DURHAM, N.C. and NESS ZIONA, Israel—Atox Bio has reported results from the randomized, double-blind, placebo-controlled Phase 3 ACCUTE trial of reltecimod for the early treatment of severe necrotizing soft tissue infection (NSTI). Sometimes referred to as the “flesh eating disease,” NSTI is a serious infection that can quickly travel from the infection site. It requires frequent, rapid surgical intervention to remove dead and infected tissue to stop further progression and the need for amputation.
In more serious cases, acute inflammation that results from this infection leads to systemic organ dysfunction in the heart, lungs and/or kidneys. Even with the best current standard of care — which includes surgical debridement, broad spectrum antibiotics and supportive intensive care — multi-organ failure occurs frequently. Mortality rates are significant in both the short and intermediate term. Patients who do survive often face long, expensive hospital and rehabilitation center stays. There are approximately 30,000 cases of NSTI in the U.S. each year, with a similar number in Europe. There are currently no therapies approved for this indication.
“Patients with NSTI are critically ill and could greatly benefit from a treatment option designed specifically for their condition,” said Eileen Bulger, M.D., chief of Trauma at Harborview Medical Center, professor of Surgery at the University of Washington, and principal investigator for the ACCUTE trial. “Reltecimod has the potential to significantly advance the standard of care for NSTI by addressing a major unmet medical need for these complex and challenging patients and appears to be well tolerated.”
Reltecimod is a synthetic peptide antagonist of both superantigen exotoxins and the CD28 T-cell costimulatory receptor. By modulating — but not inhibiting — the body’s acute inflammatory response, reltecimod is designed to help control the cytokine storm that could otherwise quickly lead to morbidity and mortality. The U.S. Food & Drug Administration (FDA) granted reltecimod Fast Track status and orphan drug designation for NSTI. The European Commission has also granted reltecimod orphan designation.
The ACCUTE study, entitled “A Novel Immune Modulator for Patients with Necrotizing Soft Tissue Infections (NSTI): Results of a Multicenter, Phase 3 Randomized Controlled Trial of Reltecimod (AB 103),” is available in Annals of Surgery.
The data from the Phase 3 ACCUTE trial showed a significant difference in the percentage of patients administered reltecimod who achieved resolution of organ dysfunction/failure by day 14, versus the percentage of patients who received placebo. Resolution of organ dysfunction by day 14 has been noted in the literature, and was shown in this trial to have a beneficial effect on 90-day mortality. As this was the first pivotal study ever performed in NSTI, a necrotizing infection clinical composite endpoint (NICCE) was developed. This endpoint was designed to assess both the local and systemic components of NSTI and included the measurement of resolution of organ dysfunction/failure.
This was the first pivotal study ever performed in NSTI. The NICCE was designed to assess both the local and systemic components of NSTI, and included a modified sequential organ failure assessment (mSOFA) scoring tool to evaluate resolution of organ dysfunction. SOFA scores have been shown in previous studies to be a good indicator of prognosis in other septic conditions. All patients allowed into the study had to have significant organ dysfunction in one or more organs at baseline, and the measure of resolution of organ dysfunction using mSOFA was consistent with SEPSIS-3 definitions.
Elevated mSOFA at day 14 (defined as mSOFA >1) delineates persistent organ dysfunction in which a patient could require prolonged ventilation, ongoing blood pressure support and dialysis, or other interventions for complications of acute kidney injury at a time point associated with the development of chronic, critical illness. At the day 14 time point, mSOFA offers a categorical tool to help distinguish patients at risk for persistent organ dysfunction associated with longer term morbidity and mortality.
Blinded study drug (reltecimod or saline placebo) was administered with a single 10-minute infusion. All patients received the available standard of care, which includes surgical debridement, broad spectrum antibiotics and supportive intensive care. Organ dysfunction and failure can progress rapidly in these patients, and intervening as early as possible once organ dysfunction has begun is considered critical for any immune-based therapy. For this reason, patients were required to be administered the blinded study drug within 6 hours of being scheduled for surgery to confirm the NSTI diagnosis, often before all of a patient’s clinical information is available.
While statistical significance on the primary composite endpoint was not achieved in the modified intent to treat (mITT) population, the efficacy assessment in the clinically evaluable (CE) population demonstrated a p-value of 0.039. The CE population was considered relevant because of the potential to inadvertently enroll patients with unrelated chronic organ conditions which could not be cured by an acute treatment for NSTI. That could confound estimates of treatment effects, so Atox Bio considers the CE population the more clinically relevant and statistically appropriate analysis population.
Of the 290 patients enrolled in the study, 13 were excluded from the CE analysis population for failure to meet predefined study entry criteria. All exclusions were identified programmatically from the study database and reviewed by blinded medical and statistical reviewers prior to unblinding the trial.
52.6% of patients receiving reltecimod achieved clinical success on the NICCE primary endpoint, versus 40.3% on placebo. In the evaluation of resolution of organ dysfunction as described above, reltecimod demonstrated a strong, clinically meaningful effect over patients receiving standard of care alone. 70.9% of patients on reltecimod achieving resolution of organ dysfunction by day 14, versus 53.4% on placebo.
In this study in patients who survived to day 14, whether on reltecimod or placebo, those who had resolved organ dysfunction by day 14 had a 90-day mortality of 2.4%, versus 21.5% in patients who had persistent organ dysfunction at day 14 in the CE analysis population. In those patients surviving to day 14, the day 14 to day 90 mortality was 5.9% on reltecimod versus 11.5% on placebo in the CE analysis population. In the mITT analysis, the day 14 to day 90 mortality was 6.5% on reltecimod versus 11.2% on placebo.
Reltecimod was well tolerated in this study, with similar profiles of adverse events between the reltecimod and placebo treatment groups. The most common adverse events (~5%) reported in patients treated with reltecimod were anemia, acute kidney injury, atrial fibrillation and peripheral edema.
Atox has reviewed the topline results of this trial with the FDA. Based on these discussions, the company plans to submit a New Drug Application (NDA) in the third quarter of 2020 under the Accelerated Approval Pathway, with resolution of organ dysfunction as the basis for this approval pathway.
“Successful completion of the ACCUTE trial is a major milestone for Atox Bio that reinforces our commitment to patients with NSTI. This is a potentially life-threatening condition, with significant morbidity and long-term mortality that has no FDA-approved treatment,” added Dan Teleman, CEO of Atox Bio. “Reltecimod has been designed to modulate rather than completely suppress acute inflammation that can lead to a dysregulated immune response and we are actively working to bring this important new potential therapy to patients.”