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Urgent Need for Antibiotics; Biotechs Carrying the Load

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By Peter Winter,
BioWorld Insight Editor

Global concern that R&D on new antibiotics has languished in recent years has certainly not escaped the attention of policymakers. The UK, for example, became the latest country to add its voice to the growing crisis about antimicrobial resistance by releasing a five-year strategy last week to address the critically thin pipeline of new antibiotics and the increasing incidence of infections that are becoming more and more difficult to treat.

With antimicrobial drug resistance seen as a major health security challenge, the subject was also high on the agenda at the meeting of G8 science ministers, who met in London June 12 ahead of the G8 summit in Northern Ireland. (See BioWorld Insight, June 24, 2013.)

The release of the UK strategy coincided with the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Denver, where progress reports on innovative products designed to combat difficult-to-treat infectious diseases were being presented.

Taking Stock

The meeting provided the opportunity to take an inventory of just how many novel antibiotics are in the latter stages of development. The tally does not inspire confidence that we will have enough new drugs in the near future to replace those that are becoming ineffective.

The total reinforces the findings from a recent report from the Washington-based Infectious Diseases Society of America (IDSA) that identified just seven new drugs in Phase II or Phase III development for the treatment of infections caused by multidrug-resistant gram-negative bacilli bacteria. (See BioWorld Today, April 22, 2013.)

What is clear from the ICAAC event is that biotech companies are now in the forefront of this research and have picked up the slack left by pharma companies who have exited the space over the past several years due to several factors such as low returns on investments and an uncertain regulatory pathway for antibiotics.

“There is no doubt that it will be compounds developed by biotech companies that will significantly contribute toward the IDSA’s 10 x ‘20 Initiative,” Barry Eisenstein, senior vice president of scientific affairs at Cubist Pharmaceuticals Inc., told BioWorld Insight.

The initiative refers to the goal of 10 approved new antibiotics by 2020; since it was launched three years ago the FDA has approved Teflaro (ceftaroline fosamil), a broad-spectrum bactericidal cephalosporin from Cerexa Inc. and its parent company Forest Laboratories Inc. The drug is indicated for community-acquired bacterial pneumonia (CABP), including cases caused by Streptococcus pneumoniae bacteremia, and acute bacterial skin and skin structure infection (ABSSSI), including cases caused by methicillin-resistant Staphylococcus aureus (MRSA). (See BioWorld Today, Nov. 2, 2010.)

Although the transaction has yet to close, Cubist’s acquisition of Optimer Pharmaceuticals Inc. provides access to their antibiotic product for Clostridium difficile, Dificid (fidaxomicin), which was approved in 2011 and added a further compound towards IDSA’s goal.

Adding to the Goal

“We could have the privilege of contributing additional products to IDSA’s target in the near future,” Eisenstein said. “This stems from our acquisition of Trius Therapeutics Inc., which has a planned new drug application [NDA] filing for tedizolid phosphate towards the end of the year, and our own late-stage antibiotic candidate for gram-negative infections ceftolozane/tazobactam that could be ready for NDA filings in 2014.”

Cubist completed its acquisition of Trius, paying about $704 million in cash up front. The deal, disclosed in late July, gives Cubist rights to Trius’ late-stage antibiotic candidate, tedizolid phosphate, which sailed through Phase III trials, meeting all primary and secondary endpoints in two studies in patients with ABSSSI.

With their two acquisitions, there is no doubt that Cubist has solidified its position as a leader in the development of antibiotics.

That was evident at ICAAC with the company contributing no less than 24 posters and presentations on developments in its pipeline. Twelve were dedicated to ceftolozane/tazobactam, its late-stage antibiotic candidate for gram-negative infections, Steve Gilman, chief scientific officer at Cubist told BioWorld Insight.

The antibiotic candidate has been granted FDA fast-track status in the qualified infectious disease product (QIDP) indications hospital-acquired bacterial pneumonia (HABP)/ventilator-associated bacterial pneumonia (VABP), complicated urinary tract infections (cUTI), and complicated intra-abdominal infections (cIAI).

“With the rate of drug resistance among HABP and VABP pathogens increasing, some of these infections are becoming almost untreatable,” Gilman explained. “This is why there is a very large unmet medical need in this area.”

Ceftolozane is a cephalosporin with in vitro activity against multidrug-resistant Pseudomonas aeruginosa and most Enterobacteriaceae. It is administered with tazobactam in a 2:1 ratio, which broadens its potential coverage to include extended-spectrum beta-lactamase (ESBL)-producing organisms.

Gilman said the company is finishing its Phase III trials evaluating the safety and efficacy of ceftolozane/tazobactam in patients with cUTIs and in patients with cIAIs and top line data are expected toward the end of the year.

The climate for antibiotics research and development has certainly improved since last year’s passage of the FDA Safety and Innovation Act, with its Generating Antibiotic Incentives Now (GAIN) provision, noted Eisenstein.

Other Presentations

Among other companies at ICAAC reporting Phase III data was The Medicines Co., which presented results from its Phase III SOLO clinical trial program of oritavancin under investigation for the treatment of ABSSSI caused by susceptible gram-positive bacteria, including MRSA.

SOLO I and SOLO II were multicenter, double-blind, randomized trials, which evaluated the efficacy and safety of a single 1 ,200 mg dose of oritavancin compared to seven to 10 days of twice-daily vancomycin in adults with ABSSSI, including MRSA infections.

In July, The Medicines Co. reported positive Phase III data for oritavancin, a semi-synthetic lipoglycopeptide antibiotic, in ABSSSI, putting the product on schedule for a 2014 approval. The trial showed a 20 percent reduction in lesion size compared to vancomycin. (See BioWorld Today, July 3, 2013.)

The Parsippany, N.J.-based company plans to submit an NDA in the fourth quarter of this year, with an application in Europe to follow next year.

Durata Therapeutics Inc. also presented new pivotal clinical results from its two Phase III DISCOVER (Dalbavancin for Infections of the Skin Compared to Vancomycin at an Early Response) studies and new in vitro data of dalbavancin, further characterizing the effect of the investigational treatment against gram-positive bacteria. Dalbavancin is a second-generation, semi-synthetic lipoglycopeptide, which consists of lipophilic side-chains attached to glycopeptides.

In the two randomized, double-blind studies, dalbavancin was shown to be non-inferior to the comparator regimen, vancomycin with an option to switch to oral linezolid, in treating ABSSSI. In both studies, dalbavancin met its primary and secondary endpoints. Recipients in the dalbavancin arms of the studies had fewer treatment emergent adverse events than those in the comparator arms. The in vitro data showed activity against S. aureus strains, including methicillin-resistant strains, recovered from patients with osteomyelitis-related wounds.

The data, the company said, will be used to support an anticipated NDA submission to the FDA.