New options for new and old patients. Antonella Castagna

Transcription

1 New options for new and old patients Antonella Castagna

2 Disclosures I have received funding for Advisory Boards, Speaker Panels and for preparation of educational materials from the following: Gilead Sciences ViiV Healthcare Janssen-Cilag Merck Sharp & Dohme

3 Life expectancy at age 18 in ART initiators in key populations (N=92,415), Althoff KN, CROI 2018

4 Faces of Frailty in Aging with HIV Infection Thurn M, Curr HIV/AIDS Rep (2017) 14:31 37

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6 HIV-1 drug resistance in low-income and middle-income countries Some LMICs might be reaching WHO s 10% threshold for changing first-line nonnucleoside reverse NNRTI based ART to integrase inhibitor-based ART. Gupta J LID 2018

7 Proportion of Subjects, % Study 1489: B/F/TAF vs ABC/3TC/DTG in Treatment-Naïve Adults Virologic Outcome at Week 48 by FDA Snapshot Analysis ,4 93, % (-4.8 to 3.6%) B/F/TAF ABC/3TC/DTG ,7 1 2,5 4,4 HIV-1 RNA < 50 copies/ml HIV-1 RNA 50 copies/ml No HIV-1 RNA Data Mean changes in CD4 cell count (cells/µl) at Week 48: +233 B/F/TAF vs +229 ABC/3TC/DTG (p=0.81) B/F/TAF vs ABC/3TC/DTG: Non-inferior efficacy at Week 48 Gallant J, et al. IAS Paris, France. Oral #MOAB0105LB Gallant J et al. Lancet. 7

8 Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial Margolis DA, Lancet 2017

9 Treatment and management strategies Reducing ART exposure Drug dose Dosing frequency Number of drugs New agents New mechanism of action Different ART formulations Long-acting oral Implantable Long-acting injectable

10 Overview of the multiple mechanisms of RT inhibition by EFdA Michailidis E, J Biol Chem 2014

11 Matthews R et al. IAS 2017

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13 MULTIPLE DAILY DOSES OF MK-8591 AS LOW AS 0.25 MG ARE EXPECTED TO SUPPRESS HIV Matthews R, CROI 2018

14 MK-8591 A Phase 2B, Randomized, Double-Blind, Active-Comparator-Controlled, Dose-Ranging Clinical Trial to Evaluate the Safety, Tolerability, Antiretroviral Activity, and Pharmacokinetics of MK-8591 given in Combination With Doravirine (DOR) and Lamivudine (3TC) in HIV-1-Infected Treatment-Naïve Adults (NCT )

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16 SDMs in NL4-3 background (subtype B) GSK : Profile of a 2nd Generation MI Binds tightly and reversibly to HIV-1 Gag 1 Greater potency and coverage of Gag polymorphs compared to 1 st - generation MI 1 Low serum binding 1 Low-dose prediction with half-life supportive of once-daily dosing No significant safety issues identified in early clinical studies Broad Polymorphic Coverage of BMS Virus (HIV-1 NL 4-3) Subtype B, % LANL databas e EC 50, nm 1. Nowicka-Sans et al. Maturation Inhibitor Mechanistic Studies Differential Inhibition of Gag Polymorphs. Poster 539, Session P-I1 (February 25, 2:30-4pm PST). * Assay conducted in the presence of 40% human serum + 27 mg/ml human serum albumin; Surrogate genotypes for subtype C; Percentage of subtype B isolates in the Los Alamos database (2010). BVM, Bevirimat; SDM, site directed mutant; WT, wild-type BVM 176 Fold change in EC 50 vs. WT BVM BMS- BMS- 176 WT (NL 4-3 ) WT + serum* V362I Q369H V370A V370M ΔV ΔV370/T3 71A 1.9 >400 0 > > > T371A ΔT Lataillade et al; CROI 2015, Abstract 114LB

17 2nd Generation HIV Maturation Inhibitors Clin trial Gov 2018

18 HIV Capsid Acts at Multiple Stages in the Viral Life Cycle PRODUCER CELL Reverse Transcription TARGET CELL Gag Capsid Core Capsid Core Disassembly NUCLEUS Gag-Pol Maturation Preintegration complex NUCLEUS Capsid Core Assembly Nuclear Translocation Integration 18

19 HIV Capsid Acts at Multiple Stages in the Viral Life Cycle PRODUCER CELL Reverse Transcription TARGET CELL Gag Capsid Core Capsid Core Disassembly NUCLEUS NUCLEUS Gag-Pol Maturation Capsid Core Assembly For a full single round of replication the EC 50 is 85 pm Infectious Virus Production EC 50 = 240 pm X Preintegration complex X Nuclear Translocation Target Cell Infection EC 50 = 53 pm Integration Tse W, et al. CROI Seattle, WA. Oral #38. 19

20 Tse W, et al. CROI Seattle, WA. Oral #38. 20

21 Tse W, et al. CROI Seattle, WA. Oral #38.

22 Discovery of Novel Potent HIV Capsid Inhibitors with Long-Acting Potential GS-CA1: First-in-class picomolar inhibitor of HIV capsid function resulting in aberrant core assembly Inhibition of multiple steps in HIV replication cycle Single subcutaneous injection maintains plasma concentrations in animal model well above paec 95 for >10 wks High potency against all major HIV subtypes & mutants resistant to current ARVs Resistance maps to conserved inhibitor binding site in p24 Mutants with greatest fold change have reduced fitness A compound has been selected for clinical development High potency Low metabolic clearance Slow release kinetics from injection Ideal for low dose long-acting administration paec95, plasma-binding-adjusted effective concentration required to inhibit replication by 95% Tse W, et al. CROI Seattle, WA. Oral #38 22

23 How HIV entry inhibitors block virus from entering a cell pro-140 Adapted from Gulick RM, Top Antiv Med 2018

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25 The return of PRO 140 (Leronlimab) Adapted from Thompson M, Curr Opin HIV/AIDS 2018

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28 Fostemsavir Fostemsavir (FTR) is a prodrug metabolised to temsavir (TMR), 1 a first-in-class, investigational attachment inhibitor that is currently being evaluated in HIV-1-infected HTE patients Active against CCR5-, CXCR4- and dual-tropic (R5X4) strains of HIV Unique resistance profile with no in vitro crossresistance to other classes of ARVs 2,5 Conversion of fostemsavir to temsavir Gastrointestinal lumen Fostemsavir (prodrug) Alkaline phosphatase Temsavir (active moiety) Temsavir Blood plasma Kozal et al. EACS 2017; Milan, Italy. Oral PS8/5.

29 FOSTEMSAVIR 16th European AIDS Conference; October 25-27, 2017; Milan, Italy

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36 BL substitutions in HIV-1 gp120 at positions S375, M434, M426, and M475, and subjects undergoing resistance testing through week 48 Lateillade M, et al. JAIDS 2018

37 Treatment-Emergent Genotypic and Phenotypic Resistance Profile Through Week 48 Lateillade M, et al JAIDS 2018

38 ANTI-CD4 an alternative way to inhibit HIV replication Yuan R, J HIV and Retrovirus, 2016

39 CROI 2017

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41 CROI 2017

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43 48-Week Safety and Efficacy On-Treatment Analysis of Ibalizumab in Patients with Multi-Drug Resistant HIV-1 EMU B, IDWEEK 2017

44 48-Week Safety and Efficacy On-Treatment Analysis of Ibalizumab in Patients with Multi-Drug Resistant HIV-1 EMU B, IDWEEK 2017

45 IBalizumab The binding specificity of ibalizumab to domain 2 of CD4 allows ibalizumb to block viral entry into host cells without causing immunosuppression. Epitope mapping studies indicate that ibalizumab binds to a conformational epitope located primarily in domain 2 of the extracellular portion of the CD4 receptor. This epitope is positioned on the surface of CD4 opposite to the site in domain 1 that is required for CD4 binding of the MHC class II molecules and therefore does not interfere with CD4-mediated immune functions. Additionally, ibalizumab does not interfere with gp120 attachment to CD4 FDA approuved on

46 Antibody target sites on the HIV-1 envelope spike Schematic representation of the HIV-1 envelope spike. Each of the monomer units of the trimer is composed of a gp120 and gp41 trans- membrane protein. The four best-characterized broadly neutralizing target sites are highlighted and include the CD4-binding site (orange), the glycanassociated epitopes on the base of the V3 loop (purple), the V1/V2 loop (green), and on gp41 (gray). Klein F, Science

47 HIV Cure PGT121 Combined with GS-9620 Delays Viral Rebound in SHIV-Infected Rhesus Monkeys Rhesus macaques infected with SHIV-SF162P3, randomized into 4 groups SHIV Infection Ab Washout Stop cart Week ART (TDF/FTC/DTG) Placebo, n=11 GS-9620, n=11 PGT121, n=11 Combo, n=11 GS-9620: A potent and selective, orally delivered TLR7 agonist PGT121: A broadly neutralizing antibody (bnab) 47 Barouch, et al. CROI Boston, MA. Oral 73LB

48 Barouch, et al. CROI Boston, MA. Oral 73LB

49 Potential use of bnabs in HIV-1 therapy Klein F, Science 2013