The positive readout in patients with non-relapsing secondary progressive multiple sclerosis comes on the heels of back-to-back failures in which tolebrutinib was unable to improve relapse rates in patients with relapsing MS.
Sanofi on Friday announced that its investigational BTK inhibitor tolebrutinib delayed the onset of disability progression by 31% in patients with non-relapsing secondary progressive multiple sclerosis.
The results come from the Phase III HERCULES study, a double-blinded randomized trial that compared daily oral tolebrutinib against placebo in terms of confirmed disease progression at six months, defined using scores in the expanded disability status scale.
Friday’s readout from HERCULES also showed that 10% of patients on tolebrutinib experienced confirmed disability improvement, versus around 5% in the placebo arm. This corresponded to an 88% increase in the likelihood of improvement, with a nominal p-value of 0.021, according to Sanofi.
In terms of safety, preliminary data from HERCULES pointed to a “slight increase” in adverse events among patients treated with tolebrutinib. Of the patients treated with the BTK inhibitor, 4.1% saw liver enzyme elevations greater than thrice the upper limit of normal, as compared with only 1.6% among placebo comparators. “All but one” case of liver enzyme elevation resolved without medical intervention.
One patient in the tolebrutinib arm underwent liver transplantation and died due to complications related to the surgery. This fatality occurred after Sanofi revised its protocol to have more stringent and frequent monitoring, which has since “mitigated such serious liver sequelae.”
Tolebrutinib “has demonstrated its ability to delay disability by targeting underlying drivers” of non-relapsing secondary progressive multiple sclerosis (nrSPMS), Houman Ashrafian, Sanofi’s head of R&D, said in a statement. The company will bring these finding to global regulatory authorities, with submissions set to start in the second half of 2024.
Jefferies analyst Peter Welford called HERCULES’ readout “promising” in a note to investors. “We view data as positive to enable global filings and approvals given current unmet need for nrSPMS with no effective drugs available.”
Importantly, Friday’s findings from HERCULES now makes tolebrutinib a “de-risked $2-3bn opportunity,” Welford wrote.
Designed to be administered orally, tolebrutinib is a small molecule inhibitor of the BTK protein, which under healthy circumstances is important for the development and activity of antibody-producing B cells. Tolebrutinib’s mechanism of action allows it to suppress B cells and the disease-driving microglia.
Sanofi secured the rights to tolebrutinib in August 2020, when it acquired Principia Biopharma for almost $3.7 billion. The drug candidate has since become a pillar of Sanofi’s multiple sclerosis program, alongside the late-stage antibody frexalimab and the Phase II RIPK1 inhibitor oditrasertib.
However, tolebrutinib’s clinical development has not been without its challenges.
In June 2022, the FDA slapped a partial clinical hold on the drug and suspended enrollment in its Phase III trials due to drug-induced liver injuries. Earlier this month, Sanofi reported back-to-back Phase III failures for tolebrutinib, which was unable to significantly improve relapse rates in the patients with relapsing forms of MS.
