Firm will work with global licensee Pfizer to address agency’s clinical and CMC issues.

Israeli firm Protalix BioTherapeutics received a Complete Response Letter from FDA relating to the firm’s NDA for taliglucerase alfa, a plant cell-expressed form of glucocerebrosidase (GCD) for the treatment of Gaucher disease. The product has since 2009 been partnered with Pfizer, which holds worldwide commercialization rights to taliglucerase alfa, excluding Israel.

FDA’s CRL relates primarily to clinical queries and issues associated with chemistry, manufacturing, and control (CMC), Protalix states. Specifically, additional data are requested from the Phase III switchover trial and long-term extension studies, full data from which were not available when the original NDA was submitted, Protalix points out. FDA also wants information regarding testing specifications and assay validation. No new clinical studies have been requested.

Pfizer says it will work with Protalix to address FDA’s requests by providing technical, analytical, and regulatory expertise. “While we are disappointed by the receipt of the CRL, we appreciate FDA’s efforts to complete the review of our NDA,” remarks David Aviezer, Ph.D., Protalix’ president and CEO. “FDA inspected our manufacturing facilities finding them acceptable. FDA also did not identify any issues in its audit of our clinical sites.”

Protalix aims to meet with FDA as soon as possible to clarify the regulatory path for taliglucerase alfa. Meanwhile, patient enrollment remains open in a multicenter, pediatric study with the drug, and patients currently enrolled in the switchover study and extension trial will continue to receive treatment. In the U.S., Gaucher disease patients can receive taliglucerase alfa under an expanded access protocol. The treatment is similarly being made available to patients in a number of other countries under special access agreements and named patient provisions.

Protalix is exploiting its plant cell-based ProCellEx recombinant protein expression system to develop novel and biosimilar protein-based therapeutics, both in house and through partnerships. Taliglucerase alfa is the firm’s lead clinical candidate. Also undergoing early clinical evaluation is PR-105, a plant cell-expressed PEGylated recombinant human acetylcholinestrase (AChE) in development as a potential therapeutic and prophylactic biodefense countermeasure against nerve agents attack. This program is being carried out under a license agreement with Yissum Research and Development (the technology transfer arm of the Hebrew University of Jerusalem, Israel), and with the Boyce Thompson Institute. A Phase I trial has successfully been completed, and preclinical studies suggest PRX-105 protects against exposure to nerve gas agent analogs in both prophylactic and post-exposure settings, Protalix notes.

The firm’s preclinical pipeline includes candidates for the treatment of Fabry disease and autoimmune diseases, along with an orally bioavailable Gaucher disease product. The Fabry disease therapy, PRX-102, is a plant cell-expressed recombinant alpha-galactosidase-A enzyme, which Protalix hopes will demonstrate lower immunogenicity and improved substrate clearance compared with the currently marketed treatments Fabrazyme® and Replagel®. The firm has already held a pre-IND meeting with FDA, and plans to submit an IND application for PRX-102 later this year.

PRX-106 is a plant cell-expressed recombinant anti-TNF fusion protein being developed for autoimmune indications, including rheumatoid arthritis. The fusion protein comprises the soluble form of the human TNF receptor (TNFR) fused to the Fc component of a human antibody IgG1 domain.

Taliglucerase alfa is administered intravenously, and Protalix is separately developing an orally available glucocerebrosidase enzyme for Gaucher disease therapy, which is expressed in and naturally encapsulated by carrot cells. Protalix hopes the cellulose cell wall that makes plant cells resistant to enzyme degradation in the digestive tract will serve as an effective delivery vehicle to get the enzyme in an active form into the bloodstream. Phase I trials being planned will test oral GCD in healthy individuals who are carriers of Gaucher disease and who show reduced enzymatic activity at baseline.

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