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Paul Rizzoli, MD
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Christopher Gottschalk, MD
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VIDEO: Adipogenic genes upregulated in high-BMI sucralose users
CHICAGO – , there was significant upregulation of genes that promote intracellular glucose transport. Genes known to be adipogenic and those governing sweet taste receptors also were significantly upregulated with sucralose exposure.
“Effects of sucralose are particularly more detrimental in obese individuals who are prediabetic or diabetic, rather than nonobese consumers of low-calorie sweetener,” said Sabyasachi Sen, MD, during a press conference at the annual meeting of the Endocrine Society.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
These new findings, together with in vitro examination of human adipose-derived mesenchymal stromal cells (MSCs) exposed to sucralose, are helping solve the puzzle of how a sweetener that delivers no energy may contribute to metabolic derangement, said Dr. Sen, professor of endocrinology at George Washington University in Washington.
Dr. Sen and his collaborators first exposed the MSCs to concentrations of sucralose ranging from 0 mM to 0.2 mM – a physiologic level for high sucralose consumers – to the supraphysiologic concentration of 1 mM.
The adipogenic genes CEBPa and FABP4 were upregulated in the sucralose-exposed MSCs, which also showed more intracellular fat droplet accumulation. Reactive oxygen species increased in the MSCs in a dose-dependent fashion as well, said Dr. Sen in a video interview.
All of this upregulation, said Dr. Sen, was pushing the MSCs toward becoming fat cells. “At the same time, we saw that there are certain genes that were upregulating that were allowing more glucose to enter the cell.” The increase in reactive oxygen species paralleled what was seen in a similar model that used glucose rather than sucralose, he said.
The investigators then took subcutaneous fat biopsies from four normal-weight individuals (body mass index, 23.4-24.8 kg/m2), and from 14 obese individuals (BMI, 32-64 kg/m2). Each group had sucralose users and nonusers. Using mRNA gene expression profiles, they saw that glucose transporter genes, adipogenic genes, and antioxidant genes were upregulated among sucralose consumers with obesity, significantly more than for the normal-weight participants.
The pattern, said Dr. Sen, was strikingly similar to what had been seen with the MSC-sucralose exposure findings. “The upregulation that we saw in the petri dish could now be seen in the human fat samples,” he said.
“We think that the sucralose is … allowing more glucose to enter the cell,” said Dr. Sen. “We think that we actually have figured out a mechanism.” He and his colleagues next plan to tag glucose molecules to follow what actually happens as they enter cells in the presence of sucralose.
When Dr. Sen’s patients ask whether they should switch to low-calorie sweetened beverages, he answers with an emphatic “no.” “I say, ‘It’s not going to do you any good, because it still may allow glucose to enter the cells … you’re going to come back to the same status quo’ ” in the context of obesity and insulin resistance, he said.
Dr. Sen reported that he has no relevant disclosures.
SOURCE: Sen S et al. ENDO 2018, Abstract SUN-071.
CHICAGO – , there was significant upregulation of genes that promote intracellular glucose transport. Genes known to be adipogenic and those governing sweet taste receptors also were significantly upregulated with sucralose exposure.
“Effects of sucralose are particularly more detrimental in obese individuals who are prediabetic or diabetic, rather than nonobese consumers of low-calorie sweetener,” said Sabyasachi Sen, MD, during a press conference at the annual meeting of the Endocrine Society.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
These new findings, together with in vitro examination of human adipose-derived mesenchymal stromal cells (MSCs) exposed to sucralose, are helping solve the puzzle of how a sweetener that delivers no energy may contribute to metabolic derangement, said Dr. Sen, professor of endocrinology at George Washington University in Washington.
Dr. Sen and his collaborators first exposed the MSCs to concentrations of sucralose ranging from 0 mM to 0.2 mM – a physiologic level for high sucralose consumers – to the supraphysiologic concentration of 1 mM.
The adipogenic genes CEBPa and FABP4 were upregulated in the sucralose-exposed MSCs, which also showed more intracellular fat droplet accumulation. Reactive oxygen species increased in the MSCs in a dose-dependent fashion as well, said Dr. Sen in a video interview.
All of this upregulation, said Dr. Sen, was pushing the MSCs toward becoming fat cells. “At the same time, we saw that there are certain genes that were upregulating that were allowing more glucose to enter the cell.” The increase in reactive oxygen species paralleled what was seen in a similar model that used glucose rather than sucralose, he said.
The investigators then took subcutaneous fat biopsies from four normal-weight individuals (body mass index, 23.4-24.8 kg/m2), and from 14 obese individuals (BMI, 32-64 kg/m2). Each group had sucralose users and nonusers. Using mRNA gene expression profiles, they saw that glucose transporter genes, adipogenic genes, and antioxidant genes were upregulated among sucralose consumers with obesity, significantly more than for the normal-weight participants.
The pattern, said Dr. Sen, was strikingly similar to what had been seen with the MSC-sucralose exposure findings. “The upregulation that we saw in the petri dish could now be seen in the human fat samples,” he said.
“We think that the sucralose is … allowing more glucose to enter the cell,” said Dr. Sen. “We think that we actually have figured out a mechanism.” He and his colleagues next plan to tag glucose molecules to follow what actually happens as they enter cells in the presence of sucralose.
When Dr. Sen’s patients ask whether they should switch to low-calorie sweetened beverages, he answers with an emphatic “no.” “I say, ‘It’s not going to do you any good, because it still may allow glucose to enter the cells … you’re going to come back to the same status quo’ ” in the context of obesity and insulin resistance, he said.
Dr. Sen reported that he has no relevant disclosures.
SOURCE: Sen S et al. ENDO 2018, Abstract SUN-071.
CHICAGO – , there was significant upregulation of genes that promote intracellular glucose transport. Genes known to be adipogenic and those governing sweet taste receptors also were significantly upregulated with sucralose exposure.
“Effects of sucralose are particularly more detrimental in obese individuals who are prediabetic or diabetic, rather than nonobese consumers of low-calorie sweetener,” said Sabyasachi Sen, MD, during a press conference at the annual meeting of the Endocrine Society.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
These new findings, together with in vitro examination of human adipose-derived mesenchymal stromal cells (MSCs) exposed to sucralose, are helping solve the puzzle of how a sweetener that delivers no energy may contribute to metabolic derangement, said Dr. Sen, professor of endocrinology at George Washington University in Washington.
Dr. Sen and his collaborators first exposed the MSCs to concentrations of sucralose ranging from 0 mM to 0.2 mM – a physiologic level for high sucralose consumers – to the supraphysiologic concentration of 1 mM.
The adipogenic genes CEBPa and FABP4 were upregulated in the sucralose-exposed MSCs, which also showed more intracellular fat droplet accumulation. Reactive oxygen species increased in the MSCs in a dose-dependent fashion as well, said Dr. Sen in a video interview.
All of this upregulation, said Dr. Sen, was pushing the MSCs toward becoming fat cells. “At the same time, we saw that there are certain genes that were upregulating that were allowing more glucose to enter the cell.” The increase in reactive oxygen species paralleled what was seen in a similar model that used glucose rather than sucralose, he said.
The investigators then took subcutaneous fat biopsies from four normal-weight individuals (body mass index, 23.4-24.8 kg/m2), and from 14 obese individuals (BMI, 32-64 kg/m2). Each group had sucralose users and nonusers. Using mRNA gene expression profiles, they saw that glucose transporter genes, adipogenic genes, and antioxidant genes were upregulated among sucralose consumers with obesity, significantly more than for the normal-weight participants.
The pattern, said Dr. Sen, was strikingly similar to what had been seen with the MSC-sucralose exposure findings. “The upregulation that we saw in the petri dish could now be seen in the human fat samples,” he said.
“We think that the sucralose is … allowing more glucose to enter the cell,” said Dr. Sen. “We think that we actually have figured out a mechanism.” He and his colleagues next plan to tag glucose molecules to follow what actually happens as they enter cells in the presence of sucralose.
When Dr. Sen’s patients ask whether they should switch to low-calorie sweetened beverages, he answers with an emphatic “no.” “I say, ‘It’s not going to do you any good, because it still may allow glucose to enter the cells … you’re going to come back to the same status quo’ ” in the context of obesity and insulin resistance, he said.
Dr. Sen reported that he has no relevant disclosures.
SOURCE: Sen S et al. ENDO 2018, Abstract SUN-071.
REPORTING FROM ENDO 2018
VIDEO: How to prepare PTCL patients for transplant
LA JOLLA, CALIF. – according to Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York.
“If you’re really trying to go to transplant, you want a complete remission or close to it. So that’s often been combination chemotherapy. But I think what we’re learning is, when some of the newer agents are combined, we’re seeing higher complete response rates. And we’re doing a better job at picking subtype specific approaches,” Dr. Horwitz said in a video interview at the annual T-cell Lymphoma Forum.
Dr. Horwitz also explored the role for reduced-intensity regimens in older patients, the use of radiation conditioning, and which new agents look most promising in peripheral T-cell lymphoma.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
SOURCE: Horwitz SM. TCLF 2018.
LA JOLLA, CALIF. – according to Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York.
“If you’re really trying to go to transplant, you want a complete remission or close to it. So that’s often been combination chemotherapy. But I think what we’re learning is, when some of the newer agents are combined, we’re seeing higher complete response rates. And we’re doing a better job at picking subtype specific approaches,” Dr. Horwitz said in a video interview at the annual T-cell Lymphoma Forum.
Dr. Horwitz also explored the role for reduced-intensity regimens in older patients, the use of radiation conditioning, and which new agents look most promising in peripheral T-cell lymphoma.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
SOURCE: Horwitz SM. TCLF 2018.
LA JOLLA, CALIF. – according to Steven M. Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York.
“If you’re really trying to go to transplant, you want a complete remission or close to it. So that’s often been combination chemotherapy. But I think what we’re learning is, when some of the newer agents are combined, we’re seeing higher complete response rates. And we’re doing a better job at picking subtype specific approaches,” Dr. Horwitz said in a video interview at the annual T-cell Lymphoma Forum.
Dr. Horwitz also explored the role for reduced-intensity regimens in older patients, the use of radiation conditioning, and which new agents look most promising in peripheral T-cell lymphoma.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
SOURCE: Horwitz SM. TCLF 2018.
REPORTING FROM TCLF 2018
VIDEO: Everolimus/letrozole promising for recurrent endometrial cancer
NEW ORLEANS – Combined treatment for 28 days with the mammalian target of rapamycin inhibitor everolimus plus the aromatase inhibitor letrozole in 37 women with recurrent endometrial cancer produced an overall objective response rate of 24% and an average progression-free survival rate of 6.3 months in a randomized phase 2 study with a total of 74 patients. The treatment was also relatively well tolerated, with more serious adverse vents of anemia and hyperglycemia.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
But the most attention-grabbing finding of this study was that, in the subset of 15 women who had received no prior chemotherapy, the objective response rate on this regimen was 53% and median progression-free survival was 21.6 months, Brian M. Slomovitz, MD, said at the annual meeting of the Society of Gynecologic Oncology.
This level of response in the chemotherapy-naive subgroup was “very high, and not what we expected,” Dr. Slomovitz, , professor of ob.gyn. and human genetics and director of gynecologic oncology at the University of Miami, said in a video interview. “This is something we need to further investigate to see if we can make this part of standard care.”
Although he conceded that the data from this study were too limited to warrant a regulatory indication, he suggested that it might be enough to gain the everolimus plus letrozole combination used in the study citation as a treatment option in clinical guidelines. The next step should be a phase 3 trial that compares the everolimus plus letrozole combination with the traditional chemotherapy regimen of carboplatin plus paclitaxel, Dr. Slomovitz added.
The Everolimus and Letrozole or Hormonal Therapy to Treat Endometrial Cancer phase 2 trial, initiated by the Gynecologic Oncology Group, ran at 26 U.S. centers, and randomized patients with stage III or IV recurrent, advanced, or persistent endometrial cancer who had either no or at most one prior course of chemotherapy. The study design also excluded patients who had previously been treated with an mammalian target of rapamycin inhibitor or hormonal therapy for their endometrial cancer. The control arm placed 37 patients on a standard hormonal therapy regimen of tamoxifen plus medroxyprogesterone, with 36 of patients in this subgroup evaluable.
The overall results in the two treatment arms were roughly similar, except for the striking benefit seen with everolimus(Afinitor) plus letrozole(Femara) in the chemotherapy-naive patents; 15 patients in each arm had not received any chemotherapy before entering the study. In this subgroup, among the patients who received conventional hormonal therapy, the objective response rate was 43% and progression-free survival was 6.6 months.
The two arms also differed by their pattern of grade 3 or 4 adverse events. Among the patients on everolimus plus letrozole, the most common were anemia (24%) and hyperglycemia (14%), both expected consequences of the regimen. The hormonal therapy arm led to an 8% incidence of thromboembolic events, which did not occur in the everolimus plus letrozole arm.
Another attraction of the everolimus and letrozole regimen is that it is oral and avoids the need for drug infusions, Dr. Slomovitz noted.
The investigator-initiated study received funding from Novartis, the company that markets everolimus and letrozole. Dr. Slomovitz has been an advisor to Advaxis, AstraZeneca, Clovis, Genmab, Jannsen, and Tesaro, and he has received research funding from Novartis.
SOURCE: Slomovitz BM et al. SGO 2018, abstract 1.
The results from this study are exciting, with fairly compelling response rates. The rate of progression-free survival with everolimus and letrozole treatment is very impressive, compared with traditional chemotherapy using carboplatin and paclitaxel. The median progression-free survival rate of 21.6 months seen among the chemotherapy naive patients who received everolimus and letrozole showed a 7-month edge over the 14-month median progression-free survival previously reported with chemotherapy. This difference is very provocative and could be practice changing, but it of course needs further evaluation.
Paola A. Gehrig, MD , is professor of ob.gyn. and director of gynecologic oncology at the University of North Carolina in Chapel Hill. She made these comments as designated discussant for the study. She had no disclosures.
The results from this study are exciting, with fairly compelling response rates. The rate of progression-free survival with everolimus and letrozole treatment is very impressive, compared with traditional chemotherapy using carboplatin and paclitaxel. The median progression-free survival rate of 21.6 months seen among the chemotherapy naive patients who received everolimus and letrozole showed a 7-month edge over the 14-month median progression-free survival previously reported with chemotherapy. This difference is very provocative and could be practice changing, but it of course needs further evaluation.
Paola A. Gehrig, MD , is professor of ob.gyn. and director of gynecologic oncology at the University of North Carolina in Chapel Hill. She made these comments as designated discussant for the study. She had no disclosures.
The results from this study are exciting, with fairly compelling response rates. The rate of progression-free survival with everolimus and letrozole treatment is very impressive, compared with traditional chemotherapy using carboplatin and paclitaxel. The median progression-free survival rate of 21.6 months seen among the chemotherapy naive patients who received everolimus and letrozole showed a 7-month edge over the 14-month median progression-free survival previously reported with chemotherapy. This difference is very provocative and could be practice changing, but it of course needs further evaluation.
Paola A. Gehrig, MD , is professor of ob.gyn. and director of gynecologic oncology at the University of North Carolina in Chapel Hill. She made these comments as designated discussant for the study. She had no disclosures.
NEW ORLEANS – Combined treatment for 28 days with the mammalian target of rapamycin inhibitor everolimus plus the aromatase inhibitor letrozole in 37 women with recurrent endometrial cancer produced an overall objective response rate of 24% and an average progression-free survival rate of 6.3 months in a randomized phase 2 study with a total of 74 patients. The treatment was also relatively well tolerated, with more serious adverse vents of anemia and hyperglycemia.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
But the most attention-grabbing finding of this study was that, in the subset of 15 women who had received no prior chemotherapy, the objective response rate on this regimen was 53% and median progression-free survival was 21.6 months, Brian M. Slomovitz, MD, said at the annual meeting of the Society of Gynecologic Oncology.
This level of response in the chemotherapy-naive subgroup was “very high, and not what we expected,” Dr. Slomovitz, , professor of ob.gyn. and human genetics and director of gynecologic oncology at the University of Miami, said in a video interview. “This is something we need to further investigate to see if we can make this part of standard care.”
Although he conceded that the data from this study were too limited to warrant a regulatory indication, he suggested that it might be enough to gain the everolimus plus letrozole combination used in the study citation as a treatment option in clinical guidelines. The next step should be a phase 3 trial that compares the everolimus plus letrozole combination with the traditional chemotherapy regimen of carboplatin plus paclitaxel, Dr. Slomovitz added.
The Everolimus and Letrozole or Hormonal Therapy to Treat Endometrial Cancer phase 2 trial, initiated by the Gynecologic Oncology Group, ran at 26 U.S. centers, and randomized patients with stage III or IV recurrent, advanced, or persistent endometrial cancer who had either no or at most one prior course of chemotherapy. The study design also excluded patients who had previously been treated with an mammalian target of rapamycin inhibitor or hormonal therapy for their endometrial cancer. The control arm placed 37 patients on a standard hormonal therapy regimen of tamoxifen plus medroxyprogesterone, with 36 of patients in this subgroup evaluable.
The overall results in the two treatment arms were roughly similar, except for the striking benefit seen with everolimus(Afinitor) plus letrozole(Femara) in the chemotherapy-naive patents; 15 patients in each arm had not received any chemotherapy before entering the study. In this subgroup, among the patients who received conventional hormonal therapy, the objective response rate was 43% and progression-free survival was 6.6 months.
The two arms also differed by their pattern of grade 3 or 4 adverse events. Among the patients on everolimus plus letrozole, the most common were anemia (24%) and hyperglycemia (14%), both expected consequences of the regimen. The hormonal therapy arm led to an 8% incidence of thromboembolic events, which did not occur in the everolimus plus letrozole arm.
Another attraction of the everolimus and letrozole regimen is that it is oral and avoids the need for drug infusions, Dr. Slomovitz noted.
The investigator-initiated study received funding from Novartis, the company that markets everolimus and letrozole. Dr. Slomovitz has been an advisor to Advaxis, AstraZeneca, Clovis, Genmab, Jannsen, and Tesaro, and he has received research funding from Novartis.
SOURCE: Slomovitz BM et al. SGO 2018, abstract 1.
NEW ORLEANS – Combined treatment for 28 days with the mammalian target of rapamycin inhibitor everolimus plus the aromatase inhibitor letrozole in 37 women with recurrent endometrial cancer produced an overall objective response rate of 24% and an average progression-free survival rate of 6.3 months in a randomized phase 2 study with a total of 74 patients. The treatment was also relatively well tolerated, with more serious adverse vents of anemia and hyperglycemia.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
But the most attention-grabbing finding of this study was that, in the subset of 15 women who had received no prior chemotherapy, the objective response rate on this regimen was 53% and median progression-free survival was 21.6 months, Brian M. Slomovitz, MD, said at the annual meeting of the Society of Gynecologic Oncology.
This level of response in the chemotherapy-naive subgroup was “very high, and not what we expected,” Dr. Slomovitz, , professor of ob.gyn. and human genetics and director of gynecologic oncology at the University of Miami, said in a video interview. “This is something we need to further investigate to see if we can make this part of standard care.”
Although he conceded that the data from this study were too limited to warrant a regulatory indication, he suggested that it might be enough to gain the everolimus plus letrozole combination used in the study citation as a treatment option in clinical guidelines. The next step should be a phase 3 trial that compares the everolimus plus letrozole combination with the traditional chemotherapy regimen of carboplatin plus paclitaxel, Dr. Slomovitz added.
The Everolimus and Letrozole or Hormonal Therapy to Treat Endometrial Cancer phase 2 trial, initiated by the Gynecologic Oncology Group, ran at 26 U.S. centers, and randomized patients with stage III or IV recurrent, advanced, or persistent endometrial cancer who had either no or at most one prior course of chemotherapy. The study design also excluded patients who had previously been treated with an mammalian target of rapamycin inhibitor or hormonal therapy for their endometrial cancer. The control arm placed 37 patients on a standard hormonal therapy regimen of tamoxifen plus medroxyprogesterone, with 36 of patients in this subgroup evaluable.
The overall results in the two treatment arms were roughly similar, except for the striking benefit seen with everolimus(Afinitor) plus letrozole(Femara) in the chemotherapy-naive patents; 15 patients in each arm had not received any chemotherapy before entering the study. In this subgroup, among the patients who received conventional hormonal therapy, the objective response rate was 43% and progression-free survival was 6.6 months.
The two arms also differed by their pattern of grade 3 or 4 adverse events. Among the patients on everolimus plus letrozole, the most common were anemia (24%) and hyperglycemia (14%), both expected consequences of the regimen. The hormonal therapy arm led to an 8% incidence of thromboembolic events, which did not occur in the everolimus plus letrozole arm.
Another attraction of the everolimus and letrozole regimen is that it is oral and avoids the need for drug infusions, Dr. Slomovitz noted.
The investigator-initiated study received funding from Novartis, the company that markets everolimus and letrozole. Dr. Slomovitz has been an advisor to Advaxis, AstraZeneca, Clovis, Genmab, Jannsen, and Tesaro, and he has received research funding from Novartis.
SOURCE: Slomovitz BM et al. SGO 2018, abstract 1.
REPORTING FROM SGO 2018
Key clinical point: Treatment of recurrent endometrial cancer with everolimus and letrozole shows promise.
Major finding: Among 15 chemotherapy-naive patients, objective responses occurred in 53% and median progression-free survival was 21.6 months.
Study details: A multicenter, phase 2 randomized study in 74 patients.
Disclosures: The investigator-initiated study received funding from Novartis, the company that markets everolimus(Afinitor) and letrozole(Femara). Dr. Slomovitz has been an advisor to Advaxis, AstraZeneca, Clovis, Genmab, Jannsen, and Tesaro, and he has received research funding from Novartis.
Source: Slomovitz BM et al. SGO 2018, abstract 1.
VIDEO: Andexanet alfa effectively reverses factor Xa anticoagulant
ORLANDO – Andexanet alfa, a new agent that reverses the anticoagulant effect of direct factor Xa inhibitors, showed an acceptable level of efficacy and safety in 227 patients who received the drug in the agent’s pivotal trial.
These results, which placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind), approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa), suggest that andexanet is likely on track for its own Food and Drug Administration marketing approval, Stuart Connolly, MD, said at the annual meeting of the American College of Cardiology.
Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa) previously announced that it expected Food and Drug Administration action on its marketing application by May 2018.
Andexanet reversal “has similar efficacy and safety as seen with other reversal agents” for other types of anticoagulants, said Dr. Connolly, a professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont. In the trial results he reported, andexanet treatment of patients who were bleeding while on treatment with a direct factor Xa inhibitor had an 83% rate of hemostatic efficacy and an 11% rate of thrombotic events. By comparison, idarucizumab, the FDA-approved reversal agent for the anticoagulant dabigatran, produced a 68% hemostatic efficacy and a 6% rate of thrombotic events in the idarucizumab pivotal trial, RE-VERSE AD (N Engl J Med. 2015 Aug 6;373[6]:511-20).
The Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4) enrolled 227 patients at any of 60 centers, with efficacy data available from 132 of the patients. About 60% of the patients had an intracranial bleed, and about 30% had a gastrointestinal bleed, and their average age was 77 years. Roughly three-quarters of patients were on an anticoagulant for atrial fibrillation, with the rest treated for venous thromboembolism, with 4% having both conditions. The most commonly used direct factor Xa inhbitors in these patients were apixaban (Eliquis) in 105 and rivaroxaban (Xarelto) in 75. The ANNEXA-4 study has not enrolled patients treated with a direct factor Xa inhibitor anticoagulant and undergoing surgery, a setting that will be the subject of a future study, Dr. Connolly said.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by about 75%-90% within minutes of starting the bolus and remained depressed at that level during the infusion but then began recovering by 2 hours after the stop of infusion. Andexanet is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops.
“There is no doubt that andexanet rapidly decreases anti–factor Xa activity,” he said.
Adjudicated efficacy results were available for 132 patients and showed good or excellent hemostasis achieved on andexanet in 109 patients (83%), Dr. Connolly reported. The effect on hemostasis was consistent regardless of patient age, sex, bleeding site, type of anticoagulant, and dosage tested.
Thrombotic events during the 30 days following treatment occurred in 24 of 227 patients (11%) who received andexanet and were evaluable for safety. Notably, no clustering of thrombotic events occurred early, even among the 129 patients who restarted on an anticoagulant during the 30 days after treatment. Among the 129 patients who restarted on an anticoagulant, 9 (7%) had a thrombotic event during the 30-day follow-up, compared with 15 events among 98 patients (15%) who did not restart on an anticoagulant.
Dr. Connolly acknowledged that a limitation of the ANNEXA-4 study is the absence of a control group, but he added that he and his associates believed randomizing patients with a serious bleed to placebo control would not have been “practical, feasible, or ethical.”
ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola, and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. Dr. Kirtane has received research support from several device manufacturers.
SOURCE: Connolly S. ACC 2018.
Treatment with andexanet alfa produced good or excellent hemostasis in 83% of patients in the ANNEXA-4 study, which is what matters when patients are bleeding. Clinicians want to know that you can restore coagulation to a level where you can stop bleeding, and that’s what the results show.
The lack of a reversal agent until now for direct-acting factor Xa inhibitor drugs has probably been a modest but real obstacle to widespread adoption of these agents. We can look at the example of another new oral anticoagulant, dabigatran (Pradaxa), which works by a different mechanism, specifically by inhibiting thrombin. After a reversal agent for dabigatran, idarucizumab (Praxbind) received Food and Drug Administration approval and became available in late 2015, an uptick in dabigatran prescriptions occurred. That experience shows that patients and providers want the safety net of a reversal agent. They want to know that, if there is bleeding or need for urgent surgery, there is a way to facilitate restoration of hemostasis.
It’s the same with direct factor Xa inhibitors: Some patients are concerned about the lack of a reversal agent, and having such an agent may help increase access to these agents for such patients. I think that, once andexanet becomes available for routine U.S. practice, we’ll see an uptick in prescribing of direct factor Xa inhibitors. Also, some patients who have opted for treatment with warfarin will switch to a safer class of drugs, the direct factor X a inhibitors. A myth exists that reversal agents can easily negate the anticoagulant effect of warfarin. The reality is that, despite having treatments that reverse warfarin’s effect, this is often not an easy process in actual practice.
On the safety side, there was no indication in the ANNEXA-4 results of rebound thrombosis with andexanet alfa treatment. Patients receiving a direct factor Xa inhibitor are prothrombotic – that’s why they are on an anticoagulant – so their risk for a thrombotic event is always there, especially when they are not fully anticoagulated, such as when a reversal agent is administered. We need to look to restarting treatment with an anticoagulant because these patients have a high thrombotic risk.
Gregory Piazza, MD , is a cardiologist at Brigham and Women’s Hospital in Boston. He has been an advisor to Portola Pharmaceuticals, the company developing andexanet alfa, as well as to Bayer and Pfizer, and he has received research funding from Bristol-Myers Squibb, Janssen, and Daiichi Sankyo. He made these comments in an interview .
Treatment with andexanet alfa produced good or excellent hemostasis in 83% of patients in the ANNEXA-4 study, which is what matters when patients are bleeding. Clinicians want to know that you can restore coagulation to a level where you can stop bleeding, and that’s what the results show.
The lack of a reversal agent until now for direct-acting factor Xa inhibitor drugs has probably been a modest but real obstacle to widespread adoption of these agents. We can look at the example of another new oral anticoagulant, dabigatran (Pradaxa), which works by a different mechanism, specifically by inhibiting thrombin. After a reversal agent for dabigatran, idarucizumab (Praxbind) received Food and Drug Administration approval and became available in late 2015, an uptick in dabigatran prescriptions occurred. That experience shows that patients and providers want the safety net of a reversal agent. They want to know that, if there is bleeding or need for urgent surgery, there is a way to facilitate restoration of hemostasis.
It’s the same with direct factor Xa inhibitors: Some patients are concerned about the lack of a reversal agent, and having such an agent may help increase access to these agents for such patients. I think that, once andexanet becomes available for routine U.S. practice, we’ll see an uptick in prescribing of direct factor Xa inhibitors. Also, some patients who have opted for treatment with warfarin will switch to a safer class of drugs, the direct factor X a inhibitors. A myth exists that reversal agents can easily negate the anticoagulant effect of warfarin. The reality is that, despite having treatments that reverse warfarin’s effect, this is often not an easy process in actual practice.
On the safety side, there was no indication in the ANNEXA-4 results of rebound thrombosis with andexanet alfa treatment. Patients receiving a direct factor Xa inhibitor are prothrombotic – that’s why they are on an anticoagulant – so their risk for a thrombotic event is always there, especially when they are not fully anticoagulated, such as when a reversal agent is administered. We need to look to restarting treatment with an anticoagulant because these patients have a high thrombotic risk.
Gregory Piazza, MD , is a cardiologist at Brigham and Women’s Hospital in Boston. He has been an advisor to Portola Pharmaceuticals, the company developing andexanet alfa, as well as to Bayer and Pfizer, and he has received research funding from Bristol-Myers Squibb, Janssen, and Daiichi Sankyo. He made these comments in an interview .
Treatment with andexanet alfa produced good or excellent hemostasis in 83% of patients in the ANNEXA-4 study, which is what matters when patients are bleeding. Clinicians want to know that you can restore coagulation to a level where you can stop bleeding, and that’s what the results show.
The lack of a reversal agent until now for direct-acting factor Xa inhibitor drugs has probably been a modest but real obstacle to widespread adoption of these agents. We can look at the example of another new oral anticoagulant, dabigatran (Pradaxa), which works by a different mechanism, specifically by inhibiting thrombin. After a reversal agent for dabigatran, idarucizumab (Praxbind) received Food and Drug Administration approval and became available in late 2015, an uptick in dabigatran prescriptions occurred. That experience shows that patients and providers want the safety net of a reversal agent. They want to know that, if there is bleeding or need for urgent surgery, there is a way to facilitate restoration of hemostasis.
It’s the same with direct factor Xa inhibitors: Some patients are concerned about the lack of a reversal agent, and having such an agent may help increase access to these agents for such patients. I think that, once andexanet becomes available for routine U.S. practice, we’ll see an uptick in prescribing of direct factor Xa inhibitors. Also, some patients who have opted for treatment with warfarin will switch to a safer class of drugs, the direct factor X a inhibitors. A myth exists that reversal agents can easily negate the anticoagulant effect of warfarin. The reality is that, despite having treatments that reverse warfarin’s effect, this is often not an easy process in actual practice.
On the safety side, there was no indication in the ANNEXA-4 results of rebound thrombosis with andexanet alfa treatment. Patients receiving a direct factor Xa inhibitor are prothrombotic – that’s why they are on an anticoagulant – so their risk for a thrombotic event is always there, especially when they are not fully anticoagulated, such as when a reversal agent is administered. We need to look to restarting treatment with an anticoagulant because these patients have a high thrombotic risk.
Gregory Piazza, MD , is a cardiologist at Brigham and Women’s Hospital in Boston. He has been an advisor to Portola Pharmaceuticals, the company developing andexanet alfa, as well as to Bayer and Pfizer, and he has received research funding from Bristol-Myers Squibb, Janssen, and Daiichi Sankyo. He made these comments in an interview .
ORLANDO – Andexanet alfa, a new agent that reverses the anticoagulant effect of direct factor Xa inhibitors, showed an acceptable level of efficacy and safety in 227 patients who received the drug in the agent’s pivotal trial.
These results, which placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind), approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa), suggest that andexanet is likely on track for its own Food and Drug Administration marketing approval, Stuart Connolly, MD, said at the annual meeting of the American College of Cardiology.
Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa) previously announced that it expected Food and Drug Administration action on its marketing application by May 2018.
Andexanet reversal “has similar efficacy and safety as seen with other reversal agents” for other types of anticoagulants, said Dr. Connolly, a professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont. In the trial results he reported, andexanet treatment of patients who were bleeding while on treatment with a direct factor Xa inhibitor had an 83% rate of hemostatic efficacy and an 11% rate of thrombotic events. By comparison, idarucizumab, the FDA-approved reversal agent for the anticoagulant dabigatran, produced a 68% hemostatic efficacy and a 6% rate of thrombotic events in the idarucizumab pivotal trial, RE-VERSE AD (N Engl J Med. 2015 Aug 6;373[6]:511-20).
The Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4) enrolled 227 patients at any of 60 centers, with efficacy data available from 132 of the patients. About 60% of the patients had an intracranial bleed, and about 30% had a gastrointestinal bleed, and their average age was 77 years. Roughly three-quarters of patients were on an anticoagulant for atrial fibrillation, with the rest treated for venous thromboembolism, with 4% having both conditions. The most commonly used direct factor Xa inhbitors in these patients were apixaban (Eliquis) in 105 and rivaroxaban (Xarelto) in 75. The ANNEXA-4 study has not enrolled patients treated with a direct factor Xa inhibitor anticoagulant and undergoing surgery, a setting that will be the subject of a future study, Dr. Connolly said.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by about 75%-90% within minutes of starting the bolus and remained depressed at that level during the infusion but then began recovering by 2 hours after the stop of infusion. Andexanet is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops.
“There is no doubt that andexanet rapidly decreases anti–factor Xa activity,” he said.
Adjudicated efficacy results were available for 132 patients and showed good or excellent hemostasis achieved on andexanet in 109 patients (83%), Dr. Connolly reported. The effect on hemostasis was consistent regardless of patient age, sex, bleeding site, type of anticoagulant, and dosage tested.
Thrombotic events during the 30 days following treatment occurred in 24 of 227 patients (11%) who received andexanet and were evaluable for safety. Notably, no clustering of thrombotic events occurred early, even among the 129 patients who restarted on an anticoagulant during the 30 days after treatment. Among the 129 patients who restarted on an anticoagulant, 9 (7%) had a thrombotic event during the 30-day follow-up, compared with 15 events among 98 patients (15%) who did not restart on an anticoagulant.
Dr. Connolly acknowledged that a limitation of the ANNEXA-4 study is the absence of a control group, but he added that he and his associates believed randomizing patients with a serious bleed to placebo control would not have been “practical, feasible, or ethical.”
ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola, and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. Dr. Kirtane has received research support from several device manufacturers.
SOURCE: Connolly S. ACC 2018.
ORLANDO – Andexanet alfa, a new agent that reverses the anticoagulant effect of direct factor Xa inhibitors, showed an acceptable level of efficacy and safety in 227 patients who received the drug in the agent’s pivotal trial.
These results, which placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind), approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa), suggest that andexanet is likely on track for its own Food and Drug Administration marketing approval, Stuart Connolly, MD, said at the annual meeting of the American College of Cardiology.
Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa) previously announced that it expected Food and Drug Administration action on its marketing application by May 2018.
Andexanet reversal “has similar efficacy and safety as seen with other reversal agents” for other types of anticoagulants, said Dr. Connolly, a professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont. In the trial results he reported, andexanet treatment of patients who were bleeding while on treatment with a direct factor Xa inhibitor had an 83% rate of hemostatic efficacy and an 11% rate of thrombotic events. By comparison, idarucizumab, the FDA-approved reversal agent for the anticoagulant dabigatran, produced a 68% hemostatic efficacy and a 6% rate of thrombotic events in the idarucizumab pivotal trial, RE-VERSE AD (N Engl J Med. 2015 Aug 6;373[6]:511-20).
The Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4) enrolled 227 patients at any of 60 centers, with efficacy data available from 132 of the patients. About 60% of the patients had an intracranial bleed, and about 30% had a gastrointestinal bleed, and their average age was 77 years. Roughly three-quarters of patients were on an anticoagulant for atrial fibrillation, with the rest treated for venous thromboembolism, with 4% having both conditions. The most commonly used direct factor Xa inhbitors in these patients were apixaban (Eliquis) in 105 and rivaroxaban (Xarelto) in 75. The ANNEXA-4 study has not enrolled patients treated with a direct factor Xa inhibitor anticoagulant and undergoing surgery, a setting that will be the subject of a future study, Dr. Connolly said.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by about 75%-90% within minutes of starting the bolus and remained depressed at that level during the infusion but then began recovering by 2 hours after the stop of infusion. Andexanet is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops.
“There is no doubt that andexanet rapidly decreases anti–factor Xa activity,” he said.
Adjudicated efficacy results were available for 132 patients and showed good or excellent hemostasis achieved on andexanet in 109 patients (83%), Dr. Connolly reported. The effect on hemostasis was consistent regardless of patient age, sex, bleeding site, type of anticoagulant, and dosage tested.
Thrombotic events during the 30 days following treatment occurred in 24 of 227 patients (11%) who received andexanet and were evaluable for safety. Notably, no clustering of thrombotic events occurred early, even among the 129 patients who restarted on an anticoagulant during the 30 days after treatment. Among the 129 patients who restarted on an anticoagulant, 9 (7%) had a thrombotic event during the 30-day follow-up, compared with 15 events among 98 patients (15%) who did not restart on an anticoagulant.
Dr. Connolly acknowledged that a limitation of the ANNEXA-4 study is the absence of a control group, but he added that he and his associates believed randomizing patients with a serious bleed to placebo control would not have been “practical, feasible, or ethical.”
ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola, and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. Dr. Kirtane has received research support from several device manufacturers.
SOURCE: Connolly S. ACC 2018.
REPORTING FROM ACC 18
Key clinical point:
Major finding: Hemostatic efficacy of andexanet alfa was 83%, and thrombotic events occurred in 11%.
Study details: ANNEXA-4, a single arm cohort study with 227 patients.
Disclosures: ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis.
Source: Connolly S. ACC 2018.
VIDEO: Researchers closing in on the elusive ‘male pill’
CHICAGO –
It blocks gonadotropin signaling and testosterone production in the testes. When capsules ranging in dose from 100 mg to 400 mg were given once daily to 100 men in a randomized, placebo controlled trial, the drop in testosterone was more than sufficient to block sperm production. Testosterone levels jumped back up to normal after the end of the 28-day trial, all without inducing liver toxicity or other serious problems.
“We are very excited [about] the results. It’s a big step forward in the development of the male pill. Our last great advance in male contraception was over 300 years ago with the development of the condom,” said senior investigator Stephanie Page, MD, PhD, head of the division of metabolism, endocrinology, and nutrition at the University of Washington, Seattle.
Some men reported a drop in libido that resolved by the end of the study. There was also mild weight gain and small reductions in HDL cholesterol. A few tweaks to the formulation or dosing might fix those problems. “Overall, we were very encouraged about the safety profile,” Dr. Page said.
She explained the work, its promise, and the next steps in a video interview at the Endocrine Society’s annual meeting. The National Institutes of Health is funding development. Dr. Page didn’t have any relevant disclosures.
SOURCE: Page S et al. ENDO 2018, Abstract OR15-2.
CHICAGO –
It blocks gonadotropin signaling and testosterone production in the testes. When capsules ranging in dose from 100 mg to 400 mg were given once daily to 100 men in a randomized, placebo controlled trial, the drop in testosterone was more than sufficient to block sperm production. Testosterone levels jumped back up to normal after the end of the 28-day trial, all without inducing liver toxicity or other serious problems.
“We are very excited [about] the results. It’s a big step forward in the development of the male pill. Our last great advance in male contraception was over 300 years ago with the development of the condom,” said senior investigator Stephanie Page, MD, PhD, head of the division of metabolism, endocrinology, and nutrition at the University of Washington, Seattle.
Some men reported a drop in libido that resolved by the end of the study. There was also mild weight gain and small reductions in HDL cholesterol. A few tweaks to the formulation or dosing might fix those problems. “Overall, we were very encouraged about the safety profile,” Dr. Page said.
She explained the work, its promise, and the next steps in a video interview at the Endocrine Society’s annual meeting. The National Institutes of Health is funding development. Dr. Page didn’t have any relevant disclosures.
SOURCE: Page S et al. ENDO 2018, Abstract OR15-2.
CHICAGO –
It blocks gonadotropin signaling and testosterone production in the testes. When capsules ranging in dose from 100 mg to 400 mg were given once daily to 100 men in a randomized, placebo controlled trial, the drop in testosterone was more than sufficient to block sperm production. Testosterone levels jumped back up to normal after the end of the 28-day trial, all without inducing liver toxicity or other serious problems.
“We are very excited [about] the results. It’s a big step forward in the development of the male pill. Our last great advance in male contraception was over 300 years ago with the development of the condom,” said senior investigator Stephanie Page, MD, PhD, head of the division of metabolism, endocrinology, and nutrition at the University of Washington, Seattle.
Some men reported a drop in libido that resolved by the end of the study. There was also mild weight gain and small reductions in HDL cholesterol. A few tweaks to the formulation or dosing might fix those problems. “Overall, we were very encouraged about the safety profile,” Dr. Page said.
She explained the work, its promise, and the next steps in a video interview at the Endocrine Society’s annual meeting. The National Institutes of Health is funding development. Dr. Page didn’t have any relevant disclosures.
SOURCE: Page S et al. ENDO 2018, Abstract OR15-2.
REPORTING FROM ENDO 2018
VIDEO: Stem cells may reverse premature menopause, restore fertility
CHICAGO –
Neither of the women had menstruated for about 5 years; both were in premature menopause and wanted desperately to start a family. Estrogen levels began increasing soon after treatment, and night sweats and other symptoms of menopause almost disappeared. After a year, the treated ovary was almost the size of a normal premenopausal ovary. There weren’t any complications or side effects, and both women are now pursuing pregnancy.
The results are “very exciting, very encouraging,” said senior investigator Ayman Al-Hendy, MD, PhD, a gynecology professor at the University of Illinois at Chicago.
“The eggs are there, but they are not active.” Something about the stem cells seems “to activate these eggs to become fertilizable,” he said.
Far more work is planned on the project, and there’s no shortage of volunteers; premature menopause is a devastating diagnosis to young women hoping to start families.
Dr. Al-Hendy explained the procedure and the next steps in a video interview at the Endocrine Society annual meeting.
The work is supported by MD Stem Cells and the National Institutes of Health. Dr. Al-Hendy didn’t have any relevant disclosures.
SOURCE: Al-Hendy A et al. ENDO 2018, Abstract OR33-6.
CHICAGO –
Neither of the women had menstruated for about 5 years; both were in premature menopause and wanted desperately to start a family. Estrogen levels began increasing soon after treatment, and night sweats and other symptoms of menopause almost disappeared. After a year, the treated ovary was almost the size of a normal premenopausal ovary. There weren’t any complications or side effects, and both women are now pursuing pregnancy.
The results are “very exciting, very encouraging,” said senior investigator Ayman Al-Hendy, MD, PhD, a gynecology professor at the University of Illinois at Chicago.
“The eggs are there, but they are not active.” Something about the stem cells seems “to activate these eggs to become fertilizable,” he said.
Far more work is planned on the project, and there’s no shortage of volunteers; premature menopause is a devastating diagnosis to young women hoping to start families.
Dr. Al-Hendy explained the procedure and the next steps in a video interview at the Endocrine Society annual meeting.
The work is supported by MD Stem Cells and the National Institutes of Health. Dr. Al-Hendy didn’t have any relevant disclosures.
SOURCE: Al-Hendy A et al. ENDO 2018, Abstract OR33-6.
CHICAGO –
Neither of the women had menstruated for about 5 years; both were in premature menopause and wanted desperately to start a family. Estrogen levels began increasing soon after treatment, and night sweats and other symptoms of menopause almost disappeared. After a year, the treated ovary was almost the size of a normal premenopausal ovary. There weren’t any complications or side effects, and both women are now pursuing pregnancy.
The results are “very exciting, very encouraging,” said senior investigator Ayman Al-Hendy, MD, PhD, a gynecology professor at the University of Illinois at Chicago.
“The eggs are there, but they are not active.” Something about the stem cells seems “to activate these eggs to become fertilizable,” he said.
Far more work is planned on the project, and there’s no shortage of volunteers; premature menopause is a devastating diagnosis to young women hoping to start families.
Dr. Al-Hendy explained the procedure and the next steps in a video interview at the Endocrine Society annual meeting.
The work is supported by MD Stem Cells and the National Institutes of Health. Dr. Al-Hendy didn’t have any relevant disclosures.
SOURCE: Al-Hendy A et al. ENDO 2018, Abstract OR33-6.
REPORTING FROM ENDO 2018
VIDEO: Fezolinetant drops testosterone levels in PCOS
CHICAGO – currently in development. The proof-of-concept phase 2 trial, which saw no concerning safety signals for the medication, fezolinetant, sets the stage for a larger, and perhaps longer, study to learn more about the neurokinin 3 receptor antagonist’s efficacy against PCOS.
“The primary outcome for this phase 2 trial was to see if we could lower testosterone levels in these PCOS patients,” said Graeme Fraser, PhD, chief scientific officer for Ogeda, discussing the poster he and his colleagues presented at the annual meeting of the Endocrine Society.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Testosterone levels decreased: Measured at about 3 hours postdose, which is the approximate pharmacokinetic Cmax [maximum serum concentration], there was … a more than 30% decrease in testosterone levels,” said Dr. Fraser. By week 12, he said, “there was a very consistent decrease of 30% of testosterone levels. So that was quite good; we successfully hit the primary outcome.”
At 12 weeks, the higher dose of fezolinetant decreased testosterone by 0.64 nmol/L, compared with the 0.04 nmol/L seen with placebo (P less than .01).
Fezolinetant downregulates the activity of candy neurons in the hypothalamus, said Dr. Fraser in an interview. In turn, gonadotropin-releasing hormone (GNRH) pulse frequency is reduced, lowering luteinizing hormone (LH) levels. Since LH drives testosterone levels, this drops as well – a beneficial effect in PCOS, with its cardinal symptom of hyperandrogenism.
The double-blind, placebo-controlled study was conducted in Western Europe; 73 participants were randomized into three groups: 27 to a placebo group, 23 to a treatment group given 60 mg of fezolinetant once daily, and 23 to a treatment group given 180 mg of fezolinetant once daily. All groups received treatment for 12 weeks.
A total of 26 patients on placebo, 21 on 60-mg fezolinetant, and 17 on 180-mg fezolinetant completed the study. Patients who completed the study were included in the safety analysis, while all who took the study medication were included in the intent-to-treat analysis for primary and secondary outcome measures.
All participants had PCOS with hyperandrogenism, mean age was about 31 years, and about three quarters of enrollees were white, though local regulations restricted the collection of race and ethnicity data in some cases. One secondary outcome measure of the study was how fezolinetant affected the LH:FSH (follicle-stimulating hormone) ratio. “Patients with PCOS tend to have a very high GNRH [gonadotropin-releasing hormone] pulse frequency, which leads to a very high LH:FSH ratio,” said Dr. Fraser.
At baseline, the LH:FSH ratio was about 3. “With treatment, that ratio normalized to about 1, which is where it is in healthy women,” he said. The decrease in LH:FSH ratio occurred in a dose-dependent fashion and was statistically significant (P less than .001 for 180 mg fezolinetant versus placebo).
Dr. Fraser and his collaborators also tracked anti-müllerian hormone (AMH) levels, ovarian volume, and number of follicles. Although the investigators saw trends toward reduction in AMH levels and toward smaller ovarian volumes, these trends weren’t significant. “It was somewhat ambitious, I guess, to consider we’d hit these endpoints within 12 weeks,” he said. There were no serious drug-related adverse events.
“Most importantly, I would say, we did not get an increase in menses frequency, and, of course, that’s an important marker for fertility,” said Dr. Fraser. “There’s a debate in PCOS about whether this disease is driven by a malfunction in the brain or a malfunction in the ovaries. I guess on face value, perhaps this problem is in the ovaries.”
With the trends toward lower AMH and ovarian volumes, the research team is left wondering what would happen if the duration of therapy were extended. “Perhaps, the system would have been reset, and the frequency would have been restored. … So one thought that we have is to prolong the study in future trials and see if that could lead to an increase in fertility in PCOS,” said Dr. Fraser.
Fezolinetant is also being studied for menopause-related hot flashes in the United States and Europe.
Dr. Fraser is an employee of Ogeda, which sponsored the trial. Ogeda is a wholly owned subsidiary of Astelas.
SOURCE: Fraser G et al. ENDO 2018, Abstract SAT-305-LB.
CHICAGO – currently in development. The proof-of-concept phase 2 trial, which saw no concerning safety signals for the medication, fezolinetant, sets the stage for a larger, and perhaps longer, study to learn more about the neurokinin 3 receptor antagonist’s efficacy against PCOS.
“The primary outcome for this phase 2 trial was to see if we could lower testosterone levels in these PCOS patients,” said Graeme Fraser, PhD, chief scientific officer for Ogeda, discussing the poster he and his colleagues presented at the annual meeting of the Endocrine Society.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Testosterone levels decreased: Measured at about 3 hours postdose, which is the approximate pharmacokinetic Cmax [maximum serum concentration], there was … a more than 30% decrease in testosterone levels,” said Dr. Fraser. By week 12, he said, “there was a very consistent decrease of 30% of testosterone levels. So that was quite good; we successfully hit the primary outcome.”
At 12 weeks, the higher dose of fezolinetant decreased testosterone by 0.64 nmol/L, compared with the 0.04 nmol/L seen with placebo (P less than .01).
Fezolinetant downregulates the activity of candy neurons in the hypothalamus, said Dr. Fraser in an interview. In turn, gonadotropin-releasing hormone (GNRH) pulse frequency is reduced, lowering luteinizing hormone (LH) levels. Since LH drives testosterone levels, this drops as well – a beneficial effect in PCOS, with its cardinal symptom of hyperandrogenism.
The double-blind, placebo-controlled study was conducted in Western Europe; 73 participants were randomized into three groups: 27 to a placebo group, 23 to a treatment group given 60 mg of fezolinetant once daily, and 23 to a treatment group given 180 mg of fezolinetant once daily. All groups received treatment for 12 weeks.
A total of 26 patients on placebo, 21 on 60-mg fezolinetant, and 17 on 180-mg fezolinetant completed the study. Patients who completed the study were included in the safety analysis, while all who took the study medication were included in the intent-to-treat analysis for primary and secondary outcome measures.
All participants had PCOS with hyperandrogenism, mean age was about 31 years, and about three quarters of enrollees were white, though local regulations restricted the collection of race and ethnicity data in some cases. One secondary outcome measure of the study was how fezolinetant affected the LH:FSH (follicle-stimulating hormone) ratio. “Patients with PCOS tend to have a very high GNRH [gonadotropin-releasing hormone] pulse frequency, which leads to a very high LH:FSH ratio,” said Dr. Fraser.
At baseline, the LH:FSH ratio was about 3. “With treatment, that ratio normalized to about 1, which is where it is in healthy women,” he said. The decrease in LH:FSH ratio occurred in a dose-dependent fashion and was statistically significant (P less than .001 for 180 mg fezolinetant versus placebo).
Dr. Fraser and his collaborators also tracked anti-müllerian hormone (AMH) levels, ovarian volume, and number of follicles. Although the investigators saw trends toward reduction in AMH levels and toward smaller ovarian volumes, these trends weren’t significant. “It was somewhat ambitious, I guess, to consider we’d hit these endpoints within 12 weeks,” he said. There were no serious drug-related adverse events.
“Most importantly, I would say, we did not get an increase in menses frequency, and, of course, that’s an important marker for fertility,” said Dr. Fraser. “There’s a debate in PCOS about whether this disease is driven by a malfunction in the brain or a malfunction in the ovaries. I guess on face value, perhaps this problem is in the ovaries.”
With the trends toward lower AMH and ovarian volumes, the research team is left wondering what would happen if the duration of therapy were extended. “Perhaps, the system would have been reset, and the frequency would have been restored. … So one thought that we have is to prolong the study in future trials and see if that could lead to an increase in fertility in PCOS,” said Dr. Fraser.
Fezolinetant is also being studied for menopause-related hot flashes in the United States and Europe.
Dr. Fraser is an employee of Ogeda, which sponsored the trial. Ogeda is a wholly owned subsidiary of Astelas.
SOURCE: Fraser G et al. ENDO 2018, Abstract SAT-305-LB.
CHICAGO – currently in development. The proof-of-concept phase 2 trial, which saw no concerning safety signals for the medication, fezolinetant, sets the stage for a larger, and perhaps longer, study to learn more about the neurokinin 3 receptor antagonist’s efficacy against PCOS.
“The primary outcome for this phase 2 trial was to see if we could lower testosterone levels in these PCOS patients,” said Graeme Fraser, PhD, chief scientific officer for Ogeda, discussing the poster he and his colleagues presented at the annual meeting of the Endocrine Society.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Testosterone levels decreased: Measured at about 3 hours postdose, which is the approximate pharmacokinetic Cmax [maximum serum concentration], there was … a more than 30% decrease in testosterone levels,” said Dr. Fraser. By week 12, he said, “there was a very consistent decrease of 30% of testosterone levels. So that was quite good; we successfully hit the primary outcome.”
At 12 weeks, the higher dose of fezolinetant decreased testosterone by 0.64 nmol/L, compared with the 0.04 nmol/L seen with placebo (P less than .01).
Fezolinetant downregulates the activity of candy neurons in the hypothalamus, said Dr. Fraser in an interview. In turn, gonadotropin-releasing hormone (GNRH) pulse frequency is reduced, lowering luteinizing hormone (LH) levels. Since LH drives testosterone levels, this drops as well – a beneficial effect in PCOS, with its cardinal symptom of hyperandrogenism.
The double-blind, placebo-controlled study was conducted in Western Europe; 73 participants were randomized into three groups: 27 to a placebo group, 23 to a treatment group given 60 mg of fezolinetant once daily, and 23 to a treatment group given 180 mg of fezolinetant once daily. All groups received treatment for 12 weeks.
A total of 26 patients on placebo, 21 on 60-mg fezolinetant, and 17 on 180-mg fezolinetant completed the study. Patients who completed the study were included in the safety analysis, while all who took the study medication were included in the intent-to-treat analysis for primary and secondary outcome measures.
All participants had PCOS with hyperandrogenism, mean age was about 31 years, and about three quarters of enrollees were white, though local regulations restricted the collection of race and ethnicity data in some cases. One secondary outcome measure of the study was how fezolinetant affected the LH:FSH (follicle-stimulating hormone) ratio. “Patients with PCOS tend to have a very high GNRH [gonadotropin-releasing hormone] pulse frequency, which leads to a very high LH:FSH ratio,” said Dr. Fraser.
At baseline, the LH:FSH ratio was about 3. “With treatment, that ratio normalized to about 1, which is where it is in healthy women,” he said. The decrease in LH:FSH ratio occurred in a dose-dependent fashion and was statistically significant (P less than .001 for 180 mg fezolinetant versus placebo).
Dr. Fraser and his collaborators also tracked anti-müllerian hormone (AMH) levels, ovarian volume, and number of follicles. Although the investigators saw trends toward reduction in AMH levels and toward smaller ovarian volumes, these trends weren’t significant. “It was somewhat ambitious, I guess, to consider we’d hit these endpoints within 12 weeks,” he said. There were no serious drug-related adverse events.
“Most importantly, I would say, we did not get an increase in menses frequency, and, of course, that’s an important marker for fertility,” said Dr. Fraser. “There’s a debate in PCOS about whether this disease is driven by a malfunction in the brain or a malfunction in the ovaries. I guess on face value, perhaps this problem is in the ovaries.”
With the trends toward lower AMH and ovarian volumes, the research team is left wondering what would happen if the duration of therapy were extended. “Perhaps, the system would have been reset, and the frequency would have been restored. … So one thought that we have is to prolong the study in future trials and see if that could lead to an increase in fertility in PCOS,” said Dr. Fraser.
Fezolinetant is also being studied for menopause-related hot flashes in the United States and Europe.
Dr. Fraser is an employee of Ogeda, which sponsored the trial. Ogeda is a wholly owned subsidiary of Astelas.
SOURCE: Fraser G et al. ENDO 2018, Abstract SAT-305-LB.
REPORTING FROM ENDO 2018
Balance risk with reality for pre-conception diabetic counseling
CHICAGO – In particular, “several retrospective studies have shown that the risk for congenital malformations is increased with higher hemoglobin A1c levels,” said Susan Kirk, MD, speaking at a “Meet the Professor” session at the annual meeting of the Endocrine Society.
However, pointed out Dr. Kirk, fact-based counseling about pregnancy risks for women with type 1 or type 2 diabetes can – and should – occur within the framework of a strong and accepting physician-patient relationship.
Most women with diabetes have received pre-conception counseling about the risks of pregnancy with diabetes and the importance of glycemic control. “Despite that, I think many of us are often surprised by the percentage of unplanned pregnancies,” said Dr. Kirk, of the University of Virginia, Charlottesville, in an interview.
“What I have learned is that the desire to become pregnant is so strong, and the contemplation of all the adverse events that can happen … is really scary, not only to the woman but to her partner as well.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Kirk continued, “The more compassion you can show, and the more emphasis that you can place on the fact that she’s most likely to have a healthy baby, the chances are she’ll work with you from the beginning to get her control where she needs to be.”
Target numbers for hemoglobin A1c have become lower over the past several years, with the American Diabetes Association now recommending pre-conception levels below 6.5%. “There’s no randomized controlled trial that defines what that ideal number should be, but with the passage of time and some larger studies, we now know that ‘as close to normal as possible’ should be the goal,” Dr. Kirk said. This means that if women can tolerate the lower blood glucose levels without serious symptoms of hypoglycemia, a level of less than 6% is more preferable still, she said.
In terms of medication management for women with diabetes who become pregnant, physicians need to think about angiotensin converting enzyme inhibitors and statins, both of which are contraindicated for use during pregnancy. If a patient is pregnant or trying for a pregnancy, “I will stop those, and either leave them off all medicine entirely, or transition them to something that’s safe for use during pregnancy,” said Dr. Kirk.
It’s important to know if women have any microvascular complications because these are likely to progress during pregnancy, said Dr. Kirk. “The good news is, it all goes back to where she started before pregnancy after she has the baby,” though pre-existing advanced renal disease or eye disease may still cause concern for permanent damage. “If there are changes in the back of the eye that are suggestive of proliferative retinopathy, she should absolutely try to get that taken care of before she gets pregnant.”
The use of prenatal vitamins is another area where strong evidence is lacking, said Dr. Kirk. What is known is the folic acid supplementation “has been proven beyond a doubt to lower the rate of neural tube complications. And it’s cheap, and it’s easy to take. So any woman who’s even hinting at getting pregnant should be placed on those,” she said.
Dr. Kirk had no financial disclosures.
SOURCE: Kirk S. ENDO 2018, Session M-02-3.
CHICAGO – In particular, “several retrospective studies have shown that the risk for congenital malformations is increased with higher hemoglobin A1c levels,” said Susan Kirk, MD, speaking at a “Meet the Professor” session at the annual meeting of the Endocrine Society.
However, pointed out Dr. Kirk, fact-based counseling about pregnancy risks for women with type 1 or type 2 diabetes can – and should – occur within the framework of a strong and accepting physician-patient relationship.
Most women with diabetes have received pre-conception counseling about the risks of pregnancy with diabetes and the importance of glycemic control. “Despite that, I think many of us are often surprised by the percentage of unplanned pregnancies,” said Dr. Kirk, of the University of Virginia, Charlottesville, in an interview.
“What I have learned is that the desire to become pregnant is so strong, and the contemplation of all the adverse events that can happen … is really scary, not only to the woman but to her partner as well.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Kirk continued, “The more compassion you can show, and the more emphasis that you can place on the fact that she’s most likely to have a healthy baby, the chances are she’ll work with you from the beginning to get her control where she needs to be.”
Target numbers for hemoglobin A1c have become lower over the past several years, with the American Diabetes Association now recommending pre-conception levels below 6.5%. “There’s no randomized controlled trial that defines what that ideal number should be, but with the passage of time and some larger studies, we now know that ‘as close to normal as possible’ should be the goal,” Dr. Kirk said. This means that if women can tolerate the lower blood glucose levels without serious symptoms of hypoglycemia, a level of less than 6% is more preferable still, she said.
In terms of medication management for women with diabetes who become pregnant, physicians need to think about angiotensin converting enzyme inhibitors and statins, both of which are contraindicated for use during pregnancy. If a patient is pregnant or trying for a pregnancy, “I will stop those, and either leave them off all medicine entirely, or transition them to something that’s safe for use during pregnancy,” said Dr. Kirk.
It’s important to know if women have any microvascular complications because these are likely to progress during pregnancy, said Dr. Kirk. “The good news is, it all goes back to where she started before pregnancy after she has the baby,” though pre-existing advanced renal disease or eye disease may still cause concern for permanent damage. “If there are changes in the back of the eye that are suggestive of proliferative retinopathy, she should absolutely try to get that taken care of before she gets pregnant.”
The use of prenatal vitamins is another area where strong evidence is lacking, said Dr. Kirk. What is known is the folic acid supplementation “has been proven beyond a doubt to lower the rate of neural tube complications. And it’s cheap, and it’s easy to take. So any woman who’s even hinting at getting pregnant should be placed on those,” she said.
Dr. Kirk had no financial disclosures.
SOURCE: Kirk S. ENDO 2018, Session M-02-3.
CHICAGO – In particular, “several retrospective studies have shown that the risk for congenital malformations is increased with higher hemoglobin A1c levels,” said Susan Kirk, MD, speaking at a “Meet the Professor” session at the annual meeting of the Endocrine Society.
However, pointed out Dr. Kirk, fact-based counseling about pregnancy risks for women with type 1 or type 2 diabetes can – and should – occur within the framework of a strong and accepting physician-patient relationship.
Most women with diabetes have received pre-conception counseling about the risks of pregnancy with diabetes and the importance of glycemic control. “Despite that, I think many of us are often surprised by the percentage of unplanned pregnancies,” said Dr. Kirk, of the University of Virginia, Charlottesville, in an interview.
“What I have learned is that the desire to become pregnant is so strong, and the contemplation of all the adverse events that can happen … is really scary, not only to the woman but to her partner as well.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Kirk continued, “The more compassion you can show, and the more emphasis that you can place on the fact that she’s most likely to have a healthy baby, the chances are she’ll work with you from the beginning to get her control where she needs to be.”
Target numbers for hemoglobin A1c have become lower over the past several years, with the American Diabetes Association now recommending pre-conception levels below 6.5%. “There’s no randomized controlled trial that defines what that ideal number should be, but with the passage of time and some larger studies, we now know that ‘as close to normal as possible’ should be the goal,” Dr. Kirk said. This means that if women can tolerate the lower blood glucose levels without serious symptoms of hypoglycemia, a level of less than 6% is more preferable still, she said.
In terms of medication management for women with diabetes who become pregnant, physicians need to think about angiotensin converting enzyme inhibitors and statins, both of which are contraindicated for use during pregnancy. If a patient is pregnant or trying for a pregnancy, “I will stop those, and either leave them off all medicine entirely, or transition them to something that’s safe for use during pregnancy,” said Dr. Kirk.
It’s important to know if women have any microvascular complications because these are likely to progress during pregnancy, said Dr. Kirk. “The good news is, it all goes back to where she started before pregnancy after she has the baby,” though pre-existing advanced renal disease or eye disease may still cause concern for permanent damage. “If there are changes in the back of the eye that are suggestive of proliferative retinopathy, she should absolutely try to get that taken care of before she gets pregnant.”
The use of prenatal vitamins is another area where strong evidence is lacking, said Dr. Kirk. What is known is the folic acid supplementation “has been proven beyond a doubt to lower the rate of neural tube complications. And it’s cheap, and it’s easy to take. So any woman who’s even hinting at getting pregnant should be placed on those,” she said.
Dr. Kirk had no financial disclosures.
SOURCE: Kirk S. ENDO 2018, Session M-02-3.
REPORTING FROM ENDO 2018
