Ibalizumab ( Trogarzo ) Prepared by: Brian R. Wood, MD David - - PowerPoint PPT Presentation

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Ibalizumab ( Trogarzo ) Prepared by: Brian R. Wood, MD David Spach, MD Last Updated: July 9, 2020 Ibalizumab ( Trogarzo) Trogarzo [tro-gar-zo] Entry Inhibitor Intravenous Infusion: Loading Dose followed by Dosing Every 2 Weeks Source:

SLIDE 1

Ibalizumab (Trogarzo)

Prepared by: Brian R. Wood, MD David Spach, MD

Last Updated: July 9, 2020

SLIDE 2

Ibalizumab (Trogarzo)

Source: Photograph courtesy of Theratechnologies, Inc.

Entry Inhibitor

Intravenous Infusion: Loading Dose followed by Dosing Every 2 Weeks

Trogarzo

[tro-gar-zo]

SLIDE 3

Ibalizumab (Trogarzo)

Indication:
Heavily treatment-experienced adults with multidrug resistant

HIV-1 failing their current antiretroviral regimen

Dosing (Intravenous):
Loading dose: 2,000 mg IV
Maintenance dose: 800 mg IV every 2 weeks
Contraindications
None
Use During Pregnancy
Insufficient data
Common Adverse Events (≥5%)
Diarrhea (8%), dizziness (8%), nausea (5%), and rash (5%)

SLIDE 4

Host Receptors and HIV Entry

CD4 Cell

HIV

CD4 CCR5 CXCR4

HIV

Host Receptors

SLIDE 5

HIV Cell Entry: Binding to Host Cell CD4 Receptor

CD4

HIV

gp41 gp120

Intracellular Space

Host Cell CCR5 CCR5 CD4 binding site

SLIDE 6

HIV Cell Entry: Binding to Host Cell CD4 Receptor

CD4

HIV

Intracellular Space

Host Cell CCR5 CCR5 CD4 binding site

SLIDE 7

HIV Cell Entry

Binding to Host Cell CD4 Receptor

Extracellular Space

CD4

Intracellular Space

Host Cell

HIV

CCR5 CCR5

SLIDE 8

HIV Cell Entry

Binding to Host CCR5 Co-Receptor

Extracellular Space

CD4

Intracellular Space

Host Cell

HIV

V3 V3 CCR5 CCR5

SLIDE 9

CD4 Receptor

Source: Bour S, et al. Microbiol Rev. 1995:59:63-93.

Cytoplasmic tail (38 aa)

D1 D2 D3 D4

Extracellular Region (370 aa) D1-D4 Domains Transmembrane region (25 aa)

CD4 Receptor

SLIDE 10

CD4 Receptor and Ibalizumab Binding

D1 D2 D3 D4

Host Cell

Ibalizumab

Intracellular Space

Host Cell

CD4 Receptor

SLIDE 11

Ibalizumab

CD4 Directed Post-Attachment HIV Inhibitor

Extracellular Space

CD4 Receptor

HIV

Ibalizumab

CCR5 CCR5

Intracellular Space

Host Cell

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Salvage Antiretroviral Therapy
TMB-301: Ibalizumab plus OBR for Adults Failing ART

Ibalizumab Summary of Key Studies

SLIDE 13

Ibalizumab

SLIDE 14

Ibalizumab for Antiretroviral Salvage

TMB-301: Study

SLIDE 15

Ibalizumab Added to OBR for Adults Failing ART TMB-301: Study Design

Source: Emu B, et al. N Engl J Med. 2018;379:645-54.

TMB-301: Study Design

Study design:
Single-arm, open label study of ibalizumab (IBA) added to optimized

background therapy (OBR) for individuals failing ART

Primary endpoint: proportion achieving ≥0.5 log10 decrease in HIV RNA

7 days after initiating IBA therapy (day 14 of study)

Secondary endpoints: virologic outcomes, safety, and tolerability at 24 weeks
Inclusion Criteria:
Adults with HIV, on ART for ≥6 months, HIV RNA >1,000 copies/mL, and

≥3 class drug resistance (but ≥1 remaining active drug)

Day 14 Add OBR with ≥1 active agent Day 7 IBA IV 2,000 mg loading dose Day 21 IBA 800 mg IV q2 weeks Days 1-7 Failing ART (n = 40)

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Ibalizumab Added to OBR for Adults Failing ART TMB-301: Study Design

Source: Emu B, et al. N Engl J Med. 2018;379:645-54.

Baseline Characteristics of the 40 Participants in TMB-301 Characteristic N = 40 Median age (range)—years 53 (23-65) Male 34 (85%) Non-white 18 (45%) Mean duration since HIV diagnosis—years 20±8 Mean CD4 count—cells/mm3 150±182 Mean HIV RNA—copies/mL) 100,287 Participants with HIV RNA >100,000 copies/mL 7 (18%)

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Ibalizumab Added to OBR for Adults Failing ART TMB-301: Efficacy at Day 14

Source: Emu B, et al. N Engl J Med. 2018;379:645-54.

83 60 3 20 40 60 80 100 >0.5 log >1 log Patients (%)

Decrease in HIV RNA Level at Day 14 Ibalizumab Monotherapy Control

IBA Monotherapy = after 7 days of IBA added to failing ART (functional monotherapy) Control = after 7 days of baseline failing ART

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Ibalizumab Added to OBR for Adults Failing ART TMB-301: Efficacy at Week 24

Source: Emu B, et al. N Engl J Med. 2018;379:645-54.

55 48 50 43 20 40 60 80 100 >1.0 log >2.0 log <200 copies/mL <50 copies/mL Patients (%)

Decrease in HIV RNA Level at Week 24

Optimized background regimen (OBR) added at day 14

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Ibalizumab Added to OBR for Adults Failing ART TMB-301: Efficacy at Week 25, by Baseline CD4 Cell Count

Week 25 Virologic Response (Intention-to-Treat Analysis)

Source: Emu B, et al. N Engl J Med. 2018;379:645-54.

43 18 61 50 24 70

20 40 60 80 100 All <50 cells/μL ≥50 cells/μL Patients (%) Baseline CD4 Count

<50 Copies/mL <200 Copies/mL

17/40 20/40 3/17 4/17 14/23 16/23

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Ibalizumab Added to OBR for Adults Failing ART TMB-301: Efficacy at Week 24

Source: Emu B, et al. N Engl J Med. 2018;379:645-54.

Conclusions: “In patients with multidrug-resistant HIV-1 infection who had advanced disease and limited treatment options, ibalizumab had significant antiviral activity during a 25-week study. Evidence of the emergence of diminished ibalizumab susceptibility was observed in vitro in patients who had virologic failure.”

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Acknowledgment

The National HIV Curriculum is an AIDS Education and Training Center (AETC) Program supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) as part of an award totaling $800,000 with 0% financed with non-governmental sources. This project is led by the University of Washington’s Infectious Diseases Education and Assessment (IDEA) Program.

The content in this presentation are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by HRSA, HHS, or the U.S. Government.