Biohaven’s Zavegepant has Potential Positive Impact in Phase II COVID-19 Study Though Broad MOA, Limited Understanding of Immune System's Role Raises Some Expert Concern

Published : 10 Oct 2020

Biohaven Pharmaceutical’s (NYSE: BHVN) Phase II zavegepant for hospitalized COVID-19 patients requiring supplemental oxygen could decrease pulmonary inflammation, experts said. However, limited knowledge of the drug’s mechanism of action in COVID-19 and within the broader immune response raises the possibility that the treatment could have limited efficacy or carry unintended safety consequences, experts said.

Existing animal studies and literature suggest that zavegepant, a calcitonin gene-related peptide (CGRP) antagonist originally developed for migraines, could reduce the severe inflammatory response in critically ill COVID-19 patients, experts said. As a primary outcome, the Phase II study (NCT04346615) has a pulmonary resolution of symptoms or progression to ventilator support or death, according to a 9 April company press release. Yet, given the lack of primary endpoint sensitivity, the small trial size could make it difficult to assess efficacy without another infection-related coprimary endpoint, one expert said.

Because the migraine patient population, for which CGRP antagonists have previously been studied, is healthier overall than hospitalized COVID-19 patients, existing safety data can not necessarily be extrapolated to COVID-19, experts said. Blocking CGRP, a potent vasodilator, generally has not affected blood pressure in migraine patients, but it is unclear whether this will change in more critically ill patients, they added.

The 120-patient, randomized, placebo-controlled trial has an expected primary completion date of April 2021, according to ClinicalTrials.gov, which lists the trial as Phase II/III.

According to a GlobalData consensus, Biohaven has expected peak sales of USD 563m in 2026 for all indications. A Biohaven representative said the company is not available for comment. Biohaven has a market cap of USD 4.14bn.

Broad MOA offers success potential but the risk remains

In COVID-19 patients, the virus may activate nerve endings to release CGRP, potentially contributing to the increased inflammatory response that can be detrimental in more severe cases, said Greg Dussor, Ph.D., associate professor, UT Dallas School of Brain and Behavioral Sciences. Blocking CGRP through an antagonist, in turn, could help limit the immune response, added Andrew Russo, Ph.D., professor of molecular physiology and biophysics, University of Iowa, Iowa City. While knowledge of the exact function of CGRP is limited, there is preclinical evidence linking CGRP to a type 2 immune response in mice with asthma, he added (Sui et al. Science 2018; 360(6393): 1–10).

Based on animal studies and available literature, Dr. Carrie Robertson, consultant, Department of Neurology, Mayo Clinic, Minnesota, said she is hopeful that zavegepant will provide additional benefit in patients with acute respiratory distress syndrome related to COVID-19. Because CGRP is likely only one component of a much more complex immune response to the coronavirus, the study is necessary to determine if and to what extent zavegepant can blunt severe inflammatory response, said Dussor.

Still, because CGRP is a multifunctional peptide found throughout the body, there is a risk that blocking it through an antagonist could unexpectedly and adversely affect other organ systems, Russo said. Dussor agreed, adding that the uncertainty surrounding CGRP’s role in the immune system makes it a legitimate possibility that blocking the peptide through an agonist could worsen the condition of patients with COVID-19.

Administration mode has benefits, trial design raises concerns

As an intranasal CGRP antagonist, zavegepant offers a faster onset and increased likelihood of directly targeting CGRP in the lungs compared to other oral or intravenous CGRP antagonists, Dussor said. As a result, zavegepant’s mode of administration likely played an important role in the FDA’s approval of initial clinical studies for COVID-19, he added.

In Biohaven’s study, patients will receive 10mg of zavegepant intranasally every eight hours for 14 days, according to ClinicalTrials.gov. As the primary endpoint, the study will measure the difference between intervention and placebo groups on a six-point severity scale, ranging from death to hospitalization on noninvasive ventilation to non hospitalization, ClinicalTrials.gov stated.

While outcomes along this scale are important in critically ill patients, its lack of sensitivity could mean a much larger study would be necessary to determine its effect, Dussor said. Additionally, it could preclude Biohaven from gaining more nuanced findings, such as a smaller signal indicating that CGRP antagonism at an earlier disease stage would provide an improved effect, he added.

Further, an additional, infection-related primary endpoint, such as the bronchoalveolar lavage fluids in patients’ lungs, could provide useful data on the extent to which CGRP antagonism affects the inflammatory response, Russo said.

The clean safety profile in migraine, but uncertainty lingers in COVID-19

Though CGRP is among the most potent vasodilators in the body, blocking CGRP in migraine studies has generally not led to increased blood pressure or any treatment-related serious adverse events (SAEs), said Dussor and Michael Ossipov, Ph.D., professor, College of Medicine, University of Arizona. As a result, it is possible that CGRP does not play a critical role in maintaining homeostasis in most patients, they agreed. Additionally, because zavegepant preferentially targets AMY1 CGRP, one of two forms of CGRP in the body, it is possible that CGRP can continue to maintain its cardioprotective functions even as it is partially dampened by a CGRP antagonist, Russo added.

That said, in patients with limited vasodilation capacity stemming from underlying causes such as high blood pressure or elevated levels of CGRP working to maintain normal levels, there could be an elevated risk, Ossipov and Dussor added. Although there has been little human evidence of worsened heart attacks or strokes due to CGRP antagonism, a recent rodent study suggested CGRP antagonism makes ischemic stroke more severe, Dussor added (Mulder et al. Annals of Neurology 2020; 88(4): 771–784).

While similar results have not been seen in human patients, there may be too little data available to determine the impact of CGRP antagonism on ischemic events in real-world patients, Dussor said. There is no evidence suggesting that patients would continue to experience dampened CGRP and any resulting risk of adverse consequences after they stop taking the drug, he added.

Uncontrolled hypertension and diabetes were listed among the exclusion criteria for the study of zavegepant in migraine patients but were not specifically listed in the exclusion criteria in the study of zavegepant for COVID-19 patients, according to ClinicalTrials.gov.

Nevertheless, though there is limited knowledge of COVID-19 and the effects of dampening CGRP in severely ill patients, most experts agreed that the well-accepted clean safety profile of CGRP antagonists in human studies likely played an important role in the FDA’s decision to approve Biohaven’s study. In the first-generation class of CGRP antagonists in migraine, hepatotoxicity was a concern, Ossipov said. However, the concern was unrelated to the drug class’ mechanism of action, and the second-generation class, of which zavegepant is a part, has no such concerns, he added.

There have been no SAEs reported in the completed Phase II/III migraine trial (NCT03872453), and the majority of adverse events (AEs) were mild, according to a December 2019 company press release. The only AEs reported in more than 5% of patients were dysgeusia (13.5–16.1% for zavegepant and 3.5% for placebo) and nasal discomfort (1.3–5.2% in the zavegepant arms, and 0.2% in the placebo arm).

Still, because the patient population in existing migraine studies is healthier overall than the patient population of hospitalized COVID-19 patients, the extent to which existing safety data can be extrapolated could be limited, Russo said. The ongoing Phase II study of zavegepant for COVID-19 and the completed Phase II/III study of zavegepant for migraine allowed investigators to exclude any potential participants who they deemed had a history of illness that could pose an additional risk by participating in the study, according to ClinicalTrials.gov.

Source: GlobalData.com