UPDATED: FDA pandemic delays strike again with Israeli microcap the latest to receive a CRL based on inspection setbacks
Israeli microcap Protalix Therapeutics and its partners at Italian pharma company Chiesi received bad news regarding their Fabry disease program.
The FDA issued the pair a complete response letter for the candidate, known as pegunigalsidase alfa, the companies said Wednesday. Regulators were unable to conduct an inspection of a manufacturing site in Israel due to Covid-19 travel restrictions, leading to the rejection, according to Protalix.
No concerns were raised over the safety and efficacy of the drug candidate, Protalix added.
“While disappointing, we remain confident in the strength of our data and in the depth of our program,” said Protalix CEO Dror Bashan in a statement. “We remain committed to the program and to working with the FDA and Chiesi toward the approval of PRX‑102.”
Protalix joins a growing number of pharma companies that have said their FDA pitches were scuttled primarily as a result of the pandemic, with regulators unable to complete inspections in time for the review process. Pegunigalsidase alfa had been submitted under the accelerated approval pathway and had already seen its PDUFA pushed back from January.
On May 7, the FDA reached out to Endpoints News to clarify that, as a general rule, “the lack of an inspection alone is not a reason for a complete response letter.”
The restrictions have hit both large pharmas and small biotechs, from Novartis, Mallinckrodt and Bristol Myers Squibb to North Carolina-based Liquidia Technologies and now Protalix. Even in the face of expected OKs, like with Novartis’ inclisiran, the FDA has struggled to conduct timely inspections and instead been forced to prioritize the review.
Generally, the new system has been more friendly to those with new molecules with higher clinical needs. And similar to Protalix’s case, the agency did not conduct an onsite inspection at all for inclisiran, Novartis said at the time of its CRL.
Another wrinkle in the Protalix rejection comes from the recent full approval of Sanofi Genzyme’s Fabrazyme, long the standard of care in Fabry disease. When Protalix resubmits its pitch following a Type A meeting, any submission will have to be in the context of that approval, the CRL reportedly said.
Given that both Fabrazyme and pegunigalsidase alfa are enzyme replacement therapies, that could hint toward the higher concentration the Protalix candidate showed in its Phase III trial. Back when the first results came in June 2019, high levels of pegunigalsidase alfa circulated in the bloodstream after 28 days, with a mean concentration of 138 ng/mL among 15 evaluable patients.
In contrast, Fabrazyme had historically shown a mean concentration of 20 ng/mL at 10 hours post infusion.
More recently though, Protalix has ostensibly been working to show it can prove better than Fabrazyme. This past February, the company released topline results from a small Phase III study where patients would switch over from Fabrazyme to their experimental drug, showing that an IV infusion of pegunigalsidase alfa every four weeks was well-tolerated with no patients developing anti-drug antibodies.
Fabry disease is a rare genetic disorder that prevents the body from making the alpha-Galactosidase-A enzyme, resulting in abnormal deposits of fatty substances in blood vessel walls. The ultimate consequences of these deposits can range from pain and impaired peripheral sensation to kidney and heart failure.
May 7 update: This article has been updated to include the FDA’s clarification that the lack of an inspection alone is not the reason for a CRL.
Social: from Protalix website