Biohaven—addressing neurological disorders
With several products in advanced clinical stages, such as oral CGRP-receptor antagonists and glutamate modulators, Biohaven is welcoming collaborations on these programs and broadening its pipeline further.
Biohaven Pharmaceuticals, Inc., is a clinical-stage biopharmaceutical company with a portfolio of innovative, late-stage product candidates targeting neurological diseases. The compounds are oral small molecules based on two distinct mechanistic platforms: calcitonin gene-related peptide (CGRP)- receptor antagonists, and glutamate modulators. Both therapeutic strategies could affect approaches to a diverse set of unmet needs.
Biohaven’s lead compounds are the CGRP-receptor antagonist rimegepant and the glutamate modulator trigriluzole (BHV-4157). Rimegepant, an oral formulation for the treatment of acute migraine, is in two phase 3 clinical trials; topline results are expected in the first quarter of 2018. Trigriluzole is in development for the treatment of ataxias, obsessive-compulsive disorder and Alzheimer’s disease.
In addition, Biohaven has several other programs in development, including a CGRP-receptor antagonist for episodic and chronic migraine, and glutamate modulators for multiple neurologic and neuropsychiatric disorders (Fig. 1).
“Biohaven’s goal is to build a broad portfolio of best-in-class and first-in-class therapies for severe neurologic disorders,” said Vlad Coric, CEO of Biohaven. “As we continue to make rapid clinical progress across both our lead technology platforms, we are also seeking new opportunities to bring patients the next generation of novel and innovative treatments.”
Figure 1: Biohaven Pharma’s portfolio of innovative, late-stage neurology assets. The company’s smallmolecule product candidates represent two distinct therapeutic strategies—calcitonin gene-related peptide (CGRP)-receptor antagonists and glutamate modulators—with the potential to affect treatment approaches.
Taking on migraine
Migraine is a debilitating condition that alters a person’s daily activities. The most common migraine symptoms are pulsating moderate-to-severe headaches, nausea, sensitivity to light (photophobia) and sound (phonophobia), and visual disturbances. Migraine is the world’s third most prevalent illness and seventh highest specific cause of disability.
Triptans, the current standard of care for migraine, are a class of serotonin 5-HT1B/1D–receptor agonists that constrict blood vessels in the brain and relieve swelling. But the class is contraindicated in patients at risk of cardiovascular events because of its vasoconstrictive properties. In addition, triptans are associated with headache recurrence and medication-misuse headaches. Biohaven’s rimegepant is an investigational agent that targets the mechanisms at the root of migraine.
Rimegepant is an oral CGRP-receptor antagonist that suppresses pain transmission between neurons. In addition, CGRP-receptor inhibition blocks the pathologic dilation of arteries without relying on active vasoconstriction, thus precluding the side effects of triptans. The overall effect is a reduction in neurogenic inflammation.
This novel mechanism, combined with the drug’s oral bioavailability and high potency at the CGRP receptor, make rimegepant a potential best-in-class molecule for the treatment of acute migraine. Rimegepant offers patients a ‘whenever, wherever’ ease of self-administration, in contrast to the need for intravenous infusion or subcutaneous needle administration of CGRP-targeting monoclonal antibodies.
The intellectual property rights for rimegepant are in-licensed from Bristol-Myers Squibb and are covered by five families of patents. Rimegepant has been dosed in almost 700 subjects and studied in six clinical trials in healthy volunteers and in patients with migraine, and has shown effectiveness against the most common migraine symptoms. In a phase 2b trial, rimegepant demonstrated comprehensive and durable treatment effects in acute migraine.
Glutamate modulation: a proven mechanism
Glutamate plays an essential role in 90% of all brain synapses, and dozens of severe disorders can be traced to glutamate dysregulation. These include Alzheimer’s disease, anxiety disorders and other neurologic diseases.
At Yale University, and later at Biohaven, the team led by Coric advanced trigriluzole, a third-generation tripeptide prodrug of riluzole, into the clinic. Trigriluzole has high oral bioavailability, bypasses first-round metabolism and is not associated with a negative food effect, which maximizes its therapeutic impact and addresses most limitations of riluzole. Biohaven has filed several US and international patent applications covering trigriluzole and other prodrugs of riluzole.
“We believe that trigriluzole represents a potential best-in-class glutamate modulating compound for the potential treatment of a number of neuropsychiatric disorders and could provide a robust alternative to riluzole in ALS,” said Coric.
As Biohaven continues to drive the completion of its clinical programs, the company also welcomes discussions toward broadening its pipeline of highly innovative drug candidates for neurologic disorders. The company’s broad experience with the development of new solutions for neurologic disorders, including a number of orphan diseases, makes Biohaven a partner of choice for potential collaborators interested in expanding their own reach and impact in the space.
Vlad Coric, CEO
Biohaven Pharmaceuticals, Inc.
New Haven, Connecticut, USA