12:00 AM
Apr 06, 2009
 |  BioCentury  |  Regulation

Victoza rat's nest

Last week's FDA advisory committee meeting on Victoza liraglutide from Novo Nordisk A/S took an unexpected turn, with a preclinical thyroid cancer signal rather than cardiovascular risk falling into place as the stumbling block on the path to an approval recommendation.

Going forward, Novo Nordisk's ability to get Victoza approved in the U.S. will depend on its ability to persuade FDA to overcome precedent by approving a compound that causes tumors in both genders of two species at exposure levels close to human dosing. The agency also must be convinced that elevated calcitonin seen in clinical trials of Victoza - a biomarker of thyroid C cell hyperplasia and medullary thyroid carcinoma - are not signs of a process that eventually will lead to cancer.

Novo had mixed success in persuading the Endocrinologic and Metabolic Drugs Advisory Committee on these points.

The company failed to convince panel members they could be certain the mechanism of action by which Victoza causes thyroid cancer in rodents is completely different from, and therefore is not relevant to, human effects.

The committee voted 12-1 that Novo had not demonstrated that the preclinical findings are not relevant to humans.

The committee voted 6-6, with one abstention, that available data on thyroid C cell tumors preclude marketing of Victoza.

The company was more successful at allaying questions about an imbalance in the number of patients who developed papillary thyroid cancer in its clinical trials, as well as concerns about the robustness of its data on cardiovascular risk.

The committee was convinced that screening for thyroid cancer prompted by the preclinical data led investigators to discover papillary thyroid cancers that were not caused by Victoza. It voted 12-0, with one abstention, that the papillary tumor data should not prevent marketing.

The vote on the CV issue was closer, with an 8-5 majority agreeing the sponsor had provided enough data to rule out an unacceptable risk. Novo committed to conduct a large post-market cardiovascular outcomes trial.

The intense focus on safety issues left little time for presentations on efficacy, and FDA did not ask the committee to assess Victoza's overall risk/benefit profile.

The votes on thyroid cancer safety issues, coupled with FDA's suggestion that thyroid tumors in rodents seem to be a class effect of long-acting GLP-1 analogs, ensure that Amylin Pharmaceuticals Inc. will have to address new questions about the safety of exenatide once weekly, an extended release version of its GLP-1 analog Byetta exenatide.

Amylin is developing the once-weekly formulation with Eli Lilly and Co., its marketing partner for Byetta. Last week's panel meeting does not alter Amylin's plans to file an NDA before the end of the quarter, Orville Kolterman, SVP of R&D, told BioCentury (see "Class Warfare," A10).

Preclinical signal

Novo hadn't highlighted the preclinical cancer signal prior to last week's meeting, although attentive readers of a February 2009 paper on one of the company's Phase III trials of Victoza in The Lancet would have noticed that it reported "calcitonin concentrations were measured on the basis of C-cell tumour findings in the rodent carcinogenicity studies."

The Lancet paper concluded: "After 52 weeks, calcitonin concentrations did not differ in participants taking liraglutide and those taking [Amaryl] glimepiride" from sanofi-aventis Group.

While investors and competitors were surprised to learn last week that concerns about carcinogenicity pose a serious threat to the approvability of Victoza, Novo has been aware of the issue, and working diligently to address it, for a long time, EVP and CSO Mads Thomsen told BioCentury.

"The first time we dosed rats [for a prolonged period] we saw proliferation," he said. The observation prompted the company to study the issue in mice, which Thomsen said led to the discovery that the phenomenon was not limited to a single species.

This kind of finding often prompts drug developers...

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