This Time, FDA Panel Endorses Diabetes Drug Dapagliflozin

Miriam E. Tucker

December 13, 2013

A US Food and Drug Advisory (FDA) panel has voted 10 to 1 in favor of approval for AstraZeneca and Bristol-Myers Squibb's diabetes drug dapagliflozin.

The proposed indication is "as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus" as monotherapy, as initial therapy with metformin, or as an add-on to other oral glucose-lowering agents or insulin.

Dapagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor, which reduces resorption of glucose in the kidney, resulting in increased urinary glucose excretion with a consequent lowering of plasma glucose levels as well as weight loss.

If approved by the FDA, dapagliflozin would be the second SGLT2 inhibitor on the US market. The FDA cleared canagliflozin (Invokana, Janssen Pharmaceuticals) for marketing in March of this year and is expected to announce a decision on a third SGLT-2 drug, empagliflozin (Boehringer Ingelheim/Lilly) by the end of March 2014.

Dapagliflozin is already approved in 38 countries, including those of the European Union and Australia.

The new vote by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) follows the FDA's previous rejection of dapagliflozin in January 2012, primarily due to concerns about bladder cancer and liver toxicity. That decision followed EMDAC's negative 9 to 6 vote in July 2011.

This time, Bristol-Myers Squibb presented new results that allayed the previous concerns to the extent that EMDAC panel members were willing to vote yes, but many expressed lingering discomfort with the data's remaining shortcomings. All the panelists strongly advised that the sponsors move forward with a planned large postmarketing trial designed to provide enough statistical power to answer outstanding questions about cardiovascular safety as well as malignancy and liver toxicity.

Indeed, data presented by Bristol-Myers Squibb from 2 new trials designed specifically to address CVD safety in high-risk diabetes patients actually raised new uncertainties that hadn't been previously come up as a major issue about dapagliflozin. In a separate vote, the committee split 10 yes to 4 no regarding whether it believes that there was sufficient evidence that dapagliflozin's cardiovascular safety profile is acceptable in accordance with the FDA's 2008 guidance for all new diabetes drugs.

New Safety Data; CVD Emerges as Potential Concern

At the hearing, Bristol-Myers Squibb presented safety data from 24 clinical trials involving 11,000 patients (6000 receiving dapagliflozin), representing 50% more patient-years than were available at the time of the previous EMDAC meeting, with follow-up for up to 4 years.

In a meta-analysis, the hazard ratio for the primary cardiovascular end point of CV death, MI, stroke, and hospitalization for unstable angina (MACE+) had worsened slightly from 2011, from 0.67 to 0.81 with the new data, although there was still no signal for increased CV risk.

The numbers that raised the CVD issue this time around came from an analysis of 1887 patients with a history of CVD. Here, the hazard ratio for MACE+ was 0.98, but for the FDA-preferred end point, MACE (MACE+ without unstable angina), the hazard ratio was 1.11.

Panel members disagreed about the significance of this. Kevin D. McBryde, MD, director of the Minority Health Institute at the National Institute of Diabetes, Digestive and Kidney Diseases, voted no on the CVD question. "In high-risk diabetic patients, I think there may be concern about CV events, and the remaining studies did not relieve me of that concern."

But Wyndham Wilson, MD, senior investigator and deputy chief, Lymphoid Malignancy Branch, at the National Cancer Institute, voted yes to the CVD question: "I felt that the sponsor had followed the FDA guidance, and I felt comfortable at this point that there is not a sufficient cardiac adverse signal to warrant holding the drug up, but I think this needs to be studied more carefully."

The concern about possible liver toxicity had come primarily from a single dapagliflozin patient who had experienced liver injury and liver-function abnormalities that Bristol-Myers Squibb hepatologist reviewers had deemed probably related to the drug. Newly available information suggests that the case was more likely to be idiopathic autoimmune hepatitis rather than drug-induced liver injury, said James List, MD, PhD, from Bristol-Myers Squibb.

However, FDA reviewer Frank Pucino, PharmD, said, "An association with dapagliflozin cannot be excluded."

With regard to bladder cancer, there has been 1 additional case among dapagliflozin recipients since 2011, bringing the total to 10. However, most of them were found to have had hematuria at baseline or shortly after starting dapagliflozin, too soon for cancer to have developed, according to Dean F. Bajorin, MD, a specialist in genitourinary cancer at Memorial Sloan Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, speaking on behalf of Bristol-Myers Squibb and AstraZeneca.

A review all tumor types, both Dr. List and Dr. Bajorin pointed out, reveals no statistically significant associations with dapagliflozin. Some types, such as bladder, breast, and pancreas cancers, were numerically higher among the dapagliflozin patients, but others, such as lymphoma and renal and gastrointestinal cancers, were more common among the placebo patients.

But Dr. Pucino said the FDA has remaining concerns, noting that the numeric imbalance in bladder cancer — the greatest malignancy concern with dapagliflozin — was not seen with canagliflozin. "Possible bladder-cancer promotion secondary to changes in the microenvironment of the bladder and renal function in response to dapagliflozin is incompletely assessed."

DECLARE Postmarketing Study

In voting for approval of dapagliflozin, every panel member cited the importance of DECLARE-TIMI 58, Bristol-Myers Squibb and AstraZeneca's postmarketing trial that has already begun recruiting the first of an anticipated 17,150 patients. It aims to document 1390 CV events in a total of 77,000 patient-years, with anticipated median follow-up of 4 to 5 years. The study will also monitor for hepatic events and malignancies.

Erica H. Brittain, PhD, a biostatistician at the National Institute for Allergy and Infectious Diseases, had voted against approval of dapagliflozin in 2011 but voted for it this time.

"Even though my official vote has changed, my feeling hasn't changed very much, because not much has changed since then… It's really critical that DECLARE get done. I'm voting contingent on the notion that it will be finished," she said.

Milton Packer, MD, the Gayle and Paul Stoffel Distinguished Chair in Cardiology and professor and chair of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas, praised dapagliflozin.

"It lowers hemoglobin A1c, lowers blood pressure, and causes weight loss; all of these are all good things. My concern about CV safety and bladder cancer are still concerns, but we approve lots of drugs with uncertainties… DECLARE will absolutely be completed," he concluded.

FDA advisory panel members are vetted for conflicts of interest and waivers are granted for participation if necessary. No waivers were granted for this meeting.

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