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Open Label Multiple Dose Phase 1 Assessment of Long Acting Rilpivirine

This study evaluates the safety, acceptability, and pharmacokinetics/pharmacodynamics of long-acting Rilpivirine (RPV) administered via intramuscular injection. Results show mild to moderate injection site pain and significant accumulation of RPV in various matrices. Viral inhibition against rectal explant infection persists up to 4 months after the last injection, with greater suppression of Clade C virus compared to Clade B. Cervical explant infection was only suppressed at one time point.

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Open Label Multiple Dose Phase 1 Assessment of Long Acting Rilpivirine

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  1. An Open Label Multiple Dose Phase 1 Assessment of Long Acting RilpivirineIan McGowan MD PhD FRCP on behalf of the MWRI-01 Study Team TUAC0103

  2. Disclosures • Consultant • ABIVAX • Novicol Health Sciences • Employment • Chief Medical Officer at AELIX Therapeutics

  3. Introduction

  4. Long Acting (LA) PrEP • Increasing interest in using LA PrEP for the prevention of HIV infection • LA PrEP may reduce adherence challenges associated with oral and topical PrEP • Proof of concept efficacy data from the NHP (cabotegravir) and the humanized mouse (rilpivirine) models • Status of LA PREP studies • LA Rilpivirine stopped in Phase 2a • Cabotegravir in Phase 2b/3 TUAC0103

  5. Previous Single Dose Data Pharmacodynamics (PD) Pharmacokinetics (PK) PK/PD McGowan I et al. Lancet HIV 2016 TUAC0103

  6. Methods

  7. Study Objectives • Primary • To evaluate the safety and acceptability of LA rilpivirine (RPV) given as an intramuscular (IM) injection • Secondary • To determine the PK profile of LA RPV following single and multiple IM injections • Exploratory • To evaluate cervical, vaginal, and rectal explant HIV infection following exposure to LA RPV TUAC0103

  8. MWRI-01 Study Design 1200 mg 600 mg 1200 mg 1200 mg 1200 mg 1200 mg 600 mg 1200 mg 1200 mg 1200 mg PK/PD samples TUAC0103

  9. Methods • Pharmacokinetics • RPV concentrations in all matrices were quantified by validated high-pressure liquid chromatography-mass spectrometry1 • Pharmacodynamics • Ex vivo explant infection2 with Clade B (HIV-1BaL) and wild type Clade C viruses • Explant endpoint: Weight-adjusted cummulative supernatant Day 14 HIV-1 p24 1Else LJ et al. Bioanalysis 2014 2McGowan I et al. Lancet HIV 2016

  10. Results of Multiple Dosing

  11. Demographics TUAC0103

  12. Overall Adverse Events TUAC0103

  13. Injection Site Pain (ISP) TUAC0103

  14. Extremely likely Product Feedback Nervous Painful Likely to Product Use @ injections injections use $25 $50 $100 Extremely unlikely TUAC0103

  15. Extremely likely Barriers to Use Extremely unlikely Cost Side Protection Stigma Harmful Needles Effects TUAC0103

  16. Plasma PK 1st dose (SD) 2nd dose (MD2) 3rd dose (MD3) 3rd dose (PK tail) RPV (ng/mL) Time (days) 1st dose: single dose (SD) 2nd dose: multi-dose (MD2) 3rd dose: multi-dose (MD3) Data presented as geometric mean (90% confidence intervals) TUAC0103

  17. Rectal Tissue PK 1st dose (SD) 2nd dose (MD2) 3rd dose (MD3) 3rd dose (PK tail) RPV (ng/mL) Time (days) TUAC0103

  18. Vaginal and Cervical Tissue PK 1st dose (SD) 2nd dose (MD2) 3rd dose (MD3) 3rd dose (PK tail) RPV (ng/mL) Time (days) TUAC0103

  19. Rectal Tissue PD TUAC0103

  20. Vaginal and Cervical Tissue PD TUAC0103

  21. Rectal Tissue PK/PD Clade B virus (HIV-1BaL) Clade C virus (G147-1) O Female O Male TUAC0103

  22. Cervical Tissue PK/PD [RPV] in tissue [RPV] in plasma TUAC0103

  23. Conclusions

  24. Overall Summary (1) • Three 1200 mg doses of LA RPV given IM were safe and acceptable • Mild to moderate injection site pain was the most common adverse event • RPV Accumulation • Modest but significant accumulation of RPV was seen in all matrices TUAC0103

  25. Overall Summary (2) • Viral inhibition of both Clade B and Clade C rectal explant infection persisted out up to 4 months after the last injection of LA RPV • Magnitude of suppression of Clade C >> Clade B explant infection • Cervical explant infection was only suppressed at one time point • 2 months after the first injection of LA RPV TUAC0103

  26. Acknowledgements • The MWRI-01 participants • University of Pittsburgh Clinical and Stats Support • Ross Cranston • Beatrice Chen • Sharon Achilles • James Egan • Patty Peters • Carly Mowry • Carol Mitchell • Stacey Edick • Kaleab Abebe • Cindy Jacobson • University of Pittsburgh Lab Support • Charlene Dezzutti • Kathy Duffill • Aaron Siegel • Urvi Parikh • John Mellors • Alexyi Nikorov • Laura Janocko • University of Pittsburgh Recruitment and Project Management Support • Jarret Engstrom • Rhonda Brand • Kathy McCarthy • University of Liverpool • David Back • Laura Else • Janssen R & D • Peter Williams • Marita Stevens • Maria Saraiva • Alpha StatConsult LLC • Nicola Richardson-Harman • Bill & Melinda Gates Foundation • Lut Van Damme

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