PHILADELPHIA – "We've gone from no randomized controlled trial to three," Sean Pittock told reporters at the American Academy of Neurology (AAN) annual meeting this week. "It's a glorious example of what you can do with precision medicine."

Pittock, the director of the Mayo Clinic's Center for Multiple Sclerosis and Autoimmune Neurology, was referring to the landscape of neuromyelitis optica spectrum disorders (NMOSD), also known as Devic's disease.

In Tuesday's emerging science session, Pittock presented data from the phase III PREVENT trial of Soliris (eculizumab, Alexion Pharmaceuticals Inc.) showing a 95% reduction in relapse risk. The data were also published in The New England Journal of Medicine on May 3, 2019.

Viela Bio's inebilizumab, too, reduced relapse risk, by 77%. Trial data for the N-MOmentum trial were presented by Bruce Cree, professor of clinical neurology at the University of California San Francisco Weill Institute for Neurosciences, in the Tuesday plenary session.

Roche Holding AG will also be reporting subgroup analyses from the phase III SakuraSky trial of satralizumab for relapse prevention in NMOSD. Top-line data reported from SakuraSky and a companion trial, SakuraStar, last year demonstrated that satralizumab, too, reduces the risk of relapse in NMOSD.

NMOSD is in some ways similar to multiple sclerosis (MS) – it used to frequently be misdiagnosed as MS – in that it attacks the myelin sheath that makes neuronal high-speed communication possible. The distinction between MS and NMOSD became much clearer with the discovery that the majority of NMOSD patients have antibodies to a water channel, aquaporin 4 (AQP4).

AQP4 is expressed on the astrocytes that support the myelin sheath, which is itself made up of oligodendrocytes.

Clinically, in NMOSD, the target of autoimmune attack is frequently the optic nerve.

A key difference between MS and NMOSD is that in NMOSD, "the attacks are the problem, not the progression that happens between attacks," Pittock said. While MS has a number of treatment options for the relapsing-remitting patients, those treatments do not prevent the disease from ultimately advancing into the progressive phase. NMOSD has no such progressive phase, and so preventing attacks – which can lead to blindness, paralysis and, in rare cases, death – addresses the cause of disability.

None of the three therapies directly target AQP4 antibodies, so each had the potential to be effective in both AQP4 antibody-positive and AQP4 antibody-negative disease.

But there are reports that AQP4 antibody-negative patients respond differently to the therapies currently used off-label to treat them. "We don't exactly know what the underlying biology is in that population," Viela Bio Chief Medical Officer Jorn Drappa told BioWorld.

The three trials dealt with the uncertainty around aquaporin in different ways.

PREVENT restricted enrollment to patients with AQP-4 antibodies, while N-MOmentum and SakuraSky enrolled all NMOSD patients.

In the N-MOmentum trial, patients could enroll after review of their cases by an eligibility committee, a strategy that resulted in low enrollment of AQP4-negative patients. The AQP4-negative group was "too small a group to draw definitive conclusions," Drappa said.

Whether inebilizumab would be effective in those patients, he said, is "really guesswork" at this time. Inebilizumab targets CD19 – the target of CAR T-cell therapies Kymriah and Yescarta – which is expressed on all B cells, so there is no reason to assume it is antigen-specific.

In the SakuraSky trial, as in N-MOmentum, satralizumab's effect was statistically significant in the AQP4 antibody-positive patients as well as in the intent-to-treat-population, but not in the AQP4 antibody-negative population analyzed by itself.

In SakuraSky, "the data doesn't say that it does not work," Hideki Garren, global head of multiple sclerosis and neuroimmunology at Roche subsidiary Genentech Inc., told BioWorld. The statistical analysis showed trends toward effectiveness, and the study groups were not powered for subgroup analysis.

Nevertheless, the AQP4-negative group had less of a response than the AQP4-positive group, where the risk reduction was 79%, and "we don't understand why," Garren acknowledged. Satralizumab targets the interleukin-6 (IL-6) receptor, and is thought to act via multiple mechanisms, including but by no means limited to preventing the activation of B cells and their precursors.

Soliris, too, has a mechanism of action that is not directly related to AQP4. Its target is complement C5, a late component of the complement cascade.

"How much antibodies activate complement depends on the antibody," Alexion's executive vice president and head of research & development, John Orloff, told BioWorld. And the antibody to AQP4 "activates complement quite well."

At an AAN press conference, Pittock went a step further.

AQP4-negative NMOSD patients frequently have antibodies to myelin oligodendrocyte glycoprotein (MOG), leading to some controversy around diagnostics categories.

Pittock said that because it targets oligodendrocytes, rather than the supporting astrocytes, "I would argue that [MOG-antibody positive NMOSD] is a distinct disease."

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