Tolebrutinib – A New Era of MS Treatments Targeting Progression in Non-Relapsing MS

May 28, 2025 | Life with MS, News, Treatments, Uncategorised

Tolebrutinib is the first and only disease modifying therapy (DMT) showing positive signs of slowing progression in non-relapsing secondary progressive MS (SPMS). While current DMTs focus on dampening the inflammatory aspects of MS, this significant breakthrough heralds a potential new era of therapies which look to target the underlying progression in MS.

Currently in NZ, or globally, there is no approved treatment for patients with non-relapsing Secondary Progressive MS. Since the NZ DMT access criteria was changed in 2022, many people with SPMS who have inflammatory activity have been able to access DMTs if their EDSS is under 6.5. Siponimod (Mayzent) is still under review by Pharmac, however results indicate that those who would benefit are those with signs of inflammatory activity.

In recent years, MS research has become increasingly focussed on underlying progression, in particular, identifying smouldering lesions, slowly expanding lesions (SELs) and progression in the absence of relapses (PIRA). With this greater knowledge, researchers can target treatments towards the underlying progression.

At MSNZs MS Brain Health Seminar in July 2024, Professor Helmut Butzkueven noted the exciting potential of BTK inhibitors, in particular tolebrutinib. At the time, studies were still underway. These have now concluded and the results published.

How does Tolebrutinib work?

Tolebrutinib is an oral BTK-inhibitor, of which there are several being studied right now. Tolebrutinib inhibits an enzyme called “Bruton’s tyrosine kinase,” which works by selectively targeting B cells that have the BTK enzyme (a biological molecule that speeds up reactions within cells).

B cells are immune cells that play a role in the response that affects the brain and spinal cord in MS. BTK inhibitors do not target all B cells, just those with the BTK enzyme.

Alongside this, Tolebrutinib penetrates the brain and spinal cord, crossing the blood-brain barrier to target and regulates immune cells in the brain called microglia. It is these immune cells which researchers have shown are linked to inflammation in the brain, nerve degeneration and MS progression.

What Studies have taken place?

Three large, multi-national Phase 3 clinical trials have taken place, taking an average of 2.5 years. Researchers investigated the effects of tolebrutinib on those with relapsing MS (GEMINI 1 and 2), and non-relapsing secondary progressive MS (HERCULES).

GEMINI 1 and 2 (relapsing MS) compared whether tolebrutinib and teriflunomide (Aubagio and funded in NZ) taken as oral tablets daily, reduced relapse rated and disability progression.

HERCULES (non-relapsing secondary progressive MS) compared tolebrutinib with placebo, to assess impacts on disability progression, and new and enlarging lesions.

What are the results telling us?

The results of HERCULES now been published in The New England Journal of Medicine. 1131 participants with non-relapsing SPMS were randomly assigned to receive tolebrutinib (754 people) or placebo (377 people). Overall, researchers found that:

• tolebrutinib lowered the risk of confirmed disability progression (sustained for at least 6 months) by 31% compared with placebo.
• People taking tolebrutinib were nearly twice as likely to experience a lasting improvement in their disability than those in the placebo arm.
• Those in the tolebrutinib arm had lower rates of new or enlarging lesions compared to placebo.

Results have also been published for GEMINI 1 and 2.  974 patients with relapsing MS were enrolled in GEMINI 1, and 899 in GEMINI 2.

• Results were less favourable for those with relapsing MS with relapse rates considered as non-superior (similar) to those treated with teriflunomide.
• In the first six months of the trial, the level of disability worsened in 8.3% of people receiving tolebrutinib and 11.3% of people on teriflunomide.
• At the same time, 12.6% confirmed improvement in their disability with tolebrutinib, compared to 10.4% with teriflunomide.

Due to the studies end points being relapse rate reduction, these studies did not meet their goals. However, as observations suggest a reduction in worsening disability on teriflunomide, this doesn’t discount future investigation with alternative end points.

Were there any side effects?

• Most side effects were mild. As the trials took place during the pandemic, therefore COVID-19 was the most commonly reported side effect.
• In HERCULES, the most common side effects were urinary tract infections, falls and respiratory infections.
• In GEMINI, side effects included inflammation of the nose and throat headache, hair loss and minor bleeding
• A small percentage of participants taking tolebrutinib reported raised liver enzymes but these resolved without lingering after-effects.
• Unfortunately, one person in the HERCULES trial died from liver failure following a liver transplant, determined to be related to tolebrutinib treatment. Adverse events can happen in clinical trials, particularly in patients with weakened immune systems.

 What next?

This is an exciting development in the treatment space, and hopefully we will begin to see more treatments come available which target the underlying progression in MS. There are several other BTK inhibitor treatments also being trialled across the globe which we are watching with interest.

We caution that the safety and efficacy of tolebrutinib has not yet been evaluated by any regulatory body and is a critical step. The FDA in America has designated tolebrutinib a “breakthrough treatment” and granted fast track review status. We await the results of this review. Multiple Sclerosis New Zealand has reached out to Sanofi to understand their intentions and any timelines for applying for registration in New Zealand with Medsafe.

We know there will be a lot of interest in this treatment but caution that we do not have a timeline on when, or even if, tolebrutinib might become available in NZ. We will endeavour to keep you updated as this progresses.

We invite you to share your initial thoughts or feedback, telling us what it would mean to you, and your whānau, to access medicines which slow progression. We will look to include patient stories in future submissions. Please add your thoughts to this form.