Teva Pharmaceutical Industries is facing possible delays for its migraine drug candidate, fremanezumab, following a Warning Letter issued by the US Food and Drug Administration (FDA) to Celltrion, an Incheon, South Korea-based life-sciences company, which is manufacturing the active pharmaceutical ingredient (API).

In January 2018, the FDA issued a Warning Letter to Celltrion for good manufacturing practice (GMP) violations for finished pharmaceuticals for the company’s facility in Incheon. The Warning Letter was in response to an inspection the FDA carried out from May 22 to June 2, 2017 at the company’s drug-manufacturing facility in Incheon, South Korea.

Celltrion is the sole source for API production for fremanezumab, noted Teva in its 2017 earnings release on February 8, 2018. In December 2017, the FDA accepted Teva’s biologics license application (BLA) for fremanezumab and granted it fast-track designation for the prevention of cluster headaches. On February 2, 2018, the European Medicines Agency accepted a marketing authorization application for fremanezumab.

 “We are in active dialogue with the FDA in an effort to maintain our priority date for the approval of fremanezumab,” said Teva in its release. “They [Celltrion] have received a Warning Letter, and we are in active dialogue with FDA in order to ensure that this Warning Letter would not affect the supplies of API from Celltrion to our fremanezumab program,” said Teva’s President and Chief Executive Officer Kåre Schultz, in the company’s 2017 earning call on February 8, 2018. “We are optimistic that we will be able to prove that the API manufacturing is in good shape, but it of course remains to be settled in a discussion with FDA,” said Schultz.

Fremanezumab is an anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibody, and Amgen and Novartis are developing CGRP migraine drugs. Amgen is advancing a Phase III CGRP drug for treating migraines called Aimovig (erenumab). Meanwhile, Novartis is progressing with its Phase III CGRP migraine drug, erenumab.

The Celltrion manufacturing plant also produces the APIs for Teva’s and Celltrion’s biosimilar candidates for Rituxan (rituximab) (CT-P10) and Herceptin (trastuzumab) (CT-P6), two of Roche’s cancer drugs. Rituxan and Herceptin respectively had global 2017 sales of CHF 7.3 billion ($7.8 billion) and CHF 7.01 billion ($7.5 billion). Teva and Celltrion entered into an exclusive partnership to commercialize CT-P6 and CT-P10 in the US and Canada in October 2016. The BLAs for both CT-P6 and CT-P10 were accepted for review by the FDA fin 2017 or standard review with FDA regulatory action expected during the first half of 2018 at the time at the time of acceptance. “It is likely that the remediation by Celltrion of the issues addressed in the Warning Letter will result in a delayed approval of the biosimilar products by the FDA,” said Teva in its 2017 earnings release on February 8, 2018.

Source: Teva Pharmaceutical Industries (earnings release) and  Teva Pharmaceutical Industries (earnings call)