Israeli biotech Protalix BioTherapeutics' quest for U.S. approval of its Gaucher disease drug Uplyso (taliglucerase alfa) hit a wall on Feb. 25, when FDA issued a "complete response" letter asking for further data from a pair of Phase III trials as well as additional information for the chemistry, manufacturing and controls section of the filing.

While FDA did not request new trials or pre-clinical studies, the additional work is likely to push an agency decision back to late 2011 or early 2012, analysts said. On a same-day call with analysts, Protalix CEO and President David Aviezer expressed confidence that the biotech and its partner Pfizer Inc. can work out a relatively quick plan of action with FDA.

Protalix partnered with Pfizer in December 2009 to develop and commercialize Uplyso. At the time, Pfizer saw a link-up as one of the first steps in its fledgling but ambitious efforts to enter both the orphan disease and biosimilars space. The big pharma paid $60 million upfront for worldwide commercialization rights to Uplyso and agreed to share the drug's development and commercialization costs, as well as all revenues on a 60/40 basis, under the deal (Also see "Pfizer Partners With Protalix On Gaucher Drug Eyeing Lower Cost Plant-Based Production" - Pink Sheet, 1 December, 2009.).

The timing seemed fortuitous because until 2009, Genzyme Corp., which Sanofi-Aventis is in the process of purchasing for $20.1 billion, enjoyed a monopoly in the U.S. Gaucher market. Its pioneering drug Cerezyme (imiglucerase) brought in more than $1.2 billion in sales in 2008. However, manufacturing issues resulted in a shortage of that drug, enabling Protalix and another new, albeit much larger, entrant, Shire Plc to step in to help meet demand. The companies initially were able to sell their experimental Gaucher therapies, Vpriv (velaglucerase alfa) and Uplyso, respectively, under FDA emergency access protocols.

Shire's Vpriv obtained FDA approval in February 2010 and posted $143 million in sales last year, while Cerezyme slumped to an annual total of $720 million, down 42% from 2008. Meanwhile, Israel-based Protalix completed a rolling NDA for Uplyso in April 2010, with FDA accepting the filing in July and setting a Feb. 25, 2011 action date.

Addressing investors following the announcement of the "complete response" letter, Aviezer said, "While we're disappointed with the delay, we're encouraged with the FDA's response for the following reasons. First, FDA did not request any new clinical or preclinical studies and, second, we did not see any issues that cannot be addressed in an amendment for approval."

He noted that full data from the switchover and extension trials were not available when the NDA was filed - such data were included in a European filing and 120-day questions are expected from the European Medicines Agency in April, which may indicate Uplyso also will face delays in Europe.

FDA has inspected and accepted Protalix's manufacturing facilities and also was satisfied with its audits of clinical trial sites, Aviezer said. Earlier this month, Protalix reported interim efficacy data from the switchover study, which tested Uplyso in patients who previously received Cerezyme.

Efficacy Data Promising In Switchover Study

Data from the trial indicated that patients can be switched safely from Cerezyme to Uplyso, with interim data on 15 patients showing over nine months that signals such as hemoglobin and platelet count, spleen volume and liver volume all remained stable. None of the 15 patients showed a sustained clinical deterioration, according to the company.

In a Feb. 25 note, UBS Investment Research analyst Christopher Schaefer suggested that FDA's concerns about Uplyso, a plant cell-derived recombinant enzyme replacement therapy, are about safety, not efficacy. Cerezyme and Vpriv are both mammalian-based ERTs. Uplyso would be the first plant-derived recombinant protein approved for human therapeutic use.

"We believe that as the efficacy of taliglucerase has never been in question, the FDA likely wants to review a larger safety database prior to approval," Schaefer wrote.

Interim safety data from 25 patients in the switchover trial showed Uplyso was well-tolerated with no drug-related adverse events reported, Hapoalim Securities analyst Jon LeCroy reported in a Feb. 25 note. Despite that encouraging data, LeCroy predicted that Uplyso approval would be delayed at least 12 months and he reduced his peak sales estimate from $628 million to $478 million.

Analyst Ram Selvaraju of Noble Financial Capital Markets still thinks Uplyso could bring in $520 million a year by 2020 because "the drug's plant-derived production source could enable it to be priced very aggressively versus existing therapies," he wrote Feb. 25. "Therefore, we expect Protalix and its partner Pfizer to manage to claim significant market share even in this relatively small patient population."

Selvaraju added that approval of Uplyso could position Protalix as the subject of a bidding war between companies eager to apply its ProCellEx platform to other uses, including follow-on biologics.

"As [Uplyso] would be the first plant cell-derived recombinant protein approved for human therapeutic use ... once this precedent has been established, we would expect the value attributed to the Protalix platform to also rise considerably," he said. "We believe that Protalix could thereafter become the focus of acquisition efforts by larger-cap companies focused on the deploying the proprietary ProCellEx platform owned by Protalix in order to manufacture biosimilar drugs in a more cost-effective manner than is currently achievable using mammalian cell-based technologies."

-Joseph Haas (j.haas@elsevier.com)

FDA Delays Approval Of Protalix/Pfizer Gaucher Drug; Seeks More Data From Late-Stage Trials

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