FDA Accepts Atox Bio’s Drug Application, Sets 2021 Date for Decision

A first aid kit is typically all that’s needed to treat routine cuts and scrapes. But in rare instances, even these superficial wounds are enough to grant bacteria entry to the body, sparking infection in the skin that quickly spreads throughout the body.

Patients fighting these “flesh-eating bacteria” have no FDA-approved drugs available. Atox Bio has moved one step closer to making its experimental drug a new treatment option. The Israel-based company, which maintains U.S. headquarters in Durham, recently announced that the FDA has accepted the new drug application for reltecimod, a drug developed for patients with necrotizing soft-tissue infections (NSTI). The FDA set a Sept. 30, 2021 deadline for a regulatory decision.

NSTI, sometimes called flesh-eating disease, causes inflammation of tissue surrounding the muscle, nerves and fat. Obstruction of the blood supply leads to cell death. The standard of care includes antibiotics or surgical debridement, which is the removal of the damaged, dead, or infected tissue. In some cases, amputation is necessary.

Inflammation caused by these infections can also lead to dysfunction of the heart, lungs and kidneys, potentially becoming fatal. Atox notes that patients who do survive may face long and expensive hospital stays for treatment, as well as rehabilitation stays. Citing hospital discharge data, Atox estimates that the U.S. accounts for 30,000 NSTI cases annually, comparable to its estimates for Europe.

The Atox drug isn’t meant to replace currently available NSTI treatments. In fact, it doesn’t target the infection directly. Instead, the intravenously administered drug is intended to address the dysfunction and organ failure experienced by patients who have these infections. Atox aims to tamp down the immune response that affects the organ without completely blocking that response.

Reducing inflammation that causes organ failure

Reltecimod is a synthetic peptide that binds to CD28, a protein found on T cells that modulates immune response. According to Atox, this approach is intended to reduce the acute inflammation that leads to systemic organ failure. The company says its drug is pathogen agnostic and has the potential to address injury caused by various types of infections. The company had advanced reltecimod to a Phase 3 test in patients with sepsis-associated acute kidney injury but ended the study earlier this year due to slow enrollment, according to records in a federal clinical trials database. Atox is now focusing on NSTI, seeking FDA approval of the drug as a treatment for organ dysfunction or failure in patients 12 or older.

The NSTI Phase 3 clinical trial enrolled 290 patients. The main goal of the placebo-controlled study was to assess the drug according to a composite endpoint consisting of a measure of both local and systemic components of the infection, along with measuring resolution of organ dysfunction or failure. That drug was administered in conjunction with standard NSTI treatments, such as surgical debridement and antibiotics.

In clinical trial results released in July, Atox reported that 48.6% of patients treated with its drug met the main study goal compared to 39.9% of patients given a placebo – results that were not statistically significant. But Atox added that this analysis included patients who did not meet predefined criteria for the clinical trial, such as those who have unrelated organ conditions that can’t be addressed by an acute NSTI drug. When those patients are excluded, Atox says the data for its drug look better.

In these “clinically evaluable” patients that met the clinical trial criteria, Atox reported that 52.6% of those treated with reltecimod achieved the study’s main goal compared to 40.3% of those who received a placebo. In evaluating organ dysfunction, 70.9% of patients these clinically evaluable patients in the treatment group achieved resolution of organ dysfunction by day 14 compared to 53.4% in the placebo group. That time frame is important. Atox pointed to other studies showing that patients whose organ dysfunction lasts two weeks or longer are more likely to require long-term care, develop recurrent infections, and face an increased risk of death.

Company seeking accelerated FDA review

Despite failing to show statistical significance measured against the Phase 3 study’s main goal, Atox contends the remaining data support the case for its drug. The company submitted its application under the FDA’s accelerated approval program, which permits earlier approval for drugs that address an unmet medical need. Drugs reviewed under this program can be assessed according to a surrogate endpoint – a sign or measure in the clinical trial that predicts the drug is helping patients. Surrogate endpoints are sometimes used to evaluate drugs for rare diseases or conditions that have few treatment options, and the results for the clinically evaluable patients in the reltecimod study could serve as such an endpoint.

Atox CEO Dan Teleman said in an email that the company cannot comment about regulatory matters outside of the FDA’s formal review process. If the FDA grants accelerated approval to reltecimod, the company would need to confirm the drug’s benefit with a post-marketing study. If that clinical trial does not demonstrate the drug’s benefit, the FDA could withdraw the drug from the market.

In addition to seeking the FDA’s approval, Teleman said Atox is exploring potential regulatory submissions in other markets, including the European Union. He added that the drug’s targeting of the immune system allows for potentially wider use in other conditions associated with acute inflammation, such as septic shock. The company is also exploring other applications of its technology for modulating immune responses.

The science underlying reltecimod is based on the research of Raymond Kaempfur and Gila Arad, both professors in the faculty of medicine at the Hebrew University of Jerusalem. Their work led to the founding of Atox in 2003. In 2014, the U.S. Biomedical Advanced Research and Development Authority (BARDA) awarded Atox a four-and-a-half-year contract valued at up to $24 million to support the development of reltecimod for treating NSTI.

Atox formed its U.S. operation in Durham in June 2015, Teleman said. Later that year, the first patient enrolled in reltecimod’s Phase 3 study in NSTI. The Durham office, which employs 10, serves as Atox’s U.S. headquarters and is responsible for clinical and medical affairs, regulatory, clinical quality, and commercial work.

Payments under the BARDA contract were pegged to the progress of reltecimod. The agency exercised its most recent option payment in June 2019, bringing its total financial commitment to the drug’s clinical development to $22 million. The company’s investors include SR One, OrbiMed, Lundbeckfonden Ventures, Arix Bioscience, and Adams Street Partners.