Necrotizing soft-tissue infection (NSTI) makes for attention-grabbing headlines using its common name of flesh-eating bacteria. The rapidly progressing condition, which triggers systemic toxicities and organ failure, strikes some 21,000 individuals each year in the U.S., alone, killing approximately one-third of them – usually after an arsenal of hospital-based treatment.

Atox Bio Inc. hopes to improve those odds with lead compound AB103, a rationally designed short peptide that modulates the inflammatory response by binding to the CD28 dimer interface. Data from an animal model of NSTI published in March 2013 in the Journal of Infectious Diseases showed that administration of a single dose of AB103, given several hours after infection even without antibiotics, increased survival in animals and reduced tissue necrosis, inflammation and bacterial burden at the site of infection without compromising immune response.

Last year, the company, based in Ness Ziona, Israel, reported top-line results from a Phase IIa trial showing AB103 produced meaningful improvement compared to placebo across multiple endpoints in NSTI. Patients treated with AB103 had faster resolutions of organ dysfunction, spent fewer days in intensive care, required fewer days of assisted ventilation and needed fewer surgical procedures to remove infected tissue. In addition, systemic inflammatory biomarkers demonstrated a faster decline in treated patients compared to placebo.

AB103 has orphan and fast-track status in the U.S.

A spinout of the Hebrew University of Jerusalem, Atox Bio was co-founded in 2003 by molecular biologist Raymond Kaempfer, who serves as the company's chief scientific officer, and colleague Gila Arad. The two worked to identify the mechanism of action for toxins secreted by virulent bacteria that were involved in the pathogenesis of NSTI and other severe infections, such as toxic shock.

Because such toxins, in theory, could be used as biological weapons, the scientists' work initially attracted interest from the U.S. Army, the Defense Advanced Research Projects Agency and the National Institutes of Health. Combined, the agencies provided $12 million in grants that allowed AB103 to advance to an investigational new drug application without outside funding, according to Dan Teleman, Atox Bio's CEO.

The company subsequently raised more than $7 million from Esperante Ventures and a private U.S.-based investor to move AB103 through Phase IIa in NSTI.

Contrary to most anti-infective technologies, Atox Bio is less focused on killing the gram-positive or gram-negative bacteria – AB103 works equally well against both – that cause NSTI than on preventing the strong immunological response triggered by resulting toxins. That inflammatory response, rather than the bacteria themselves, is responsible for most of the major necrotic tissue damage associated with NSTI, according to Teleman.

"Antibiotics are not sufficient," he told BioWorld Today. "One needs to intervene on the immune level in order to modulate the immune response and allow it to more effectively fight the infection."

Targeting the CD28 dimer interface using a peptide drug that modulates but doesn't entirely block the immune response offers the delicate balance needed to treat severe infections, Teleman maintained.

"The immune response is critical to fighting infections," he pointed out. "We just want to shave off, in a sense, the anti-inflammatory response triggered by those bacteria. The biological target we are working on is able to do just that, which is very different from what other companies are doing in the immune modulation space."

In fact, Atox Bio is believed to be the only biotech pursuing NSTI as an initial indication in an immune-modulating therapy. The mechanism of action also could be applied to other indications characterized by acute inflammation, such as severe intra-abdominal infections, in critically ill patients without other treatment options. And sepsis is another potentially lucrative target that a string of biotechs – including Astrazeneca plc and Btg plc, Eisai Inc., Centocor Inc. (now Centocor Ortho Biotech), Immunex Corp. (now part of Amgen Inc.), XOMA Ltd. and Icos Corp. (now part of Eli Lilly and Co.) – previously failed to crack.

"This approach is also valuable from a regulatory perspective, because the types of infections we're targeting are the ones left behind by everyone else," Teleman said.

It's a practical approach, too. NSTI-related costs for multiple hospitalizations, surgeries and rehabilitation often exceed $100,000. "A drug like ours that is able to show an effect on ICU days, ventilator days, debridement and organ failure also is expected to affect the health care costs of those patients, which would be a major benefit to payers," Teleman pointed out.

The company is engaged in discussions with the FDA about the breakthrough drug designation for AB103 and about the trial design for a Phase IIb study of up to 120 NSTI patients, which the company hopes to initiate by year-end. Based on the IIa study, which fully enrolled in less than eight months, the IIb findings could report about a year later.

From there, Teleman hopes a single Phase III study will suffice to file a new drug application (NDA). If all goes well, the company could launch AB103 in the U.S. by 2019, he said. The company also is beginning to explore a regulatory pathway in Europe.

Atox Bio is now raising its next financing round, with a target of $12 million, to complete the Phase IIb and begin another Phase II in a follow-on indication. In parallel with the fundraising effort, Teleman is entertaining partnering discussions to collaborate on the next phase of AB103's development. The company will assess its long-term game plan after completing the IIb in NSTI.

"We're potentially able to develop the drug on our own after the NDA stage," Teleman said. "That gives us flexibility in terms of our strategic options. We're obviously going to be very open to partnering options. We'll be looking at all of those scenarios after the Phase IIb data become available."