Antibiotic Pipeline Profile: Narrowing The Spectrum Of Drug Activity

FDA's push to define a regulatory pathway that will encourage development of drugs for single pathogens could be good news for the handful of companies betting on the approach.

The agency is considering a flexible approach to single-species antibiotic development, in line with the agency's flexible position on orphan drugs. A recent advisory committee discussion looked at a wide menu of options, but disagreement on issues including non-inferiority design and animal models illustrate the challenges ahead. (Also see "Flexible 'Menu' Of Antibacterial Development Options Suggested By US FDA Panel" - Pink Sheet, 18 Apr, 2017.)

Regulatory uncertainty can be a danger for small emerging companies that can lack resources to wait out delays and reversals. And most of the sponsors who have earned QIDP status and progressed to advanced development with single pathogen treatment candidates are small, with limited revenue, like Summit Therapeutics PLC, Polyphor Ltd., and MGB Biopharma Ltd.Debiopharm Group has marketed products, but in areas outside infectious disease. Actelion Pharmaceuticals Ltd. similarly lacks infectious disease marketing experience, but it will likely be transformed by its acquisition by Johnson & Johnson.

The rise of personalized medicine in oncology provides hopeful echoes for the emergence of narrowly targeted antibiotics. But biomarker-driven development for cancer was predicated on a parallel revolution in genomics technology, which allowed precise characterization of tumors.

Diagnostics Could Aid Drug Development

While efforts are underway to encourage development of rapid diagnostics to identify bacteria, personalized antibacterial therapy is largely aspirational. Without the ability to identify pathogens quickly, physicians will continue to use broad-spectrum agents in acutely ill patients. FDA hopes to foster coordinated development of antimicrobial drugs and antimicrobial susceptibility tests (ASTs), building on a draft guidance and public workshop in September 2016. (Also see "Coordinating Antibiotics, Test Development Could Shorten Approval Times, US FDA Says" - Medtech Insight, 26 Sep, 2016.)

In February 2017, FDA approved bioMerieux SA's Vidas Brahms PCT assay for hospital and emergency room use to help providers manage antibiotic use in lower respiratory tract infections and sepsis.

The Vidas Brahms test uses procalcitonin (PCT) as a biomarker to identify patients with bacterial infections, reducing unnecessary antibiotic use. High PCT levels suggest bacterial infection; low levels suggest a viral or non-infectious cause.

The Vidas Brahms approval is notable – the February 510(k) clearance is FDA's first for a PCT test to inform antibiotic management decisions in lower respiratory tract infections and sepsis; Vidas Brahms was first approved for monitoring critically ill sepsis patients over time. (Also see "US FDA Panel To Meet on Transplant IVDs, Test For Managing Antibiotics" - Medtech Insight, 3 Oct, 2016.)

Vidas Brahms cannot, however, identify specific bacteria. "Because PCT may indicate the presence of a variety of bacterial infections, it does not detect the exact cause of a patient's symptoms," FDA emphasized in its Feb. 23 approval announcement.

Many Ways To Tackle C. Difficile

The aptly named, tough to treat Clostridium difficile bacteria, which thrives in patients whose guts have been depleted of beneficial bacteria by broad-spectrum antibiotic use, is a high public health priority. C. diff drug development has also become one of the most innovative spaces in infectious disease. New approaches mining the gut microbiome, in particular, are gaining speed. (Also see "Scrip Asks… Is The Microbiome Hype Or Happening?" - Scrip, 12 Apr, 2017.)

Merck & Co. Inc.'s Zinplava (bezlotoxumab) was approved in October 2016 as a non-antibiotic therapy without a QIDP designation; the monoclonal antibody binds to and neutralizes C. diff toxin B. Zinplava is the first product approved by FDA with an indication to reduce recurrence of C. diff in patients receiving antibacterials who are at high risk of recurrence. (Also see "Merck’s C. Diff Drug Zinplava Clears FDA With Heart Failure Warning" - Pink Sheet, 25 Oct, 2016.)

C. diff is also one of the few bacterial infections to draw the attention and investment of big pharma (and not just Merck). Pfizer Inc. and Sanofi have C. diff vaccines in Phase III development. (Also see "Pfizer To Take Zinplava Rival Into Phase III For C Diff" - Scrip, 30 Jan, 2017.) J&J is acquiring Actelion, which has a novel C. diff-specific antibiotic, cadazolid, in Phase III. (Also see "J&J’s $30bn For Actelion Buys Immediate And Longer-Term Value" - Scrip, 26 Jan, 2017.)

Cadazolid is an oral inhibitor of C. diff protein synthesis that has been awarded QIDP status for treatment of C. diff-associated diarrhea (CDAD) and C. diff infection. Actelion conducted two identical Phase III trials – the IMPACT studies, enrolling more than 1,200 patients with CDAD – but only one met the primary endpoint of non-inferiority to vancomycin for clinical cure rate two days after end of treatment. A third trial could be necessary to meet FDA's approval standards. (Also see "Actelion Setback Ahead Of J&J Deal Closure" - Scrip, 8 Jun, 2017.)

Summit Therapeutics outlined Phase III plans for its novel narrow spectrum antibiotic ridinilazole in February 2017 after an end-of-Phase II meeting with FDA and a scientific advice process with European regulators. The company envisions two Phase III trials in patients with C. diff infection, each with around 700 patients, that would compare ridinilazole with vancomycin.

Summit has high aspirations for ridinilazole's Phase III trials, which it expects will use a primary endpoint of superiority to vancomycin on sustained clinical response (SCR), a composite of cure at end of treatment and no recurrence after 30 days. The Phase II CoDIFY trial showed statistical superiority to vancomycin on SCR, "a result which was driven by a large numerical reduction in recurrent disease," the company noted in a June 14 earnings release.

Summit hopes to begin Phase III in the first half of 2018, but the company is still seeking funding for the trials. "We do not expect to be able to complete these trials without significant additional capital," Summit said in its annual 20-F report to the Securities and Exchange Commission for 2016. The June quarterly results repeated the same options: "potentially entering into a collaboration with a third party or securing meaningful non-dilutive funding from government entities and philanthropic, non-government and not for profit organizations."

FDA has also granted QIDP status to C. diff candidates from MGB Biopharma and Morphochem AG that are poised for Phase II. Morphochem's narrow spectrum antimicrobial MCB3837 targets Clostridia and other Gram-positive pathogens while sparing intestinal flora. (Also see "Keeping Track: FDA Approves Adlyxin, Accepts Brineura, Lowers Hurdle For Xadago" - Pink Sheet, 29 Jul, 2016.) MGB's minor groove binder MGB-BP-3 is an oral narrow spectrum agent that is not systemically absorbed. The company plans to test it in patients with C. diff-associated diarrhea caused by the most virulent ribotype of C. Diff, B1/NAP1/027, but is evaluating funding sources.

Specifically Targeting Staphylococcus And Pseudomonas

First-in-class narrow spectrum approaches have advanced to the Phase II stage for infections caused by Pseudomonas and Staphylococcus bacteria.

Polyphor aims to start enrolling patients by the first quarter of 2018 in a Phase III trial of murepavadin, a Pseudomonas-specific macrocycle antibiotic from a new class Polyphor calls Outer Membrane Protein Targeting Antibiotics (OMPTA). Murepavadin has a QIDP for treatment of ventilator-associated bacterial pneumonia (VABP) caused by Pseudomonas aeruginosa. Roche had collaborated on the product, but withdrew in late 2015; Polyphor completed a private financing in April that will fund pivotal trials in nosocomial pneumonia (both HABP and VABP).

After end-of-Phase II (EOP2) meetings with FDA, Polyphor is finalizing plans for a Phase III trial with a 28-day mortality endpoint "and a non-inferiority margin which corresponds to an overall trial size of less than 300 patients," the company said in May. Polyphor highlighted "the productive interactions and the valuable direction we received from the FDA."

Debiopharm's first-in-class FABL inhibitor afabicin (Debio 1450) is selective for Staphylococcus and has shown activity against strains resistant to marketed antibiotics. The company has reported animal data showing the antibiotic also causes minimal disturbance to gut microbiota. A Phase II study in 330 acute bacterial skin and skin structure infections (ABSSSI) clinically documented as due to Staphylococci met its primary endpoint of non-inferiority to vancomycin/linezolid, Debiopharm reported in January.

Afabicin has both oral and I.V. formulations. The company calls it "perfectly suited to tackle several hard-to-treat infections caused by Staphylococci." Afabicin holds QIDP status for both ABSSSI, which it presents as nearing Phase III, and bone and joint infections.