HIV Alert- Novel Strategies and Agents for HIV Management.2016

HIV Alert: Novel Strategies and Agents for HIV Management

This program is supported by independent educational grants from Gilead Sciences and ViiV Healthcare.

Slide credit: clinicaloptions.com

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Faculty

Daniel R. Kuritzkes, MDChief, Division of Infectious DiseasesBrigham and Women's HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts

Paul E. Sax, MDClinical DirectorHIV Program and Division of Infectious DiseasesBrigham and Women's HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts

Faculty Disclosure Information

Daniel R. Kuritzkes, MD, has disclosed that he has received consulting fees from Bionor, Gilead Sciences, GlaxoSmithKline, InnaVirVax, Merck, ViiV.

Paul E. Sax, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, and ViiV and funds for research support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and ViiV.


Program Overview

Long-Acting Antiretroviral Therapy Dual-Therapy Regimens Emerging Investigational Agents


Long-Acting Antiretroviral Therapy


Long-Acting Antiretroviral Therapy

Regimens/agents

– Cabotegravir + rilpivirine

– MK-8591 (EFdA)

– Broadly neutralizing antibodies (bNAbs)

Key questions:

– Can we move away from daily oral therapy for HIV?

– Are long-acting therapies as effective as oral therapies?

– What about toxicity?

– What pts might be ideal candidates for long-acting therapy?

– How can resistance be prevented if pts miss doses?


LATTE-2: Cabotegravir IM + Rilpivirine IM for Long-Acting Maintenance ART Multicenter, open-label phase IIb study

– Cabotegravir: integrase inhibitor

Margolis DA, et al. CROI 2016. Abstract 31LB.

CAB 400 mg IM + RPV 600 mg IM Q4W†

(n = 115)

CAB 600 mg IM + RPV 900 mg IM Q8W‡

(n = 115)

6 pts discontinued for AEs or death in induction analysis. *Pts with HIV-1 RNA < 50 c/mL from Wk 16 to Wk 20 continued to maintenance phase. †Loading dose: Day 1, CAB 800 mg + RPV 600 mg. ‡Loading dose: Day 1, CAB 800 mg + RPV 900 mg; Wk 4, CAB 600 mg.

ART-naive HIV-infected pts withCD4+ cell count > 200 cells/mm3

(N = 309) CAB 30 mg PO + ABC/3TC PO QD(n = 56)

CAB 30 mg PO QD + ABC/3TC

Wk 32primary analysis

Wk 20

Induction Phase* Maintenance Phase

Wk 1 Wk 96Wk 16: RPV PO added



LATTE-2: Wk 32 Efficacy and Safety

No INSTI, NNRTI, or NRTI resistance mutations detected

Most frequent ISRs were pain (67%), swelling (7%), and nodules (6%)– ISR events/injection: 0.53– 99% of ISRs grade 1/2; none

grade 4– 1% of pts withdrew for ISRs

Margolis DA, et al. CROI 2016. Abstract 31LB.

9594 91

4< 1 4 < 15 5

VirologicSuccess

VirologicNon-

response

No Virologic

Data

HIV

-1 R

NA

<50

c/m

L (%

) 100

80

60

40

20

0

IM CAB + RPV Q4W (n = 115)IM CAB + RPV Q8W (n = 115)Oral CAB + ABC/3TC (n = 56)

Treatment Differences (95% CI):Q4W IM vs Oral: 2.8 (-5.8 to 11.5)Q8W IM vs Oral: 3.7 (-4.8 to 12.2)

AEs, %Pooled IM

Arms(n = 230)

Oral Arm(n = 56)

Drug-related grade 3/4 AEs (excluding ISRs)

3 0

Serious AEs 6 5

AEs leading to withdrawal 3 2



LATTE-2: Wk 32 Pt Satisfaction With Maintenance Therapy vs Oral Induction

Pts

(%)

How satisfied are you with your current treatment?

(vs oral induction treatment)

100

80

60

40

20

0Q8W

(n = 106)Q4W

(n = 100)Oral CAB(n = 49)

More Neutral Less

100

80

60

40

20

0Q8W (n = 106)

Q4W (n = 100)

Oral CAB(n = 49)

More Neutral Less

How satisfied would you be to continue with your present form of treatment?

(vs oral induction treatment)

97 96 71

29

3 1

3

98 98 71

29

2 1

1

Margolis DA, et al. CROI 2016. Abstract 31LB. Slide credit: clinicaloptions.com



Other Potential Long-Acting ARVs

1. Friedman EJ, et al. CROI 2016. Abstract 437LB. 2. Caskey M, et al. Nature. 2015;522:487-491.3. Lynch RM, et al. Sci Transl Med. 2015;7:319ra206.

Agent MoA Study results

MK-8591 (EFdA) NRTI[1]

Phase I study: treatment-naive pts, single 10-mg dose (N = 6)

Mean t1/2: 108 hrs Mean VL reduction at 10 days postdose: 1.78 log10

3BNC117,VRC01

Broadly neutralizing antibodies (bNAbs)

3BNC117: single infusion reduced VL up to 2.5 log10

(n = 17); mean t1/2: 9 days[2]

VRC01: single infusion reduced VL up to 1.8 log10 in treatment-naive pts (n = 8); 2 minimal responders exhibited resistant virus at BL[3]



Long-Acting Antiretroviral Agents: Potential Use Potential challenges with long-acting CAB + RPV IM:

– What dosing interval might be approved: Q4W or Q8W?

– Oral induction phase

– IM dose volume/ISRs

– What if a dose is missed?

What pts might be ideal candidates for long-acting therapy?

– Pts with chaotic lifestyles?

– Pts with good clinic attendance who dislike daily pills?


Dual-Therapy Regimens


Dual-Therapy Regimens

Potential regimens/agents:

– DTG + 3TC or RPV

– Boosted PI + 3TC or RAL

Key questions:

– Can regimens that include 2 agents be as effective as regimens with 3+ agents for first-line, switch/maintenance, or salvage therapy?

– If so, can the costs of HIV treatment be reduced by using dual therapy regimens?

– Can the use of NRTIs be limited or eliminated with these regimens?


Boosted PI Dual Therapy: Phase III or IV Studies

Study Treatment Setting N Regimen Results

NEAT001[1] Initial 805 DRV/RTV + RALSimilar efficacy as DRV/RTV + FTC/TDF; poor efficacy in pts with high viral loads, low CD4+ cell counts

GARDEL[2] Initial 426 LPV/RTV + 3TC Similar efficacy as LPV/RTV + 2 NRTIs

MODERN[3] Initial 797 DRV/RTV + MVC Inferior efficacy vs DRV/RTV + 2 NRTIs

OLE[4] Switch 250 LPV/RTV + 3TC Similar efficacy as continued standard ART

KITE[5] Switch 60 LPV/RTV + RAL Small study; encouraging efficacy

SALT[6] Switch 286 ATV/RTV + 3TC Similar efficacy as ATV/RTV + 2 NRTIs

ATLAS-M[7] Switch 266 ATV/RTV + 3TC Improved efficacy vs ATV/RTV + 2 NRTIs

Slide credit: clinicaloptions.comReferences in slidenotes.


PADDLE: Dolutegravir + Lamivudine for Treatment-Naive Pts

Figueroa MI, et al. EACS 2015. Abstract 1066.

Open-label, single-arm phase IV exploratory trial

Treatment-naive pts with HIV-1 RNA > 5000-100,000

copies/mL; CD4+ cell count ≥ 200 cells/mm3;HBsAg negative

(N = 20)

Second Cohort

Dolutegravir 50 mg QD +Lamivudine 300 mg QD

(n = 10)

Dolutegravir 50 mg QD +Lamivudine 300 mg QD

(n = 10)

First Cohort

Second cohort to be enrolled following confirmation of

first cohort success at Wk 8

Included 4 pts with HIV-1 RNA > 100,000 copies/mL at BL

20/20 pts achieved HIV-1 RNA < 50 copies/mL by Wk 8



Boosted PI Dual Therapy After Treatment Failure: Selected Studies

Study Treatment Setting N Regimen Results

EARNEST[1] Failure 1277 LPV/RTV + RALSimilar efficacy as

LPV/RTV + 2/3 NRTIs; improved efficacy vs LPV/RTV monotherapy

SECOND-LINE[2] Failure 541 LPV/RTV + RAL Similar efficacy as

LPV/RTV + 2/3 NRTIs

ACTG A5273[3] Failure 512 LPV/RTV + RAL Similar efficacy as

LPV/RTV + best available NRTIs


1. Paton NI, et al. N Engl J Med. 2014;371:234-247. 2. Amin J, et al. PLoS One. 2015;10:e0118228.3. La Rosa AM, et al. CROI 2016. Abstract 30.



Dual-Therapy Regimens: Potential Use

Potential for use as first-line, switch, induction/maintenance, or salvage therapy in select pts

Considerations for use:

– Treatment regimens that include fewer agents might allow:

– NRTI-sparing/limiting

– Drug–drug interaction avoidance

– Cost savings:

– Modeling study suggested that, should DTG + 3TC demonstrate high virologic suppression rates in a larger trial, use of this regimen as first-line or induction/maintenance therapy could result in US savings of > $500 million[1]

– Implications for developing countries (decreased lab monitoring vs NRTIs)

– Regimens with 3TC as only NRTI should not be used in pts with HBV infection

1. Girouard MP, et al. Clin Infect Dis. 2016;62:784-791.



Dual-Therapy Regimens: What is Coming?

Study Description

SWORD-1 and -2[1,2]

Phase III, planned N = 510 per study DTG + RPV as maintenance therapy for virologically

suppressed pts on 2 NRTIs + third drug

ACTG A5353[3] Phase II, planned N = 120 DTG + 3TC for treatment-naive pts

DUALIS[4]

Phase III, planned N = 320 DRV/RTV + DTG as switch therapy for virologically

suppressed pts on DRV/RTV + 2 NRTIs

1. ClinicalTrials.gov. NCT02429791. 2. ClinicalTrials.gov. NCT02422797. 3. ClinicalTrials.gov. NCT02582684. 4. ClinicalTrials.gov. NCT02486133.


Additional Emerging Investigational Agents

Emerging Investigational Agents

Agent Mechanism of ActionDoravirine[1] NNRTI; activity against common NNRTI resistance mutations

GS-9883 (bictegravir)[2] Unboosted INSTIFostemsavir (BMS-663068)[3,4]

Prodrug metabolized to attachment inhibitor; binds gp120 to prevent viral attachment and CD4+ cell entry

BMS-955176[5] Maturation inhibitor; reversibly binds to HIV Gag protein

Ibalizumab (TNX-355)[6] Entry inhibitor; antibody to CD4


1. Gatell JM, et al. CROI 2016. Abstract 470. 2. ClinicalTrials.gov. NCT02607956. 3. Feinberg J, et al. IDWeek 2015. Abstract 1075. 4. Thompson M, et al. CROI 2015. Abstract 545. 5. Hwang C, et al. IAS 2015. Abstract TUAB0106LB. 6. Jacobson JM, et al. Antimicrob Agents Chemother. 2009;53:450-457.

Key question:

– Where might emerging investigational agents fit into the current landscape for HIV treatment?


Emerging Investigational Agents: Potential Use and Current StudiesAgent Implications Ongoing Trials

DoravirineNNRTI

Notable: • New NNRTI• Phase II: similar efficacy with improved

tolerability vs EFV for treatment-naive pts in combination with FTC/TDF[1]

Phase III, tx naive: DOR vs DRV/RTV, both with FTC/TDF or ABC/3TC[2]

Phase III, switch: DOR/3TC/TDF[3] Potential use: first-line, switch

GS-9883 (bictegravir)INSTI

Notable: • Unboosted INSTI coformulated with

FTC/TAF• Phase II results yet to be presented[4]

Phase III, tx naive: GS-9883/FTC/TAF vs DTG + FTC/TAF[5] or DTG/ABC/3TC[6]

Phase III, switch:GS-9883/FTC/TAF from varied regimens (eg, EVG/COBI/FTC/TAF or DTG/ABC/3TC)[7-9]

Potential use: first-line, switch

1. Gatell JM, et al. CROI 2016. Abstract 470. 2. ClinicalTrials.gov. NCT02275780. 3. ClinicalTrials.gov. NCT02397096. 4. ClinicalTrials.gov. NCT02397694. 5. ClinicalTrials.gov. NCT02607956. 6. ClinicalTrials.gov. NCT02607930. 7. ClinicalTrials.gov. NCT02603120. 8. ClinicalTrials.gov. NCT02603107. 9. ClinicalTrials.gov. NCT02652624.


Emerging Investigational Agents: Potential Use and Current Studies

1. Thompson M, et al. CROI 2015. Abstract 545. 2. ClinicalTrials.gov. NCT02362503.3. Hwang C, et al. IAS 2015. Abstract TUAB0106LB.4. ClinicalTrials.gov. NCT02386098.

Agent Implications Ongoing Trials

FostemsavirAttachmentinhibitor

Notable: • Novel ARV class• Phase IIb: generally similar

responses vs ATV/RTV in tx-experienced pts when combined with RAL + TDF[1]

Phase III: pts with ARV experience/resistance[2]

Potential use: pts with multiple tx failures and drug-resistant virus

BMS-955176Maturation inhibitor

Notable: • Novel ARV class• Phase IIa: dose-finding study;

efficacy noted[3]

Phase II: BMS-955176 + ATV ± RTV + DTG at varied doses in experienced pts[4]

Potential use: under exploration


1. ClinicalTrials.gov. NCT00784147. 2. ClinicalTrials.gov. NCT02707861. 3. ClinicalTrials.gov. NCT02475629.

Agent Implications Ongoing Trial(s)

Ibalizumab (TNX-355)Entryinhibitor

Notable: • Phase IIb: tx-experienced pts

treated with OBR + IV Q2W or Q4W; Wk 24 viral suppression in 28% to 44% of pts[1]

FDA breakthrough therapy and orphan drug designations; 2 current phase III trials assessing OBR + Q2W dose for pts with multidrug resistant HIV[2,3] Potential use: salvage therapy/tx-

experienced pts

Other Emerging Investigational Agents

Summary

Strategy Regimens/Agents Potential Future Implications in HIV Treatment

Long-acting ART

Cabotegravir + RPV MK-8591 (EFdA) bNAbs

Long-acting regimens could remove the need for daily pills

May have role in maintenance therapy

Dual therapy DTG + 3TC or RPV PI/RTV + 3TC or RAL

Dual therapy regimens might be used in first-line, switch, induction/maintenance, or salvage settings

Could allow treatment simplification, cost savings vs 3+ drug regimens, minimization of DDIs, AEs

Investigational agents

Doravirine GS-9883 (bictegravir)

Novel agents with potential utility for treatment-naive or switch pts

Fostemsavir BMS-955176 Ibalizumab

Novel agents with potential utility for treatment-experienced pts


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HIV Alert- Novel Strategies and Agents for HIV Management.2016