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

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Presentation on theme: "An Open Label Multiple Dose Phase 1 Assessment of Long Acting Rilpivirine Ian McGowan MD PhD FRCP on behalf of the MWRI-01 Study Team TUAC0103."— Presentation transcript:

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

2 Disclosures Consultant Employment ABIVAX Novicol Health Sciences
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 I added the acronym to the title TUAC0103

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

6 Methods

7 Study Objectives Primary Secondary Exploratory
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 PK/PD samples TUAC0103 BL +1M +2M +3M +4M +5M +6M
1200 mg Female (N=8) Arm 1A Arm 2A Arm 3A 1200 mg 600 mg Male (N=4) Arm 1B Arm 2B Arm 3B 1200 mg 600 mg PK/PD samples X TUAC0103

9 Methods Pharmacokinetics Pharmacodynamics
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 1200mg Overall (n=12) Female (n=8) Male (n=4)
Race Black 2 (16.7%) 1 (12.5%) 1 (25.0%) White 9 (75.0%) 6 (75.0%) 3 (75.0%) More than 1 race 1 (8.3%) 0 (0.0%) Ethnicity Hispanic Not 11 (91.7%) 7 (87.5%) 4 (100%) Age ± SD 28.9 ± 7.9 26.8 ± 7.1 33.3 ± 8.4 Weight (lbs.) ± SD 160.0 ± 40.7 137.1 ± 24.5 205.8 ± 21.7 Height ± SD 67.2 ± 4.6 64.9 ± 3.2 71.8 ± 3.6 BMI ± SD 24.5 ± 3.7 22.8 ± 2.9 28.0 ± 2.6 TUAC0103

12 Overall Adverse Events
Grade Overall 1200mg n=12 Female n=8 Male n=4 Number of AE % of Total AE % of Total AE Number of AE 1 138 70.8 94 74.0 44 64.7 2 55 28.2 33 26.0 22 32.4 3 1.0 0.0 2.9 4 Total 195 100 127 68 Two G3 (unrelated) finger laceration and subsequent infection TUAC0103

13 Injection Site Pain (ISP)
Grade Overall 1200mg n=12 Female n=8 Male n=4 Number of AE % of Total ISP AE Number of AE 1 2 16.7 25.0 10 83.3 6 75.0 4 100 3 0.0 TUAC0103

14 Product Feedback Extremely likely
Nervous Painful Likely to Product injections injections use $ $ $100 Extremely unlikely TUAC0103

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

16 Plasma PK RPV (ng/mL) Time (days)
1st dose (SD) 2nd dose (MD2) 3rd dose (MD3) 3rd dose (PK tail) GMR (90% CI) AUC (1 month) AUC (2 months) MALES (Arm 3B) MD2/SD 1.04 ( ) 1.07 ( ) MD3/SD 1.66 ( ) 1.64 ( ) MD3/MD2 1.59 ( ) 1.54 ( ) RPV (ng/mL) GMR (90% CI) AUC (1 month) AUC (2 months) FEMALES (Arm 3A) MD2/SD 1.31 ( ) 1.29 ( ) MD3/SD 1.20 ( ) 1.31 ( ) MD3/MD2 0.91 ( ) 1.01 ( ) I re-jigged the dose explanation box plasma exposure/AUC (expressed as ng*day/ml) over 1 & 2 months following the 2nd dose (MD2; day 56-84/112) and 3rd dose (MD3; day /168) were compared with exposures achieved with the 1st dose (SD) and previous dose (MD2), using geometric mean ratios (90% Confidence intervals). The changes in PK parameters (accumulation) are considered significant when the CI do not cross the value 1 (shown in bold text). MALES: There is evidence of accumulation following the third dose in males (MD3 significantly different from SD & MD2). FEMALES: There is evidence of accumulation in plasma following the second dose (MD2 significantly different from SD), however, there doesn't appear to be any further accumulation following the third dose (MD3 vs. MD2). 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 RPV (ng/mL) Time (days) TUAC0103 GMR (90% CI)
1st dose (SD) 2nd dose (MD2) 3rd dose (MD3) 3rd dose (PK tail) GMR (90% CI) Rectal Tissue 2 months post dose MALES (Arm 3B) MD2/SD 1.48 ( ) MD3/SD 1.15 ( ) MD3/MD2 0.77 ( ) RPV (ng/mL) I moved everything down a bit [RT] (expressed as ng/ml) taken at 2 months post dose following the 2nd dose (day 112) and 3rd dose (day 168) were compared with [RT] achieved with the 1st dose (SD; day 56) and previous dose (MD2), using geometric mean ratios (90% Confidence intervals). The changes in PK parameters (accumulation) are considered significant when the CI do not cross the value 1 (shown in bold text). MALES: There is evidence of accumulation following the second dose in males (MD2 significantly different from SD), but no further accumulation observed after the third dose (MD3 vs. MD2/SD), in fact levels fell slightly. FEMALES: [RT] significant accumulation was observed after the third dose only, as compared with the 1st dose (MD3 significantly higher than SD). GMR (90% CI) Rectal tissue 2 months post dose FEMALES (Arm 3A) MD2/SD 1.33 ( ) MD3/SD 1.44 ( ) MD3/MD2 1.08 ( ) Time (days) TUAC0103

18 Vaginal and Cervical Tissue PK
1st dose (SD) 2nd dose (MD2) 3rd dose (MD3) 3rd dose (PK tail) GMR (90% CI) Cervical tissue 2 months post dose FEMALES (Arm 3A; cervical tissue) MD2/SD 1.37 ( ) MD3/SD 1.55 ( ) MD3/MD2 1.12 ( ) RPV (ng/mL) Again, moved down [VT] (expressed as ng/ml) taken at 2 months post dose following the 2nd dose (day 112) and 3rd dose (day 168) were compared with [VT] achieved with the 1st dose (SD; day 56) & previous dose (MD2) using geometric mean ratios (90% Confidence intervals). The changes in PK parameters (accumulation) are considered significant when the CI do not cross the value 1 (shown in bold). There is evidence of accumulation in VT following the second/third doses (MD2 & MD3 significantly different from SD), however, there doesn't appear to be any further accumulation following the third dose (MD3 vs. MD2). [ET] (expressed as ng/ml) taken at 2 months post dose following the 2nd dose (day 112) and 3rd dose (day 168) were compared with [ET] achieved with the 1st dose (SD; day 56) & previous dose (MD2), using geometric mean ratios (90% Confidence intervals). The changes in PK parameters (accumulation) are considered significant when the CI do not cross the value 1 (shown in bold). There is evidence of accumulation in ET following the second dose (MD2 & MD3 significantly different from SD), however, as with VT, there doesn't appear to be any further accumulation following the third dose (MD3 vs. MD2). GMR (90% CI) Vaginal tissue 2 months post dose FEMALES (Arm 3A; Vaginal Tissue) MD2/SD 1.68 ( ) MD3/SD 1.84 ( ) MD3/MD2 1.09 ( ) 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 Moved down a bit 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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