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Biohaven seeks to fill gap in treatment of Alzheimer's symptoms with troriluzole

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Biohaven seeks to fill gap in treatment of Alzheimer's symptoms with troriluzole

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This is the fifth story in an S&P Global Market Intelligence series focusing on Alzheimer's disease. The Healthcare News Team will examine promising therapies, and the failures that have riddled the drug pipeline along the way.

Many researchers and companies in the Alzheimer's disease space are focused on developing treatments that can slow or reverse the condition, but Biohaven Pharmaceutical Holding Co. Ltd. is looking to fill the gap in therapies for existing symptoms with its drug candidate, troriluzole.

The U.S. Food and Drug Administration has approved only two types of medications for treating the well-known memory loss and confusion associated with Alzheimer's disease: cholinesterase inhibitors, including Eisai Co. Ltd.'s Aricept, Novartis AG's Exelon and Johnson & Johnson's Razadyne, and memantine, marketed as Allergan PLC's Namenda. These medications address symptoms rather than correcting the course of the disease and are the only drugs approved specifically for Alzheimer's, which has no cure.

"The vast majority of agents are aiming for disease modification not symptomatic treatment," Biohaven's executive director of neurology, Irfan Qureshi, said. "We believe that when people have symptoms, that's when they're in the office, that's the huge unmet need that we need to address with the medication."

Stifel analyst Paul Matteis said in an April 3 note that symptomatic therapies are still important in treating Alzheimer's.

Biohaven does not currently have any approved treatments. The company's most prominent prospect is the migraine treatment rimegepant, which is expected to receive FDA approval in 2020. Leerink analysts estimate that therapy could bring in as much as $1.27 billion in revenue.

Troriluzole, on the other hand, could fetch $1 billion in sales for the symptomatic Alzheimer's indication by the end of 2027 for Biohaven.

Targeting glutamate

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Alzheimer's disease occurs when abnormal clumps of proteins called tau tangles and beta-amyloid plaques form in the brain. Drug research has largely focused on removing beta-amyloid plaques as a link between Alzheimer's and tau has yet to be established.

New Haven, Conn.-based Biohaven's drug troriluzole moderates glutamate, the main excitatory neurotransmitter in the brain that is involved in learning and memory. Too much glutamate can overwhelm neurons in the brain, causing cell death and inflammation. This can lead to an increase in amyloid and tau.

Dysregulation of glutamate is often seen in many neuro-degenerative diseases, including Alzheimer's, according to Biohaven's Qureshi.

"When you look at [the] brain in people who have Alzheimer's disease, one of the pathological hallmarks, a defining feature, is really loss of glutamate synapses," Qureshi said. "And that's the thing that correlates the most with disease symptoms."

When glutamate transporters do not function properly, glial cells — which surround the neurons for support and protection — can fail, according to a November 2018 note from Leerink analysts Mark Goodman and Roanna Ruiz.

Troriluzole is a third-generation version of the drug riluzole, which was FDA-approved for treating the nervous system disorder amyotrophic lateral sclerosis, better known as ALS. The therapy regulates glutamate transporters responsible for glial cell failure, and increases activity and expression of glutamate.

Goodman and Ruiz said that preclinical data has shown that riluzole reduces amyloid and tau buildup and rescues cognitive symptoms.

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"This is a clinically validated mechanism," Qureshi added. "It's not theoretical like amyloid or tau."

Allergan's Namenda, which was approved for use in the U.S. in 2003, has already proven this approach, as the therapy acts on the postsynaptic neuron as an NMDA antagonist. NMDA, or N-methyl-D-aspartate, is a type of glutamate receptor. However, according to Qureshi, Namenda is not as strong as Biohaven's candidate. Goodman and Ruiz said that NMDA antagonists can also have debilitating side effects.

"Glutamate is a very finicky target," Qureshi noted. "Even though it's been well-known that glutamate deregulation is a core feature in AD, there really hasn't been a lot of developmental focus on glutamate aside from something like Namenda … because this is a difficult target, there haven't been great ways to do it."

Looking forward

Biohaven's troriluzole, in the form of a 280-milligram once-daily oral capsule, is now in a phase 2/3 trial called T2 Protect, which is aiming to improve Alzheimer's symptoms. Biohaven is working on getting the drug approved for symptoms of the disease before possibly evaluating troriluzole for slowing it.

"That allows us to do a trial that's far more efficient than a disease modification study," Qureshi explained. "If we see a disease-modifying benefit, we would have to do a much longer trial to prove that in a well-controlled study."

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