The initial 750-liter cGMP production run on Fujifilm’s pAVEway platform yielded an unprecedented 5.5 kilograms of >95% pure SYN-004 active pharmaceutical ingredient (API) drug substance, which will be used to support Synthetic Biologics’ planned Phase I and II clinical trials, and continued research and development studies.

SYN-004 is believed to be the first and only therapy designed to neutralize intravenous (IV) antibiotics in the gut. It is intended to protect and maintain the balance of bacterial flora in the gastrointestinal (GI) tract, or gut microbiome, and to potentially prevent the devastating effects of C. difficile infection. Research continues to demonstrate that protection of the microbiome plays an increasingly important role in the prevention of a variety of GI, metabolic and CNS disorders. The U.S. Centers for Disease Control and Prevention (CDC) have classified C. diff as an “urgent public health threat”, surpassing Methicillin-resistant Staphylococcus aureus (MRSA) as the number one hospital-acquired infection in the United States. C. difficile is a multidrug-resistant bacterium that infects 1.1 million U.S. patients annually, and 30,000 patients die with a C. difficile infection annually.

“We are extremely impressed by the quality, quantity and efficiency of the initial SYN-004 API manufacturing work by Fujifilm,” said Jeffrey Riley, Chief Executive Officer of Synthetic Biologics. “Fujifilm not only exceeded our yield expectations, but also provided exemplary customer service through its diligent approach and skillful execution in developing the cGMP process for SYN-004.”

Riley concluded, “Importantly, with a solid new GMP manufacturing process, Synthetic Biologics remains on schedule to file an Investigational New Drug (IND) application for SYN-004, and initiate Phase Ia and Ib clinical studies for the prevention of C. difficileinfection in the second half of 2014. Preliminary Phase I topline data is expected by year-end 2014, and a Phase II efficacy study of SYN-004 is planned to begin in the first half of 2015.”

The GMP manufacturing process was initiated after a successful evaluation by Fujifilm that produced high yielding cell lines that exhibited consistent biological activity of SYN-004. Fujifilm successfully improved SYN-004 expression titers by greater than 25-fold (14 grams of SYN-004 per liter of culture broth), compared to the Bacillus platform previously employed for SYN-004’s first-generation predecessor. Fujifilm’s pAVEway™ platform (an E. coli system) utilizes proprietary expression vectors harboring palindromic DNA looping to provide tightly controlled gene expression, which can enable very high expression levels.  The newly developed, single chromatography column purification process reproducibly yielded 40-50% SYN-004 drug substance recovery at purity levels great than 95%, another marked manufacturing improvement over the previous purification process.

Steve Bagshaw, Chief Executive Officer of FUJIFILM Diosynth Biotechnologies said, “We are pleased to demonstrate the remarkable versatility of our pAVEway™ expression system, and support Synthetic Biologics’ clinical development of its SYN-004 product. We look forward to a productive relationship with Synthetic Biologics as its API supplier.”

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Date: August 29, 2014
Source: Synthetic Biologics