From a frozen shoulder to cells that fight melanoma: four stories

In a phase 3 trial, a second-line drug brought a liver marker back to normal in 85% of people with primary biliary cholangitis

On 5 November 2026 Hepatology published ELSPIRE, a double-blind, placebo-controlled phase 3 trial of elafibranor in primary biliary cholangitis, an autoimmune disease in which the small bile ducts inside the liver are slowly destroyed. The usual first treatment is ursodeoxycholic acid. The trial enrolled 92 people in whom alkaline phosphatase, a blood marker of bile duct injury, stayed mildly raised on that treatment or who could not tolerate it: above the upper limit of normal but below 1.67 times that limit, a level that common definitions still count as an adequate response. Participants were randomly assigned 2:1 to elafibranor, a PPAR alpha/delta agonist, or placebo for 52 weeks.

At week 52, alkaline phosphatase was in the normal range in 85.3% of people on elafibranor and in 23.3% on placebo, a difference of 62.0 percentage points (95% CI 44.3 to 79.7). On average the marker fell by 36.5% with the drug and by 4.2% with placebo. More people on elafibranor also reached a complete biochemical response, with normal alkaline phosphatase, bilirubin, transaminases, albumin and INR. The authors reported no new safety signals.

Elafibranor already has accelerated approval in the United States and conditional approval in the European Union for adults with this disease who respond inadequately to ursodeoxycholic acid or cannot tolerate it; ELSPIRE asks whether the bar should be a fully normal value. In earlier studies a normal value went with better long-term survival without transplant, but this one-year trial of 92 people measured a blood marker, not fewer complications, transplants or deaths. Several co-authors are employees of Ipsen, which develops the drug; the abstract does not name the trial funder.

Two years after a mitral valve was replaced through a vein, leakage stayed almost eliminated, though a quarter of patients had died

On 3 November 2026 the Journal of the American College of Cardiology published two-year results of ENCIRCLE, a single-arm trial of the SAPIEN M3 system. It replaces a leaking mitral valve with a catheter brought through a vein and across the wall between the upper chambers of the heart, without opening the chest. The 299 patients had symptomatic moderate-to-severe or severe mitral regurgitation, a mean age of 75.5 years, and had been judged unsuitable both for surgery and for clip repair of the valve.

At two years, 97.0% of evaluated patients had no more than mild leakage, and 87.0% were in the two mildest heart failure classes. The Kansas City Cardiomyopathy Questionnaire, a quality-of-life score, rose by 17.2 points on average, while the six-minute walk distance did not change significantly (+9 metres). By two years 25.1% of patients had died and 23.0% had been admitted with heart failure, 35.6% combined. Disabling stroke occurred in 6.6%, clinically significant valve thrombosis in 7.1% and haemolysis needing treatment in 7.6%.

Without a comparison group the trial cannot show how much the valve changed survival in patients this frail; two-year data were available for 202 of 210 eligible patients. The trial was funded by the manufacturer, Edwards Lifesciences. In the United States the system is approved for such patients when a heart team judges them unsuitable for surgery or clip repair.

Engineered immune cells shrank tumours in 10 of 15 people whose melanoma had resisted immunotherapy

On 3 November 2026 Nature Medicine published a pooled analysis of two early trials of amsokigene autoleucel (OBX-115), a therapy made from tumour-infiltrating lymphocytes: immune cells taken from a patient's own tumour, multiplied in the laboratory and infused back. The cells are engineered to carry a membrane-bound form of interleukin-15, a signal that keeps them active, and that signal can be turned up or down with acetazolamide, an existing oral drug. This removes the need for interleukin-2, which current TIL therapy requires. All 37 participants had advanced melanoma that had progressed despite immune checkpoint inhibitors, and all received lymphodepleting chemotherapy before the cells.

No toxicity that limited treatment was reported, and there were no intensive care admissions and no treatment-related deaths. Severe drops in blood counts were common: neutropenia in 64.9% and low white cell or lymphocyte counts in 56.8% each. Among the 15 patients in the key efficacy set, tumours shrank in 10 (66.7%; 95% CI 38% to 88%), including two complete responses.

These are small single-arm trials, and response here means tumour shrinkage, not longer survival. The first patient treated developed brain swelling around a previously irradiated metastasis, after which the protocol was modified. Several authors are employees of the developer, Obsidian Therapeutics, which also funded trial-related services. A separate pivotal phase 2 cohort is under way.

In 189 trials of frozen shoulder, only two treatments had moderate-certainty support, and only in the short term

On 4 November 2026 The BMJ published a systematic review and network meta-analysis of randomised trials in adhesive capsulitis, or frozen shoulder, a painful stiffening of the shoulder joint capsule. The authors pooled 189 trials with 12,988 adults comparing 59 interventions, from injections and physiotherapy to shockwave therapy and manipulation under anaesthesia.

Moderate-certainty evidence suggested that extracorporeal shockwave therapy probably reduced pain in the short term compared with usual care, by about 2 points on a 0 to 10 scale (95% CI 0.97 to 2.97). Manipulation of the shoulder under anaesthesia probably improved forward elevation of the arm in the short term, by about 26° on its own and 33° when combined with a steroid injection into the joint. Gains in function and movement with shockwave therapy were low-certainty, and at mid-term follow-up the evidence was low or very low certainty.

About 71% of the trials behind the main results were at high risk of bias, and harms were reported too unevenly to compare safety; the authors stress that no reported harm is not evidence of no harm. Most treatment effects remain uncertain, and long-term comparisons are lacking. The authors report support from Chinese research funding programmes. Which approach suits a particular shoulder is a question for your doctor.

This article is for information only and does not replace a consultation with a doctor. Nothing in it is a recommendation to start, stop or change treatment.

Sources

• Kowdley KV, Lawitz E, Bowlus CL, et al. Treatment with elafibranor to normalize alkaline phosphatase in patients with primary biliary cholangitis and incomplete response to ursodeoxycholic acid: Results from the phase III randomized controlled ELSPIRE trial. Hepatology. 2026. PMID 42987205, doi:10.1097/HEP.0000000000001906

• Webb J, Guerrero ME, Muhammad KI, et al. Percutaneous Transcatheter Mitral Valve Replacement for Symptomatic Mitral Regurgitation: 2-Year Outcomes From the ENCIRCLE Trial. J Am Coll Cardiol. 2026. PMID 42980633, doi:10.1016/j.jacc.2026.10.047, NCT04153292

• Amaria RN, Chesney JA, Betof AS, et al. Regulatable membrane-bound IL-15 engineered TIL cell therapy for immune checkpoint inhibitor-resistant advanced melanoma: pooled analysis of phase 1 and 1/2 trials. Nat Med. 2026. PMID 42977756, doi:10.1038/s41591-026-04743-6, NCT05470283, NCT06060613

• Meng J, Liu P, Gomes NS, et al. Interventions for adhesive capsulitis: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2026;395:e101057. PMID 42982479, doi:10.1136/bmj-2026-101057