Rectal Gels for PrEP Are They an Option? Ian McGowan MD DPhil FRCP University of Pittsburgh, PA, USA 24th July, Paris, France

Overview What are rectal microbicides? Are they needed? Where is the science? What are the obstacles to the development of a safe and effective rectal microbicide? Scientific Regulatory Programmatic Rectal Gels for PrEP: are they an option?

What Are Rectal Microbicides? Topical products that are designed to prevent, or significantly reduce, the acquisition of sexually transmitted diseases including HIV infection Gels, enemas, or inserts Daily administration or event driven use Antiretroviral or non-antiretroviral

Rectal Microbicide Formulations

Are They Needed? People like choices e.g. contraception Topical products are behaviorally congruent Ideal approach for event driven use No PrEP agent / formulation has a perfect TPP But Oral PrEP is licensed, safe, highly effective, and increasingly available Dual compartment protection may require systemic administration of PrEP agents Public health and research resources are limited

Where is the Science? Good non-clinical animal model data to support the safety and effectiveness of topical PrEP agents including candidate rectal microbicides Multiple products have advanced through Phase 1 evaluation generating supportive safety, acceptability, and PK/PD data A tenofovir gel has been evaluated in a Phase 2 international multicenter study (MTN-017) As of yet no Phase 2B/3 effectiveness studies

Would This Approach Work? “HIV” (99mTc-SC) in Ejaculate “Microbicide”(111In-DTPA) CHARM-02 Study (Hiruy H et al. AIDS Res Hum Retroviruses 2015)

CHARM-01 Explant Data McGowan I et al. PLoS ONE 2015

What are the obstacles to the development of a safe and effective rectal microbicide?

Scientific Gels and inserts may not provide the comprehensive mucosal coverage needed to prevent HIV infection Topical products may not provide mucosal and systemic protection Men and women are at risk of HIV infection associated with condomless anal sex Topical products are unlikely to provide dual compartment protection unless used in both compartments

What the Consumers Want

What They Get

Regulatory With the increasing availability of oral PrEP the feasibility of conducting classical placebo controlled Phase 3 effectiveness studies has ended The alternative design strategies are likely to require very large/expensive trial designs Non-Inferiority (NI) studies But HPTN-083 is a Phase 2B/3 NI Study (N=4,500) evaluating LA cabotegravir In the absence of novel design strategies, demonstration of rectal microbicide efficacy may not be possible WEWS02: How to Assess the Efficacy of New Strategies for the Prevention of HIV-infection?

Programatic Oral PrEP increasingly available 2nd generation oral PrEP FTC/TAF Study being funded by Gilead Sciences (the DISCOVER Study) Antiretroviral intravaginal ring (dapivirine) positioned for regulatory review and potential licensure LA PrEP (cabotegravir) in Phase 2B/3 development. Data anticipated Q4 2021 What else do we need?

Dr. Carl Dieffenbach, February 2017

Rectal Gels for PrEP: are they an option? Another option Rectal Gels for PrEP: are they an option?