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Masitinib Voluntary Hold Reinforces Need for ALS-Focused Drug Development

On June 3rd, AB Science announced that they were putting all clinical studies of their lead compound masitinib—including a Phase 3 trial in ALS—on voluntary hold, based on what the company termed a “potential risk” of ischemic heart disease (IHD) with this drug.

Following the announcement, AB Science clarified the hold on a company webcast. In summary, clinical trials of masitinib, including its Phase 3 ALS trial, are still ongoing, but no new patients will be enrolled until French regulatory authorities complete an investigation of the risk of IHD following masitinib treatment. Currently, patients receiving masitinib in the ALS trial may continue treatment at their treating doctor’s discretion. Following this investigation and potential parallel inquiries from other regulatory agencies, AB Science will decide on a path forward. The company outlines potential outcomes, which range from a modest delay in clinical trials to program termination, in detail here

At THE CORE, we have watched the masitinib program with interest, because drugs like masitinib—tyrosine kinase inhibitors (TKIs)—work very well in our patient-derived laboratory models of ALS, and other labs around the world have observed similar effects. We published data showing that sunitinib, a TKI developed to treat stomach cancer, protects ALS motor neurons, and found that other TKIs including bosutinib, nilotinib, imatinib, and dasatinib—all developed to treat a type of leukemia and other cancers—were also helpful. These findings were supported by other research groups: a 2017 paper from Kyoto University supported bosutinib’s effects in ALS, leading to a small study of bosutinib for people with ALS in Japan; a group at Northwestern University found that imatinib showed benefits in ALS; a Georgetown team found that nilotinib has positive effects in laboratory models of related neurodegenerative diseases, and initiated small clinical studies in AD, PD, and Huntington’s disease to further evaluate its potential.

So, why aren’t we pushing harder to repurpose FDA-approved TKIs for ALS? The disappointing setback in masitinib’s program highlights a key problem: drugs that were developed for cancer—masitinib was initially developed to treat mast cell tumors in dogs—do not readily reach brain cells in living beings. This means that while TKIs may look great in a Petri dish with ALS motor neurons, they haven’t looked as promising in animal models, and have shown unexpected and serious side effects in our hands. We learned that sunitinib, for example, gets pumped out of the brain as soon as it enters. Researchers at THE CORE tried a range of strategies to get sunitinib to stay in the brain, but ultimately the only approaches that showed a positive impact on ALS—very high doses, administered with another drug to stop the brain from pumping it out—were toxic and therefore couldn’t be tried in people. [See more: on a recent Project ALS webinar, researchers Sebastian Thams and Emily Lowry describe efforts to repurpose TKIs like sunitinib for ALS, and challenges they encountered.]

No FDA-approved TKI was designed to reach the brain, and based on disappointing results with sunitinib and other existing drugs, THE CORE has shifted its focus to making better versions of kinase inhibitors. We are working closely with medicinal chemists to develop compounds that are not only extremely effective in protecting motor neurons in a dish, but also bathe the brain, and are well-tolerated at the relevant ALS doses. Prosetin, which targets a kinase called MAP4K, is THE CORE’s first drug candidate of this type, and our team is working to optimize and thoroughly test other types of kinase inhibitors that show stand-out motor neuron rescue in the lab. Our takeaway? Repurposing drugs from cancer and other diseases may not yield the effective treatments we so badly need—while we hope that the masitinib trial can continue safely, and eventually yield positive results, it’s clear that brain diseases like ALS require a focused, dedicated approach to drug development.

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