GAIN Act gives Zavante a shot at new antibiotic development
- San Diego startup Zavante Therapeutics announced Wednesday its injectable antibiotic, Zolyd (fosfomycin) met the primary endpoint in its Phase 2/3 trial ZEUS, showing statistical non-inferiority to Pfizer's Zosyn (piperacillin/tazobactam) in hospitalized patients with complicated urinary tract infections. A new drug application is planned for early 2018.
- In this group of hard-to-treat patients, intravenous Zolyd treatment led to clinical cure with microbiologic eradication in 64.7% compared with 54.5% with intravenous piperacillin/tazobactam. Clinical cure rates were 90.8% compared with 91.6% respectively.
- Zolyd was generally well-tolerated in the ZEUS study, with mostly mild and transient treatment-emergent side effects. There were serious adverse events in five patients receiving Zolyd and six patients receiving the antibiotic combination.
In his Nobel Prize lecture in 1945, Sir Alexander Fleming warned of the issues of antibiotic resistance: "It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant."
And now in 2017, the world is facing the consequences. Every year, 700,000 people die of antimicrobial-resistant infections, and this could grow as high as 10 million by 2050, with a cumulative cost of $10 trillion.
"Increasing antimicrobial resistance is significantly limiting the number of therapies available to treat infections in U.S. hospitals," said Evelyn J. Ellis-Grosse, CSO of Zavante Therapeutics, in a statement on the news.
A number of companies are taking different approaches to dealing with the threat, including new antibacterials, antibiotic potentiators (resistance breakers), vaccines and antibodies. Zavante Therapeutics, a 2013 startup based in California, is repurposing an old oral antibiotic widely used in Europe as a U.S. intravenous drug.
"One of the challenges with antibiotics is that there have been no new classes in the past few decades," Ted Schroeder, president and CEO of Zavante, said to BioPharma Dive in an interview. "While fosfomycin is an older drug in the rest of the world, fosfomycin is effectively new to the U.S. market."
Merck & Co. and CEPA's broad spectrum fosfomycin, as Monuril/Monurol, has been available in Europe and elsewhere since the 1970s, mostly as an oral formulation, though this is poorly bioavailable. The lack of patent protection, however, made it uneconomic to extend it as an intravenous dose to the U.S.
This all changed with the passing of President Obama's GAIN (Generating Antibiotic Incentives Now) Act, and Zavante took the opportunity to move fosfomycin into development in its intravenous form as Zolyd.
"Fosfomycin became of interest as antibiotic resistance increased, but it only had three years of patent protection. We saw the opportunity through the GAIN Act, and its incentives, including additional exclusivity, to bring a novel class of drug to patients. Its development wouldn't have been possible without this," said Schroeder.
Under the act, certain antibacterial and antifungal drugs for life-threatening infections gain Qualified Infectious Disease Product (QIDP) and Fast Track designation, along with priority FDA review and an additional five years of market exclusivity.
Zolyd is a first-in-class injectable epoxide antibiotic with a differentiated mechanism of action and broad spectrum of activity against Gram-negative and Gram-positive pathogens, including multi-drug resistant (MDR) pathogens. The QIDP designation covers Zolyd for complicated urinary tract infections, hospital-acquired or ventilator-associated bacterial pneumonia, acute bacterial skin and skin structure infections, and complicated intra-abdominal infections.
"We're not sure yet where this will be indicated in the patient pathway, but I suspect it will be for critically and seriously ill patients with a confirmed or suspected multidrug-resistant Gram-negative infection who need aggressive treatment," said Schroeder. "Zolyd is the only intravenous antibiotic in its class, and has a unique mechanism of action. This means that it could be an ideal candidate for combinations, and there is no indication of cross-resistance."
Schroeder added that, after years of use in Europe, there doesn't seem to have been much development of resistance to fosfomycin.
"The next step for Zolyd will be to file a New Drug Application in the early part of 2018. This will depend on the stability data as we need to transfer the manufacturing to a different plant," said Schroeder. "We are a small team and so for now, our focus is on Zolyd. In the future we would look to licensing in other late-stage products for use in the hospital setting."
- Zavante Press release
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