Ianalumab's Road to Approval for Sjogren's Looks Bumpier

— Pivotal studies, now published, yield mixed results; new phase III trial now underway

Findings from a pair of randomized trials in Sjögren's disease with the anti-B cell biologic ianalumab have now been published and it's no longer clear that they're sufficient to support regulatory approvals.

The two trials were called NEPTUNUS-1opens in a new tab or window and NEPTUNUS-2opens in a new tab or window and were almost identical in design. Some resultsopens in a new tab or window were presented last year at the American College of Rheumatology's annual meeting, indicating that their primary endpoint (more change from baseline in disease activity than with placebo) was met in both studies. P values approached the usual 0.05 threshold for insignificance, but pooling the data made them look stronger.

Now a fuller presentation has been published in the New England Journal of Medicineopens in a new tab or window, and it makes ianalumab look even less impressive. As reported by Thomas Grader-Beck, MD, of Johns Hopkins University in Baltimore, and colleagues, improvement in important symptoms such as salivation and dryness, relative to placebo, was not demonstrated. Also, a responder analysis failed to show any real difference between ianalumab and placebo, in terms of proportion of patients with clinically substantial improvement.

In summing up the results, Grader-Beck and colleagues made no grand claims for the drug, offering instead a short just-the-facts paragraph highlighting the primary endpoint success but also noting "the effect was small and there were no significant differences" in key secondary outcomes.

In an accompanying editorial, an Italian researcher was equally circumspect. Simone Negrini, MD, PhD, of the University of Turin, wrote that these mixed findings "should not be dismissed. Two randomized populations within one program yielded nearly identical estimates, which makes a pharmacologic effect more credible than a lone positive trial."

"In a field accustomed to disappointment, that consistency matters," he added.

But he then went on to note, like the investigators, that the effect size was small and so many other outcomes didn't show any definite effect. He concluded that it was still uncertain that ianalumab could be "a useful therapy" and the research to date represents only "a first step."

Drugmaker Novartis' plans for ianalumab in Sjögren's disease remain uncertain. The company had promised to submit marketing applicationsopens in a new tab or window early in 2026, but its annual report, released in February, pushed the timeline to the third quarteropens in a new tab or window. That ended 3 weeks ago and the company has been mum about whether it followed through.

What the company has definitely done is start a new placebo-controlled phase III trial, THALASSAopens in a new tab or window, in Sjögren's patients with high symptom burden. THALASSA was first listed in May, with a planned 570 participants and an estimated primary completion date of August 2029.

Trial Details

NEPTUNUS-1 enrolled 275 patients, randomizing them 1:1 to ianalumab or placebo given monthly. NEPTUNUS-2 had 504 patients and three arms: two the same as in the first trial, plus a third that administered ianalumab or placebo every 3 months. Changes in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI)opens in a new tab or window scores were the trials' main outcome measure, with significantly greater improvement with ianalumab versus placebo as the primary endpoint.

ESSDAI scores at baseline averaged about 12. After 1 year of treatment, scores declined by an average of 6.4 and 6.5 points with ianalumab monthly in NEPTUNUS-1 and NEPTUNUS-2, respectively, versus 5.1 and 5.5 points with placebo. The mean differences of 1.3 and 1.0 points were both statistically significant at P<0.05, although just barely (P=0.0496 in NEPTUNUS-1), due to the strong placebo effect. Pooling these data yielded a P value of 0.003 for the difference, which was still only a little greater than 1 ESSDAI point. The arm with 3-month dosing showed no difference from placebo.

Other key analyses were mostly negative for ianalumab. Chief among them was the responder analysis, which defined a clinically important response as a 5-point drop in ESSDAI scores for a given patient. The percentages with such responses with monthly dosing were as follows:

• NEPTUNUS-1: 57.4% ianalumab, 48.3% placebo
• NEPTUNUS-2: 59.8% ianalumab, 55.2% placebo

P values were not reported for these differences, but 95% confidence intervals showed considerable overlap.

Numerical trends like these were seen for a host of other outcomes, including changes in so-called ESSPRIopens in a new tab or window, SSSDopens in a new tab or window, and FACIT-Fopens in a new tab or window scores (the first two comprise a variety of patient-reported symptom measures while FACIT-F focuses on fatigue).

And as Grader-Beck reported in last year's conference presentation, Patient Global Assessment scores were significantly better in only one of the trials, and ianalumab provided little improvement in salivation for participants with low baseline flow. The published results demonstrated the latter in more detail: In NEPTUNUS-1, stimulated salivary flow was almost the same with ianalumab versus placebo, while a numerical trend favoring the drug in NEPTUNUS-2 missed statistical significance.

Adverse effects were not concerning, as the investigators and Negrini agreed. The latter wrote, "Safety through 1 year was reassuring, with no clear excess of serious adverse events or serious infections," but added that any longer-term issues will assume extra importance given the drug's modest efficacy.

Novartis has other irons in the fire besides Sjögren's with ianalumab. It has trials underway for lupus nephritis, systemic lupus, systemic sclerosis, and certain blood diseases, although for those, the company doesn't anticipate regulatory filings until late next year at the earliest.