MedicalResearch.com Interview with:
Mark D. Eisner, MD, MPH
Vice President, Product Development Immunology
Infectious Disease and Ophthalmology
MedicalResearch.com: What is the background for this study?
Response: CAPSTONE-2 is a Phase III multicenter, randomized, double-blind study that evaluated the efficacy and safety of a single dose of baloxavir marboxil compared with placebo and oseltamivir in people 12 years and older who are at a high risk of complications from the flu. The Centers for Disease Control and Prevention (CDC) defines people at high risk for serious flu complications to include adults 65 years of age or older, or those who have conditions such as asthma, chronic lung disease, morbid obesity or heart disease.
A total of 2,184 participants enrolled in the study and were randomly assigned to receive a single, oral dose of 40 mg or 80 mg of baloxavir marboxil (according to body weight), placebo or 75 mg of oseltamivir twice daily for five days. The primary objective of the study evaluated the efficacy of a single dose of baloxavir marboxil compared with placebo by measuring the time to improvement of influenza symptoms. Key secondary endpoints compared outcomes in baloxavir marboxil versus placebo or oseltamivir – these included time to resolution of fever, time to cessation of viral shedding, infectious virus detection in swabs of the nose and throat, prescription of antibiotics and influenza-related complications.
Genentech announced initial results from the study on July 16, 2018 but the full data was presented for the first time during a late-breaking oral presentation at the annual IDWeek meeting in San Francisco, CA on October 6, 2018.
Baloxavir marboxil is a first-in-class, single-dose investigational oral medicine with a novel proposed mechanism of action designed to target the influenza A and B viruses, including oseltamivir-resistant strains and avian strains (e.g. H7N9, H5N1). Baloxavir marboxil is the first potential influenza treatment to demonstrate a clinically meaningful benefit for people highly vulnerable to serious influenza complications in clinical trials.
The FDA accepted a New Drug Application (NDA) and granted Priority Review to baloxavir marboxil as a single-dose, oral treatment for acute, uncomplicated influenza in people 12 years and older. The NDA was based on results from the Phase III CAPSTONE-1 study of a single dose of baloxavir marboxil compared with placebo or oseltamivir 75 mg, twice daily for five days, in otherwise healthy people with the flu. Results from a placebo-controlled Phase II study in otherwise healthy people with the flu were included as supporting data in the NDA. The FDA is expected to make a decision on approval by December 24, 2018.
MedicalResearch.com: What are the main findings?
Response: The Phase III CAPSTONE-2 study showed that treatment with baloxavir marboxil significantly reduced the time to improvement of influenza symptoms versus placebo (median time of 73.2 hours versus 102.3 hours; p<0.0001) in people at high risk of complications from the flu. The CAPSTONE-2 study also showed that baloxavir marboxil demonstrated efficacy (reduced time to improvement of influenza symptoms) in influenza type A/H3N2 (median time of 75.4 hours and 100.4 hours; p<0.05) and type B (median time of 74.6 hours and 100.6 hours; p<0.05) versus placebo.
In addition, results for the overall patient population of the study showed numerically shorter time to improvement of influenza symptoms of baloxavir marboxil versus oseltamivir with a median time to improvement of symptoms of 73.2 hours for baloxavir marboxil compared with 81.0 hours for oseltamivir (p=0.8347). In the subpopulation of people with influenza type B, a subgroup where some antiviral treatments have shown only limited efficacy or inconclusive data, baloxavir marboxil was significantly more efficacious than oseltamivir in reducing the time to improvement of symptoms (median time of 74.6 hours versus 101.6 hours; p<0.05).
Baloxavir marboxil demonstrated efficacy compared to placebo and oseltamivir for key secondary endpoints, including reducing the time that the virus continued to be released from the body (viral shedding; median time of 48.0 hours for baloxavir marboxil versus 96.0 hours for both placebo and oseltamivir; p<0.0001). Baloxavir marboxil also reduced the use of antibiotics and incidence of influenza-related complications (3.4 percent and 2.8 percent respectively) compared to placebo (7.5 percent and 10.4 percent; p=0.01 and p<0.05). Baloxavir marboxil was well-tolerated and no new safety signals were identified. Baloxavir marboxil had a numerically lower overall incidence of reported adverse events (25.1 percent) compared with placebo (29.7 percent) or oseltamivir (28.0 percent).
MedicalResearch.com: What should readers take away from your report?
Response: There are currently no antiviral medicines approved to specifically treat this high-risk population. Baloxavir marboxil has the potential to offer an improved treatment for one of the most common, yet serious, infectious diseases worldwide, in both otherwise healthy and high-risk populations.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: The CAPSTONE-2 study assessed the safety and efficacy of baloxavir marboxil in people at high risk of complications from the flu, including older people and those living with certain medical conditions. These data are not included in the NDA pending FDA approval. We have shared the results of the CAPSTONE-2 study with the FDA, and look forward to discussing next steps since there are currently no antiviral medicines approved to specifically treat this high-risk population.
Baloxavir marboxil will also be further studied in a Phase III development program including pediatric populations and severely ill hospitalized people with influenza.
Genentech recently announced that they have entered into a private-public partnership with the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services (HSS). As part of the agreement, BARDA will provide funding that will support the development of baloxavir marboxil for severely ill hospitalized people with influenza, with the potential for funding of other studies.
MedicalResearch.com: Is there anything else you would like to add?
Response: Influenza is one of the most common infectious diseases and represents a serious threat to public health. Current treatments – including vaccines and antivirals – have limitations as flu viruses are constantly changing so new antiviral medicines are necessary. We are committed to addressing this unmet need through our agreement with Shionogi & Co., Ltd., and are working with the FDA to bring baloxavir marboxil to people in the United States as soon as possible.
IDWeek 2018 Abstract – Phase 3 Trial of Baloxavir Marboxil in High-Risk Influenza Patients (CAPSTONE-2 Study)
Michael G. Ison, MD MS, FIDSA1, Simon Portsmouth, MD2, Yuki Yoshida, MS3, Takao Shishido, PhD3, Frederick Hayden, MD4 and Takeki Uehara, PhD3, (1)Northwestern University, Chicago, IL, (2)Shionogi Inc., Florham Park, NJ, (3)Shionogi & Co., Ltd., Osaka, Japan, (4)Medicine, University of Virginia, Charlottesville, VA
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