A remyelinating agent remains a distant hope

Keenly awaited early data from Atara that many hoped would show convincing evidence that ATA188 was driving the remyelination of nerves damaged by multiple sclerosis ultimately disappointed. Not that the project is being written off, but signals remain weak and hard to interpret; phase 2 data due next year will hopefully provide a clearer picture.

Remyelination is the next frontier for MS treatment, and Atara is one of a handful of companies with novel clinical projects, trying to prove that this is possible. Very varied mechanisms are being employed to achieve this end, from Abbvie’s antibody elezanumab to Clene’s nanotechnology; several academic groups are also exploring repurposed drugs.

Disability improvement, or at the very least stable disease, is the ultimate goal. Existing MS drugs achieve this for a while, by dampening down the immune attack that causes the damage to the myelin, and they do this very effectively. This is particularly true with some of the latest drugs to reach the market like Roche’s Ocrevus and Novartis’s Mayzent. There is even some suggestion that the latter might help promote remyelination.

But developing an active remyelinating agent is another matter entirely. This is not helped by the fact that the processes behind nerve degeneration in MS are still not fully understood, and that different mechanisms could cause relapsing/remitting and progressive forms of the disease.

Biggest hopes?

Biogen’s opicinumab was arguably the biggest hope this field of research has seen – the antibody was thought to promote the development of oligodendrocytes, the cells that maintain the myelin coating around nerves. The project failed an important test back in 2016, and Biogen finally abandoned work a few years later.

The company has pushed on, however, and currently has a small-molecule remyelinating agent, BIIB061, due to enter phase 2 shortly. At a recent R&D day Biogen also mentioned two preclinical neuro-repair agents, although nothing has been disclosed about their mechanisms.

Abbvie also has a presence here with elezanumab, an antibody against repulsive guidance molecule A. RGMa is thought to block the growth of nerve endings and inhibit regeneration after CNS damage. The project, which is also being investigated in spinal cord injuries and stroke, has been put through two relatively large phase 2 MS trials, from which results should emerge soon.

Clene’s approach has also attracted a fair amount of attention, although much remains to be proven. The company describes its lead asset, CNM-Au8, as a “bioenergetic nanocatalyst”. This comprises a concentrated, aqueous suspension of clean surfaced faceted nanocrystalline gold, which is said to act as a catalyst to various intracellular biological reactions, including those involved in repairing and reversing neuronal damage.

Data from an imaging study released in August failed to excite investors, however, and strong results from ongoing larger trials, in MS and other neurodegenerative conditions like ALS, will be required to build hope.

Projects that more recently moved into the clinic include NVG-291 from Nervgen, being tested in healthy volunteers. It is said to work by modulating protein tyrosine phosphatase sigma, a receptor thought to be involved in impeding the recovery of nerve cells. The small Canadian developer hopes to move into phase 2 in MS next year, as well as pushing forward in Alzheimer’s and spinal cord injury, although funding would presumably need securing first.

Pipeline Therapeutics, which is working on several early-stage neuro-regenerative assets, has PIPE-307 earmarked for MS. A healthy volunteer study started this year. The company believes the project, a selective muscarinic M1 receptor antagonist, might work by driving the maturation of oligodendrocyte precursor cells into those that can produce myelin.

Academics and charities are also driving research. A few years ago a trial called CCMR-One, run by Cambridge University, found signals of remyelination with bexarotene in relapsing remitting disease. But this RXR agonist and off-patent skin cancer drug caused too many side effects to push on.

The same research unit hopes to start the CCMR-two trial this year, studying a combination of clemastine and metformin, respectively an anti-histamine and front-line diabetes medicine.

Clemastine is believed to work in MS by signalling stem cells to commence repair, and showed early promise as a remyelinating agent in the Rebuild trial. Metformin is thought to play a role in stem cell signalling, and could promote remyelination in a similar way to bexarotene. Both are also being tested in various other academic-sponsored studies and settings.

Much work is also ongoing preclinically at various small start-ups. But neurodegeneration is an incredibly tough area littered with many failures. It is encouraging to see so many different approaches in the pipeline, but it is success stories that are really needed.