Why Is Hep C Still On The Rise? And What Atea Is Doing About It
By Janet Hammond, MD, Ph.D., chief development officer, Atea Pharmaceuticals
Hepatitis C virus (HCV), a complex bloodborne infection with varying geographic prevalence, different geographical distribution of genotypes and degrees of drug resistance, affects 2.4 to 4 million people in the U.S. and an estimated 50 million people worldwide. Left untreated, chronic HCV leads to cirrhosis, and it is the leading cause of liver cancer in the U.S., Europe, and Japan. Direct-acting antivirals (DAAs), a class of small molecule therapeutics that inhibit viral replication and will cure HCV in a matter of months, have been available for more than a decade, yet the World Health Organization records upward of a million new HCV infections annually and, in the U.S., HCV diagnoses of new infections outpace cure rates annually. The question is: Why aren’t current DAAs adequately addressing this global public health burden?
Understanding Patient Care Is Complicated But Critical
The population of people currently living with HCV is different than it was a decade ago when the most commonly prescribed DAAs were first launched. At that time, many patients had been infected for decades (often due to contaminated blood products through lack of effective screening) and were desperate for a cure. Today’s HCV patient is typically younger and has been infected for a shorter period of time and therefore is less likely to have cirrhosis. A large number of patients are undiagnosed, despite guidelines recommending screening all adults over 35 in the U.S. at least once. Market research conducted by Atea Pharmaceuticals has shown that approximately 80% of patients are taking concomitant medications for other health conditions, and many have life circumstances that make follow-up care after diagnosis a challenge.
Meanwhile, though highly effective, the current therapies, which vary in treatment duration from eight to 12 weeks for both cirrhotic and non-cirrhotic patients, may pose risks for drug-drug interactions with common medications such as oral contraceptives and statins, as well as protease-inhibitor-containing drugs and immunosuppressants. Additionally, some HCV therapies must be taken with food to ensure proper absorption. These factors can deter doctors from prescribing and patients from taking the treatment. To adapt to the evolving needs of these HCV patients, an improved treatment option with a best-in-class profile that combines the key attributes of short duration, lower risk for drug-drug interactions, and convenience with no food effect is needed.
Prior Knowledge Is The Blueprint For Streamlined Clinical Programs
In my 20-plus years leading clinical development programs for antiviral therapies, including HCV, I’ve learned the blueprint for designing and executing efficient clinical trials is building upon the existing virologic disease and therapeutic knowledge and leveraging a clinical study design that expedites data collection for quicker decision-making. It also includes investing time and effort to develop effective strategies for engaging clinical trial sites and their patients globally, as well as providing the necessary education for healthcare providers and patients so that novel therapies are well understood and utilized.
First, build upon, learn from, and continuously innovate beyond existing knowledge. There is substantial scientific precedent for building upon existing knowledge from earlier clinical programs to design new trials. One such precedent is bringing a new treatment option to patients by developing regimens that have synergistic in vitro antiviral effects with favorable side effect profiles. Atea Pharmaceuticals is currently developing a next-generation treatment for HCV in an ongoing global Phase 3 program and has leveraged this approach by strategically combining two molecules — bemnifosbuvir and ruzasvir, each of which had already independently demonstrated safety and efficacy in HCV in previous clinical trials. This gave us confidence to execute a single-arm Phase 2 trial, proceeding without an active comparator or placebo. While this was a less traditional approach, it enabled us to enroll and complete the trial with fewer patients and much more quickly than we would have needed if the trial included a comparator arm.
To facilitate faster, more informed decision-making, we designed our single-arm Phase 2 study with a lead-in cohort of 60 non-cirrhotic patients. This lead-in cohort served as a sample representative of the broader HCV patient population. The single-arm design leveraged historical data from approved regimens, which allowed us to move more quickly and obtain a greater depth of learning with our own therapy. Although the accepted measure of cure for HCV is sustained virologic response (SVR) at 12 weeks post-treatment (SVR12), we conducted an interim analysis by measuring and reporting SVR4 data. The use of SVR4 as an interim decision endpoint signaled that we could confidently commence enrollment of patients with more advanced liver disease following the interim analysis. Additionally, it positioned us to validate using a representative sample that the regimen was demonstrating efficacy, which allowed us to affirm that the clinical program had long-term viability. The early positive SVR4 data empowered us to make decisions for the ongoing development – the high correlation between SVR4 and SVR12 allowed us to initiate planning for our Phase 3 trial – which is the first new regimen in late-stage development for HCV in nearly a decade and the first Phase 3 trial conducted comparing two DAA regimens – while the Phase 2 trial was still ongoing.
Global Partnerships Are Essential To Success
Building close relationships with the teams at global clinical trial sites is key to executing a successful clinical program. A critical part of achieving this is providing support as needed throughout the program. Getting to know the team members at each site on a personal level helped them to be fully engaged and equally invested in bringing a best-in-class treatment option to patients as quickly as possible. Our team understands that responsiveness is essential and answers questions from clinical trial sites as they come in. We also have frequent calls with the teams at each site, as this often allows for the best clarification of questions and helps maintain close relationships across the sites. As part of our site selection and initiation process, many of the sites were visited by Atea personnel, or by representatives from our CRO, which has culminated in a network of trusted colleagues across the globe who not only champion our work but bring a deep understanding of their respective patients, in addition to knowledge of country and local regulatory guidelines as we navigate each milestone of the program. While each country has unique nuances, conducting global studies has helped establish familiarity on both sides and taught us how to navigate their respective processes successfully and proven useful for more rapid implementation of subsequent trials. In our experience, this incremental progress toward the eradication of HCV requires a truly global, multidisciplinary effort.
Meeting The Needs Of Today’s – And Tomorrow’s – Patients
Despite being one of the rare instances of a viral infection with a definitive cure, HCV is proving challenging to eradicate. As the needs of HCV patients and their healthcare providers continue to evolve, so too must the profiles of our treatment options. Atea is advancing a global Phase 3 program with a next-generation regimen for HCV that has a best-in-class profile of short duration, low risk for drug-drug interactions, and convenience with no food effect. This profile is ideal for the test-to-treat model of care, which, with its increasing adoption, is expected to have a major impact on the global eradication of HCV. By following this blueprint — understanding patient needs, building upon existing knowledge, and establishing strong global relationships — companies like ours can bring innovative therapies to patients and healthcare providers as quickly and seamlessly as possible.
About the Expert:
Janet Hammond, MD, Ph.D., is the chief development officer at Atea Pharmaceuticals. An expert in virology and antiviral therapeutic drug discovery and development, Janet has more than 20 years of pharmaceutical and biopharmaceutical experience working across biotech companies including AbbVie, F. Hoffman-La Roche, Valeant Pharmaceuticals, Bristol-Myers Squibb, and GlaxoSmith Kline. Janet specializes in clinical development program leadership, product discovery and translational activities, product life cycle management, medical affairs, safety, and pharmacovigilance. Janet holds an MD and Ph.D. from the University of Cape Town, South Africa, and a Sc.M. in clinical investigation from Johns Hopkins University School of Hygiene and Public Health. She is a Fellow of the South African College of Physicians in Internal Medicine and trained as a Clinical Fellow in the Division of Infectious Diseases at Duke University and as a Post Doctoral Clinical and Research Fellow in the Divisions of Clinical Pharmacology and Infectious Diseases at John Hopkins University School of Medicine.