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Antibiotics: The Triumph Of Hope Over Experience?

This article was originally published in Pharmaceutical Approvals Monthly

Executive Summary

Johnson & Johnson's swift exit from its collaboration with Basilea for Zevtera (ceftobiprole) is only the latest setback for the antibacterial field, which has had little success in producing NME approvals in recent years.

Antibiotics: The Triumph Of Hope Over Experience?

Johnson & Johnson's swift exit from its collaboration with Basilea for Zevtera (ceftobiprole) is only the latest setback for the antibacterial field, which has had little success in producing NME approvals in recent years.

J&J terminated its license after FDA's December 2009 "complete response" letter was followed Feb. 19 by a negative opinion by the European Committee for Medicinal Products for Human Use. Both regulatory agencies pointed to data integrity problems with the NDA; FDA said two new well-controlled trials would be needed.

Basilea is not taking J&J's exit lying down. The company has requested arbitration, pointing to the deficiencies FDA identified in J&J's conduct of the clinical trial program. Ceftobiprole also received a "complete response" letter in November 2008 that cited data integrity problems with the clinical trials.

Data integrity issues have been a persistent problem in the antibiotic field, starting with the Ketek disaster (The RPM Report, March 2008). But a bigger issue for antibacterial R&D has been FDA's evolving standards for non-inferiority trials. Numerous antibiotic submissions have been referred for additional clinical work (Pharmaceutical Approvals Monthly, September 2009). So, despite several applications coming in to FDA, Theravance's Vibativ (telavancin) was the first antibiotic NME approved in two years (Pharmaceutical Approvals Monthly, January 2009).

Given ceftobiprole's action letter, hope for a 2010 approval letter in the antibacterial NME field rests on Forest's ceftaroline.

Like ceftobiprole, ceftaroline is a cephalosporin seeking an indication for complicated skin and skin structure infections. Forest's NDA also seeks indications in community-acquired bacterial pneumonia and methicillin-resistant Staphylococcus aureus infection ('The Pink Sheet' DAILY, Jan. 19, 2010).

Forest's long-term plans for ceftaroline include a combination with a beta lactamase inhibitor, NXL-104, that increases the range of susceptible pathogens "by overcoming the most common resistant mechanism utilized by many Gram negative bacteria." Dirk Thye, president of Forest subsidiary Cerexa, said during a Jan. 7 pipeline review. "We anticipate moving [the ceftaroline/NXL-104 combo] into Phase II in the second half of 2010."

Ceftaroline "easily achieved non-inferiority" in cSSSI trials, Thye reported, and response rates in MRSA, MSSA, and strep were "very high" and comparable to the comparator. In CABP, however, he called the results "important and remarkable" because "when you pool the results from the two studies, ceftaroline is statistically superior to ceftriaxone."

Additionally, Thye said, "the safety profile of ceftaroline is very good. ... Cephalosporins have been used for decades and are known to be quite safe."

- Bridget Silverman ([email protected])



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