Myron S Cohen MD YearganBate Eminent Professor Medicine Microbiology and Epidemiology Director Institute for Global Health amp Infectious Diseases Long Acting Parenteral PrEP Drug Development ID: 676538
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Slide1
ART for Prevention…What Happens Next?
Myron S. Cohen, MDYeargan-Bate Eminent ProfessorMedicine, Microbiology and Epidemiology Director, Institute for Global Health & Infectious DiseasesSlide2
Long Acting Parenteral
PrEPSlide3
Drug Development PhasesNon Human Primate PROTECTIONPhase 1 studies (HIV negative people)
-Safety -Preliminary PK/PDSlide4
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
Clinical Pharmacolo
g
y
&
TherapeuticsSlide5
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.
Rilpivirine
Resistance: The TailSlide6
ARM 1N = 91
Daily Oral
TMC278Six injections of TMC278 LA
every 8 weeksFollow-up phase(tail phase)
ARM
2
N = 45
Daily oral
placebo
Six injections of TMC278
LA placebo
every 8 weeks
HPTN 076: Safety and acceptability of injectable
rilpivirine for PrEP
136 HIV-uninfected, women ages 18-45 years
WEEKS 4 52 76
Primary objective
:
Evaluate the safety of
injectable rilpivirine through 48 weeks in women in SSA and the U.S.
HPTN
076Slide7
HPTN 076 – Rilpivirine Study Sites
US Sites
Newark, NJ
International Sites
Cape Town, South Africa
Harare, Zimbabwe
Bronx, NY
HPTN
076
Study Fully
E
nrolled Slide8
CABOTEGRAVIR:GSK126744 Long Acting (744LA)
Muller et al, European Journal of Pharmaceutics and Biopharaceutics,2011
Spreen
, 7th IAS, 2013; Min, ICAAC, 2009Taoda, International Congress on Drug Therapy in HIV Infection, 2012
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
formulationSlide9
CAB LA (GSK744) is an Effective PrEP Agent in Rectal Challenge in Rhesus Macaques
9
Weekly SHIV 162p3 50xTCID50 Intrarectal Challenge in Male Rhesus Macaques
(viral challenge weekly 0-7)
SHIV 162p3 50xTCID50 Intrarectal
Challenge in Male Rhesus Macaques
(weekly viral challenge starting at Week 0)
Andrews et al. 20
th
CROI 2013
8/8 protected
8/8 infected
Drug+virus challenges
Washout
GSK744
GSK744
GSK744
Drug+virus challenges
Range of GSK744 exposure in POC study
Open symbols =
point of infection
Andrews et al. 21
st
CROI 2014Slide10
ÉCLAIR: Cabotegravir LA for PrEP in Low-Risk, HIV-Uninfected Men
Markowitz M, et al. 23rd CROI. Boston, 2016. Abstract 106.
Cabotegravir LA 800 mg
IM every 12 weeks
(n=94)
Saline Placebo
IM every 12 weeks
(n=21)
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
Week 0 4 5
41
Injection Phase
Cabotegravir
30 mg qd
(n=105)
Placebo
(n=21)
Oral Phase
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%.Slide11
ARM 1
N
= 79Daily OralCBT30mg
Injections of CAB 800 mg every 12 weeks x 3
Follow-up Phase
(Tail Phase)
ARM
2
N
= 27
Daily Oral
Placebo
Injections of
CAB placebo every 12 weeks x 3
HPTN 077: Safety, tolerability and
pharmacokinetics of injectable cabotegravir (CAB) in men and women
HIV-uninfected,
ages
18-65
194
WEEKS 4 41 81
HPTN 077
Primary objective
:
Evaluate the safety and tolerability of the injectable CAB in HIV-uninfected men and womenCohort 1Cohort 2 ARM 1N = 66Daily OralCBT30mgInjections of CAB 600 mg every 4 weeks x 2then every 8 weeks X3Follow-up Phase(Tail Phase)ARM 2N = 22Daily OralPlaceboInjections of CAB placebo every 4 weeks x 2then every 8 weeks x 3WEEKS 4 41 85 Slide12
HPTN 077 – Cabotegravir Study Sites
US Sites
Los Angeles, California
Chapel Hill, North Carolina
International Sites
Soweto, South Africa
Durban, South Africa
Lilongwe, Malawi
Rio de Janeiro, Brazil
San Francisco, California
Washington, DC
HPTN
077
Enrollment completeSlide13
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. Spreen11GlaxoSmithKline, Infectious Diseases, Research Triangle Park, NC, USA; 2Central 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, BelgiumSlide14
Step 1
Daily oral CAB and
oral TDF/FTC placebo
Daily oral TDF/FTC and oral CAB placebo
Step 2CAB 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 d
aily oral TDF/FTC
Step 3
Open-label daily oral TDF/FTC to
cover the PK tail, for up to 48 weeks
CAB
HPTN 083
HPTN 083: Efficacy of injectable
cabotegravir
(CAB) for PrEP in MSM and transgender women
TDF/FTC
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)
Primary objective
: HIV IncidenceSlide15
Dr. Sinead Delaney Protocol ChairStudy design under discussion NOTE PARTNERSHIP BETWEEN NIH/HPTN and VIIV, PEPFAR, USAID, and BMGF
HPTN 084: Cabotegravir PrEP for WomenSlide16
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 studyOpen-label
1:1 Randomization
Primary objective
: HIV IncidenceSlide17
Blinded versus UnblindedBlinded
ParticipantsReceive both injection and pillsKnow if pill is active, will only work if takenQuestion answeredCloser to efficacy of drug itselfDifference in characteristics of adherers minimalUnblindedParticipants
R
eceive either injection or pillThose on pill know it will work only if takenQuestion answeredCloser to effectiveness of interventionAdherer characteristics will differ between armsBehavior changes are possible Slide18
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?Slide19
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