PrEP: Is Longer Better?

Myron S. Cohen, MD

Yeargan-Bate Eminent Professor

Medicine, Microbiology and Epidemiology

Director, Institute for Global Health & Infectious Diseases

TDF/FTC was FDA

Approved for use for

Prevention on

July 16, 2012

Success depends entirely on adherence

Alternatives to daily dosing are possible

Truvada PrEP uptake has been limited to date

Perhaps longer acting agents will prove more attractive?

Long Acting Parenteral PrEP

Cabotegravir Nanosuspension• Drug nanocrystal suspended in aqueous vehicle

• Nanomilled to increase surface area and drug dissolution rate

• Allows ~100% drug loading vs. matrix approaches for lower injection volumes

Müller, et al. European Journal of Pharmaceutics

and Biopharmaceutics 78 (2011) 1-9

Cabotegravir 200 mg/mL Mean Concentration-Time Profile

Following Single Dose Injection

Spreen, et al. JAIDS 2015

LATTE-2: Cabotegravir IM + Rilpivirine IM for Long-Acting Maintenance ART

Multicenter, open-label phase IIb study– Primary endpoints: HIV-1 RNA < 50 c/mL by FDA snapshot, PDVF, and safety at maintenance Wk 32

Slide credit: clinicaloptions.comMargolis DA, et al. CROI 2016. Abstract 31LB.

CAB 400 mg IM + RPV 600 mg IM Q4W(n = 115)

CAB 600 mg IM + RPV 900 mg IM Q8W(n = 115)

*Pts with HIV-1 RNA < 50 c/mL from Wk 16 to Wk 20 continued to maintenance phase. In snapshot induction analysis, 14 pts had virologic non-response and 13 pts had no virologic data in window, including 6 pts who discontinued for AEs or death and 7 pts who discontinued for other reasons.

ART-naive HIV-infected pts withCD4+ cell count >

200 cells/mm3

(N = 309) CAB 30 mg PO + ABC/3TC PO QD(n = 56)

CAB 30 mg PO QD + ABC/3TC

Wk 32primary analysis;

dose selection

Wk 20

Induction Phase* Maintenance Phase

Wk 1 Wk 96Wk 16: RPV PO Added

Step 1Daily oral CAB and

TDF/FTC placebo

TDF/FTC and

oral CAB placebo

Step 2

CAB LA at two time points 4

weeks apart and every 8 weeks

thereafter and TDF/FTC placebo

TDF/FTC and injectable

placebo at two time points 4

weeks apart and every 8 weeks

thereafter

Step 3

Open-label TDF/FTC to

cover the PK tail, for up to 48

weeks

Open-label TDF/FTC for up to 48

weeks

Primary Objective: HIV Incidence, double blind double dummy, non-inferiority

N=4500; Study duration: Enrollment 24-30 months; follow-up up to 4.5 y

Enrollment goals:

• Minimum 50% of US enrollment Black MSM (~ 950)

• Overall minimum 10%TGW (~ 450)

• Overall > 50% under age 30

HPTN 083: CAB LA to Prevent HIV

Acquisition in MSM and TGW

28 Sites in the U.S.

5 Sites in Peru

1 Site in South Africa

1 Site in India

3 Sites in Thailand

1 Site in Vietnam

4 Sites in Brazil

2 Sites in Argentina

45 HPTN 083 Research Sites WorldwideAs of October 2016

Step 1Oral

5 WeeksDaily oral CAB

30 mgTDF/FTC

300 mg/ 200 mg

Step 2Injection

Phase

CAB LA 600 mg IMat two time points

4 weeks apart / every 8 weeks

TDF/FTC Daily Visits every 8 weeks

TDF/FTC use measured

Step 3Follow Up

Phase

TDF/FTC for all subjects

HPTN 084: CAB LAPrevent HIV Acquisition in Females

Delaney-Moretlwe and Hossinipour

Primary outcome: Reduce HIV incidence (superiority)

N= 3600 HIV negative women

• HIV Prevention Trials Network

• National Institutes for Health

• OGAC/PEPFAR

• United States Agency for International

Development

• Bill & Melinda Gates Foundation

• ViiV Healthcare

• Gilead Sciences, Inc.

The Cabotegravir PrEP Partnership

MK-8591

• Non-obligate chain terminator; inhibits reverse transcriptase by preventing translocation

• Potent activity (PBMC EC50 = 0.2 nM) with broad subtype and mutant coverage (HIV-1, HIV-2, MDR strains)

• MK-8591-TP exhibits persistence (t1/2 = 103 hr) in human PBMCs allowing for extended-duration dosing

• Parenteral formulations exhibited >180-day extended release after a single injection in rats

– Ongoing studies suggest the potential to provide coverage for durations up to 1 year

10

Michailidis et al (2009) JBC

Subcutaneous PrEP Implants

• Simple insertion AND removal

• Long-acting (months to years)

• PrEP + contraception?

• Current development:

– TAF, EFdA (MK-8591)

Schlesinger, et al, Pharm Res 2016; Gunawardana, et al., AAC 2015

• V1V2-Glycan – bind to trimer cap

• V3-glycan, N332 supersite

• gp41 MPER – near membrane

• gp120/41 interface – bind to parts of

both gp120 and gp41

• CD4 binding site of gp120 – where the

virus attaches to CD4

Neutralizing Ab to HIV-1

V3-glycan V1V2-glycan

CD4 binding site

gp41

MPER

gp120/41

interface

Christina Corbaci, Andrew Ward,

VRC01, 3BNC11

• PGb126 protects against rectal/vaginal challenge Moldt, AIDS 2016

• VRC01 delivered by AAV prevents infection Saunders, JV 2015

• Combination BnABs selected through modelingWagh, PLOS Path 2016

• Single dose BnaB(s) protect repeated challenges Gautam, Nature 2016

• PG121 protection is “distal” to the mucosaLiu, Science 2016

BnABs Prevent SHIV in Non-Human Primates

Science. 2016 Sep 2;353(6303):1045-1049

Jinyan Liu, Khader Ghneim, Devin Sok, William Bosche, Yuan Li, Elizabeth Chipriano, Brian Berkemeier, Kelli Oswald,Erica Borducchi, Crystal Cabral, Lauren Peter, Amanda Brinkman, Mayuri Shetty, Jessica Jimenez, Jade Mondesir,Benjamin Lee, Patricia Giglio, Abishek Chandrashekar, Peter Abbink, Arnaud Colantonio, Courtney Gittens, ChantelleBaker, Wendeline Wagner, Mark Lewis, Wenjun Li, Rafick-Pierre Sekaly, Jeffrey Lifson, Dennis Burton, Dan H. Barouch

Antibody-mediated protection

against SHIV challenge includes

systemic clearance of distal virus

• Animals infused with PGT121 (or placebo) day -1

• Vaginal exposure to SHIV on day 0

• SHIV RNA and DNA detected in tissues 1-3 days after exposure (distal to the site of infection)

• SHIV was then eliminated by PGT 121 (and inflammation) over 7 days, but not in controls

Current mAbs are More Potent and

Broadly Reactive than Previous mAbs

CAVD David Montefiori (PI)NVITAL Bailer, Louder et al.

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VRC01 Protects against Mucosal

SHIV162P3 Challenge in NHP

4/4 protected

0/4 protected

4/4 protected

1/4 protected

20 mg/kg infusion of VRC01

The AMP Studies: Highlights

Cohort IV Treatment n= Schedule

North + South

American MSM

(2400)

HVTN 704 / HPTN 085

VRC01 10 mg/kg 800

Every 8 wks

x 10 dosesVRC01 30 mg/kg 800

Placebo Control 800

Sub-Saharan

African women

(1500)

HVTN 703 / HPTN 081

VRC01 10 mg/kg 500

Every 8 wks

x 10 dosesVRC01 30 mg/kg 500

Placebo Control 500

• Two different infusion doses:

Important to know if lower dose of 10 mg/kg can protect

• Powered to associate mAb serum level with protection

HVTN 704/HPTN 085,

MSM + TG

HVTN 703/HPTN 081,

Women

45 AMP Research Sites WorldwideAs of September 2016

HVTN 704/HPTN 085 (MSM+TG)

20

0

500

1000

1500

2000

2500

3000

AMP MSM+TG: Cumulative Enrollment vs Projections

(as of 19 September 2016)

Target Cumulative Enrolled

THANK YOU