Basilea/Astellas change primary endpoint of Phase III trial of anti-fungal
This article was originally published in Scrip
Basilea Pharmaceutica and partner Astellas Pharma have agreed with the US FDA to change the primary endpoint of a Phase III trial investigating their broad-spectrum antifungal isavuconazole for the treatment of invasive aspergillosis, but said that the trial's timelines for completion remain unchanged from previous guidance of 2013 and also insisted that the efficacy hurdle has not been raised.
The primary endpoint is being changed from non-inferiority of overall response to voriconazole, to non-inferiority of all-cause mortality at six weeks, which was previously a secondary endpoint. Overall response (clinical, mycological and radiological response) will continue to be assessed in the study as a secondary endpoint.
Basilea said that the change in primary endpoint would strengthen the regulatory case for the drug, being less subject to bias than response would be in a non-inferiority trial, and was in-line with current regulatory thinking and trials of other companies' compounds in invasive aspergillosis. It also said that there was a good correlation with response and mortality, and there was no reason to think the efficacy or safety of the compound had changed in any way. It has not amended the primary endpoint of the other Phase III trials of isavuconazole in Candida infection or invasive rare fungal infections, it said.
In February, Basilea agreed a worldwide licensing deal with Astellas for isavuconazole in a deal valued at more than $510 million (scripintelligence.com, 24 February 2010). The companies say that the compound has the potential to become the best-in-class azole, with advantages over the current standard in invasive aspergillosis, voriconazole, including being broader-spectrum and a better pharmacokinetic and pharmacodynamic profile. The water-soluble compound can be administered intravenously or orally.
In June, Astellas expanded the Phase III study in invasive aspergillosis to include more patients (510), causing a delay of 12-18 months. In September, it said it was delaying the initiation of studies in the product's Phase III clinical programme to the end of the year or early 2011, to use drug product from the commercial-scale production line, which covers the estimated demand for clinical trial material at all sites globally.
Basilea has also faced major regulatory hurdles this year with its other major pipeline product, the broad-spectrum antibiotic ceftobiprole (Zevtera), which had been in development in partnership with Johnson& Johnson to treat complicated skin and soft tissue infections (cSSTI) .
An inspection of study sites by the FDA showed that the studies, for which Janssen-Cilag was responsible, had not been conducted in compliance with good clinical practice at some sites in the US. Last February, Janssen-Cilag agreed to return the rights to ceftobiprole to Basilea over a 12-month transition period. In February 2009, Basilea submitted a request for arbitration relating to damages incurred from Janssen-Cilag as a result of the delayed approval of ceftobiprole, as well as delays in milestone payments as a result of the faulty trials. Basilea still expects an arbitration decision before the end of the year.