Rectal Microbicides: Where We’re Heading Craig Hendrix, MD Johns Hopkins University Microbicide Trial Network

Rectal Microbicide Need Oral PrEP not for everyone Prevention options improve overall adherence Contraceptive development experience Desire for products that can be used around the time of sex (on demand) Desire for products that conform to commonly practiced anal sex behaviors, e.g., a lube or douche (behaviorally-congruent) rather than using an applicator to deliver a gel

Rectal Microbicide Feasibility On demand oral PrEP (Truvada) efficacy high Ipergay 86 % risk reduction On demand vaginal tenofovir efficacy modest CAPRISA 004, FACTS 001 ~60% with good adherence Animal models: rectal tenofovir protects from anal monkey HIV Behaviorally-congruent formulations “piggy-back” onto common sexual practices to potentially improve uptake & adherence

Gaps in Knowledge Will a lube, douche, suppository, or insert (tablet) be … capable of delivering enough drug to the rectum? acceptable for use before anal sex? Can any drug protect both the rectum and vagina with one dose? Do single doses before sex deliver enough drug? Does any product protect from other STIs as well as HIV? To address these key questions …

…The Rectal Road Continues 7 drugs, 4 formulations being tested as rectal microbicides in 8 studies *5 MTN rectal microbicide studies being developed, 2 expected to launch in 2017 *3 Program Project grant studies ongoing or in development …all funded by the NIH (Thank you!)

MTN-026 Study Phase 1 rectal safety, acceptability, and PK/PD evaluation of 0.05% dapivirine gel Dapivirine proven efficacy in women (vaginal ring) Men and women (cis and transgender) (N=27) Clinical sites Pittsburgh and Birmingham

MTN-033 Study Phase 1 evaluation of dapivirine gel as lube Compare application of gel as sexual lubricant (using phallus & simulated anal sex) to applicator dosing of gel MSM and transgender women (N=16) Outcome: Measure distribution of drug in colon tissue N Period 1 Washout Period 2 Sequence A 8 DPV gel (2.5 g) Applicator 2-4 weeks DPV gel (10.0 g) Phallic device Sequence B

MTN-035 Study Acceptability, tolerability and adherence study (no active ingredient) Placebo enema (douche), rectal insert (fast- dissolving tablet), & suppository MSM and transgender women (N=210) Design under development

MTN-037 Study MIV-150 / Carrageenan / Zinc gel Active against HIV, HSV, & HPV in lab & animal studies Men and women (cis and transgender) (N=24) Study Design Single dose of gel Dose escalation from 4 mL to 32 mL of gel Safety, acceptability, drug concentration, tissue protection

MTN-039 Study Phase 1 rectal insert Active ingredient: Elvitegravir (integrase inhibitor licensed for treatment) Safety, acceptability, drug tissue concentration, biopsy susceptibility to infection CONRAD collaboration Men and women (cis and transgender) (N = 20) Single dose study

DREAM Program On demand rectal douche as “behaviorally-congruent” rectal microbicide DREAM 01 Clinical Study– Single ascending dose study Each of 16 participants receives a series of 3 enemas, gradually increasing dose Assess safety, acceptability, drug concentration, susceptibility of colon biopsies to infection UCLA, Pitt, & JHU PI: Craig Hendrix Johns Hopkins University

ImQuest Program DuoGel: Dual Compartment (Rectal & Vaginal) Gel Active Ingredient: IQP-0528 Non-nucleoside reverse transcriptase inhibitor Clinical First-in-Human Phase 1, Single rectal dose 8 men & 8 women Safety, drug concentration, biopsy susceptibility to infection, acceptability Enrolling now at Johns Hopkins University PI: Robert Buckheit, Jr., ImQuest BioSciences, Inc.

Griffithsin rectal gel PREVENT Program Development of Griffithsin (GRFT) rectal microbicide GRFT has activity against HIV, HSV, and HCV Preclinical program NHP studies ongoing Phase 1 study University of Pittsburgh Scheduled for 2018 Griffithsin rectal gel PI: Kenneth Palmer, University of Louisville

Study Timeline & Gaps Being Filled Active Drug Gel w/ Applicator Gel as Lube Douche Insert Suppository Placebo √√√√√ √ √, MTN-035 06/18-02/20 MTN-035 Tenofovir √√√√√√ DREAM 01 11/16-4/18 Maraviroc Dapivirine MTN-026 09/17-12/18 MTN-033 12/17-01/19 MIV-150/Zn/CG MTN-037 01/18-05/19 Elvitegravir MTN-039 05/18-07/19 IQP-0528 ImQuest 02 08/17-10/18 Griffithsin PREVENT 2018-2019 On Demand Behaviorally- Congruent All by Q1 2020 Multi-purpose STI Vaginal & Rectal √ completed study; √ Phase 2; Estimated start-completion dates for Enrolling & Planned studies

Conclusions Rectal microbicide promise based on tenofovir success: On demand Ipergay, vaginal microbicide efficacy, animal studies Community remains supportive of rectal microbicides Desire for on demand rectal microbicide Preferably in a formulation already used before anal sex In Response, 8 Rectal Microbicide studies 7 drugs, 4 formulations provide options to select best candidate for further safety & efficacy testing completed by 2020

Thank You!

Acknowledgements The Microbicide Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver  National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.