Sanofi and Regeneron are facing a possible delay on one potentially big drug, sarilumab, after receiving a complete response letter tied to manufacturing problems at a plant in France. But Leerink analysts think the plant’s shortcomings could spell issues for another potential blockbuster, dupilumab, an experimental, first-in-class treatment for eczema.
Analysts Geoffrey Porges and Seamus Fernandez point to the Form 483 the plant in Le Trait, France was issued during a re-inspection last July that their firm obtained through the Freedom of Information Act. The plant is also handling the fill-finish work for dupilumab, which in September won priority review from the FDA, putting it on course for a March PDUFA date and launch shortly after under the brand name Dupixent.
The document contains 13 observations, some for problems left unresolved from an earlier inspection, and include sharp rebukes to the company for repeatedly refusing “requested documentation for review of the CBER regulated product…” It also points to issues with mold and bacteria contamination at the plant that the FDA says Sanofi did not thoroughly explore to sufficiently determine a root cause.
“Frankly, now we have the letter in hand, the list of issues cited is longer, and somewhat more concerning, than we had anticipated,” the analysts wrote.
A Sanofi spokeswoman today said in an emailed statement, “At this time, we do not expect dupilumab to be impacted by the identified manufacturing deficiencies at Le Trait. We are working towards resolving these deficiencies expeditiously and expect to have these issues resolved before the expected March 29th PDUFA.”
She said the company has submitted a comprehensive corrective action plan to the FDA and has started implementing the fixes. “We anticipate resolving these issues expeditiously and/or potentially utilizing redundant capabilities.” the statement said.
Leerink told investors in a note last week that Regeneron and Sanofi have indicated to them the companies are working together, and with the FDA, to solve the issues quickly and completely. The two say that the companies have indicated they might use another facility to fill and finish the drug. But they point out there is no guarantee that they drugmakers could get FDA approval for another facility to meet the expected launch date.
“We can only presume that good sense has prevailed in the respective companies, and that product is already being filled for the launch at another facility without such regulatory and compliance liabilities,” their note said.
The FDA’s concerns with operations at the Le Trait plant first came to light a month ago, when instead of getting an approval for sarilumab, an expected blockbuster that will compete with AbbVie’s Humira, the FDA issued a complete response letter for the drug. Sanofi CEO Olivier Brandicourt acknowledged during an earnings call that "manufacturing deficiencies, not specifically related to sarilumab," were at the heart of the CRL.
In response to a question during an earnings call, Brandicourt acknowledged that Le Trait also was filling product for the eczema drug candidate but said Sanofi expected the matter to be resolved before the expected March 29's PDUFA date for the drug. He did not spell out what those deficiencies were.
In the highly redacted Form 483, shared by Leerink, the FDA noted that retained samples from some lots contained “visual particulates” and that Sanofi didn’t do an investigation to explain how they had been released. It notes “failure of two consecutive media fills on a line where Chaetomium subaffine was discovered. There were problems with airflow and problems with the design of some equipment.
In its note, Leerink observed that the length of the findings seem to stem from “the FDA’s prior inspection and from frustration at the non-responsiveness of the manufacturer to what the agency considers standard GMP practices.”
Will this ultimately lead to delay of a drugs that are expected to be a big sellers for the companies and which Sanofi badly needs? Leerink had this to say: “The lack of specific product quality observations by the FDA provides some assurance that with skill, resources and a healthy dose of contrition, Sanofi could address these issues to the satisfaction of the FDA, and thus secure the approval of sarilumab and provide assurances about the timeline for dupilumab.”