A great deal has transpired in the antibiotics world since the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last convened one year ago. As researchers and antibiotic drug developers alike head to Denver this week for this annual meeting the focus will be squarely on new product pipeline progress and whether these innovative products nearing the marketplace will be enough to alleviate the growing concern about multidrug drug resistance in virulent bacteria.

According to discussions at this year’s World Economic Forum (WEC) the irresponsible use of antibiotics promotes resistance in bacteria – a problem that is getting worse and risks becoming a global crisis since research and development of new classes of antibiotics are still lagging behind bacteria’s ability to mutate and gain resistance. “Many people take for granted that antibiotics will always be available when we need them, but soon this may no longer be the case,” states WEC’s Global Risks 2013 report.

For delegates attending ICAAC, momentum in antibiotics innovation is building, which may ultimately prove WEC’s statement wrong given the promising arsenal of new drugs in the latter stages of development.

Tide May be Turning

There is no doubt that the climate for antibiotics development has warmed due to last year’s passage of the FDA Safety and Innovation Act, with its Generating Antibiotic Incentives Now (GAIN) provision, and pressure from the government to develop new therapies. As a result antibiotics developers are encountering a smoother regulatory road than has previously existed.

The FDA has so far granted 17 of the 20 qualified infectious disease product (QIDP) applications submitted under the act, which provides an additional five years of exclusivity for anti-infectives targeting specified pathogens. The agency also has created a list of pathogens that qualify as targets for antibacterial and antifungal drugs being developed under the GAIN provision.

There is no doubt that the FDA is more than willing to help antibiotic drug developers, Cempra Inc. president and CEO, Prabhavathi Fernandes, told BioWorld Insight.

In June the company disclosed a successful end-of-Phase II meeting with the FDA. It was encouraging, she explained, because the agency said that a new drug application for the firm’s macrolide antibiotic solithromycin in community-acquired bacterial pneumonia (CABP) can be based on one study for testing intravenous (I.V.)-to-oral administration and one for oral dosing of their candidate antibiotic. In addition, the FDA, last week, designated oral solithromycin (CEM-101), as a QIDP.

To help fund its planned Phase III I.V.-to-oral stepdown study, which is expected to start in the fourth quarter of this year, the company raised more than $54 million in a public offering. An ongoing pivotal trial testing oral dosing of solithromycin was launched last year, and data from that study are expected in 2014, Fernandez said. (See BioWorld Today, Dec. 20, 2012.)

“Solithromycin is the first macrolide in 20 years with both oral and I.V. administration forms in clinical development,” Fernandez said. “We have been pleased with the results we have seen so far; solithromycin has a good safety profile and is generally well tolerated.”

At the American Thoracic Society International Conference in May the company presented data demonstrating the antibacterial and enhanced immunomodulatory activity of solithromycin versus levofloxacin in a Phase II clinical trial in outpatients with CABP. Solithromycin’s efficacy profile was found to be comparable to levofloxacin’s while solithromycin demonstrated favorable tolerability versus levofloxacin.

In addition to their recent public offering Cempra was awarded a five-year contract valued at up to $58 million by the Biomedical Advanced Research and Development Authority (BARDA) for the development of solithromycin to treat infections in pediatric populations and for the treatment of infections by bioterror threat pathogens.

Basilea Pharmaceutica AG also landed a $89 million contract from the BARDA for development of its antibiotic, BAL30072, which has shown activity against a range of gram-negative bacteria, including multidrug-resistant P. aeruginosa and species of Acinetobacter. The drug is a monosulfactam with an attached dihydroxypyridone moiety, which is thought to accelerate intracellular uptake of the drug via the siderophore receptors of the target pathogen’s iron transport system. Basilea is developing it for severe nosocomial infections. (See BioWorld Today, June 26, 2013.)

Glaxosmithkline plc, of London, and BARDA have agreed to a collaboration that will support the development of several antibiotics. The public-private agreement calls for the Department of Health and Human Services to provide $40 million for the initial 18-month agreement and up to $200 million if the agreement is renewed over five years.

“There is an urgent need to address antibiotic resistance and new models are needed to deal with this challenging area of drug development,” noted David Payne, head of GSK’s Antibacterial Discovery Performance Unit in a release describing the initiative. “We strongly believe that innovative public-private partnerships such as this are integral to solving this critical healthcare issue.”

Late-Stage Development

In addition to Cempra’s drug, there are several other late-stage products in the pipeline. Paratek Pharmaceuticals Inc., of Boston, for example, received a QIDP for lead antibiotic candidate, omadacycline for both intravenous and oral formulations to treat acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. The company has completed studies necessary to advance omadacycline, a tetracycline-derived broad-spectrum antibiotic, into Phase III development. (See BioWorld Today, Jan. 4, 2013.)

In July, The Medicines Co. reported positive Phase III data for oritavancin, a semi-synthetic lipoglycopeptide antibiotic, in acute bacterial skin and skin structure infections, putting the product on schedule for a 2014 approval. The trial showed a 20 percent reduction in lesion size compared to vancomycin.

Rib-X Pharmaceuticals Inc., of New Haven, Conn., has started a Phase III trial testing delafloxacin, a fluoroquinolone antibiotic, in patients with acute bacterial skin and skin structure infections. The PROCEED (PROve Clinical Efficacy and Effect of Delafloxacin) study is designed to test delafloxacin 300 mg, given intravenously every 12 hours, compared to vancomycin 15 mg/kg plus aztreonam 2 g I.V., also given every 12 hours. The study includes clinical and microbiological endpoints to assess the efficacy. Rib-X reached an agreement with the FDA on a special protocol assessment for the trial. Delafloxacin previously demonstrated efficacy against infections caused by methicillin-resistant Staphylococcus aureus and a range of Gram-positive and Gram-negative bacteria. A second Phase III study, evaluating an oral formulation of the drug, is set to start later this year or early in 2014. (See BioWorld Today, May 5, 2013.)

Tetraphase Pharmaceuticals Inc., of Watertown, Mass., which recently joined publicly listed antibiotic-focused biotechnology companies, Trius Therapeutics Inc. (2010) and Cempra Inc. (2012) by raising $75 million in an IPO, is working with a technology platform based on tetracycline. Its latest infusion of cash from the IPO will support the company’s Phase III trial with lead product TP-434 (eravacycline) for complicated intra-abdominal infections (cIAI). The company recently reported it had dosed the first patient in the study. (See BioWorld Today, Sept. 4, 2013.)

The trial is the first of two planned Phase III studies of eravacycline, with the second study expected to test the broad-spectrum oral and intravenous antibiotic in complicated urinary tract infections. The cIAI study will enroll 536 adults, randomized to receive eravacycline or ertapenem, with clinical response at the test-of-cure (TOC) visit in the microbiological intent-to-treat patient population as the primary endpoint.

Editor’s Note: The second part in this series will review the ICAAC meeting and dive into the business and financial developments in the space, including the impact of Cubist Pharmaceuticals Inc.’s $1.6 billion double acquisition of Optimer Pharmaceuticals Inc. and Trius Therapeutics Inc.