Basilea Pharmaceutica Ltd. is seeking another U.S. partner for the late-stage antibiotic ceftobiprole after FDA said additional clinical trials would be required before approval, the company announced June 25.

The firm has made clear that after more than seven years trying to get the drug approved in the U.S., it does not intend to initiate new Phase III trials for ceftobiprole without a partner – and FDA has clarified that it does not intend to approve the drug without new trials.

However, the commercial launch of the broad-spectrum intravenous antibiotic remains on track for the second half of the year in Europe, where ceftobiprole was approved for community-acquired and hospital-acquired pneumonia in October 2013 Also see "Basilea Plans European Ceftobiprole Launches In Second-Quarter 2014" - Pink Sheet, 19 February, 2014.. It will be the first of several hospital products the Swiss-based company hopes to launch.

In the U.S., the drug has traveled a long and rocky road, negatively impacted by faulty clinical trial procedures, leading to Basilea’s breakup with its original big pharma partner, Johnson & Johnson, and also by FDA’s changing requirements for antibiotic products.

Basilea originally partnered ceftobiprole with J&J in 2005, and the big pharma filed an NDA in May 2007 seeking approval for resistant skin infections, an indication that since has seen several new drug approvals and regulatory filings ([A#14140623004]). Ceftobiprole was deemed “approvable” in March 2008 and received a “complete response” letter in November 2008, citing issues with clinical trial procedures by a third party and requesting site audits. A third “complete response” letter followed in 2009 ([A#14091230005]).

The long review timeline and regulatory issues soured the relationship between J&J and Basilea, which eventually won damages from J&J in arbitration proceedings for shoddy trial management ([A#14101129008]). The two previously had broken off their partnership in February 2010, with Basilea regaining full rights to the drug.

Basilea refocused regulatory approval of ceftobiprole in the area of lung infections and filed the drug in Europe for the treatment of pneumonia in 2012, based on the results of two Phase III clinical trials. Basilea requested a consultation meeting with FDA to get a recommendation on the indications that potentially could be supported by the existing data package. The outcome of that meeting led Basilea to conduct a post-hoc analysis of its existing data in pneumonia.

But in the latest update, Basilea said FDA confirmed that the current ceftobiprole studies would need to be complemented with prospective data in community- and hospital-acquired pneumonia in accordance with the agency’s new guidelines. FDA released draft guidance for antibiotics used to treat community-acquired pneumonia in 2009 and hospital-acquired pneumonia in 2010 and updated the guidances again earlier this year, meaning that FDA’s thinking on the clinical trial requirements has changed twice since Basilea conducted the Phase III pneumonia studies.

FDA has been working to clarify approval requirements for new antibiotics and has been more open to exploring new clinical trial approaches after regulatory and commercial challenges stymied antibiotic drug development for several years, and as the need for new antibiotics that can fight resistant infections has grown. It is one reason some drug makers are showing renewed interest in the space ([A#00130107001.]).

But, in the case of ceftobiprole, despite what Basilea says was a positive post hoc analysis that met the new endpoints required by FDA, the agency is standing by the requirement for prospective studies. “FDA will not allow us to go ahead with filing based on a post hoc analysis,” Chief Medical Officer Achim Kaufhold said in a same-day conference call. “They want to see data generated by prospective trials.”

U.S. Opportunity Depends On Partner

CEO Ronald Scott said the company has been in discussion with potential partners for the U.S. rights to ceftobiprole.

“One of the points that was outstanding was what does the FDA require,” he said. “Now, we have a clearer view of what FDA requires. We will go back to potential partners and lay out exactly what the FDA has said.”

But finding a partner for the program may not be easy given the need for additional clinical trial work and potential lengthy timeline to approval, which Scott indicated could be three to four years. As big pharma has backed away from antibiotic R&D, development has fallen primarily to a handful of start-ups and mid-sized specialists like Cubist Pharmaceuticals Inc. and The Medicines Co.

Basilea is partnered already on another anti-infective with the Japanese pharma Astellas Pharma Inc., which could be a potential partner for ceftobiprole as well. However, while Scott said Basilea would not exclude anyone from the negotiating table, he indicated that putting the responsibility for two of its most important assets in the hands of one partner could raise questions about what kind of deal structure would be appropriate.

Astellas bought worldwide development and commercial rights to Basilea’s antifungal isavuconazole in 2010, but the companies amended the agreement in 2014 so that Basilea gained back rights to the product outside of North America, while giving up co-promotion rights in North America in exchange. The companies are on track to file for regulatory approval for invasive aspergillosis and mucormycosis in Europe and the U.S. this year.

Basilea Ceftobiprole Saga Wages On; U.S. Development Ditched

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