The anticoagulant recombinant protein AndexXa (andexanet alfa) intended to treat patients with life-threatening or uncontrolled bleeding was submitted to the US Food and Drug Administration (FDA) under its accelerated approval programme in December 2015.
But last week, San Francisco-based Portola suffered a blow, receiving an FDA complete response letter (CRL), a predominant portion of which was requesting additional information relating to chemistry, manufacturing, and controls (CMC).
“We are probably more surprised in this area because we had a pre-approval inspection in April during the traditional debrief that took place, we felt very confident that the process or the communications led us to believe we were in control, that the inspection went well,” CEO Bill Lis told stakeholders during a conference call Thursday.
He said this resulted in “very few, if any, non-critical observations” and added the CRL therefore has “has caught us off guard.”
According to Portola, ‘generation 1’ batches of the product used in Phase II/III/IV and the BLA submission were supplied by third-party manufacturer CMC Biologics using a 2,500L stainless steel reactor.
The firm is also using CMC Biologics’ six by 2,000L single-use bioreactor configuration for the Changes Being Effected (CBE) supplementary FDA submission, and has also contracted contract manufacturing organisation (CMO) Lonza to undertake a higher yield process for the intended EU and US expansion – once approved – at a scale of 10,000L.
Dotting the ‘I’s…
John Curnutte, EVP of R&D, said the ability to make the drug was not in question, but rather the issues came down to “this well-known problem with breakthrough therapy where the clinical development and the review goes so quickly that all of the i’s are not always dotted and t's crossed, with regard to much of the analytic book keeping and validation that is required for usual approval pathway.”
“But,” he continued, “as they came down the stretch it's clear that they wanted to see many more of those resolved prior to our, prior to the approval.”
Following the news of the CRL, Portola’s share price dropped 21%.