CROI 2013: New Drugs for Treatment and PrEPdepts.washington.edu/nwaetc/presentations/uploads/91/... · 2014. 5. 29. · NORTHWEST AIDS EDUCATION AND TRAINING CENTER CROI 2013: New

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

Source: Pozniak A et al, CROI 2013, Abstract 179LB

DTG 50 mg QD + RAL placebo + 2 drugs

(at least 1 fully active) (n = 354)

RAL 400 mg BID + DTG placebo + 2 drugs

(at least 1 fully active) (n = 361)

*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

Study Design Protocol -  N = 715 HIV-infected adults -  Double-blind, double-dummy

-  Ongoing phase 3 trial

-  ARV-experienced

-  Integrase inhibitor-naïve

-  Resistance to at least 2 drug classes (but not to integrase inhibitors) and HIV RNA >400 copies/mL

-  Randomized 1:1

Dolutegravir (DTG) vs. Raltegravir (RAL) for Salvage SAILING Study: Results

Week 24 Interim Analysis: Virologic Response (FDA Snapshot)

79 83

70 70 77

53

0

20

40

60

80

100

All VL ≤50,000 VL >50,000

HIV

RN

A <

50 c

opie

s/m

l

Dolutegravir + BR Raltegravir + BR

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)

•  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 disoproxil fumarate (TDF)

Tenofovir alafenamide fumarate (TAF)

Tenofovir (TFV)

Cathepsin A!

Tenofovir Alafenamide (TAF, formerly GS-7340)

Source: Zolopa AR, CROI 2013, Abstract 99LB

EVG-COBI-FTC-TAF (n = 112)

EVG-COBI-FTC-TDF (n = 51)

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

Study Design Protocol -  Randomized, double-blind, controlled -  Phase 2

-  HIV-infected adults with HIV RNA >5,000, normal GFR, no resistance to TDF, FTC

-  Randomized 2:1

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

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

MA p17 CA p24 p1 NC p7 p2 p6

N-terminus! C-terminus!

Cleavage sites!

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?