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 Slide 4 of 35 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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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
Slide 4 of 35
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
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)
Slide 9 of 35
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
Slide 10 of 35
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
Slide 11 of 35
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
Slide 13 of 35
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
Slide 14 of 35
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
Slide 15 of 35
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%
Slide 16 of 35
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
Slide 17 of 35
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