User login
FDA okays first-ever new drug for rare bone disorder
Affecting roughly 400 people in the United States and 900 worldwide, FOP is an autosomal dominant condition in which bone develops in soft connective tissue areas of the body where it isn’t normally present (heterotopic ossification), such as the ligaments, tendons, and skeletal muscles. This leads to severe restriction in mobility and function, to the point that people lose the ability to feed or care for themselves. Most are completely disabled by age 30 years and median life expectancy is 56 years, with death often caused by bone formation around the rib cage restricting respiration.
“As a clinician caring for patients with FOP, I personally see the daily challenges and stresses that our patients and their families must contend with ... since the accumulation of heterotopic ossification in FOP is progressive, irreversible, and life altering. This medication is an important treatment option for our FOP community,” said endocrinologist Edward Hsiao, MD, professor of medicine at the University of California, San Francisco, in a statement from Ipsen.
Taken orally, palovarotene selectively targets the gamma subtype of retinoic acid receptors that regulate skeletal development and ectopic bone in the retinoid signaling pathway. The drug mediates interactions between these receptors, growth factors, and proteins within that pathway to reduce new abnormal bone formation.
It is now FDA approved for the treatment of FOP in female patients aged 8 years or older and male patients aged 10 years or older. The recommended dosing is 5 mg daily or weight-based equivalent for pediatric patients under 14 years of age, which can be modified or increased for flare-up symptoms. It is contraindicated during pregnancy.
The FDA approval was based on 18-month data from the phase 3, multicenter, open-label MOVE trial that included 107 adult and pediatric patients, over 10% of the world’s population with FOP. All received oral palovarotene and were compared with untreated individuals from a prior natural history study of the condition. The drug reduced annualized heterotopic ossification volume by 54%.
Side effects were typical of those seen with other systemic retinoid drugs, including mucocutaneous events such as dryness of the skin and mucous membranes, alopecia, drug eruption, rash, and pruritus, and musculoskeletal events, such as arthralgia and premature growth plate closure in growing children.
According to Dr. Hsiao, who was a MOVE investigator, the study “showed that Sohonos can decrease new heterotopic ossification, and that palovarotene can be tolerated by many patients with FOP. Sohonos is not for everyone. As with all medicines there are risks in this case especially for young children who may develop early growth plate closure. In addition, Sohonos has the same side effects as other retinoids.”
The FDA approval of palovarotene follows its rejection for marketing authorization in the European Union in July 2023.
Reached for comment, an Ipsen spokesperson said in an interview: “We reached the end of the regulatory process in the European Union for Sohonos and are disappointed the European Commission decided not to approved palovarotene for people with FOP in Europe.”
The company is developing another drug, fidrisertib, for treating FOP. A pivotal phase 2 trial for that drug is now recruiting patients. Asked where Ipsen might try to market fidrisertib, the spokesperson replied:“At this point, our focus is on the completion of the pivotal trial.”
Meanwhile, in the United States, the FOP community is celebrating the palovarotene approval. In a statement, Michelle Davis, executive director of the International Fibrodysplasia Ossificans Progressiva Association, said: “FOP is life altering to the individuals diagnosed and their families. There’s not a day that goes by where those impacted don’t worry about the debilitating physical pain of muscle that is replaced by bone, another joint locking, or the relentless emotional toll of losing the ability to do an activity they love, or hold a loved one close. ... The first treatment for FOP has been proven to reduce the volume of new abnormal bone growth, which may result in better health outcomes for people living with FOP.”
Ipsen is offering a patient support program to assist with education, coverage, and reimbursement (1-866-435-5677).
A version of this article appeared on Medscape.com.
Affecting roughly 400 people in the United States and 900 worldwide, FOP is an autosomal dominant condition in which bone develops in soft connective tissue areas of the body where it isn’t normally present (heterotopic ossification), such as the ligaments, tendons, and skeletal muscles. This leads to severe restriction in mobility and function, to the point that people lose the ability to feed or care for themselves. Most are completely disabled by age 30 years and median life expectancy is 56 years, with death often caused by bone formation around the rib cage restricting respiration.
“As a clinician caring for patients with FOP, I personally see the daily challenges and stresses that our patients and their families must contend with ... since the accumulation of heterotopic ossification in FOP is progressive, irreversible, and life altering. This medication is an important treatment option for our FOP community,” said endocrinologist Edward Hsiao, MD, professor of medicine at the University of California, San Francisco, in a statement from Ipsen.
Taken orally, palovarotene selectively targets the gamma subtype of retinoic acid receptors that regulate skeletal development and ectopic bone in the retinoid signaling pathway. The drug mediates interactions between these receptors, growth factors, and proteins within that pathway to reduce new abnormal bone formation.
It is now FDA approved for the treatment of FOP in female patients aged 8 years or older and male patients aged 10 years or older. The recommended dosing is 5 mg daily or weight-based equivalent for pediatric patients under 14 years of age, which can be modified or increased for flare-up symptoms. It is contraindicated during pregnancy.
The FDA approval was based on 18-month data from the phase 3, multicenter, open-label MOVE trial that included 107 adult and pediatric patients, over 10% of the world’s population with FOP. All received oral palovarotene and were compared with untreated individuals from a prior natural history study of the condition. The drug reduced annualized heterotopic ossification volume by 54%.
Side effects were typical of those seen with other systemic retinoid drugs, including mucocutaneous events such as dryness of the skin and mucous membranes, alopecia, drug eruption, rash, and pruritus, and musculoskeletal events, such as arthralgia and premature growth plate closure in growing children.
According to Dr. Hsiao, who was a MOVE investigator, the study “showed that Sohonos can decrease new heterotopic ossification, and that palovarotene can be tolerated by many patients with FOP. Sohonos is not for everyone. As with all medicines there are risks in this case especially for young children who may develop early growth plate closure. In addition, Sohonos has the same side effects as other retinoids.”
The FDA approval of palovarotene follows its rejection for marketing authorization in the European Union in July 2023.
Reached for comment, an Ipsen spokesperson said in an interview: “We reached the end of the regulatory process in the European Union for Sohonos and are disappointed the European Commission decided not to approved palovarotene for people with FOP in Europe.”
The company is developing another drug, fidrisertib, for treating FOP. A pivotal phase 2 trial for that drug is now recruiting patients. Asked where Ipsen might try to market fidrisertib, the spokesperson replied:“At this point, our focus is on the completion of the pivotal trial.”
Meanwhile, in the United States, the FOP community is celebrating the palovarotene approval. In a statement, Michelle Davis, executive director of the International Fibrodysplasia Ossificans Progressiva Association, said: “FOP is life altering to the individuals diagnosed and their families. There’s not a day that goes by where those impacted don’t worry about the debilitating physical pain of muscle that is replaced by bone, another joint locking, or the relentless emotional toll of losing the ability to do an activity they love, or hold a loved one close. ... The first treatment for FOP has been proven to reduce the volume of new abnormal bone growth, which may result in better health outcomes for people living with FOP.”
Ipsen is offering a patient support program to assist with education, coverage, and reimbursement (1-866-435-5677).
A version of this article appeared on Medscape.com.
Affecting roughly 400 people in the United States and 900 worldwide, FOP is an autosomal dominant condition in which bone develops in soft connective tissue areas of the body where it isn’t normally present (heterotopic ossification), such as the ligaments, tendons, and skeletal muscles. This leads to severe restriction in mobility and function, to the point that people lose the ability to feed or care for themselves. Most are completely disabled by age 30 years and median life expectancy is 56 years, with death often caused by bone formation around the rib cage restricting respiration.
“As a clinician caring for patients with FOP, I personally see the daily challenges and stresses that our patients and their families must contend with ... since the accumulation of heterotopic ossification in FOP is progressive, irreversible, and life altering. This medication is an important treatment option for our FOP community,” said endocrinologist Edward Hsiao, MD, professor of medicine at the University of California, San Francisco, in a statement from Ipsen.
Taken orally, palovarotene selectively targets the gamma subtype of retinoic acid receptors that regulate skeletal development and ectopic bone in the retinoid signaling pathway. The drug mediates interactions between these receptors, growth factors, and proteins within that pathway to reduce new abnormal bone formation.
It is now FDA approved for the treatment of FOP in female patients aged 8 years or older and male patients aged 10 years or older. The recommended dosing is 5 mg daily or weight-based equivalent for pediatric patients under 14 years of age, which can be modified or increased for flare-up symptoms. It is contraindicated during pregnancy.
The FDA approval was based on 18-month data from the phase 3, multicenter, open-label MOVE trial that included 107 adult and pediatric patients, over 10% of the world’s population with FOP. All received oral palovarotene and were compared with untreated individuals from a prior natural history study of the condition. The drug reduced annualized heterotopic ossification volume by 54%.
Side effects were typical of those seen with other systemic retinoid drugs, including mucocutaneous events such as dryness of the skin and mucous membranes, alopecia, drug eruption, rash, and pruritus, and musculoskeletal events, such as arthralgia and premature growth plate closure in growing children.
According to Dr. Hsiao, who was a MOVE investigator, the study “showed that Sohonos can decrease new heterotopic ossification, and that palovarotene can be tolerated by many patients with FOP. Sohonos is not for everyone. As with all medicines there are risks in this case especially for young children who may develop early growth plate closure. In addition, Sohonos has the same side effects as other retinoids.”
The FDA approval of palovarotene follows its rejection for marketing authorization in the European Union in July 2023.
Reached for comment, an Ipsen spokesperson said in an interview: “We reached the end of the regulatory process in the European Union for Sohonos and are disappointed the European Commission decided not to approved palovarotene for people with FOP in Europe.”
The company is developing another drug, fidrisertib, for treating FOP. A pivotal phase 2 trial for that drug is now recruiting patients. Asked where Ipsen might try to market fidrisertib, the spokesperson replied:“At this point, our focus is on the completion of the pivotal trial.”
Meanwhile, in the United States, the FOP community is celebrating the palovarotene approval. In a statement, Michelle Davis, executive director of the International Fibrodysplasia Ossificans Progressiva Association, said: “FOP is life altering to the individuals diagnosed and their families. There’s not a day that goes by where those impacted don’t worry about the debilitating physical pain of muscle that is replaced by bone, another joint locking, or the relentless emotional toll of losing the ability to do an activity they love, or hold a loved one close. ... The first treatment for FOP has been proven to reduce the volume of new abnormal bone growth, which may result in better health outcomes for people living with FOP.”
Ipsen is offering a patient support program to assist with education, coverage, and reimbursement (1-866-435-5677).
A version of this article appeared on Medscape.com.
FDA approves elranatamab for multiple myeloma
The B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody (BsAb) was given Priority Review in February and had previously received Breakthrough Therapy Designation for relapsed or refractory multiple myeloma (RRMM), according to Pfizer.
FDA approval was based on favorable response and duration of response rates in the single-arm, phase 2 MagnetisMM-3 trial. The trial showed meaningful responses in heavily pretreated patients with RRMM who received elranatamab as their first BCMA-directed therapy.
The overall response rate in 97 BCMA-naive patients (cohort A) who previously received at least four lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, was 58%, with an estimated 82% maintaining the response for 9 months or longer. Median time to first response was 1.2 months.
In 63 patients who received at least four prior lines of therapy, which also included a BCMA-directed therapy, the overall response rate was 33% after median follow-up of 10.2 months. An estimated 84% maintained a response for at least 9 months.
Elranatamab was given subcutaneously at a dose of 76 mg weekly on a 28-day cycle with a step-up priming dose regimen. The priming regimen included 12 mg and 32 mg doses on days 1 and 4, respectively, during cycle 1. Patients who received at least six cycles and showed at least a partial response for 2 or more months had a biweekly dosing interval.
Elranatamab carries a boxed warning for cytokine release syndrome (CRS) and neurologic toxicity, as well as warnings and precautions for infections, neutropenia, hepatotoxicity, and embryo–fetal toxicity. Therefore, the agent is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS).
The boxed warning is included in the full prescribing information.
A confirmatory trial to gather additional safety and efficacy data was launched in 2022. Continued FDA approval is contingent on confirmed safety and efficacy data.
A version of this article first appeared on Medscape.com.
The B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody (BsAb) was given Priority Review in February and had previously received Breakthrough Therapy Designation for relapsed or refractory multiple myeloma (RRMM), according to Pfizer.
FDA approval was based on favorable response and duration of response rates in the single-arm, phase 2 MagnetisMM-3 trial. The trial showed meaningful responses in heavily pretreated patients with RRMM who received elranatamab as their first BCMA-directed therapy.
The overall response rate in 97 BCMA-naive patients (cohort A) who previously received at least four lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, was 58%, with an estimated 82% maintaining the response for 9 months or longer. Median time to first response was 1.2 months.
In 63 patients who received at least four prior lines of therapy, which also included a BCMA-directed therapy, the overall response rate was 33% after median follow-up of 10.2 months. An estimated 84% maintained a response for at least 9 months.
Elranatamab was given subcutaneously at a dose of 76 mg weekly on a 28-day cycle with a step-up priming dose regimen. The priming regimen included 12 mg and 32 mg doses on days 1 and 4, respectively, during cycle 1. Patients who received at least six cycles and showed at least a partial response for 2 or more months had a biweekly dosing interval.
Elranatamab carries a boxed warning for cytokine release syndrome (CRS) and neurologic toxicity, as well as warnings and precautions for infections, neutropenia, hepatotoxicity, and embryo–fetal toxicity. Therefore, the agent is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS).
The boxed warning is included in the full prescribing information.
A confirmatory trial to gather additional safety and efficacy data was launched in 2022. Continued FDA approval is contingent on confirmed safety and efficacy data.
A version of this article first appeared on Medscape.com.
The B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody (BsAb) was given Priority Review in February and had previously received Breakthrough Therapy Designation for relapsed or refractory multiple myeloma (RRMM), according to Pfizer.
FDA approval was based on favorable response and duration of response rates in the single-arm, phase 2 MagnetisMM-3 trial. The trial showed meaningful responses in heavily pretreated patients with RRMM who received elranatamab as their first BCMA-directed therapy.
The overall response rate in 97 BCMA-naive patients (cohort A) who previously received at least four lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, was 58%, with an estimated 82% maintaining the response for 9 months or longer. Median time to first response was 1.2 months.
In 63 patients who received at least four prior lines of therapy, which also included a BCMA-directed therapy, the overall response rate was 33% after median follow-up of 10.2 months. An estimated 84% maintained a response for at least 9 months.
Elranatamab was given subcutaneously at a dose of 76 mg weekly on a 28-day cycle with a step-up priming dose regimen. The priming regimen included 12 mg and 32 mg doses on days 1 and 4, respectively, during cycle 1. Patients who received at least six cycles and showed at least a partial response for 2 or more months had a biweekly dosing interval.
Elranatamab carries a boxed warning for cytokine release syndrome (CRS) and neurologic toxicity, as well as warnings and precautions for infections, neutropenia, hepatotoxicity, and embryo–fetal toxicity. Therefore, the agent is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS).
The boxed warning is included in the full prescribing information.
A confirmatory trial to gather additional safety and efficacy data was launched in 2022. Continued FDA approval is contingent on confirmed safety and efficacy data.
A version of this article first appeared on Medscape.com.
Noteworthy advances in treatment and management of IBD
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
AT DDW 2023
Bulevirtide shows promise in chronic hepatitis D
shows an ongoing phase 3 study conducted in the United States and four other countries.
The findings were published in the New England Journal of Medicine.
Led by Heiner Wedemeyer, MD, of Hannover Medical School in Germany, the study included 150 patients with HDV, with and without compensated cirrhosis (mean age, 42 years; 57% male; 83% White). They were randomly assigned to receive 2 mg or 10 mg of bulevirtide subcutaneously daily for 144 weeks or, as a control group, receive no treatment for 48 weeks, followed by 10 mg of bulevirtide daily for 96 weeks. All patients were followed for 96 weeks after treatment ends.
For the primary endpoint, the combined viral and ALT response at week 48 was similar in the 2-mg (45%) and 10-mg (48%) groups, compared with 2% in the control group (one patient). Twelve percent of patients in the 2-mg group and 20% of patients in the 10-mg group had a clinical benefit, compared with none of the patients in the control group.
Among those with a combined response, normalization of the ALT level occurred in most patients by week 24, while the HDV RNA level continued to decline between week 24 and week 48, the authors wrote.
“This surrogate end point is considered to be a reasonably likely predictor of improved clinical outcomes in patients with HDV; however, longer-term data are needed to confirm the clinical benefit of bulevirtide,” the investigators wrote.
The results offer a glimmer of hope, Marc Ghany, MD, MHSc, of the National Institute of Diabetes and Digestive and Kidney Diseases wrote in an accompanying editorial. “The goal of HDV therapy is to improve patient survival by preventing progression to cirrhosis, liver failure, and liver cancer,” he wrote.
In safety results, headache, pruritus, fatigue, and eosinophilia were more common in the bulevirtide groups than in the control group. All adverse events were mild to moderate.
HDV infects about 5% of people with chronic HBV and relies on HBV surface antigen (HBsAg) for transmission and infectivity. Bulevirtide is derived from a region of the large envelope protein of HBsAg and irreversibly binds to the hepatocyte entry receptor for both HDV and HBV.
Bulevirtide has received conditional approval in the European Union. In 2022, the Food and Drug Administration declined to approve bulevirtide over concerns about production and delivery of the drug. There are no approved treatments for HDV in the United States.
The study was supported by Gilead Sciences. Dr. Wedemeyer disclosed research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences. He and other coauthors disclosed financial relationships with Gilead and other pharmaceutical companies.
shows an ongoing phase 3 study conducted in the United States and four other countries.
The findings were published in the New England Journal of Medicine.
Led by Heiner Wedemeyer, MD, of Hannover Medical School in Germany, the study included 150 patients with HDV, with and without compensated cirrhosis (mean age, 42 years; 57% male; 83% White). They were randomly assigned to receive 2 mg or 10 mg of bulevirtide subcutaneously daily for 144 weeks or, as a control group, receive no treatment for 48 weeks, followed by 10 mg of bulevirtide daily for 96 weeks. All patients were followed for 96 weeks after treatment ends.
For the primary endpoint, the combined viral and ALT response at week 48 was similar in the 2-mg (45%) and 10-mg (48%) groups, compared with 2% in the control group (one patient). Twelve percent of patients in the 2-mg group and 20% of patients in the 10-mg group had a clinical benefit, compared with none of the patients in the control group.
Among those with a combined response, normalization of the ALT level occurred in most patients by week 24, while the HDV RNA level continued to decline between week 24 and week 48, the authors wrote.
“This surrogate end point is considered to be a reasonably likely predictor of improved clinical outcomes in patients with HDV; however, longer-term data are needed to confirm the clinical benefit of bulevirtide,” the investigators wrote.
The results offer a glimmer of hope, Marc Ghany, MD, MHSc, of the National Institute of Diabetes and Digestive and Kidney Diseases wrote in an accompanying editorial. “The goal of HDV therapy is to improve patient survival by preventing progression to cirrhosis, liver failure, and liver cancer,” he wrote.
In safety results, headache, pruritus, fatigue, and eosinophilia were more common in the bulevirtide groups than in the control group. All adverse events were mild to moderate.
HDV infects about 5% of people with chronic HBV and relies on HBV surface antigen (HBsAg) for transmission and infectivity. Bulevirtide is derived from a region of the large envelope protein of HBsAg and irreversibly binds to the hepatocyte entry receptor for both HDV and HBV.
Bulevirtide has received conditional approval in the European Union. In 2022, the Food and Drug Administration declined to approve bulevirtide over concerns about production and delivery of the drug. There are no approved treatments for HDV in the United States.
The study was supported by Gilead Sciences. Dr. Wedemeyer disclosed research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences. He and other coauthors disclosed financial relationships with Gilead and other pharmaceutical companies.
shows an ongoing phase 3 study conducted in the United States and four other countries.
The findings were published in the New England Journal of Medicine.
Led by Heiner Wedemeyer, MD, of Hannover Medical School in Germany, the study included 150 patients with HDV, with and without compensated cirrhosis (mean age, 42 years; 57% male; 83% White). They were randomly assigned to receive 2 mg or 10 mg of bulevirtide subcutaneously daily for 144 weeks or, as a control group, receive no treatment for 48 weeks, followed by 10 mg of bulevirtide daily for 96 weeks. All patients were followed for 96 weeks after treatment ends.
For the primary endpoint, the combined viral and ALT response at week 48 was similar in the 2-mg (45%) and 10-mg (48%) groups, compared with 2% in the control group (one patient). Twelve percent of patients in the 2-mg group and 20% of patients in the 10-mg group had a clinical benefit, compared with none of the patients in the control group.
Among those with a combined response, normalization of the ALT level occurred in most patients by week 24, while the HDV RNA level continued to decline between week 24 and week 48, the authors wrote.
“This surrogate end point is considered to be a reasonably likely predictor of improved clinical outcomes in patients with HDV; however, longer-term data are needed to confirm the clinical benefit of bulevirtide,” the investigators wrote.
The results offer a glimmer of hope, Marc Ghany, MD, MHSc, of the National Institute of Diabetes and Digestive and Kidney Diseases wrote in an accompanying editorial. “The goal of HDV therapy is to improve patient survival by preventing progression to cirrhosis, liver failure, and liver cancer,” he wrote.
In safety results, headache, pruritus, fatigue, and eosinophilia were more common in the bulevirtide groups than in the control group. All adverse events were mild to moderate.
HDV infects about 5% of people with chronic HBV and relies on HBV surface antigen (HBsAg) for transmission and infectivity. Bulevirtide is derived from a region of the large envelope protein of HBsAg and irreversibly binds to the hepatocyte entry receptor for both HDV and HBV.
Bulevirtide has received conditional approval in the European Union. In 2022, the Food and Drug Administration declined to approve bulevirtide over concerns about production and delivery of the drug. There are no approved treatments for HDV in the United States.
The study was supported by Gilead Sciences. Dr. Wedemeyer disclosed research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences. He and other coauthors disclosed financial relationships with Gilead and other pharmaceutical companies.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Experts highlight benefits and offer caveats for first postpartum depression pill
For the first time, the Food and Drug Administration approved a pill taken once daily for 14 days to help women manage the often strong, sometimes overpowering symptoms of postpartum depression.
for a condition that affects an estimated 1 in 8 women in the United States. What will it mean for easing symptoms such as hopelessness, crankiness, and lack of interest in bonding with the baby or, in the case of multiples, babies – and in some cases, thoughts of death or suicide?
A fast-acting option
“We don’t have many oral medications that are fast-acting antidepressants, so this is incredibly exciting,” said Sarah Oreck, MD, a psychiatrist in private practice in Los Angeles who specializes in reproductive psychiatry. The rapid response is likely because the medication targets the hormonal mechanism underlying postpartum depression, she added.
Zuranolone (Zurzuvae, Biogen/Sage) is different from most other antidepressants – it is designed to be taken for a shorter period. Also, Because zuranolone is a pill, it is more convenient to take than the other FDA-approved treatment, the IV infusion brexanolone (Zulresso, Sage).
“It’s obviously game changing to have something in pill form. The infusion has to be done at an infusion center to monitor people for any complications,” said Kimberly Yonkers, MD, a psychiatrist specializing in women’s health, a Distinguished Life Fellow of the American Psychiatric Association (APA), and the Katz Family Chair of Psychiatry at the University of Massachusetts Chan Medical School/UMass Memorial Medical Center in Worcester.
Women may experience improvement in postpartum depression in as soon as 3 days after starting the medication. In contrast, “typical antidepressants can take up to 2 weeks before patients notice a difference and 4 to 8 weeks to see a full response. A fast-acting pill that can be taken orally could be an ideal option for the 15% to 20% of women who experience postpartum depression,” said Priya Gopalan, MD, a psychiatrist with UPMC Western Psychiatric Hospital and Magee-Womens Hospital in Pittsburgh.
The medical community, and reproductive psychiatrists in particular, has always suspected differences in the biological underpinnings of postpartum depression and major depressive disorder, Dr. Oreck said. “We know that postpartum depression looks different from major depressive disorder and that hormonal shifts during pregnancy and postpartum are a huge risk factor for postpartum depression,” she said.
Although selective serotonin reuptake inhibitors (SSRIs) are helpful and currently the standard of care for treating moderate to severe postpartum depression in combination with therapy, Dr. Oreck added, early studies suggest that zuranolone may work faster and potentially be more effective than SSRIs in treating the condition.
Zuranolone is a version of a naturally occurring hormone called allopregnanolone, a metabolite of progesterone. Concentrations of allopregnanolone rise dramatically during pregnancy and then drop precipitously after childbirth. Zuranolone works through modulating GABA-A, a neurotransmitter implicated in the development of depression.
“It is encouraging that postpartum individuals may now have more options to manage a debilitating condition that affects them and their families,” said Christopher Zahn, MD, interim CEO and chief of clinical practice and health equity and quality for the American College of Obstetricians and Gynecologists (ACOG).
ACOG recommends women be screened for depression at least three times – during early pregnancy, later in pregnancy, and again after delivery. A decision to start this or any other medicine should be individualized and based on shared decision-making between a patient and doctor, Dr. Zahn added.
The cost of zuranolone is not yet known. Dr. Yonkers said cost of the infusion can serve as a cautionary tale for the manufacturer. Some reports put the infusion cost at $34,000. “Cost is going to be an important component to this. The previous intervention was priced so high that it was not affordable to many people and it was difficult to access.”
Beyond ‘baby blues’
The APA has changed the name from “postpartum depression” to “peripartum depression” because evidence suggests feelings and symptoms also can start late in pregnancy. “It means you don’t have to wait until somebody delivers to screen for depression. We have to recognize that depression can occur during pregnancy,” Dr. Yonkers said. “In fact it is not uncommon during the third trimester.”
No matter when it starts, the condition can be “very serious,” particularly if the person already experiences depression, including bipolar disorder, Dr. Yonkers added.
Postpartum depression “is more than just ‘baby blues.’ It is a potentially debilitating illness that causes feelings of intense sadness and worthlessness, making it difficult to care for and bond with your newborn,” Dr. Gopalan said.
Can be a medical emergency
Severe postpartum depression requires immediate attention and treatment.
“One of the things we have to be cautious about is for people with previous predisposition to hurt themselves,” Dr. Yonkers said. “It is therefore important to consider somebody’s medical and behavioral health history as well.
“For an individual with recurring depression or severe episodes of depression, this may not be sufficient, because they are just going to get these 14 days of therapy,” Dr. Yonkers said. “They may need ongoing antidepressants.
“It may not be the right pill for everybody,” Dr. Yonkers added. She recommended everyone be followed closely during and after treatment “to make sure they are responding and to monitor for relapse.”
The science that led to approval
The clinical trials showed early response in patients with severe postpartum depression. Researchers conducted two studies of women who developed a major depressive episode in the third trimester of pregnancy or within 4 weeks of delivery. They found women who took zuranolone once in the evening for 14 days “showed significantly more improvement in their symptoms compared to those in the placebo group.”
The antidepressant effect lasted at least 4 weeks after stopping the medication.
Drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection were the most common side effects. The label has a boxed warning noting that the medication can affect a person’s ability to drive and perform other potentially hazardous activities. Use of zuranolone may also cause suicidal thoughts and behavior, according to an FDA news release announcing the approval.
The start of more help for mothers?
Zuranolone is not a cure-all. As with most psychiatric prescriptions, the medication likely will work best in conjunction with behavioral health treatments such as psychotherapy, use of other medications, behavioral management, support groups, and self-care tools such as meditation, exercise, and yoga, Dr. Gopalan said.
Dr. Oreck said she hopes this first pill approval will lead to more discoveries. “I hope this is the beginning of more innovation and development of novel treatments that can target women’s mental health issues specifically – female reproductive hormones impact mental health in unique ways and it’s exciting to finally see research and development dollars dedicated to them,” she said. “The FDA approval of this pill provides the potential to improve the lives of millions of Americans suffering from postpartum depression.”
Dr. Oreck, Dr. Yonkers, Dr. Gopalan, and Dr. Zahn have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
For the first time, the Food and Drug Administration approved a pill taken once daily for 14 days to help women manage the often strong, sometimes overpowering symptoms of postpartum depression.
for a condition that affects an estimated 1 in 8 women in the United States. What will it mean for easing symptoms such as hopelessness, crankiness, and lack of interest in bonding with the baby or, in the case of multiples, babies – and in some cases, thoughts of death or suicide?
A fast-acting option
“We don’t have many oral medications that are fast-acting antidepressants, so this is incredibly exciting,” said Sarah Oreck, MD, a psychiatrist in private practice in Los Angeles who specializes in reproductive psychiatry. The rapid response is likely because the medication targets the hormonal mechanism underlying postpartum depression, she added.
Zuranolone (Zurzuvae, Biogen/Sage) is different from most other antidepressants – it is designed to be taken for a shorter period. Also, Because zuranolone is a pill, it is more convenient to take than the other FDA-approved treatment, the IV infusion brexanolone (Zulresso, Sage).
“It’s obviously game changing to have something in pill form. The infusion has to be done at an infusion center to monitor people for any complications,” said Kimberly Yonkers, MD, a psychiatrist specializing in women’s health, a Distinguished Life Fellow of the American Psychiatric Association (APA), and the Katz Family Chair of Psychiatry at the University of Massachusetts Chan Medical School/UMass Memorial Medical Center in Worcester.
Women may experience improvement in postpartum depression in as soon as 3 days after starting the medication. In contrast, “typical antidepressants can take up to 2 weeks before patients notice a difference and 4 to 8 weeks to see a full response. A fast-acting pill that can be taken orally could be an ideal option for the 15% to 20% of women who experience postpartum depression,” said Priya Gopalan, MD, a psychiatrist with UPMC Western Psychiatric Hospital and Magee-Womens Hospital in Pittsburgh.
The medical community, and reproductive psychiatrists in particular, has always suspected differences in the biological underpinnings of postpartum depression and major depressive disorder, Dr. Oreck said. “We know that postpartum depression looks different from major depressive disorder and that hormonal shifts during pregnancy and postpartum are a huge risk factor for postpartum depression,” she said.
Although selective serotonin reuptake inhibitors (SSRIs) are helpful and currently the standard of care for treating moderate to severe postpartum depression in combination with therapy, Dr. Oreck added, early studies suggest that zuranolone may work faster and potentially be more effective than SSRIs in treating the condition.
Zuranolone is a version of a naturally occurring hormone called allopregnanolone, a metabolite of progesterone. Concentrations of allopregnanolone rise dramatically during pregnancy and then drop precipitously after childbirth. Zuranolone works through modulating GABA-A, a neurotransmitter implicated in the development of depression.
“It is encouraging that postpartum individuals may now have more options to manage a debilitating condition that affects them and their families,” said Christopher Zahn, MD, interim CEO and chief of clinical practice and health equity and quality for the American College of Obstetricians and Gynecologists (ACOG).
ACOG recommends women be screened for depression at least three times – during early pregnancy, later in pregnancy, and again after delivery. A decision to start this or any other medicine should be individualized and based on shared decision-making between a patient and doctor, Dr. Zahn added.
The cost of zuranolone is not yet known. Dr. Yonkers said cost of the infusion can serve as a cautionary tale for the manufacturer. Some reports put the infusion cost at $34,000. “Cost is going to be an important component to this. The previous intervention was priced so high that it was not affordable to many people and it was difficult to access.”
Beyond ‘baby blues’
The APA has changed the name from “postpartum depression” to “peripartum depression” because evidence suggests feelings and symptoms also can start late in pregnancy. “It means you don’t have to wait until somebody delivers to screen for depression. We have to recognize that depression can occur during pregnancy,” Dr. Yonkers said. “In fact it is not uncommon during the third trimester.”
No matter when it starts, the condition can be “very serious,” particularly if the person already experiences depression, including bipolar disorder, Dr. Yonkers added.
Postpartum depression “is more than just ‘baby blues.’ It is a potentially debilitating illness that causes feelings of intense sadness and worthlessness, making it difficult to care for and bond with your newborn,” Dr. Gopalan said.
Can be a medical emergency
Severe postpartum depression requires immediate attention and treatment.
“One of the things we have to be cautious about is for people with previous predisposition to hurt themselves,” Dr. Yonkers said. “It is therefore important to consider somebody’s medical and behavioral health history as well.
“For an individual with recurring depression or severe episodes of depression, this may not be sufficient, because they are just going to get these 14 days of therapy,” Dr. Yonkers said. “They may need ongoing antidepressants.
“It may not be the right pill for everybody,” Dr. Yonkers added. She recommended everyone be followed closely during and after treatment “to make sure they are responding and to monitor for relapse.”
The science that led to approval
The clinical trials showed early response in patients with severe postpartum depression. Researchers conducted two studies of women who developed a major depressive episode in the third trimester of pregnancy or within 4 weeks of delivery. They found women who took zuranolone once in the evening for 14 days “showed significantly more improvement in their symptoms compared to those in the placebo group.”
The antidepressant effect lasted at least 4 weeks after stopping the medication.
Drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection were the most common side effects. The label has a boxed warning noting that the medication can affect a person’s ability to drive and perform other potentially hazardous activities. Use of zuranolone may also cause suicidal thoughts and behavior, according to an FDA news release announcing the approval.
The start of more help for mothers?
Zuranolone is not a cure-all. As with most psychiatric prescriptions, the medication likely will work best in conjunction with behavioral health treatments such as psychotherapy, use of other medications, behavioral management, support groups, and self-care tools such as meditation, exercise, and yoga, Dr. Gopalan said.
Dr. Oreck said she hopes this first pill approval will lead to more discoveries. “I hope this is the beginning of more innovation and development of novel treatments that can target women’s mental health issues specifically – female reproductive hormones impact mental health in unique ways and it’s exciting to finally see research and development dollars dedicated to them,” she said. “The FDA approval of this pill provides the potential to improve the lives of millions of Americans suffering from postpartum depression.”
Dr. Oreck, Dr. Yonkers, Dr. Gopalan, and Dr. Zahn have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
For the first time, the Food and Drug Administration approved a pill taken once daily for 14 days to help women manage the often strong, sometimes overpowering symptoms of postpartum depression.
for a condition that affects an estimated 1 in 8 women in the United States. What will it mean for easing symptoms such as hopelessness, crankiness, and lack of interest in bonding with the baby or, in the case of multiples, babies – and in some cases, thoughts of death or suicide?
A fast-acting option
“We don’t have many oral medications that are fast-acting antidepressants, so this is incredibly exciting,” said Sarah Oreck, MD, a psychiatrist in private practice in Los Angeles who specializes in reproductive psychiatry. The rapid response is likely because the medication targets the hormonal mechanism underlying postpartum depression, she added.
Zuranolone (Zurzuvae, Biogen/Sage) is different from most other antidepressants – it is designed to be taken for a shorter period. Also, Because zuranolone is a pill, it is more convenient to take than the other FDA-approved treatment, the IV infusion brexanolone (Zulresso, Sage).
“It’s obviously game changing to have something in pill form. The infusion has to be done at an infusion center to monitor people for any complications,” said Kimberly Yonkers, MD, a psychiatrist specializing in women’s health, a Distinguished Life Fellow of the American Psychiatric Association (APA), and the Katz Family Chair of Psychiatry at the University of Massachusetts Chan Medical School/UMass Memorial Medical Center in Worcester.
Women may experience improvement in postpartum depression in as soon as 3 days after starting the medication. In contrast, “typical antidepressants can take up to 2 weeks before patients notice a difference and 4 to 8 weeks to see a full response. A fast-acting pill that can be taken orally could be an ideal option for the 15% to 20% of women who experience postpartum depression,” said Priya Gopalan, MD, a psychiatrist with UPMC Western Psychiatric Hospital and Magee-Womens Hospital in Pittsburgh.
The medical community, and reproductive psychiatrists in particular, has always suspected differences in the biological underpinnings of postpartum depression and major depressive disorder, Dr. Oreck said. “We know that postpartum depression looks different from major depressive disorder and that hormonal shifts during pregnancy and postpartum are a huge risk factor for postpartum depression,” she said.
Although selective serotonin reuptake inhibitors (SSRIs) are helpful and currently the standard of care for treating moderate to severe postpartum depression in combination with therapy, Dr. Oreck added, early studies suggest that zuranolone may work faster and potentially be more effective than SSRIs in treating the condition.
Zuranolone is a version of a naturally occurring hormone called allopregnanolone, a metabolite of progesterone. Concentrations of allopregnanolone rise dramatically during pregnancy and then drop precipitously after childbirth. Zuranolone works through modulating GABA-A, a neurotransmitter implicated in the development of depression.
“It is encouraging that postpartum individuals may now have more options to manage a debilitating condition that affects them and their families,” said Christopher Zahn, MD, interim CEO and chief of clinical practice and health equity and quality for the American College of Obstetricians and Gynecologists (ACOG).
ACOG recommends women be screened for depression at least three times – during early pregnancy, later in pregnancy, and again after delivery. A decision to start this or any other medicine should be individualized and based on shared decision-making between a patient and doctor, Dr. Zahn added.
The cost of zuranolone is not yet known. Dr. Yonkers said cost of the infusion can serve as a cautionary tale for the manufacturer. Some reports put the infusion cost at $34,000. “Cost is going to be an important component to this. The previous intervention was priced so high that it was not affordable to many people and it was difficult to access.”
Beyond ‘baby blues’
The APA has changed the name from “postpartum depression” to “peripartum depression” because evidence suggests feelings and symptoms also can start late in pregnancy. “It means you don’t have to wait until somebody delivers to screen for depression. We have to recognize that depression can occur during pregnancy,” Dr. Yonkers said. “In fact it is not uncommon during the third trimester.”
No matter when it starts, the condition can be “very serious,” particularly if the person already experiences depression, including bipolar disorder, Dr. Yonkers added.
Postpartum depression “is more than just ‘baby blues.’ It is a potentially debilitating illness that causes feelings of intense sadness and worthlessness, making it difficult to care for and bond with your newborn,” Dr. Gopalan said.
Can be a medical emergency
Severe postpartum depression requires immediate attention and treatment.
“One of the things we have to be cautious about is for people with previous predisposition to hurt themselves,” Dr. Yonkers said. “It is therefore important to consider somebody’s medical and behavioral health history as well.
“For an individual with recurring depression or severe episodes of depression, this may not be sufficient, because they are just going to get these 14 days of therapy,” Dr. Yonkers said. “They may need ongoing antidepressants.
“It may not be the right pill for everybody,” Dr. Yonkers added. She recommended everyone be followed closely during and after treatment “to make sure they are responding and to monitor for relapse.”
The science that led to approval
The clinical trials showed early response in patients with severe postpartum depression. Researchers conducted two studies of women who developed a major depressive episode in the third trimester of pregnancy or within 4 weeks of delivery. They found women who took zuranolone once in the evening for 14 days “showed significantly more improvement in their symptoms compared to those in the placebo group.”
The antidepressant effect lasted at least 4 weeks after stopping the medication.
Drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection were the most common side effects. The label has a boxed warning noting that the medication can affect a person’s ability to drive and perform other potentially hazardous activities. Use of zuranolone may also cause suicidal thoughts and behavior, according to an FDA news release announcing the approval.
The start of more help for mothers?
Zuranolone is not a cure-all. As with most psychiatric prescriptions, the medication likely will work best in conjunction with behavioral health treatments such as psychotherapy, use of other medications, behavioral management, support groups, and self-care tools such as meditation, exercise, and yoga, Dr. Gopalan said.
Dr. Oreck said she hopes this first pill approval will lead to more discoveries. “I hope this is the beginning of more innovation and development of novel treatments that can target women’s mental health issues specifically – female reproductive hormones impact mental health in unique ways and it’s exciting to finally see research and development dollars dedicated to them,” she said. “The FDA approval of this pill provides the potential to improve the lives of millions of Americans suffering from postpartum depression.”
Dr. Oreck, Dr. Yonkers, Dr. Gopalan, and Dr. Zahn have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
‘Triple G’ agonist hits new weight loss heights
A novel triple agonist to receptors for three nutrient-stimulated hormones led to weight loss as high as 24% among people with overweight or obesity but who did not have type 2 diabetes when used at the highest tested dose for 48 weeks. The results are from a phase 2 study of retatrutide that was published in The New England Journal of Medicine (2023 Aug 10. doi: 10.1056/NEJMoa2301972).
This level of weight loss is “unprecedented” for a medication administered for 48 weeks, Mary-Elizabeth Patti, MD, said in an editorial that accompanied the report.
The findings “offer further optimism ... that effective pharmacologic management of obesity and related disorders is possible,” wrote Dr. Patti, a principal investigator at the Joslin Diabetes Center in Boston.
The study randomly assigned 338 adults with obesity or overweight – a body mass index (BMI) of ≥ 27 kg/m2 – and at least one weight-related complication to receive either weekly subcutaneous injections of retatrutide in any of six dose regimens or placebo over 48 weeks. The primary outcome was weight change from baseline after 24 weeks.
The highest dose of retatrutide safely produced an average 17.5% drop from baseline weight, compared with an average 1.6% reduction in the placebo group, after 24 weeks, a significant difference.
After 48 weeks, the highest retatrutide dose safely cut baseline weight by an average of 24.2%, compared with an average 2.1% drop among placebo control patients, Ania M. Jastreboff, MD, PhD, and her coauthors wrote in their report. Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-response pattern.
Weight losses never before seen
“I have never seen weight loss at this level” after nearly 1 year of treatment, Dr. Jastreboff said when she discussed these findings in a press conference at the annual scientific sessions of the American Diabetes Association in San Diego in late June.
A separate presentation at the ADA meeting documented unprecedented weight loss levels in a study of 281 people with obesity or overweight and type 2 diabetes.
“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who formally presented the results from the study of retatrutide in people with type 2 diabetes at the ADA meeting.
The mechanism behind retatrutide’s potent weight-loss effect seems likely tied to its action on three human receptors that naturally respond to three nutrient-stimulated hormones that control appetite, metabolism, fat mobilization, and related functions.
The three hormones that the retatrutide molecule simultaneously mimics are glucagon-like peptide-1 (GLP-1), such as agents in the class of GLP-1 agonists that includes liraglutide (Victoza/Saxenda) and semaglutide (Ozempic/Wegovy); the glucose-dependent insulinotropic polypeptide (GIP), the receptor that is also activated by tirzepatide (Mounjaro), a dual-incretin receptor agonist that mimics both GLP-1 and GIP; and glucagon. Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development.
Retatrutide is currently unique among agents with reported clinical results by having agonist effects on the receptors for all three of these hormones, a property that led Dr. Patti to call retatrutide a “triple G” hormone-receptor agonist in her editorial.
Triple agonist has added effect on liver fat clearance
The glucagon-receptor agonism appears to give retatrutide added effects beyond those of the GLP-1 agonists or GLP-1/GIP dual agonists that are increasingly used in U.S. practice.
A prespecified subgroup analysis of the no diabetes/Jastreboff study (but that was not included in the NEJM report) showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those whose liver volume was at least 10% fat at study entry).
That percentage increased to about 90% of people receiving these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the ADA meeting.
“When you add glucagon activity, liver-fat clearance goes up tremendously,” observed Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
The average age of the participants in the new study of the use of retatrutide for those with obesity/overweight but not diabetes was 48 years. By design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m2.
Treatment with retatrutide was also significantly associated with improvements in several cardiometabolic measures in exploratory analyses, including systolic and diastolic blood pressure, A1c, fasting glucose, insulin, and some (but not all) lipids, Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn., and her coauthors reported in the NEJM article.
The safety profile of retatrutide was consistent with reported phase 1 findings for the agent among people with type 2 diabetes and resembled the safety profiles of other agents based on GLP-1 or GIP–GLP-1 mimicry for the treatment of type 2 diabetes or obesity.
The most frequently reported adverse events from retatrutide were transient, mostly mild to moderate gastrointestinal events. They occurred primarily during dose escalation. Discontinuation of retatrutide or placebo because of adverse events occurred in 6% to 16% of the participants who received retatrutide and in none of the participants who received placebo.
Lilly, the company developing retatrutide, previously announced the launch of four phase 3 trials to gather further data on retatrutide for use in a marketing-approval application to the Food and Drug Administration.
The four trials – TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 – are evaluating the safety and efficacy of retatrutide for chronic weight management for those with obesity or overweight, including those who also have obstructive sleep apnea, knee osteoarthritis, type 2 diabetes, or cardiovascular disease.
The study was sponsored by Lilly, the company developing retatrutide. Dr. Patti has been a consultant to AstraZeneca, Dexcom, Hanmi, and MBX. She has received funding from Dexcom and has been a monitor for a trial funded by Fractyl. Dr. Jastreboff, Dr. Kaplan, and Dr. Rosenstock have reported financial relationships with Lilly as well as other companies.
A version of this article first appeared on Medscape.com.
A novel triple agonist to receptors for three nutrient-stimulated hormones led to weight loss as high as 24% among people with overweight or obesity but who did not have type 2 diabetes when used at the highest tested dose for 48 weeks. The results are from a phase 2 study of retatrutide that was published in The New England Journal of Medicine (2023 Aug 10. doi: 10.1056/NEJMoa2301972).
This level of weight loss is “unprecedented” for a medication administered for 48 weeks, Mary-Elizabeth Patti, MD, said in an editorial that accompanied the report.
The findings “offer further optimism ... that effective pharmacologic management of obesity and related disorders is possible,” wrote Dr. Patti, a principal investigator at the Joslin Diabetes Center in Boston.
The study randomly assigned 338 adults with obesity or overweight – a body mass index (BMI) of ≥ 27 kg/m2 – and at least one weight-related complication to receive either weekly subcutaneous injections of retatrutide in any of six dose regimens or placebo over 48 weeks. The primary outcome was weight change from baseline after 24 weeks.
The highest dose of retatrutide safely produced an average 17.5% drop from baseline weight, compared with an average 1.6% reduction in the placebo group, after 24 weeks, a significant difference.
After 48 weeks, the highest retatrutide dose safely cut baseline weight by an average of 24.2%, compared with an average 2.1% drop among placebo control patients, Ania M. Jastreboff, MD, PhD, and her coauthors wrote in their report. Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-response pattern.
Weight losses never before seen
“I have never seen weight loss at this level” after nearly 1 year of treatment, Dr. Jastreboff said when she discussed these findings in a press conference at the annual scientific sessions of the American Diabetes Association in San Diego in late June.
A separate presentation at the ADA meeting documented unprecedented weight loss levels in a study of 281 people with obesity or overweight and type 2 diabetes.
“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who formally presented the results from the study of retatrutide in people with type 2 diabetes at the ADA meeting.
The mechanism behind retatrutide’s potent weight-loss effect seems likely tied to its action on three human receptors that naturally respond to three nutrient-stimulated hormones that control appetite, metabolism, fat mobilization, and related functions.
The three hormones that the retatrutide molecule simultaneously mimics are glucagon-like peptide-1 (GLP-1), such as agents in the class of GLP-1 agonists that includes liraglutide (Victoza/Saxenda) and semaglutide (Ozempic/Wegovy); the glucose-dependent insulinotropic polypeptide (GIP), the receptor that is also activated by tirzepatide (Mounjaro), a dual-incretin receptor agonist that mimics both GLP-1 and GIP; and glucagon. Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development.
Retatrutide is currently unique among agents with reported clinical results by having agonist effects on the receptors for all three of these hormones, a property that led Dr. Patti to call retatrutide a “triple G” hormone-receptor agonist in her editorial.
Triple agonist has added effect on liver fat clearance
The glucagon-receptor agonism appears to give retatrutide added effects beyond those of the GLP-1 agonists or GLP-1/GIP dual agonists that are increasingly used in U.S. practice.
A prespecified subgroup analysis of the no diabetes/Jastreboff study (but that was not included in the NEJM report) showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those whose liver volume was at least 10% fat at study entry).
That percentage increased to about 90% of people receiving these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the ADA meeting.
“When you add glucagon activity, liver-fat clearance goes up tremendously,” observed Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
The average age of the participants in the new study of the use of retatrutide for those with obesity/overweight but not diabetes was 48 years. By design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m2.
Treatment with retatrutide was also significantly associated with improvements in several cardiometabolic measures in exploratory analyses, including systolic and diastolic blood pressure, A1c, fasting glucose, insulin, and some (but not all) lipids, Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn., and her coauthors reported in the NEJM article.
The safety profile of retatrutide was consistent with reported phase 1 findings for the agent among people with type 2 diabetes and resembled the safety profiles of other agents based on GLP-1 or GIP–GLP-1 mimicry for the treatment of type 2 diabetes or obesity.
The most frequently reported adverse events from retatrutide were transient, mostly mild to moderate gastrointestinal events. They occurred primarily during dose escalation. Discontinuation of retatrutide or placebo because of adverse events occurred in 6% to 16% of the participants who received retatrutide and in none of the participants who received placebo.
Lilly, the company developing retatrutide, previously announced the launch of four phase 3 trials to gather further data on retatrutide for use in a marketing-approval application to the Food and Drug Administration.
The four trials – TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 – are evaluating the safety and efficacy of retatrutide for chronic weight management for those with obesity or overweight, including those who also have obstructive sleep apnea, knee osteoarthritis, type 2 diabetes, or cardiovascular disease.
The study was sponsored by Lilly, the company developing retatrutide. Dr. Patti has been a consultant to AstraZeneca, Dexcom, Hanmi, and MBX. She has received funding from Dexcom and has been a monitor for a trial funded by Fractyl. Dr. Jastreboff, Dr. Kaplan, and Dr. Rosenstock have reported financial relationships with Lilly as well as other companies.
A version of this article first appeared on Medscape.com.
A novel triple agonist to receptors for three nutrient-stimulated hormones led to weight loss as high as 24% among people with overweight or obesity but who did not have type 2 diabetes when used at the highest tested dose for 48 weeks. The results are from a phase 2 study of retatrutide that was published in The New England Journal of Medicine (2023 Aug 10. doi: 10.1056/NEJMoa2301972).
This level of weight loss is “unprecedented” for a medication administered for 48 weeks, Mary-Elizabeth Patti, MD, said in an editorial that accompanied the report.
The findings “offer further optimism ... that effective pharmacologic management of obesity and related disorders is possible,” wrote Dr. Patti, a principal investigator at the Joslin Diabetes Center in Boston.
The study randomly assigned 338 adults with obesity or overweight – a body mass index (BMI) of ≥ 27 kg/m2 – and at least one weight-related complication to receive either weekly subcutaneous injections of retatrutide in any of six dose regimens or placebo over 48 weeks. The primary outcome was weight change from baseline after 24 weeks.
The highest dose of retatrutide safely produced an average 17.5% drop from baseline weight, compared with an average 1.6% reduction in the placebo group, after 24 weeks, a significant difference.
After 48 weeks, the highest retatrutide dose safely cut baseline weight by an average of 24.2%, compared with an average 2.1% drop among placebo control patients, Ania M. Jastreboff, MD, PhD, and her coauthors wrote in their report. Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-response pattern.
Weight losses never before seen
“I have never seen weight loss at this level” after nearly 1 year of treatment, Dr. Jastreboff said when she discussed these findings in a press conference at the annual scientific sessions of the American Diabetes Association in San Diego in late June.
A separate presentation at the ADA meeting documented unprecedented weight loss levels in a study of 281 people with obesity or overweight and type 2 diabetes.
“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who formally presented the results from the study of retatrutide in people with type 2 diabetes at the ADA meeting.
The mechanism behind retatrutide’s potent weight-loss effect seems likely tied to its action on three human receptors that naturally respond to three nutrient-stimulated hormones that control appetite, metabolism, fat mobilization, and related functions.
The three hormones that the retatrutide molecule simultaneously mimics are glucagon-like peptide-1 (GLP-1), such as agents in the class of GLP-1 agonists that includes liraglutide (Victoza/Saxenda) and semaglutide (Ozempic/Wegovy); the glucose-dependent insulinotropic polypeptide (GIP), the receptor that is also activated by tirzepatide (Mounjaro), a dual-incretin receptor agonist that mimics both GLP-1 and GIP; and glucagon. Survodutide is a dual GLP-1 and glucagon receptor agonist in phase 2 development.
Retatrutide is currently unique among agents with reported clinical results by having agonist effects on the receptors for all three of these hormones, a property that led Dr. Patti to call retatrutide a “triple G” hormone-receptor agonist in her editorial.
Triple agonist has added effect on liver fat clearance
The glucagon-receptor agonism appears to give retatrutide added effects beyond those of the GLP-1 agonists or GLP-1/GIP dual agonists that are increasingly used in U.S. practice.
A prespecified subgroup analysis of the no diabetes/Jastreboff study (but that was not included in the NEJM report) showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those whose liver volume was at least 10% fat at study entry).
That percentage increased to about 90% of people receiving these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the ADA meeting.
“When you add glucagon activity, liver-fat clearance goes up tremendously,” observed Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
The average age of the participants in the new study of the use of retatrutide for those with obesity/overweight but not diabetes was 48 years. By design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m2.
Treatment with retatrutide was also significantly associated with improvements in several cardiometabolic measures in exploratory analyses, including systolic and diastolic blood pressure, A1c, fasting glucose, insulin, and some (but not all) lipids, Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn., and her coauthors reported in the NEJM article.
The safety profile of retatrutide was consistent with reported phase 1 findings for the agent among people with type 2 diabetes and resembled the safety profiles of other agents based on GLP-1 or GIP–GLP-1 mimicry for the treatment of type 2 diabetes or obesity.
The most frequently reported adverse events from retatrutide were transient, mostly mild to moderate gastrointestinal events. They occurred primarily during dose escalation. Discontinuation of retatrutide or placebo because of adverse events occurred in 6% to 16% of the participants who received retatrutide and in none of the participants who received placebo.
Lilly, the company developing retatrutide, previously announced the launch of four phase 3 trials to gather further data on retatrutide for use in a marketing-approval application to the Food and Drug Administration.
The four trials – TRIUMPH-1, TRIUMPH-2, TRIUMPH-3, and TRIUMPH-4 – are evaluating the safety and efficacy of retatrutide for chronic weight management for those with obesity or overweight, including those who also have obstructive sleep apnea, knee osteoarthritis, type 2 diabetes, or cardiovascular disease.
The study was sponsored by Lilly, the company developing retatrutide. Dr. Patti has been a consultant to AstraZeneca, Dexcom, Hanmi, and MBX. She has received funding from Dexcom and has been a monitor for a trial funded by Fractyl. Dr. Jastreboff, Dr. Kaplan, and Dr. Rosenstock have reported financial relationships with Lilly as well as other companies.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Medical treatment for appendicitis effective long-term
TOPLINE:
Most patients who receive antibiotics rather than surgical treatment for appendicitis have successful long-term outcomes, but some may require surgery up to 20 years later.
METHODOLOGY:
- Follow-up on 292 patients involved in two randomized controlled trials conducted in the 1990s by the Swedish National Patient Registry
- Both trials divided patients into two groups: those who underwent appendectomy and those who received antibiotic treatment for appendicitis.
- Researchers looked at rates of recurrent appendicitis that required surgery later in life.
TAKEAWAY:
- 29% of patients in the nonoperative group who were discharged successfully during the initial study eventually underwent surgery.
- Some patients who initially received antibiotics required surgery up to 20 years later.
- 9.5% of patients who didn’t undergo surgery went to a surgical outpatient clinic for abdominal pain, compared with 0.01% of those who had surgery.
IN PRACTICE:
“More than half of the patients treated nonoperatively did not experience recurrence and avoided surgery over approximately 2 decades. There is no evidence for long-term risks of nonoperative management other than that of recurrence of appendicitis,” the authors report.
SOURCE:
Simon Eaton, PhD, of UCL Great Ormond Street Institute of Child Health in London, was the corresponding author of the study, published online in JAMA Surgery. The study was funded by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Swedish Research Council.
LIMITATIONS:
The data were retrospective, so the researchers could not track how patients’ circumstances and characteristics changed over time. Most patients were male, and the researchers lacked histopathology results for patients for whom nonsurgical treatment succeeded initially but who later required appendectomy. They also relied on diagnostic standards used in the 1990s, when the initial studies were performed; these were less sophisticated and accurate than recent standards.
DISCLOSURES:
Coauthor Jan Svensson, MD, PhD, reported receiving grants from the Lovisa Foundation during the conduct of the study. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
TOPLINE:
Most patients who receive antibiotics rather than surgical treatment for appendicitis have successful long-term outcomes, but some may require surgery up to 20 years later.
METHODOLOGY:
- Follow-up on 292 patients involved in two randomized controlled trials conducted in the 1990s by the Swedish National Patient Registry
- Both trials divided patients into two groups: those who underwent appendectomy and those who received antibiotic treatment for appendicitis.
- Researchers looked at rates of recurrent appendicitis that required surgery later in life.
TAKEAWAY:
- 29% of patients in the nonoperative group who were discharged successfully during the initial study eventually underwent surgery.
- Some patients who initially received antibiotics required surgery up to 20 years later.
- 9.5% of patients who didn’t undergo surgery went to a surgical outpatient clinic for abdominal pain, compared with 0.01% of those who had surgery.
IN PRACTICE:
“More than half of the patients treated nonoperatively did not experience recurrence and avoided surgery over approximately 2 decades. There is no evidence for long-term risks of nonoperative management other than that of recurrence of appendicitis,” the authors report.
SOURCE:
Simon Eaton, PhD, of UCL Great Ormond Street Institute of Child Health in London, was the corresponding author of the study, published online in JAMA Surgery. The study was funded by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Swedish Research Council.
LIMITATIONS:
The data were retrospective, so the researchers could not track how patients’ circumstances and characteristics changed over time. Most patients were male, and the researchers lacked histopathology results for patients for whom nonsurgical treatment succeeded initially but who later required appendectomy. They also relied on diagnostic standards used in the 1990s, when the initial studies were performed; these were less sophisticated and accurate than recent standards.
DISCLOSURES:
Coauthor Jan Svensson, MD, PhD, reported receiving grants from the Lovisa Foundation during the conduct of the study. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
TOPLINE:
Most patients who receive antibiotics rather than surgical treatment for appendicitis have successful long-term outcomes, but some may require surgery up to 20 years later.
METHODOLOGY:
- Follow-up on 292 patients involved in two randomized controlled trials conducted in the 1990s by the Swedish National Patient Registry
- Both trials divided patients into two groups: those who underwent appendectomy and those who received antibiotic treatment for appendicitis.
- Researchers looked at rates of recurrent appendicitis that required surgery later in life.
TAKEAWAY:
- 29% of patients in the nonoperative group who were discharged successfully during the initial study eventually underwent surgery.
- Some patients who initially received antibiotics required surgery up to 20 years later.
- 9.5% of patients who didn’t undergo surgery went to a surgical outpatient clinic for abdominal pain, compared with 0.01% of those who had surgery.
IN PRACTICE:
“More than half of the patients treated nonoperatively did not experience recurrence and avoided surgery over approximately 2 decades. There is no evidence for long-term risks of nonoperative management other than that of recurrence of appendicitis,” the authors report.
SOURCE:
Simon Eaton, PhD, of UCL Great Ormond Street Institute of Child Health in London, was the corresponding author of the study, published online in JAMA Surgery. The study was funded by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Swedish Research Council.
LIMITATIONS:
The data were retrospective, so the researchers could not track how patients’ circumstances and characteristics changed over time. Most patients were male, and the researchers lacked histopathology results for patients for whom nonsurgical treatment succeeded initially but who later required appendectomy. They also relied on diagnostic standards used in the 1990s, when the initial studies were performed; these were less sophisticated and accurate than recent standards.
DISCLOSURES:
Coauthor Jan Svensson, MD, PhD, reported receiving grants from the Lovisa Foundation during the conduct of the study. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
For CLL, BTKi combo bests chemoimmunotherapy
The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).
“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.
There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.
Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”
The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.
According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.
The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.
From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).
Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.
Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.
However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.
In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”
The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)
As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.
All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.
Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).
Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.”
Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”
He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.
The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.
The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).
“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.
There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.
Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”
The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.
According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.
The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.
From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).
Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.
Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.
However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.
In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”
The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)
As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.
All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.
Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).
Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.”
Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”
He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.
The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.
The analysis of the open-label FLAIR trial, published in The Lancet Oncology, tracked 771 patients with CLL for a median follow-up of 53 months (interquartile ratio, 41-61 months) and found that median progression-free survival was not reached with ibrutinib/rituximab versus 67 months with FCR (hazard ratio, 0.44, P < .0001).
“This paper is another confirmation to say that Bruton’s tyrosine kinase inhibitors are more powerful than even our strongest chemoimmunotherapy. That’s very reassuring,” said hematologist/oncologist Jan A. Burger, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, in an interview. He did not take part in the analysis but is familiar with its findings.
There are caveats to the study. More patients in the ibrutinib/rituximab arm died of cardiac events, possibly reflecting a known risk of those drugs. And for unclear reasons, there was no difference in overall survival – a secondary endpoint – between the groups. The study authors speculate that this may be because some patients on FCR progressed and turned to effective second-line drugs.
Still, the findings are consistent with the landmark E1912 trial, the authors wrote, and adds “to a body of evidence that suggests that the use of ibrutinib-based regimens should be considered for patients with previously untreated CLL, especially those with IGHV-unmutated CLL.”
The study, partially funded by industry, was led by Peter Hillmen, PhD, of Leeds (England) Cancer Center.
According to Dr. Burger, FCR was the standard treatment for younger, fitter patients with CLL about 10-15 years ago. Then Bruton’s tyrosine kinase inhibitors such as ibrutinib entered the picture. But, as the new report notes, initial studies focused on older patients who weren’t considered fit enough to tolerate FCR.
The new study, like the E1912 trial, aimed to compare ibrutinib-rituximab versus FCR in younger, fitter patients.
From 2014 to 2018, researchers assigned 771 patients (median age, 62 years; IQR 56-67; 73% male; 95% White; 66% with World Health Organization performance status, 0) to FCR (n = 385) or ibrutinib/rituximab (n = 386).
Nearly three-quarters (74%) in the FCR group received six cycles of therapy, and 97% of those in the ibrutinib-rituximab group received six cycles of rituximab. Those in the ibrutinib-rituximab group also received daily doses of ibrutinib. Doses could be modified. The data cutoff was May 24, 2021.
Notably, there was no improvement in overall survival in the ibrutinib/rituximab group: 92.1% of patients lived 4 years versus 93.5% in the FCR group. This contrasts with an improvement in overall survival in the earlier E1912 study in the ibrutinib/rituximab group.
However, the study authors noted that overall survival in the FCR group is higher than in earlier studies, perhaps reflecting the wider availability of targeted therapy. The final study analysis will offer more insight into overall survival.
In an interview, hematologist David A. Bond, MD, of Ohio State University, Columbus, who is familiar with the study findings, said “the lack of an improvement in overall survival could be due to differences in available treatments at relapse, as the FLAIR study was conducted more recently than the prior E1912 study.” He added that “the younger ages in the E1912 study may have led to less risk for cardiovascular events or deaths for the patients treated with ibrutinib in the E1912 study.”
The previous E1912 trial showed a larger effect for ibrutinib/rituximab versus FCR on progression-free survival (HR, 0.37, P < .001 for E1912 and HR, 0.44, P< .0001 for the FLAIR trial). However, the study authors noted that FLAIR trial had older subjects (mean age, 62 vs 56.7 in the E1912 trial.)
As for grade 3 or 4 adverse events, leukopenia was most common in the FCR group (n = 203, 54%), compared with the ibrutinib/rituximab group (n = 55, 14%). Serious adverse events were reported in 205 (53%) of patients in the ibrutinib/rituximab group versus 203 (54%) patients in the FCR group.
All-cause infections, myelodysplastic syndrome, acute myeloid leukemia, Richter’s transformation, and other diagnosed cancers were rare but more common in the FCR group. Deaths from COVID-19 were the same at 3 in each group; 2 of 29 deaths in the FCR group and 3 of 30 deaths in the ibrutinib/rituximab group were considered to be likely linked to treatment.
Sudden unexplained or cardiac deaths were more common in the ibrutinib-rituximab group (n = 8, 2%) vs. the FCR group (n = 2, less than 1%).
Dr. Bond said “one of the takeaways for practicing hematologists from the FLAIR study is that cardiovascular complications and sudden cardiac death are clearly an issue for older patients with hypertension treated with ibrutinib. Patients should be monitored for signs or symptoms of cardiovascular disease and have close management of blood pressure.”
Dr. Burger also noted that cardiac problems are a known risk of ibrutinib. “Fortunately, we have second-generation Bruton’s tyrosine kinase inhibitors that could be chosen for patients when we are worried about side effects.”
He said that chemotherapy remains the preferred – or only – treatment in some parts of the world. And patients may prefer FCR to ibrutinib because of the latter drug’s side effects or a preference for therapy that doesn’t take as long.
The study was funded by Cancer Research UK and Janssen. The study authors reported relationships with companies such as Lilly, Janssen, AbbVie, AstraZeneca, BeiGene, Gilead, and many others. Dr. Burger reports financial support for clinical trials from Pharmacyclics, AstraZeneca, Biogen, and Janssen. Dr. Bond reported no disclosures.
FROM THE LANCET ONCOLOGY
Generic inhalers for COPD support hold their own
Sometimes we get what we pay for. Other times we pay too much.
That’s the message of a study published in Annals of Internal Medicine, which finds that a generic maintenance inhaler is as effective at managing symptoms of chronic obstructive pulmonary disorder (COPD) as a pricier branded alternative.
In 2019, the Food and Drug Administration approved Wixela Inhub (the combination corticosteroid/long-acting beta2 adrenergic agonist fluticasone-salmeterol; Viatris) as a generic dry powder inhaler for managing symptoms of COPD. This approval was based on evidence of the generic’s effectiveness against asthma, although COPD also was on the product label. The study authors compared Wixela’s effectiveness in controlling symptoms of COPD with that of the brand name inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline), which uses the same active ingredients.
The result: “The generic looks to be as safe and effective as the brand name. I don’t see a clinical reason why one would ever need to get the brand name over the generic version,” said study author William Feldman, MD, DPhil, MPH, a health services researcher and pulmonologist at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Same types of patients, different inhalers, same outcomes
Dr. Feldman and colleagues compared the medical records of 10,000 patients with COPD who began using the branded inhaler to the records of another 10,000 patients with COPD who opted for the generic alternative. Participants in the two groups were evenly matched by age, sex, race, and ethnicity, region, severity of COPD, and presence of other comorbidities, according to the researchers. Participants were all older than age 40, and the average age in both groups was 72 years.
The researchers looked for a difference in a first episode of a moderate exacerbation of COPD, defined as requiring a course of prednisone for 5-14 days. They also looked for cases of severe COPD exacerbation requiring hospitalization in the year after people began using either the generic or brand name inhaler. And they looked for differences across 1 year in rates of hospitalization for pneumonia.
For none of those outcomes, however, did the type of inhaler appear to matter. Compared with the brand-name drug, using the generic was associated with nearly identical rates of moderate or severe COPD exacerbation (hazard ratio, 0.97; 95% confidence interval, 0.90-1.04. The same was true for the proportion of people who went to the hospital for pneumonia at least once (HR, 0.99; 95% CI, 0.86-1.15).
“To get through the FDA as an interchangeable generic, the generic firms have to show that their product can be used in just the same way as the brand-name version,” Dr. Feldman said, which may explain why the generic and brand-name versions of the inhaler performed so similarly.
Dr. Feldman cautioned that the price savings for patients who opt for the generic over the branded product are hard to determine, given the vagaries of different insurance plans and potential rebates when using the branded project. As a general matter, having a single generic competitor will not lower costs much, Dr. Feldman noted, pointing to 2017 research from Harvard that found a profusion of generic competitors is needed to significantly lower health care costs.
“I don’t want to in any way underestimate the importance of getting that first generic onto the market, because it sets the stage for future generics,” Dr. Feldman said.
“There are very few generic options for patients with COPD,” said Surya Bhatt, MD, director of the Pulmonary Function and Exercise Physiology Lab at the University of Alabama at Birmingham. Even the rescue inhalers that people with COPD use to manage acute episodes of the condition are usually branded at this time, Dr. Bhatt noted, with few generic options.*
“The results are quite compelling,” said Dr. Bhatt, who was not involved in the research. Although the trial was not randomized, he commended the researchers for stratifying participants in the two groups to be as comparable as possible.
Dr. Bhatt noted that the FDA’s 2019 approval – given that the agency requires bioequivalence studies between branded and generic products – was enough to cause him to begin prescribing the generic inhaler. The fact that this approval was based on asthma but not also COPD is not a concern.
“There are so many similarities between asthma, COPD, and some obstructive lung diseases,” Dr. Bhatt noted.
In his experience, the only time someone with COPD continues using the branded inhaler – now that a potentially cheaper generic is available – is when their insurance plan makes their out-of-pocket cost minimal. Otherwise, brand loyalty does not exist.
“Patients are generally okay with being on a generic for inhalers, just because of the high cost,” Dr. Bhatt said.
The study was primarily supported by the National Heart, Lung, and Blood Institute. Dr. Feldman reported funding from Arnold Ventures, the Commonwealth Fund, and the FDA, and consulting relationships with Alosa Health and Aetion. Dr. Bhatt reported no relevant financial relationships.
*Correction, 8/16/23: An earlier version of this article mischaracterized Dr. Bhatt's comments on the availability of generic options.
A version of this article first appeared on Medscape.com.
Sometimes we get what we pay for. Other times we pay too much.
That’s the message of a study published in Annals of Internal Medicine, which finds that a generic maintenance inhaler is as effective at managing symptoms of chronic obstructive pulmonary disorder (COPD) as a pricier branded alternative.
In 2019, the Food and Drug Administration approved Wixela Inhub (the combination corticosteroid/long-acting beta2 adrenergic agonist fluticasone-salmeterol; Viatris) as a generic dry powder inhaler for managing symptoms of COPD. This approval was based on evidence of the generic’s effectiveness against asthma, although COPD also was on the product label. The study authors compared Wixela’s effectiveness in controlling symptoms of COPD with that of the brand name inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline), which uses the same active ingredients.
The result: “The generic looks to be as safe and effective as the brand name. I don’t see a clinical reason why one would ever need to get the brand name over the generic version,” said study author William Feldman, MD, DPhil, MPH, a health services researcher and pulmonologist at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Same types of patients, different inhalers, same outcomes
Dr. Feldman and colleagues compared the medical records of 10,000 patients with COPD who began using the branded inhaler to the records of another 10,000 patients with COPD who opted for the generic alternative. Participants in the two groups were evenly matched by age, sex, race, and ethnicity, region, severity of COPD, and presence of other comorbidities, according to the researchers. Participants were all older than age 40, and the average age in both groups was 72 years.
The researchers looked for a difference in a first episode of a moderate exacerbation of COPD, defined as requiring a course of prednisone for 5-14 days. They also looked for cases of severe COPD exacerbation requiring hospitalization in the year after people began using either the generic or brand name inhaler. And they looked for differences across 1 year in rates of hospitalization for pneumonia.
For none of those outcomes, however, did the type of inhaler appear to matter. Compared with the brand-name drug, using the generic was associated with nearly identical rates of moderate or severe COPD exacerbation (hazard ratio, 0.97; 95% confidence interval, 0.90-1.04. The same was true for the proportion of people who went to the hospital for pneumonia at least once (HR, 0.99; 95% CI, 0.86-1.15).
“To get through the FDA as an interchangeable generic, the generic firms have to show that their product can be used in just the same way as the brand-name version,” Dr. Feldman said, which may explain why the generic and brand-name versions of the inhaler performed so similarly.
Dr. Feldman cautioned that the price savings for patients who opt for the generic over the branded product are hard to determine, given the vagaries of different insurance plans and potential rebates when using the branded project. As a general matter, having a single generic competitor will not lower costs much, Dr. Feldman noted, pointing to 2017 research from Harvard that found a profusion of generic competitors is needed to significantly lower health care costs.
“I don’t want to in any way underestimate the importance of getting that first generic onto the market, because it sets the stage for future generics,” Dr. Feldman said.
“There are very few generic options for patients with COPD,” said Surya Bhatt, MD, director of the Pulmonary Function and Exercise Physiology Lab at the University of Alabama at Birmingham. Even the rescue inhalers that people with COPD use to manage acute episodes of the condition are usually branded at this time, Dr. Bhatt noted, with few generic options.*
“The results are quite compelling,” said Dr. Bhatt, who was not involved in the research. Although the trial was not randomized, he commended the researchers for stratifying participants in the two groups to be as comparable as possible.
Dr. Bhatt noted that the FDA’s 2019 approval – given that the agency requires bioequivalence studies between branded and generic products – was enough to cause him to begin prescribing the generic inhaler. The fact that this approval was based on asthma but not also COPD is not a concern.
“There are so many similarities between asthma, COPD, and some obstructive lung diseases,” Dr. Bhatt noted.
In his experience, the only time someone with COPD continues using the branded inhaler – now that a potentially cheaper generic is available – is when their insurance plan makes their out-of-pocket cost minimal. Otherwise, brand loyalty does not exist.
“Patients are generally okay with being on a generic for inhalers, just because of the high cost,” Dr. Bhatt said.
The study was primarily supported by the National Heart, Lung, and Blood Institute. Dr. Feldman reported funding from Arnold Ventures, the Commonwealth Fund, and the FDA, and consulting relationships with Alosa Health and Aetion. Dr. Bhatt reported no relevant financial relationships.
*Correction, 8/16/23: An earlier version of this article mischaracterized Dr. Bhatt's comments on the availability of generic options.
A version of this article first appeared on Medscape.com.
Sometimes we get what we pay for. Other times we pay too much.
That’s the message of a study published in Annals of Internal Medicine, which finds that a generic maintenance inhaler is as effective at managing symptoms of chronic obstructive pulmonary disorder (COPD) as a pricier branded alternative.
In 2019, the Food and Drug Administration approved Wixela Inhub (the combination corticosteroid/long-acting beta2 adrenergic agonist fluticasone-salmeterol; Viatris) as a generic dry powder inhaler for managing symptoms of COPD. This approval was based on evidence of the generic’s effectiveness against asthma, although COPD also was on the product label. The study authors compared Wixela’s effectiveness in controlling symptoms of COPD with that of the brand name inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline), which uses the same active ingredients.
The result: “The generic looks to be as safe and effective as the brand name. I don’t see a clinical reason why one would ever need to get the brand name over the generic version,” said study author William Feldman, MD, DPhil, MPH, a health services researcher and pulmonologist at Harvard Medical School and Brigham and Women’s Hospital, both in Boston.
Same types of patients, different inhalers, same outcomes
Dr. Feldman and colleagues compared the medical records of 10,000 patients with COPD who began using the branded inhaler to the records of another 10,000 patients with COPD who opted for the generic alternative. Participants in the two groups were evenly matched by age, sex, race, and ethnicity, region, severity of COPD, and presence of other comorbidities, according to the researchers. Participants were all older than age 40, and the average age in both groups was 72 years.
The researchers looked for a difference in a first episode of a moderate exacerbation of COPD, defined as requiring a course of prednisone for 5-14 days. They also looked for cases of severe COPD exacerbation requiring hospitalization in the year after people began using either the generic or brand name inhaler. And they looked for differences across 1 year in rates of hospitalization for pneumonia.
For none of those outcomes, however, did the type of inhaler appear to matter. Compared with the brand-name drug, using the generic was associated with nearly identical rates of moderate or severe COPD exacerbation (hazard ratio, 0.97; 95% confidence interval, 0.90-1.04. The same was true for the proportion of people who went to the hospital for pneumonia at least once (HR, 0.99; 95% CI, 0.86-1.15).
“To get through the FDA as an interchangeable generic, the generic firms have to show that their product can be used in just the same way as the brand-name version,” Dr. Feldman said, which may explain why the generic and brand-name versions of the inhaler performed so similarly.
Dr. Feldman cautioned that the price savings for patients who opt for the generic over the branded product are hard to determine, given the vagaries of different insurance plans and potential rebates when using the branded project. As a general matter, having a single generic competitor will not lower costs much, Dr. Feldman noted, pointing to 2017 research from Harvard that found a profusion of generic competitors is needed to significantly lower health care costs.
“I don’t want to in any way underestimate the importance of getting that first generic onto the market, because it sets the stage for future generics,” Dr. Feldman said.
“There are very few generic options for patients with COPD,” said Surya Bhatt, MD, director of the Pulmonary Function and Exercise Physiology Lab at the University of Alabama at Birmingham. Even the rescue inhalers that people with COPD use to manage acute episodes of the condition are usually branded at this time, Dr. Bhatt noted, with few generic options.*
“The results are quite compelling,” said Dr. Bhatt, who was not involved in the research. Although the trial was not randomized, he commended the researchers for stratifying participants in the two groups to be as comparable as possible.
Dr. Bhatt noted that the FDA’s 2019 approval – given that the agency requires bioequivalence studies between branded and generic products – was enough to cause him to begin prescribing the generic inhaler. The fact that this approval was based on asthma but not also COPD is not a concern.
“There are so many similarities between asthma, COPD, and some obstructive lung diseases,” Dr. Bhatt noted.
In his experience, the only time someone with COPD continues using the branded inhaler – now that a potentially cheaper generic is available – is when their insurance plan makes their out-of-pocket cost minimal. Otherwise, brand loyalty does not exist.
“Patients are generally okay with being on a generic for inhalers, just because of the high cost,” Dr. Bhatt said.
The study was primarily supported by the National Heart, Lung, and Blood Institute. Dr. Feldman reported funding from Arnold Ventures, the Commonwealth Fund, and the FDA, and consulting relationships with Alosa Health and Aetion. Dr. Bhatt reported no relevant financial relationships.
*Correction, 8/16/23: An earlier version of this article mischaracterized Dr. Bhatt's comments on the availability of generic options.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
Ancestry may predict bipolar patients’ response to lithium
Lithium remains the first-line treatment for BPD, but clinical improvement occurs in less than one-third of patients, and factors that might affect response, especially genetic factors, have not been well studied, wrote Ana M. Díaz-Zuluaga, MD, of University of Antioquia, Medellín, Colombia, and colleagues.
Previous genetic research identified four linked single nucleotide polymorphisms (SNPs) in a single locus on chromosome 21 that were associated with lithium response, but the study was limited to individuals with European and Asian ancestry, the researchers said.
In a study published in the Journal of Affective Disorders, the researchers identified 172 adults aged 18 and older with a diagnosis of BPD I or II based on the DSM-IV-TR criteria. Participants had been taking lithium continuously for at least 6 months. Lithium response was defined using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with BD, also known as the Alda scale. Total Alda scale scores of 7 or higher indicated a responder phenotype; scores less than 7 were considered nonresponders.
Ancestry was determined using DNA samples and the software Structure Version 2.2, and participants were classified as Amerindian, African, or European.
The overall response rate to lithium was 15.11% (26 of 172 patients). In a univariate analysis, no significant differences emerged between responders and nonresponders in demographics or clinical characteristics. However, patients responsive to lithium were significantly less likely of African ancestry, compared with nonresponders (0.1 vs. 0.2, P = .005) and more likely of European ancestry (0.5 vs. 0.3, P = .024), and had fewer depressive episodes (2 vs. 3.9, P = .002). The difference in responders vs. nonresponders of Amerindian ancestry was not statistically significant (0.4 vs. 0.5, P = .204).
The researchers then used machine learning based on Advanced Recursive Partitioning Approaches (ARPAs) to create classification trees with and without ancestry components for predicting response to lithium. “Variable importance analysis shows that the most important predictor is the probability of Amerindian ancestry component, followed by the Amerindian and European ancestral components individual variances, and then by the African and European ancestry components,” the researchers wrote.
Without the ancestry component, the sensitivity and specificity for predicting a treatment response to lithium were 50% and 94.5% respectively, with an area under the curve of 72.2%.
“However, when ancestral components are included in the model, the sensitivity and specificity are 93 % and 84 %, respectively,” with an AUC of 89.2%, the researchers said.
Clinical predictors of treatment response included disease duration, number of depressive episodes, total number of affective episodes, and number of manic episodes.
The findings were limited by several factors including the cross-sectional design and potential impact of other psychotropic drugs, the researchers noted. A replication of the study in an independent dataset is needed to validate the findings, they said.
However, the study is the first known to explore the effect of ancestry on bipolar patients’ response to lithium, and suggests that ancestry components have potential predictive value in the clinical setting that could support a more personalized approach to treatment, the researchers said.
The study was supported by PRISMA U.T., Colciencias, Invitaci
Lithium remains the first-line treatment for BPD, but clinical improvement occurs in less than one-third of patients, and factors that might affect response, especially genetic factors, have not been well studied, wrote Ana M. Díaz-Zuluaga, MD, of University of Antioquia, Medellín, Colombia, and colleagues.
Previous genetic research identified four linked single nucleotide polymorphisms (SNPs) in a single locus on chromosome 21 that were associated with lithium response, but the study was limited to individuals with European and Asian ancestry, the researchers said.
In a study published in the Journal of Affective Disorders, the researchers identified 172 adults aged 18 and older with a diagnosis of BPD I or II based on the DSM-IV-TR criteria. Participants had been taking lithium continuously for at least 6 months. Lithium response was defined using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with BD, also known as the Alda scale. Total Alda scale scores of 7 or higher indicated a responder phenotype; scores less than 7 were considered nonresponders.
Ancestry was determined using DNA samples and the software Structure Version 2.2, and participants were classified as Amerindian, African, or European.
The overall response rate to lithium was 15.11% (26 of 172 patients). In a univariate analysis, no significant differences emerged between responders and nonresponders in demographics or clinical characteristics. However, patients responsive to lithium were significantly less likely of African ancestry, compared with nonresponders (0.1 vs. 0.2, P = .005) and more likely of European ancestry (0.5 vs. 0.3, P = .024), and had fewer depressive episodes (2 vs. 3.9, P = .002). The difference in responders vs. nonresponders of Amerindian ancestry was not statistically significant (0.4 vs. 0.5, P = .204).
The researchers then used machine learning based on Advanced Recursive Partitioning Approaches (ARPAs) to create classification trees with and without ancestry components for predicting response to lithium. “Variable importance analysis shows that the most important predictor is the probability of Amerindian ancestry component, followed by the Amerindian and European ancestral components individual variances, and then by the African and European ancestry components,” the researchers wrote.
Without the ancestry component, the sensitivity and specificity for predicting a treatment response to lithium were 50% and 94.5% respectively, with an area under the curve of 72.2%.
“However, when ancestral components are included in the model, the sensitivity and specificity are 93 % and 84 %, respectively,” with an AUC of 89.2%, the researchers said.
Clinical predictors of treatment response included disease duration, number of depressive episodes, total number of affective episodes, and number of manic episodes.
The findings were limited by several factors including the cross-sectional design and potential impact of other psychotropic drugs, the researchers noted. A replication of the study in an independent dataset is needed to validate the findings, they said.
However, the study is the first known to explore the effect of ancestry on bipolar patients’ response to lithium, and suggests that ancestry components have potential predictive value in the clinical setting that could support a more personalized approach to treatment, the researchers said.
The study was supported by PRISMA U.T., Colciencias, Invitaci
Lithium remains the first-line treatment for BPD, but clinical improvement occurs in less than one-third of patients, and factors that might affect response, especially genetic factors, have not been well studied, wrote Ana M. Díaz-Zuluaga, MD, of University of Antioquia, Medellín, Colombia, and colleagues.
Previous genetic research identified four linked single nucleotide polymorphisms (SNPs) in a single locus on chromosome 21 that were associated with lithium response, but the study was limited to individuals with European and Asian ancestry, the researchers said.
In a study published in the Journal of Affective Disorders, the researchers identified 172 adults aged 18 and older with a diagnosis of BPD I or II based on the DSM-IV-TR criteria. Participants had been taking lithium continuously for at least 6 months. Lithium response was defined using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with BD, also known as the Alda scale. Total Alda scale scores of 7 or higher indicated a responder phenotype; scores less than 7 were considered nonresponders.
Ancestry was determined using DNA samples and the software Structure Version 2.2, and participants were classified as Amerindian, African, or European.
The overall response rate to lithium was 15.11% (26 of 172 patients). In a univariate analysis, no significant differences emerged between responders and nonresponders in demographics or clinical characteristics. However, patients responsive to lithium were significantly less likely of African ancestry, compared with nonresponders (0.1 vs. 0.2, P = .005) and more likely of European ancestry (0.5 vs. 0.3, P = .024), and had fewer depressive episodes (2 vs. 3.9, P = .002). The difference in responders vs. nonresponders of Amerindian ancestry was not statistically significant (0.4 vs. 0.5, P = .204).
The researchers then used machine learning based on Advanced Recursive Partitioning Approaches (ARPAs) to create classification trees with and without ancestry components for predicting response to lithium. “Variable importance analysis shows that the most important predictor is the probability of Amerindian ancestry component, followed by the Amerindian and European ancestral components individual variances, and then by the African and European ancestry components,” the researchers wrote.
Without the ancestry component, the sensitivity and specificity for predicting a treatment response to lithium were 50% and 94.5% respectively, with an area under the curve of 72.2%.
“However, when ancestral components are included in the model, the sensitivity and specificity are 93 % and 84 %, respectively,” with an AUC of 89.2%, the researchers said.
Clinical predictors of treatment response included disease duration, number of depressive episodes, total number of affective episodes, and number of manic episodes.
The findings were limited by several factors including the cross-sectional design and potential impact of other psychotropic drugs, the researchers noted. A replication of the study in an independent dataset is needed to validate the findings, they said.
However, the study is the first known to explore the effect of ancestry on bipolar patients’ response to lithium, and suggests that ancestry components have potential predictive value in the clinical setting that could support a more personalized approach to treatment, the researchers said.
The study was supported by PRISMA U.T., Colciencias, Invitaci
FROM THE JOURNAL OF AFFECTIVE DISORDERS