Ian McGowan's presentation at the AIDS 2021 satellite "Rectal Microbicides - Making HIV Prevention Gel" - July 22, 2012

1. The Science of Rectal Microbicides
Can We Make Them And Will
People Use Them?
Ian McGowan MD PhD FRCP
Magee-Womens Research Institute
University of Pittsburgh

2. Microbicides are products that
can be applied to the vaginal or
rectal mucosa with the intent of
preventing or significantly
reducing the risk of acquiring
STIs including HIV

3. How do Microbicides Work?
McGowan I, Biologicals, 2006

4. Why Rectal Microbicides?
 Unprotected receptive anal intercourse
(RAI) is the highest risk sexual activity
for HIV transmission
 Men and women in the developed and
developing world practice RAI
 Most people use lube for anal sex
 Animal studies have shown that rectal
microbicides can prevent HIV infection

5. The Target Audience

6. Lube or a Rectal Microbicide?

7. Osmolality
The concentration of a solution in terms of osmoles
of solutes per kilogram of solvent
Iso-osmolar fluids Hyperosmolar fluids
(~ 300) (~ 3,000)

8. Is Lube Safe?
Lubricant Osmolality (mmol/kg)
Semen 321
PRÉ 502
KY Jelly 2510
ID Glide 3150
Elbow Grease 3865
Astroglide 6113
Gynol II (N9) 1245
Wet Platinum NA

9. How to Make a
Rectal Microbicide

10. Phase 1 Studies
 Safety
 General
 Mucosal
 Acceptability
 Adherence
 (Efficacy)

11. Anatomy 101

12. Rectal Mucosa

13. A Phase 1 RM Study
0.1%
Baseline
Screening Enrollment Randomization 0.25%
Endoscopy
Placebo
2nd 7 single 3rd
Single dose
Endoscopy Doses Endoscopy
Anton et al. PloS ONE 2011

14. Oral or Topical ARV PrEP?
Blood Mucosa
Oral
Topical
Concentration of ARV

15. RMP-02/MTN-006
Safety, PK / PD, acceptability
Single 7 Day
Open label rectal Rectal
Baseline Oral tenofovir tenofovir tenofovir
Evaluation (N = 18) (N = 18) (N = 18)
2:1 2:1
Anton et al. CROI 2011

16. Product Acceptability
80
Tenofovir
Placebo
% of participants
60
40
20
0
Like Discomfort Likelihood of
Use

17. Enough Drug?
Concentration of TVF-DP
(fmol/mg)
Route Oral Rectal (S) Rectal (7D)
N Detectable 7/18 10/12 12/12

18. In Vitro Explant Challenge
Endoscopic biopsies
+
Virus
+/-
Drug

19. Did the Microbicide Work?
Oral Dose Single Rectal Dose Multiple Rectal Dose
15000
10000
Viral
Infection
In Rectal 5000
Biopsies
0
0 1 2 3 4
Drug Concentration in the Biopsies

20. MTN-007
7-14 day 7-14 day
2% N-9 interval interval
(N=17)
1% TFV Baseline Single 7 day daily
N=65
(N=16) Evaluation dose doses
HEC
(N=16)
Screening Endoscopy
No Safety/behavioral
Treatment assessment
(N=16)
PI: Ian McGowan

21. Gastrointestinal Symptoms
GI Adverse Events MTN-007 RMP-02/MTN-006
in the Tenofovir Arm (N = 16) (N = 12)
RG Formulation Original Formulation
N %
Abdominal pain 6 50%
Rectal urgency 5 42%
Bloating 5 42%
Nausea 4 33%
Diarrhea 7 58%
Flatulence 3 25%
Proctalgia 0 0%
Other 5 42%
Total 12 100%

22. Gastrointestinal Symptoms
GI Adverse Events MTN-007 RMP-02/MTN-006
in the Tenofovir Arm (N = 16) (N = 12)
RG Formulation Original Formulation
N % N %
Abdominal pain 3 16% 6 50%
Rectal urgency 0 0% 5 42%
Bloating 0 0% 5 42%
Nausea 0 0% 4 33%
Diarrhea 1 6% 7 58%
Flatulence 6 38% 3 25%
Proctalgia 1 6% 0 0%
Other 4 25% 5 42%
Total 9 56% 12 100%

23. Changes in the Rectal Mucosa
Placebo Gel
(N = 16)
Tenofovir Gel
(N = 642)

24. Other Rectal Microbicide
Studies

25. CHARM Program
 Combination HIV Antiretroviral Rectal
Microbicide Program
 Development of rectal specific ARV
microbicides
 Humanized mouse model
 Phase 1 studies
 Tenofovir
 Maraviroc
 Tenofovir & Maraviroc
IPCP: U19 AI082637

26. Project Gel
NICHD R01: Ian McGowan & Alex Carballo-Dieguez

27. Microbicide Safety and
Acceptability in Young Men
Stage 1A Stage 1B Stage 2
Screening 3 month acceptability & Phase 1 Tenofovir
adherence study with rectal
240 MSM placebo gel safety study
Consensual RAI 120 MSM 42 MSM
in last month
RAI in last 3 months 80% adherence in
URAI in last year Stage 1B
STI negative
R01 HD059533

28. Phase 2 Studies

29. MTN-017
 Phase 2 rectal  Endpoints
safety study of  Safety
tenofovir gel  Adherence
 N = 186  Self report
 International sites  Objective
 measures
United States (4)
 Acceptability
 Thailand (2)
 PK/PD
 South Africa (1)
 Peru (1)

30. MTN-017
8 weeks 8 weeks 8 weeks
TNF Gel TNF Gel Oral
BL
Daily With sex Truvada
TNF Gel TNF Gel Oral
BL
With sex Daily Truvada
Oral TNF Gel TNF Gel
BL
Truvada With sex Daily

31. Phase 2B/3 Studies

32. Combination Prevention
Conventional HIV Prevention Package + PrEP
SC ± Oral ± Rectal ± Vaginal
± HIV Vaccine

33. What Will Phase 3 Look Like?
 Option 1: Tenofovir gel versus placebo +
standard prevention package
 Option 2: Tenofovir gel versus placebo +
standard prevention package + permission to
use PrEP (HVTN 505)
 Option 3: Tenofovir gel versus placebo +
standard prevention package + Truvada

34. Social Marketing

35. Rectal Microbicide Timeline*
2010 2011 2012 2013 2014 2015 2016 2017 2018
Phase 1
Phase 2
Phase 2B
Review
Available
Vaginal
microbicides
*An approximation based on tenofovir 1% gel

36. Summary
 Rectal microbicides are needed for men and
women in the developed and developing
world who are at risk of HIV associated with
unprotected RAI
 RM development has moved from Phase 1 to
Phase 2
 PK/PD models should increase likelihood of
success in Phase 2B/3
 Planning for an RM effectiveness study needs
to start now.

37. Acknowledgements