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Baricitinib’s approval for alopecia areata: Considerations for starting patients on treatment
On June 13, the FDA approved baricitinib, a Janus kinase inhibitor (Olumiant, Lilly), for severe AA, and two other options may not be far behind. Pfizer and Concert Pharmaceuticals have JAK inhibitors in late-stage development for AA. JAK inhibitors, including baricitinib, are already on the market for treating rheumatoid arthritis and other autoimmune diseases.
Meanwhile, dermatologists have been fielding calls from hopeful patients and sorting out who should get the treatment, how to advise patients on risks and benefits, and what tests should be used before and after starting treatment.
Uptake for new systemic drugs, such as biologics, can be slow in dermatology, noted Adam Friedman, MD, professor and chair of dermatology, George Washington University, Washington, as some doctors like to stick with what they know.
He told this news organization that he hopes that uptake for baricitinib is quicker, as it is the only approved oral systemic treatment for patients with severe alopecia areata, which affects about 300,000 people a year in the United States. Other treatments, including steroid injections in the scalp, have lacked efficacy and convenience.
Beyond the physical effects, the mental toll of patchy hair clumps and missing brows and lashes can be devastating for patients with alopecia areata.
Fielding patient inquiries
Word of the FDA approval spread fast, and calls and emails are coming into dermatologists’ offices and clinics from interested patients.
Physicians should be ready for patients with any kind of hair loss, not just severe alopecia areata, to ask about the drug, Dr. Friedman said. Some patients contacting him don’t fit the indication, which “highlights how disabling hair loss” is for people, considering that, in general, “people see this and think it is for them.”
Baricitinib is not a new drug, but a drug with a new indication. It had already been approved for treating moderate to severe RA in patients who have had an inadequate response to one or more tumor necrosis factor blockers, and for treating COVID-19 in certain hospitalized adults.
Boxed warning
Patients may ask about the boxed warning in the baricitinib label about the increased risk for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis.
Natasha A. Mesinkovska, MD, PhD, an investigator in the clinical trials that led to FDA approval of baricitinib and the chief scientific officer at the National Alopecia Areata Foundation, told this news organization that several aspects of the label are important to point out.
One is that the warning is for all the JAK inhibitors used to treat RA and other inflammatory conditions, not just baricitinib. Also, the warning is based mostly on data on patients with RA who, she noted, have substantial comorbidities and have been taking toxic immunosuppressive medications. The RA population is also typically many years older than the alopecia areata population.
“Whether the warnings apply to the alopecia areata patients is as yet unclear,” said Dr. Mesinkovska, who is also an associate professor of dermatology at the University of California, Irvine.
Patients are also asking about how well it works.
In one of the two trials that led up to the FDA approval, which enrolled patients with at least 50% scalp hair loss for over 6 months, 22% of the patients who received 2 mg of baricitinib and 35% of those who received 4 mg saw adequate hair coverage (at least 80%) at week 36, compared with 5% on placebo. In the second trial, 17% of those who received 2 mg and 32% who received 4 mg saw adequate hair coverage, compared with 3% on placebo.
Common side effects associated with baricitinib, according to the FDA, are lower respiratory tract infections, headache, acne, high cholesterol, increased creatinine phosphokinase, urinary tract infection, liver enzyme elevations, folliculitis, fatigue, nausea, genital yeast infections, anemia, neutropenia, abdominal pain, herpes zoster (shingles), and weight gain.
The risk-benefit discussions with patients should also include potential benefits beyond hair regrowth on the scalp. Loss of hair in the ears and nose can affect hearing and allergies, Dr. Mesinkovska said.
“About 30%-50% with alopecia areata, depending on age group or part of the world, will have allergies,” she said.
Patients should also know that baricitinib will need to be taken “for a very long time,” Dr. Mesinkovska noted. It’s possible that could be forever and that stopping the medication at any point may result in hair falling out again, she says, but duration will vary from case to case.
The good news is that it has been well tolerated. “We give a lot of medications for acne like doxycycline and other antibiotics and people have more stomach problems and angst with those than with [baricitinib],” she said.
Regrowth takes time
Benjamin Ungar, MD, a dermatologist at the Alopecia Center of Excellence at Mount Sinai, New York, told this news organization that an important message for patients is that hair regrowth takes time. For some other skin conditions, patients start treatment and see almost instant improvement.
“That is not the case for alopecia areata,” he said. “The expectation is that it will take months for regrowth in general.”
He said he hasn’t started prescribing baricitinib yet, but plans to do so soon.
“Obviously, I’ll have conversations with patients about it, but it’s a medication I’m going to be using, definitely. I have no reservations,” Dr. Ungar said.
After initial testing, physicians may find that some patients might not be ideal candidates, he added. People with liver disease, a history of blood clots, abnormal blood counts, or low neutrophils are among those who may not be the best candidates for baricitinib.
For most with severe alopecia areata, though, baricitinib provides hope.
“Treatment options have been not readily available, often inaccessible, ineffective, often dangerous,” he said. “There’s a treatment now that can be accessed, generally is safe and is effective for many people.”
Be up front with patients about the unknown
Additionally, it’s important to tell patients what is not yet known, the experts interviewed say.
“Alopecia areata is a chronic disease. We don’t have long-term data on the patient population yet,” Dr. Friedman said.
Also unknown is how easy it will be for physicians to get insurance to reimburse for baricitinib, which, at the end of June, was priced at about $5,000 a month for the 4-mg dose. FDA approval was important in that regard. Previously, some claims had been rejected for drugs used off label for AA.
“We dermatologists know how much it affects patients,” Dr. Mesinkovska said. “As long as we stick by what we know and convey to insurers how much it affects people’s lives, they should cover it.”
Another unknown is what other drugs can be taken with baricitinib. In clinical trials, it was used alone, she said. Currently, concomitant use of other immune suppressants – such as methotrexate or prednisone – is not recommended. But it remains to be seen what other medications will be safe to use at the same time as more long-term data are available.
Lynne J. Goldberg, MD, professor of dermatology, pathology, and laboratory medicine, Boston University, and director of the Hair Clinic at Boston Medical Center, said that she received a slew of emails from patients asking about baricitinib, but most of them did not have alopecia areata and were not candidates for this treatment.
She said that nurses in her clinic have been instructed on what to tell patients about which patients the drug is meant to treat, side effects, and benefits.
Access won’t be immediate
Dr. Goldberg said the drug’s approval does not mean immediate access. The patient has to come in, discuss the treatment, and get lab tests first. “It’s not a casual drug. This is a potent immunosuppressant drug. You need lab tests and once you start it you need blood tests every 3 months to stay on it.”
Those tests may vary by physician, but people will generally need a standard blood count and a comprehensive metabolic panel and lipid panel. “There’s nothing esoteric,” she said.
She added that physicians will need to check for presence of infections including tuberculosis and hepatitis B and C before prescribing, just as they would before they start prescribing a biologic.
“You don’t want to reactivate something,” she noted.
But, Dr. Goldberg added, the benefits for all who have been either living with only patches of hair or no hair or who put on a wig or hat every day are “life changing.”
Dr. Mesinkovska is on the advisory boards and runs trials for Eli Lilly, Pfizer, and Concert Pharmaceuticals. Dr. Friedman, Dr. Goldberg, and Dr. Ungar reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
On June 13, the FDA approved baricitinib, a Janus kinase inhibitor (Olumiant, Lilly), for severe AA, and two other options may not be far behind. Pfizer and Concert Pharmaceuticals have JAK inhibitors in late-stage development for AA. JAK inhibitors, including baricitinib, are already on the market for treating rheumatoid arthritis and other autoimmune diseases.
Meanwhile, dermatologists have been fielding calls from hopeful patients and sorting out who should get the treatment, how to advise patients on risks and benefits, and what tests should be used before and after starting treatment.
Uptake for new systemic drugs, such as biologics, can be slow in dermatology, noted Adam Friedman, MD, professor and chair of dermatology, George Washington University, Washington, as some doctors like to stick with what they know.
He told this news organization that he hopes that uptake for baricitinib is quicker, as it is the only approved oral systemic treatment for patients with severe alopecia areata, which affects about 300,000 people a year in the United States. Other treatments, including steroid injections in the scalp, have lacked efficacy and convenience.
Beyond the physical effects, the mental toll of patchy hair clumps and missing brows and lashes can be devastating for patients with alopecia areata.
Fielding patient inquiries
Word of the FDA approval spread fast, and calls and emails are coming into dermatologists’ offices and clinics from interested patients.
Physicians should be ready for patients with any kind of hair loss, not just severe alopecia areata, to ask about the drug, Dr. Friedman said. Some patients contacting him don’t fit the indication, which “highlights how disabling hair loss” is for people, considering that, in general, “people see this and think it is for them.”
Baricitinib is not a new drug, but a drug with a new indication. It had already been approved for treating moderate to severe RA in patients who have had an inadequate response to one or more tumor necrosis factor blockers, and for treating COVID-19 in certain hospitalized adults.
Boxed warning
Patients may ask about the boxed warning in the baricitinib label about the increased risk for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis.
Natasha A. Mesinkovska, MD, PhD, an investigator in the clinical trials that led to FDA approval of baricitinib and the chief scientific officer at the National Alopecia Areata Foundation, told this news organization that several aspects of the label are important to point out.
One is that the warning is for all the JAK inhibitors used to treat RA and other inflammatory conditions, not just baricitinib. Also, the warning is based mostly on data on patients with RA who, she noted, have substantial comorbidities and have been taking toxic immunosuppressive medications. The RA population is also typically many years older than the alopecia areata population.
“Whether the warnings apply to the alopecia areata patients is as yet unclear,” said Dr. Mesinkovska, who is also an associate professor of dermatology at the University of California, Irvine.
Patients are also asking about how well it works.
In one of the two trials that led up to the FDA approval, which enrolled patients with at least 50% scalp hair loss for over 6 months, 22% of the patients who received 2 mg of baricitinib and 35% of those who received 4 mg saw adequate hair coverage (at least 80%) at week 36, compared with 5% on placebo. In the second trial, 17% of those who received 2 mg and 32% who received 4 mg saw adequate hair coverage, compared with 3% on placebo.
Common side effects associated with baricitinib, according to the FDA, are lower respiratory tract infections, headache, acne, high cholesterol, increased creatinine phosphokinase, urinary tract infection, liver enzyme elevations, folliculitis, fatigue, nausea, genital yeast infections, anemia, neutropenia, abdominal pain, herpes zoster (shingles), and weight gain.
The risk-benefit discussions with patients should also include potential benefits beyond hair regrowth on the scalp. Loss of hair in the ears and nose can affect hearing and allergies, Dr. Mesinkovska said.
“About 30%-50% with alopecia areata, depending on age group or part of the world, will have allergies,” she said.
Patients should also know that baricitinib will need to be taken “for a very long time,” Dr. Mesinkovska noted. It’s possible that could be forever and that stopping the medication at any point may result in hair falling out again, she says, but duration will vary from case to case.
The good news is that it has been well tolerated. “We give a lot of medications for acne like doxycycline and other antibiotics and people have more stomach problems and angst with those than with [baricitinib],” she said.
Regrowth takes time
Benjamin Ungar, MD, a dermatologist at the Alopecia Center of Excellence at Mount Sinai, New York, told this news organization that an important message for patients is that hair regrowth takes time. For some other skin conditions, patients start treatment and see almost instant improvement.
“That is not the case for alopecia areata,” he said. “The expectation is that it will take months for regrowth in general.”
He said he hasn’t started prescribing baricitinib yet, but plans to do so soon.
“Obviously, I’ll have conversations with patients about it, but it’s a medication I’m going to be using, definitely. I have no reservations,” Dr. Ungar said.
After initial testing, physicians may find that some patients might not be ideal candidates, he added. People with liver disease, a history of blood clots, abnormal blood counts, or low neutrophils are among those who may not be the best candidates for baricitinib.
For most with severe alopecia areata, though, baricitinib provides hope.
“Treatment options have been not readily available, often inaccessible, ineffective, often dangerous,” he said. “There’s a treatment now that can be accessed, generally is safe and is effective for many people.”
Be up front with patients about the unknown
Additionally, it’s important to tell patients what is not yet known, the experts interviewed say.
“Alopecia areata is a chronic disease. We don’t have long-term data on the patient population yet,” Dr. Friedman said.
Also unknown is how easy it will be for physicians to get insurance to reimburse for baricitinib, which, at the end of June, was priced at about $5,000 a month for the 4-mg dose. FDA approval was important in that regard. Previously, some claims had been rejected for drugs used off label for AA.
“We dermatologists know how much it affects patients,” Dr. Mesinkovska said. “As long as we stick by what we know and convey to insurers how much it affects people’s lives, they should cover it.”
Another unknown is what other drugs can be taken with baricitinib. In clinical trials, it was used alone, she said. Currently, concomitant use of other immune suppressants – such as methotrexate or prednisone – is not recommended. But it remains to be seen what other medications will be safe to use at the same time as more long-term data are available.
Lynne J. Goldberg, MD, professor of dermatology, pathology, and laboratory medicine, Boston University, and director of the Hair Clinic at Boston Medical Center, said that she received a slew of emails from patients asking about baricitinib, but most of them did not have alopecia areata and were not candidates for this treatment.
She said that nurses in her clinic have been instructed on what to tell patients about which patients the drug is meant to treat, side effects, and benefits.
Access won’t be immediate
Dr. Goldberg said the drug’s approval does not mean immediate access. The patient has to come in, discuss the treatment, and get lab tests first. “It’s not a casual drug. This is a potent immunosuppressant drug. You need lab tests and once you start it you need blood tests every 3 months to stay on it.”
Those tests may vary by physician, but people will generally need a standard blood count and a comprehensive metabolic panel and lipid panel. “There’s nothing esoteric,” she said.
She added that physicians will need to check for presence of infections including tuberculosis and hepatitis B and C before prescribing, just as they would before they start prescribing a biologic.
“You don’t want to reactivate something,” she noted.
But, Dr. Goldberg added, the benefits for all who have been either living with only patches of hair or no hair or who put on a wig or hat every day are “life changing.”
Dr. Mesinkovska is on the advisory boards and runs trials for Eli Lilly, Pfizer, and Concert Pharmaceuticals. Dr. Friedman, Dr. Goldberg, and Dr. Ungar reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
On June 13, the FDA approved baricitinib, a Janus kinase inhibitor (Olumiant, Lilly), for severe AA, and two other options may not be far behind. Pfizer and Concert Pharmaceuticals have JAK inhibitors in late-stage development for AA. JAK inhibitors, including baricitinib, are already on the market for treating rheumatoid arthritis and other autoimmune diseases.
Meanwhile, dermatologists have been fielding calls from hopeful patients and sorting out who should get the treatment, how to advise patients on risks and benefits, and what tests should be used before and after starting treatment.
Uptake for new systemic drugs, such as biologics, can be slow in dermatology, noted Adam Friedman, MD, professor and chair of dermatology, George Washington University, Washington, as some doctors like to stick with what they know.
He told this news organization that he hopes that uptake for baricitinib is quicker, as it is the only approved oral systemic treatment for patients with severe alopecia areata, which affects about 300,000 people a year in the United States. Other treatments, including steroid injections in the scalp, have lacked efficacy and convenience.
Beyond the physical effects, the mental toll of patchy hair clumps and missing brows and lashes can be devastating for patients with alopecia areata.
Fielding patient inquiries
Word of the FDA approval spread fast, and calls and emails are coming into dermatologists’ offices and clinics from interested patients.
Physicians should be ready for patients with any kind of hair loss, not just severe alopecia areata, to ask about the drug, Dr. Friedman said. Some patients contacting him don’t fit the indication, which “highlights how disabling hair loss” is for people, considering that, in general, “people see this and think it is for them.”
Baricitinib is not a new drug, but a drug with a new indication. It had already been approved for treating moderate to severe RA in patients who have had an inadequate response to one or more tumor necrosis factor blockers, and for treating COVID-19 in certain hospitalized adults.
Boxed warning
Patients may ask about the boxed warning in the baricitinib label about the increased risk for serious infections, mortality, malignancy, major adverse cardiovascular events, and thrombosis.
Natasha A. Mesinkovska, MD, PhD, an investigator in the clinical trials that led to FDA approval of baricitinib and the chief scientific officer at the National Alopecia Areata Foundation, told this news organization that several aspects of the label are important to point out.
One is that the warning is for all the JAK inhibitors used to treat RA and other inflammatory conditions, not just baricitinib. Also, the warning is based mostly on data on patients with RA who, she noted, have substantial comorbidities and have been taking toxic immunosuppressive medications. The RA population is also typically many years older than the alopecia areata population.
“Whether the warnings apply to the alopecia areata patients is as yet unclear,” said Dr. Mesinkovska, who is also an associate professor of dermatology at the University of California, Irvine.
Patients are also asking about how well it works.
In one of the two trials that led up to the FDA approval, which enrolled patients with at least 50% scalp hair loss for over 6 months, 22% of the patients who received 2 mg of baricitinib and 35% of those who received 4 mg saw adequate hair coverage (at least 80%) at week 36, compared with 5% on placebo. In the second trial, 17% of those who received 2 mg and 32% who received 4 mg saw adequate hair coverage, compared with 3% on placebo.
Common side effects associated with baricitinib, according to the FDA, are lower respiratory tract infections, headache, acne, high cholesterol, increased creatinine phosphokinase, urinary tract infection, liver enzyme elevations, folliculitis, fatigue, nausea, genital yeast infections, anemia, neutropenia, abdominal pain, herpes zoster (shingles), and weight gain.
The risk-benefit discussions with patients should also include potential benefits beyond hair regrowth on the scalp. Loss of hair in the ears and nose can affect hearing and allergies, Dr. Mesinkovska said.
“About 30%-50% with alopecia areata, depending on age group or part of the world, will have allergies,” she said.
Patients should also know that baricitinib will need to be taken “for a very long time,” Dr. Mesinkovska noted. It’s possible that could be forever and that stopping the medication at any point may result in hair falling out again, she says, but duration will vary from case to case.
The good news is that it has been well tolerated. “We give a lot of medications for acne like doxycycline and other antibiotics and people have more stomach problems and angst with those than with [baricitinib],” she said.
Regrowth takes time
Benjamin Ungar, MD, a dermatologist at the Alopecia Center of Excellence at Mount Sinai, New York, told this news organization that an important message for patients is that hair regrowth takes time. For some other skin conditions, patients start treatment and see almost instant improvement.
“That is not the case for alopecia areata,” he said. “The expectation is that it will take months for regrowth in general.”
He said he hasn’t started prescribing baricitinib yet, but plans to do so soon.
“Obviously, I’ll have conversations with patients about it, but it’s a medication I’m going to be using, definitely. I have no reservations,” Dr. Ungar said.
After initial testing, physicians may find that some patients might not be ideal candidates, he added. People with liver disease, a history of blood clots, abnormal blood counts, or low neutrophils are among those who may not be the best candidates for baricitinib.
For most with severe alopecia areata, though, baricitinib provides hope.
“Treatment options have been not readily available, often inaccessible, ineffective, often dangerous,” he said. “There’s a treatment now that can be accessed, generally is safe and is effective for many people.”
Be up front with patients about the unknown
Additionally, it’s important to tell patients what is not yet known, the experts interviewed say.
“Alopecia areata is a chronic disease. We don’t have long-term data on the patient population yet,” Dr. Friedman said.
Also unknown is how easy it will be for physicians to get insurance to reimburse for baricitinib, which, at the end of June, was priced at about $5,000 a month for the 4-mg dose. FDA approval was important in that regard. Previously, some claims had been rejected for drugs used off label for AA.
“We dermatologists know how much it affects patients,” Dr. Mesinkovska said. “As long as we stick by what we know and convey to insurers how much it affects people’s lives, they should cover it.”
Another unknown is what other drugs can be taken with baricitinib. In clinical trials, it was used alone, she said. Currently, concomitant use of other immune suppressants – such as methotrexate or prednisone – is not recommended. But it remains to be seen what other medications will be safe to use at the same time as more long-term data are available.
Lynne J. Goldberg, MD, professor of dermatology, pathology, and laboratory medicine, Boston University, and director of the Hair Clinic at Boston Medical Center, said that she received a slew of emails from patients asking about baricitinib, but most of them did not have alopecia areata and were not candidates for this treatment.
She said that nurses in her clinic have been instructed on what to tell patients about which patients the drug is meant to treat, side effects, and benefits.
Access won’t be immediate
Dr. Goldberg said the drug’s approval does not mean immediate access. The patient has to come in, discuss the treatment, and get lab tests first. “It’s not a casual drug. This is a potent immunosuppressant drug. You need lab tests and once you start it you need blood tests every 3 months to stay on it.”
Those tests may vary by physician, but people will generally need a standard blood count and a comprehensive metabolic panel and lipid panel. “There’s nothing esoteric,” she said.
She added that physicians will need to check for presence of infections including tuberculosis and hepatitis B and C before prescribing, just as they would before they start prescribing a biologic.
“You don’t want to reactivate something,” she noted.
But, Dr. Goldberg added, the benefits for all who have been either living with only patches of hair or no hair or who put on a wig or hat every day are “life changing.”
Dr. Mesinkovska is on the advisory boards and runs trials for Eli Lilly, Pfizer, and Concert Pharmaceuticals. Dr. Friedman, Dr. Goldberg, and Dr. Ungar reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Will the headache field embrace rofecoxib?
In June, the Concord, Mass.–based company Tremeau Pharmaceuticals announced that the Food and Drug Administration was letting it proceed with a phase 3 clinical trial to test rofecoxib, the once-bestselling painkiller known as Vioxx, in patients with migraine.
The anti-inflammatory drug, a cyclooxygenase-2 (COX-2) inhibitor, received its first FDA approval in 1999 and became widely prescribed for arthritis and acute pain. In 2004 it was withdrawn by its manufacturer, Merck, after being shown to raise the risk of cardiovascular events.
In clinical trials and in real-world epidemiological studies, rofecoxib was associated with elevated heart attack, stroke, and related deaths; one 2005 study estimated that it had been responsible for some 38,000 excess deaths in the United States before being withdrawn. In 2007 Merck, beset with allegations that it had suppressed and mischaracterized rofecoxib’s safety data, paid out nearly $5 billion to settle thousands of lawsuits filed by patients and their families.
, an indication for which it received an orphan drug designation in 2017 and the agency’s green light for trials in 2020.
Brad Sippy, Tremeau’s chief executive officer, said that his company chose the two indications in part because both patient populations have low cardiovascular risk. Migraine patients are generally younger than the arthritis populations formerly treated with rofecoxib and are unlikely to take the drug for more than a day or 2 at time, avoiding the risks associated with extended exposure.
A crowded market
The past several years have seen the emergence of a cornucopia of new migraine treatments, including monoclonal antibodies such as erenumab (Aimovig, Amgen), which help prevent attacks by blocking the vasodilator calcitonin gene-related peptide, or CGRP. In addition to the standard arsenal of triptans and nonsteroidal anti-inflammatory drugs for acute pain relief, migraine patients can now choose among serotonin-blocking agents such as lasmiditan (Reyvow, Eli Lilly), known as “ditans,” and small-molecule CGRP antagonists such as ubrogepant (Ubrelvy, Abbie), known as “gepants.” Some NSAIDs, including one COX inhibitor, have been formulated into rapidly absorbed powders or liquids for migraine.
Mr. Sippy said he sees a role for rofecoxib even in this crowded space. “Migraine as you know is a multimodal situation – few people say that only one drug works for them,” he said. “We think this is an option that would basically be like a high dose of ibuprofen,” but with less frequent dosing and lower gastrointestinal and platelet effects compared with ibuprofen and other NSAIDs.
An improved formulation
Rofecoxib “crosses the blood brain barrier very readily – better than other COX inhibitors on the market,” Mr. Sippy added. “It was well absorbed in its original formulation, and our product is even better absorbed than the original – we estimate it’s probably an hour quicker to [peak concentration].” In addition, he said, “our formulation is more efficient at delivering the drug so we don’t need as much active ingredient – our 17.5 milligrams gets you the same systemic exposure as 25 milligrams of the old product.”
A different mechanism of action
Neurologist Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews and professor of neurology at the University of California, Los Angeles, said that he was “cautiously optimistic” that “if used correctly and not too frequently, [rofecoxib] will find its niche in migraine treatment.”
“Patients liked Vioxx,” said Dr. Rapoport, past president of the International Headache Society. Even people currently on prevention “need to have an acute care drug handy.” While some patients on monoclonal antibodies have had success with gepants for acute care, “these both target the same pathway. It’s always nice to have options with a different mechanism of action.”
One of the arguments Tremeau has cited for reintroducing rofecoxib has been an urgent need for alternatives to opioid painkillers. Indeed some analysts have linked the demise of Vioxx with a subsequent increase in opioid prescribing.
Dr. Rapoport noted that he never prescribes opioids or butalbital, a barbiturate, for migraine, and that most headache specialists avoid them in clinical practice. But in the emergency setting, he said, patients receive them all too frequently.
Mr. Sippy said that opioid prescribing, while not unknown in migraine, was a bigger problem in hemophilic arthropathy, the first indication his company has pursued for rofecoxib. People with hemophilia “have a kind of arthritis that would respond well to an anti-inflammatory drug but they can’t take NSAIDs due to bleeding risk. This is why so many end up on opioids. Rofecoxib, as a COX-2 inhibitor, doesn’t have any effect on platelet aggregation, which would make it another option.”
No unique risks at prescribed doses
The migraine indication originally started out narrower: Patients with both migraine and bleeding disorders. “But in talking with the FDA, they encouraged us to develop it for migraine,” Mr. Sippy said. The company is considering pursuing a third indication: menstrual pain co-occurring with migraine. Tremeau has not ruled out seeking an indication in patients with arthritis who cannot take other painkillers, whether opioids or NSAIDs.
Five years ago, when Tremeau first announced its plans to bring rofecoxib back – indeed the company was set up for that purpose and has only this and another COX-2 inhibitor in development – some experts warned that there is little to prevent the drug from being used off-label, whether in higher doses or for other diseases.
“That’s something else we’re seeking to solve in addition to going for younger populations,” said Mr. Sippy, who worked at Merck during the Vioxx crisis and later headed neurology at Sunovion before starting his own company.
“We’re going for the former middle dose as our high dose and now we know that you don’t want to take more than the prescribed amount. If it doesn’t work you get off it; you don’t want to dose-creep on it. That’s been a key insight: At the appropriate dose, this product has no unique risk relative to the drug class and potentially some unique benefits,” he said.
Risk versus benefit
Joseph Ross, MD, a health policy researcher at Yale University in New Haven, Conn., who in a 2018 editorial expressed concerns about rofecoxib’s revival, said in an email that he felt its use in migraine could be justified, with caveats.
During Vioxx’s original approval and time on the market, “there was a cardiovascular risk associated with use that was not being transparently and clearly reported to patients and clinicians,” Dr. Ross said.
“In terms of testing the product for use in patients with migraine – a population of generally younger patients at lower risk of cardiovascular disease – my only concern is that the risk is clearly communicated and that there is adequate postmarket safety surveillance,” he said. “If patients are making fully informed decisions, the potential benefit of the drug with respect to pain control may be worth the risks.”
Dr. Rapoport serves as an adviser for AbbVie, Amgen, Biohaven, Cala Health, Collegium Pharmaceutical, Satsuma, Teva, Theranica and Xoc; he is on the speakers bureau of AbbVie, Amgen, Biohaven, Impel, Lundbeck, and Teva. Dr. Ross disclosed research support from Johnson and Johnson, the Medical Device Innovation Consortium, and the Laura and John Arnold Foundation, along with government grants; he is also an expert witness in a lawsuit against Biogen.
In June, the Concord, Mass.–based company Tremeau Pharmaceuticals announced that the Food and Drug Administration was letting it proceed with a phase 3 clinical trial to test rofecoxib, the once-bestselling painkiller known as Vioxx, in patients with migraine.
The anti-inflammatory drug, a cyclooxygenase-2 (COX-2) inhibitor, received its first FDA approval in 1999 and became widely prescribed for arthritis and acute pain. In 2004 it was withdrawn by its manufacturer, Merck, after being shown to raise the risk of cardiovascular events.
In clinical trials and in real-world epidemiological studies, rofecoxib was associated with elevated heart attack, stroke, and related deaths; one 2005 study estimated that it had been responsible for some 38,000 excess deaths in the United States before being withdrawn. In 2007 Merck, beset with allegations that it had suppressed and mischaracterized rofecoxib’s safety data, paid out nearly $5 billion to settle thousands of lawsuits filed by patients and their families.
, an indication for which it received an orphan drug designation in 2017 and the agency’s green light for trials in 2020.
Brad Sippy, Tremeau’s chief executive officer, said that his company chose the two indications in part because both patient populations have low cardiovascular risk. Migraine patients are generally younger than the arthritis populations formerly treated with rofecoxib and are unlikely to take the drug for more than a day or 2 at time, avoiding the risks associated with extended exposure.
A crowded market
The past several years have seen the emergence of a cornucopia of new migraine treatments, including monoclonal antibodies such as erenumab (Aimovig, Amgen), which help prevent attacks by blocking the vasodilator calcitonin gene-related peptide, or CGRP. In addition to the standard arsenal of triptans and nonsteroidal anti-inflammatory drugs for acute pain relief, migraine patients can now choose among serotonin-blocking agents such as lasmiditan (Reyvow, Eli Lilly), known as “ditans,” and small-molecule CGRP antagonists such as ubrogepant (Ubrelvy, Abbie), known as “gepants.” Some NSAIDs, including one COX inhibitor, have been formulated into rapidly absorbed powders or liquids for migraine.
Mr. Sippy said he sees a role for rofecoxib even in this crowded space. “Migraine as you know is a multimodal situation – few people say that only one drug works for them,” he said. “We think this is an option that would basically be like a high dose of ibuprofen,” but with less frequent dosing and lower gastrointestinal and platelet effects compared with ibuprofen and other NSAIDs.
An improved formulation
Rofecoxib “crosses the blood brain barrier very readily – better than other COX inhibitors on the market,” Mr. Sippy added. “It was well absorbed in its original formulation, and our product is even better absorbed than the original – we estimate it’s probably an hour quicker to [peak concentration].” In addition, he said, “our formulation is more efficient at delivering the drug so we don’t need as much active ingredient – our 17.5 milligrams gets you the same systemic exposure as 25 milligrams of the old product.”
A different mechanism of action
Neurologist Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews and professor of neurology at the University of California, Los Angeles, said that he was “cautiously optimistic” that “if used correctly and not too frequently, [rofecoxib] will find its niche in migraine treatment.”
“Patients liked Vioxx,” said Dr. Rapoport, past president of the International Headache Society. Even people currently on prevention “need to have an acute care drug handy.” While some patients on monoclonal antibodies have had success with gepants for acute care, “these both target the same pathway. It’s always nice to have options with a different mechanism of action.”
One of the arguments Tremeau has cited for reintroducing rofecoxib has been an urgent need for alternatives to opioid painkillers. Indeed some analysts have linked the demise of Vioxx with a subsequent increase in opioid prescribing.
Dr. Rapoport noted that he never prescribes opioids or butalbital, a barbiturate, for migraine, and that most headache specialists avoid them in clinical practice. But in the emergency setting, he said, patients receive them all too frequently.
Mr. Sippy said that opioid prescribing, while not unknown in migraine, was a bigger problem in hemophilic arthropathy, the first indication his company has pursued for rofecoxib. People with hemophilia “have a kind of arthritis that would respond well to an anti-inflammatory drug but they can’t take NSAIDs due to bleeding risk. This is why so many end up on opioids. Rofecoxib, as a COX-2 inhibitor, doesn’t have any effect on platelet aggregation, which would make it another option.”
No unique risks at prescribed doses
The migraine indication originally started out narrower: Patients with both migraine and bleeding disorders. “But in talking with the FDA, they encouraged us to develop it for migraine,” Mr. Sippy said. The company is considering pursuing a third indication: menstrual pain co-occurring with migraine. Tremeau has not ruled out seeking an indication in patients with arthritis who cannot take other painkillers, whether opioids or NSAIDs.
Five years ago, when Tremeau first announced its plans to bring rofecoxib back – indeed the company was set up for that purpose and has only this and another COX-2 inhibitor in development – some experts warned that there is little to prevent the drug from being used off-label, whether in higher doses or for other diseases.
“That’s something else we’re seeking to solve in addition to going for younger populations,” said Mr. Sippy, who worked at Merck during the Vioxx crisis and later headed neurology at Sunovion before starting his own company.
“We’re going for the former middle dose as our high dose and now we know that you don’t want to take more than the prescribed amount. If it doesn’t work you get off it; you don’t want to dose-creep on it. That’s been a key insight: At the appropriate dose, this product has no unique risk relative to the drug class and potentially some unique benefits,” he said.
Risk versus benefit
Joseph Ross, MD, a health policy researcher at Yale University in New Haven, Conn., who in a 2018 editorial expressed concerns about rofecoxib’s revival, said in an email that he felt its use in migraine could be justified, with caveats.
During Vioxx’s original approval and time on the market, “there was a cardiovascular risk associated with use that was not being transparently and clearly reported to patients and clinicians,” Dr. Ross said.
“In terms of testing the product for use in patients with migraine – a population of generally younger patients at lower risk of cardiovascular disease – my only concern is that the risk is clearly communicated and that there is adequate postmarket safety surveillance,” he said. “If patients are making fully informed decisions, the potential benefit of the drug with respect to pain control may be worth the risks.”
Dr. Rapoport serves as an adviser for AbbVie, Amgen, Biohaven, Cala Health, Collegium Pharmaceutical, Satsuma, Teva, Theranica and Xoc; he is on the speakers bureau of AbbVie, Amgen, Biohaven, Impel, Lundbeck, and Teva. Dr. Ross disclosed research support from Johnson and Johnson, the Medical Device Innovation Consortium, and the Laura and John Arnold Foundation, along with government grants; he is also an expert witness in a lawsuit against Biogen.
In June, the Concord, Mass.–based company Tremeau Pharmaceuticals announced that the Food and Drug Administration was letting it proceed with a phase 3 clinical trial to test rofecoxib, the once-bestselling painkiller known as Vioxx, in patients with migraine.
The anti-inflammatory drug, a cyclooxygenase-2 (COX-2) inhibitor, received its first FDA approval in 1999 and became widely prescribed for arthritis and acute pain. In 2004 it was withdrawn by its manufacturer, Merck, after being shown to raise the risk of cardiovascular events.
In clinical trials and in real-world epidemiological studies, rofecoxib was associated with elevated heart attack, stroke, and related deaths; one 2005 study estimated that it had been responsible for some 38,000 excess deaths in the United States before being withdrawn. In 2007 Merck, beset with allegations that it had suppressed and mischaracterized rofecoxib’s safety data, paid out nearly $5 billion to settle thousands of lawsuits filed by patients and their families.
, an indication for which it received an orphan drug designation in 2017 and the agency’s green light for trials in 2020.
Brad Sippy, Tremeau’s chief executive officer, said that his company chose the two indications in part because both patient populations have low cardiovascular risk. Migraine patients are generally younger than the arthritis populations formerly treated with rofecoxib and are unlikely to take the drug for more than a day or 2 at time, avoiding the risks associated with extended exposure.
A crowded market
The past several years have seen the emergence of a cornucopia of new migraine treatments, including monoclonal antibodies such as erenumab (Aimovig, Amgen), which help prevent attacks by blocking the vasodilator calcitonin gene-related peptide, or CGRP. In addition to the standard arsenal of triptans and nonsteroidal anti-inflammatory drugs for acute pain relief, migraine patients can now choose among serotonin-blocking agents such as lasmiditan (Reyvow, Eli Lilly), known as “ditans,” and small-molecule CGRP antagonists such as ubrogepant (Ubrelvy, Abbie), known as “gepants.” Some NSAIDs, including one COX inhibitor, have been formulated into rapidly absorbed powders or liquids for migraine.
Mr. Sippy said he sees a role for rofecoxib even in this crowded space. “Migraine as you know is a multimodal situation – few people say that only one drug works for them,” he said. “We think this is an option that would basically be like a high dose of ibuprofen,” but with less frequent dosing and lower gastrointestinal and platelet effects compared with ibuprofen and other NSAIDs.
An improved formulation
Rofecoxib “crosses the blood brain barrier very readily – better than other COX inhibitors on the market,” Mr. Sippy added. “It was well absorbed in its original formulation, and our product is even better absorbed than the original – we estimate it’s probably an hour quicker to [peak concentration].” In addition, he said, “our formulation is more efficient at delivering the drug so we don’t need as much active ingredient – our 17.5 milligrams gets you the same systemic exposure as 25 milligrams of the old product.”
A different mechanism of action
Neurologist Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews and professor of neurology at the University of California, Los Angeles, said that he was “cautiously optimistic” that “if used correctly and not too frequently, [rofecoxib] will find its niche in migraine treatment.”
“Patients liked Vioxx,” said Dr. Rapoport, past president of the International Headache Society. Even people currently on prevention “need to have an acute care drug handy.” While some patients on monoclonal antibodies have had success with gepants for acute care, “these both target the same pathway. It’s always nice to have options with a different mechanism of action.”
One of the arguments Tremeau has cited for reintroducing rofecoxib has been an urgent need for alternatives to opioid painkillers. Indeed some analysts have linked the demise of Vioxx with a subsequent increase in opioid prescribing.
Dr. Rapoport noted that he never prescribes opioids or butalbital, a barbiturate, for migraine, and that most headache specialists avoid them in clinical practice. But in the emergency setting, he said, patients receive them all too frequently.
Mr. Sippy said that opioid prescribing, while not unknown in migraine, was a bigger problem in hemophilic arthropathy, the first indication his company has pursued for rofecoxib. People with hemophilia “have a kind of arthritis that would respond well to an anti-inflammatory drug but they can’t take NSAIDs due to bleeding risk. This is why so many end up on opioids. Rofecoxib, as a COX-2 inhibitor, doesn’t have any effect on platelet aggregation, which would make it another option.”
No unique risks at prescribed doses
The migraine indication originally started out narrower: Patients with both migraine and bleeding disorders. “But in talking with the FDA, they encouraged us to develop it for migraine,” Mr. Sippy said. The company is considering pursuing a third indication: menstrual pain co-occurring with migraine. Tremeau has not ruled out seeking an indication in patients with arthritis who cannot take other painkillers, whether opioids or NSAIDs.
Five years ago, when Tremeau first announced its plans to bring rofecoxib back – indeed the company was set up for that purpose and has only this and another COX-2 inhibitor in development – some experts warned that there is little to prevent the drug from being used off-label, whether in higher doses or for other diseases.
“That’s something else we’re seeking to solve in addition to going for younger populations,” said Mr. Sippy, who worked at Merck during the Vioxx crisis and later headed neurology at Sunovion before starting his own company.
“We’re going for the former middle dose as our high dose and now we know that you don’t want to take more than the prescribed amount. If it doesn’t work you get off it; you don’t want to dose-creep on it. That’s been a key insight: At the appropriate dose, this product has no unique risk relative to the drug class and potentially some unique benefits,” he said.
Risk versus benefit
Joseph Ross, MD, a health policy researcher at Yale University in New Haven, Conn., who in a 2018 editorial expressed concerns about rofecoxib’s revival, said in an email that he felt its use in migraine could be justified, with caveats.
During Vioxx’s original approval and time on the market, “there was a cardiovascular risk associated with use that was not being transparently and clearly reported to patients and clinicians,” Dr. Ross said.
“In terms of testing the product for use in patients with migraine – a population of generally younger patients at lower risk of cardiovascular disease – my only concern is that the risk is clearly communicated and that there is adequate postmarket safety surveillance,” he said. “If patients are making fully informed decisions, the potential benefit of the drug with respect to pain control may be worth the risks.”
Dr. Rapoport serves as an adviser for AbbVie, Amgen, Biohaven, Cala Health, Collegium Pharmaceutical, Satsuma, Teva, Theranica and Xoc; he is on the speakers bureau of AbbVie, Amgen, Biohaven, Impel, Lundbeck, and Teva. Dr. Ross disclosed research support from Johnson and Johnson, the Medical Device Innovation Consortium, and the Laura and John Arnold Foundation, along with government grants; he is also an expert witness in a lawsuit against Biogen.
Irritable bowel syndrome therapy removed from market (again)
Zelnorm (tegaserod), an oral short-term treatment of irritable bowel syndrome and constipation (IBS-C), is being removed from the U.S. market effective June 30, according to the manufacturer, Alfasigma.
The Italian pharmaceutical company said the drug is being removed for business purposes, not because of any concern involving its safety or efficacy, nor has it been recalled.
The drug has been through a teeter totter of regulations since its inception.
When it was first introduced in 2002, Zelnorm was a first-of-its-kind drug and was intended to treat all women with IBS-C in the short term. But it was removed from the market 5 years later following concerns about cardiovascular side effects. Clinical data showed an increased incidence of stroke and angina in women taking Zelnorm.
Despite these concerns, the U.S. Food and Drug Administration voted to reintroduce the drug into the market in 2019, but only for women without a history of heart health problems.
Though Alfasigma will stop making the drug, a company news release said current users can continue use for a while.
“Patients will continue to have access to Zelnorm (tegaserod) for as long as the existing supply of product remains in the trade channel,” Alfasigma said in a news release about the drug removal. The company urged its customers to discuss alternative IBS medications with their doctor.
Zelnorm is a serotonin agonist, meaning it binds to receptors and stops the release of serotonin into the system. These sorts of drugs can decrease the pain associated with IBS and help increase gut motility in order to pass stool. Other drugs besides Zelnorm that use this mechanism include alosetron and cilansetron.
A version of this article first appeared on Medscape.com.
Zelnorm (tegaserod), an oral short-term treatment of irritable bowel syndrome and constipation (IBS-C), is being removed from the U.S. market effective June 30, according to the manufacturer, Alfasigma.
The Italian pharmaceutical company said the drug is being removed for business purposes, not because of any concern involving its safety or efficacy, nor has it been recalled.
The drug has been through a teeter totter of regulations since its inception.
When it was first introduced in 2002, Zelnorm was a first-of-its-kind drug and was intended to treat all women with IBS-C in the short term. But it was removed from the market 5 years later following concerns about cardiovascular side effects. Clinical data showed an increased incidence of stroke and angina in women taking Zelnorm.
Despite these concerns, the U.S. Food and Drug Administration voted to reintroduce the drug into the market in 2019, but only for women without a history of heart health problems.
Though Alfasigma will stop making the drug, a company news release said current users can continue use for a while.
“Patients will continue to have access to Zelnorm (tegaserod) for as long as the existing supply of product remains in the trade channel,” Alfasigma said in a news release about the drug removal. The company urged its customers to discuss alternative IBS medications with their doctor.
Zelnorm is a serotonin agonist, meaning it binds to receptors and stops the release of serotonin into the system. These sorts of drugs can decrease the pain associated with IBS and help increase gut motility in order to pass stool. Other drugs besides Zelnorm that use this mechanism include alosetron and cilansetron.
A version of this article first appeared on Medscape.com.
Zelnorm (tegaserod), an oral short-term treatment of irritable bowel syndrome and constipation (IBS-C), is being removed from the U.S. market effective June 30, according to the manufacturer, Alfasigma.
The Italian pharmaceutical company said the drug is being removed for business purposes, not because of any concern involving its safety or efficacy, nor has it been recalled.
The drug has been through a teeter totter of regulations since its inception.
When it was first introduced in 2002, Zelnorm was a first-of-its-kind drug and was intended to treat all women with IBS-C in the short term. But it was removed from the market 5 years later following concerns about cardiovascular side effects. Clinical data showed an increased incidence of stroke and angina in women taking Zelnorm.
Despite these concerns, the U.S. Food and Drug Administration voted to reintroduce the drug into the market in 2019, but only for women without a history of heart health problems.
Though Alfasigma will stop making the drug, a company news release said current users can continue use for a while.
“Patients will continue to have access to Zelnorm (tegaserod) for as long as the existing supply of product remains in the trade channel,” Alfasigma said in a news release about the drug removal. The company urged its customers to discuss alternative IBS medications with their doctor.
Zelnorm is a serotonin agonist, meaning it binds to receptors and stops the release of serotonin into the system. These sorts of drugs can decrease the pain associated with IBS and help increase gut motility in order to pass stool. Other drugs besides Zelnorm that use this mechanism include alosetron and cilansetron.
A version of this article first appeared on Medscape.com.
FDA warning: Lymphoma drug heightens risk of death
The U.S. Food and Drug Administration issued a warning today that the cancer drug duvelisib (Copiktra, Verastem), a PI3 kinase inhibitor, may increase the risk of death and serious side effects.
Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working.
However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib, compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
“The trial also found Copiktra was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood,” states the warning, which advises prescribers to weigh the risks and benefits of continued use versus use of other treatments.
More specifically, median 5-year overall survival among 319 patients with CLL or SLL in the DUO trial was 52.3 months with duvelisib versus 63.3 months with the monoclonal antibody ofatumumab (hazard ratio, 1.09 overall and 1.06 among patients who received at least two prior lines of therapy).
Serious adverse events of grade 3 or higher were also more common in those treated with duvelisib.
Of note, in April, the FDA also announced that it was withdrawing approval of the relapsed or refractory follicular lymphoma indication for duvelisib following a voluntary request by the drug manufacturer Secura Bio.
A public meeting will be scheduled to discuss the findings of the trial and whether the drug should continue to be prescribed.
This FDA warning follows the agency’s June 1 withdrawal of approval for umbralisib (Ukoniq), another PI3 kinase inhibitor, following an investigation into a “possible increased risk of death.”
As reported by this news organization, umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
“These safety findings were similar for other medicines in the same PI3 kinase inhibitor class, which were discussed at an advisory committee meeting of non-FDA experts in April 2022,” according to the FDA warning.
The FDA urges patients and health care professionals to report side effects involving duvelisib or other medicines to the FDA MedWatch program.
A version of this article first appeared on Medscape.com
The U.S. Food and Drug Administration issued a warning today that the cancer drug duvelisib (Copiktra, Verastem), a PI3 kinase inhibitor, may increase the risk of death and serious side effects.
Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working.
However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib, compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
“The trial also found Copiktra was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood,” states the warning, which advises prescribers to weigh the risks and benefits of continued use versus use of other treatments.
More specifically, median 5-year overall survival among 319 patients with CLL or SLL in the DUO trial was 52.3 months with duvelisib versus 63.3 months with the monoclonal antibody ofatumumab (hazard ratio, 1.09 overall and 1.06 among patients who received at least two prior lines of therapy).
Serious adverse events of grade 3 or higher were also more common in those treated with duvelisib.
Of note, in April, the FDA also announced that it was withdrawing approval of the relapsed or refractory follicular lymphoma indication for duvelisib following a voluntary request by the drug manufacturer Secura Bio.
A public meeting will be scheduled to discuss the findings of the trial and whether the drug should continue to be prescribed.
This FDA warning follows the agency’s June 1 withdrawal of approval for umbralisib (Ukoniq), another PI3 kinase inhibitor, following an investigation into a “possible increased risk of death.”
As reported by this news organization, umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
“These safety findings were similar for other medicines in the same PI3 kinase inhibitor class, which were discussed at an advisory committee meeting of non-FDA experts in April 2022,” according to the FDA warning.
The FDA urges patients and health care professionals to report side effects involving duvelisib or other medicines to the FDA MedWatch program.
A version of this article first appeared on Medscape.com
The U.S. Food and Drug Administration issued a warning today that the cancer drug duvelisib (Copiktra, Verastem), a PI3 kinase inhibitor, may increase the risk of death and serious side effects.
Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working.
However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib, compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
“The trial also found Copiktra was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood,” states the warning, which advises prescribers to weigh the risks and benefits of continued use versus use of other treatments.
More specifically, median 5-year overall survival among 319 patients with CLL or SLL in the DUO trial was 52.3 months with duvelisib versus 63.3 months with the monoclonal antibody ofatumumab (hazard ratio, 1.09 overall and 1.06 among patients who received at least two prior lines of therapy).
Serious adverse events of grade 3 or higher were also more common in those treated with duvelisib.
Of note, in April, the FDA also announced that it was withdrawing approval of the relapsed or refractory follicular lymphoma indication for duvelisib following a voluntary request by the drug manufacturer Secura Bio.
A public meeting will be scheduled to discuss the findings of the trial and whether the drug should continue to be prescribed.
This FDA warning follows the agency’s June 1 withdrawal of approval for umbralisib (Ukoniq), another PI3 kinase inhibitor, following an investigation into a “possible increased risk of death.”
As reported by this news organization, umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
“These safety findings were similar for other medicines in the same PI3 kinase inhibitor class, which were discussed at an advisory committee meeting of non-FDA experts in April 2022,” according to the FDA warning.
The FDA urges patients and health care professionals to report side effects involving duvelisib or other medicines to the FDA MedWatch program.
A version of this article first appeared on Medscape.com
FDA unveils 5-year plan for ALS and other neurodegenerative diseases
The agency’s Action Plan for Rare Neurodegenerative Diseases including Amyotrophic Lateral Sclerosis (ALS) aims to advance the development of safe and effective medical products and facilitate patient access to novel treatments.
“The effects of rare neurodegenerative diseases are devastating, with very few effective therapeutic options available to patients. We recognize the urgent need for new treatments that can both improve and extend the lives of people diagnosed with these diseases,” FDA Commissioner Robert M. Califf, MD, said in a news release.
“To face that challenge and to accelerate drug development, we need innovative approaches to better understand these diseases while also building on current scientific and research capabilities,” Dr. Califf acknowledged.
“This action plan, especially including the use of public-private partnerships and direct involvement of patients, will ensure the FDA is working toward meeting the task set forth by Congress to enhance the quality of life for those suffering by facilitating access to new therapies,” Dr. Califf added.
Blueprint to ‘aggressively’ move forward
The action plan represents a “blueprint” for how the agency will “aggressively” move forward to address challenges in drug development for rare neurodegenerative diseases to improve patient health, the FDA said.
The plan was created in accordance with provisions in the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) that President Biden signed into law in late 2021.
Targeted activities include establishing the FDA Rare Neurodegenerative Diseases Task Force and the public-private partnership for rare neurodegenerative diseases, developing disease-specific science strategies over the next 5 years, and leveraging ongoing FDA regulatory science efforts.
The ALS Science Strategy is part of the plan focused specifically on ALS. It provides a “forward-leaning” framework for FDA activities, which include efforts to improve characterization of disease pathogenesis and natural history, boost clinical trial infrastructure and agility to enable early selection of promising therapeutic candidates for further development, optimize clinical trial design, improve access to the trials, streamline clinical trial operations, and reduce the time and cost of drug development.
The FDA says patient engagement, public workshops, research projects, coordination across FDA centers and offices, and collaboration with the National Institutes of Health will be key to the success of implementation of the ALS Science Strategy.
A version of this article first appeared on Medscape.com.
The agency’s Action Plan for Rare Neurodegenerative Diseases including Amyotrophic Lateral Sclerosis (ALS) aims to advance the development of safe and effective medical products and facilitate patient access to novel treatments.
“The effects of rare neurodegenerative diseases are devastating, with very few effective therapeutic options available to patients. We recognize the urgent need for new treatments that can both improve and extend the lives of people diagnosed with these diseases,” FDA Commissioner Robert M. Califf, MD, said in a news release.
“To face that challenge and to accelerate drug development, we need innovative approaches to better understand these diseases while also building on current scientific and research capabilities,” Dr. Califf acknowledged.
“This action plan, especially including the use of public-private partnerships and direct involvement of patients, will ensure the FDA is working toward meeting the task set forth by Congress to enhance the quality of life for those suffering by facilitating access to new therapies,” Dr. Califf added.
Blueprint to ‘aggressively’ move forward
The action plan represents a “blueprint” for how the agency will “aggressively” move forward to address challenges in drug development for rare neurodegenerative diseases to improve patient health, the FDA said.
The plan was created in accordance with provisions in the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) that President Biden signed into law in late 2021.
Targeted activities include establishing the FDA Rare Neurodegenerative Diseases Task Force and the public-private partnership for rare neurodegenerative diseases, developing disease-specific science strategies over the next 5 years, and leveraging ongoing FDA regulatory science efforts.
The ALS Science Strategy is part of the plan focused specifically on ALS. It provides a “forward-leaning” framework for FDA activities, which include efforts to improve characterization of disease pathogenesis and natural history, boost clinical trial infrastructure and agility to enable early selection of promising therapeutic candidates for further development, optimize clinical trial design, improve access to the trials, streamline clinical trial operations, and reduce the time and cost of drug development.
The FDA says patient engagement, public workshops, research projects, coordination across FDA centers and offices, and collaboration with the National Institutes of Health will be key to the success of implementation of the ALS Science Strategy.
A version of this article first appeared on Medscape.com.
The agency’s Action Plan for Rare Neurodegenerative Diseases including Amyotrophic Lateral Sclerosis (ALS) aims to advance the development of safe and effective medical products and facilitate patient access to novel treatments.
“The effects of rare neurodegenerative diseases are devastating, with very few effective therapeutic options available to patients. We recognize the urgent need for new treatments that can both improve and extend the lives of people diagnosed with these diseases,” FDA Commissioner Robert M. Califf, MD, said in a news release.
“To face that challenge and to accelerate drug development, we need innovative approaches to better understand these diseases while also building on current scientific and research capabilities,” Dr. Califf acknowledged.
“This action plan, especially including the use of public-private partnerships and direct involvement of patients, will ensure the FDA is working toward meeting the task set forth by Congress to enhance the quality of life for those suffering by facilitating access to new therapies,” Dr. Califf added.
Blueprint to ‘aggressively’ move forward
The action plan represents a “blueprint” for how the agency will “aggressively” move forward to address challenges in drug development for rare neurodegenerative diseases to improve patient health, the FDA said.
The plan was created in accordance with provisions in the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS) that President Biden signed into law in late 2021.
Targeted activities include establishing the FDA Rare Neurodegenerative Diseases Task Force and the public-private partnership for rare neurodegenerative diseases, developing disease-specific science strategies over the next 5 years, and leveraging ongoing FDA regulatory science efforts.
The ALS Science Strategy is part of the plan focused specifically on ALS. It provides a “forward-leaning” framework for FDA activities, which include efforts to improve characterization of disease pathogenesis and natural history, boost clinical trial infrastructure and agility to enable early selection of promising therapeutic candidates for further development, optimize clinical trial design, improve access to the trials, streamline clinical trial operations, and reduce the time and cost of drug development.
The FDA says patient engagement, public workshops, research projects, coordination across FDA centers and offices, and collaboration with the National Institutes of Health will be key to the success of implementation of the ALS Science Strategy.
A version of this article first appeared on Medscape.com.
FDA panel backs adding Omicron component to COVID boosters
A federal advisory panel on June 28 recommended updating COVID-19 booster vaccines in the United States to include an Omicron component, while urging the need for more information on how well these shots work on emerging strains of the virus.
The Vaccines and Related Biological Products Advisory Committee of the Food and Drug Administration voted 19-2 in favor of a new formulation – although what that formulation will be is yet to be determined. The FDA often incorporates the views of its advisers into its decisions, although it is not bound to do so.
In this case, though, top FDA staff at the meeting seemed inclined to encourage the development of COVID vaccines modified to keep up with an evolving virus. Two Omicron subvariants, BA.4 and BA.5, which first appeared in South Africa in March 2022, have spread to the United States and have begun to increase rapidly in proportion to the virus population, the FDA said in a briefing for the meeting.
New information from the Centers for Disease Control and Prevention shows the two highly infectious subvariants now make up more than half the number of new COVID cases in the US.
Double-duty vaccine
In summarizing the message of the advisory committee, Peter W. Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation & Research, said panelists had lent support to modifying vaccines to protect against both the original, or “ancestral” viral strain, and against Omicron, perhaps emphasizing the newly emerging subvariants.
Dr. Marks emphasized that this is a challenging decision, as no one has a “crystal ball” to forecast how SARS-CoV-2 will evolve.
“We are trying to use every last ounce of what we can from predictive modeling and from the data that we have that’s emerging, to try to get ahead of a virus that has been very crafty,” he said.”It’s pretty darn crafty.”
Limited data
Voting “no” were Paul Offit, MD, of Children’s Hospital of Philadelphia and Henry Bernstein, DO, MHCM, of Hofstra/Northwell Health in New Hyde Park, N.Y.
Both Dr. Offit and Dr. Bernstein earlier in the meeting expressed doubts about the evidence gathered to date in favor of a strain change. Dr. Offit had noted that protection seems to persist from the vaccines now available.
“To date, the current prototypical vaccines, the ancestral strain vaccines do protect against serious illness,” he said. “We don’t yet have a variant that is resistant to protection against serious illness.“
Dr. Bernstein said he was “struggling” with the question as well, given the limited data gathered to date about the vaccines and emerging strains of the virus.
Other panelists also expressed reservations, while supporting the concept of altering vaccines to teach the body to fight the emerging strains as well as the original one.
Panelist Wayne Marasco, MD, PhD, of Harvard Medical School, Boston, who voted yes, noted the difficulties of keeping up with the rapidly evolving virus, saying it’s possible that Omicron strains BA.4 and BA.5 could peak within months. That could be before the vaccines are even distributed – if all goes to plan – in the fall.
“This is a step in the right direction, but we have to reevaluate this as we move forward,” Dr. Marasco said, adding that a good strategy would be to elicit antibody response to bridge more than one variant of the virus.
Even panelists like Dr. Marasco who voted yes stressed the need for further data collection about how vaccines may be adapted to a changing virus. But they also acknowledged a need to give vaccine makers a clear indication of what the medical community expects in terms of changes to these shots.
“With the waning vaccine efficacy and the confluence of risk this fall, we need to make a move sooner rather than later and direct our sponsors in the proper direction,” said FDA panelist Michael Nelson, MD, PhD, of the University of Virginia, Charlottesville, said before the vote.
A version of this article first appeared on Medscape.com.
A federal advisory panel on June 28 recommended updating COVID-19 booster vaccines in the United States to include an Omicron component, while urging the need for more information on how well these shots work on emerging strains of the virus.
The Vaccines and Related Biological Products Advisory Committee of the Food and Drug Administration voted 19-2 in favor of a new formulation – although what that formulation will be is yet to be determined. The FDA often incorporates the views of its advisers into its decisions, although it is not bound to do so.
In this case, though, top FDA staff at the meeting seemed inclined to encourage the development of COVID vaccines modified to keep up with an evolving virus. Two Omicron subvariants, BA.4 and BA.5, which first appeared in South Africa in March 2022, have spread to the United States and have begun to increase rapidly in proportion to the virus population, the FDA said in a briefing for the meeting.
New information from the Centers for Disease Control and Prevention shows the two highly infectious subvariants now make up more than half the number of new COVID cases in the US.
Double-duty vaccine
In summarizing the message of the advisory committee, Peter W. Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation & Research, said panelists had lent support to modifying vaccines to protect against both the original, or “ancestral” viral strain, and against Omicron, perhaps emphasizing the newly emerging subvariants.
Dr. Marks emphasized that this is a challenging decision, as no one has a “crystal ball” to forecast how SARS-CoV-2 will evolve.
“We are trying to use every last ounce of what we can from predictive modeling and from the data that we have that’s emerging, to try to get ahead of a virus that has been very crafty,” he said.”It’s pretty darn crafty.”
Limited data
Voting “no” were Paul Offit, MD, of Children’s Hospital of Philadelphia and Henry Bernstein, DO, MHCM, of Hofstra/Northwell Health in New Hyde Park, N.Y.
Both Dr. Offit and Dr. Bernstein earlier in the meeting expressed doubts about the evidence gathered to date in favor of a strain change. Dr. Offit had noted that protection seems to persist from the vaccines now available.
“To date, the current prototypical vaccines, the ancestral strain vaccines do protect against serious illness,” he said. “We don’t yet have a variant that is resistant to protection against serious illness.“
Dr. Bernstein said he was “struggling” with the question as well, given the limited data gathered to date about the vaccines and emerging strains of the virus.
Other panelists also expressed reservations, while supporting the concept of altering vaccines to teach the body to fight the emerging strains as well as the original one.
Panelist Wayne Marasco, MD, PhD, of Harvard Medical School, Boston, who voted yes, noted the difficulties of keeping up with the rapidly evolving virus, saying it’s possible that Omicron strains BA.4 and BA.5 could peak within months. That could be before the vaccines are even distributed – if all goes to plan – in the fall.
“This is a step in the right direction, but we have to reevaluate this as we move forward,” Dr. Marasco said, adding that a good strategy would be to elicit antibody response to bridge more than one variant of the virus.
Even panelists like Dr. Marasco who voted yes stressed the need for further data collection about how vaccines may be adapted to a changing virus. But they also acknowledged a need to give vaccine makers a clear indication of what the medical community expects in terms of changes to these shots.
“With the waning vaccine efficacy and the confluence of risk this fall, we need to make a move sooner rather than later and direct our sponsors in the proper direction,” said FDA panelist Michael Nelson, MD, PhD, of the University of Virginia, Charlottesville, said before the vote.
A version of this article first appeared on Medscape.com.
A federal advisory panel on June 28 recommended updating COVID-19 booster vaccines in the United States to include an Omicron component, while urging the need for more information on how well these shots work on emerging strains of the virus.
The Vaccines and Related Biological Products Advisory Committee of the Food and Drug Administration voted 19-2 in favor of a new formulation – although what that formulation will be is yet to be determined. The FDA often incorporates the views of its advisers into its decisions, although it is not bound to do so.
In this case, though, top FDA staff at the meeting seemed inclined to encourage the development of COVID vaccines modified to keep up with an evolving virus. Two Omicron subvariants, BA.4 and BA.5, which first appeared in South Africa in March 2022, have spread to the United States and have begun to increase rapidly in proportion to the virus population, the FDA said in a briefing for the meeting.
New information from the Centers for Disease Control and Prevention shows the two highly infectious subvariants now make up more than half the number of new COVID cases in the US.
Double-duty vaccine
In summarizing the message of the advisory committee, Peter W. Marks, MD, PhD, the director of the FDA’s Center for Biologics Evaluation & Research, said panelists had lent support to modifying vaccines to protect against both the original, or “ancestral” viral strain, and against Omicron, perhaps emphasizing the newly emerging subvariants.
Dr. Marks emphasized that this is a challenging decision, as no one has a “crystal ball” to forecast how SARS-CoV-2 will evolve.
“We are trying to use every last ounce of what we can from predictive modeling and from the data that we have that’s emerging, to try to get ahead of a virus that has been very crafty,” he said.”It’s pretty darn crafty.”
Limited data
Voting “no” were Paul Offit, MD, of Children’s Hospital of Philadelphia and Henry Bernstein, DO, MHCM, of Hofstra/Northwell Health in New Hyde Park, N.Y.
Both Dr. Offit and Dr. Bernstein earlier in the meeting expressed doubts about the evidence gathered to date in favor of a strain change. Dr. Offit had noted that protection seems to persist from the vaccines now available.
“To date, the current prototypical vaccines, the ancestral strain vaccines do protect against serious illness,” he said. “We don’t yet have a variant that is resistant to protection against serious illness.“
Dr. Bernstein said he was “struggling” with the question as well, given the limited data gathered to date about the vaccines and emerging strains of the virus.
Other panelists also expressed reservations, while supporting the concept of altering vaccines to teach the body to fight the emerging strains as well as the original one.
Panelist Wayne Marasco, MD, PhD, of Harvard Medical School, Boston, who voted yes, noted the difficulties of keeping up with the rapidly evolving virus, saying it’s possible that Omicron strains BA.4 and BA.5 could peak within months. That could be before the vaccines are even distributed – if all goes to plan – in the fall.
“This is a step in the right direction, but we have to reevaluate this as we move forward,” Dr. Marasco said, adding that a good strategy would be to elicit antibody response to bridge more than one variant of the virus.
Even panelists like Dr. Marasco who voted yes stressed the need for further data collection about how vaccines may be adapted to a changing virus. But they also acknowledged a need to give vaccine makers a clear indication of what the medical community expects in terms of changes to these shots.
“With the waning vaccine efficacy and the confluence of risk this fall, we need to make a move sooner rather than later and direct our sponsors in the proper direction,” said FDA panelist Michael Nelson, MD, PhD, of the University of Virginia, Charlottesville, said before the vote.
A version of this article first appeared on Medscape.com.
FDA approves Qsymia for treating teens with obesity
The indication is for use as additional therapy along with a reduced-calorie diet and increased physical activity in youth with obesity, defined as a body mass index of the 95th percentile or greater when standardized for age and sex.
Qsymia was first approved in July 2012 for chronic weight management in adults with an initial BMI of 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) with one or more weight-related comorbidities, as an adjunct to lifestyle modification.
About 1 in 5 adolescents in the United States has obesity, according to the FDA.
The drug is the fourth to be approved for treating obesity in youth, along with liraglutide (Saxenda) and orlistat (Alli, Xenical), both approved down to age 12, and phentermine for those aged 16 and older.
The Qsymia approval was based on data from a phase 4 double-blind, placebo-controlled trial of 223 youth aged 12-16 with obesity who had not lost weight with lifestyle modifications. They were randomly assigned to Qsymia in doses of 7.5 mg phentermine/46 mg topiramate, 15 mg phentermine/92 mg topiramate, or placebo once daily, along with lifestyle counseling for all.
At 56 weeks, those taking the lower Qsymia dose lost an average of 4.8% of their BMI, and those on the higher dose lost 7.1%. In contrast, the placebo group gained about 3.3% of their BMI.
Because Qsymia increases the risk for oral clefts (lip and palate) in a fetus if taken during pregnancy, female patients should obtain negative pregnancy tests before starting the drug, take monthly pregnancy tests while on the drug, and use effective contraception throughout. Also because of the oral cleft risk, Qsymia is available only through an FDA program called a Risk Evaluation and Mitigation Strategy.
Additional potential adverse effects with Qsymia include increased heart rate and suicidal behavior/ideation. Patients should be advised to monitor for mood changes and discontinue the drug if depression or suicidal thoughts develop. The drug has also been linked to slowing of linear growth, so growth should be monitored in adolescents taking the drug, according to the FDA.
Qsymia is also associated with acute myopia, secondary angle closure glaucoma, visual problems, sleep disorders, cognitive impairment, metabolic acidosis, and decreased renal function.
The most common adverse reactions reported in the pediatric clinical trial included depression, dizziness, joint pain, fever, flu, and ankle sprain.
A version of this article first appeared on Medscape.com.
The indication is for use as additional therapy along with a reduced-calorie diet and increased physical activity in youth with obesity, defined as a body mass index of the 95th percentile or greater when standardized for age and sex.
Qsymia was first approved in July 2012 for chronic weight management in adults with an initial BMI of 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) with one or more weight-related comorbidities, as an adjunct to lifestyle modification.
About 1 in 5 adolescents in the United States has obesity, according to the FDA.
The drug is the fourth to be approved for treating obesity in youth, along with liraglutide (Saxenda) and orlistat (Alli, Xenical), both approved down to age 12, and phentermine for those aged 16 and older.
The Qsymia approval was based on data from a phase 4 double-blind, placebo-controlled trial of 223 youth aged 12-16 with obesity who had not lost weight with lifestyle modifications. They were randomly assigned to Qsymia in doses of 7.5 mg phentermine/46 mg topiramate, 15 mg phentermine/92 mg topiramate, or placebo once daily, along with lifestyle counseling for all.
At 56 weeks, those taking the lower Qsymia dose lost an average of 4.8% of their BMI, and those on the higher dose lost 7.1%. In contrast, the placebo group gained about 3.3% of their BMI.
Because Qsymia increases the risk for oral clefts (lip and palate) in a fetus if taken during pregnancy, female patients should obtain negative pregnancy tests before starting the drug, take monthly pregnancy tests while on the drug, and use effective contraception throughout. Also because of the oral cleft risk, Qsymia is available only through an FDA program called a Risk Evaluation and Mitigation Strategy.
Additional potential adverse effects with Qsymia include increased heart rate and suicidal behavior/ideation. Patients should be advised to monitor for mood changes and discontinue the drug if depression or suicidal thoughts develop. The drug has also been linked to slowing of linear growth, so growth should be monitored in adolescents taking the drug, according to the FDA.
Qsymia is also associated with acute myopia, secondary angle closure glaucoma, visual problems, sleep disorders, cognitive impairment, metabolic acidosis, and decreased renal function.
The most common adverse reactions reported in the pediatric clinical trial included depression, dizziness, joint pain, fever, flu, and ankle sprain.
A version of this article first appeared on Medscape.com.
The indication is for use as additional therapy along with a reduced-calorie diet and increased physical activity in youth with obesity, defined as a body mass index of the 95th percentile or greater when standardized for age and sex.
Qsymia was first approved in July 2012 for chronic weight management in adults with an initial BMI of 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) with one or more weight-related comorbidities, as an adjunct to lifestyle modification.
About 1 in 5 adolescents in the United States has obesity, according to the FDA.
The drug is the fourth to be approved for treating obesity in youth, along with liraglutide (Saxenda) and orlistat (Alli, Xenical), both approved down to age 12, and phentermine for those aged 16 and older.
The Qsymia approval was based on data from a phase 4 double-blind, placebo-controlled trial of 223 youth aged 12-16 with obesity who had not lost weight with lifestyle modifications. They were randomly assigned to Qsymia in doses of 7.5 mg phentermine/46 mg topiramate, 15 mg phentermine/92 mg topiramate, or placebo once daily, along with lifestyle counseling for all.
At 56 weeks, those taking the lower Qsymia dose lost an average of 4.8% of their BMI, and those on the higher dose lost 7.1%. In contrast, the placebo group gained about 3.3% of their BMI.
Because Qsymia increases the risk for oral clefts (lip and palate) in a fetus if taken during pregnancy, female patients should obtain negative pregnancy tests before starting the drug, take monthly pregnancy tests while on the drug, and use effective contraception throughout. Also because of the oral cleft risk, Qsymia is available only through an FDA program called a Risk Evaluation and Mitigation Strategy.
Additional potential adverse effects with Qsymia include increased heart rate and suicidal behavior/ideation. Patients should be advised to monitor for mood changes and discontinue the drug if depression or suicidal thoughts develop. The drug has also been linked to slowing of linear growth, so growth should be monitored in adolescents taking the drug, according to the FDA.
Qsymia is also associated with acute myopia, secondary angle closure glaucoma, visual problems, sleep disorders, cognitive impairment, metabolic acidosis, and decreased renal function.
The most common adverse reactions reported in the pediatric clinical trial included depression, dizziness, joint pain, fever, flu, and ankle sprain.
A version of this article first appeared on Medscape.com.
FDA approves liso-cel as second-line therapy for LBCL
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
Class I recall for Medtronic’s HeartWare HVAD batteries
Medtronic is recalling a single lot of HeartWare Ventricular Assist Device (HVAD) System batteries because of welding defects that may cause separation of the two cell battery packs used to power the system, according to an alert on the Food and Drug Administration website.
“The welding defect may cause the battery to malfunction and no longer provide power or prevent the battery from holding a full charge or properly recharging,” the FDA said.
The agency has identified this as a class I recall, the most serious type because of the potential for serious injury or death.
Medtronic reports one death associated with this recall and two complaints in the affected lot.
Back in April, as reported by this news organization, Medtronic alerted providers that patients implanted with the Medtronic HVAD System who develop pump thrombosis could have a welding defect in the internal pump that causes the pump to malfunction.
The batteries from the recalled lot have a model number of 1650DE, were manufactured from April 13 to 19, 2021 and distributed from April 20 to July 19, 2021. The recall affects a total of 429 devices.
On May 5, 2022, Medtronic sent an urgent medical device correction notice to customers asking them to identify and quarantine all affected batteries and notify affected patients. The notice includes a patient template to help communicate directly with patients.
It also includes a customer confirmation form to initiate an exchange. The completed form should be returned to [email protected].
Medtronic is replacing the affected batteries with new product and has implemented actions to improve control of the welding process.
The Medtronic HVAD System was approved as a bridge to heart transplantation in 2012. Since then, it’s been fraught with problems.
Earlier in June, the company announced it was stopping all sales of the device and advised physicians to stop implanting it, as reported by this news organization.
Problems related to the Medtronic HVAD System should be reported to the FDA’s MedWatch program.
A version of this article first appeared on Medscape.com.
Medtronic is recalling a single lot of HeartWare Ventricular Assist Device (HVAD) System batteries because of welding defects that may cause separation of the two cell battery packs used to power the system, according to an alert on the Food and Drug Administration website.
“The welding defect may cause the battery to malfunction and no longer provide power or prevent the battery from holding a full charge or properly recharging,” the FDA said.
The agency has identified this as a class I recall, the most serious type because of the potential for serious injury or death.
Medtronic reports one death associated with this recall and two complaints in the affected lot.
Back in April, as reported by this news organization, Medtronic alerted providers that patients implanted with the Medtronic HVAD System who develop pump thrombosis could have a welding defect in the internal pump that causes the pump to malfunction.
The batteries from the recalled lot have a model number of 1650DE, were manufactured from April 13 to 19, 2021 and distributed from April 20 to July 19, 2021. The recall affects a total of 429 devices.
On May 5, 2022, Medtronic sent an urgent medical device correction notice to customers asking them to identify and quarantine all affected batteries and notify affected patients. The notice includes a patient template to help communicate directly with patients.
It also includes a customer confirmation form to initiate an exchange. The completed form should be returned to [email protected].
Medtronic is replacing the affected batteries with new product and has implemented actions to improve control of the welding process.
The Medtronic HVAD System was approved as a bridge to heart transplantation in 2012. Since then, it’s been fraught with problems.
Earlier in June, the company announced it was stopping all sales of the device and advised physicians to stop implanting it, as reported by this news organization.
Problems related to the Medtronic HVAD System should be reported to the FDA’s MedWatch program.
A version of this article first appeared on Medscape.com.
Medtronic is recalling a single lot of HeartWare Ventricular Assist Device (HVAD) System batteries because of welding defects that may cause separation of the two cell battery packs used to power the system, according to an alert on the Food and Drug Administration website.
“The welding defect may cause the battery to malfunction and no longer provide power or prevent the battery from holding a full charge or properly recharging,” the FDA said.
The agency has identified this as a class I recall, the most serious type because of the potential for serious injury or death.
Medtronic reports one death associated with this recall and two complaints in the affected lot.
Back in April, as reported by this news organization, Medtronic alerted providers that patients implanted with the Medtronic HVAD System who develop pump thrombosis could have a welding defect in the internal pump that causes the pump to malfunction.
The batteries from the recalled lot have a model number of 1650DE, were manufactured from April 13 to 19, 2021 and distributed from April 20 to July 19, 2021. The recall affects a total of 429 devices.
On May 5, 2022, Medtronic sent an urgent medical device correction notice to customers asking them to identify and quarantine all affected batteries and notify affected patients. The notice includes a patient template to help communicate directly with patients.
It also includes a customer confirmation form to initiate an exchange. The completed form should be returned to [email protected].
Medtronic is replacing the affected batteries with new product and has implemented actions to improve control of the welding process.
The Medtronic HVAD System was approved as a bridge to heart transplantation in 2012. Since then, it’s been fraught with problems.
Earlier in June, the company announced it was stopping all sales of the device and advised physicians to stop implanting it, as reported by this news organization.
Problems related to the Medtronic HVAD System should be reported to the FDA’s MedWatch program.
A version of this article first appeared on Medscape.com.
FDA panel rejects pimavanserin for Alzheimer’s psychosis
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
