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MS highs and lows in the clinic
The neurodegenerative disease multiple sclerosis (MS) affects millions, and to date, no curative therapies have been approved. But despite the difficulty of halting or potentially reversing the effects of the diseases, several companies are hard at work driving molecules through the clinic.
On the “high” end of things, clinical-stage biopharmaceutical company Clene Nanomedicine Inc. recently dosed the first patient enrolled in its Phase 2 REPAIR-MS study. REPAIR-MS is investigating the company’s lead nanocatalytic therapy, CNM-Au8, for the treatment of MS. The compound has shown promising preclinical data thus far, and in addition to REPAIR-MS, Clene is also evaluating CNM-Au8 in its VISIONARY-MS Phase 2 study.
The REPAIR-MS trial is a single-center, open-label, sequential group, investigator-blinded study to evaluate the brain metabolic effects, safety, pharmacokinetics and pharmacodynamics of CNM-Au8 in MS patients. Specifically, Clene hopes to gain a better understanding of exactly how the therapeutic affects central nervous system biomarkers related to bioenergetics, neuronal metabolism and oxidative stress, which are indicators of target engagement for CNM-Au8. Dr. Benjamin Greenberg is leading the study, which is being conducted at the University of Texas Southwestern Medical Center. According to Dr. Robert Glanzman, chief medical officer at Clene, “Participants will undergo 31phosphorous magnetic resonance spectroscopy (31P-MRS) imaging to show how treatment with CNM-Au8 results in bioenergetic improvement of impaired neuronal redox state.”
“We are excited to advance CNM-Au8 clinically into our second Phase 2 study for MS patients,” said Rob Etherington, president and CEO of Clene. “Our preclinical data with CNM-Au8 demonstrated improvements in cellular bioenergetics, specifically within neurons and oligodendrocytes, which led to the initiation of the VISIONARY-MS Phase 2 study and now the REPAIR-MS Phase 2 trial. Currently, there are no therapies approved for remyelination, and we believe CNM-Au8 has the strong potential for myelin repair and protection of neurons in patients with MS, which affects more than 2.5 million individuals worldwide and is one of the most common neurological disorders.”
On the lower end of things, MedDay Pharmaceuticals shared in early March that the second pivotal Phase 3 trial of MD1003, an investigational neurometabolic modulator designed to target both neurodegenerative and demyelination processes, did not meet its primary and secondary endpoints. It was hoped that this SPI2 trial would confirm the results of MedDay’s first positive Phase 3 trial, MS-SPI. Full results were to be shared at the American Academy of Neurology 2020 Annual Meeting, which was cancelled due to the pandemic.
“We are clearly disappointed that SPI2 did not meet its primary and secondary endpoints. Going forward, we will continue to evaluate the trial data and confer with regulators,” commented Catherine Moukheibir, CEO of MedDay Pharmaceuticals. “We would like to thank our collaborators including the participating clinicians, medical staff and, most importantly, the patients for all of their efforts and participation in the trial. All were invaluable partners throughout the process of completing the SPI2 trial.”
The primary endpoint for this study was reversal of functional disability as measured by the proportion of patients with an improvement in either the Expanded Disability Status Scale (EDSS) or in the time needed to walk 25 feet (TW25) over a 12-month time frame and confirmed at 15 months. Secondary endpoints included relative reduction in the risk of disability progression; global impression of response to treatment evaluated independently by both the patient and the evaluating physician; and mean change in TW25.
“We will review the findings in detail to understand these outcomes to help inform future clinical research in progressive MS and other neurological diseases,” added Dr. Frédéric Sedel, chief scientific officer and co-founder of MedDay Pharmaceuticals. “I remain confident of the importance of the neurometabolic approach to neurodegenerative diseases with high unmet medical need.”
But to end things on a high note, AB Science SA reported in February that its lead candidate masitinib met its primary endpoint in the company’s Phase 2B/3 study in primary progressive and non-active secondary progressive multiple sclerosis. The pre-specified primary endpoint was absolute change from baseline on EDSS, considering all measurements from week 12 to week 96. Masitinib was found to significantly delay disease progression as measured by the time to reach an EDSS score of 7.0 (which corresponds to disability severe enough for patients to require a wheelchair).
Patrick Vermersch, Professor of Neurology at Lille University in France and coordinating investigator of the study, said, “People with primary progressive (PPMS) and non-active secondary progressive (nSPMS) forms of multiple sclerosis account for half of all MS patients. While numerous treatments based on targeting of B cells and T cells of the adaptive immune system are available for patients with relapsing forms of MS, these strategies have failed or had inconclusive results in PPMS and nSPMS. Consequently, there remains a very high medical need for people with PPMS and nSPMS. Masitinib does not target the adaptive immune system and the results from this study represent a scientific breakthrough because this is the first time that the novel strategy of targeting the innate immune system via mast cells and microglia has been able to significantly slow progression of clinical disability in progressive forms of MS. These data are extremely encouraging and may provide new hope for progressive MS patients.”