FDA Rejects Alvotech’s Stelara Biosimilar as Manufacturing Problems Continue

FDA_iStock, JHVEPhoto

Pictured: FDA signage outside its office in Washington, DC/iStock, JHVEPhoto

The FDA on Thursday denied to approve Alvotech’s AVT04, which it was proposing as a biosimilar to Johnson & Johnson’s Stelara (ustekinumab), marking the fourth regulatory rejection for the Iceland-based company since last year.

In its Complete Response Letter (CRL), the regulator pointed to “deficiencies” at Alvotech’s manufacturing facility in Reykjavik, Iceland, which were identified by the FDA during a site inspection in March 2023. The company did not specifically outline what these issues were but noted in its announcement on Thursday that the CRL was “expected.”

According to Alvotech, the FDA did not flag any other issues with its Biologics License Application (BLA) for AVT04, and the company intends to file a resubmission “shortly.” This would trigger another six-month review cycle and a new target action date.

“Based on our latest interactions with the FDA we are currently expecting that the agency will reinspect our facility in the beginning of next year,” Alvotech CEO Robert Wessman said in a statement, adding that the company is aiming to make AVT04 available to patients no later than February 2025 “pending a satisfactory inspection and BLA approval.”

Alvotech and commercialization partner Teva Pharmaceuticals signed a settlement and license agreement with J&J in June 2023, opening the U.S. market up to AVT04 no later than Feb. 21, 2025.

However, problems at the Alvotech Reykjavik plant have held back more than the Stelara biosimilar program. Alvotech’s biosimilar to AbbVie’s blockbuster arthritis treatment Humira (adalimumab), dubbed AVT02, has been turned down by the FDA three times in the past year. The first CRL came in September 2022, when the FDA flagged “certain deficiencies” that it documented at the Iceland-based manufacturing site during a March 2022 inspection.

In a warning letter at the time, the FDA’s investigators detected “an unacceptably high number of mold recoveries” in drug manufacturing rooms, along with high levels of bacterial contamination. The plant also had put in place “inadequate” corrective and preventive measures to prevent similar contaminations from happening in the future, according to the regulator.

The follow-up investigation in March 2023 no longer included these specific issues, suggesting that Alvotech had already resolved them.

The report did, however, point out that the Iceland campus “has not been effective in carrying out its duties of ensuring that drug products are manufactured in accordance with current good manufacturing practices (cGMP) to ensure safety, efficacy, purity, and overall quality of drug substances.”

This could have contributed to the CRL announced on Thursday.

The FDA rejected AVT02’s BLA for the second time in April 2023, also due to manufacturing issues at the Reykjavik plant. The third CRL came just months later, in June 2023, blocking the biosimilar’s bid for interchangeability.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

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