Transcript Slides - View the full AIDS 2016 programme

ART for Prevention…
What Happens Next?
Myron S. Cohen, MD
Yeargan-Bate Eminent Professor
Medicine, Microbiology and Epidemiology
Director, Institute for Global Health & Infectious Diseases
Long Acting Parenteral PrEP
Drug Development Phases
• Non Human Primate PROTECTION
• Phase 1 studies (HIV negative people)
-Safety
-Preliminary PK/PD
AGA Jackson, LJ Else, PMM Mesquita, D Egan, DJ Back, Z Karolia,
L Ringner-Nackter, CH Higgs, BC Herold, BG Gazzard and M Boffito
Clin Pharmacol Ther. 314, 2014
Rilpivirine Resistance: The Tail
Penrose KJ, Parikh UM, Hamanishi KA,
Panousis C, Else L, Back D, Boffito M,
Jackson A, Mellors JW.
Selection of rilpivirine resistant HIV-1 in a
seroconverter on long-acting rilpivirine
(TMC278LA) from the lowest dose arm of
the SSAT 040 trial.
HIV R4P Meeting 2014, Cape Town, South
Africa, Abstract OA27.01.
HPTN 076
HPTN 076: Safety and acceptability of injectable
rilpivirine for PrEP
136 HIV-uninfected, women ages 18-45 years
WEEKS
4
ARM 1
N = 91
Daily Oral
TMC278
ARM 2
N = 45
Daily oral
placebo
52
Six injections of TMC278 LA
every 8 weeks
Six injections of TMC278 LA
placebo
every 8 weeks
76
Follow-up phase
(tail phase)
Primary objective: Evaluate the safety of injectable rilpivirine through 48
weeks in women in SSA and the U.S.
HPTN 076
HPTN 076 – Rilpivirine Study Sites
US Sites
Bronx, NY
Newark, NJ
International Sites
Cape Town, South
Africa
Harare, Zimbabwe
Study Fully Enrolled
CABOTEGRAVIR:
GSK126744 Long Acting (744LA)
Favorable attributes for PrEP:
• High genetic barrier to resistance
• PK profile – half life of 21-50 days -allows once-daily oral or 1-3 month
injectable dosing using nanosuspension
formulation
Muller et al, European Journal of Pharmaceutics and Biopharaceutics,2011
Spreen, 7th IAS, 2013; Min, ICAAC, 2009
Taoda, International Congress on Drug Therapy in HIV Infection, 2012
CAB LA (GSK744) is an Effective PrEP Agent in
Rectal Challenge in Rhesus Macaques
Drug+virus challenges
Drug+virus challenges
GSK744
GSK744
100
10
8/8 protected
80
Placebo
GSK744LAP
60
40
p<0.0001
20
8/8 infected
0
0
2
4
6
8
Plasma GSK744 (mg/mL)
Percent Aviremic in Plasma
GSK744
Washout
1
0.10
0.01
10 12 14 16
Weeks Post First Challenge
Weekly SHIV 162p3 50xTCID50 Intrarectal
Challenge in Male Rhesus Macaques
(viral challenge weekly 0-7)
Andrews et al. 20th CROI 2013
0
2
II33
IP0
Range of GSK744 exposure in POC study
FH3
IK9
IK7
IH7
HI0
Open symbols =EP5
point of infection
IG7
HV3
4
6
8
10 12 14 16 18
HN
II64
Weeks post first challenge
SHIV 162p3 50xTCID50 Intrarectal
Challenge in Male Rhesus Macaques
(weekly viral challenge starting at Week 0)
Andrews et al. 21st CROI 2014
9
ÉCLAIR: Cabotegravir LA for PrEP in Low-Risk, HIVUninfected Men
Oral Phase
Injection Phase
Phase 2a
Double-blind
Men 18 to 65 years of age
Low-risk of acquiring HIV
No PEP or ART
No liver disease
5:1 randomization
Cabotegravir
30 mg qd
(n=105)
Cabotegravir LA 800 mg
IM every 12 weeks
(n=94)
Placebo
(n=21)
Saline Placebo
IM every 12 weeks
(n=21)
Week 0
Baseline characteristics (cabotegravir oral phase):
Median age: 31 years.
White/black race/ethnicity: 56%/31%.
Hispanic/Latino race/ethnicity: 15%.
Median height: 176 cm.
Median BMI: 26 kg/m2.
Risk for HIV acquisition:
Homosexual contact: 85%.
Heterosexual contact: 21%
Occupational exposure: 2%.
Markowitz M, et al. 23rd CROI. Boston, 2016. Abstract 106.
4 5
41
HPTN 077
HPTN 077: Safety, tolerability and pharmacokinetics
of injectable cabotegravir (CAB) in men and women
4
WEEKS
Cohort 1
194
ARM 1
N = 79
ARM 2
N = 27
HIVuninfected,
ages 18-65
Cohort 2
41
81
Daily
Oral
Injections of CAB 800 mg
every 12 weeks x 3
CBT
Follow-up
30mg
Phase
(Tail Phase)
Daily
Injections of CAB placebo
Oral
every 12 weeks x 3
Placebo
4
WEEKS
41
ARM 1
N = 66
Daily
Oral
CBT
30mg
Injections of CAB 600 mg
every 4 weeks x 2
then every 8 weeks X3
ARM 2
N = 22
Daily
Oral
Placebo
Injections of CAB placebo
every 4 weeks x 2
then every 8 weeks x 3
85
Follow-up
Phase
(Tail Phase)
Primary objective: Evaluate the safety and tolerability of the injectable CAB
in HIV-uninfected men and women
HPTN 077
HPTN 077 – Cabotegravir Study Sites
US Sites
Los Angeles, California
San Francisco, California
Washington, DC
Chapel Hill, North Carolina
International Sites
Soweto, South Africa
Durban, South Africa
Lilongwe, Malawi
Rio de Janeiro, Brazil
Enrollment complete
Cabotegravir and Rilpivirine
As Two-Drug Oral Maintenance
Therapy: LATTE Week 96
Results
David A. Margolis,1 Cynthia C. Brinson,2
Graham H.R. Smith,3 Jerome de Vente,4 Debbie P.
Hagins,5 Sandy K. Griffith,1 Marty H. St. Clair,1 Kimberly
Smith,6 Peter E. Williams,7 William R. Spreen1
1GlaxoSmithKline,
Infectious Diseases, Research Triangle Park, NC, USA;
Texas Clinical Research, Austin, TX, USA; 3Maple Leaf Medical Clinic,
Toronto, ON, Canada; 4Living Hope Foundation, Long Beach, CA, USA; 5Chatham
County Health Department, Savannah, GA, USA; 6ViiV Healthcare, Research
Triangle Park, NC, USA; 7Janssen R&D, Beerse, Belgium
2Central
22nd Conference on Retroviruses and Opportunistic Infections; February 23-26, 2015; Seattle, WA
HPTN 083
HPTN 083: Efficacy of injectable cabotegravir
(CAB) for PrEP in MSM and transgender women
•
•
•
•
N = 4500;
Goals: 10% TGW overall; 50% of US BMSM; 50% overall < 30 year old
Study duration: 3-5 years
Sites in North and South America; Asia; SSA (limited)
CAB
TDF/FTC
Step 1
Daily oral CAB and
oral TDF/FTC placebo
Daily oral TDF/FTC and
oral CAB placebo
Step 2
CAB injection x 2, 4 weeks apart
then every 8 weeks
plus daily oral TDF/FTC placebo
Placebo injection x 2, 4 weeks apart
then every 8 weeks
plus daily oral TDF/FTC
Step 3
Open-label daily oral TDF/FTC to
cover the PK tail, for up to 48 weeks
Primary objective: HIV Incidence
HPTN 084: Cabotegravir PrEP for Women
• Dr. Sinead Delaney Protocol Chair
• Study design under discussion
NOTE PARTNERSHIP BETWEEN
NIH/HPTN and VIIV, PEPFAR, USAID, and
BMGF
HPTN 084: Efficacy of Injectible Cabotegravir
for PrEP in HIV-uninfected Women
• In the early stages of protocol
development
• Sites will be in sub-Saharan Africa
• Team currently discussing:
•
•
•
Superiority study
Open-label
1:1 Randomization
Primary objective: HIV Incidence
Blinded versus Unblinded
Blinded
• Participants
– Receive both injection
and pills
– Know if pill is active,
will only work if taken
• Question answered
– Closer to efficacy of
drug itself
– Difference in
characteristics of
adherers minimal
Unblinded
• Participants
– Receive either injection
or pill
– Those on pill know it
will work only if taken
• Question answered
– Closer to effectiveness
of intervention
– Adherer characteristics
will differ between arms
– Behavior changes are
possible
MK-8591 (Efda) CROI 2016!
-EC50 in PBMCs of 0.2 nM
-Half life in PBMCs100 hours
HIV treatment?
Peroral weekly prevention?
Development of a long acting implant
BC and PrEP implant combined?
The best drug development plan?
THANK YOU FOR LISTENING