HealthDay News — Sotatercept is associated with a greater improvement in exercise capacity than placebo among patients with pulmonary arterial hypertension (PAH) receiving stable background therapy, according to a study published online March 6 in the New England Journal of Medicine to coincide with the annual meeting of the American College of Cardiology, held from March 4 to 6 in New Orleans.

Marius M. Hoeper, MD, from Hannover Medical School in Germany, and colleagues randomly assigned (1:1) adults with PAH (World Health Organization functional class II or III), who were receiving stable background therapy, to receive subcutaneous sotatercept (163 patients; starting dose, 0.3mg per kg of body weight; target dose, 0.7mg per kg) or placebo (160 patients) every 3 weeks.

The researchers found that the median change from baseline to week 24 in the 6-minute walk distance was 34.4 m (95% CI, 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, −0.3 to 3.5) in the placebo group, yielding a Hodges-Lehmann estimate of the difference between the groups of 40.8 m. Eight of 9 secondary end points were significantly improved with sotatercept vs placebo, but the cognitive-emotional impacts domain of the Pulmonary Arterial Hypertension-Symptoms and Impact Physical Impacts, Cardiopulmonary Symptoms score was not different between the groups. Adverse events, including epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure, occurred more frequently with sotatercept than placebo.

“This is the most impressive reduction in the pulmonary arterial pressure that we’ve ever seen in pretreated patients with PAH,” Hoeper said in a statement. “For me, it’s one of the strongest signals suggesting that we truly achieved some regression of the disease’s adverse changes in the pulmonary vessels.”

Acceleron Pharma supported the study. Acceleron is owned by Merck, the manufacturer of sotatercept.

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Phosphodiesterase-5 inhibitors (PDE5i) reduce the likelihood of major adverse cardiovascular events in men with both coronary artery disease (CAD) and erectile dysfunction (ED), according to study findings presented at the American Urological Association’s 2023 annual meeting in Chicago, Illinois.

In addition, investigators found that the cardiac benefit of PDE5i is more pronounced with tadalafil than sildenafil.

In a retrospective study of 41,287 men with CAD (but not pulmonary hypertension) and ED, Albert Ha, MD, of Columbia University’s Irving Medical Center in New York, New York, and colleagues found that men who took tadalafil and sildenafil had a significant 33% and 22% lower 5-year risk for heart failure, respectively, compared with men who received no PDE5i treatment after propensity-score matching. Tadalafil and sildenafil recipients had 25% and 12% lower 5-year risks for myocardial infarction and 41% and 35% lower 5-year risks for overall mortality, respectively.

Further, compared with sildenafil recipients, tadalafil-treated patients had significant 15%, 14%, and 15%, lower 5-year risks forheart failure, myocardial infarction, and overall mortality, respectively.

“I think our study is the first to tease out specific differences among individual PDE5i in relation to cardiac outcomes, with our preliminary results suggesting that tadalafil may be superior to other PDE5i like sildenafil in relation to heart failure, myocardial infarction, and mortality, ” Dr Ha said in an interview. “Since erectile dysfunction is a common harbinger for cardiac disease later in life, it is important for patients to understand what drugs may best address their medical issues, especially in a time when medical care may be siloed in different (and oftentimes disconnected) specialties. “

As for the greater cardiac benefit observed with tadalafil, Dr Ha said, “We speculate that this may be due to differences in pharmacokinetics, with tadalafil offering more specific inhibition of PDE5 enzymes with less cross reactivity, as well as a longer duration of efficacy. As such, this may promote medication compliance, particularly in patients with both ED and CAD. However, our results are preliminary, and as such, we cannot definitely conclude that clinicians should preferentially prescribe tadalafil until additional research is performed.”

The study population included 12,214 sildenafil users, 6751 tadalafil users, and 22,321 men who received no treatment. Dr Ha’s team performed propensity-score matching using baseline comorbidities of hypertension, ischemic heart disease, cerebral infarction, diabetes, and hyperlipidemia.

Reference

Ha H, Wayne G, Jacobs M, Kalogeropoulos A, Alukal J. Phosphodiesterase-5 inhibitor use and progression to heart failure in men with coronary artery disease and erectile dysfunction. Presented at: AUA 2023, Chicago, Illinois, April 28-May 1. Presentation PD11-10.

Resmetirom for Nonalcoholic Steatohepatitis (NASH) With Liver Fibrosis

PDUFA date: March 14, 2024

In patients with NASH, thyroid hormone beta activity in the liver is reduced, resulting in hepatic function impairment. Resmetirom is an oral thyroid hormone receptor (THR)-β selective agonist designed to target the underlying cause of NASH. The NDA submission included data from four phase 3 studies, including the pivotal MAESTRO-NASH trial (ClinicalTrials.gov Identifier: NCT03900429), which evaluated the efficacy and safety of resmetirom in more than 1000 patients with biopsy-proven NASH and fibrosis. Findings showed the trial met its dual primary endpoints: NASH resolution with at least a 2-point reduction in nonalcoholic fatty liver disease activity score (NAS) and with no worsening of fibrosis, or at least a 1-stage improvement in fibrosis with no worsening of NAS after 52 weeks of treatment.

Atidarsagene Autotemcel for Metachromatic Leukodystrophy

PDUFA date: March 18, 2024

Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal storage disease caused by a mutation in the arylsulfatase-A gene. This results in a buildup of sulfatides in the brain and other areas of the body. Atidarsagene autotemcel is a hematopoietic stem cell-based gene therapy that was evaluated in a clinical trial that included 39 pediatric patients with early-onset MLD. At the time of analysis, treatment with the one-time gene therapy resulted in a statistically significant and clinically meaningful improvement in severe motor impairment-free survival. If approved, atidarsagene autotemcel would be the first and only treatment for early-onset MLD in the US.

Sotatercept for Pulmonary Arterial Hypertension

PDUFA date: March 26, 2024

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening blood vessel disorder caused by hyperproliferation of cells in the arterial walls in the lung. The disease is characterized by the constriction of small pulmonary arteries and elevations in pulmonary arterial pressure. The BLA for sotatercept, a first-in-class activin receptor type IIA-Fc fusion protein, is supported by data from the double-blind, placebo-controlled phase 3 STELLAR trial. The study included 323 adult patients with PAH (WHO Group 1). Results showed a statistically significant and clinically meaningful improvement in 6-minute walk distance among patients treated with sotatercept compared with placebo.

Vadadustat for Anemia Due to Chronic Kidney Disease

PDUFA date: March 27, 2024

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor designed to mimic the physiologic effect of altitude on oxygen availability. This results in increased red blood cell production and improved oxygen delivery to tissues. The NDA submission included data from 36 clinical trials involving over 8000 patients. Findings from the INNO2VATE program, which included 2 open-label, active-controlled phase 3 trials, showed that vadadustat was noninferior to darbepoetin alfa in adult patients on dialysis with anemia due to CKD. Vadadustat was also found to be noninferior to a long-acting erythropoiesis-stimulating agent for the maintenance treatment of anemia due to CKD, in hemodialysis patients in the phase 3 FO₂CUS study.

Omalizumab for Reducing Allergic Reactions to Multiple Foods

PDUFA date: March 2024

Omalizumab, an anti-immunoglobulin E (IgE) antibody, is under review for the reduction of allergic reactions, including anaphylaxis, that may occur with accidental exposure to 1 or more foods in adults and pediatric patients aged 1 year and older with food allergy. The BLA is supported by data from the phase 3 OUtMATCH trial, which evaluated the safety and efficacy of omalizumab in patients 1 to 55 years of age who are allergic to peanuts and at least 2 other common foods. Findings showed that compared with placebo, omalizumab significantly increased the amount of peanut (primary endpoint), milk, egg, and cashew (key secondary endpoints) participants could consume without an allergic reaction.

Visit our Drugs in the Pipeline section to stay up-to-date on all the latest drugs in development.

During its daylong meeting, the FDA Anesthesiology and Respiratory Therapy Devices Panel reviewed ways to better evaluate the accuracy of pulse oximeters in patients with darker skin. Although there is more work to be done when it comes to making pulse oximeters more accurate, panel member Jeffrey Feldman, MD, said the benefits of these devices still outweigh their limitations.

“This technology has and continues to save lives on a daily basis in this country. … It needs to be improved. We need to look at health disparities, and we need to do better,” he said after the meeting, CNN reported. “But we also need to recognize how valuable this technology is for patients every day, at home, and in the hospital.”

Precisely because the general public can use these devices at home to check their oxygen levels, the panel homed in on how to ensure the accuracy of pulse oximeters for all skin tones before they reach drugstore shelves. So, the panel focused on the structure of company trials testing the products.

Back in 2013, the FDA issued premarket guidance for developers of pulse oximeters, recommending that they have “a range of skin pigmentation” represented in their clinical studies of the devices, including at least two “darkly pigmented subjects or 15 percent of the study group,” whichever is larger.

Now, the FDA is weighing proposals to update these clinical trials to include more diverse groups of people, with at least 24 participants spanning the entire range of skin tones on the 10-shade Monk Skin Tone scale.

“There’s no question that more diversity needs to be a part of whatever new requirements that they would issue,” Feldman said. “The prior requirements in 2013 were small numbers and really not very diverse — the only requirement was for up to two patients of color — and so that I think has proven to be inadequate to predict real-world performance.”

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Liqrev^® (sildenafil) Oral Suspension has been made available by CMP Pharma for patients who have difficulty swallowing sildenafil tablets.

Liqrev is indicated for the treatment of pulmonary arterial hypertension (World Health Organization Group I) in adults to improve exercise ability and delay clinical worsening. The Food and Drug Administration-approved product is expected to address dosing inconsistencies that may come from crushing or compounding sildenafil tablets.

The ready-to-use liquid is available in a strawberry flavor in 122mL bottles. Liqrev has a 24-month shelf life.

While pediatric use is approved for Viatris Specialty LLC’s Revatio (sildenafil tablets), Liqrev is not labeled for this patient population because of marketing exclusivity rights.

The table below is a review of notable updates that occurred in October 2023 for investigational products in development (not an inclusive list). Click on the status to view our full coverage.

Opsynvi is a combination of macitentan, an endothelin receptor antagonist (ERA), and tadalafil, a phosphodiesterase 5 (PDE5) inhibitor. The individual components of Opsynvi are both indicated for the treatment of patients with PAH. Macitentan reduces the risk of clinical worsening events and hospitalization, while tadalafil improves exercise ability.

The approval of Opsynvi was based on data from the phase 3 A DUE trial (ClinicalTrials.gov Identifier: NCT03904693), which compared the efficacy and safety of Opsynvi to monotherapy with macitentan or tadalafil in 187 patients with PAH (WHO FC II-III), who were treatment naïve or on a stable dose of an ERA or a PDE5 inhibitor for at least 3 months. Patients with pulmonary vascular resistance (PVR) of at least 240 dyn·s/cm⁵ were randomly assigned to receive Opsynvi (n=108), macitentan 10mg (n=35), or tadalafil 40mg (n=44) once daily.

The primary endpoint was PVR measured 16 weeks after treatment initiation (expressed as the ratio of geometric means to baseline). Findings showed treatment with Opsynvi led to a statistically significantly greater reduction in PVR compared with macitentan (treatment effect ratio, -29% [95% CI, -39%, -18%; P <.0001]), and vs tadalafil (treatment effect ratio, -28% [95% CI, -36%, -20%]; P <.0001). This effect was found to be consistent among treatment-naïve patients as well as those who were previously exposed to an ERA or PDE5 inhibitor.

The most common adverse reactions reported with Opsynvi were edema/fluid retention, anemia, and headache/migraine. The prescribing information for Opsynvi includes a Boxed Warning regarding the risk of embryo-fetal toxicity. For female patients, Opsynvi is available only through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS).

Opsynvi is supplied as a film-coated tablet in 2 dosage strengths: macitentan 10mg/tadalafil 20mg and macitentan 10mg/tadalafil 40mg.

Commenting on the approval, Kelly Chin, MD, Professor of Internal Medicine and Director of the Pulmonary Hypertension Program at UT Southwestern Medical Center, and an investigator in the A DUE study, said: “As administration of macitentan and tadalafil together are commonly prescribed for initial therapy for PAH, the introduction of a single tablet combining both is promising for clinicians treating patients as it may help bridge the gap between clinical guidelines and everyday clinical practice, while offering a patient-friendly approach to support initial combination therapy and rapid escalation for the appropriate patients.” 

Opsynvi is expected to be available in mid-April 2024.

Treprostinil is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) to diminish symptoms associated with exercise; and for patients who require transition from epoprostenol, to reduce the rate of clinical deterioration. The treatment is administered by either subcutaneous or intravenous infusion.

The recall (NDC #42023-206-01) includes the following lots, which were distributed nationwide to wholesalers and hospitals between June 16, 2022 and August 7, 2023: 

• Lot # 57014; Expiration date 4/2024
• Lot # 56911; Expiration date 4/2024
• Lot # 58528; Expiration date 5/2024
• Lot # 58529; Expiration date 5/2024
• Lot # 60064; Expiration date 7/2024
• Lot # 60075; Expiration date 7/2024
• Lot # 67939; Expiration date 3/2025

At this time, there have been no reports of adverse events associated with this recall. Administration of an injectable product that contains particulates can result in local adverse reactions (eg, irritation, swelling) and potentially serious systemic events (eg, stroke, death).

Adverse reactions and quality issues should be reported to the FDA’s MedWatch program.

Treprostinil is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) to diminish symptoms associated with exercise; and for patients who require transition from epoprostenol, to reduce the rate of clinical deterioration. The treatment is administered by either subcutaneous or intravenous infusion.

The recalled product has Lot# 57014, with an expiration date of April 2024. It was distributed nationwide between June 16, 2022 and October 17, 2022.

At this time, there have been no reports of adverse events associated with this recall. Administration of an injectable product that contains particulates can result in local adverse reactions (eg, irritation, swelling) and potentially serious systemic events (eg, stroke, death).

Adverse reactions and quality issues should be reported to the FDA’s MedWatch program.

The table below is a review of notable updates that occurred in September 2023 for investigational products in development (not an inclusive list). Click on the status to view our full coverage.

The Food and Drug Administration (FDA) has accepted for Priority Review the Biologics License Application (BLA) for sotatercept for the treatment of adults with pulmonary arterial hypertension (PAH) (WHO Group 1). 

Sotatercept is a first-in-class activin receptor type IIA-Fc fusion protein. The application is supported by data from the double-blind, placebo-controlled phase 3 STELLAR study (ClinicalTrials.gov Identifier: NCT04576988), which evaluated the efficacy and safety of sotatercept in 323 adult patients with PAH (WHO Group 1). 

Study participants who were receiving stable background PAH therapy were randomly assigned 1:1 to receive either sotatercept or placebo administered subcutaneously every 3 weeks. The primary endpoint was exercise capacity, which was measured by the change from baseline in 6-minute walk distance (6MWD) at 24 weeks.

Results showed a statistically significant and clinically meaningful improvement in 6MWD among patients treated with sotatercept compared with placebo (34.4m vs 1.0m, respectively; Hodges-Lehmann estimated difference, 40.8m [95% CI, 27.5-54.1]; P <.001). 

Sotatercept was also associated with statistically significant improvements in 8 out of 9 secondary outcome measures, including the proportion of participants achieving multicomponent improvement (defined as improvement in 6MWD, improvement in N-terminal pro-B-type natriuretic peptide level, and either improvement in WHO functional class [FC] or maintenance of WHO FC II), and the outcome measure of time to death or the first occurrence of a clinical worsening event. An assessment of the Cognitive/Emotional Impacts domain score of PAH-SYMPACT^® did not result in a statistical significant change.

Compared with placebo, the following adverse events occurred more frequently with sotatercept: epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.

“Despite advances in the treatment of PAH over the last 2 decades, there is still a significant need to improve outcomes for patients,” said Dr Joerg Koglin, senior vice president, global clinical development, Merck Research Laboratories. “The FDA’s acceptance of this application is an exciting milestone in our journey to bring this novel activin signaling inhibitor to patients. Based on the profound improvements across primary and secondary outcome measures in the phase 3 STELLAR trial, we believe sotatercept has the potential to transform the treatment of patients with PAH.”

A Prescription Drug User Fee Act target date of March 26, 2024 has been set for the application.