the future of prep - breach - homeprevention the future of prep breach spring meeting, la hulpe 2017...
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Prevention
The Future of PrEP
Breach Spring Meeting, La Hulpe 2017
Jan van Lunzen, MD PhD, DTM&HProfessor of MedicineSenior Global Medical DirectorViiV Healthcare, London, UK
CONFIDENTIAL – FOR INTERNAL USE AND PLANNING PURPOSES ONLY
Disclaimer
• JvL is a full term employee at ViiV Healthcare, London, UK
Contents
1 Where are we?
2 Intravaginal rings
3 Passive immunization
4 Long-acting strategies - Injectables
5 Long-acting strategies - Implants
6 Where are we going?
7 Summary and outlook
Prevention
Where are we?
Current status of completed PrEP trials
Clinical Trial Evidence for HIV Prevention Options (February 2016)
Prevention of sexual transmission
Adapted from: Salim S. Abdool Karim, CAPRISA
Effectiveness (%)
Prevention in people who inject drugs
Effect size
(CI)
Bangkok Tenofovir Study – daily oral TDF(PWID– Thailand)
0 100-130
PROUD – daily oral TDF/FTC(MSM – United Kingdom)
IPERGAY – event-driven TDF/FTC (MSM – Canada, France)
Partners PrEP – daily oral TDF/FTC(Serodiscordant couples – Kenya, Uganda)
Partners PrEP – daily oral TDF(Serodiscordant couples – Kenya, Uganda)
TDF2 – daily TDF/FTC(Heterosexual men and women – Botswana)
iPrEx – daily oral TDF/FTC(MSM – North and South America, South Africa, Thailand)
CAPRISA 004 – BAT-24 dosing vaginal tenofovir gel(Women – South Africa)
RV 144 – six injectable ALVAC/AIDSVAX(Heterosexual men and women – Thailand)
The Ring Study – monthly vaginal ring containing dapivirine(Women – South Africa, Uganda)
ASPIRE – monthly vaginal ring containing dapivirine(Women – Malawi, South Africa, Uganda, Zimbabwe)
MTN 003/VOICE – daily dosing vaginal tenofovir gel(Women – South Africa, Uganda, Zimbabwe)
FEM-PrEP – daily oral TDF/FTC(Women – Kenya, South Africa, Tanzania)
FACTS 001 – event-driven vaginal tenofovir gel(Women – South Africa)
MTN 003/VOICE – daily oral TDF/FTC(Women – South Africa, Uganda, Zimbabwe)
MTN 003/VOICE – daily oral TDF(Women – South Africa, Uganda, Zimbabwe)
86% (58; 97)
86% (44; 99)
75% (55; 87)
67% (44; 81)
62% (22; 84)
44% (15; 63)
39% (6; 60)
31% (1; 51)
31% (1; 51)
27% (1; 46)
15% (-21; 40)
6% (-21; 40)
0% (-40; 30)
-4% (-49; 27)
-49% (-129; 3)
49% (10; 72)
20 40 60 80-40 -20-60
R
R
DELIVERY SYSTEM
Tenofovir disoproxil
fumarate (TDF)
Dapivirine
Tenofovir/
emtricitabine (TDF/FTC)
Tenofovir
Vaginal gel Vaginal
ring
Oral
pills
VaccineALVAC/AIDSVAX
ACTIVE DRUG
R
Relationship Between Effectiveness and
Adherence in Microbicide & PrEP Trials
Pearson correlation = 0.86, p=0.003
-60
-40
-20
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80 90
Eff
ec
tiv
en
ess
(%
)
Percentage of Participants’ Samples with detectable drug levels
CAPRISA 004
iPrEX
TDF2
PartnersPrep (TDF)
PartnersPreP (FTC)
FemPrEP
VOICE (TDF)
VOICE (Truvada)
VOICE (TFV gel)
SS Abdool Karim, personal communication
Partners PrEP (TDF)
Partners PrEP (Truvada)
IPERGAY(Truvada)
PROUD(Truvada)
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
The Ring Study 31% (1; 52)
ASPIRE 27% (1; 46)
Prevention
Intravaginal Rings
Dapivirine IVR Studies
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Dapivirine Intravaginal Ring Study Results
The Ring Study ASPIRE
Relative reduction in HIV-1
incidence overall
31%(95% CI 1 to 52,
p=0.04)
27%(95% CI 1 to 46,
p=0.046)
Reduction in an as-
randomized analysis among
women > 21 yo
37%(95% CI 3.5 to 59,
p=0.43)
56%(95% CI 31 to 71,
p=0.0003)
Reduction in women ≤ 21 yo15%
(95% CI -60 to 55,
p=0.07)
-27%(95% CI -131 to 31,
p=0.45)
• no safety concerns or clinically relevant differences in safety parameters
were observed between active and placebo rings
• adherence measures were significantly lower among women 18-21 yo
compared to women > 21 yo
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Table heading
CONFIDENTIAL – FOR INTERNAL USE AND PLANNING PURPOSES ONLY
Prevention Product Preference
IVRs are new to RLS and NOT a preferred platform
Luecke et al. JIAIDSS 2016, 19:20875 Quaife et al. IAC 2016
DPV IVR Summary
• Impact and uptake are unknown due to low efficacy in younger women and lack
of familiarity with the platform
• Success will require a lot of coordinated effort
• Cost at current scale ~$7/ring; target cost at advanced scale-up ~$2-3/ring
Opportunities Threats
User-controlled and flexible for infrequent sex Low overall efficacy
No theoretical concerns about long-term systemic
side effects
No efficacy and continued adherence challenges in
young SSA women
No oral lead-in or lead-out coverage needed Eliminate requirement for daily adherence
Could be less expensive than injectable Reduced discretion, can be detected by partner, may
involve partner negotiation
Likely to get guideline recommendation (age groups
unknown)
Not a common delivery platform in SSA; significant
education and market shaping required
No protection from anal intercourse
US/EU uptake expected to be low
Prevention
Passive Immunization
Broadly-Neutralizing Antibodies (bNAbs)
CONFIDENTIAL – FOR INTERNAL USE AND PLANNING PURPOSES ONLY
Gruell and Klein, MMW 2015
Clinical Investigation of bNAbs in HIV-1 infection
Prevention
A
B
C
Intensification
Prevention of Rebound
New bNAbs/combination
D “shock and kill”Inducer Inducer
Passive Immunisation
Therapy ART
Planned; KwaZulu-Natal
(FRESH cohort, Ragon/RU)
Planned; Acute Infection
(Cologne, DZIF study sites)
Ongoing
(Rockfeller University)
Initiated (12/2015)
(Cologne, Rockfeller University)
Initiated (3/2016)
(Cologne, Aarhus, New York)
VRC01 Phase I study (safety and PK)
Monoclonal antibody potency and breadth
Bi-specific
Antibodies
(T cell – Env)
Dual-affinity re-
targeting
(DARTs)
Fc-Modification
(Half-life)
Fc-Modification
(ADCC)
CD3 gp160
Sung et al., 2015Pegu et al., 2015
CD3 gp160
Inter/Intraspike
crosslinking
Activity
Galimidi et al., 2015Bournazos et al., 2014
gp160 gp160
e.g. LS
Mutation
Half-life ADCC
FcRn Affinity FcR Affinity
e.g.
GASDALIE
Mutation
Gautam et al., 2016
Bi-specific
Antibodies
(Env – Env)
gp160 gp160
Ko et al., 2014
Strategies to advance HIV bNAbs
Prevention
Prevention
Prevention
bNAb Summary
• Current AMP dose-ranging studies are PoC only and designed for optimization
of future studies with improved product; no regulatory or commercial intent
• High priority area of investment for NIH
Opportunities Threats
Long-acting modifications in pipeline show much less
frequent infusions needed (2/year)
PoC has not been demonstrated yet
Enrolment has been brisk demonstrating acceptability
of infusion model
Long-term tolerability and cost of infusions unknown
Pre-existing “natural” escape mutants, selection of
escape variants in the population
Prevention
Long-acting strategies
Injectables
CONFIDENTIAL – FOR INTERNAL USE AND PLANNING PURPOSES ONLY
Cabotegravir LA and Rilpivirine LA:
Comparative information Attribute Cabotegravir LA Rilpivirine LA
Drug concentration 200 mg/mL 300 mg/mL
Refrigeration/stabilityNo; store up to 30°C
24 monthsYes; store at 2–8°C
36 months
Protect from light No Yes
Dose – monthly 400 mg (2 mL) 600 mg (2 mL)
Dose – bimonthly 600 mg (3 mL) 900 mg (3 mL)
Dosage instructions/needle gaugeHCP administration
Gluteal IM25 G
HCP administrationGluteal IM
21 G
t1/2 with single dose (range or SD)~40 days
(25–54 days)44–61 days(±24 days)
Drug interactions
Barrier to resistance
Low liability as perpetrator or victim
High
Low liability as perpetrator; victim of CYP3A4 induction/inhibition
Low
25
Cab Development: Simultaneous Global Registration
programs underway in two indications
Pearson correlation = 0.86, p=0.003
Treatment
Prevention
MSM/TGWÉCLAIR(n=127)
Prevention
womenHPTN 077*
(n=200)
Indication Phase 2 Phase 3
Early Phase
LATTE-1
LATTE-2
HPTN 083(n=4500)
FLAIR (I/M)
ATLAS (switch)
HPTN 084(n=3600)
*Includes both men and women
Dec 2016 FSFV
end 2017 FSFV
Oct 2016 FSFV
ARM 1
N = 79
Daily Oral
CAB
30mg
Injections of CABLA 800 mg every 12
weeks at three time points Follow-up
Phase
(Tail Phase)ARM 2
N = 27
Daily Oral
PlaceboInjections of CABLA placebo
every 12 weeks at three time points
HPTN 077: Phase IIa Safety, Tolerability and PK of Cabotegravir in HIV-
uninfected Men and Women
HIV-
uninfected,
ages 18-65
200
WEEKS 4 41 81
Primary objective: Safety and tolerability of the cabotegravir LA injectable through Week 41 in HIV- uninfected men and women
Cohort 1
N=110
Cohort 2
N=90
ARM 1
N = 66
Daily Oral
CAB
30mg
Injections of CABLA 600 mg every 4
weeks at two time points and then
every 8 weeks at three additional time
pointsFollow-up
Phase
(Tail Phase)ARM 2
N = 22
Daily Oral
Placebo
Injections of CABLA placebo every 4
weeks at two time points and then
every 8 weeks at three additional time
points
WEEKS 4 41 85
• enrollment is complete and f/u is ongoing
• 67% are women
Prevention
Prevention
Prevention
Prevention
Prevention
HIV PrEP CAB LA Injectable Development Issue:Unknown resistance risk yet to be characterized
• CAB LA trailing drug levels last many months and may lead to INI resistance with seroconversion event
• As of 4Q16 – drug concentration range / time period of risk is unknown
• Mitigation while on PrEP: adherence to injection dosing schedule
• Mitigation after CAB LA PrEP: continue HIV prevention measures, which may include oral ARV PrEP to cover PK tail, in settings of continued HIV risk
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Time (weeks)
0 4 8 12 16 20 24 28 32 36 40 44 48
Pla
sm
a G
SK
1265744 (
g/m
L)
0.1
1
100mg IM
200mg IM
400mg IM
800mg IM (split)
100mg SC
200mg SC
400mg SC (split)
4*PAIC90 (0.664mg/mL)
1*PAIC90 (0.166mg/mL)
PrEP and Drug Resistance: Current KnowledgeDrug resistance risk mitigated in TVD and DPV to date
TDF/FTC – very favorable benefit/risk• Low incidence in clinical trials (0.05%) and post-approval settings• Highest risk if PrEP started during undiagnosed acute HIV infection• Nearly all resistance occurs to low genetic barrier drug – FTC
Dapivirine IVR (non-systemic)• No excess risk compared to placebo control arm in Phase 3 studies
Rilpivirine LA • PK tail reported to persist up to 18 months or more• One case report of RPV resistance selection during PK tail in Phase 1 while drug
levels at or below PA-IC90• RPV has lower genetic barrier vs. CAB
Cabotegravir LA • PK tail persists 6-12 months or more• Absolute risk is unknown as is drug concentration range and time period• CAB has high barrier to resistance in vitro, similar to DTG• NHP challenge studies – no resistance in breakthrough infections• CDC NHP study in acute infection setting suggests resistance risk (observed in 3/6
animals , submitted to CROI 2017)
33
EFdA (MK 8591)
• Non obligate chain terminator
• Inhibits reverse transcriptase by preventing translocation
• Potent antiviral activity (PBMC EC50 = 0.2 nM) with broad subtype and
mutant coverage
Grober J et al. CROI 2016; Boston MA, Abstract 98
• Low dose amenable to extended duration parenteral formulation
• >180 extended release from solid state formulations after a single dose
MK-8591 parenteral formulations release
effective drug levels for >180 days
Friedman et al. CROI 2016; Boston MA, Abstract 437LB
Prevention
Long-acting strategies
Implants
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Solid implants
Solid implants
Durasert (Psivida)-Retinal implant-Eg. Iluvien : rate of 0.25 μg/day and lasts 36 months
Duros (Durect)-matchstick size implant-up to 1000mg drug concentration
ITCA650 (Intarcia)-matchstick size-same tech as Duros (on left)-sustained release up to 1yr
MicroCHIP drug delivery (MicroCHIP)-programmable, remote-controlled release of drugs
Durin (Durect)-biodegradable implant-drug core surrounded by a rate-controlling sheath-can be a pellet or rod-sustained release up to 6mths
SynBiosys (Innocorepharmaceuticals)-for sc or ocular delivery -biodegradable; sustained release up to 6mths-Low temperature processing
Diabetic macular edema (Iluvien); diabetes (Pfizer)
Prostate cancer (Viadur)
Diabetes (approval est 2016)
Osteoporosis Prostate cancer, retinal disease, Parkinson's, bone repair, post surgical pain
Longest ShortestDuration of sustained release
POC status
FDA approved/CE
Clinical development
Preclinical
Implantable LA Delivery Technologies
Thin-Film Polymer Device (TFPD)
• FDA-approved, tunable,
polycaprolactone membrane
• Removable but then degrades after drug
delivered
• Release with CAB Na++ salt
demonstrated in vitro; improvements
expected with base
Implantable rods
• Removable 4mm x 40mm rods
• Biodegradable or non-biodegradable or
‘pod’ technology
• PoC studies for TAF in dogs show
successful delivery of 0.92 mg/day for 40
days
• PoC studies for CAB in RM to start in
2016
Implants Summary
• Perceived ‘holy grail’ for LA agents
• Development has only reached animal phase
• Feasibility (replacement/removal frequency, no. of rods) will be driven by
intrinsic potency
• TAF, CAB, RPV, EFdA are current candidates
Opportunities Threats
Implantable dose formulation maybe ahead ofsimilar CAB LA efforts
Unproven safety and efficacy in humans
Removable implant mitigates safety risks andeliminates oral lead-in and lead-out
FTIH trials have not started. Approval would comesignificantly after CAB LA.
Could be less expensive than injectable Requires use of trochanter device for implantationand removal; labor and resource intensive
Linear release kinetics without burst phase observedwith injectable LA nanoformulations
Fibrosis around implant and removal are not trivial
Non-biodegradable, removable devices will requirehigh potency to allow for infrequent removalprocedures
Prevention
Presentation Title
Arial 40pt Red
Subtitle and Other Information
CONFIDENTIAL – FOR INTERNAL USE AND PLANNING PURPOSES ONLY
Acknowledgements
Special thanks to:
• Alex Rinehart, Director, Global HIV Prevention Strategy
• Mark Shafer, Global Medical Lead, Cabotegravir
• Bill Spreen, Global Development Lead, Cabotegravir
• Florian Klein, Rockefeller University, NY and University of Cologne
Prevention
Back up slides
PK Tail Management - Next Stepsfocus on patient safety while generating needed data to inform risk and final plans
• Phase III studies: current plans
• Characterize PK tail length and all cases of HIV infection and outcome
• After CAB LA PrEP: continue HIV prevention measures, to include TDF/FTC to cover
PK tail, as patient safety measure (participants will be at continued HIV risk after
primary endpoint met and studies are closed out)
• Study results may prompt change in plans (e.g., CAB superiority finding – open label
extension for continued CAB access)
• Post Phase III studies
• Seek regulatory feedback following internal modelling and solution development on
understanding risk of resistance
• Seek insights from implementers and target users on the implications of different tail
strategies at upcoming ad boards Q1 2017
• Consider supplemental preclinical studies (e.g., in vitro or NHP) to provide insight
• Explore potential use of CAB oral instead of TDF/FTC to cover PK tail
• Investigate clinical study methods /analyses to individualize mitigation steps
• Risk stratification - TDF/FTC appropriate for only those at continued HIV risk
• If needed, TDF/FTC duration can be tailored by patient factor (e.g., BMI)
44
14 subjects had
detectable CAB
52 weeks after
injection 3
CAB Concentration Ranges by Visit: Drug Persists in a Minority of Subjects 52 Weeks After Last Injection
Ford et al. HIVR4P 2016; Chicago, IL. Abstract OA12.06LB.
CT Injection 3
45