First Evidence of Delayed Disability Progression in Nonrelapsing Secondary Progressive Multiple Sclerosis

For the first time, a medication has been shown to delay confirmed disability progression in individuals with nonrelapsing secondary progressive multiple sclerosis (MS).

The findings involve the investigational oral BTK inhibitor tolebrutinib and come from the phase 3 HERCULES study, whose results were shared in a platform presentation at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting on Sept. 20 by Cleveland Clinic neurologist Robert Fox, MD, chair of the study’s global steering committee.

“In delaying onset of confirmed disability progression by 31% relative to placebo, tolebrutinib met the HERCULES trial’s primary endpoint,” says Dr. Fox, staff in the Mellen Center for Multiple Sclerosis Treatment and Research and Vice Chair for Research in Cleveland Clinic’s Neurological Institute. “This represents very real progress on the path to effective therapy to delay disability progression in patients with secondary progressive MS, a population with substantial unmet need for effective therapies.”

While the results are encouraging, tolebrutinib still needs to undergo regulatory review for potential commercial approval, notes Dr. Fox.

Late-stage trial results with a new class of MS therapy

Tolebrutinib is a brain-penetrant member of a new class of oral drugs known as Bruton tyrosine kinase (BTK) inhibitors. It acts by modulating B lymphocytes and activated microglia in the central nervous system, which is believed to address at least some of the underlying mechanisms of disability accumulation in MS associated with neuroinflammation in the brain and spinal cord.

The agent has been assessed in phase 3 studies for the treatment of various forms of MS. In two phase 3 companion trials to HERCULES — GEMINI 1 and GEMINI 2, both in patients with relapsing forms of MS, and both presented at the ECTRIMS meeting as well — tolebrutinib failed to meet the primary endpoint of reducing the annualized relapse rate compared with active therapy with teriflunomide.

However, in the GEMINI trials tolebrutinib demonstrated a delay in the secondary endpoint of onset of confirmed disability worsening. “This secondary finding from the GEMINI studies is supportive of the primary results from HERCULES and suggests a consistent impact on disability accumulation with this therapy,” Dr. Fox observes.

The ongoing phase 3 PERSEUS study is assessing time to onset of confirmed disability progression with tolebrutinib therapy in patients with primary progressive MS. Results are expected as early as 2025.

Design of HERCULES

The phase 3 HERCULES trial (NCT04411641) focused on a patient population distinct from that of GEMINI 1 and 2 — namely, individuals with nonrelapsing secondary progressive MS.

A total of 1,131 such patients (aged 18-60 years) were randomized from multiple centers around the world, including Cleveland Clinic. All patients had documented disability progression in the 12 months before screening but had no clinical relapses in the 24 months before screening. All had an Expanded Disability Status Scale (EDSS) score from 3.0 to 6.5 at screening.

Participants were randomized 2:1 to oral tolebrutinib 60 mg daily (n = 754) or placebo (n = 377) in a double-blind fashion. Treatment lasted 24 to 48 months, with all patients continuing until a prespecified number of six-month confirmed disability progression (CDP) events were observed.

The primary endpoint was time to onset of six-month CDP, defined as an increase from baseline EDSS score of ≥ 1.0 point (for baseline scores ≤ 5.0) or ≥ 0.5 points (for baseline scores > 5.0) confirmed over at least six months.

Safety and tolerability were assessed in terms of adverse event rates, and secondary endpoints included the following:

• Time to onset of three-month CDP (defined as for six-month CDP, except over at least three months)
• Time to onset of six-month confirmed disability improvement (CDI), defined as a reduction from baseline EDSS score of ≥ 1.0 point confirmed over at least six months
• Number of new or enlarging T2 lesions on MRI
• Percentage change in brain volume

Key efficacy results

The tolebrutinib and placebo groups were highly comparable on all baseline characteristics. Mean patient age in both groups was 48.9 years, and mean EDSS scores were 5.59 in the placebo group and 5.49 in the tolebrutinib group (median score was 6.0 in both groups). About three-quarters of patients in each group had been on one or more prior disease-modifying therapies. The proportion of patients completing the trial was 77% in both groups.

Over a median 45 months of follow-up, the cumulative incidence of six-month CDP (primary endpoint) was 26.9% in the tolebrutinib group versus 37.2% in the placebo group (hazard ratio = 0.69; 95% CI, 0.55-0.88; P = .0026).

A similar risk reduction was seen in time to three-month CDP: 32.6% had reached this endpoint by 45 weeks in the tolebrutinib group versus 41.5% in the placebo group (P = .013).

Notably, a significantly higher share of patients achieved improvement in disability with tolebrutinib therapy, with a six-month CDI rate of 10.0% versus 5.0% with placebo (P = .021).

Tolebrutinib was associated with significantly fewer new/enlarging T2 lesions versus placebo (annualized rate of 1.8 vs. 2.9; P = .011), but there was no significant difference between groups in brain volume loss, which was low in both groups.

Safety findings

Rates of adverse events were broadly comparable between the treatment groups, with a slight increase in respiratory infections in the tolebrutinib group. Treatment-emergent adverse events led to treatment discontinuation in 3.9% of the tolebrutinib group versus 2.9% of the placebo group.

Elevated alanine aminotransferase (ALT) levels (> 3 times upper limit of normal) were observed in 4.1% of tolebrutinib recipients versus 1.6% of placebo recipients. This included peak ALT increases to > 20 times the upper limit of normal in 0.5% of tolebrutinib recipients, all of which occurred within the first three months of treatment and most of which resolved without sequelae.

“These liver enzyme findings prompted implementation of frequent liver monitoring during the first three months of treatment midway through the trial in order to allow early detection of ALT increases to prevent rare cases of very high ALT spikes,” Dr. Fox notes. “Liver enzyme elevations have been reported with other BTK inhibitors in the setting of MS as well, so this merits vigilance around the liver effects of these therapies.”

Regulatory consideration expected soon

Whereas more than 20 disease-modifying therapies are approved by the FDA to treat relapsing forms of MS, no treatments are currently approved for nonrelapsing secondary progressive MS.

“Patients with this secondary progressive form of disease experience a gradual but relentless worsening of function and increase in disability over time,” Dr. Fox explains. “A means to slow this disability progression is desperately needed. These findings from HERCULES suggest that tolebrutinib could potentially be the first approved treatment for this group of patients.”

Clinical trial data for the drug are expected to be submitted for FDA review soon, with a possible decision on potential approval coming as early as 2025.

The HERCULES trial was funded by Sanofi, developer of tolebrutinib. Dr. Fox reports consulting for, and receiving research support from, Sanofi and a number of other pharmaceutical companies.