Onglyza (saxagliptin) for Type-2 diabetes OK with FDA, but cardiovascular risks a worry

Onglyza, probably the first drug to treat type-2 diabetes as adjunct to diet & exercise, has been recommeded by US FDA. But some members in the committee still feel that the evidence submitted to the drug’s safety in cardio vascular risks is inadequate.

Developed jointly  by Bristol-Myers Squibb and AstraZeneca for the treatment of type-2 diabetes,  Onglyza application to the FDA seeks its use as a single agent (monotherapy), as an adjunct to diet and exercise, use in combination with three types of commonly used oral anti-diabetic (OAD) medications – metformin, thiazolidinediones and sulfonylureas (SUs). The application seeks when the single agent alone does not provide adequate blood sugar  control, as an adjunct to diet and exercise – and use in initial combination therapy with metformin, as an adjunct to diet and exercise.

Onglyza clinical development programme included more than 5,000 individuals. Among these. more than 4,000 of the participants were given Onglyza. Data presented included safety and efficacy results from six pivotal phase-III trials. It also had post hoc pooled analyses evaluating cardiovascular risk in the phase-IIb and phase-III studies. These studies included individuals followed for up to 2.5 years and more than 3,700 person-years of exposure to Onglyza. According to the BMS and Astra Zeneca the post hoc pooled analyses did not show evidence of a cardiovascular safety signal in individuals taking Onglyza.

The new drug application (NDA) for Onglyza was submitted to the FDA on June 30, 2008, and has an action date of April 30, 2009. Onglyza was specifically designed to be a selective inhibitor with extended binding to the DPP-4 enzyme, with dual routes of clearance. DPP-4 inhibitors are a class of compounds that work by affecting the action of natural hormones in the body called incretins.

Onglyza was supported by 8 out of the ten-membered US Food and Drug Administration’s (FDA) Endocrinologic and Metabolic Drugs Advisory Committee. They found the human trial data submitted by Bristol-Myers Squibb Company and  AstraZeneca enough to support Onglyza (saxagliptin) as new drug for the treatment of adults with type-2 diabetes.

Majority of the FDA committee members also expressed the view that the clinical data evidence was sufficient to rule out unacceptable cardiovascular (heart failure) risk relative to comparators in the programme.

Still,  all of them voted “no” in response to whether data were adequate to deem post-marketing cardiovascular trials unnecessary.

Onglyza’s clinical data presented mentioned 11 cardiovascular events in 24-week, short-term study periods and 40 cardiovascular events from short-term and long-term study periods with a median 62-week exposure. In fact this data made the committee consider further long-term, post-marketing studies including higher-risk patients were necessary.

“The numbers of events are too low to provide an adequate assessment. It is a restricted population, so it does not give us a good overall assessment of cardiovascular safety,” pointed out Kathleen Wyne, MD, Ph D, who was one of two voted against the ruling in the 10-member FDA panel which reviewed the trial data.

New FDA guideline seeks more evidence on safety of diabetes drugs

The FDA review committee was examining whether Onglyza (saxagliptin) met recommendations from a recent FDA guidance released in December 2008, which recommended manufacturers developing new type 2 diabetes drugs provide evidence that the therapy will not increase risk for cardiovascular events.

The FDA draft guidance, issued on December 2008 was considered a step to ensure the continuing health and safety of the US diabetic population without hampering the availability of new and improved drugs for better diabetes control in America.

The guidance formulates a policy designed to quantify coronary heart disease risk and a means to evaluate it in diabetes products that are in phase-2 and phase-3 development. FDA has created a meta-analysis to determine the extent of CHD risk vs. comparators during the development programme must yield a CHD risk ratio within acceptable bounds. For ratios of 1.8 or greater pre-approval studies will be required for new drug application submission, as they should. For low ratio products with ratios less than 1.3, further studies may not be essential to the approval process. For agents with intermediate CHD risk ratios of 1.3 to 1.8, generally post-marketing studies will likely be required and linked to the approval process.

The FDA directive imposes certain experimental design requirements for all phase-2 and phase-3 trials to insure that an accurate meta-analysis can be performed upon the phase-2 and phase-3 trials data to generate a useful CHD risk ratio to comparator (placebo).

“We need to better understand the safety of new antidiabetic drugs; therefore, companies should conduct a more thorough examination of their drug’s cardiovascular risks during the product’s development stage,” Mary Parks, MD, director of the Division of Metabolism and Endocrinology Products, Center for Drug Evaluation and Research, said in a press release.

Also, the FDA recommends that committees of outside cardiologists analyze any cardiovascular events to ensure that product labeling includes comprehensive information on safety and effectiveness. 

BMS, AstraZeneca to review FDA ruling on Onglyza

However, trials on saxagliptin trials were completed prior to the new guidance. The  post-hoc evaluation of cardiovascular events was performed on randomized, controlled periods for completed phase-2 and -3 trials.

While voting in favour of the FDA review committee ruling Dr Kenneth Burman, MD, chief of the Endocrine Section in the Department of Medicine at Washington Hospital Center in Washington D.C said, “Saxagliptin was caught in the interregnum between the former cardiovascular requirements and the new publication of guidelines in December 2008, and any effort to assess data in such a study will intrinsically have flaws. We have taken those into account the best way we can.”

Nevertheless, the FDA is not bound by the Advisory Committee’s recommendations. Generally, FDA takes its advice into consideration when reviewing new drug applications.

Bristol-Myers Squibb and AstraZeneca will review the information leading to the Committee’s decision and continue to work closely with the FDA to support the review of Onglyza, the companies said in a statement.

 “I worry about approving a drug and not requiring any longer-term trial, regardless of the drug,” Michael Proschan, PhD, mathematical  statistician in the Office of Biostatistical Research, National Heart, Lung and Blood Institute, National Institutes of Health in Bethesda, Md., said during the committee meeting.

“There is enough uncertainty for a longer-term trial and perhaps enrollment of people with coronary disease, so we can obtain further evidence,” he added.