FDA vote split for liraglutide use in patients with type 2 diabetes

Committee said tumor findings in animals were relevant to human beings.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee remains undecided on whether or not to recommend approval for liraglutide.

The committee convened to evaluate whether liraglutide (Novo Nordisk) met recommendations from an FDA guidance released in December 2008, regarding cardiovascular events with new type 2 diabetes drugs. The committee also focused on findings from liraglutide studies demonstrating benign and malignant thyroid C-cell tumors in rats and mice.

The committee voted 12-1 that animal C-cell tumor findings from liraglutide treatment were relevant to human beings.

In response to whether available data on thyroid C-cell tumors should permit marketing of the drug, the committee vote was split 6-6 with one abstention.

The committee voted 12-0 with one abstention that available papillary thyroid cancer data permits marketing of liraglutide, with the assumption that the remainder of the risk/benefit data are acceptable.

Committee members also voted 8-5 that adequate evidence was provided to conclude liraglutide ruled out unacceptable cardiovascular risk.

“The animal data were worrisome, and I did not see sufficient human data,” said Peter Savage, MD, director of the Division of Epidemiology and Clinical Applications, National Heart, Lung and Blood Institute, National Institutes of Health, in Bethesda, Md. – by Christen Haigh

For more information:

• FDA Center for Drug Evaluation and Research: Endocrinologic and Metabolic Drugs Advisory Committee Meeting; April 2, 2009; Silver Springs, Md.

Liraglutide caused C-cell stimulation in mice leading to hyperplasia and neoplasia including medullary thyroid carcinoma almost certainly through a GLP-1 receptor stimulation of the C-cells. The drug caused C-cell neoplasia and medullary thyroid carcinoma in rats, but the FDA did not think this was mediated through simple GLP-1 receptor stimulation, whereas the company thought it was.

In humans there was no compelling evidence of C-cell stimulation based on my review of the data. Any differences seen in calcitonin concentrations between groups (liraglutide vs. placebo vs. active comparator) was in a range that would be considered very low normal if conventional calcitonin assays could measure that low.

Nonetheless, the committee was concerned that they could not prove that the rodent data would not/might not apply to humans.

The C-cell disease found in individuals during the liraglutide development program did not support an effect of liraglutide on C-cell disorders; specifically, one medullary thyroid carcinoma and one medullary thyroid carcinoma in situ found in the comparator group.

Three cell hyperplasia and one nodular hyperplasia (medullary thyroid carcinoma in situ) were found in the liraglutide group. The randomization was 2:1 in terms of numbers liraglutide vs. comparators. Three of the four patients discovered with C-cell disease had abnormal calcitonin concentrations at baseline.

– Gilbert H. Daniels, MD

Co-Director, Thyroid Clinic at Massachusetts General Hospital Cancer Center, Boston

Papillary thyroid cancer is common and found in 3% to 5% of autopsies in North America. This coupled with its generally excellent prognosis serves as a sound basis for not screening patients for thyroid nodules or thyroid cancer. Thus, finding a cluster of papillary thyroid cancers in patients being screened for anatomic thyroid abnormalities comes as no surprise and should not generally serve as a basis for major concern.

– Jeffrey Garber, MD

Endocrine Today Editorial Board member