AstraZeneca's Rezield Hits Another Regulatory Wall

FDA issues a second "complete response" letter for the respiratory syncytial virus prophylaxis agent, this time seeking a new clinical trial.

FDA's request for another clinical trial before approving MedImmune's Rezield for prevention of respiratory syncytial virus could reflect an advisory committee's recommendations that the company show some advantage over its currently approved RSV agent, Synagis , particularly in sicker children.

FDA hit MedImmune, an AstraZeneca subsidiary, with another "complete response" letter for Rezield (motavizumab). In an Aug. 30 statement, AstraZeneca said the agency "has requested evidence from an additional clinical trial that supports a satisfactory risk/benefit profile in the population(s) for which the prophylaxis indication is being requested." MedImmune is seeking approval for prevention of serious lower respiratory tract disease caused by RSV in children at high risk of the disease.

The company did not provide further details about the type of trial FDA requested. In an email, an AstraZeneca spokesman said: "The exact nature of a trial will be evaluated. The company continues to believe in the clinical benefit of motavizumab, and it will conduct a complete review of the ["complete response" letter], continue ongoing constructive dialogue with FDA as well as make a decision regarding next steps in due course."

However, if the discussion and recommendations from the June 2 Antiviral Drugs Advisory Committee are any indication, FDA may be pushing MedImmune to study Rezield in a larger population of sicker children than was studied in the pivotal trials.

The committee voted 14-3 against recommending approval (Also see "AstraZeneca's Rezield Might Itself Be Saved By Sicker Patients" - Pink Sheet, 2 Jun, 2010.). Panel members said motavizumab carried a heightened risk of hypersensitivity and skin reactions compared with the parent compound, Synagis (palivizumab), with no evidence of an efficacy advantage.

In one of the Phase III pivotal trials, motavizumab was shown to be non-inferior, though not superior, to palivizumab in reducing RSV hospitalizations. However, the non-inferiority findings were driven by results from Southern Hemisphere patients. Agency reviewers cited concerns that the overall results were sensitive to misclassification of a few events, and the use of testing assays by some study sites may have biased decisions on whether to hospitalize.

Committee members suggested motavizumab might find its niche in prophylaxis for sicker children, where the risk of hypersensitivity reactions could be outweighed by the benefit of potentially better efficacy than seen with palivizumab. Committee members cited the need for additional efficacy, safety and immunology data in sicker patients to determine whether motavizumab prevented more deaths or reduced the number of days spent in hospital or on ventilator compared with palivizumab.

Second Letter For The Second-Generation Product

FDA's new request for additional clinical data is particularly notable given that the agency did not make such a request in its first "complete response" letter, issued in November 2008.

In that letter, FDA sought additional information on various safety and efficacy issues, including whether local RSV testing at some study sites biased decisions about hospital admission, the degree to which motavizumab and palivizumab interfered with local commercially available immunologic assays, reducing their sensitivity, and the sensitivity and accuracy of central laboratory testing for RSV detection.

MedImmune conducted a comprehensive chart review assessing local RSV testing practices and submitted its results to the agency in December 2009. In briefing materials for the advisory committee meeting, FDA said the chart review attempted to clarify the use of local testing by comparing test results availability and the exact times admission orders were written. However, the issue remained unsettled because it was likely some test results were available prior to official reporting, and missing data precluded determination of the sequence of local testing and admission orders for approximately 40 percent of respiratory admissions, FDA said.

It now appears, from a time and resource perspective, that AstraZeneca may have been better off if FDA had required a new clinical trial as part of the initial "complete response" letter (Also see "Would AstraZeneca Be Better Off If Rezield Had Gotten A Harsher FDA Letter?" - Pink Sheet, 7 Jun, 2010.).

AstraZeneca said it holds intangible assets of $445 million relating to motavizumab that could be subject to impairment after its review of the letter is completed. In response to a question asking when the company expected to make a decision on whether to continue development of motavizumab in the U.S., a spokesman responded: "We need to fully evaluate the questions posted in the ["complete response" letter] before determining next steps."

FDA's original user fee date on the application was June 24, but that date was pushed back two months for reasons undisclosed by the agency (Also see "FDA Delays Action On MedImmune's Rezield Despite Negative Panel Vote" - Pink Sheet, 25 Jun, 2010.). One possible explanation is that the agency needed more time to investigate allegations in a wrongful termination suit filed against MedImmune that challenged motavizumab study data integrity (Also see "Motavizumab's Data Integrity Worries Grow As FDA Shows Interest In Lawsuit" - Pink Sheet, 7 Jun, 2010.).

The lawsuit, filed by Petrus Roelvink, former R&D director of MedImmune's Infectious Diseases Department, was recently dismissed by a judge in Maryland's Montgomery County Circuit Court, who granted AstraZeneca's motion to compel arbitration in the dispute.

AstraZeneca said no data integrity issues were raised in the "complete response" letter.

-Sue Sutter ( [email protected] )