Phase I clinical trial could show potential for neuro disorders
Big News from Biohaven
CGRP is an important neuropeptide thought to be involved in multiple neuro-inflammatory and neuro-immune diseases. CGRP receptor antagonism interrupts pathologic signals in CGRP-mediated diseases, such as migraine. After the success of this approach in migraine, Biohaven Pharmaceutical Holding Company Ltd. of New Haven, Connecticut, is exploring the potential of this approach in other neuro-inflammatory and neuro-immune diseases, including COVID-19.
In June Sosei Heptares of Tokyo initiated a Phase 1 clinical trial in collaboration with Biohaven with lead candidate HTL0022562 (BHV3100). The first healthy subject was dosed with the drug candidate, a novel, small molecule CGRP receptor antagonist discovered by Sosei Heptares and the lead compound in a portfolio of CGRP antagonists licensed to Biohaven in December 2020 for development as new therapies for CGRP-mediated disorders.
The trial is a Phase 1, randomized, double-blind, placebo-controlled, first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of a single ascending dose and multiple ascending doses of subcutaneous HTL0022562 in healthy adult subjects. The trial will enroll 88 subjects at a single center in the UK and be completed in 2022. The preclinical development program has demonstrated its promising and differentiated properties for further investigation in human trials, according to the companies.
Under the global collaboration and license agreement with Biohaven, Sosei Heptares will conduct the Phase 1 clinical trial, receiving a milestone payment for its initiation and eligibility for development costs for conducting the trial. Biohaven will lead all future studies and development activities, and Sosei Heptares will be eligible for further milestone payments and royalties.
Sosei Heptares and Biohaven entered a global collaboration and license agreement in December 2020 under which Biohaven received exclusive global rights to develop, manufacture and commercialize a portfolio of novel, small-molecule CGRP receptor antagonists discovered by Sosei Heptares for the treatment of CGRP-mediated disorders. Sosei Heptares received an upfront payment of US$10 million on signing in cash and Biohaven common shares and is eligible to receive additional research funding, up to US$370 million in development, regulatory and commercialization milestone payments, plus tiered royalties on net sales of products resulting from the collaboration.
Biohaven is a commercial-stage biopharmaceutical company with a portfolio of therapies to treat patients with debilitating neurological and neuropsychiatric diseases, including rare disorders. Biohaven's neuroinnovation portfolio includes FDA-approved NURTEC™ ODT (rimegepant) for the acute treatment of migraine and a broad pipeline of late-stage product candidates across three mechanistic platforms: CGRP receptor antagonism for the acute and preventive treatment of migraine; glutamate modulation for obsessive-compulsive disorder, Alzheimer's disease, and spinocerebellar ataxia; and myeloperoxidase (MPO) inhibition for multiple system atrophy and amyotrophic lateral sclerosis.
Biohaven’s progress is fueled by experience in drug development along with support of biopharma investors. Biohaven has combined internal development and research with intellectual property licensed from companies and institutions including Bristol-Myers Squibb Company, AstraZeneca AB, Yale University, Catalent, ALS Biopharma LLC and Massachusetts General Hospital. Since its initial public offering in 2017, Biohaven has made rapid progress with multiple compounds across its CGRP receptor antagonist, glutamate modulator, and myeloperoxidase (MPO) inhibitor platforms.
Nurtec™ ODT (Rimegepant 75 mg) received FDA approval in February 2020 and is the only orally disintegrating CGRP antagonist for acute treatment of migraine. At the same time, Biohaven is advancing novel acute and preventive treatments for migraine with zavegepant and rimegepant. In addition to continued exploration of CGRP receptor antagonists , multiple clinical trials are ongoing for product candidates across the company’s neuroinnovative platforms.
According to Biohaven’s website, “Clinicians use a number of pharmacologic agents for the acute treatment of migraine. A study published by the American Headache Society in 2015 concluded that the medications deemed effective for the acute treatment of migraine fell into the following classes: triptans, ergotamine derivatives, NSAIDs, opioids and combination medications. While triptans are a standard treatment for patients who suffer from migraine, their use is limited in some patient populations and by issues such as an incomplete effect or headache recurrence (only about 30% of patients from clinical trials are pain free at two hours after taking triptans). According to a recent study published in the journal Headache, an estimated 2.6 million migraine sufferers in the United States have a cardiovascular event, condition or procedure that limits the potential of triptans as a treatment option (Buse et al., 2017). Thus, there remains a significant unmet medical need for a novel migraine-specific medication that does not increase the risk of cardiovascular liability.”
The CGRP receptor is located within pain-signaling pathways, intracranial arteries and mast cells and its activation is thought to play a causal role in migraine pathophysiology. For example, research and clinical studies have shown that serum levels of CGRP are elevated during migraine attacks, infusion of intravenous CGRP produces persistent pain in migraine sufferers and non-migraine sufferers, and treatment with anti-migraine drugs normalizes CGRP levels. Additionally, multiple clinical studies show that small molecule CGRP receptor antagonists, which inhibit the binding of endogenous CGRP to CGRP receptors, are effective in aborting migraine attacks.
Treatment with a CGRP receptor antagonist is believed to relieve migraine through several mechanisms. Binding of CGRP receptor antagonists to CGRP receptors located on mast cells would inhibit inflammation caused by trigeminal nerve release of CGRP onto mast cells within the tough outer covering of the brain, or the meninges. By blocking the CGRP receptors located in smooth muscle cells within vessel walls, CGRP receptor antagonists would inhibit the pathologic dilation of intracranial arteries without the unwanted effect of active vasoconstriction. Binding of CGRP receptor antagonists to CGRP receptors would suppress the transmission of pain by inhibiting the central relay of pain signals from the trigeminal nerve to the caudal trigeminal nucleus.
Sosei Heptares is an international biopharmaceutical group focused on the discovery and early development of new medicines originating from its proprietary GPCR-targeted StaR® technology and structure-based drug design platform capabilities. The company is advancing a broad and deep pipeline of novel medicines across multiple therapeutic areas, including neurology, immunology, gastroenterology and inflammatory diseases. It has established partnerships with some of the world's leading pharmaceutical companies, including AbbVie, AstraZeneca, Biohaven, Genentech (Roche), GSK, Novartis, Pfizer and Takeda and additionally with multiple emerging technology companies.