Focus Group 2
The needs and challenges developing long-acting treatments for hepatitis C
Ashwin Balagopal: Rapporteur
Co-chairs: Meg Doherty & Jordan Feld
A single-shot HCV cure is desired and would address those left behind, even if not for all patients – progress since LEAP 2022.
- Estimates of dosing requirements.
- LONGEVITY project (Andrew Owen) – progress with glecapravir co-formulation.
- Broad consideration of use cases of LA agents (CID supplement 2022).
- Understanding patient preferences.
- Survey by Weld ED and Thomas DL (CID 2022): pills (51%) injection (38%); implant (6%); GRD (6%).
- UNITAID/Sue Swindells – study to better understand patient/provider preferences.
- Some understanding of best current candidates vs newer agents.
- Public-private partnership will be required – opportunity for funding agencies.
Industry perspective. Considerations involve all aspects of drug development.
- Minimal monitoring approach pioneered by the ACTG is encouraging for POC cure.
- Viral kinetics – how to deliver two drugs to establish SVR (VS <LLOD for 28-30d days after undetectable levels achieved)
- Sofosbuvir considered – unique PK properties make this challenging.
- Combination oral and injectable – resistance may develop if 8-12 weeks required.
- If 2 agents required (NS5A inhibitor and NS3 inhibitor), can expect DDIs.
- What is the unmet need given the success of oral antivirals?
- What would the reimbursement be?
- What reduction in SVR is acceptable?
- The pathway to development and approval might not be short, and there are legal aspects.
- Product development would be for bioequivalence – need to show non-inferiority vs standard oral therapy? need for P1 studies in healthy volunteers?
Questions and comments posed to Industry.
- There is an unmet global need if all populations are considered – there may be more itinerant populations than have been estimated (e.g., persons in prison are often a use case for efficacy of oral therapies, but many are not there for the full duration of treatment due to turnover).
- LA treatment is one necessary, complementary arm of an elimination strategy.
- What are the bottlenecks before industry advances on LA medicines?
- No rapid POC test exists for effective implementation of POC HCV cure.
- Some pharma questions exist that cannot be solved in isolation.
- Who pays? What are the regulatory benchmarks? How technically feasible is co-formulation?
Real-world experience with development of LA HIV treatment.
- CAB LA and RPV LA approval was slow – the “who pays?” question slowed progress.
- Unmet need may be similar to HIV – people who engage with LA HIV treatment really like it.
- Real-world surveys suggest equipoise –more people may take 1-2 shots if offered.
- LA treatments are being rolled out in LMICs.
- Timeline for HIV LA medicines.
- P1 CAB/RPV studies presented at CROI 2012 (4-5 years of pre-clinical work) and approval in 2021.
- LEN was faster – once the pipeline is built, there may be downstream advantages.
- What gaps can academia and industry fill together?
- Quantify unmet need; What will be accomplished by delivery of these products?; POC HCV test; Modeling.
How mathematical modeling can help. (Dr. Hoelek from Imperial College)
- Models can show impact.
- Consider incorporating the care cascade.
- If the care cascade is leaky (i.e., the unmet need), then quantify the leakiness and how the opportunity you are offering will affect the leakiness.
- Certain populations are more vulnerable to leakiness – likely geographically heterogeneous.
- Consider the overall cost of the product (every country values the opportunity and costs differently).
- What is the case for investment?
- Individual gain? Societal gain? Benefits regarding transmission?
- It is cost-saving for payers to treat HCV.
Advocacy perspective.
- What will it take for funders to become interested in LA HCV treatment?
- How can we address transmission and treatment as prevention?
- The care cascade is missing people, even with government buy-in.
- A rapid HCV test exists (1.5 hours) – roll out or optimization to make POC cure possible?
- Potentially a very important market – could be studied and characterized better.
Regulatory/FDA perspective.
- Oral adherence and tolerability is high – may be hard to get buy-in with an inferior SVR.
- Would pan-genotypic treatment be a requirement for a LA agent?
- What is the comparator – registrational trials or real-world experience?
- LA therapy will inherently give higher exposures (more safety data) or lower exposures (more efficacy data).
- Original trials include duration-finding, but not much dose-finding – toxicity of higher doses?
- Non-inferiority trials are not always required, but there may be questions for lower SVR.
- Interested in working with academia, industry, and pharma to identify the right studies.
- Proposed P3 “intent-to-cure” study (randomization at diagnosis to LA vs standard oral treatment) – the SVR would reflect real-world experience, accounting for theoretical loss of efficacy.
Other thoughts.
- Is there a role for intensification for shorter duration?
- What types of co-formulations would be optimal?
- Manufacturing needs its own discussion – not touched on.
- Other formulations are important and were not fully discussed (i.e., aqua suspension; capsules; polymer-based products; injectables).
Summary thoughts.
- What are the individual and societal benefits?
- What is the unmet need?
- What is the investment case?
- What formulations would work?
- What will payers accept?
- What testing is required for POC cure?
- Perfect opportunity for funders to facilitate P-P partnerships.
“It’s about getting everyone around the table to agree to do the right thing.” Dr Doherty
“This could be the opportunity for one and done.” Dr Weld