Will an Oral Lead-In Always be a Part of Long-Acting ARV drug development?
Speaker: Kimberly Struble, Senior Clinical Analyst Team Leader, Division of Antiviral Products, US FDA
Is an oral lead-in (OLI) needed?
- Sponsors can develop a new ARV de novo without an OLI, even if manufacturing an OLI is possible.
- FDA recognizes the additional feasibility and CMC considerations of developing two formulations up front before determining if OLI is needed.
- Consider the available non-clinical safety and PK data to decide if an OLI is needed.
- Is there a safety concern (hypersensitivity, liver toxicity, etc.) – Consider the magnitude and severity of target organ toxicity.
- Is PK sufficient – Is an OLI needed to reach target exposures before converting to LA?
Three approaches for development of LAI and implantable products.
- Always OLI due to PK or safety reasons.
- Strategy depends on ability to reach target exposures and rule out safety concerns.
- Dose oral to steady state then LAI (ensures target exposures are met).
- Dose oral, overlap oral + injection dosing, then LAI (rule out safety concerns).
- Strategy depends on ability to reach target exposures and rule out safety concerns.
- No OLI is needed or available (not possible [i.e., monoclonal Abs] or a company may not want to pursue it).
- Strategies surround risk mitigation.
- Stringent enrollment criteria.
- Start small – dose 1 or 2 patients and stagger dosing between patients for a specified interval.
- Stringent stopping criteria for individual patients, cohorts, or the study.
- Independent, unblinded medical monitor or data monitoring committee to oversee safety.
- Strategies surround risk mitigation.
- Hybrid approach – it is possible to transition to no OLI early in development if no PK or safety concerns.
- Strategize and prioritize the transition from OLI to all LA.
- Example: OLI used for initial safety assessment
- Safety – single and multiple dose PK studies assess target exposures in relation to EC90 to conduct DDI trials.
- OLI transition – dose-finding study with and without OLI arms. If data show no OLI needed for safety or PK reasons, then can transition to further trials without OLI.
Additional considerations when developing an oral ARV along with the LAI formulation.
- Prioritize DDI assessment – may be able to more quickly move to the direct-to-injection phase.
- Thoroughly evaluate data from in-vitro enzyme and transporter evaluations to prioritize in-vivo DDIs.
- Conducting DDI assessments with index perpetrators and substrates first for CYP mediated interactions could save time and reduce the number of trials needed.
- For transporter-mediated DDIs, need to strategize based on route of elimination and concomitant medications and safety considerations.
- Thoroughly evaluate data from in-vitro enzyme and transporter evaluations to prioritize in-vivo DDIs.
- An advantage of oral products is the ability to conduct DDI trials with a cross-over design.
- LA ARVs have long half-lives – the amount of time needed for an adequate wash out could prolong trial duration.
- Renal and hepatic assessment can be done with oral or LA formulations – we do not expect PK differences.
- PK trial duration may be shorter with oral formulations.
- Data from the oral formulation can be applied to LA, but not necessarily vice versa (hepatic first pass would be missed with LAI).
- Leverage all available oral PK data.
- Can use various quantitative clinical pharmacology approaches (such as modeling and simulation) to leverage PK data for addressing various “real life” scenarios, such as missed doses and LA treatment interruptions.
- Food effect assessment.
- A preliminary food effect assessment is needed to guide oral dosing until a complete transition to all LA formulations is made. If the development program does not include an OLI, then a dedicated food effect trial is not needed.
Summary
- Three approaches for development of LA ARVs – with OLI, without OLI, and hybrid approach.
- The need for OLI depends on individual product PK and safety profile.
- If you start with an OLI, you are not stuck with an OLI – a transition to direct-to-injection without OLI can be made early in development, providing no PK or safety concerns.