Synthetic Biologics’ Ribaxamase Setback Shows Difficulty Of C. Difficile Development

Company believes there is a path forward for developing ribaxamase in Phase III, based on discussions with the FDA, but deaths in Phase II meant loss of breakthrough designation.

Although Synthetic Biologics Inc.’ C. difficile microbiome therapy SYN-004 (ribaxamase) lost its breakthrough designation from the US FDA, looking ahead the company is focusing on the security of having a Phase III design approved by the agency. The latest setback is a sign of the challenges of the development space, which is marked by a number of trial failures.

C. difficile is a spore-forming pathogen that typically causes symptoms in individuals with altered gut microbial flora, releasing toxins. Diarrhea, pseudomembranous colitis, toxic megacolon and intestinal perforation are among the conditions linked to the infection, which can prove fatal. (Also see "Pfizer To Take Zinplava Rival Into Phase III For C Diff" - Scrip, 30 Jan, 2017.)

Two antibiotics are specifically approved for C. difficile infection – Merck & Co. Inc.’s Dificid (fidaxomicin) and the older standby vancomycin.  Merck's Zinplava (bezlotoxumab), a fully human monoclonal antibody that binds to and neutralizes the B toxin, is also approved as a vaccine for this indication. (Also see "Merck & Co Expands C Diff Franchise With US Zinplava Approval" - Scrip, 24 Oct, 2016.)

Three therapies are in Phase III – Seres Therapeutics Inc./Nestle SA's SER-109, Pfizer Inc.'s PF-06425090 and Rebiotix Inc./Ferring Pharmaceuticals AS' RBX2660. 

But it has proven a hard target for development.

Just The Latest C. Diff. Setback

Synthetic Biologics' setback underscores the difficulty of developing drugs for C. difficile. In its first-quarter earnings report on April 20, Johnson & Johnson announced the discontinuation of the Phase III candidate cadazolid, a novel quinoxolidinone antibiotic, for Clostridium difficile associated diarrhea. J&J had picked up the drug through the $30bn acquisition of Actelion in June 2017. But the same month, the drug failed to satisfy the primary endpoint in the second of two Phase III trials.

In December, Sanofi announced that it was terminating development of the ACAM-DIFF vaccine for C. difficile, following a recommendation by an independent data monitoring committee in a planned interim analysis that the drug would not meet the primary endpoint of a Phase III study. (Also see "More Vaccine Disappointment For Sanofi As First C Diff Toxoid Vaccine Fails" - Scrip, 4 Dec, 2017.) 

Seres Therapeutics' SER-109, which is derived from donors' fecal matter, failed in a randomized, placebo-controlled Phase II study of patients with recurrent C. difficile infection.  (Also see "Seres Argues Different Diagnostic Needed In Recurrent C. Difficile Trials" - Pink Sheet, 31 Jan, 2017.) The company thought that the failure was due to misdiagnosis of C. difficile, a problem that it felt could be corrected with the use of a different assay. In January 2017, Seres announced it was starting the Phase III ECOSPOR III study of SER-109 in 320 patients with recent C. difficile infection and that this single study would support registration and approval if successful, per discussions with the FDA.

Synthetic Biologics’ ribaxamase is a first-in-class oral enzyme designed to protect the gut microbiome from disruption caused by commonly used intravenous beta-lactam antibiotics, which had earned it breakthrough therapy designation with the US FDA. The drug is not systemically absorbed and protects the gut microbiome in patients, according to the company.  (Also see "Synthetic Biologics CEO On Pipeline Advances And The Microbiome" - Scrip, 15 Dec, 2017.)

Deaths In Phase II

Synthetics Biologics announced April 23 that following a review of additional data from a Phase IIb study, the FDA said that the requirements for breakthrough therapy designation were "no longer met due to the numerical imbalance in fatal adverse events observed in the study which could not be fully evaluated due to the limited safety database, and the study's method of statistical treatment of patients who did not complete the study for any reason." The company voluntarily withdrew the breakthrough therapy designation.

The Phase IIb study had compared the drug against placebo in 412 patients with upper respiratory tract infections taking ceftriaxone. Those on ribaxamase had a significantly lower rate of C. difficile infection (CDI), but there was a numerically higher rate of fatal adverse events: 11 for the test drug versus five for placebo.

However, the imbalance may not have been related to ribaxamase. "As the enrolled patients were elderly and had high co-morbidities, the death rates were in fact higher than the CDI rates. We note that none of the fatal events were considered related to the study drug or placebo as judged by the investigators and the FDA reviewers. As ribaxamase is given orally and does not enter systemic circulation, the imbalance in death events observed is highly unlikely to be aberrant," William Blair analyst Y. Katherine Xu commented in an April 23 note.

Synthetic Biologics said that it has a "preliminary agreement with the FDA" for a global Phase III study. It will include separate co-primary endpoints to evaluate the efficacy and safety of ribaxamase in patients treated with I.V. beta-lactam antibiotics. The company said that it expects the primary efficacy endpoint of the proposed Phase III clinical trial will be the reduction of the incidence of C. difficile infection for ribaxamase vs. placebo.

The company indicated that a strong single trial will be enough for approval but details about the design are not yet available. It will share more information about the Phase III study after its end-of-Phase II meeting with the agency in the second half of this year and expects to start Phase III in the second half of 2019.

Xu believes that the evaluation of CDI separately from mortality/safety, as opposed to including deaths as treatment failures for the efficacy evaluation, should increase the chance of success in Phase III.

However, Xu noted that the company does not have funding to advance the program and is working on securing partnership to fund Phase III.

Synthetic Biologics' stock price dropped by about 31% on the news to a close of $0.24 on April 23.

Breakthrough Losses

Breakthrough designation losses are rare but not unprecedented – though they are usually kept quiet. So far in the fiscal year 2018, eight BTDs have been withdrawn under FDA's Center for Drug Evaluation and Research (CDER), which received 64 breakthrough applications during that time, granting 23 and denying 16. That compares to 111 received, 50 granted, 49 denied and 12 withdrawn in fiscal year 2017.

There have been no withdrawals this year in FDA's Center for Biologics Evaluation and Research (CBER), which would likely have oversight of ribaxamase, breakthrough application were received, three designations were granted, five denied and none were withdrawn in fiscal year 2018. That compares with 25 received, nine granted 15 denied and one withdrawn in fiscal year 2017 at CBER.

According to Pink Sheet's Performance Tracker, since the breakthrough program's inception, of CDER’s 564 BTD requests, 214 were granted, 260 were denied, 73 were withdrawn before a decision, four were withdrawn after they were granted and 13 were rescinded. In CBER, since the start of the program, 118 applications have been received, 36 were granted, 72 were denied, six with withdrawn before action and none were withdrawn after they were granted or rescinded.