While the EU saw rapid-fire approvals in the multiple sclerosis space last month, the innovations centered mostly on improving existing approaches. Which areas of multiple sclerosis treatment need more options?
At the end of March, the EMA made key decisions on three treatments for multiple sclerosis (MS), a chronic neurodegenerative disease affecting 2.5 million people worldwide.
The regulator greenlit Kesimpta, a drug developed by Novartis and licensed from the Danish biotech Genmab. The EMA also gave the nod to a subcutaneous version of an approved intravenous drug from Biogen called Tysabri. Finally, the EMA’s Committee for Medicinal Products for Human Use (CHMP) recommended the approval of Ponvory, a drug developed by Johnson & Johnson and approved by the FDA in mid-March.
While the announcements seemed to coincide neatly, this was most likely due to chance, said Jon Moore, CEO of the UK biotech Pheno Therapeutics and Operating Partner at Advent Life Sciences. “These things can come along in threes just like buses sometimes do.”
However, these developments demonstrate the fierce competition in the MS field, where many patients currently lack effective treatments.
“In fact, 44% of people with MS in Europe are not satisfied with today’s treatments due to lack of efficacy, safety concerns, or tolerability issues,” a spokesperson from Novartis told me.
The drugs in the EMA spotlight follow and refine tried and tested MS treatment approaches, such as modulating inflammation and stopping immune B and T cells from destroying the protective coating of nerve cells called myelin.
In the case of Kesimpta, the antibody drug is designed to destroy harmful B cells as does Roche’s Ocrevus, except Kesimpta allows self-administration at home. Ponvory — obtained by J&J via a €28B acquisition of the Swiss firm Actelion in 2017 — reduces circulating immune cells as do the approved drugs Zeposia and Mayzent. And the EMA is currently considering the approval of Biogen’s Vumerity, which is an alternative form of the company’s approved immunomodulatory MS drug Tecfidera.
However, there are limitations to current MS approaches. One major example is that the bulk of them take aim at the most common form of MS, relapsing-remitting MS (RRMS), while the rarer forms have fewer options.
RRMS accounts for around three quarters of cases, and progresses in the form of temporary flare-ups or relapses that disappear during remission periods. In the cases of Kesimpta and Ponvory, the drugs reduced the frequency of annual relapses by at least 30% compared to the treatment standard, Aubagio, in phase III.
In contrast, a rare form of MS called primary progressive MS (PPMS) — which shows only a steady worsening of the condition — only has Ocrevus as an EMA-approved treatment.
Nonetheless, there are two prominent candidates in development in Europe that could bring new treatments for PPMS. The first of these is masitinib, developed by the French company AB Science, which specifically blocks the innate immune response in patients and slowed the progression of the condition in a phase IIb/III trial last year.
“To date, there is no treatment capable of effectively targeting the cells that play a major role in the evolution of the progressive forms of multiple sclerosis,” stated Patrick Vermersch, Professor of Neurology at the University of Lille, France, and principal coordinator of the study. “In addition, masitinib can be administered on a long-term basis as it is not an immunosuppressive treatment.”
The second is a drug called tolebrutinib, which belongs to a drug class called Bruton’s tyrosine kinase (BTK) inhibitors. Like Ocrevus and Kesimpta, these drugs get rid of disease-causing B cells. However, they are small molecules instead of antibodies, which could allow them to access the nervous system more easily. Furthermore, BTK inhibitors may be able to preferentially deplete the damaging B cells and leave alone benign B cells.
According to Moore, BTK inhibitors like tolebrutinib are causing a lot of excitement in the MS space. In September last year, for example, the French heavyweight Sanofi acquired tolebrutinib’s developer, the US company Principia Biopharma, for €3.1B ($3.7B) and the drug is currently in phase III testing.
Another major drawback of MS treatments is that they can’t undo the damage caused by the immune system to nerve cell myelin coatings. This is especially the case in older patients, whose natural repair mechanisms are slower compared to younger people. There is a growing movement aiming to restore the protective myelin coating to nerve cells by harnessing the booming field of regenerative medicine.
“In terms of remyelinating therapies, the question is where the block is,” said Moore. Treatments aiming to restore the myelin coating can have different targets, such as the cells that regenerate the myelin, or the removal of cell debris that blocks the process of regenerating myelin.
However, the precise targets to hit “are by no means clear and different processes might be the cause of the block in repair in different patients,” added Moore.
The regenerative approach in MS has seen some big failures over the last several years. Biogen’s antibody drug opicinumab proved unable to improve MS-induced disability in phase II in 2016, and the company finally discontinued the drug last year. In March last year, the French company MedDay Pharmaceuticals also saw its hopes of treating PPMS dashed when its candidate Biotin failed to slow or reverse disability in a phase III trial.
However, investors still seem keen on bankrolling emerging regenerative MS approaches. In the US, for example, Autobahn Therapeutics raised a €63M ($76M) Series B last year to fund the development of remyelinating MS treatments based on mimicking the regenerative actions of thyroid hormone. And the San Diego-based Pipeline Therapeutics closed a €66M ($80M) Series C round in February to fund the clinical development of drugs that stimulate cells to regenerate myelin.
In Europe, meanwhile, last year saw the €7.6M Series A round of Accure Therapeutics in Spain, which was launched to develop a phase II-stage drug that promotes the natural repair of damaged neurons. Pheno Therapeutics was also founded in the UK by Advent Life Sciences to discover drug candidates to stimulate remyelination.
While the top MS players continue to build on existing drug classes, smaller companies could continue to receive big windfalls as biotech funding breaks records this year. This could turbocharge the development of newer MS approaches and we could see a much more diverse EMA pipeline for MS in the coming years.
Cover image from Elena Resko
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