcerative colitis. The average age at diagnosis was 8 years.

Antibiotic use was significantly more common among the cases than the controls; 58% of the cases (21 children) had received at least one prescription during their first year of life, compared with 39% (139) of the controls. About half of those prescriptions were for otitis media.

A regression analysis indicated that cases were 2.6 times more likely than were controls to have taken antibiotics during infancy. When the investigators controlled for sex, however, the association remained significant only for boys.

“There does seem to be some link between getting an antibiotic in the first year of life and developing an inflammatory bowel disease in childhood,” Mr. Shaw said. “But this was a small sample size, and shows only an association—not a causative effect.” However, the findings are strong enough to warrant further investigation in larger groups, he said.

He speculated that early transformation of the gut biome could predispose a child to inflammatory bowel disease. “One possible mechanism is that early antibiotics might change the balance between the 'good' flora and the 'bad' flora,” he said. “There may also be some interference with proper immune system exposure to the bacteria in the gut.”

Dr. Mara T. Abreu commented in an interview, “Something is different about the environment in the developed world that leads to an increase in IBD. Therefore, it is reasonable to consider that changes in the gut microbiome may predispose to IBD.

“We also know that innate immune defects are associated with IBD, so it may be that these patients need antibiotics more often. Nevertheless, there are many good reasons to discourage needless antibiotic use in children,” said Dr. Abreu, professor of medicine and chief, division of gastroenterology, University of Miami.

Dr. Bernstein also cautioned against interpreting the findings as indicating a cause of IBD. “It's also possible that children who require antibiotics may, for other reasons, be predisposed to developing IBD,” he said. “However, if the use of antibiotics is associated with triggering IBD, it may be by [affecting] bowel flora at a vulnerable point in development.”

Dr. Deborah Proctor, who moderated the session, agreed. “A baby is born with a sterile GI tract and it gets populated with bacteria in the first 1–2 years of life. The use of antibiotics during this time could change the flora and therefore could change the ratio of bacteria. This is all speculation, since this study did not address a causal association, but if it holds up in review, physicians should think twice about prescribing antibiotics in infants,” said Dr. Proctor, medical director of the inflammatory bowel disease program at Yale University, New Haven, Conn.

Reporting from the AAP NCE 2010

Pediatric News reporters Sherry Boschert (left) and Alicia Ault will be onsite at NCE 2010. They'll be bringing you the specialty-specific news that has made Pediatric News the best-read publication in the field.

Vitals

Major Finding: Particular variants of the TOMM40 gene are associated with declines in regional gray matter volume and in verbal learning and memory that may presage Alzheimer's disease.

Data Source: Two prospective studies of healthy volunteers with TOMM40 genotyping, one involving MR imaging of 117 participants and another involving verbal learning and memory testing in 337 participants.

Disclosures: Both studies were funded by the National Institute on Aging. Neither investigator had any potential financial conflict.

People who have a newly discovered gene variant that increases the risk of Alzheimer's disease appear to experience subtle changes in both cognition and brain structure years before even the earliest signs of Alzheimer's appear.

The gene, TOMM40, was associated with small but measurable declines in verbal learning and memory, and with decreases in gray matter volume, particularly in the posterior cingulate and precuneus–both areas that are highly involved with memory retrieval.

“Brain changes in these regions are particularly interesting because they are also associated with a high amyloid burden in people with Alzheimer's,” Sterling Johnson, Ph.D., said in an interview. “Many studies have shown that these areas are active when you are recalling the recent past. So seeing changes there fits very nicely with a major symptom of Alzheimer's: recent memory loss.”

Dr. Johnson and his colleague, Dr. Mark Sager, both of the University of Wisconsin, Madison, both said the work may open an important door on the ability to risk-stratify patients for early treatment, potentially identifying them before they experience significant brain damage from the disease.

“Right now we're spending billions of dollars on trying to find a disease-modifying therapy, but we don't really know who we would give that to,” Dr. Johnson said.

In the same way that those with high cholesterol benefit most from statins, patients with a demonstrated risk of Alzheimer's would be the best candidates for any drug therapy, he noted. “Our work may eventually be able to identify in a much more targeted way groups of people who could benefit the most from early intervention, hopefully early enough to prevent them from having serious cognitive loss from Alzheimer's.”

TOMM40 has variable lengths that are defined by how many thymidine bases are contained in a specific section of the gene. The very long form (30 or more thymidine bases) is associated with an earlier onset of Alzheimer's disease, while the very short length (20 or fewer) is associated with a later onset. Some people have a long form (between 20 and 30 bases) that confers intermediate risk for Alzheimer's disease.

In 2009, Dr. Allen D. Roses of Duke University, Durham, N.C., first showed that among patients who developed Alzheimer's after 60 years of age and were homozygous or heterozygous for the apolipoprotein E e3 (APOE-3) allele, those with two copies of the long TOMM40 developed the disease an average of 7 years earlier than did those with shorter TOMM40 lengths (Pharmacogenomics J. 2009 Dec. 22 [doi:10.1038/tpj.2009.69]).

Dr. Johnson's study consisted of 117 healthy middle-aged volunteers (mean age, 57 years) who were known to be homozygous for the APOE-3 allele. APOE-3 homozygotes are thought to have a neutral risk for Alzheimer's disease. He then tested the subjects to determine what variant of TOMM40 they had.

In Dr. Johnson's study group, 38 patients were homozygous for the very short-length TOMM40, 44 had one short and one long or very long allele, and 35 were homozygous for the very long form of TOMM40.

All of the volunteers underwent brain scanning with voxel-based morphometry to assess gray matter volume in different brain regions.

The subjects with two copies of the very long TOMM40 allele had significantly less gray matter in both the ventral posterior cingulate and the precuneus than did those with two short alleles. These are both regions that show early deterioration in late-onset Alzheimer's disease.

“This is very important, because we are finding brain changes in people who are quite young,” Dr. Johnson said.

“The brain differences between the groups were very similar to, but less severe than, what is observed in full-blown Alzheimer's. It may be that the TOMM40 gene will be a useful measure of Alzheimer's risk in middle age, but additional research with longitudinal follow-up is necessary.”

Dr. Sager examined the gene's potential effect on memory in a cohort of 337 adults (mean age, 54), who were genotyped for APOE and TOMM40. Of these, 128 were homozygous for the short form of TOMM40, indicating a lower risk. The long or very long forms were seen in 219 subjects. In the low-risk group, 57% had a family history of Alzheimer's, compared with 77% of the high-risk group–a significant difference.

All subjects took the Auditory-Verbal Learning Test, which involves five trials of learning two 15-word sets. While the mean scores for both subject groups were within the normal range, the mean was significantly lower in the group with longer forms of TOMM40.

“We found significant changes in verbal learning and memory–changes that are traditionally the first cognitive changes seen in Alzheimer's,” Dr. Sager said. “Even after adjustment for age, gender, and education, people with the long form of TOMM40 were performing lower than those without it.”

He stressed that none of the subjects in either the brain volume study or the memory study had any observable memory difficulties in their everyday life. “But these findings of gray matter loss and cognitive changes in these relatively young people are very important”and suggest that “we may have the ability to find people at risk of Alzheimer's very early on in the disease process, far in advance of any significant cognitive problems.”

Patients with short TOMM40 had greater gray matter volume than did those patients with two very long versions.

Source Courtesy Sterling Johnson, Ph.D.

Major Finding: Particular variants of the TOMM40 gene are associated with declines in regional gray matter volume and in verbal learning and memory that may presage Alzheimer's disease.

Data Source: Two prospective studies of healthy volunteers with TOMM40 genotyping, one involving MR imaging of 117 participants and another involving verbal learning and memory testing in 337 participants.

Disclosures: Both studies were funded by the National Institute on Aging. Neither investigator had any potential financial conflict.

People who have a newly discovered gene variant that increases the risk of Alzheimer's disease appear to experience subtle changes in both cognition and brain structure years before even the earliest signs of Alzheimer's appear.

The gene, TOMM40, was associated with small but measurable declines in verbal learning and memory, and with decreases in gray matter volume, particularly in the posterior cingulate and precuneus–both areas that are highly involved with memory retrieval.

“Brain changes in these regions are particularly interesting because they are also associated with a high amyloid burden in people with Alzheimer's,” Sterling Johnson, Ph.D., said in an interview. “Many studies have shown that these areas are active when you are recalling the recent past. So seeing changes there fits very nicely with a major symptom of Alzheimer's: recent memory loss.”

Dr. Johnson and his colleague, Dr. Mark Sager, both of the University of Wisconsin, Madison, both said the work may open an important door on the ability to risk-stratify patients for early treatment, potentially identifying them before they experience significant brain damage from the disease.

“Right now we're spending billions of dollars on trying to find a disease-modifying therapy, but we don't really know who we would give that to,” Dr. Johnson said.

In the same way that those with high cholesterol benefit most from statins, patients with a demonstrated risk of Alzheimer's would be the best candidates for any drug therapy, he noted. “Our work may eventually be able to identify in a much more targeted way groups of people who could benefit the most from early intervention, hopefully early enough to prevent them from having serious cognitive loss from Alzheimer's.”

TOMM40 has variable lengths that are defined by how many thymidine bases are contained in a specific section of the gene. The very long form (30 or more thymidine bases) is associated with an earlier onset of Alzheimer's disease, while the very short length (20 or fewer) is associated with a later onset. Some people have a long form (between 20 and 30 bases) that confers intermediate risk for Alzheimer's disease.

In 2009, Dr. Allen D. Roses of Duke University, Durham, N.C., first showed that among patients who developed Alzheimer's after 60 years of age and were homozygous or heterozygous for the apolipoprotein E e3 (APOE-3) allele, those with two copies of the long TOMM40 developed the disease an average of 7 years earlier than did those with shorter TOMM40 lengths (Pharmacogenomics J. 2009 Dec. 22 [doi:10.1038/tpj.2009.69]).

Dr. Johnson's study consisted of 117 healthy middle-aged volunteers (mean age, 57 years) who were known to be homozygous for the APOE-3 allele. APOE-3 homozygotes are thought to have a neutral risk for Alzheimer's disease. He then tested the subjects to determine what variant of TOMM40 they had.

In Dr. Johnson's study group, 38 patients were homozygous for the very short-length TOMM40, 44 had one short and one long or very long allele, and 35 were homozygous for the very long form of TOMM40.

All of the volunteers underwent brain scanning with voxel-based morphometry to assess gray matter volume in different brain regions.

The subjects with two copies of the very long TOMM40 allele had significantly less gray matter in both the ventral posterior cingulate and the precuneus than did those with two short alleles. These are both regions that show early deterioration in late-onset Alzheimer's disease.

“This is very important, because we are finding brain changes in people who are quite young,” Dr. Johnson said.

“The brain differences between the groups were very similar to, but less severe than, what is observed in full-blown Alzheimer's. It may be that the TOMM40 gene will be a useful measure of Alzheimer's risk in middle age, but additional research with longitudinal follow-up is necessary.”

Dr. Sager examined the gene's potential effect on memory in a cohort of 337 adults (mean age, 54), who were genotyped for APOE and TOMM40. Of these, 128 were homozygous for the short form of TOMM40, indicating a lower risk. The long or very long forms were seen in 219 subjects. In the low-risk group, 57% had a family history of Alzheimer's, compared with 77% of the high-risk group–a significant difference.

All subjects took the Auditory-Verbal Learning Test, which involves five trials of learning two 15-word sets. While the mean scores for both subject groups were within the normal range, the mean was significantly lower in the group with longer forms of TOMM40.

“We found significant changes in verbal learning and memory–changes that are traditionally the first cognitive changes seen in Alzheimer's,” Dr. Sager said. “Even after adjustment for age, gender, and education, people with the long form of TOMM40 were performing lower than those without it.”

He stressed that none of the subjects in either the brain volume study or the memory study had any observable memory difficulties in their everyday life. “But these findings of gray matter loss and cognitive changes in these relatively young people are very important”and suggest that “we may have the ability to find people at risk of Alzheimer's very early on in the disease process, far in advance of any significant cognitive problems.”

Patients with short TOMM40 had greater gray matter volume than did those patients with two very long versions.

Source Courtesy Sterling Johnson, Ph.D.

Major Finding: Particular variants of the TOMM40 gene are associated with declines in regional gray matter volume and in verbal learning and memory that may presage Alzheimer's disease.

Data Source: Two prospective studies of healthy volunteers with TOMM40 genotyping, one involving MR imaging of 117 participants and another involving verbal learning and memory testing in 337 participants.

Disclosures: Both studies were funded by the National Institute on Aging. Neither investigator had any potential financial conflict.

People who have a newly discovered gene variant that increases the risk of Alzheimer's disease appear to experience subtle changes in both cognition and brain structure years before even the earliest signs of Alzheimer's appear.

The gene, TOMM40, was associated with small but measurable declines in verbal learning and memory, and with decreases in gray matter volume, particularly in the posterior cingulate and precuneus–both areas that are highly involved with memory retrieval.

“Brain changes in these regions are particularly interesting because they are also associated with a high amyloid burden in people with Alzheimer's,” Sterling Johnson, Ph.D., said in an interview. “Many studies have shown that these areas are active when you are recalling the recent past. So seeing changes there fits very nicely with a major symptom of Alzheimer's: recent memory loss.”

Dr. Johnson and his colleague, Dr. Mark Sager, both of the University of Wisconsin, Madison, both said the work may open an important door on the ability to risk-stratify patients for early treatment, potentially identifying them before they experience significant brain damage from the disease.

“Right now we're spending billions of dollars on trying to find a disease-modifying therapy, but we don't really know who we would give that to,” Dr. Johnson said.

In the same way that those with high cholesterol benefit most from statins, patients with a demonstrated risk of Alzheimer's would be the best candidates for any drug therapy, he noted. “Our work may eventually be able to identify in a much more targeted way groups of people who could benefit the most from early intervention, hopefully early enough to prevent them from having serious cognitive loss from Alzheimer's.”

TOMM40 has variable lengths that are defined by how many thymidine bases are contained in a specific section of the gene. The very long form (30 or more thymidine bases) is associated with an earlier onset of Alzheimer's disease, while the very short length (20 or fewer) is associated with a later onset. Some people have a long form (between 20 and 30 bases) that confers intermediate risk for Alzheimer's disease.

In 2009, Dr. Allen D. Roses of Duke University, Durham, N.C., first showed that among patients who developed Alzheimer's after 60 years of age and were homozygous or heterozygous for the apolipoprotein E e3 (APOE-3) allele, those with two copies of the long TOMM40 developed the disease an average of 7 years earlier than did those with shorter TOMM40 lengths (Pharmacogenomics J. 2009 Dec. 22 [doi:10.1038/tpj.2009.69]).

Dr. Johnson's study consisted of 117 healthy middle-aged volunteers (mean age, 57 years) who were known to be homozygous for the APOE-3 allele. APOE-3 homozygotes are thought to have a neutral risk for Alzheimer's disease. He then tested the subjects to determine what variant of TOMM40 they had.

In Dr. Johnson's study group, 38 patients were homozygous for the very short-length TOMM40, 44 had one short and one long or very long allele, and 35 were homozygous for the very long form of TOMM40.

All of the volunteers underwent brain scanning with voxel-based morphometry to assess gray matter volume in different brain regions.

The subjects with two copies of the very long TOMM40 allele had significantly less gray matter in both the ventral posterior cingulate and the precuneus than did those with two short alleles. These are both regions that show early deterioration in late-onset Alzheimer's disease.

“This is very important, because we are finding brain changes in people who are quite young,” Dr. Johnson said.

“The brain differences between the groups were very similar to, but less severe than, what is observed in full-blown Alzheimer's. It may be that the TOMM40 gene will be a useful measure of Alzheimer's risk in middle age, but additional research with longitudinal follow-up is necessary.”

Dr. Sager examined the gene's potential effect on memory in a cohort of 337 adults (mean age, 54), who were genotyped for APOE and TOMM40. Of these, 128 were homozygous for the short form of TOMM40, indicating a lower risk. The long or very long forms were seen in 219 subjects. In the low-risk group, 57% had a family history of Alzheimer's, compared with 77% of the high-risk group–a significant difference.

All subjects took the Auditory-Verbal Learning Test, which involves five trials of learning two 15-word sets. While the mean scores for both subject groups were within the normal range, the mean was significantly lower in the group with longer forms of TOMM40.

“We found significant changes in verbal learning and memory–changes that are traditionally the first cognitive changes seen in Alzheimer's,” Dr. Sager said. “Even after adjustment for age, gender, and education, people with the long form of TOMM40 were performing lower than those without it.”

He stressed that none of the subjects in either the brain volume study or the memory study had any observable memory difficulties in their everyday life. “But these findings of gray matter loss and cognitive changes in these relatively young people are very important”and suggest that “we may have the ability to find people at risk of Alzheimer's very early on in the disease process, far in advance of any significant cognitive problems.”

Patients with short TOMM40 had greater gray matter volume than did those patients with two very long versions.

Source Courtesy Sterling Johnson, Ph.D.

A range of new amyloid imaging agents has the potential to improve both the diagnosis of Alzheimer's disease and research protocols into potential Alzheimer's therapies.

Trials of two new

Studies of another class of molecules, called luminescent conjugated oligothiophenes (LCOs), are beginning to show differences in the ways in which amyloid is deposited in the brains of Alzheimer's patients who are homozygous for the apolipoprotein E e4 allele (APOE e4) compared with those who are homozygous for the e3 allele.

Florbetaben and florbetapir are both

“The field has been moving much more toward the development of in vivo diagnostic agents that would allow us to make a diagnosis with reasonably good confidence and to move beyond using the autopsy as the gold standard of Alzheimer's diagnosis,” he said in an interview. “In the research setting, having a firm diagnosis will allow us to pick subjects for trials on the basis of whether they have amyloid in the brain. Current estimates are that as many as 15% of Alzheimer's trial participants actually don't have amyloid present, which probably contributes a lot of noise to the trials.”

Both florbetaben and florbetapir are similar to the Pittsburgh compound B (PiB)–the first compound capable of visualizing amyloid plaques in a living patient during a positron-emission tomography scan. But PiB has a very short half-life, seriously limiting its large-scale clinical applicability, said Dr. Sabbagh.

“PiB PET was a great first step in the realm of amyloid imaging, but its development has been mired by the fact that it's a

Florbetapir Amyloid Imaging

Dr. Sabbagh has been an investigator on two florbetapir trials, both of which were presented at the meeting in Honolulu, which this newspaper covered remotely.

In a phase III trial of florbetapir, amyloid burden seen in PET scans highly correlated with plaques seen in the same patients at autopsy. A second study showed that repeated florbetapir amyloid imaging could detect differences in the levels of amyloid binding over time in a group of healthy controls and patients with mild cognitive impairment.

In the end-of-life study, headed by Dr. Christopher Clark of Avid, the tracer was used to examine plaque burden in 35 Alzheimer's patients with less than 6 months to live. After death, brain sections from regions seen as plaque-damaged were examined histopathologically to determine correlation with PET results.

The autopsies showed a strong correlation between amyloid burden and both the visual ratings of the florbetapir PET scans and the patients' mean modified scores on the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery.

The longitudinal follow-up study, conducted by Dr. Reisa Sperling of Brigham and Women's Hospital in Boston, comprised 47 patients with confirmed mild cognitive impairment (MCI) who were matched with 62 elderly healthy controls.

After a neuropsychological testing battery, all of the patients underwent PET imaging with florbetapir. The images were visually scored as amyloid positive or negative by three readers blinded to the diagnoses. Testing 6 and 12 months later included symptom reassessment, the dementia severity rating scale, and informant-based functional assessment.

Images were positive for amyloid in 38% patients with MCI at baseline, compared with 13% of the healthy controls. Florbetapir uptake correlated positively with the dementia severity rating scale in both groups, with higher baseline amyloid related to greater functional impairment at follow-up.

By 1 year, none of the healthy controls had progressed to MCI. However, 4 of the 18 amyloid-positive MCI patients (22%) had progressed to Alzheimer's disease, compared with 1 of the 29 amyloid-negative MCI patients (3%).

Although the results are encouraging, Dr. Sabbagh said, “it's too early to tell if florbetapir can be used as a prognostic agent,” as well as a diagnostic agent.

Dr. Sperling and Dr. Sabbagh have received research grants and support from Avid.

Florbetaben Studies

The studies for Bayer's compound, florbetaben, focused on its sensitivity and specificity, and its ability to differentiate Alzheimer's from other forms of dementia.

Dr. Osama Sabri of the University of Leipzig, Germany, lead a phase II trial that comprised 150 subjects imaged with the compound; 81 of these had probable Alzheimer's disease. The PET images were visually rated by three blinded readers.

More than 95% of the images were considered to be of high quality. The investigators found that florbetaben had a sensitivity of 80% and a specificity of 90% for the discrimination of Alzheimer's patients from healthy controls. They also found that the APOE e4 was significantly more common in the amyloid-positive than the amyloid-negative patients (65% vs. 22%, respectively).

“The sensitivity and specificity were reasonably good for this compound,” Dr. Sabbagh said.

The differential diagnosis study, lead by Dr. Victor Villemagne of the Austin Hospital, Melbourne, used florbetaben PET imaging in 26 Alzheimer's patients, 11 with frontotemporal lobar degeneration (FTLD), 6 with Lewy body dementia (LBD), and 26 healthy controls.

The Alzheimer's patients showed significantly higher uptake of the compound in neocortical areas compared with all the other groups.

Nearly all of the Alzheimer's patients (96%) showed diffuse cortical uptake, whereas only white matter binding was seen in most of the healthy controls (85%), FTLD patients (91%), and LBD patients (67%).

“This should not be surprising, because frontotemporal dementia is a tauopathy, not related to amyloid, and Lewy body patients and normal controls should not have amyloid in their brain,” Dr. Sabbagh said. “It's reasonable to say that this compound has the potential to discriminate one form of cognitive disorder from another.”

Both florbetaben studies were sponsored by Bayer Schering Pharma. Dr. Villemagne and Dr. Sabri have both received research grants and support from the company.

Plaque Differences Detected

New agents called luminescent conjugated oligothiophenes (LCOs) are beginning to reveal to scientists how APOE status affects the way in which beta-amyloid protein aggregates in the brain of Alzheimer's patients.

These compounds have shown that Alzheimer's patients with a double copy of APOE e4 develop beta-amyloid aggregates in brain blood vessels that are clearly different in structure or conformation from the aggregates in the brain substance, while in those who are homozygous for the APOE e3 allele, the protein clumps in both the vascular and core structures take on apparently identical conformation, said Dr. Samuel E. Gandy, who serves as associate director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine, New York.

LCOs intercalate into protein structures and fluoresce different colors depending on the discrete conformational shape they take when encountering different proteins.

When the compounds encounter amyloid plaques, they tend to glow orange; when they encounter neurofibrillary tau tangles, they tend to glow yellowish green.

Dr. Gandy has been an adviser or consultant for Amicus Therapeutics Ltd.; DiaGenic ASA; Elan Pharmaceuticals Inc.; and Johnson & Johnson Pharmaceutical Research & Development, LLC.

Oligothiophenes glow yellow in amyloid from patients with APOE e4/e4, and orange in those with APOE e3/e3.

Source Images Courtesy Dr. Samuel E. Gandy

A florbetapir PET scan shows more amyloid (red) in an Alzheimer's patient (bottom) than in a healthy volunteer.

Source Courtesy Avid Radiopharmaceuticals Inc.

A range of new amyloid imaging agents has the potential to improve both the diagnosis of Alzheimer's disease and research protocols into potential Alzheimer's therapies.

Trials of two new

Studies of another class of molecules, called luminescent conjugated oligothiophenes (LCOs), are beginning to show differences in the ways in which amyloid is deposited in the brains of Alzheimer's patients who are homozygous for the apolipoprotein E e4 allele (APOE e4) compared with those who are homozygous for the e3 allele.

Florbetaben and florbetapir are both

“The field has been moving much more toward the development of in vivo diagnostic agents that would allow us to make a diagnosis with reasonably good confidence and to move beyond using the autopsy as the gold standard of Alzheimer's diagnosis,” he said in an interview. “In the research setting, having a firm diagnosis will allow us to pick subjects for trials on the basis of whether they have amyloid in the brain. Current estimates are that as many as 15% of Alzheimer's trial participants actually don't have amyloid present, which probably contributes a lot of noise to the trials.”

Both florbetaben and florbetapir are similar to the Pittsburgh compound B (PiB)–the first compound capable of visualizing amyloid plaques in a living patient during a positron-emission tomography scan. But PiB has a very short half-life, seriously limiting its large-scale clinical applicability, said Dr. Sabbagh.

“PiB PET was a great first step in the realm of amyloid imaging, but its development has been mired by the fact that it's a

Florbetapir Amyloid Imaging

Dr. Sabbagh has been an investigator on two florbetapir trials, both of which were presented at the meeting in Honolulu, which this newspaper covered remotely.

In a phase III trial of florbetapir, amyloid burden seen in PET scans highly correlated with plaques seen in the same patients at autopsy. A second study showed that repeated florbetapir amyloid imaging could detect differences in the levels of amyloid binding over time in a group of healthy controls and patients with mild cognitive impairment.

In the end-of-life study, headed by Dr. Christopher Clark of Avid, the tracer was used to examine plaque burden in 35 Alzheimer's patients with less than 6 months to live. After death, brain sections from regions seen as plaque-damaged were examined histopathologically to determine correlation with PET results.

The autopsies showed a strong correlation between amyloid burden and both the visual ratings of the florbetapir PET scans and the patients' mean modified scores on the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery.

The longitudinal follow-up study, conducted by Dr. Reisa Sperling of Brigham and Women's Hospital in Boston, comprised 47 patients with confirmed mild cognitive impairment (MCI) who were matched with 62 elderly healthy controls.

After a neuropsychological testing battery, all of the patients underwent PET imaging with florbetapir. The images were visually scored as amyloid positive or negative by three readers blinded to the diagnoses. Testing 6 and 12 months later included symptom reassessment, the dementia severity rating scale, and informant-based functional assessment.

Images were positive for amyloid in 38% patients with MCI at baseline, compared with 13% of the healthy controls. Florbetapir uptake correlated positively with the dementia severity rating scale in both groups, with higher baseline amyloid related to greater functional impairment at follow-up.

By 1 year, none of the healthy controls had progressed to MCI. However, 4 of the 18 amyloid-positive MCI patients (22%) had progressed to Alzheimer's disease, compared with 1 of the 29 amyloid-negative MCI patients (3%).

Although the results are encouraging, Dr. Sabbagh said, “it's too early to tell if florbetapir can be used as a prognostic agent,” as well as a diagnostic agent.

Dr. Sperling and Dr. Sabbagh have received research grants and support from Avid.

Florbetaben Studies

The studies for Bayer's compound, florbetaben, focused on its sensitivity and specificity, and its ability to differentiate Alzheimer's from other forms of dementia.

Dr. Osama Sabri of the University of Leipzig, Germany, lead a phase II trial that comprised 150 subjects imaged with the compound; 81 of these had probable Alzheimer's disease. The PET images were visually rated by three blinded readers.

More than 95% of the images were considered to be of high quality. The investigators found that florbetaben had a sensitivity of 80% and a specificity of 90% for the discrimination of Alzheimer's patients from healthy controls. They also found that the APOE e4 was significantly more common in the amyloid-positive than the amyloid-negative patients (65% vs. 22%, respectively).

“The sensitivity and specificity were reasonably good for this compound,” Dr. Sabbagh said.

The differential diagnosis study, lead by Dr. Victor Villemagne of the Austin Hospital, Melbourne, used florbetaben PET imaging in 26 Alzheimer's patients, 11 with frontotemporal lobar degeneration (FTLD), 6 with Lewy body dementia (LBD), and 26 healthy controls.

The Alzheimer's patients showed significantly higher uptake of the compound in neocortical areas compared with all the other groups.

Nearly all of the Alzheimer's patients (96%) showed diffuse cortical uptake, whereas only white matter binding was seen in most of the healthy controls (85%), FTLD patients (91%), and LBD patients (67%).

“This should not be surprising, because frontotemporal dementia is a tauopathy, not related to amyloid, and Lewy body patients and normal controls should not have amyloid in their brain,” Dr. Sabbagh said. “It's reasonable to say that this compound has the potential to discriminate one form of cognitive disorder from another.”

Both florbetaben studies were sponsored by Bayer Schering Pharma. Dr. Villemagne and Dr. Sabri have both received research grants and support from the company.

Plaque Differences Detected

New agents called luminescent conjugated oligothiophenes (LCOs) are beginning to reveal to scientists how APOE status affects the way in which beta-amyloid protein aggregates in the brain of Alzheimer's patients.

These compounds have shown that Alzheimer's patients with a double copy of APOE e4 develop beta-amyloid aggregates in brain blood vessels that are clearly different in structure or conformation from the aggregates in the brain substance, while in those who are homozygous for the APOE e3 allele, the protein clumps in both the vascular and core structures take on apparently identical conformation, said Dr. Samuel E. Gandy, who serves as associate director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine, New York.

LCOs intercalate into protein structures and fluoresce different colors depending on the discrete conformational shape they take when encountering different proteins.

When the compounds encounter amyloid plaques, they tend to glow orange; when they encounter neurofibrillary tau tangles, they tend to glow yellowish green.

Dr. Gandy has been an adviser or consultant for Amicus Therapeutics Ltd.; DiaGenic ASA; Elan Pharmaceuticals Inc.; and Johnson & Johnson Pharmaceutical Research & Development, LLC.

Oligothiophenes glow yellow in amyloid from patients with APOE e4/e4, and orange in those with APOE e3/e3.

Source Images Courtesy Dr. Samuel E. Gandy

A florbetapir PET scan shows more amyloid (red) in an Alzheimer's patient (bottom) than in a healthy volunteer.

Source Courtesy Avid Radiopharmaceuticals Inc.

A range of new amyloid imaging agents has the potential to improve both the diagnosis of Alzheimer's disease and research protocols into potential Alzheimer's therapies.

Trials of two new

Studies of another class of molecules, called luminescent conjugated oligothiophenes (LCOs), are beginning to show differences in the ways in which amyloid is deposited in the brains of Alzheimer's patients who are homozygous for the apolipoprotein E e4 allele (APOE e4) compared with those who are homozygous for the e3 allele.

Florbetaben and florbetapir are both

“The field has been moving much more toward the development of in vivo diagnostic agents that would allow us to make a diagnosis with reasonably good confidence and to move beyond using the autopsy as the gold standard of Alzheimer's diagnosis,” he said in an interview. “In the research setting, having a firm diagnosis will allow us to pick subjects for trials on the basis of whether they have amyloid in the brain. Current estimates are that as many as 15% of Alzheimer's trial participants actually don't have amyloid present, which probably contributes a lot of noise to the trials.”

Both florbetaben and florbetapir are similar to the Pittsburgh compound B (PiB)–the first compound capable of visualizing amyloid plaques in a living patient during a positron-emission tomography scan. But PiB has a very short half-life, seriously limiting its large-scale clinical applicability, said Dr. Sabbagh.

“PiB PET was a great first step in the realm of amyloid imaging, but its development has been mired by the fact that it's a

Florbetapir Amyloid Imaging

Dr. Sabbagh has been an investigator on two florbetapir trials, both of which were presented at the meeting in Honolulu, which this newspaper covered remotely.

In a phase III trial of florbetapir, amyloid burden seen in PET scans highly correlated with plaques seen in the same patients at autopsy. A second study showed that repeated florbetapir amyloid imaging could detect differences in the levels of amyloid binding over time in a group of healthy controls and patients with mild cognitive impairment.

In the end-of-life study, headed by Dr. Christopher Clark of Avid, the tracer was used to examine plaque burden in 35 Alzheimer's patients with less than 6 months to live. After death, brain sections from regions seen as plaque-damaged were examined histopathologically to determine correlation with PET results.

The autopsies showed a strong correlation between amyloid burden and both the visual ratings of the florbetapir PET scans and the patients' mean modified scores on the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery.

The longitudinal follow-up study, conducted by Dr. Reisa Sperling of Brigham and Women's Hospital in Boston, comprised 47 patients with confirmed mild cognitive impairment (MCI) who were matched with 62 elderly healthy controls.

After a neuropsychological testing battery, all of the patients underwent PET imaging with florbetapir. The images were visually scored as amyloid positive or negative by three readers blinded to the diagnoses. Testing 6 and 12 months later included symptom reassessment, the dementia severity rating scale, and informant-based functional assessment.

Images were positive for amyloid in 38% patients with MCI at baseline, compared with 13% of the healthy controls. Florbetapir uptake correlated positively with the dementia severity rating scale in both groups, with higher baseline amyloid related to greater functional impairment at follow-up.

By 1 year, none of the healthy controls had progressed to MCI. However, 4 of the 18 amyloid-positive MCI patients (22%) had progressed to Alzheimer's disease, compared with 1 of the 29 amyloid-negative MCI patients (3%).

Although the results are encouraging, Dr. Sabbagh said, “it's too early to tell if florbetapir can be used as a prognostic agent,” as well as a diagnostic agent.

Dr. Sperling and Dr. Sabbagh have received research grants and support from Avid.

Florbetaben Studies

The studies for Bayer's compound, florbetaben, focused on its sensitivity and specificity, and its ability to differentiate Alzheimer's from other forms of dementia.

Dr. Osama Sabri of the University of Leipzig, Germany, lead a phase II trial that comprised 150 subjects imaged with the compound; 81 of these had probable Alzheimer's disease. The PET images were visually rated by three blinded readers.

More than 95% of the images were considered to be of high quality. The investigators found that florbetaben had a sensitivity of 80% and a specificity of 90% for the discrimination of Alzheimer's patients from healthy controls. They also found that the APOE e4 was significantly more common in the amyloid-positive than the amyloid-negative patients (65% vs. 22%, respectively).

“The sensitivity and specificity were reasonably good for this compound,” Dr. Sabbagh said.

The differential diagnosis study, lead by Dr. Victor Villemagne of the Austin Hospital, Melbourne, used florbetaben PET imaging in 26 Alzheimer's patients, 11 with frontotemporal lobar degeneration (FTLD), 6 with Lewy body dementia (LBD), and 26 healthy controls.

The Alzheimer's patients showed significantly higher uptake of the compound in neocortical areas compared with all the other groups.

Nearly all of the Alzheimer's patients (96%) showed diffuse cortical uptake, whereas only white matter binding was seen in most of the healthy controls (85%), FTLD patients (91%), and LBD patients (67%).

“This should not be surprising, because frontotemporal dementia is a tauopathy, not related to amyloid, and Lewy body patients and normal controls should not have amyloid in their brain,” Dr. Sabbagh said. “It's reasonable to say that this compound has the potential to discriminate one form of cognitive disorder from another.”

Both florbetaben studies were sponsored by Bayer Schering Pharma. Dr. Villemagne and Dr. Sabri have both received research grants and support from the company.

Plaque Differences Detected

New agents called luminescent conjugated oligothiophenes (LCOs) are beginning to reveal to scientists how APOE status affects the way in which beta-amyloid protein aggregates in the brain of Alzheimer's patients.

These compounds have shown that Alzheimer's patients with a double copy of APOE e4 develop beta-amyloid aggregates in brain blood vessels that are clearly different in structure or conformation from the aggregates in the brain substance, while in those who are homozygous for the APOE e3 allele, the protein clumps in both the vascular and core structures take on apparently identical conformation, said Dr. Samuel E. Gandy, who serves as associate director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine, New York.

LCOs intercalate into protein structures and fluoresce different colors depending on the discrete conformational shape they take when encountering different proteins.

When the compounds encounter amyloid plaques, they tend to glow orange; when they encounter neurofibrillary tau tangles, they tend to glow yellowish green.

Dr. Gandy has been an adviser or consultant for Amicus Therapeutics Ltd.; DiaGenic ASA; Elan Pharmaceuticals Inc.; and Johnson & Johnson Pharmaceutical Research & Development, LLC.

Oligothiophenes glow yellow in amyloid from patients with APOE e4/e4, and orange in those with APOE e3/e3.

Source Images Courtesy Dr. Samuel E. Gandy

A florbetapir PET scan shows more amyloid (red) in an Alzheimer's patient (bottom) than in a healthy volunteer.

Source Courtesy Avid Radiopharmaceuticals Inc.

CHICAGO - By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

"We are being bombarded every year by increasingly resistant bacteria," Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago."

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

"The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved," despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. "You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic," said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. "Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin," he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. "You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available," Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA "the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped," he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. "It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials," said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. "No one knows this drug’s future," Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials "and look good," Dr. Rosen said. "They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression."

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. "This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue," Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

"Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner," he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. "It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes."

Placebo-controlled studies "are unconscionable" in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. "The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more," he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. "If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme," he concluded.

The FDA issued the following statement:

"The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development."

Disclosures: Dr. Rosen reported having no relevant financial disclosures.

CHICAGO - By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

"We are being bombarded every year by increasingly resistant bacteria," Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago."

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

"The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved," despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. "You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic," said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. "Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin," he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. "You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available," Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA "the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped," he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. "It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials," said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. "No one knows this drug’s future," Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials "and look good," Dr. Rosen said. "They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression."

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. "This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue," Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

"Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner," he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. "It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes."

Placebo-controlled studies "are unconscionable" in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. "The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more," he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. "If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme," he concluded.

The FDA issued the following statement:

"The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development."

Disclosures: Dr. Rosen reported having no relevant financial disclosures.

CHICAGO - By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

"We are being bombarded every year by increasingly resistant bacteria," Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago."

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

"The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved," despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. "You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic," said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. "Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin," he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. "You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available," Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA "the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped," he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. "It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials," said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. "No one knows this drug’s future," Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials "and look good," Dr. Rosen said. "They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression."

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. "This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue," Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

"Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner," he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. "It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes."

Placebo-controlled studies "are unconscionable" in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. "The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more," he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. "If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme," he concluded.

The FDA issued the following statement:

"The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development."

Disclosures: Dr. Rosen reported having no relevant financial disclosures.

CHICAGO – By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

“We are being bombarded every year by increasingly resistant bacteria,” Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago.”

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

“The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved,” despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. “You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic,” said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. “Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin,” he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. “You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available,” Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA “the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped,” he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. “It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials,” said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. “No one knows this drug’s future,” Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials “and look good,” Dr. Rosen said. “They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression.”

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. “This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue,” Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

“Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner,” he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. “It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes.”

Placebo-controlled studies “are unconscionable” in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. “The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more,” he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. “If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme,” he concluded.

Dr. Rosen reported having no relevant financial disclosures.

Prepared Response From the FDA

The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development.

CHICAGO – By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

“We are being bombarded every year by increasingly resistant bacteria,” Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago.”

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

“The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved,” despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. “You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic,” said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. “Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin,” he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. “You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available,” Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA “the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped,” he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. “It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials,” said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. “No one knows this drug’s future,” Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials “and look good,” Dr. Rosen said. “They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression.”

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. “This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue,” Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

“Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner,” he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. “It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes.”

Placebo-controlled studies “are unconscionable” in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. “The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more,” he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. “If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme,” he concluded.

Dr. Rosen reported having no relevant financial disclosures.

Prepared Response From the FDA

The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development.

CHICAGO – By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

“We are being bombarded every year by increasingly resistant bacteria,” Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago.”

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

“The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved,” despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. “You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic,” said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. “Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin,” he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. “You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available,” Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA “the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped,” he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. “It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials,” said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. “No one knows this drug’s future,” Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials “and look good,” Dr. Rosen said. “They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression.”

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. “This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue,” Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

“Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner,” he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. “It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes.”

Placebo-controlled studies “are unconscionable” in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. “The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more,” he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. “If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme,” he concluded.

Dr. Rosen reported having no relevant financial disclosures.

Prepared Response From the FDA

The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development.

CHICAGO – By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

“We are being bombarded every year by increasingly resistant bacteria,” Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago.”

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

“The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved,” despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. “You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic,” said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. “Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin,” he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. “You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available,” Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA “the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped,” he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. “It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials,” said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. “No one knows this drug’s future,” Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials “and look good,” Dr. Rosen said. “They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression.”

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. “This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue,” Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

“Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner,” he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. “It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes.”

Placebo-controlled studies “are unconscionable” in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. “The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more,” he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. “If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme,” he concluded.

Dr. Rosen reported having no relevant financial disclosures.

Prepared Response From the FDA

The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development.

CHICAGO – By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

“We are being bombarded every year by increasingly resistant bacteria,” Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago.”

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

“The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved,” despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. “You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic,” said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. “Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin,” he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. “You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available,” Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA “the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped,” he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. “It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials,” said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. “No one knows this drug’s future,” Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials “and look good,” Dr. Rosen said. “They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression.”

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. “This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue,” Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

“Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner,” he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. “It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes.”

Placebo-controlled studies “are unconscionable” in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. “The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more,” he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. “If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme,” he concluded.

Dr. Rosen reported having no relevant financial disclosures.

Prepared Response From the FDA

The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development.

CHICAGO – By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

“We are being bombarded every year by increasingly resistant bacteria,” Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago.”

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

“The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved,” despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. “You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic,” said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. “Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin,” he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. “You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available,” Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA “the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped,” he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. “It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials,” said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. “No one knows this drug’s future,” Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials “and look good,” Dr. Rosen said. “They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression.”

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. “This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue,” Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

“Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner,” he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. “It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes.”

Placebo-controlled studies “are unconscionable” in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. “The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more,” he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. “If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme,” he concluded.

Dr. Rosen reported having no relevant financial disclosures.

Prepared Response From the FDA

The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development.

Another potential Alzheimer's disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer's drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

"Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism," he said in an interview. "IDENTITY had a lot going for it. This was a tough one to swallow."

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

"This is disappointing news for the millions of Alzheimer's patients and their families worldwide who anxiously await a successful treatment for this devastating illness," Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up "will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued."

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. "I would be very cautious on interpreting these data until the full analysis has unfolded."

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. "They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy." Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer's plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

"In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18)," Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

"By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease," he said. "The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?"

It may be time, he said, to think of Alzheimer's as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. "Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage."

Dr. Sabbagh said he wondered if some of the Alzheimer's drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. "My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop."

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. "A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different."

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.

Another potential Alzheimer's disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer's drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

"Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism," he said in an interview. "IDENTITY had a lot going for it. This was a tough one to swallow."

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

"This is disappointing news for the millions of Alzheimer's patients and their families worldwide who anxiously await a successful treatment for this devastating illness," Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up "will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued."

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. "I would be very cautious on interpreting these data until the full analysis has unfolded."

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. "They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy." Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer's plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

"In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18)," Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

"By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease," he said. "The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?"

It may be time, he said, to think of Alzheimer's as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. "Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage."

Dr. Sabbagh said he wondered if some of the Alzheimer's drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. "My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop."

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. "A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different."

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.

Another potential Alzheimer's disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer's drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

"Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism," he said in an interview. "IDENTITY had a lot going for it. This was a tough one to swallow."

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

"This is disappointing news for the millions of Alzheimer's patients and their families worldwide who anxiously await a successful treatment for this devastating illness," Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up "will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued."

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. "I would be very cautious on interpreting these data until the full analysis has unfolded."

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. "They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy." Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer's plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

"In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18)," Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

"By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease," he said. "The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?"

It may be time, he said, to think of Alzheimer's as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. "Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage."

Dr. Sabbagh said he wondered if some of the Alzheimer's drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. "My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop."

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. "A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different."

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.

CHICAGO – Patients with severe acne are missing out on the skin-clearing benefits of oral contraceptives and need to know that OCs can be prescribed for acne without a pelvic examination by a gynecologist, according to Dr. Bethanee Schlosser.

"When talking to teens and their parents, it's important to explain that a pelvic exam is not necessary before giving these medications to young women," she said.

©Tina Sbrigato/iStockphoto.com

It appears that patients aren't privy to this information, and are reluctant to ask for oral contraceptives as acne medication.

"That may be the biggest hurdle keeping these patients from getting adequate treatment for their acne," she said.

In 2004, the World Health Organization released guidelines stating that pelvic exams and Pap smears are no longer required before administering combination oral contraceptives.

Dr. Schlosser noted, however, that she does ask all of her female patients when they had their last full gynecologic exam, Pap smear included, and encourages them to stay current.

Oral Contraceptives

Three combination oral contraceptives are approved for the treatment of acne in women in the United States: ethinyl estradiol and norgestimate, ethinyl estradiol and norethindrone, and ethinyl estradiol and drospirenone.

Drospironone, an analogue of spironolactone, reduces sebum production and increases sex hormone–binding globulin, thus reducing circulating androgens, Dr. Schlosser said. "Some women will come to me, though, and say that their ob.gyn. has told them they can’t take any pill containing drospirenone or spironolactone," because of its possible effect on potassium levels, especially in combination with other drugs that increase serum potassium (ACE inhibitors, angiotensin receptor blockers, potassium-sparing diuretics, heparin, aldosterone antagonists, and nonsteroidal anti-inflammatories).

Dr. Schlosser pointed to a 2009 study of 27 women with either severe papular or nodulocystic acne who were treated with a combined oral contraceptive containing 30 mg ethinyl estradiol, 3 mg drospirenone, and 100 mg spironolactone. None of the patients had a significant elevation in serum potassium level; there were no reports of adverse events serious enough to require discontinuation of treatment. At follow up, 85% of subjects were entirely clear of acne lesions or had excellent improvement, 7% were mildly improved, and 7% were not improved (J. Am. Acad. Derm. 2880;58:60-2). 

A 2008 study looked only at the risk of hyperkalemia among 22,429 women who used the drospirenone-containing contraceptive compared with 44,858 who used other oral contraceptives (Contraception 2008;78:377-83). There was no significant between-group difference in the incidence of hyperkalemia.

This type of treatment is not an overnight acne cure, Dr. Schlosser stressed. “I tell women you have to allow at least three cycles of use before you start to judge efficacy. Patients can continue to get more benefit from 3-6 months of use, too.”

A 2007 Cochrane review of the three U.S. Food and Drug Administration–approved acne-fighting oral contraceptives found no significant differences in effectiveness, she said.

The Role of Androgen Testing

Elevated androgens are a large contributor to acne in women, and both the estradiol and progestins in combination oral contraceptives work to decrease them, said Dr. Schlosser, director of the women’s skin health program at Northwestern University, Chicago. Androgen testing may be appropriate for some women.

"If a woman complains of sudden onset of acne, or acne that is severe or recalcitrant to traditional therapy, I would say testing is a good idea. You might also consider it for women with androgenic features – hirsutism, deep voice, muscular habitus, or androgenic alopecia," she said.

Because these features can also be symptoms of polycystic ovary syndrome, Dr. Schlosser also suggested checking for acanthosis nigricans, central obesity, irregular menses, and infertility.

Androgen testing is most informative when performed at the onset of menses. "This is because androgen secretion follows the same pattern as estradiol, which peaks in midcycle and falls to a nadir at the beginning of menstruation," Dr. Schlosser said. "I print out a lab request, and tell the patient to have her blood drawn on the first day of her period." Morning testing is better, if possible, because of the hormone’s diurnal secretion.

Total testosterone is the most sensitive test for androgen levels in women with acne. However, "it’s important to note that the levels associated with acne can be elevated compared to controls, but still within the normal reference ranges," she said. Total testosterone level can also be falsely elevated in obese women, "because insulin reduces the liver’s secretion of sex hormone–binding globulin," she said.

Treatment Risks

There are some contraindications to the use of oral contraceptives for the treatment of acne, Dr. Schlosser noted. Hypercoagulability, a history of venous thromboembolism (VTE), stroke or coronary artery disease, any gynecologic cancer, uncontrolled hypertension, abnormal liver function tests, pregnancy, or abnormal vaginal bleeding should be considered before prescribing.

Oral contraceptives do increase the risk of venous thromboembolism, although that risk is highly dependent on other factors as well, including advancing age and tobacco use. Dr. Schlosser said a concrete, direct link between oral contraceptives and VTE risk has yet to be found, but he hopes an ongoing case-control study of more than 50,000 oral contraceptive users (including up to 5 years of follow-up data) will provide answers.

Finally, Dr. Schlosser added, the single greatest risk of VTE among women is pregnancy and the postpartum period. "So I would say if you’re treating acne in a woman of childbearing age with an oral contraceptive, you are also protecting her from the biggest risk factor she has for thromboembolic events."

Disclosures: Dr. Schlosser said she had no relevant financial disclosures.

CHICAGO – Patients with severe acne are missing out on the skin-clearing benefits of oral contraceptives and need to know that OCs can be prescribed for acne without a pelvic examination by a gynecologist, according to Dr. Bethanee Schlosser.

"When talking to teens and their parents, it's important to explain that a pelvic exam is not necessary before giving these medications to young women," she said.

©Tina Sbrigato/iStockphoto.com

It appears that patients aren't privy to this information, and are reluctant to ask for oral contraceptives as acne medication.

"That may be the biggest hurdle keeping these patients from getting adequate treatment for their acne," she said.

In 2004, the World Health Organization released guidelines stating that pelvic exams and Pap smears are no longer required before administering combination oral contraceptives.

Dr. Schlosser noted, however, that she does ask all of her female patients when they had their last full gynecologic exam, Pap smear included, and encourages them to stay current.

Oral Contraceptives

Three combination oral contraceptives are approved for the treatment of acne in women in the United States: ethinyl estradiol and norgestimate, ethinyl estradiol and norethindrone, and ethinyl estradiol and drospirenone.

Drospironone, an analogue of spironolactone, reduces sebum production and increases sex hormone–binding globulin, thus reducing circulating androgens, Dr. Schlosser said. "Some women will come to me, though, and say that their ob.gyn. has told them they can’t take any pill containing drospirenone or spironolactone," because of its possible effect on potassium levels, especially in combination with other drugs that increase serum potassium (ACE inhibitors, angiotensin receptor blockers, potassium-sparing diuretics, heparin, aldosterone antagonists, and nonsteroidal anti-inflammatories).

Dr. Schlosser pointed to a 2009 study of 27 women with either severe papular or nodulocystic acne who were treated with a combined oral contraceptive containing 30 mg ethinyl estradiol, 3 mg drospirenone, and 100 mg spironolactone. None of the patients had a significant elevation in serum potassium level; there were no reports of adverse events serious enough to require discontinuation of treatment. At follow up, 85% of subjects were entirely clear of acne lesions or had excellent improvement, 7% were mildly improved, and 7% were not improved (J. Am. Acad. Derm. 2880;58:60-2). 

A 2008 study looked only at the risk of hyperkalemia among 22,429 women who used the drospirenone-containing contraceptive compared with 44,858 who used other oral contraceptives (Contraception 2008;78:377-83). There was no significant between-group difference in the incidence of hyperkalemia.

This type of treatment is not an overnight acne cure, Dr. Schlosser stressed. “I tell women you have to allow at least three cycles of use before you start to judge efficacy. Patients can continue to get more benefit from 3-6 months of use, too.”

A 2007 Cochrane review of the three U.S. Food and Drug Administration–approved acne-fighting oral contraceptives found no significant differences in effectiveness, she said.

The Role of Androgen Testing

Elevated androgens are a large contributor to acne in women, and both the estradiol and progestins in combination oral contraceptives work to decrease them, said Dr. Schlosser, director of the women’s skin health program at Northwestern University, Chicago. Androgen testing may be appropriate for some women.

"If a woman complains of sudden onset of acne, or acne that is severe or recalcitrant to traditional therapy, I would say testing is a good idea. You might also consider it for women with androgenic features – hirsutism, deep voice, muscular habitus, or androgenic alopecia," she said.

Because these features can also be symptoms of polycystic ovary syndrome, Dr. Schlosser also suggested checking for acanthosis nigricans, central obesity, irregular menses, and infertility.

Androgen testing is most informative when performed at the onset of menses. "This is because androgen secretion follows the same pattern as estradiol, which peaks in midcycle and falls to a nadir at the beginning of menstruation," Dr. Schlosser said. "I print out a lab request, and tell the patient to have her blood drawn on the first day of her period." Morning testing is better, if possible, because of the hormone’s diurnal secretion.

Total testosterone is the most sensitive test for androgen levels in women with acne. However, "it’s important to note that the levels associated with acne can be elevated compared to controls, but still within the normal reference ranges," she said. Total testosterone level can also be falsely elevated in obese women, "because insulin reduces the liver’s secretion of sex hormone–binding globulin," she said.

Treatment Risks

There are some contraindications to the use of oral contraceptives for the treatment of acne, Dr. Schlosser noted. Hypercoagulability, a history of venous thromboembolism (VTE), stroke or coronary artery disease, any gynecologic cancer, uncontrolled hypertension, abnormal liver function tests, pregnancy, or abnormal vaginal bleeding should be considered before prescribing.

Oral contraceptives do increase the risk of venous thromboembolism, although that risk is highly dependent on other factors as well, including advancing age and tobacco use. Dr. Schlosser said a concrete, direct link between oral contraceptives and VTE risk has yet to be found, but he hopes an ongoing case-control study of more than 50,000 oral contraceptive users (including up to 5 years of follow-up data) will provide answers.

Finally, Dr. Schlosser added, the single greatest risk of VTE among women is pregnancy and the postpartum period. "So I would say if you’re treating acne in a woman of childbearing age with an oral contraceptive, you are also protecting her from the biggest risk factor she has for thromboembolic events."

Disclosures: Dr. Schlosser said she had no relevant financial disclosures.

CHICAGO – Patients with severe acne are missing out on the skin-clearing benefits of oral contraceptives and need to know that OCs can be prescribed for acne without a pelvic examination by a gynecologist, according to Dr. Bethanee Schlosser.

"When talking to teens and their parents, it's important to explain that a pelvic exam is not necessary before giving these medications to young women," she said.

©Tina Sbrigato/iStockphoto.com

It appears that patients aren't privy to this information, and are reluctant to ask for oral contraceptives as acne medication.

"That may be the biggest hurdle keeping these patients from getting adequate treatment for their acne," she said.

In 2004, the World Health Organization released guidelines stating that pelvic exams and Pap smears are no longer required before administering combination oral contraceptives.

Dr. Schlosser noted, however, that she does ask all of her female patients when they had their last full gynecologic exam, Pap smear included, and encourages them to stay current.

Oral Contraceptives

Three combination oral contraceptives are approved for the treatment of acne in women in the United States: ethinyl estradiol and norgestimate, ethinyl estradiol and norethindrone, and ethinyl estradiol and drospirenone.

Drospironone, an analogue of spironolactone, reduces sebum production and increases sex hormone–binding globulin, thus reducing circulating androgens, Dr. Schlosser said. "Some women will come to me, though, and say that their ob.gyn. has told them they can’t take any pill containing drospirenone or spironolactone," because of its possible effect on potassium levels, especially in combination with other drugs that increase serum potassium (ACE inhibitors, angiotensin receptor blockers, potassium-sparing diuretics, heparin, aldosterone antagonists, and nonsteroidal anti-inflammatories).

Dr. Schlosser pointed to a 2009 study of 27 women with either severe papular or nodulocystic acne who were treated with a combined oral contraceptive containing 30 mg ethinyl estradiol, 3 mg drospirenone, and 100 mg spironolactone. None of the patients had a significant elevation in serum potassium level; there were no reports of adverse events serious enough to require discontinuation of treatment. At follow up, 85% of subjects were entirely clear of acne lesions or had excellent improvement, 7% were mildly improved, and 7% were not improved (J. Am. Acad. Derm. 2880;58:60-2). 

A 2008 study looked only at the risk of hyperkalemia among 22,429 women who used the drospirenone-containing contraceptive compared with 44,858 who used other oral contraceptives (Contraception 2008;78:377-83). There was no significant between-group difference in the incidence of hyperkalemia.

This type of treatment is not an overnight acne cure, Dr. Schlosser stressed. “I tell women you have to allow at least three cycles of use before you start to judge efficacy. Patients can continue to get more benefit from 3-6 months of use, too.”

A 2007 Cochrane review of the three U.S. Food and Drug Administration–approved acne-fighting oral contraceptives found no significant differences in effectiveness, she said.

The Role of Androgen Testing

Elevated androgens are a large contributor to acne in women, and both the estradiol and progestins in combination oral contraceptives work to decrease them, said Dr. Schlosser, director of the women’s skin health program at Northwestern University, Chicago. Androgen testing may be appropriate for some women.

"If a woman complains of sudden onset of acne, or acne that is severe or recalcitrant to traditional therapy, I would say testing is a good idea. You might also consider it for women with androgenic features – hirsutism, deep voice, muscular habitus, or androgenic alopecia," she said.

Because these features can also be symptoms of polycystic ovary syndrome, Dr. Schlosser also suggested checking for acanthosis nigricans, central obesity, irregular menses, and infertility.

Androgen testing is most informative when performed at the onset of menses. "This is because androgen secretion follows the same pattern as estradiol, which peaks in midcycle and falls to a nadir at the beginning of menstruation," Dr. Schlosser said. "I print out a lab request, and tell the patient to have her blood drawn on the first day of her period." Morning testing is better, if possible, because of the hormone’s diurnal secretion.

Total testosterone is the most sensitive test for androgen levels in women with acne. However, "it’s important to note that the levels associated with acne can be elevated compared to controls, but still within the normal reference ranges," she said. Total testosterone level can also be falsely elevated in obese women, "because insulin reduces the liver’s secretion of sex hormone–binding globulin," she said.

Treatment Risks

There are some contraindications to the use of oral contraceptives for the treatment of acne, Dr. Schlosser noted. Hypercoagulability, a history of venous thromboembolism (VTE), stroke or coronary artery disease, any gynecologic cancer, uncontrolled hypertension, abnormal liver function tests, pregnancy, or abnormal vaginal bleeding should be considered before prescribing.

Oral contraceptives do increase the risk of venous thromboembolism, although that risk is highly dependent on other factors as well, including advancing age and tobacco use. Dr. Schlosser said a concrete, direct link between oral contraceptives and VTE risk has yet to be found, but he hopes an ongoing case-control study of more than 50,000 oral contraceptive users (including up to 5 years of follow-up data) will provide answers.

Finally, Dr. Schlosser added, the single greatest risk of VTE among women is pregnancy and the postpartum period. "So I would say if you’re treating acne in a woman of childbearing age with an oral contraceptive, you are also protecting her from the biggest risk factor she has for thromboembolic events."

Disclosures: Dr. Schlosser said she had no relevant financial disclosures.

CHICAGO - In the not-too distant future, dermatologists may be sending patients off to the beach with a bagful of chemoprevention tricks to outwit ultraviolet radiation and reduce the risk of sun-related skin cancers.

"In addition to sunscreen, we'll be using these chemopreventive agents not only to reduce histologic response to ultraviolet light, but to repair the DNA damage that occurs as a result of overexposure to the sun," said Dr. Craig Elmets at the American Academy of Dermatology's 2010 meeting. "Instead of sending patients to the beach covered up with long pants, long sleeves, and a hat, we can send them off to engage in their normal behavior with less worry about the long-term consequences."

Photo credit: Michele G. Sullivan

Although sunscreens remain the first line of defense against cancer-inducing ultraviolet radiation, they need backup, said Dr. Elmets, professor and chair of the department of dermatology and director of the Skin Disease Research Center at the University of Alabama, Birmingham. Theoretically, sunscreens work well, but in reality, their efficacy is less than ideal. "They are greasy and messy, and people don't really enjoy applying them. And most people don't use nearly enough to achieve the sun protection factor stated on the label; in fact, studies show that most people only use about 25% of the necessary amount."

Sunscreens also have limited effect, he said. "Over a 5-year period, sunscreens will reduce squamous cell carcinomas by about 35%, but they have very little effect on basal cell carcinoma."

A number of agents are being investigated for the chemoprevention of skin cancers. Some are oral, some are topical, and all have shown promising results in both animal and human studies.

Dimericine is a form of the bacterial enzyme T4 endonuclease. When encapsulated in a liposome and applied topically, the compound appears to boost the body’s DNA repair response by increasing base excision repair, Dr. Elmets said.

A 2001 study allocated 30 patients with xeroderma pigmentosum to either Dimericine or placebo for 1 year, in addition to sunscreen. Patients in the active group had a 68% reduction in actinic keratoses and a 30% reduction in basal cell carcinoma (Lancet 2001;24;926-9).

Dr. Elmets is the lead investigator in one of two ongoing dimericine trials. The first is a phase II study randomizing kidney transplant patients with nonmelanoma skin cancer to either the drug or placebo for 12 months, with an outcome of new nonmelanoma skin cancers.

The second study is a phase III study aiming to recruit up to 30 patients with xeroderma pigmentosum who will be allocated to dimericine or placebo, with the primary end point of new actinic keratoses.

"Another exciting molecule that may have good chemopreventive potential is GDC-0449," Dr. Elmets said. The compound is a systemic hedgehog pathway antagonist. "The hedgehog pathway is an important regulator of cell growth and differentiation during embryogenesis. But mutations are associated with basal cell carcinomas in both children and adults," he said. Animal research has shown that inhibiting this pathway can reduce tumor growth.

A 2009 study involved 33 patients with metastatic or locally advanced basal cell carcinoma who took the drug at different doses. Eighteen achieved a response; 2 were complete and 16 were partial. Disease stabilized in 15 patients and progressed in 4 (N. Engl. J. Med. 2009;361:1164-72).

Twenty-four trials are either in progress or recruiting, studying GDC-0449’s safety and efficacy in a variety of cancers, including basal cell nevus syndrome, and pancreatic, gastrointestinal, lung, breast, and brain cancers.

DMFO (alpha-difluoromethylornithine, also known as eflornithine) irreversibly inhibits ornithine decarboxylase, an enzyme unregulated in many tumors. Dr. Elmets described a recent phase III trial of 219 patients with a history of nonmelanoma skin cancer. After 4-5 years of follow-up (more than 1,200 person/years), there was no significant difference in the total numbers of nonmelanoma skin cancers between the active and placebo group. But new basal cell carcinomas were 33% less common in the active group than the placebo group (Cancer Prev. Res. 2010;3:35-47).

There are 20 active or completed trials looking at this agent in relation to several cancers, including bladder, GI, neuroblastoma, and trypanosomosis.

The cyclooxygenase 2 inhibitor celecoxib is even in the skin cancer race. "COX-2 is dramatically upregulated in actinic keratoses and squamous cell carcinomas, and also in the interstitial space around basal carcinoma tumor islands," Dr. Elmets said. "When given orally, it inhibits COX-2 expression, reducing the prostaglandin E2 production implicated in skin cancers."

A recent study of 60 patients with basal cell nevus syndrome treated with celecoxib found that those with less severe disease had a 20% increase in the number of basal cell carcinomas over 24 months, compared with a 50% increase in those taking placebo (Cancer Prev. Res. 2010;3:25-34). Celecoxib is also being investigated for use in GI, prostate, and lung cancers.

Finally, Dr. Elmets said, an ancient – and familiar – drink holds intriguing possibilities. The primary catechin in green tea, EGCG, (epigallocatechin-3-gallate) is a potent antioxidant that appears to reduce histologic and clinical damage from exposure to ultraviolet lights A and B. "When ECGC is applied topically or given to animals to drink in their water, they show a dramatic reduction in new skin cancers. In humans, it reduces UVA and UVB erythema," Dr. Elmets said.

Because of its broad antioxidant properties, EGCG is the subject of numerous clinical trials examining its potential in other cancers, Alzheimer’s disease, muscular dystrophy, photoaging, and weight loss.

Disclosures: Dr. Elmets has received research support from Pfizer Inc. and holds an intellectual property right on the use of EGCG as a skin cancer chemopreventive agent.

CHICAGO - In the not-too distant future, dermatologists may be sending patients off to the beach with a bagful of chemoprevention tricks to outwit ultraviolet radiation and reduce the risk of sun-related skin cancers.

"In addition to sunscreen, we'll be using these chemopreventive agents not only to reduce histologic response to ultraviolet light, but to repair the DNA damage that occurs as a result of overexposure to the sun," said Dr. Craig Elmets at the American Academy of Dermatology's 2010 meeting. "Instead of sending patients to the beach covered up with long pants, long sleeves, and a hat, we can send them off to engage in their normal behavior with less worry about the long-term consequences."

Photo credit: Michele G. Sullivan

Although sunscreens remain the first line of defense against cancer-inducing ultraviolet radiation, they need backup, said Dr. Elmets, professor and chair of the department of dermatology and director of the Skin Disease Research Center at the University of Alabama, Birmingham. Theoretically, sunscreens work well, but in reality, their efficacy is less than ideal. "They are greasy and messy, and people don't really enjoy applying them. And most people don't use nearly enough to achieve the sun protection factor stated on the label; in fact, studies show that most people only use about 25% of the necessary amount."

Sunscreens also have limited effect, he said. "Over a 5-year period, sunscreens will reduce squamous cell carcinomas by about 35%, but they have very little effect on basal cell carcinoma."

A number of agents are being investigated for the chemoprevention of skin cancers. Some are oral, some are topical, and all have shown promising results in both animal and human studies.

Dimericine is a form of the bacterial enzyme T4 endonuclease. When encapsulated in a liposome and applied topically, the compound appears to boost the body’s DNA repair response by increasing base excision repair, Dr. Elmets said.

A 2001 study allocated 30 patients with xeroderma pigmentosum to either Dimericine or placebo for 1 year, in addition to sunscreen. Patients in the active group had a 68% reduction in actinic keratoses and a 30% reduction in basal cell carcinoma (Lancet 2001;24;926-9).

Dr. Elmets is the lead investigator in one of two ongoing dimericine trials. The first is a phase II study randomizing kidney transplant patients with nonmelanoma skin cancer to either the drug or placebo for 12 months, with an outcome of new nonmelanoma skin cancers.

The second study is a phase III study aiming to recruit up to 30 patients with xeroderma pigmentosum who will be allocated to dimericine or placebo, with the primary end point of new actinic keratoses.

"Another exciting molecule that may have good chemopreventive potential is GDC-0449," Dr. Elmets said. The compound is a systemic hedgehog pathway antagonist. "The hedgehog pathway is an important regulator of cell growth and differentiation during embryogenesis. But mutations are associated with basal cell carcinomas in both children and adults," he said. Animal research has shown that inhibiting this pathway can reduce tumor growth.

A 2009 study involved 33 patients with metastatic or locally advanced basal cell carcinoma who took the drug at different doses. Eighteen achieved a response; 2 were complete and 16 were partial. Disease stabilized in 15 patients and progressed in 4 (N. Engl. J. Med. 2009;361:1164-72).

Twenty-four trials are either in progress or recruiting, studying GDC-0449’s safety and efficacy in a variety of cancers, including basal cell nevus syndrome, and pancreatic, gastrointestinal, lung, breast, and brain cancers.

DMFO (alpha-difluoromethylornithine, also known as eflornithine) irreversibly inhibits ornithine decarboxylase, an enzyme unregulated in many tumors. Dr. Elmets described a recent phase III trial of 219 patients with a history of nonmelanoma skin cancer. After 4-5 years of follow-up (more than 1,200 person/years), there was no significant difference in the total numbers of nonmelanoma skin cancers between the active and placebo group. But new basal cell carcinomas were 33% less common in the active group than the placebo group (Cancer Prev. Res. 2010;3:35-47).

There are 20 active or completed trials looking at this agent in relation to several cancers, including bladder, GI, neuroblastoma, and trypanosomosis.

The cyclooxygenase 2 inhibitor celecoxib is even in the skin cancer race. "COX-2 is dramatically upregulated in actinic keratoses and squamous cell carcinomas, and also in the interstitial space around basal carcinoma tumor islands," Dr. Elmets said. "When given orally, it inhibits COX-2 expression, reducing the prostaglandin E2 production implicated in skin cancers."

A recent study of 60 patients with basal cell nevus syndrome treated with celecoxib found that those with less severe disease had a 20% increase in the number of basal cell carcinomas over 24 months, compared with a 50% increase in those taking placebo (Cancer Prev. Res. 2010;3:25-34). Celecoxib is also being investigated for use in GI, prostate, and lung cancers.

Finally, Dr. Elmets said, an ancient – and familiar – drink holds intriguing possibilities. The primary catechin in green tea, EGCG, (epigallocatechin-3-gallate) is a potent antioxidant that appears to reduce histologic and clinical damage from exposure to ultraviolet lights A and B. "When ECGC is applied topically or given to animals to drink in their water, they show a dramatic reduction in new skin cancers. In humans, it reduces UVA and UVB erythema," Dr. Elmets said.

Because of its broad antioxidant properties, EGCG is the subject of numerous clinical trials examining its potential in other cancers, Alzheimer’s disease, muscular dystrophy, photoaging, and weight loss.

Disclosures: Dr. Elmets has received research support from Pfizer Inc. and holds an intellectual property right on the use of EGCG as a skin cancer chemopreventive agent.

CHICAGO - In the not-too distant future, dermatologists may be sending patients off to the beach with a bagful of chemoprevention tricks to outwit ultraviolet radiation and reduce the risk of sun-related skin cancers.

"In addition to sunscreen, we'll be using these chemopreventive agents not only to reduce histologic response to ultraviolet light, but to repair the DNA damage that occurs as a result of overexposure to the sun," said Dr. Craig Elmets at the American Academy of Dermatology's 2010 meeting. "Instead of sending patients to the beach covered up with long pants, long sleeves, and a hat, we can send them off to engage in their normal behavior with less worry about the long-term consequences."

Photo credit: Michele G. Sullivan

Although sunscreens remain the first line of defense against cancer-inducing ultraviolet radiation, they need backup, said Dr. Elmets, professor and chair of the department of dermatology and director of the Skin Disease Research Center at the University of Alabama, Birmingham. Theoretically, sunscreens work well, but in reality, their efficacy is less than ideal. "They are greasy and messy, and people don't really enjoy applying them. And most people don't use nearly enough to achieve the sun protection factor stated on the label; in fact, studies show that most people only use about 25% of the necessary amount."

Sunscreens also have limited effect, he said. "Over a 5-year period, sunscreens will reduce squamous cell carcinomas by about 35%, but they have very little effect on basal cell carcinoma."

A number of agents are being investigated for the chemoprevention of skin cancers. Some are oral, some are topical, and all have shown promising results in both animal and human studies.

Dimericine is a form of the bacterial enzyme T4 endonuclease. When encapsulated in a liposome and applied topically, the compound appears to boost the body’s DNA repair response by increasing base excision repair, Dr. Elmets said.

A 2001 study allocated 30 patients with xeroderma pigmentosum to either Dimericine or placebo for 1 year, in addition to sunscreen. Patients in the active group had a 68% reduction in actinic keratoses and a 30% reduction in basal cell carcinoma (Lancet 2001;24;926-9).

Dr. Elmets is the lead investigator in one of two ongoing dimericine trials. The first is a phase II study randomizing kidney transplant patients with nonmelanoma skin cancer to either the drug or placebo for 12 months, with an outcome of new nonmelanoma skin cancers.

The second study is a phase III study aiming to recruit up to 30 patients with xeroderma pigmentosum who will be allocated to dimericine or placebo, with the primary end point of new actinic keratoses.

"Another exciting molecule that may have good chemopreventive potential is GDC-0449," Dr. Elmets said. The compound is a systemic hedgehog pathway antagonist. "The hedgehog pathway is an important regulator of cell growth and differentiation during embryogenesis. But mutations are associated with basal cell carcinomas in both children and adults," he said. Animal research has shown that inhibiting this pathway can reduce tumor growth.

A 2009 study involved 33 patients with metastatic or locally advanced basal cell carcinoma who took the drug at different doses. Eighteen achieved a response; 2 were complete and 16 were partial. Disease stabilized in 15 patients and progressed in 4 (N. Engl. J. Med. 2009;361:1164-72).

Twenty-four trials are either in progress or recruiting, studying GDC-0449’s safety and efficacy in a variety of cancers, including basal cell nevus syndrome, and pancreatic, gastrointestinal, lung, breast, and brain cancers.

DMFO (alpha-difluoromethylornithine, also known as eflornithine) irreversibly inhibits ornithine decarboxylase, an enzyme unregulated in many tumors. Dr. Elmets described a recent phase III trial of 219 patients with a history of nonmelanoma skin cancer. After 4-5 years of follow-up (more than 1,200 person/years), there was no significant difference in the total numbers of nonmelanoma skin cancers between the active and placebo group. But new basal cell carcinomas were 33% less common in the active group than the placebo group (Cancer Prev. Res. 2010;3:35-47).

There are 20 active or completed trials looking at this agent in relation to several cancers, including bladder, GI, neuroblastoma, and trypanosomosis.

The cyclooxygenase 2 inhibitor celecoxib is even in the skin cancer race. "COX-2 is dramatically upregulated in actinic keratoses and squamous cell carcinomas, and also in the interstitial space around basal carcinoma tumor islands," Dr. Elmets said. "When given orally, it inhibits COX-2 expression, reducing the prostaglandin E2 production implicated in skin cancers."

A recent study of 60 patients with basal cell nevus syndrome treated with celecoxib found that those with less severe disease had a 20% increase in the number of basal cell carcinomas over 24 months, compared with a 50% increase in those taking placebo (Cancer Prev. Res. 2010;3:25-34). Celecoxib is also being investigated for use in GI, prostate, and lung cancers.

Finally, Dr. Elmets said, an ancient – and familiar – drink holds intriguing possibilities. The primary catechin in green tea, EGCG, (epigallocatechin-3-gallate) is a potent antioxidant that appears to reduce histologic and clinical damage from exposure to ultraviolet lights A and B. "When ECGC is applied topically or given to animals to drink in their water, they show a dramatic reduction in new skin cancers. In humans, it reduces UVA and UVB erythema," Dr. Elmets said.

Because of its broad antioxidant properties, EGCG is the subject of numerous clinical trials examining its potential in other cancers, Alzheimer’s disease, muscular dystrophy, photoaging, and weight loss.

Disclosures: Dr. Elmets has received research support from Pfizer Inc. and holds an intellectual property right on the use of EGCG as a skin cancer chemopreventive agent.

Another potential Alzheimer’s disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer’s drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

“Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism,” he said in an interview. “IDENTITY had a lot going for it. This was a tough one to swallow.”

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

“This is disappointing news for the millions of Alzheimer’s patients and their families worldwide who anxiously await a successful treatment for this devastating illness,” Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up “will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued.”

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. “I would be very cautious on interpreting these data until the full analysis has unfolded.”

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. “They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy.” Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer’s plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

“In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18),” Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

“By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease,” he said. “The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?”

It may be time, he said, to think of Alzheimer’s as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. “Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage.”

Dr. Sabbagh said he wondered if some of the Alzheimer’s drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. “My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop.”

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. “A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different.”

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.

Another potential Alzheimer’s disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer’s drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

“Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism,” he said in an interview. “IDENTITY had a lot going for it. This was a tough one to swallow.”

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

“This is disappointing news for the millions of Alzheimer’s patients and their families worldwide who anxiously await a successful treatment for this devastating illness,” Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up “will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued.”

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. “I would be very cautious on interpreting these data until the full analysis has unfolded.”

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. “They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy.” Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer’s plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

“In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18),” Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

“By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease,” he said. “The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?”

It may be time, he said, to think of Alzheimer’s as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. “Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage.”

Dr. Sabbagh said he wondered if some of the Alzheimer’s drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. “My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop.”

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. “A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different.”

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.

Another potential Alzheimer’s disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer’s drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

“Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism,” he said in an interview. “IDENTITY had a lot going for it. This was a tough one to swallow.”

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

“This is disappointing news for the millions of Alzheimer’s patients and their families worldwide who anxiously await a successful treatment for this devastating illness,” Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up “will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued.”

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. “I would be very cautious on interpreting these data until the full analysis has unfolded.”

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. “They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy.” Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer’s plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

“In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18),” Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

“By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease,” he said. “The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?”

It may be time, he said, to think of Alzheimer’s as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. “Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage.”

Dr. Sabbagh said he wondered if some of the Alzheimer’s drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. “My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop.”

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. “A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different.”

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.