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The FDA has approved an updated indication for sotatercept-csrk (WINREVAIR), an activin signaling inhibitor, for adults with pulmonary arterial hypertension (PAH) in WHO functional class III or IV. Results from the phase 3 ZENITH trial showed that sotatercept-csrk significantly reduced the risks of death, lung transplantation, and PAH-related hospitalizations compared with placebo.

WINREVAIR was initially approved based on the pivotal STELLAR study in March 2024. Today’s approval expanded the indication of WINREVAIR to include components of the clinical worsening events: hospitalization for PAH, lung transplantation and death.

In ZENITH (N=172; 86 WINREVAIR, 86 placebo), adding WINREVAIR to background therapy demonstrated a statistically significant and clinically meaningful 76% reduction in the risk of major morbidity and mortality outcomes in adults with PAH WHO functional class III or IV compared to placebo (HR: 0.24; 95% CI: 0.13, 0.43; p<0.0001). The trial’s composite primary efficacy endpoint events — time to first occurrence of all-cause death, lung transplantation or PAH-worsening hospitalization of ≥24 hours — occurred in 15 WINREVAIR-treated participants (17%) versus 47 placebo-treated participants (55%). Due to overwhelming efficacy based on the primary endpoint result, the ZENITH trial was stopped early at the interim analysis and patients were offered the opportunity to receive WINREVAIR through an open-label long-term follow-up study.

“For patients with PAH, the risk of serious events such as hospitalization, transplantation or death remains unacceptably high despite being maximally treated with traditional therapies,” said Dr. Vallerie McLaughlin, Kim A Eagle MD Endowed Professor of Cardiovascular Medicine and Director, Pulmonary Hypertension Program, University of Michigan in Ann Arbor. “Results from the pivotal ZENITH trial add to the growing body of data and support the potential for WINREVAIR as standard of care.”

Healthcare providers should monitor hemoglobin and platelets before each dose of WINREVAIR for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine if dose adjustments are required. WINREVAIR may increase hemoglobin and may lead to erythrocytosis, which if severe may increase the risk of thromboembolic events or hyperviscosity syndrome. WINREVAIR also may decrease platelet count and lead to severe thrombocytopenia, which may increase the risk of bleeding; thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion. Treatment should not be initiated if platelet count is <50,000/mm. See additional Selected Safety Information below.

The most common adverse reactions (≥10% for WINREVAIR and at least 5% more than placebo) in ZENITH were infections (67.4% vs 44.2%), epistaxis (45.3% vs 9.3%), diarrhea (25.6% vs 17.4%), telangiectasia (25.6% vs 3.5%), increased hemoglobin (15.1% vs 1.2%), rash (10.5% vs 4.7%), erythema (10.5% vs 3.5%) and gingival bleeding (10.5% vs 2.3%).The median duration of exposure was longer in the WINREVAIR group (435 days) than in the placebo group (268 days). In the WINREVAIR group, 1 patient (1%) discontinued study intervention due to an adverse event, compared with 4 patients (5%) in the placebo group.

“Merck’s leadership in PAH research is anchored in a comprehensive clinical program that continues to advance science and deliver meaningful evidence for physicians and patients,” said Dr. Joerg Koglin, senior vice president, global clinical development, Merck Research Laboratories. “This approval represents another step forward in our mission to deliver on the promise of WINREVAIR, an activin signaling inhibitor with an indication recognizing its impact to adult patients with PAH on the risk of clinical worsening events, including death, lung transplantation and PAH hospitalization.”

About ZENITH

The ZENITH study (NCT04896008) was a global, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in which 172 adult participants with PAH (WHO FC III or IV) at high risk of mortality were randomized in a 1:1 ratio to either WINREVAIR (target dose 0.7 mg/kg) (n=86) plus background PAH therapy or placebo (n=86) plus background PAH therapy administered subcutaneously once every 3 weeks.

The most common PAH etiologies were idiopathic PAH (50%), PAH associated with connective tissue diseases (CTD) (28%), and heritable PAH (11%). The mean time since PAH diagnosis to screening was 8 years. The study excluded patients diagnosed with human immunodeficiency virus (HIV)-associated PAH, PAH associated with portal hypertension, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement. Participants were on background PAH treatment, 72% on triple therapy, 28% on double therapy and 59% on prostacyclin infusion therapy. There were more participants in WHO FC III (74%) compared to WHO FC IV (26%). The REVEAL Lite 2 risk score was <9 for 2% of participants, 9 to 10 for 67% of participants and ≥11% for 30% of participants. The primary efficacy endpoint was time to first confirmed major morbidity or mortality event. Events were defined as all-cause death, lung transplantation or PAH worsening-related hospitalization of ≥24 hours. Secondary endpoints included overall survival and several additional measures.

About WINREVAIR™ (sotatercept-csrk) for injection, for subcutaneous use, 45 mg, 60 mg

WINREVAIR is FDA-approved for the treatment of adults with pulmonary arterial hypertension (PAH, WHO Group 1 pulmonary hypertension) to improve exercise capacity and World Health Organization (WHO) functional class (FC), and reduce the risk of clinical worsening events, including hospitalization for PAH, lung transplantation and death. WINREVAIR is the first activin signaling inhibitor therapy approved to treat PAH. WINREVAIR improves the balance between pro-proliferative and anti-proliferative signaling to modulate vascular proliferation. In preclinical models, WINREVAIR induced cellular changes that were associated with thinner vessel walls, partial reversal of right ventricular remodeling and improved hemodynamics.

WINREVAIR is the subject of a licensing agreement with Bristol Myers Squibb.

A team of researchers at the UCLA Health Jonsson Comprehensive Cancer Center has identified a potential new strategy to prevent, and even reverse, immune checkpoint inhibitor–induced type 1 diabetes, a rare but life-threatening side effect of cancer immunotherapy, using an existing class of autoimmune drugs.

The study, published in JCI Insight, identifies a new group of immune cells involved in the development immune checkpoint inhibitor–induced type 1 diabetes and shows that JAK inhibitors, which are already FDA-approved for conditions like psoriasis and arthritis, can stop the autoimmune attack on insulin-producing cells in the pancreas and, in some cases, even reverse the damage in preclinical models.

The findings point to a new way to protect patients from this serious endocrine-related complication of cancer immunotherapy-one that currently has no effective way to prevent or reverse its effects-without compromising the effectiveness of their cancer treatment.

“This is one of the first times we’ve found a way to intervene in these toxicities in a meaningful way,” said Dr. Melissa Lechner, assistant professor of medicine in the division of endocrinology, diabetes and metabolism at the David Geffen School of Medicine at UCLA and senior author of the study. “As more patients receive immunotherapy for early-stage and potentially curable cancers, preventing long-term autoimmune damage is becoming a critical part of survivorship care. This study brings us closer to protecting patients without compromising the life-saving benefits of their treatment.”

Checkpoint inhibitors like pembrolizumab and nivolumab have revolutionized cancer treatment by activating the immune system to attack tumors, but they can also cause serious autoimmune side effects. More than two-thirds of patients who receive these therapies experience some form of immune-related toxicity. While rare, one of the most severe is type 1 diabetes, which affects 1% to 2% of patients and is often permanent. Nearly 90% of those who develop it require ICU care for life-threatening complications and are left insulin-dependent for life.

To better understand the mechanisms underlying this type of type 1 diabetes that is triggered by immune checkpoint inhibitors, Lechner and her team analyzed immune responses in mice models to see if they could identify the immune cell populations responsible for this toxicity.

While past research has primarily focused on CD8+ T cells, the team discovered that a previously unrecognized population of immune cells called CD4+ T follicular helper (Tfh) cells plays a major role in driving the aggressive autoimmune attack on insulin-producing beta cells in the pancreas during cancer immunotherapy. These cells produce two key signaling molecules, IL-21 and interferon gamma (IFNγ), which fuel the immune attack on the pancreas.

The team then tested whether JAK inhibitors, which block the IL-21 and IFNγ pathways, could prevent the onset of immune checkpoint inhibitor–induced type 1 diabetes in mice.

They found the treatment not only blocked the effects of IL-21 and IFNγ, but they were able to reduce the number of Tfh cells and, in some cases, restore normal blood sugar levels, suggesting the potential to not only prevent but also reverse the disease.

“This is the first study to identify Tfh cells and the IL-21/IFNγ pathway as key drivers of checkpoint inhibitor–induced type 1 diabetes,” said Lechner. “Importantly, we show that this pathway can be therapeutically targeted with a drug that is already FDA-approved and widely available without weakening the immune system’s ability to fight cancer.”

The group had also previously shown that the same cell population was involved in thyroid toxicities from checkpoint inhibitors, suggesting a shared mechanism across multiple autoimmune side effects.

“These CD4+ T cells seem to play a common role in different autoimmune toxicities,” said Lechner. They could even potentially be used as a predictive biomarker to identify at-risk patients before symptoms start.”

The team is now working to launch a first-in-human clinical trial to test the approach in patients with cancer who develop diabetes after immunotherapy.

“If we can make immunotherapy safer, especially for patients with pre-existing autoimmune disease who are often excluded from trials, we can extend the reach of these therapies,” Lechner said. “And we can start to offer real solutions to the thousands of patients living with permanent side effects.”

Reference:

Nicole L. Huang, Jessica G. Ortega, Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy, JCI Insight, DOI:10.1172/jci.insight.188843.

A new population-based study published in the journal of Advances in Therapy revealed that individuals diagnosed with glaucoma may face a significantly higher risk of death and stroke when compared to their peers without the eye disease. The research analyzed health data from more than 56,000 adults aged 50 and older over a 3-year period, just before the onset of the COVID-19 pandemic.

This research retrospectively examined 14,138 individuals with newly diagnosed glaucoma in 2017 and a control group of 42,414 age- and sex-matched individuals without glaucoma from January 1, 2017, to February 1, 2020. The primary focus was overall survival, while secondary outcomes included the incidence of major cardiovascular events like stroke, heart attack, and peripheral arterial disease.

The study relied on administrative health data from the Lombardy Region and the glaucoma diagnosis was confirmed using records of antiglaucoma drug prescriptions, hospital admissions, surgical interventions, or exemption status for glaucoma-related healthcare costs.

The proportion of deaths among glaucoma patients was 11.6%, when compared to 10.5% among non-glaucoma individuals. When adjusted for age, sex, and comorbidities, glaucoma patients had a 7% increased risk of death (Hazard Ratio [HR] 1.07; 95% Confidence Interval [CI]: 1.01–1.14; p=0.015).

The risk of stroke was also elevated in the glaucoma group, with a hazard ratio of 1.10 (95% CI: 1.01–1.20), suggesting a modest but statistically significant association. No notable differences were observed between the two groups regarding the incidence of heart attack or peripheral arterial disease across the study period.

Hazard ratios for death and peripheral arterial disease varied by age group which indicated that the impact of glaucoma on systemic health risks may differ across age strata. The patients with glaucoma had markedly higher rates of chronic conditions like diabetes (16.7% vs. 11.0%) and hypertension (62.2% vs. 58.1%) when compared to those without glaucoma, highlighting the complex health profiles of these individuals.

Overall, these findings point to the need for comprehensive care in patients with glaucoma, particularly among older adults. While glaucoma is primarily considered an eye disease, this study illuminates its potential role as a marker of systemic vulnerability. 

Source:

Quaranta, L., Galbussera, A. A., Tettamanti, M., Novella, A., Pasina, L., Fortino, I., Leoni, O., Oddone, F., Giammaria, S., Kużniak, M., Weinreb, R. N., & Nobili, A. (2025). Relationships among glaucoma, cardiovascular diseases, and mortality. Advances in Therapy. https://doi.org/10.1007/s12325-025-03282-9

A case-control study of Medicare data has found that older adults with Alzheimer’s disease or other forms of dementia who were newly prescribed benzodiazepines or antipsychotics in hospice care had higher mortality compared with those not receiving these medications. The study, published in JAMA Network Open by Wang L. and colleagues, analyzed prescribing patterns and outcomes in a large population of hospice patients. Researchers noted that these medications were typically initiated about three days after hospice enrollment, with patients having an average hospice stay of over 135 days. The findings underscore the potential risks associated with psychotropic medication use in vulnerable populations with advanced cognitive decline.