Elusys Therapeutics’ Anthrax Drug Gains FDA Approval in Adults and Children

Mar 21 2016

PINE BROOK, New Jersey—Elusys Therapeutics Inc.’s injectable anthrax antitoxin, branded Anthim (obiltoxaximab), became the newest member of the elite club of drugs to gain FDA approval through the agency’s Animal Rule. Anthim received the agency’s nod to treat adult and pediatric patients for inhalational anthrax due to Bacillus anthracis in combination with antibacterial drugs and for prophylaxis of inhalational anthrax when alternative therapies are not available or appropriate.

To advance its candidate, privately held Elusys, of Pine Brook, N.J., received more than $240 million in development grants and contracts from the Department of Defense, NIH and Biomedical Advanced Research and Development Authority (BARDA). In November 2015, the company was awarded a $45 million delivery order from the U.S. government to produce Anthim for the U.S. Centers for Disease Control and Prevention’s Strategic National Stockpile (SNS), the repository of critical medical supplies for public health emergency preparedness. Those revenues will begin flowing this year, according to Elizabeth Posillico, president and CEO, and FDA approval allows the company to begin wooing additional governments and other potential customers.

Anthrax occurs mainly in animals but can be spread in humans through contact with infected animals or animal products or through intentional spread of B. anthracis spores as a biowarfare or bioterrorism agent. When spores are introduced through the lungs, inhalational anthrax develops in two phases. Patients first experience flu-like symptoms for three to four days, then abruptly transition to systemic illness, including
high fever, shortness of breath, excessive sweating and shock.  Due to the rapid progression to life-threatening symptoms, the treatment window is hours to a few days. Untreated, the fatality rate for inhalational anthrax is estimated at up to 90 percent.

Anthim is a monoclonal antibody (MAb) that binds to the protective antigen component of anthrax toxin. Its toxin neutralizing activity prevents entry of anthrax toxin into susceptible cells, avoiding further spread of the toxin throughout the body and the ensuing tissue damage that leads to death. In its approved formulation, Anthim is supplied as single-dose vials for intravenous (I.V.) infusion. The drug had FDA orphan drug designation.

In keeping with FDA guidance on the Animal Rule, which aplies to the approval of drugs when human efficacy studies are not ethical and field trials are not feasible, the effectiveness of Anthim both for treatment and prophylaxis of inhalational anthrax was demonstrated in multiple studies in cynomolgus macaque and NZW rabbit models, which tested the efficacy of Anthim compared to placebo and the efficacy of Anthim in combination with antibacterial drugs relative to the antibacterial drugs alone. The primary endpoint was survival following challenge with B. anthracis.

Two studies in NZW rabbit and two studies in cynomolgus macaques evaluated Anthim 16 mg/kg I.V. 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 – 93 percent and 62 percent with Anthim in the rabbit studies compared to 0 percent with placebo and 47 percent and 31 percent to 35 survival with Anthim in the macaque studies compared to 6 percent or 0 percent with placebo.

Administration of Anthim in combination with the antibacterial drugs levofloxacin, ciprofloxacin and doxycycline resulted in higher survival outcomes than antibacterial therapy alone in multiple studies where Anthim and antibacterial therapy were delivered at various doses and treatment times, according to Elusys.

Anthim administered as prophylaxis also resulted in higher survival outcomes compared to placebo in multiple studies where treatment was given at various doses and treatment times. In a cynomolgus macaque study that evaluated Anthim 16 mg/kg administered 72, 48 or 24 hours prior to exposure, survival was 100 percent at all three time points (14/14, 14/14, 15/15, respectively) at day 56 (end of study).  Animal efficacy studies are conducted under widely varying conditions, so survival rates cannot be directly compared between studies and may not reflect rates observed in clinical practice, the company cautioned.

To assess the safety and pharmacokinetics (PK) of Anthim, Elusys also conducted a half-dozen phase I trials that, combined, enrolled more than 550 healthy adults, according to Cortellis Clinical Trials Intelligence. The most frequently reported adverse reactions were headache, pruritus, infections of the upper respiratory tract, cough, vessel puncture site bruise, infusion site swelling, urticaria, nasal congestion and pain at the infusion site and in the extremity.

The drug was approved with a boxed warning about potential hypersensitivity, including anaphylaxis. Thus, for prophylaxis, Anthim is recommended only when its benefit to prevent inhalational anthrax outweighs the risk.  No safety or PK studies were performed in the pediatric population, so dosing in these patients was derived using a population PK approach.

Anthim does not have direct antibacterial activity, is not expected to cross the blood-brain barrier and does not prevent or treat meningitis, according to Elusys.

“The Animal Rule was the only way we could move this forward,” Posillico told BioWorld Today. “We’ve been working on this over the years, so we’ve had to work through some of the development changes from our side as well as the learning curve for the FDA. We were actually fortunate, because there are two good animal models for anthrax, which was one of the first indications to be looked at using the Animal Rule. That really minimized some potential problems we could have had if those models hadn’t been developed.”

The Animal Rule, first issued in 2002, has raised the hackles of some drug developers, dating back to 2009, when Human Genome Sciences Inc., now a unit of London-based Glaxosmithkline plc, received a complete response letter to its application for the inhalational anthrax candidate, raxibacumab. In that case, regulators questioned whether the animal model used by the company adequately reflected findings from patients with inhalational anthrax whose response to antimicrobials approximated the 55 percent seen during the spread of anthrax spores in the mail in the fall of 2001. (See BioWorld Today, Oct. 26, 2009, Oct. 27, 2009, Nov. 17, 2009, and Dec. 4, 2009.)

The first product approval under the rule came in 2012.  Levaquin (levofloxacin, Johnson & Johnson) got the FDA’s nod to treat patients with plague and to reduce the risk of developing plague after exposure to Yersinia pestis, the acterium that causes the disease. In December of that year, the FDA finally approved raxibacumab to treat inhalational anthrax as the first MAb approved under the Animal Rule.  A month earlier, the FDA’s Anti-Infective Drugs Advisory Committee had voted 16 to 1, with one abstention, in support of the clinical benefit of raxibacumab to treat inhalational anthrax.

In 2013, the FDA finally said it would clear up uncertainties about the development pathway by finalizing draft guidance on product development under the Animal Rule, after the Oncologic Drugs and the Medical Imaging Drugs advisory committees jointly voted to recommend approval of Amgen Inc.’s Neupogen (filgrastim) as a treatment for acute radiation syndrome under the rule and said they supported the application of animal data to all drugs in the same class. (See BioWorld Today, May 7, 2013, and July 30, 2013.)

But in 2014, instead of finalizing the Animal Rule guidance, the agency revised the 6-year-old proposed recommendations. The new draft addressed a broader scope of issues, including vaccine development, cellular and gene therapy development, study conduct, and data quality and integrity, and included sections on general expectations for animal studies related to the animals used, animal care interventions, study reports and natural history studies. (See BioWorld Today, June 3, 2014.)

The development path for Anthim went “quite well,” Posillico reported.  Founded in 2000, Elusys has focused exclusively on the development of its single asset, which the company is advancing in intra-muscular (IM) and other formulations as additional enhancements to the SNS for field and emergency use. Its investors include Essex Woodlands LLC, Invesco Private Capital, Crescendo Ventures, Medimmune Ventures and Pfizer Inc. (See BioWorld Today, Sept. 9, 2011.)

BARDA has funded additional studies, including the IM formulation. Those data were submitted as part of the biologics license application for Anthim and Posillico expects to meet with the agency in the next quarter to determine how many additional safety studies are needed to submit a supplemental filing.

Elusys also plans to exploit other opportunities in the biodefense space. The company is evaluating a range of potential customers, including other federal agencies responsible for emergency preparedness and public health,  military units and global agencies such as the United Nations nd World Health Organization. Elusys already has initiated conversations with government agencies in European and other North American countries, according to Posillico. Revenues would come from manufacturing the product, and Elusys could handle a global market largely on its own, perhaps with the use of distributors in certain markets, Posillico said.

Based on stability studies of the clinical material, a seven-year stability study is ongoing for the commercial material, but Anthim currently has 18 months of shelf life so re-stocking could provide another source of income.  Once revenues from the SNS contract begin to flow in the second half of the year, Elusys also plans to examine opportunities, with an eye to building a pipeline of anti-infectives, with a focus on MAb delivery. Long term, the company could stay independent, go public or look for a suitor.

“All of the above” are on the table, Posillico said. “We’re just now in a position to see a revenue stream. The M&A market is good, so we’ll also look at whether there’s interest in the program.”

Marie Powers, News Editor, Bioworld Today, March 21, 2016 edition