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FDA DECISION ALERT
April 20, 2020

CDER-Approved NDA for EGATEN™ (triclabendazole)

Christina Purpura and Tony Louder
Contributing writers, Aetion

On February 13, 2019, the FDA approved Novartis’ EGATEN™ (triclabendazole), which was granted Orphan Drug Designation and Fast Track. Triclabendazole (TCBZ) is indicated “to treat fascioliasis, a parasitic infestation caused by two species of flatworms or trematodes that mainly affect the liver, sometimes referred to as ‘liver flukes.’” 

TCBZ was developed by CIBA-Geigy (Novartis’ predecessor) in 1978, and it was introduced for veterinary use as Fasinex in 1983. Its first human use was in 1986. 

Egaten was registered in Egypt in 1997; then put on the World Health Organization (WHO)’s list of essential drugs in 1997; then registered in France in 2002.

Key findings from the FDA’s Multi-Discipline Review and Other Review(s) are summarized below. Supportive evidence of safety includes real-world data (RWD): both compassionate use program data and post-market data.

Substantial evidence for effectiveness is provided by —

  • Patient-level published trials (Hien, Maco, and Keiser). The Hien study was a randomized controlled trial comparing TCBZ (n=50) to artesunate (n=50). It was pivotal in demonstrating the efficacy of TCBZ. The Maco study was an open-label, randomized, dose-ranging trial (n=84); it provided supportive evidence of a TCBZ treatment effect compared to the no treatment/ineffective treatment control. Keiser carried out two exploratory phase-2 trials; patients who remained Fasciola-positive following artemether dosing were treated with TCBZ (n=16).
  • Six CIBA/WHO trials, which were dose-finding, open-label, non-randomized studies (n=245), strongly favoring 20 mg/kg TCBZ.
  • Supportive evidence from the literature (n=247).

The FDA’s review of data for TCBZ 20 mg/kg and the use of TCBZ worldwide have not identified any major safety concerns. The primary safety population for TCBZ includes the Keiser, Maco, and CIBA/WHO studies. Supportive evidence of safety was provided by —

  • Three historical studies sponsored by the Egyptian government using TCBZ (CGP 23030, the interim human formulation) for fascioliasis (n=135). 
  • Three historical studies of Fasinex for treatment of paragonimiasis, caused by the lung fluke Paragonimus westermanii (n=236).
  • Publications referenced by the Applicant (n=558), which represent uncontrolled and controlled trials. Many other patients are represented in other smaller trials, case reports, and case series; while contributing to the overall evidence, these smaller reports were not specifically cited. 

A report from the Named Patient Program (n=115). 

  • Purpose: Use RWD to understand the risks associated with TCBZ.
  • What was done: 115 patients were administered CGP 23030 (the interim human formulation) worldwide through the compassionate use program between 1986 and 1998.
  • Outcome: The FDA’s review of the data did not identify any major safety concerns. Adverse events consisted mostly of abdominal pain and biliary colic, which occurred within the first few days after treatment and were transient (caveat: the details were scant).

Post-market data, Novartis Global Safety Database (n=2.6M treatment courses)

  • Purpose: Use RWD to understand the risks associated with TCBZ.
  • What was done: Worldwide, between 2006 and 2018, Novartis donated an estimated 2.6 million treatment courses (single dose of 10 mg/kg).
  • Outcome: The Periodic Safety Update Report (PSUR) submitted by the Applicant for the most recent review period (November 2012 through March 2017), did not demonstrate new or significant safety signals. However, it did note a new signal for drug resistance, which has been added to the Core Data Sheet.

Novartis will conduct a thorough QT (TQT) study as a postmarket requirement and an observational study as a postmarket commitment to assess the safety of TCBZ 20 mg/kg dose.


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