1. XIX International AIDS Conference
Expanding the Method Mix: Current and planned trials of different ARV-based approaches for women
Zeda Rosenberg, Sc.D.
XIX International AIDS Conference
Washington, DC
26 July 2012

2. Need for Multiple Drugs & Formulations
More drug choices, more options for protection
Different women, different preferences
Vaginal gels, rings, films, tablets, soft gel capsules – all found to be acceptable in IPM studies in Africa
Slide last updated: 18 July 2012
Mention injectable methods on this slide (not pictured) since TMC278 is discussed at the end of the presentation.
The delivery vehicle for a drug is just as critical as the active substance itself. Scientists developing microbicides must consider the various characteristics of the product that may affect use over prolonged periods as well as issues such as cost and women’s and their partners’ preferences.
History has taught that the more product choices people have, the more likely they are to use one of them for protection. Some people might prefer a gel used around the time of sex; or a once-daily gel, film or tablet; or a vaginal ring that could be used monthly or longer.
A product’s effectiveness depends on its acceptability to women and their male partners. Even the most efficacious microbicide will not work if it is not used correctly or consistently. Feedback from clinical trials in many developing countries points to the need for microbicides that are not perceived to interfere with sexual intercourse and that can be used discreetly. It is crucial that cultural differences surrounding sexual practices are considered when developing novel delivery methods for microbicides.
Mention IPM product acceptability studies: PAS I, PAS II, IPM 011 (all these studies assessed acceptability among women, and also included interviews/focus groups with a smaller number of male partners – in various African countries and communities).
Vaginal gel applicator
Vaginal tablet, soft gel capsule, film
Vaginal ring

3. Prioritizing Products
Adherence/ Acceptability
Formulation Potential
Tablet/ capsule
Promising microbicide
DS 003
MAR
Human experience
MIV-150
Redundancy
Film
DPV
Ring
Dev. partners
Potency
Gel
Mechanism of action
Cost & resource needs
TFV
Stage of development
Manufacturing

4. Dapivirine (TMC120) Highly potent ARV (NNRTI) Developed by Janssen
Originally tested as oral therapeutic in 11 studies
Licensed to IPM in 2004
Development as topical microbicide for HIV prevention
15 Phase I/II safety studies (dapivirine ring or gel)
Good safety profile in 15 studies to date
Data on more than 700 study participants before efficacy studies
Dapivirine Ring Licensure Program started in 2012
Slide last updated: 19 July 2012
Dapivirine or TMC120, is a highly potent ARV that belongs to the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which stop the HIV virus at the replication stage.
Dapivirine was developed by Janssen R&D Ireland (previously Tibotec Pharmaceutials) which then licensed the drug to IPM. Janssen initially tested dapivirine as an oral therapeutic in 11 Phase I clinical trials, among more than 200 participants. These studies included assessments of safety, PK and clinical efficacy.
The 15 dapivirine ring and gel studies include:
Gel: Completed (1 Tibotec study; IPM 003, 004, 005B, 012); in data analysis (IPM 014A, 014B, 020 and IPM 010/ MTN 012)
Ring: Completed (IPM 001, 008, 018, 024, 013); in data analysis (IPM 015)
IPM and MTN will be starting long-term safety and efficacy studies of the dapivirine ring in 2012 (The Ring Study and ASPIRE)
IPM 026/MTN-013, a Phase I study of the first combination microbicide (dapivirine-maraviroc ring) compared to a dapivirine ring; maraviroc ring; and placebo ring. Study is now ongoing at 3 MTN-affiliated sites in US

5. Dapivirine Vaginal Ring
Potent NNRTI
Local distribution, low systemic absorption
Potential for drug combinations
Long-acting: monthly (or longer)
Could potentially improve adherence
Better adherence → better effectiveness
Easy to use, comfortable
Flexible ring, can be self-inserted
Rarely felt by women or their male partners
Little or no impact on sexual activity
Suitable for developing world
Relatively low manufacturing cost
Stability / shelf-life
Important potential new option for women
Dapivirine vaginal rings are the lead dapivirine candidate for Phase III testing and licensure.
Dapivirine is a potent ARV, safe and well tolerated as tested in over 20 Phase I and I/II clinical trials to date (in oral, gel and ring form)
Vaginal rings are a promising technology, used safely for contraception (i.e. NuvaRing) and hormone therapy for post-menopausal women (i.e. Femring) in developed countries
An acceptability study conducted by IPM in Africa shows good acceptability and a high willingness to use the vaginal ring for HIV protection (IPM 011)
The rings are flexible, can be self-inserted, easy to use, are rarely felt by women during their daily activities, and pose little or no interference with sexual activity
Dapivirine rings are designed as long-acting products, with the potential to improve product adherence, which in turn could lead to better effectiveness of the product in preventing infection
In PK studies conducted to date, there was steady drug release from matrix-type rings over one month, and very low systemic absorption
The manufacturing cost of the rings is relatively low, and therefore rings would be suitable for distribution in developing countries.

6. Vaginal Ring Acceptability
Acceptability among women
Ring was very comfortable: 95%
Ring not felt during daily activities: 99%
Willing to use if effective: 100%
Most favorable characteristics
Potential for HIV prevention
Ring does not alter sexual experience
Ring is worn every day
Male partner involvement
Important that partner accepts ring: 84%
Would use without telling partner: 63%
Most men reported not feeling ring during sex; no impact on sexual pleasure; and no side effects
Slide last updated: 30 September 2011
Data presented is from IPM 011
Open-label placebo ring, randomized crossover design; N = 170 women
Study Sites: Tanzania (1) South Africa (3)
12 weeks of placebo ring, 12 weeks of no product
Safety assessed by pelvic/speculum examination, colposcopy, and AE monitoring
Adherence assessed through self-report at each of three 4-weekly visits during ring use period
Qualitative data collected from women and male partners at study exit
Ring was used continuously for 3 months in this study, followed by an observational safety period (with no ring) of 3 months (or vice-versa)
In addition to questionnaires at each study visit: participant focus groups (n=6 groups, 49 women) and male partner interviews (n=19) conducted at end of study
- Preliminary data presented at the Microbicides 2010 Conference, Pittsburgh, and additional final data presented at CROI 2011, Boston

7. Vaginal Ring Adherence (IPM 015)
Cumulative adherence over 12 weeks (N=261)
84% had perfect adherence (ring never out)
92% had 100% daily adherence (ring never out for ≥1 day)
Ring “ever out” reported in 5% of 1082 visit intervals
Expulsions= 2%; Removals= 3%
Sex occurred without the ring at 1.2% of visit intervals

8. Summary of Social-Behavioral Data (IPM 015)
Ring was highly acceptable and women reported preferring continuous use
Ring had minimal impact on sex for women participants or male partners
High reported adherence to monthly use of ring
Expulsions were rare and decreased over time
Mostly associated with urination and bowel movement
Removals were rare but increased over time
Mostly to clean ring

9. The Ring Study (IPM 027)
Dapivirine vaginal ring long-term safety and efficacy study
Double-blind, placebo-controlled, randomized (2:1)
Targeted enrollment: women, ages 18-45
5 sites South Africa, Rwanda
Rings inserted every 4 weeks
Length of participant follow-up: 2 years
Sites initiated in South Africa: Q1-2012; Results in 2015
Study objectives
Primary: Long-term safety and efficacy of dapivirine ring when inserted once every 4 weeks over a period of 24 months
Secondary: Incidence of HIV-2; incidence of STIs; pregnancy; adherence and acceptability; frequency of drug resistance
Slide last updated: 16 July 2012

10. The ASPIRE Study (MTN-020)
A Study to Prevent Infection with a Ring for Extended Use
Dapivirine vaginal ring safety and efficacy study
Double-blind, randomized (1:1)
Targeted enrollment: women, ages 18-45
Rings inserted every 4 weeks
Length of participant follow-up: 1 year min, 2 years max
17 planned sites in Malawi, Uganda, S.Africa, Zambia and Zimbabwe
First sites initiated: July 2012 (S. Africa and Uganda); Results in 2014
Study objectives
Primary: Efficacy and safety of dapivirine ring when inserted once every 4 weeks
Secondary: acceptability; adherence; frequency of HIV-1 drug resistance; relationship between drug levels and seroconversions
Slide last updated: 16 July 2012

11. Dapivirine Ring Timelines
2012
2013
2014
2015
2016
DPV Ring Regulatory Consultations
Regulatory submissions for product approval
The Ring Study (IPM 027)
ASPIRE (MTN-020)
Drug-drug interaction study
Adolescent and pre-/peri-menopausal women safety studies
Slide last updated: 18 July 2012
DPV Ring Regulatory Consultations include: Parallel Scientific Advice procedure (Q Q1 2012); FDA/EMA consultations on CMC, design of safety trials (Q Q4-2012)
IPM 027 Regulatory Submissions: South Africa RCs received all approval to start v1.0 of IPM 027 protocol by Feb IPM submitted V1.0, amend. 1 of the protocol beginning in South Africa January Submissions in Rwanda are expected in Q
IPM 027 estimated timelines:
Inv. Mtg - mid (Feb 2012), first SIVs in SA (Feb-Mar 2012), first participant enrolled (Q1 2012)
all participants enrolled (Q4 2012), last participant visit (Q1 2015), final study report (Q3 2015)
MTN-020 estimated timelines:
first approvals received (Q1/Q2 2012), first SIVs (May 2012)
all participants enrolled (Q2 2013), last participant visit (Q2 2014), final study report (Q4 2014)
Condom compatibility study
Open-label / post-marketing studies

12. Dapivirine in other formulations
FAME 02: Dapivirine Gel and Film
Phase I safety and pharmacokinetics
60 women, ages 18-45
4 study arms
Dapivirine film, placebo film, dapivirine gel, placebo gel
Conducted by Magee Women’s Research Institute
Initiating Q3 2012

13. Maraviroc
CCR5 blocker with established safety profile as marketed oral therapeutic (Selzentry™)
Developed by Pfizer
Licensed to IPM in 2008 for microbicide indication in developing world
Clinical development:
Maraviroc rings alone and in combination with dapivirine
Preclinical development:
Maraviroc gel (rectal use)- Magee Women’s Research Institute
Maraviroc/tenofovir combination in early preclinical development
Slide last updated: 18 July 2012
Why combination microbicides?
Precedent of HAART & PMTCT
Potential increased efficacy against resistant virus
Coverage of multiple transmission pathways
Maraviroc – unique mechanism of action

14. Dapivirine/Maraviroc Ring Trial
MTN-013 / IPM 026: Phase 1 PK & safety vaginal ring
3 research centers in the United States
Study design:
4 arms: dapivirine-maraviroc ring, dapivirine ring, maraviroc ring, placebo ring
N = 48 women
28 days on product + 24 days of follow-up
Fully enrolled
Results expected Q4 2012
Data last updated: 18 July 2012
Study Locations:
Boston, MA (Fenway Institute); Birmingham, AL (University of Alabama at Birmingham); Pittsburgh, PA (University of Pittsburgh Medical Center)
Population:
Healthy, HIV-negative, sexually abstinent, years of age
Pharmacokinetics (PK)
Drug concentrations in plasma, cervicovaginal fluid & cervical tissue
Safety
Self-reported genital symptoms
Pelvic/colposcopic examination findings (including vaginal flora and vaginal pH)
Adverse Event/Serious Adverse Event reports
Laboratory evaluations of hematology, and liver and renal function
First clinical trial of a combination microbicide & first clinical trial of maraviroc for HIV prevention 14

15. TMC278 Injectable Developed by Janssen Clinical development
NNRTI approved for therapeutic use in 2011 (Edurant ™)
Clinical development
St. Stephen’s AIDS Trust
Phase I safety and PK
MWRI-01
Magee Women’s Research Institute (U. of Pittsburgh)
Phase I safety, acceptability and PK/PD
90 women and men (2:1); sequential cohorts
Planned study start: Q3 2012
Ian McGown’s study- MWRI-01. It is undergoing significant design modifications since the grant was funded (mainly due to IRB responses). It will now enroll women and men (2:1 ratio) in sequential cohorts looking at single (1200 mg and 600 mg) doses of TMC278 and then in subsequent cohorts multiple doses at 2 month or 1 month intervals. The study will assess safety, acceptability, and PK/PD. We will use ex vivo explant challenge (cervicovaginal and colorectal) and rectal / cervical secretions as the PD models. Total enrollment = 90, single site (Pittsburgh). We hope to start screening Q

16. MIV-150 NNRTI Developed by Medivir AB
Licensed to Population Council in 2003
Preclinical development
MIV-150 monthly ring
Combination rings: MIV-150/zinc acetate and MIV-150/contraceptive
Combination gel: MIV-150, zinc acetate
Info pulled from PopCouncil website
PopCouncil has developed both silicone and EVA rings, though focus seems to be shifting to EVA because PC studies showed EVA rings released 5x as much MIV-150
MIV-150 originally developed as an HIV therapeutic
Per the Pop Council website, “Based on current progress, Phase 1 trials testing the MIV-150/zinc acetate gel versus the zinc acetate alone are projected to commence in early 2012.” And per the AVAC database, the Phase I trial is planned by PC/USAID in October 2012.

17. Microbicides: What’s Next
New drugs, new mechanisms of action
DS 003
Darunavir
Integrase inhibitors
Multipurpose Prevention Products
HIV prevention plus additional indication (i.e. pregnancy prevention, prevention of other STIs, etc.)
ARVs and hormonal contraceptives
IPM, CONRAD, Pop Council
Slide last updated: 30 April 2012
MPTs:
The Pop Council is developing multipurpose prevention technologies that combine antiviral and contraceptive ingredients into one product for on-demand or long-term use. A dual-protection gel for women who have sex irregularly combines LNG, a contraceptive agent, with two antiviral agents (MIV-150 and zinc acetate). The Council is also developing this combination of drugs as an intravaginal ring for long-term use