Sanofi Submits NDA for Tolebrutinib in Multiple Sclerosis Following Mixed Phase III Results

On September 2, Sanofi released the phase III clinical data of its BTK inhibitor tolebrutinib for the treatment of multiple sclerosis (MS). Tolebrutinib met the primary endpoint in the phase III study named HERCULES, but failed to meet the primary endpoint in the two phase III clinical trials, GEMINI 1 and GEMINI 2. Sanofi executives stated that based on this clinical data, they would submit a new drug application for tolebrutinib to the FDA.

Tolebrutinib is a BTK inhibitor that Sanofi brought in for $765 million in 2017. The drug was fully acquired by Sanofi when the company purchased Principia Biopharma for $3.7 billion in 2020. It is primarily used to treat relapsing multiple sclerosis. According to reports, tolebrutinib can bind to BTK in microglial cells, preventing the activation of microglial cells and reducing the release of pro-inflammatory factors from these cells. Additionally, it modulates the function of B cells located in both peripheral and central nervous systems (CNS) by inhibiting B cell proliferation, maturation, autoantibody and cytokine production, antigen presentation, and T-cell co-stimulation. Through its dual mechanism on microglial cells and B cells, tolebrutinib can exert therapeutic effects both peripherally and in the CNS, preventing the recurrence of multiple sclerosis.

Among the competitive landscape where numerous MNCs are betting on BTK inhibitors for the treatment of autoimmune diseases, Sanofi highly values and is optimistic about the therapeutic potential of tolebrutinib.

MS is an autoimmune disease that occurs in the central nervous system, caused by the immune system attacking the myelin sheath. The inflammation and tissue damage resulting from the disease disrupt the normal functions of the brain, optic nerves, and spinal cord. Approximately 2.5 million people worldwide are affected, with the primary age of onset being between 20 and 40 years old. Currently, there is no curative therapy available.

Based on the pathogenesis, previous treatments mostly targeted the acute focal inflammation of MS, effectively reducing its relapse rate and the number of new/enlarged MRI lesions. However, clinically, it was still unable to prevent the accumulation of disability and brain volume loss (BVL) in patients, nor could it provide targeted treatment for relapsing MS. The remission phase of relapsing MS can last for months or even years, but over time, many patients gradually transition to Secondary Progressive MS (SPMS), during which the disease continues to progress.

According to the information disclosed by Sanofi, among the three Phase III clinical trials of tolebrutinib for the treatment of multiple sclerosis (MS), the HERCULES study involved patients with non-relapsing secondary progressive MS, while the other two Phase III studies (GEMINI 1 and 2) focused on relapsing MS treatment.

HERCULES Phase III Study Meets Primary Endpoint, Showing Positive Results: Sanofi's Oral Brain-Penetrant BTK Inhibitor Tolebrutinib Delays Confirmed Disability Progression (CDP) in Non-Relapsing Secondary Progressive MS (nrSPMS) Patients Compared to Placebo. In the HERCULES study, nrSPMS was defined at baseline as SPMS with an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5 and no clinical relapses in the past 24 months. Preliminary analysis of liver safety is consistent with previous clinical study data of tolebrutinib.

GEMINI 1 and 2 Phase III clinical trial results showed that, compared with Sanofi's already approved MS treatment drug Aubagio, tolebrutinib failed to achieve the primary endpoint of reducing the annualized relapse rate (ARR) in patients with relapsing MS. However, an analysis of the key secondary endpoint, based on pooled data of 6-month confirmed disability worsening (CDW), indicated that treatment with tolebrutinib significantly delayed the time to onset of disability progression.

In August 2020, Sanofi announced a $3.7 billion acquisition of Principia Biopharma. This acquisition gave Sanofi full ownership of the BTK inhibitor tolebrutinib, as well as another oral BTK inhibitor in Phase III development, rilzabrutinib, which holds promise for treating pemphigus, and a topical medication for immune-mediated diseases that re-entered Phase I development.

However, tolebrutinib is the centerpiece of Sanofi's acquisition. This $3.7 billion acquisition will allow Sanofi to avoid paying Principia potential fees related to the global exclusive license of tolebrutinib. Sanofi also stated that this acquisition would make the commercialization of tolebrutinib more efficient and expand the drug’s development scope to other central nervous system diseases and therapeutic areas.

Before this acquisition was finalized, Sanofi released the Phase II clinical data of tolebrutinib, which showed that the drug could reduce new lesions in MS patients by more than 85%. This prompted Sanofi to initiate four Phase III clinical trials in different groups of multiple sclerosis patients. Analysts at Jefferies also predicted at the time that if tolebrutinib succeeded in Phase III clinical trials, its global sales could reach up to $2 billion.

However, the good times didn't last long. In June 2022, the FDA suspended the Phase III clinical trial of tolebrutinib due to reported cases of drug-induced liver injury. As a result, Sanofi paused the clinical recruitment for this drug at U.S. trial sites and discontinued dosing for participants who had been receiving treatment for less than 60 days.

In addition, Sanofi's plan for tolebrutinib includes not only multiple sclerosis but also myasthenia gravis.

However, there are already pioneers in the myasthenia gravis market who have captured significant market share. Alexion, a subsidiary of AstraZeneca, received approval for the C5 complement inhibitor Soliris in 2017 and later obtained approval for Ultomiris in 2022. Both drugs can be used to treat refractory generalized myasthenia gravis positive for anti-acetylcholine receptor (AChR) antibodies. Between these two approvals, argenx also received the green light to market its new drug Vyvgart in the United States. Meanwhile, UCB's two molecular drugs for myasthenia gravis, zilucoplan and rozanolixizumab, have been approved. Johnson & Johnson is not far behind, as its new drug nipocalimab reached the primary endpoint in Phase III clinical trials in 2024.

After reviewing the competitive landscape for this indication, Sanofi halted the Phase III clinical trial of tolebrutinib for the treatment of myasthenia gravis in February 2023. To recoup the $3.7 billion acquisition cost, Sanofi can only pin its hopes on the clinical success of tolebrutinib in treating multiple sclerosis.

Currently, the indications for BTK inhibitors are mostly concentrated in the field of hematological tumors. Due to the intense competition in this area, some pharmaceutical companies have begun to shift their focus to another promising field for BTK inhibitors: autoimmune diseases. Among these, multiple sclerosis is a key area where companies are actively positioning themselves.

Currently, no BTK inhibitors have been approved for the MS indication, but in terms of clinical progress, aside from tolebrutinib, Roche's fenebrutinib and Novartis's remibrutinib are among the leading candidates in the new drug pipelines heavily invested in by numerous multinational corporations (MNCs).

Merck's Evobrutinib was also highly anticipated. However, in December 2023, Evobrutinib failed to outperform Sanofi's Aubagio in two Phase III multiple sclerosis clinical trials, leading to the termination of the development of Evobrutinib.

In China, Hansoh Pharmaceutical introduced LP-168, a BTK inhibitor from Guangzhou Lupo Pharmaceuticals, in August this year. In the field of autoimmune diseases, LP-168 is being developed for indications primarily focused on multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD). Preclinical studies have already demonstrated its good safety profile and potential efficacy.

For Sanofi, despite two clinical trial failures of tolebrutinib, Houman Ashrafian, head of the company's research and development department, stated that they will promptly reach out to the FDA. Based on the successful data from HERCULES, they aim to discuss the approval application for a treatment drug for non-relapsing secondary progressive MS.

When asked whether Sanofi had abandoned the new drug application for tolebrutinib in treating relapsing MS, Ashrafian stated that the company would definitely prioritize secondary progressive MS.

Currently, Sanofi is also conducting another Phase III clinical trial on tolebrutinib, named PERSEUS, for primary progressive MS, with results expected to be announced next year.