Sanofi's tolebrutinib cuts MS progression by 31% in trial

Sanofi has bolstered the case for its oral BTK inhibitor tolebrutinib as a treatment for multiple sclerosis (MS), due to be filed for approval in the latter half of this year, with new data in a secondary progressive form of the disease.

Data from the HERCULES trial presented at the ECTRIMS conference in Copenhagen, Denmark, today showed that tolebrutinib was able to delay the time to six-month disability progression by 31% compared to placebo in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS).

In addition, the proportion of patients with a confirmed improvement in disability doubled to 10% from 5% in the control arm, which HERCULES steering committee chair Robert Fox of the Cleveland Clinic in the US said reflects tolebrutinib's ability to "target the biological processes driving disease progression in the brain."

While on the whole, tolebrutinib was well-tolerated, there was a higher proportion of elevated liver enzymes with the drug compared to placebo, 4.1% versus 1.6%, which can indicate liver toxicity.

Last year, the FDA placed a partial clinical hold on tolebrutinib's phase 3 trials after cases of drug-induced liver injury were observed. Elevated liver enzymes have also been seen with other BTK drugs, and Sanofi said that in HERCULES all but one case resolved with further treatment.

Sanofi revealed the top-line result from HERCULES a few weeks ago, noting that tolebrutinib is the only drug in the oral BTK inhibitor class to have shown an improvement in disability progression in nrSPMS. However, two other trials in relapsing forms of MS – GEMINI 1 and 2 – were unable to show an improvement over Sanofi's older therapy Aubagio (teriflunomide).

The company said at the time it intended to press ahead with regulatory filings for the drug despite the GEMINI failings, focusing on the nrSPMS data.

There is a much greater need for new therapies for progressive forms of MS than for relapsing forms of the disease. While relapsing forms are characterised by sudden attacks associated with advancing disability, in non-relapsing patients, the decline is more "insidious," said Fox.

Sanofi is also running a fourth phase 3 trial called PERSEUS in patients with primary progressive MS (PPMS). Earlier this year, it abandoned its development in another neuromuscular disorder – myasthenia gravis – blaming commercial considerations.

"With no treatment options currently available for the broad population of patients with secondary progressive multiple sclerosis, tolebrutinib has demonstrated its ability to delay disability by targeting underlying drivers of the disease," commented Houman Ashrafian, Sanofi's head of R&D.

"We look forward to discussing these results with healthcare authorities and are eager to see the results of tolebrutinib in primary progressive MS when they become available next year."

Tolebrutinib is one of several oral BTK drugs that have been in clinical development for MS, alongside Merck KGaA's evobrutinib, Roche's fenebrutinib, Novartis' remibrutinib, and InnoCare Pharma's orelabrutinib.

GlobalData has previously suggested that tolebrutinib could be the leading BTK inhibitor for MS by 2030, with forecasted sales of approximately $2.6 billion across seven of the largest pharma markets, although that prediction was made before the failure of the GEMINI studies was disclosed.