State of Global Rectal Microbicide Research

Ian McGowan MD PhD FRCP

Magee-Womens Research Institute

University of Pittsburgh

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

McGowan I, Biologicals, 2006

Microbicide Mechanism of Action

Rationale for 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

Murine and non human primate studies have shown proof of concept that rectal application of ARV microbicides can prevent SIV/HIV infection

Lubricants As a Drug Delivery System

MSM

DevelopedWorld

Women

0

10

20

30

40

50

Seattle St. Louis New Orleans

Per

cen

tag

e (%

)

DevelopingWorld

Clinical Development of Rectal Microbicides

Phase 1 Studies

Early Nonoxynol-9 Studies

Low-dose N-9 gel was not associated with macroscopic rectal and penile epithelial disruption or inflammation, but histologic abnormalities were commonly observed during N-9 gel as well as during placebo gel use. Tabet S et al. Sex Trans Dis 1999

2% N-9 showed rapid exfoliation of the rectal epithelium. Phillips D et al. Contraception 2004

HPTN 056 Study Design

Screening

Week - 2 0 + 2 + 4

Baseline Week 2 Week 4

ConsentPhysicalAnoscopyRectal GC/CHHIV AbCD4 / Viral load

SigmoidoscopyIntestinal biopsy at 10cm and 30cmCell isolation and flow cytometryTissue cytokinesRectal immunoglobulinsTissue / rectal secretion viral load

McGowan et al. JAIDS 2007

UC781 Trial Design

Screening Enrollment Randomization

0.1%

0.25%

Placebo

Baseline Endoscopy

Single dose2nd

Endoscopy7 singleDoses

3rd

Endoscopy

Anton P et al. PLoS ONE 2011

Explant Data (TCID50 102)

0

1000

2000

3000

4000

5000

6000

7000

V2 V3

Visit

Cu

mu

lati

ve P

-24

at D

ay 1

4 (p

g/m

l)

0

1000

2000

3000

4000

5000

6000

7000

V2 V3Visit

Cu

mu

lati

ve P

-24

at D

ay 1

4 (p

g/m

l)

(ID=41 0)

0

1000

2000

3000

4000

5000

6000

7000

V2 V3Visit

Cu

mu

lati

ve P

-24

at D

ay 1

4 (p

g/m

l)

0

1000

2000

3000

4000

5000

6000

7000

V2 V3Visit

Cu

mu

lati

ve P

-24

at D

ay 1

4 (p

g/m

l)

0

1000

2000

3000

4000

5000

6000

7000

V2 V3Visit

Cu

mu

lati

ve P

-24

at D

ay 1

4 (p

g/m

l)

0

1000

2000

3000

4000

5000

6000

7000

V2 V3Visit

Cum

ulat

ive

P-24

at D

ay

14 (p

g/m

l)

HEC Placebo UC781 0.10% UC781 0.25%

10cm

30cm

V2: Baseline; V3: 30 minutes post single dose

Oral or Topical ARV PrEP?

Oral

Topical

Concentration of ARV

Blood Mucosa

RMP-02/MTN-006

BaselineEvaluation

Open labelOral tenofovir

(N = 18)

Single rectal

tenofovir(N = 18)

2:1

7 DayRectal

tenofovir(N = 18)

2:1

Safety, PK / PD, acceptability

Anton et al. CROI 2011

Rectal Acceptability of Vaginal Tenofovir

0

20

40

60

80

PlaceboTenofovir

Like Discomfort Likelihood ofUse

% o

f p

arti

cip

ants

Pharmacokinetics in TissueC

on

cen

tra

tion

of T

VF

-DP

(fm

ol/m

g)

Route Oral Rectal (S) Rectal (7D)

N Detectable 7/18 10/12 12/12

PK/PD Relationship

0 1 2 3 40

5000

10000

15000

r2 = 0.33P = 0.0011

Oral Dose Single Rectal Dose Multiple Rectal Dose

Log10[Tissue TFV-DP ]fmol/mg

Cum

ulati

ve p

24 (p

g/m

L)

Mucosal Safety in RM Trials Epithelial sloughing Histopathology Mucosal mononuclear cell

phenotype Mucosal cytokine mRNA Luminex Microarray gene

expression Fecal calprotectin Rectal microflora

N-9

PRÉ

MTN-007

N=60

HEC(N=15)

1% Tenofovir

(N=15)

2% N-9(N=15)

Single dose

7 day daily doses

7-14 dayinterval

EndoscopySafety/behavioral

assessment

ScreeningNo

Treatment(N=15)

BaselineEvaluation

7-14 dayinterval

DAIDS Integrated Preclinical Clinical Program for HIV Topical

Microbicides

Microbicide Development Program

First IPCP focusing on rectal microbicide development

Provided proof of concept in the SIV NHP model and development of explant platform

Phase 1 clinical trials of the vaginal formulation of tenofovir gel UC781 (RMP-01) Tenofovir (RMP-02/MTN-006)

Behavioral correlates of RAI

Anton: IPCP U19 AI060614 / August 2004

CHARM Program Combination HIV Antiretroviral Rectal

Microbicide Program NIAID/DAIDS Integrated Preclinical Clinical

Program Consortium

University of Pittsburgh UCLA Johns Hopkins UNC CONRAD / Gilead

McGowan: IPCP U19 AI082637 / September 2009

CHARM Program Overview Development of rectal specific ARV

microbicides PK/PD evaluation in humanized mouse

model Phase 1 studies

Tenofovir Maraviroc Tenofovir & Maraviroc

CHARM-01 Pre-Phase 1 single dose comparison of

current formulations of tenofovir 1% gel: Vaginal formulation Reduced glycerin formulation Rectal specific formulation

Endpoints General and mucosal safety PK/PD

Current status Version 1.0

CHARM-02

Pre-Phase 1 single dose comparison of current formulations of tenofovir 1% gel with and without simulated RAI

Endpoints Pharmacokinetics Drug distribution using SPECT/CT imaging

Current status Version 1.0

Project Gel

McGowan & Carballo-Dieguez: NICHD R01 / September 2009

Microbicide Safety and Acceptability in Young Men

NICHD R01 Pittsburgh, Boston, Puerto Rico

Phase 1 safety and acceptability of tenofovir 1% gel Ethnically diverse MSM (18-30) Consensual RAI in last month Unprotected RAI in last year

Microbicide Safety and Acceptability in Young Men

Stage 1A

Screening

240 MSM

Consensual RAI in last month

URAI in last year

Stage 1B

3 month Acceptability & Adherence study with

placebo gel

120 MSM

RAI in last 3 months

STI negative

Stage 2

Phase 1 Tenofovirrectal

safety study

42 MSM

80% adherence in Stage 1B

Phase 2 Studies

MTN-017

Phase 2 rectal safety study of tenofovir gel

N = 210 International sites

United States (3) Thailand (2) South Africa (1) Peru (1)

Endpoints Safety Adherence

Self report Objective

measures Acceptability PK/PD

MTN-01712 weeks 12 weeks 12 weeks

BLTNF Gel

Daily

TNF Gel

ID

Oral

Truvada

BLTNF Gel

ID

TNF Gel

Daily

Oral

Truvada

BLOral

Truvada

TNF Gel

ID

TNF Gel

Daily

Mucosal PK/PD subset

Phase 2B/3 Studies

Combination Prevention

SC ± Oral ± Rectal ± Vaginal

Conventional HIV Prevention Package + PrEP

± HIV Vaccine

iPrEx Study 2,499 MSM and male-

to-female transgendered women randomized to Truvada or placebo

44% reduction in HIV acquisition

Higher drug concentrations associated with increased protection

Grant R et al. NEJM 2010

TMC-278 LA Rilpivirine NNRTI IM Nanosuspension Potential for 1-3 month

delivery Phase 1 PK/PD studies

ongoing Colorectal explants Cervicovaginal explants

MWRI-01* University of Pittsburgh Liverpool University

*Funded by the Bill and Melinda Gates Foundation

Arm 1

Arm 2

Arm 3

Arm 4

1200mg

1200mg

600mg 600mg600mg

600mg

900mg 900mg

1200mg + 900mg/ 3 monthlyPossible Arm 5

Possible Arm 5/6 300mg/ 1 monthly600mg/2 monthly

Initial Enrollment Secondary Enrollment

Screen Baseline +1 +2 +3 +4 +5

MWRI-01

Effectiveness Study Designs

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

Option 4: Tenofovir gel versus Truvada versus TMC 278 LA + standard prevention package

Sample Size Parameters

Assumptions Incidence rate ~ 5% Effect size 60% Lower bound 25% Minimum FU 12

months Enrollment

300/month PrEP effect 46% Endpoints: 120

Option1 N = 2,400; FU 24

months Option 2

N = 2,400; FU 30 months

Option 3 N = 2,400; FU 37

months

The VOICE Trial

Both oral and topical tenofovir arms stopped for futility

Reasons for failure not yet known Non adherence Compartmental PK Biology

Implications for rectal microbicide development?

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

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.

Acknowledgements