NORTHWEST AIDS EDUCATION AND TRAINING CENTER

CROI 2013: New Drugs for Treatment and PrEP

Brian R. Wood, MD Medical Director, NW AETC Project ECHO Assistant Professor of Medicine, University of Washington

Presentation prepared by: Brian R. Wood, MD Last Updated: 3/14/12

Outline

• New drugs for Treatment - Dolutegravir (Integrase inhibitor) - Tenofovir alafenamide (TAF prodrug) - Cenicriviroc (CCR5-CCR2 inhibitor) - Maturation inhibitors - Attachment inhibitors • New Drugs for PrEP - GSK-744 (Integrase inhibitor) - TDF intravaginal ring Dolutegravir: SAILING Study Summary of Key Dolutegravir (DTG) Studies

• Phase 2 Trial in Treatment Naïve - SPRING I: DTG vs. EFV (each with TDF-FTC or ABC-3TC) • Phase 3 Trials in Treatment Naïve - SINGLE: DTG + ABC-3TC vs. EFV-TDF-FTC - SPRING 2: DTG vs. RAL (each with TDF-FTC or ABC-3TC) • Phase 3 Trials in Treatment-Experienced - VIKING: DTG + OBR in setting of RAL resistance - SAILING: DTG vs. RAL in setting of regimen failure Dolutegravir (DTG) vs. Raltegravir (RAL) for Salvage SAILING Study: Design

Study Design Protocol - N = 715 HIV-infected adults DTG 50 mg QD - Double-blind, double-dummy + RAL placebo + 2 drugs (at least 1 fully active) (n = 354) - Ongoing phase 3 trial - ARV-experienced - Integrase inhibitor-naïve RAL 400 mg BID - Resistance to at least 2 drug classes (but + DTG placebo + 2 drugs not to integrase inhibitors) and HIV RNA (at least 1 fully active) (n = 361) >400 copies/mL - Randomized 1:1

*Primary endpoint: proportion with VL <50 at 48 weeks by FDA snapshot analysis

*Results stratified by VL > or < 50,000, darunavir/ritonavir use, and # of fully active drugs

Source: Pozniak A et al, CROI 2013, Abstract 179LB Dolutegravir (DTG) vs. Raltegravir (RAL) for Salvage SAILING Study: Results Week 24 Interim Analysis: Virologic Response (FDA Snapshot)

Dolutegravir + BR Raltegravir + BR 100 83 79 80 77 70 70

60 53

40

HIV RNA < 50 < copies/ml RNA HIV 20

0 All VL ≤50,000 VL >50,000

Source: Pozniak A, CROI 2013, Abstract 179LB Tenofovir Alafenamide (TAF) Tenofovir Alafenamide (TAF, formerly GS-7340)

• What is it? Novel pro-drug of tenofovir (TFV)

Tenofovir alafenamide Cathepsin A! Tenofovir fumarate (TAF) (TFV) Tenofovir disoproxil fumarate (TDF)

• What is the advantage? - 10x ê plasma levels = less drug to bone, kidneys - 5x é intracellular levels = more in PBMC’s, lymph tissue, key targets - Small dose = easily co-formulated (10 mg w/cobicistat, 25 mg w/out)

Source: Zolopa AR et al, CROI 2013, Abstract 99LB Tenofovir Alafenamide (TAF, formerly GS-7340)

Study Design EVG-COBI-FTC-TAF Protocol (n = 112) - Randomized, double-blind, controlled - Phase 2 - HIV-infected adults with HIV RNA >5,000, EVG-COBI-FTC-TDF normal GFR, no resistance to TDF, FTC (n = 51) - Randomized 2:1

Key Results: - Proportion with VL <50 copies/mL at 24 weeks equivalent (87% vs. 90%) - Similar safety profile with mostly mild GI side effects - Both had increase in sCr with decrease in eGFR by week 2 but stable by week 24, though magnitude of changes less in TAF arm; less proteinuria, albuminuria and urine RBP w/TAF - Decrease in BMD at hip and spine significantly less in TAF arm

Source: Zolopa AR, CROI 2013, Abstract 99LB Other New Drugs in the Pipeline Cenicriviroc (CVC): CCR5-CCR2 Inhibitor

• CCR2 antagonism: ê metabolic syndrome, CV disease? • Once daily, well-tolerated, few drug interactions • Compared to EFV (both with TDF-FTC) at 24 weeks: - More virologic non-response with CVC (13% vs. 4%) - More virological failures at high viral loads with CVC - Increased CPK in CVC arm - More NRTI resistance in CVC arm and one switch to X4-tropism - All cholesterol types decreased with CVC, increased with EFV • Supports phase 3 study?

Sources: Gathe J et al, CROI 2013, Abstract 106 LB Maturation Inhibitors

• Small molecules that block final step in HIV gag protein processing so that non-viable particles are produced • No drug interactions, effective in multiclass resistance, led to 2-log viral load decline in phase 2 study • Prototype, bevirimat, halted d/t rapid resistance development • New, 2nd generation drugs being studied

MA p17 CA p24 p1 NC p7 p2 p6

N-terminus! C-terminus!

Cleavage sites!

Sources: Urano E et al, CROI 2013, Abstract 105 Attachment Inhibitors

• Block gp120 attachment to CD4 receptor • BMS oral drug in study; no need for dose change with ATZ or RTV

Sources: Langley D et al, CROI 2013, Abstract 542. Zhu L et al, CROI 2013, Abstract 534. New Drugs for PrEP New Drugs for PrEP

• GSK-744 (Integrase Inhibitor) - Long-acting, parenteral formulation, administered q1-3 months - 50 mg/kg IM x2, 4 weeks apart, protected macaques (N=8) from low- dose, weekly intrarectal challenges of SHIV (up to 8 challenges) - All untreated macaques (N=8) infected (at median of 2 weeks) • TDF Intravaginal Ring - 1 application q1-3 months - Releases 2.4 mg/day - Protected female macaques (N=6) from 16 challenges of SHIV over 4 months (ring changed q4 weeks) - 11/12 infections in placebo group

Sources: Andrews C et al, CROI 2013, Abstract 24LB. Smith J et al, CROI 2013, Abstract 25LB. Johnson T et al, Eur J of Pharm Sci, Dec. 2010. Questions?