Investigational New Antiretroviral Drugs and

Strategies

Slide 3 of 35

Learning Objectives

After attending this presentation, learners will be able to:

▪ Discuss investigational antiretroviral agents and

strategies for treatment-naïve people living with HIV

(PLWH)

▪ Discuss investigational antiretroviral agents and strategies for treatment-experienced PLWH

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Rationale for New Agents and

Strategies• Opportunities for improvement in ART despite remarkable

progress in last decades

▫ Long-term safety

▫ Long-acting therapy

▫ Lower antiretroviral burden

• Population with unmet need

▫ Limited treatment options due to resistance, intolerance or

adverse effects

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Selected New/Investigational Agents

Agent Class Development

Stage

Parenteral

long acting formulation

Targeting MDR

population

Two-Drug

Approach

Fostemsavir Attachment inhibitor FDA

approved

✘ ✔ ✘

Islatravir (MK-8591) Nucleoside reverse

transcriptase translocation inhibitor

Phase 2/3 ✔ ✔ ✔

Lenacapavir (GS-6207) Capsid Inhibitor Phase 2/3 ✔ ✔ ✔

Cabotegravir plus

rilpivirine LA

Integrase inhibitor +

NNRTI

FDA

resubmission

✔ ✘ ✔

(e.g., VRC07-523 LS,10-

1074, SAR441236)

Broadly neutralizing

antibodies

Phase 1/2 ✔ ✘ ✔

Leronlimab (PRO 140) Humanized monoclonal

antibody against CCR5

FDA partial

submission

✘/✔ ✔ ✘

Not in table: maturation inhibitors

Fostemsavir: First-in-Class Attachment

Inhibitor

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BRIGHTE Study: Fostemsavir in Patients With MDR HIV

Kozal M, et al. N Engl J Med 2020; 382:1232-1243.

Study Population

Treatment-experienced failing current regimen

HIV RNA ≥400 copies/mL

Randomized cohort1 or 2 classes remaining and ≥1 fully active

agent/class

Non-randomized cohort0 classes remaining and no remaining fully

active options

Failing Regimen

Fostemsavir + Failing Regimen

Day 0 8 9 Week Week48 96

Primary EndpointChange in HIV RNA

Randomized Cohort (N= 272) randomized 3:1

Fostemsavir + Optimized Background Regimen

Open-label

Fostemsavir + Optimized Background Regimen (n=99)

Non-Randomized Cohort

-0.79 (-0.88 to -0.70)†

-0.17(-0.33 to -0.01)

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BRIGHTE: Virologic and Immunologic

OutcomesWeek 48

Lataillade M, et. al. J Int AIDS Soc. 2019;22(suppl 5):1-2. Abstract MOAB0102

Kozal M, et al. N Engl J Med 2020; 382:1232-1243

Week 96

HIV RNA <40 copies/mL (Observed Analysis)

Randomized cohort: 79%

Non-randomized cohort: 59%

CD4 cell gains

Randomized cohort: increased to 205 cells/µL

Non-randomized cohort: increased to 119 cells/µL

CD4/CD8 ratio increased from 0.2 to 0.44 in the

randomized cohort

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Fostemsavir: Resistance Profile

• No cross resistance to other classes 1,2

• Tropism has no effect 3,4,5

• Amino acid substitutions at four positions in gp120 (S375H/I/N/M/T,

M426L/P, M434I/K, and M475I) that affect the susceptibility of the

virus to temsavir 1-5

• Clinical correlation of polymorphisms not completely understood

• Phenotypic cut-off yet to be established

1. Nowicka-Sans B, et al. Antimicrob Agents Chemother 2012;56:3498-3507; 2. Li Z, et al. Antimicrob Agents Chemother 2013;57:4172-4180; 1. Ray N et al J

Acquir Immune Defic Syndr 2013;64:7-15. ; 2. Zhou L et al. J Antimicrob Chemother 2014;69:573-581; 3. Latail lade M, et al. J Acquir Immune Defic Syndr

2018;77:299-307

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Fostemsavir: Clinical Profile

✔Food

Drug Interaction1,2

✔ (rifampin,

atazanavir/ritonavir)

Metabolic Profile

✔Organ Specific Adverse effects3

(nausea, diarrhea <5%)

1. Hruska M et al. 14th International Workshop on Clinical Pharmacology of HIV Therapy, Amsterdam, April 22–24, 2013. abstract; 2. Zhu L et al. Antimicrob Agents Chemother

2015;59:3816-3822; 3. Kozal M, et al. N Engl J Med 2020; 382:1232-1243

Islatravir (MK-8591): First-in-class Nucleoside

Reverse Transcriptase Translocation Inhibitor

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Islatravir: Dual Mechanisms of Action

(a) 4-ethynyl group

in aqua, the 3-hydroxyl group in

mustard and the 2-fluoro group circled

in red.(b) Translocation

inhibition and immediate chain

termination. (c) Delayed chain

termination

Markowitz and Grobler. Curr Opin HIV AIDS 2020, 15:27–32

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Islatravir: Virologic and PK Profile

Single doses of islatravir as low as

0·5 mg suppressed HIV-1 RNA

by >1·0 log at day 7

Long intracellular half-life of

islatravir-triphosphate

Schurmann D, et al. Lancet HIV 2020; 7: e164–72

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Study 011: Treatment Outcomes With Islatravir (MK-8591) +

Doravirine in Treatment-Naïve Patients

Study 011 : Treatment Outcomes With Islatravir (MK-8591) + Doravirine in Treatment-Naïve Patients

Virologic failures (n=4): all had confirmed HIV RNA <80 copies/mL, did not meet criteria for resistance testingIslatravir + doravirine was well tolerated: discontinuations due to adverse events (2%)

Molina J-M, et al. J Int AIDS Soc. 2019;22(suppl 5):102. Abstract WEAB0402LB.

Pati

en

ts (

%)

Virologic Outcomes at Week 48

0

20

40

60

80

100

HIV RNA ≥50 Copies/mL

90%

HIV RNA <50 Copies/mL No Virologic Data

ISL 0.25 mg + DOR (n=29)

ISL 0.75 mg + DOR (n=30)

ISL 2.25 mg + DOR (n=31)

DOR/3TC/TDF (n=31)90%

77%

84%

7% 7%13%

7%3% 3%

10% 10%

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Islatravir: Resistance Profile

• In-vitro:

▫ M184V/I is the main determinant of reduced susceptibility

▫ Hyper-susceptibility K65R and Q151M mutants

▫ However, ISL is more potent against common NRTI-

resistant variants (including M184V/I) than NRTIs are

against wild-type HIV-1.

• To date, ISL resistance has not been observed in any ISL

treated patient

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Islatravir: Evolving Clinical Profile

✔Food✔Drug

Interactions

Metabolic Profile 2, 3

Organ Specific Adverse effects (?

Headache 1,2)

ILLUMINATE5 Trials of 0.75mg ISL

+ DOR 100 mg

planned

1 Naïve

2 Switch

1 HTE

1 Adolescents

(Phase 2)

1. Schurmann D, et al. Lancet HIV 2020; 7: e164–72 ; 2. De Jesus E et al. IAS July 6-10, 2020. Abstract OAB0305; McComsey G, et al. CROI 2020, Abstract 686

First-in-human trial of MK-8591-eluting implants demonstrates

concentrations suitable for HIV PrEP for at least one year

Matthews et al. IAS 2019

Lenacapavir (GS-6207): First-in-Class HIV

Capsid Inhibitor

GS-6207 targets in the HIV lifecycleHIV

Capsid

Env

GagPol

CD4

Co-receptor

CD4 Cell

Lenacapavir

Nuclear

Transport

Capsid Disassembly

Lenacapavir Targets Multiple Stages in the

Viral Cycle

(EC50: 50 pM)

hivandhepatitis.com

Daar E et, al. CROI 2020. Poster Abstract 469

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Lenacapavir (GS-6207) Sustained Delivery Formulation Supports 6-

Month Dosing Interval

Begley et al. Virtual IAS 2020

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Lenacapavir Resistance Profile

• Gag cleavage site mutations and naturally occurring

polymorphisms do not confer resistance, unlike bevirimat

• Active against strains resistant to NRTIs, NNRTIs, PIs, INSTIs)

Margot et al. CROI 2020. Poster Abstract 529

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Lenacapavir: Clinical Profile

✔ Food1 Drug Interactions

Metabolic Profile

Organ Specific Adverse effects

Planned Trials

Treatment naïve: LCPV (oral) + TAF/F

induction then LCPV (SC) +

TAF or BTG maintenance

vs

LCPV (oral) + TAF/F

vs

BIC/TAF/F

Treatment

experienced: LCPV + OBR

t1/2 ≅11-13 days

1. Begley R, et al. CROI 2020. Abstract 3670

Cabotegravir plus Rilpivirine LA: First

Injectable Antiretroviral Regimen

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3 Large Phase 3 Trials

FLAIR: Treatment naïve1

Participants received DTG/ABC/3TC induction for 20 weeks then

randomized to continuation oral regimen vs. Q 4 week CAB + RPV

LA with oral lead-in

ATLAS: Virologically suppressed2

Participants suppressed on 2NRTIs + RTI or bPI or INSTI were

randomized to continuation of their regimen vs. switch to Q 4 week

CAB + RPV LA with oral lead-in

ATLAS-2M: Virologically suppressed3

Participants from ATLAS and new persons suppressed of SOC were

randomized to Q 4 weeks vs Q 8 week dosing of CAB + RPV LA with

oral lead-in

1. Orkin C, et al. NEJM 2020;382(12):1124-1135; 2. SwindellsS, et al. NEJM 2020;382(12):1112-1123; 3. Overton T, et al. CROI 2020. Abstract 34

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Virologic Failure and Resistance in

CAB + RPV LA Studies• Confirmed virologic failure was uncommon 1-2% across studies

▫ ? Influenced by BMI, drug concentration, baseline resistance

mutations, subtype A- (likely multifactorial)

• Resistance emerged to NNRTI and INSTI in some patients

▫ Pre-existing mutations found in PBMC in some of these cases

What do patients want?

ISR reported in 28.6% of all injections in

FLAIR of which <1% led to treatment withdrawal

High satisfaction rates with LA therapy

reported across studies

98% of participants in ATLAS 2M preferred CAB + RPV LA over oral therapy

94% of the ATLAS 2M participants who had

been on Q4 week dosing in ATLAS preferred Q8 week dosing

MONOCLONAL ANTIBODIES

Leronlimab (PRO 140)

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Leronlimab

Humanized IgG4 antibody directed against CCR5

Subcutaneous injection- weekly

Studies:

HIV as Monotherapy in treatment naives

Treatment experienced

Cancer, GVHD, COVID-19

Broadly Neutralizing Antibodies

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Progress in bNAb Research

Key Points:

Naturally occurring bNAbs have t1/2 of 2-3 weeks and lower viremia by 1.5 logs

Combination bNAbs have been shown to maintain viral suppression

May be able to engage the immune system and clear latently infected cells

Combination or multispecific bNAbs are promising

McClellan et al., Nature 2012

SAR441236 – what is novel?

CD4 binding

V1/V2-directed

Proximal External

Region

(MPER)

• SAR441236 is an engineered tri-

specific bNAb that combines

three HIV-1 env specificities in

one antibody. The “LS” Fc

modification extends antibody

half-life.

• SAR441236 demonstrated potent

and broad HIV-1 neutralization in

vitro and protection from SHIV

challenge in primates

• Multiple HIV-1 specificities in one

antibody molecule may improve

efficacy and simplify treatment

regimensSlide from ACTG A5377 Study Protocol

SAR441236: Tri-specific bNAb in clinical

trials

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Take Home Points

• Investigational ARV agents feature:

▫ Multiple mechanisms of action and different resistance profiles▫ Potential for use in two-drug regimens

▫ LA formulations (islatravir, lenacapavir, bNAbs, cabotegravir,

rilpivirine)

• Cabotegravir plus rilpivirine LA is in advanced stages of development

as first injectable regimen, but only for suppressed patients

• Some agents (islatravir, lenacapavir) are still being investigated in

treatment naïve and treatment experienced patients

• Fostemsavir, which is available in oral formulation only, was recently

FDA approved for treatment experienced patients

Question-and-Answer Session