long-acting antiretroviral agents for hiv treatment · 10/05/2016 1 long-acting antiretroviral...

10/05/2016

1

Long-acting antiretroviral agents for HIV treatment

Dr Paul Benn MB ChB FRCP

10/05/2016

2

Disclosures

Paul Benn is a full time employee of ViiV Healthcare

and an honorary HIV Consultant at the Mortimer

Market Centre, Central and North West London

NHS Foundation Trust, London

10/05/2016

3

Outline

Goals of antiretroviral therapy

Strengths and limitations of current antiretroviral therapy

Long-acting antiretroviral agents under investigation

Considerations for the management of long-acting ART

Conclusions

10/05/2016

4

Goals of antiretroviral therapy

reduce HIV-associated morbidity and prolong the duration and quality of survival,

restore and preserve immunologic function,

maximally and durably suppress plasma HIV viral load, and

prevent HIV transmission

ASHM antiretroviral guidelines available at http://arv.ashm.org.au/

10/05/2016

5

HIV treatment cascade Australia 2014

‘2015 Annual Surveillance Report of HIV, viral hepatitis, STIs’ available at https://kirby.unsw.edu.au/surveillance/2015-annual-surveillance-report-hiv-viral-hepatitis-stis

10/05/2016

6

Strengths and limitations of current ART

Solomon DA, Sax PE. Curr Opin HIV AIDS 2015, 10: 219-225

10/05/2016

7

New agents for HIV-1

Integrase inhibitors

Dolutegavir (approved)

Cabotegravir LA (ph II/III)

GS 9883 (ph III)

N(t)RTI

TAF (approved)

EFdA (MK 8591) (phI/II)

NNRTI

Doravirine (ph III)

Rilpivirine LA (ph II/III)

Maturation inhibitors

BMS 176 (ph II)

Attachment inhibitors

BMS 068 (ph III)

Broadly neutralising

monoclonal antibodies

10/05/2016

8

New LA agents for HIV-1

Integrase inhibitors

Dolutegavir (approved)

Cabotegravir LA (ph II/III)

GS 9883 (ph III)

N(t)RTI

TAF (approved)

EFdA (MK 8591) (phI/II)

NNRTI

Doravirine (ph III)

Rilpivirine LA (ph II/III)

Maturation inhibitors

BMS 176 (ph II)

Attachment inhibitors

BMS 068 (ph III)

Broadly neutralising

monoclonal antibodies

10/05/2016

9

Long-acting ARV agents for HIV

treatment in development

Agent Class Administration Dosing interval Phase of

development

Cabotegravir LA1 INI IM 4-8 weeks IIb/III

Rilpivirine LA1 NNRTI IM 4-8 weeks IIb/III

Ibalizumab2,4 CCR5 mAb IV 2-4 weeks III

PRO 1402,4 CCR5 mAb S/C 1-2 weeks II/III

VRC013,4 CD4 bs mAb IV or

SC infusion

3-4 weeks I/II

EFdA (MK 8591)5 NRTTI PO 1 weekly Ib

NRTTI Nucleoside reverse transcriptase translocation inhibitor

1/ Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.,2/ Pace C, Markowitz M. Curr Opin HIV AIDS 2015, 10:144–150.;

3/ Lynch RM et al. Sciencetranslationalmedicine 2015, 7; 319;;4/ https://clinicaltrials.gov/accessed april 2016 ; / Grober J et al. CROI 2016; Boston MA, Abstract 98, 6

10/05/2016

10




development






SC infusion

3-4 weeks I/II





10/05/2016

11

LATTE study – CAB-RPV maintenance

LATTE study: following induction therapy, oral CAB+RPV

maintained virologic suppression at a rate similar to

EFV+NRTIs through 96 weeks1

0

20

40

60

80

100

CAB 10 mg (n=60) CAB 30 mg (n=60)CAB 60 mg (n=61) EFV 600 mg (n=62)

12 1684BL 2 242628 32 36 40 48 60 72 84 96

Pro

port

ion,

% (

95%

CI)

1/Margolis D et al. Lancet Infect Dis. 2015;15:1145-1155

10/05/2016

12

Cabotegravir Nanosuspension

Drug crystal suspended in aqueous vehicle

Nanomilled to increase surface area and drug dissolution rate

Wet bead milling with terminal sterilization by gamma

irradiation

Higher drug loading vs. matrix approaches for lower inj. volume

R H. Müller, et al. European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 1-9

Component Function

Cabotegravir free acid

(d50 ~200 nm)

Active drug

Mannitol Tonicity agent

Surfactant System Wetting/Stabilizer

Water for Injection Solvent

CAB LA 200mg/mL

12

10/05/2016

13

CAB LA every 4 or 12 weeks achieved plasma

concentrations >4 x PA-IC90 in healthy adults

Christine T et al. Current Opin HIV & AIDS 2015; 10(4):239-245q4w, every 4 weeks

Mean GSK744 plasma concentration–time profiles

= Every 28 days injection


GSK744 5 mg/day po Ctau = 0.6 μg/mL

5

4

3

2

1

0

0 4 8 12 16 20 24 28

Pla

sma G

SK1265744 (

µg/m

L)

Time (weeks)

800 mg IM LD, 200 mg SC q4w x 3

800 mg IM LD, 200 mg IM q4w x 3

800 mg IM LD, 400 mg IM q4w x 3

800 mg IM quarterly x 2

4 x PA-IC90 (0.664 µg/mL)

10/05/2016

14

RPV plasma concentrations following RPV LA are

comparable to 25 mgPO in HIV-infected subjects

q4w, every 4 weeksC0, initial concentration; QD, once daily; RPV, rilpivirine


160

100

60

20

0

0 4 8 12 1410 16

Mean

(SD

) RPV

(ng

/m

L)

Time (weeks)

62

40

80

120

140

RPV 1200 mg IM/900 mg IM (+ GSK1265744 200 mg IM)

RPV 1200 mg IM/600 mg IM (+ GSK1265744 400 mg IM)

RPV mean C0 observed in Phase III studies of 25 mg QD (80 ng/mL)

Mean RPV plasma concentration–time profiles

10/05/2016

15

Cabotegravir + Rilpivirine as Long-Acting Maintenance

Therapy: LATTE-2:Week 32 Results

Establish proof of principle for the first ever LA HIV treatment regimen

Primary Objective

• Evaluate the safety and efficacy of CAB LA + RPV LA as maintenance therapy, and

• Select a dosing schedule of CAB LA + RPV LA for progression into phase III studies

Key Secondary Objectives

• Characterize LA pharmacokinetics

• Evaluate the tolerability and acceptability of injectable dosing

Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.

10/05/2016

16

LATTE-2 Study Design


ABC/3TC, abacavir/lamivudine; IM, intramuscular; PO, orally; Q4W, every 4 weeks; Q8W, every 8 weeks; QD, once daily. aSubjects who withdrew after at least 1 IM dose entered the long-term follow-up period. bSubjects can elect to enter LA Extension Phase beyond Week 96.

Induction period

Week 32

Primary analysis

Dosing regimen

selection

Day 1

Randomization

2:2:1

Week 48

Analysis

Dosing regimen

confirmation

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

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

Week 96b

CAB loading dose at Day 1

CAB loading doses at Day 1 and Week 4

CAB 30 mg +

ABC/3TC for

20 weeks

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

Maintenance perioda

10/05/2016

17

Baseline Characteristics:

ITT-ME Population


CDC, Centers for Disease Control and Prevention; ITT-ME, intent-to-treat maintenance exposed.

Q8W IM(n=115)

Q4W IM (n=115)

Oral CAB (n=56)

Total(N=286)

Median age, years 35.0 36.0 35.0 35.0

Female, n (%) 8 (7) 6 (5) 10 (18) 24 (8)

African American/African heritage, n (%) 17 (15) 12 (10) 15 (27) 44 (15)

CDC class C, n (%) 1 (<1) 2 (2) 0 3 (1)

Median HIV-1 RNA, log10 c/mL 4.419 4.455 4.289 4.393

≥100,000, n (%) 16 (14) 28 (24) 7 (12) 51 (18)

Median CD4+, cells/mm3 449.0 499.0 517.5 489.0

10/05/2016

18

LATTE-2 Week 32 Primary Endpoint:

HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)


*Met pre-specified threshold for concluding IM regimen is comparable to oral regimen (Bayesian posterior probability >90% that true IM response rate is no worse than -10% compared with the oral regimen).

Both Q8W and Q4W comparable to oral CAB at Week 32

Virologic outcomes Treatment differences (95% CI)

Oral

-4.8 12.2

Q8W

-5.8 11.5

Q4W

* * IM

10/05/2016

19

Snapshot Outcomes:

HIV-1 RNA <50 c/mL at Week 32 (ITT-ME)


aWeek 32 HIV-1 RNA Q8W: 53 c/mL, 70 c/mL, 91 c/mL; Q4W: 70 c/mL; oral CAB: 243 c/mL. All 5 are still in the study. bQ4W: hepatitis C, rash,

depression, and psychosis; oral CAB: hepatitis C. cQ8W: ISR; Q4W: pregnancy and prohibited medication; oral CAB: lost to follow-up, relocation.

Week 32 outcomeQ8W IM(n=115)

Q4W IM(n=115)

Oral CAB(n=56)

Virologic success 109 (95%) 108 (94%) 51 (91%)

Virologic non-response 5 (4%) 1 (<1%) 2 (4%)

Data in window not <50 c/mLa 3 (3%) 1 (<1%) 1 (2%)

Discontinued for lack of efficacy 1 (<1%) 0 1 (2%)

Discontinued for other reason while not <50 c/mL

1 (<1%) 0 0

No virologic data in window 1 (<1%) 6 (5%) 3 (5%)

Discontinued due to adverse event or deathb 0 4 (3%) 1 (2%)

Discontinued for other reasonsc 1 (<1%) 2 (2%) 2 (4%)

10/05/2016

20

Protocol-Defined Virologic Failure

(PDVF): Genotype

No INI, NNRTI, or NRTI mutations were detected

through Induction or Maintenance

Maintenance period

Q8W IM

(n=115)

Q4W IM

(n=115)

Oral CAB

(n=56)

Subjects with PDVFa 1b (1%) 0 1 (2%)

INI-r mutations 0 0 0

NRTI-r mutations 0 0 0

NNRTI-r mutations 0 0 0

aOne additional PDVF occurred during oral Induction Period due to oral medication non-adherence. bPDVF at Week 4; no

detectable RPV at Week 4 and Week 8, suggesting maladministration.

PDVF: <1.0 log10 c/mL decrease in plasma HIV-1 RNA by Week 4, OR confirmed HIV-1 RNA ≥200

c/mL after prior suppression to <200 c/mL, OR >0.5 log10 c/mL increase from nadir HIV-1 RNA value

≥200 c/mL.


10/05/2016

21

Adverse Events and Labs—

Maintenance Period


aQ8W: influenza-like illness, chills and pain, and lipase; Q4W: influenza-like illness, rash, depression, and psychosis. bNone drug related; one death (epilepsy) evaluated as not likely related to study drug. cQ8W: ISR × 2; Q4W: Churg Strauss vasculitis, hepatitis C,

depression, epilepsy, psychosis, and rash; oral CAB: hepatitis C. dMaintenance emergent. AE, adverse event; ISR, injection-site reaction.

ITT-ME population, n (%)Q8W IM(n=115)

Q4W IM (n=115)

Oral CAB(n=56)

IM subtotal (N=230)

Drug-related AEs, excluding ISRs (≥3%)

Pyrexia 3 (3) 5 (4) 0 8 (3)

Fatigue 2 (2) 4 (3) 1 (2) 6 (3)

Influenza-like illness 3 (3) 2 (2) 0 5 (2)

Grade 3 and 4 AEs, excluding ISRs 10 (9) 12 (10) 1 (2) 22 (10)

Drug-related Grade 3/4 AEsa,excluding ISRs

3 (3) 4 (3) 0 7 (3)

Serious AEsb 7 (6) 6 (5) 3 (5) 13 (6)

AEs leading to withdrawalc 2 (2) 6 (5) 1 (2) 8 (3)

Grade 3 and 4 labsd 17 (15) 20 (17) 8 (14) 37 (16)

10/05/2016

22

Adverse Events and Labs—

Maintenance Period

Q8W IM(n=115)

Q4W IM(n=115)

IM subtotal (N=230)

Number of injections 1623 2663 4286

Number of ISRs (events/injection) 1054 (0.65) 1228 (0.46) 2282 (0.53)

Grades

Grade 1 839 (80%) 1021 (83%) 1860 (82%)

Grade 2 202 (19%) 197 (16%) 399 (17%)

Grade 3 12 (1%) 10 (<1%) 22 (<1%)

Grade 4 0 0 0

Duration, days

≤7 943 (89%) 1121 (91%) 2064 (90%)

Median 3.0 3.0 3.0

• Most common ISR events overall were pain (67%), swelling (7%), and nodules (6%)

• Number of subjects reporting ISRs decreased over time, from 86% (Day 1) to 33% (Week 32)a

• 2/230 subjects (1%) withdrew as a result of injection reactions (Q8W)

aRepresents percent of subjects with a Week 32 visit (n=220).Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.

10/05/2016

23

Patient-Reported Outcomes at Week 32: Maintenance Treatment Compared With Oral Induction Treatmenta

How satisfied are you with

your current treatment?

How satisfied would you be to continue

with your present form of treatment?

3%3% 2%

1%

1%

1%

Note: based on observed case dataset of subjects who completed Week 32 questionnaires.

aHIV Treatment Satisfaction Questionnaire change version (HIVTSQc).


10/05/2016

24

Pharmacokinetics


Cτ, trough concentration; PA-IC90, protein binding–adjusted 90% inhibitory concentration; SD, standard deviation.

0 1 4 8 12 16 20 24 25 28 32

Cτ

Cτ

0 1 4 8 12 16 20 24 25 28 32

500

Cτ

10/05/2016

25

Conclusions from LATTE 2

• LATTE-2 results successfully demonstrate the potential to

maintain HIV-1 viral load <50 c/mL with LA IM CAB + RPV,

dosed once Q4W or Q8W

• Injection tolerability

– Majority of ISRs were Grade 1 to 2 pain, with a median

duration of 3 days

– Few subjects had an ISR that led to discontinuation, with high

overall reported satisfaction

• Regimen selection criteria

– Upcoming Week 48 analysis will contribute to final dose

selection for phase III studies

10/05/2016

26

Considerations for LAI ART

Acceptability

4 week oral lead in to establish safety and tolerability

RPV requires cold chain storage and protection from light

Injection site reactions over longer term

Long tail requiring coverage with oral ART for individuals wishing to defer or stop long-acting ART

Service implications e.g. training, recall systems

10/05/2016

27

Acceptability of LA therapy

LA injectable drugs can provide successful approaches for chronic indications such as contraception1 and schizophrenia2,3

Survey in US among 400 HIV positive on cART (2011)

68% male, 53% African–American, mean age of 47 yrs

Overall, 73% of patients indicated that they would definitely or probably try injectable ART;

61% with weekly dosing;

72% every 2 weekly;

84% monthly

35% were very concerned about needle use

1/ Winner B et al. N Engl J Med. 2012;366:1998–2007; 2/ Kishimoto T et al. J Clin Psychiatry 2013;74:957–965; 3/

Kamat SA et al. Drugs Context 2015;4:212267; 4/ Williams J et al. Nanomedicine 2013; 8(11): 1807–1813.

10/05/2016

28

Considerations for LAI ART

Acceptability

4 week oral lead in to establish safety and tolerability

RPV requires cold chain storage and protection from light

Injection site reactions over longer term

Long tail requiring coverage with oral ART for individuals wishing to defer or stop long-acting ART

Service implications e.g. training, recall systems

10/05/2016

29




development






SC infusion

3-4 weeks I/II




3/ Lynch RM et al. Sciencetranslationalmedicine 2015, 7; 319;;4/ https://clinicaltrials.gov/ accessed april 2016 ; / Grober J et al. CROI 2016; Boston MA, Abstract 98, 6

10/05/2016

30

VRC01 Phase I study (safety and PK)

10/05/2016

31

Virologic effects of VRC01 administration during

chronic HIV infection

Lynch R M et al. Science Translational Medicine 2015: 7, 319, pp.319

10/05/2016

32

Pre-infusion sensitivity to VRC01

Lynch R M et al. Science Translational Medicine 2015: 7, 319, pp.319

10/05/2016

33

Monoclonal antibody potency and breadth

10/05/2016

34

Newer and combined antibodies offer

improved potency and breadth

10/05/2016

35

Planned/on-going studies of monoclonal

antibodies for HIV treatment

Agent Study design Population

Ibalizumab

(mAb CCR5)

Expanded access

IV Ibalizumab + OBR

2 cohorts 800mg 2weekly or

2000mg 4 weekly for 48 weeks

Multidrug resistant

HIV

N=50

PRO 140

(mAb CCR5)

RCT PRO 140 vs PBO 1 week

Followed by single arm PRO140 +

OBR 24 weeks

Multidrug resistant

HIV

N=300

VRCO1

(mAb CD4 bs)

IV VRC01 vs PBO

40mg/kg infusion

Acute HIV infection

Brief ART

interruption

1/ https://clinicaltrials.gov/ accessed April 2016

10/05/2016

36




development






SC infusion

3-4 weeks I/II





10/05/2016

37

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

10/05/2016

38

MK-8591 PK in health volunteers

confirms QW potential

Well tolerated in healthy adult volunteers

IC MK-8591 TP exceeded PK target > 7 days with 10mg dose

Grober J et al. CROI 2016; Boston MA, Abstract 98

10/05/2016

39

Phase 1b study: Change in HIV-1 RNA Following

Single 10-mg Dose of MK-8591

Open label dose-ranging study in ART-naive pts

Single 10-mg MK-8591 dose (n = 6) suppressed HIV replication for at least 10 days

AEs: headache (n = 6) and no other AE was seen in more than 1 participant

Friedman E, et al. CROI 2016. Abstract 437LB

10/05/2016

40

Low dose amenable to extended duration parenteral formulation

>180 day 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

10/05/2016

41

Conclusions

Adherence is key to the effectiveness of antiretroviral therapy

Long-acting ART may offer patients alternative options with less frequent dosing

Further data regarding the efficacy, tolerability and implementation of long-acting ART are required

New ART agents and monoclonal antibodies may increase the availability of long-acting agents in the future

10/05/2016

42

Questions?

long-acting antiretroviral agents for hiv treatment · 10/05/2016 1 long-acting antiretroviral...

Documents