- There is currently only one disease modifying therapy (DMT) approved in Australia for people with primary progressive MS, however, this is not available on the pharmaceutical benefits scheme (PBS).
- A phase 3 clinical trial of tolebrutinib in people with primary progressive MS showed that it did not delay the onset of disability progression.
- Although the trial results were not as hoped, they are still important to help us understand MS better and guide us towards more effective treatments in the future.
- Separately, tolebrutinib has not been approved for the treatment of non-relapsing secondary progressive MS in the USA at this time.
Treatments for the progressive forms of MS remain one of the greatest unmet needs. There is currently only one disease modifying therapy (DMT) approved to treat primary progressive MS in Australia, however, this is not available on the pharmaceutical benefits scheme (PBS). Recently, a new class of therapies, known as Bruton’s tyrosine kinase (BTK) inhibitors, have provided hope that there might be a new option for therapy for those living with progressive disease.
One BTK inhibitor, known as tolebrutinib, has completed phase 3 clinical trials in both non-relapsing secondary progressive MS (full results here) and primary progressive MS.
What is tolebrutinib?
Tolebrutinib is an oral BTK inhibitor that targets B cells. B cells are a type of immune cell that plays a role in the development and activity of MS. BTK inhibitors only affect B cells that have the BTK enzyme, a biological molecule that speeds up reactions within cells. By targeting B cells with the BTK enzyme, tolebrutinib reduces the activity of these cells involved in MS, while preserving other B cells involved in building immunity in the body against infections and other attacks.
Importantly, tolebrutinib can cross the blood-brain barrier to target immune cells in the brain and spinal cord, meaning that they directly impact disease-causing cells in MS. These include microglia, the resident immune cells in the brain, in which BTK promotes inflammation.
Clinical Trial for primary progressive MS
Researchers ran a large multinational phase 3 clinical trial (PERSEUS) in people with primary progressive MS, comparing treatment with tolebrutinib (one 60 mg dose per day) to placebo (a dummy medication). Participants came from a large number of countries, including Australia. Two-thirds of participants received tolebrutinib and one-third received placebo.
In this trial, worsening disability was measured in 767 people at six months using composite confirmed disability progression” (cCDP) as the main trial result. The cCDP used a number of clinical measures such as the Expanded Disability Status Scale (EDSS), the Timed 25-Foot Walk Test (measuring mobility and leg function) and the Nine-Hole Peg Test (a task that assesses fine motor skills and dexterity). This is used to show permanent worsening rather than shorter-term changes.
Researchers measured how long it took to reach the 6-month cCDP. A longer time would indicate that tolebrutinib had a positive effect.
PERSEUS results
Unfortunately, the researchers found that tolebrutinib did not delay disability progression as measured by the worsening of disability at six months. The safety profile was similar to that of tolebrutinib in previous clinical trials. This includes the risk of liver injury, so people taking tolebrutinib need to follow strict monitoring for their liver function.
Approval of tolebrutinib as a treatment for progressive forms of MS
Given these trial results, the sponsor of tolebrutinib is not pursuing registration of tolebrutinib with the US Food and Drug Administration (FDA) as a treatment for primary progressive MS.
Although the results of this trial were not as hoped, they are still important in helping us understand MS better and guiding us towards developing effective treatments in the future.
Previous trials did find that tolebrutinib reduces the rate of relapses in people with relapsing remitting MS and lowers the risk of disability progression in people with non-relapsing secondary progressive MS.
Tolebrutinib has been under review by the US FDA for the treatment of non-relapsing secondary progressive MS. However, the FDA recently announced that it will not approve tolebrutinib at this time as it’s concerned that the risk of severe drug-induced liver injury may outweigh the treatment’s potential benefits.
The FDA has provided recommendations to address these concerns, including analysis of the ongoing extension study, to characterise the impact of weekly liver safety monitoring. The treatment sponsor is exploring alternative pathways for approval in US.
Tolebrutinib is approved for use in those with non-relapsing secondary progressive MS in other parts of the world. It is currently under review by the European Medical Agency for treating non-relapsing secondary progressive MS.
Tolebrutinib is also under review by the Therapeutic Goods Administration (TGA) for treating non-relapsing secondary progressive MS in Australia.
There is a critical unmet need for treatments for non-relapsing secondary progressive MS, with no therapies currently approved in Australia.
We look forward to outcomes of the TGA review and the additional safety data for tolebrutinib as it emerges from recently completed and ongoing studies.
