About ANTHIM^® (obiltoxaximab)

EFFICACY

Overview

Because it is not feasible or ethical to conduct controlled clinical trials in humans with inhalational anthrax, the efficacy of ANTHIM for the treatment of inhalational anthrax is based on efficacy studies in NZW rabbits and cynomolgus macaques. The animal efficacy studies are conducted under widely varying conditions, such that the survival rates observed in the animal studies cannot be directly compared between studies and may not reflect the rates observed in clinical practice.

Types of Studies

The efficacy of ANTHIM for treatment and prophylaxis of inhalational anthrax was studied in multiple studies in the cynomolgus macaques and NZW rabbit models of inhalational anthrax. These studies tested the efficacy of ANTHIM compared to placebo and the efficacy of ANTHIM in combination with antibacterial drugs relative to the antibacterial drugs alone.

Study Design

The animals were challenged with aerosolized Bacillus anthracis spores (Ames strain) at approximately 200xLD₅₀ to achieve 100% mortality if untreated. In prophylaxis studies of inhalational anthrax, animals were treated prior to the development of symptoms. In treatment studies, animals were administered treatment after exhibiting clinical signs or symptoms of systemic anthrax. Cynomolgus macaques were treated at the time of a positive serum electrochemiluminescence (ECL) assay for B. anthracis PA at a mean time of approximately 40 hours post-challenge with B. anthracis. In NZW rabbit treatment studies, animals were treated after a positive ECL assay for PA or sustained elevation of body temperature above baseline, at a mean time of approximately 30 hours post-challenge. The majority of animals triggered by temperature. In some of the treatment studies assessing the effect of ANTHIM in combination with antibacterial drugs, treatment was delayed to 72 to 96 hours post-challenge. Most study animals were bacteremic and had a positive ECL assay for PA prior to treatment. Survival was assessed at 28 days post-challenge with B. anthracis in most studies.

Results

Two studies in NZW rabbit and two studies in cynomolgus macaques evaluated treatment with ANTHIM 16 mg/kg IV single dose compared to placebo in animals with systemic anthrax. Treatment with ANTHIM alone resulted in statistically significant improvement in survival relative to placebo in both species. Survival rates were 93% and 62% with ANTHIM compared to 0 or 0 placebo survivors in rabbits and 47% and 31-35% survival with ANTHIM compared to 6% or 0% placebo survival in macaques (see table below).

Survival Proportions in Monotherapy Treatment Studies of 16 mg/kg IV, All Randomized Animals Positive for Bacteremia Prior to Treatment

IV: intravenous, CI: Confidence Interval

• ^aSurvival assessed 28 days after spore challenge
• ^bp-value is from 1-sided Boschloo Test (with Berger-Boos modification of gamma=0.001) compared to placebo
• ^cExact 95% confidence interval of difference in survival rates
• ^dANTHIM products manufactured at two different facilities were tested in two separate treatment arms.

ANTHIM administered in combination with antibacterial drugs (levofloxacin, ciprofloxacin and doxycycline) for the treatment of systemic inhalational anthrax disease resulted in higher survival outcomes than antibacterial therapy alone in multiple studies where ANTHIM and antibacterial therapy was given at various doses and treatment times (see figure below).¹

Survival Rates for ANTHIM in Combination with Antibiotics vs Antibiotic Alone Treatment (All Treated Animals)

• ^aTreatment administered at 72 hours post-challenge
• ^bTreatment administered at 96 hours post-challenge
• ^cTreatment administered 24 hours after a positive ECL assay for PA
• ^dTreatment administered at the time of a positive ECL assay for PA

ANTHIM administered as prophylaxis resulted in higher survival outcomes compared to placebo in multiple studies where treatment was given at various doses and treatment times.¹ In one study, cynomolgus macaques were administered ANTHIM 16 mg/kg at 18 hours, 24 hours or 36 hours after exposure. Survival was 6/6 (100%) at 18 hours, 5/6 (83%) at 24 hours, and 3/6 (50%) at 36 hours (see table below). Another cynomolgus macaque study evaluated ANTHIM 16 mg/kg administered 72, 48 or 24 hours prior to exposure. Survival was 100% at all three time points (14/14, 14/14, 15/15, respectively) at day 56 (end of study).

Survival Rates in Cynomologous Macaques in Postexposure Prophylaxis, All Challenged Animals

CI: Confidence Interval

• ^aSurvival assessed after spore challenge (28 days), except 16 mg/kg dose was assessed at 56 days.
• ^bp-value is from 1-sided Boschloo Test (with Berger-Boos modification of gamma=0.001) compared to control
• ^cExact 95% confidence interval of difference in survival rates

References

1. Data on file. Elusys Therapeutics, Inc. Pine Brook, NJ.