The Science of Rectal Microbicides  Can We Make Them And Will       People Use Them?       Ian McGowan MD PhD FRCP     Mag...
Microbicides are products thatcan be applied to the vaginal orrectal mucosa with the intent of   preventing or significant...
How do Microbicides Work?McGowan I, Biologicals, 2006
Why Rectal Microbicides? Unprotected receptive anal intercourse  (RAI) is the highest risk sexual activity  for HIV trans...
The Target Audience
Lube or a Rectal Microbicide?
OsmolalityThe concentration of a solution in terms of osmoles        of solutes per kilogram of solventIso-osmolar fluids ...
Is Lube Safe?           Lubricant   Osmolality (mmol/kg)Semen                                321PRÉ                       ...
How to Make aRectal Microbicide
Phase 1 Studies Safety   General   Mucosal Acceptability Adherence (Efficacy)
Anatomy 101
Rectal Mucosa
A Phase 1 RM Study                                                          0.1%                             BaselineScree...
Oral or Topical ARV PrEP?          Blood              Mucosa OralTopical          Concentration of ARV
RMP-02/MTN-006                                    Safety, PK / PD, acceptability                                         S...
Product Acceptability                    80                                                             Tenofovir         ...
Enough Drug?    Concentration of TVF-DP          (fmol/mg)Route                          Oral   Rectal (S)   Rectal (7D)N ...
In Vitro Explant ChallengeEndoscopic biopsies   +  Virus                       +/-                      Drug
Did the Microbicide Work?       Oral Dose              Single Rectal Dose       Multiple Rectal Dose               15000  ...
MTN-007                                  7-14 day          7-14 day               2% N-9              interval          in...
Gastrointestinal SymptomsGI Adverse Events         MTN-007         RMP-02/MTN-006in the Tenofovir Arm      (N = 16)       ...
Gastrointestinal SymptomsGI Adverse Events         MTN-007         RMP-02/MTN-006in the Tenofovir Arm      (N = 16)       ...
Changes in the Rectal Mucosa               Placebo Gel                 (N = 16)               Tenofovir Gel               ...
Other Rectal Microbicide        Studies
CHARM Program Combination HIV Antiretroviral Rectal  Microbicide Program Development of rectal specific ARV  microbicide...
Project GelNICHD R01: Ian McGowan & Alex Carballo-Dieguez
Microbicide Safety and         Acceptability in Young Men      Stage 1A               Stage 1B                Stage 2     ...
Phase 2 Studies
MTN-017 Phase 2 rectal           Endpoints  safety study of            Safety  tenofovir gel              Adherence N...
MTN-017     8 weeks      8 weeks    8 weeks     TNF Gel      TNF Gel      OralBL       Daily      With sex   Truvada     T...
Phase 2B/3 Studies
Combination PreventionConventional HIV Prevention Package + PrEP   SC    ±   Oral     ±   Rectal   ±   Vaginal            ...
What Will Phase 3 Look Like? Option 1: Tenofovir gel versus placebo +  standard prevention package Option 2: Tenofovir g...
Social Marketing
Rectal Microbicide Timeline*               2010 2011 2012 2013 2014 2015 2016 2017 2018Phase 1Phase 2Phase 2BReviewAvailab...
Summary Rectal microbicides are needed for men and  women in the developed and developing  world who are at risk of HIV a...
Acknowledgements
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The Science of Rectal Microbicides Can We Make Them And Will People Use Them?

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

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  • Study Objectives: Primary To evaluate the safety of tenofovir 1% gel when applied rectally Secondary To evaluate the acceptability of tenofovir 1% gel when applied rectally To evaluate the safety of HEC placebo gel when applied rectally Secondary To determine whether use of tenofovir 1% gel is associated with rectal mucosal damage To determine whether use of 2% Nonoxynol-9 gel (Gynol-II ® ) is associated with rectal mucosal damage
  • Individual symptoms/adverse events only reported once per participant at the highest grade Fisher’s exact test / two tailed
  • Individual symptoms/adverse events only reported once per participant at the highest grade Fisher’s exact test / two tailed
  • The Science of Rectal Microbicides Can We Make Them And Will People Use Them?

    1. 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. 2. Microbicides are products thatcan be applied to the vaginal orrectal mucosa with the intent of preventing or significantly reducing the risk of acquiring STIs including HIV
    3. 3. How do Microbicides Work?McGowan I, Biologicals, 2006
    4. 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. 5. The Target Audience
    6. 6. Lube or a Rectal Microbicide?
    7. 7. OsmolalityThe concentration of a solution in terms of osmoles of solutes per kilogram of solventIso-osmolar fluids Hyperosmolar fluids (~ 300) (~ 3,000)
    8. 8. Is Lube Safe? Lubricant Osmolality (mmol/kg)Semen 321PRÉ 502KY Jelly 2510ID Glide 3150Elbow Grease 3865Astroglide 6113Gynol II (N9) 1245Wet Platinum NA
    9. 9. How to Make aRectal Microbicide
    10. 10. Phase 1 Studies Safety  General  Mucosal Acceptability Adherence (Efficacy)
    11. 11. Anatomy 101
    12. 12. Rectal Mucosa
    13. 13. A Phase 1 RM Study 0.1% BaselineScreening Enrollment Randomization 0.25% Endoscopy Placebo 2nd 7 single 3rd Single dose Endoscopy Doses EndoscopyAnton et al. PloS ONE 2011
    14. 14. Oral or Topical ARV PrEP? Blood Mucosa OralTopical Concentration of ARV
    15. 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 2:1Anton et al. CROI 2011
    16. 16. Product Acceptability 80 Tenofovir Placebo% of participants 60 40 20 0 Like Discomfort Likelihood of Use
    17. 17. Enough Drug? Concentration of TVF-DP (fmol/mg)Route Oral Rectal (S) Rectal (7D)N Detectable 7/18 10/12 12/12
    18. 18. In Vitro Explant ChallengeEndoscopic biopsies + Virus +/- Drug
    19. 19. Did the Microbicide Work? Oral Dose Single Rectal Dose Multiple Rectal Dose 15000 10000 ViralInfectionIn Rectal 5000Biopsies 0 0 1 2 3 4 Drug Concentration in the Biopsies
    20. 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. 21. Gastrointestinal SymptomsGI Adverse Events MTN-007 RMP-02/MTN-006in 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. 22. Gastrointestinal SymptomsGI Adverse Events MTN-007 RMP-02/MTN-006in 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. 23. Changes in the Rectal Mucosa Placebo Gel (N = 16) Tenofovir Gel (N = 642)
    24. 24. Other Rectal Microbicide Studies
    25. 25. CHARM Program Combination HIV Antiretroviral Rectal Microbicide Program Development of rectal specific ARV microbicides Humanized mouse model Phase 1 studies  Tenofovir  Maraviroc  Tenofovir & MaravirocIPCP: U19 AI082637
    26. 26. Project GelNICHD R01: Ian McGowan & Alex Carballo-Dieguez
    27. 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 negativeR01 HD059533
    28. 28. Phase 2 Studies
    29. 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. 30. MTN-017 8 weeks 8 weeks 8 weeks TNF Gel TNF Gel OralBL Daily With sex Truvada TNF Gel TNF Gel OralBL With sex Daily Truvada Oral TNF Gel TNF GelBL Truvada With sex Daily
    31. 31. Phase 2B/3 Studies
    32. 32. Combination PreventionConventional HIV Prevention Package + PrEP SC ± Oral ± Rectal ± Vaginal ± HIV Vaccine
    33. 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. 34. Social Marketing
    35. 35. Rectal Microbicide Timeline* 2010 2011 2012 2013 2014 2015 2016 2017 2018Phase 1Phase 2Phase 2BReviewAvailableVaginalmicrobicides *An approximation based on tenofovir 1% gel
    36. 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. 37. Acknowledgements

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