Novartis' Remibrutinib Cut MS Relapses 35% and 31% Versus Teriflunomide, Short of the 45% to 60% Analysts Expected

After disclosing only top-line results earlier, Novartis presented the full REMODEL-1 and REMODEL-2 data for remibrutinib on Friday, Oct. 23, at the joint ACTRIMS-ECTRIMS meeting in Toronto. The results were published simultaneously in The Lancet.

The drug works. The open question is whether it works well enough.

The relapse numbers

Both trials compared remibrutinib 100 mg twice daily against teriflunomide (Sanofi's Aubagio) in patients with relapsing multiple sclerosis.

In REMODEL-1, the annualized relapse rate was 0.073 with remibrutinib versus 0.112 with teriflunomide (rate ratio 0.648, P=0.018). In REMODEL-2, it was 0.080 versus 0.116 (rate ratio 0.688, P=0.034). That works out to relative reductions of 35.2% and 31.2%.

Heinz Wiendl of the University of Freiburg, who presented the data, said the rate equates to roughly one relapse every 13 years.

MRI results were stronger. Annualized new and enlarging T2 lesions fell to 0.94 versus 2.71 in REMODEL-1 and 0.82 versus 2.77 in REMODEL-2, reductions of 65% and 70%. Gadolinium-enhancing lesions dropped 66% in both trials. The pooled share of patients with no evidence of disease activity was 55.0% versus 32.1%.

Disability progression: a mixed picture

Pooled data showed 3-month confirmed disability progression in 11.7% of remibrutinib patients versus 14.1% on teriflunomide. That is a hazard ratio of 0.80 and a P value of 0.090, not statistically significant.

Six-month confirmed progression was 7.7% versus 10.5% (hazard ratio 0.70, P=0.038).

Novartis describes the 6-month result as a 29.2% risk reduction with "nominal significance" and calls it a clinically meaningful delay in progression. The company also said more than 92% of remibrutinib patients stayed free of 6-month progression over 24 months. The company described the 3-month result, a 20.5% reduction, as a consistent positive trend.

Liver safety is the selling point

BTK inhibitors as a class have been linked to liver toxicity, and other late-stage programs have reported Hy's Law cases. Novartis said remibrutinib had none.

ALT above three times the upper limit of normal occurred in 2.0% of remibrutinib patients versus 7.4% on teriflunomide. "We haven't seen really a liver signal at all," Wiendl said.

Any adverse event occurred in 79.5% of remibrutinib patients versus 81.5%, and serious events in 6.0% versus 7.0%. Pooled discontinuations for adverse events were 3.1% versus 5.8%. Alopecia was 5.8% versus 13.5%.

Two patients died in the remibrutinib group: one from carbon monoxide poisoning on day three, one by suicide at month 12 in a patient with prior psychiatric illness. Investigators judged both unrelated to treatment. Bleeding events, a known concern for the class, occurred in 12.7% of remibrutinib patients versus 6.7% on teriflunomide; Wiendl said they were usually mild, transient and limited to skin manifestations.

Expectations and the Roche comparison

Reuters reported that analysts had expected relapse reductions of 45% to 60%. Reuters also noted the data came days after Roche released its own results for rival BTK inhibitor fenebrutinib, which showed a 55% reduction in annualized relapse rate versus teriflunomide in pooled Phase III data.

The trials are separate, not head to head. Reuters reported that Roche's drug showed significantly higher liver enzyme elevations than its comparator.

Analysts told Reuters before the readout that relapse improvements similar to Roche's would be needed to show the BTK class can beat the anti-CD20 therapies now used in MS: Ocrevus, Novartis' Kesimpta and TG Therapeutics' Briumvi. Neither company's trial used those drugs as the comparator.

Wiendl, a co-chair of the Novartis studies, played down the gap. "All in all, they might be quite similar in what they do in terms of reducing relapses and disability," he said.

Novartis frames the results as "comprehensive disease control" with a differentiated safety profile. Wiendl said the findings suggest remibrutinib "has the potential to deliver a meaningful, differentiated treatment option."

What Novartis needs this to be

Reuters reported that analysts estimate peak sales above $4 billion if the drug is approved for relapsing MS. Novartis is leaning on remibrutinib after recent trial setbacks for its heart drug pelacarsen and its muscle weakness therapy del-desiran, Reuters reported.

A 25 mg formulation, sold as Rhapsido, is already approved for chronic spontaneous urticaria and symptomatic dermographism. The 100 mg dose studied in REMODEL is higher than that approved 25 mg dose.

Novartis said it plans to seek regulatory approval for relapsing MS globally. It expects to submit in the U.S. by the end of the year using a priority review voucher.

The same 100 mg dose is also being tested in secondary progressive MS in the REMASTER trial. Whether the 6-month disability signal holds up there, and whether regulators weigh a nominal P value of 0.038 the way Novartis does, will shape how this drug is positioned against Roche's.