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Medscape
4 days ago
- Health
- Medscape
Experimental MS Drug Nearly Eliminates Disease Activity
PHOENIX — Frexalimab, a second-generation anti-CD40 ligand monoclonal antibody provides extended tight control of multiple sclerosis (MS) whether measured by relapse or brain imaging at 2-year follow-up, results of an open-label extension (OLE) of a phase 2 trial showed. 'At week 96, there was almost complete suppression of new gadolinium-enhancing lesions with very similar pattern seen with new or enhancing T2 lesions,' said study investigator Stephen Krieger, MD, professor of neurology, Icahn School of Medicine at Mount Sinai, New York City. Two phase 3 international studies with this drug are already enrolling. 'Part of the interest in frexalimab and anti-CD40 therapies is the idea that one can modulate both B- and T-cell activity without cell depletion,' explained Krieger, who presented the long-term open-label data on May 29 at the Consortium of Multiple Sclerosis Centers (CMSC) 2025 Annual Meeting. Near Complete Disease Suppression The latest data suggest frexalimab is fulfilling its promise. Over follow-up to date, there has been nearly complete suppression of gadolinium-enhancing (Gd+) lesions on MRI among those taking the dose now being tested in the phase 3 trials. At 2 years, with an annualized relapse rate of 0.08%, 92% of patients were relapse-free. The randomized portion of this phase 2 trial attracted attention when it was published a year ago in The New England Journal of Medicine , but the 2-year results showed that the efficacy and safety observed at 12 weeks persist. In the controlled trial, 129 patients with relapsing MS were randomized to 300-mg, 400-mg, 600-mg, or 1200-mg frexalimab or matching placebos. Suppression of Gd+ lesions was the primary endpoint. At 12 weeks, the adjusted mean of new Gd+ lesions was 1.4 in the combined placebo groups but 0.3 in the 300-mg frexalimab group and 0.2 in the 1200-mg group. Of those who participated in the randomized portion of the phase 2 trial, 97% continued into the long-term OLE. The OLE consisted of two arms: 1200-mg frexalimab administered intravenously every 4 weeks or 300-mg frexalimab administered subcutaneously every 2 weeks. At the end of 2 years, when 82% of those enrolled in the OLE were still on medication, the adjusted mean for new T1-weighted Gd+ lesions ranged from 0.1 to 0.3 across study arms whether on continuous frexalimab or switched from placebo to frexalimab. For those who were initiated on the 1200-mg dose in the controlled portion of the trial and remained on this dose for the OLE, the mean was 0.1. For the secondary endpoint of new or enlarging T2 lesions, the suppression at 2 years was almost the same. Again, the adjusted mean for new lesions across all arms ranged from 0.1 to 0.3. For those receiving the 1200-mg dose, the mean was 0.2. Mean T2 lesion volume increased in the placebo arm but not in the treatment arms during the randomized phase. After entering the OLE, T2 lesion volume fell in placebo patients now on active therapy. In the 1200-mg arm, the fall in lesion volume during the randomized phase continued into the first 24 weeks of the OLE. After 24 weeks, the lesion volume remained suppressed with no return toward baseline. Those initiated on placebo never caught up after switching to frexalimab. Relapse Rare — 2% at 96 Weeks On the 1200-mg dose of frexalimab, only 8% had any relapse recorded over the extended follow-up. In half, there was a single relapse. Only 2% had three or more relapses. While the Expanded Disability Status Scale score declined slightly among placebo patients once started on active therapy, there was no change from baseline through 96 weeks in patients started on any active therapy. As postulated by earlier preclinical and clinical studies, frexalimab had no effect on lymphocyte counts over time. Over the 96-week follow-up, levels of immunoglobulins remained unchanged, according to Krieger who showed graphs with straight lines for these values over the course of the OLE. Due to the potential of suppressing activation of both T and B cells over time, anti-CD40 therapies have long been considered a promising mechanism for control of MS. However, clinical development of first-generation drugs was abandoned because of an association with thromboembolism. 'Frexalimab has been engineered to avoid these events through a change in the Fc receptors with reduces downstream inflammatory events,' said Krieger. The long-term data support this premise. Over 2 years, there was one pulmonary embolism, but this exception was observed in a patient with a viral illness and a genetic predisposition for an inflammatory response, according to Krieger. When surveying other adverse events, 'nothing jumps out' in the OLE relative to the randomized phase. One potential exception is a rise in liver function tests observed in two (4%) patients on the 1200-mg dose. Only one of these patients discontinued therapy, and the levels returned to normal over time in both. The effects of the anti-CD40 mechanism on both the adaptive and innate immune systems suggest frexalimab might offer efficacy for both progressive and relapsing MS. In the ongoing phase 3 program, one of the trials (FREXALT) is enrolling patients with relapsing MS. The other (FREVIVA) is enrolling patients with progressive disease. Fulfilling its Promise Commenting on the results, Amit Bar-Or, MD, Chief of the Multiple Sclerosis Division, the Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, described frexalimab as 'a very interesting drug.' He agreed that the CD40 ligand is a promising target in MS but cautioned that these phase 2 data cannot answer the most interesting questions. This includes the more robust evidence of safety and efficacy from phase 3 trials, but it remains unclear whether the benefits extend beyond controlling relapsing disease. 'I think there is particular interest in whether it will also show extended benefit in progressive MS, and this will be a major focus of interest from the next set of studies,' Bar-Or said.
Wall Street Journal
03-06-2025
- Health
- Wall Street Journal
How ‘Inflammaging' Drives Cancer—and Points to New Treatments
People are more likely to get cancer as they age. Dr. Miriam Merad has an unconventional idea of how that might be reversed: using allergy drugs and other seemingly unlikely medications to damp a condition known as 'inflammaging.' The immunologist and oncologist has spent years examining malignant tumors to learn why people over age 50 account for nine in 10 cancer diagnoses in the U.S. She and her research team at the Icahn School of Medicine at Mount Sinai in New York City have homed in on an answer: the aging immune system. Their studies of individual immune cells in human lung tumors, as well as in old mice, have revealed how chronic, or pathogenic, inflammation in older people—dubbed inflammaging—interferes with the immune system and fuels cancer growth.
Medscape
16-05-2025
- Health
- Medscape
Atopic Dermatitis Linked to Higher Odds of NMSC
SAN DIEGO — Patients with atopic dermatitis (AD) are at a significantly higher risk for nonmelanoma skin cancer (NMSC), although the overall risk remains low, a new retrospective database study found. Compared with patients without AD, the odds of NMSC in patients with AD were 1.53 times higher in an adjusted analysis (odds ratio [OR], 1.53; 95% CI, 1.17-2.01; P < .05), according to a study of 2021 national survey data presented here at the annual meeting of the Society for Investigative Dermatology. 'The strength of that association surprised us, as well as the consistent findings across various demographic groups. It adds weight to the theory that AD isn't just a quality-of-life disease but may have more serious systemic consequences,' said study lead author Lara Shqair, medical student at the Icahn School of Medicine at Mount Sinai, New York City, in an interview with Medscape Medical News . Other studies have examined possible relationships between AD and NMSC. A 2024 study using US claims data linked any AD and moderate to severe AD to higher rates of NMSC (relative risk, 1.32; 95% CI, 1.30-1.35 and 1.36; 95% CI, 1.12-1.65, respectively). And a 2023 study found that among various malignancies in patients with moderate to severe AD, incidence rates were highest for NMSC (moderate AD: 4.6; 95% CI, 3.9-5.5; severe AD: 5.9; 95% CI, 3.8-9.2). However, 'what was missing was a large, nationally representative study that could give us a clearer picture of this relationship in the general United States population,' said Shqair, who presented the results at the meeting. That's where the new research comes in. Shqair and colleagues evaluated the association between AD and NMSC via 29,116 participants — 7.4% with self-reported AD and 2.7% with NMSC — in the 2021 National Health Interview Survey. Overall, an estimated 3.6 million cases of basal cell carcinoma and 1.8 million cases of squamous cell carcinoma — the two most common types of NMSC — are diagnosed in the United States each year. In an unweighted analysis, 2.0% of the non-AD population and 2.8% of the AD population had NMSC ( P < .05). After researchers weighted the data for age, sex, race, insurance type, education level, and NMSC prevalence, they determined that patients with AD had a higher risk for NMSC. Why might AD and NMSC be related? One possibility is that chronic skin inflammation promotes cancer through local immune dysregulation, Shqair said. Another possibility is that systemic immunosuppressive treatments could increase their risk, 'and there's also the role of barrier dysfunction and transcutaneous sensitization, potentially allowing more exposure to carcinogens,' she added. In the big picture, she said, excess risk is likely due to 'a combination of biological, treatment-related, and behavioral factors.' The researchers also found that women (63% of the AD cases) and patients with private insurance (64%) were more likely to have AD. In their adjusted analysis, AD was linked to higher levels of education (some college education, OR, 0.47; 95% CI, 1.18-1.83; P < .05, and holding a professional degree (OR, 2.41; 95% CI, 1.85-3.13; P < .05) vs high school degree or lower. 'People with more education may be more proactive about their health and more likely to seek dermatologic care,' Shqair said. Other factors may be at play 'such as differences in health literacy, insurance coverage, trust in the medical system, and the ability to take time off work or afford specialized care.' The study's overall message is that 'dermatologists should be aware that patients with AD, especially those with severe or long-standing disease, might be at elevated risk for NMSC,' she said. The new study complements previous analyses and is consistent with their findings, said Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Connecticut, who was not involved in the research. The apparent extra risk 'indicates patients with AD may require careful education on sun protection and may need to undergo routine skin screenings on a consistent basis,' Bunick told Medscape Medical News . 'I recommend a combination of education around risk of NMSC and the need for sun protection and the strict avoidance of tanning beds.'
