the future of prep - breach - homeprevention the future of prep breach spring meeting, la hulpe 2017...

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



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


Table heading


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)


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

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


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


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

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

32

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


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


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


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

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