The Race to Keep Muscle on GLP-1s Reaches Phase 2

The GLP-1 era has a known flaw, and it is written in body composition: when weight comes off fast, not all of it is fat. Some of it is lean mass, and for older patients that can cost function. A whole field is now racing to protect the muscle while the fat leaves. Sironax's entry just passed a milestone that tells you the race is real, and nothing yet about who is winning.

The milestone

Sironax announced on October 13, 2026 that FORGE-LM, its global phase 2 trial, has reached approximately 50 percent of targeted patient enrollment. The candidate is SIR4156, which the company describes as a first in class, orally active, allosteric activator of NAMPT, an enzyme in the main pathway cells use to make NAD+. The detail that matters most is easy to miss in the headline: SIR4156 is not being tested on its own. Every participant receives semaglutide, the drug sold for weight loss as Wegovy, and the randomized comparison is SIR4156 plus semaglutide against placebo plus semaglutide. The question is whether a pill makes the weight a GLP-1 drug takes off better quality weight.

What the company claims

The release makes two kinds of claims. One is about the trial: enrollment is about half done and the study "remains on track." The other is about the drug. NAD+ levels fall with age and metabolic dysfunction, and by restoring them, the company says, SIR4156 "has the potential" to preserve lean muscle and reduce metabolically harmful fat. The evidence offered for that second claim is entirely preclinical. In multiple animal models, according to Sironax, SIR4156 produced preferential fat loss, lean mass preservation, reduced muscle atrophy, and improved physical performance, and the company presented mouse data at the Aging Research and Drug Discovery meeting in Boston. Its own fine print concedes the gap: the safety and efficacy of SIR4156 in humans "have not yet been established," and preclinical results "may not be predictive of clinical outcomes."

How it will be measured

The trial's public record on the Australian New Zealand Clinical Trials Registry, number ACTRN12626001033336, fills in the rest. Adults aged 18 to 75 with a body mass index of 30 or more, and without diabetes, are randomized to SIR4156 tablets at 100 mg or 200 mg twice daily, or matching placebo, for 24 weeks. Semaglutide is injected once a week and stepped up on the approved schedule, from 0.25 mg to the 2.4 mg maintenance dose from week 17. The target sample size is 113 people, so half enrolled means somewhere around 55 to 60 participants.

The registered primary outcome is the percent change in total body fat mass from baseline to week 24, measured by DXA, a low dose X ray scan that separates fat, lean tissue, and bone. Lean mass is a secondary objective, alongside body weight, safety, tolerability, and drug levels. That ordering matters. The study is designed first to show that adding SIR4156 removes more fat than semaglutide alone. Whether it spares muscle is a question the trial will report on, not the one it is built to settle.

What half enrolled means

It means half enrolled. Enrollment is logistics: sites open, patients screened, doses started. It carries no information about whether SIR4156 preserves a gram of muscle, because no efficacy data has been reported, and in a blinded trial that is still recruiting, nobody outside an unblinded safety committee would have seen any. Reading one as a result is the single most common error in biotech coverage, and this page declines to make it. It is the fifth check in our guide to reading a health study in five minutes: a press release with no data table is not settled science.

Enrollment is not a result. A trial at 50 percent recruited has answered zero questions about the drug.

What is verified, and what is not

Independently checkable: the trial exists, it is registered, it has ethics approval from the Bellberry Human Research Ethics Committee in Australia, and the registry's design matches the company's description. Not checkable from outside the company: the 50 percent figure itself. The registry's accrual field still reads one participant, but that record was last updated on August 21, 2026, so it is stale rather than contradictory. The registry also labels the trial as retrospectively registered. The first participant was enrolled on May 1, 2026, and the record was registered on August 21. That is common, but registering before the first dose is the stronger standard, because it locks the endpoints in before any data exist. One more loose end: the registry describes 24 weeks of treatment, yet its biomarker schedule mentions a maintenance phase running to week 48, which the public record does not explain. As for the animal results, this site found them only in a conference presentation and the company's release, not in a peer reviewed paper.

The limits, even if it works

Suppose the readout is positive. Twenty four weeks is short; in the STEP 1 trial, semaglutide's weight loss did not bottom out until week 60. With about 113 people split across two doses and a placebo arm, each comparison is small. DXA lean mass includes water and organs as well as muscle, and it says nothing about strength. People with diabetes are excluded, so any result would not automatically carry over to them.

The lean mass question also has a trap built into it. In the STEP 1 body composition substudy of 140 participants, semaglutide reduced total lean mass in absolute kilograms even as lean mass rose as a share of body weight. A drug can look muscle sparing on the proportional measure while people still lose muscle. Any claim from FORGE-LM should be read in kilograms first. Safety is open as well: Sironax has a poster at ObesityWeek 2026 assessing the carcinogenicity risk of SIR4156 in obesity, which shows that cancer risk is on the agenda for a drug designed to raise cellular NAD+.

What comes next

Three dates to watch. November 14, 2026, when the carcinogenicity poster is scheduled at ObesityWeek in a session on preclinical models and emerging obesity therapeutics. December 31, 2026, the registry's anticipated date for the last participant enrolled. June 30, 2027, the anticipated date of last data collection, which puts a topline readout no earlier than mid 2027 if the schedule holds. When it comes, the questions, in order: did fat mass fall more with SIR4156 than with semaglutide alone; did lean mass hold up in absolute kilograms and not just as a share; did either dose move strength or function; and was the safety profile clean. For a reminder that muscle also responds to what people do, not only what they take, see our look at the IMPACT trial on building muscle after 55. FORGE-LM is now on this site's watch list, filed under "interesting question, no data yet," which is where phase 2 recruitment announcements belong.