FDA does not appear overly concerned about a renal safety signal seen in trials of Theravance's antibiotic telavancin, which will be reviewed by the Anti-Infective Drugs Advisory Committee on Nov. 19 for the treatment of complicated skin and skin structure infections

In ¹ briefing materials for the panel, FDA noted that in the pivotal trials - which showed non-inferiority to standard-of-care treatment vancomycin - also found that patients with progressive degrees of baseline renal impairment had a greater decline in clinical response rate when treated with telavancin.

A similar pattern of decrease in clinical response rate was seen in older patients. FDA said the decline may be related to decreased efficacy in older patients, since aging is correlated with a decline in creatinine clearance.

However, the issue does not appear to rise to the level of a central question in the review of the application, since FDA does not include the topic in the questions it plans to ask the committee.

The questions include the standard "do the data presented demonstrate the safety and effectiveness" query, as well as questions on pregnancy-related risks, which present a significant challenge for the product (see ² Also see "Telavancin May Require Informed Consent For Women Of Childbearing Age" - Pink Sheet, 17 November, 2008. ).

While the safety and adverse events profile for telavancin was comparable to vancomycin, overall there was an imbalance in the number of serious adverse events in the renal and urinary disorder system organ class that FDA said was a concern: 11 of the patients with those events were treated with telavancin compared to two with vancomycin.

Not only were two deaths the cause of renal insufficiency, but 15 out of 19 patients that has an serious adverse event related to renal impairment were from the telavancin treatment group, as were 13 out of 15 patients who discontinued the drug due to renal treatment-emergence AEs.

Vascular events also showed an imbalance between treatment groups, but there was no specific observation which predominated, and reported events included both venous and arterial events, as well as blood pressure.

Overall, there were 18 deaths reported for the cSSSI studies: One in a patient treated with 7.5 mg/kg, eight in patients treated with 10 mg/kg, and nine in patients treated with vancomycin. FDA assessed two of the deaths in the telavancin-treated patients to be possibly related to the study medication. One patient developed respiratory distress and hypotension and was subsequently diagnosed with acute respiratory distress syndrome and multi-system organ failure, and died 12 days after therapy was discontinued. The other patient has a history of sever heart failure and chronic renal insufficiency and developed a progressive increase in serum creatinine. He died from acute renal failure two weeks after therapy was discontinued.

The Long Road To An Advisory Committee

Theravance first submitted its NDA in December 2006. FDA issued an approvable letter the following October requesting more information about manufacturing issues and analyses to better delineate the over benefit-risk profile of telavancin. Theravance responded Jan. 21, 2008 with a safety update and the additional requested analyses.

But the regulatory woes weren't over yet. While FDA was planning an anti-infective advisory committee meeting for February 2008, it received information from clinical site inspections that called into question the reliability of some of the data contained Theravance's NDA. The meeting was cancelled.

The agency inspections revealed "major deficiencies" in good clinical practice, including retrospective alteration of efficacy data, losing or discarding critical source documents, and inadequate study monitoring, which resulted in an inspection of the CRO responsible for study monitoring.

In the end, FDA found the data reported in the NDA to be reliable save for efficacy results from three sites, which have since been excluded from efficacy analyses.

Now, Theravance faces the advisory committee hurdle, along with Targanta's oritavancin (see ³ Also see "Targanta’s Oritavacin Faces Statistical Hurdle At Advisory Committee" - Pink Sheet, 17 November, 2008. ). Arpida's iclaprim will be reviewed the next day.

-Lauren Smith (lauren.smith@elsevier.com)

Theravance’s Telavancin Prompts Renal Concerns, But No Questions From FDA

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