FDA Panel Backs Novo Nordisk Insulin–GLP-1 Combination IDegLira

SILVER SPRING, MD — A US Food and Drug Administration (FDA) advisory committee has given its blessing to a new injectable that combines fixed doses of a long-acting basal insulin with a glucagonlike peptide 1 (GLP-1) receptor agonist for diabetes.

The FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted unanimously — 16 to 0 — that the product, a combination of the GLP-1 agonist liraglutide (Victoza, Novo Nordisk) and the long-acting insulin degludec (Tresiba, Novo Nordisk) — should be approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

The product, developed by Novo Nordisk, has been known as IDegLira in clinical trials but is already approved in Europe under the brand name Xultophy .

The FDA generally follows its panels' advice.

"Is the combination needed in the healthcare armamentarium to treat diabetes mellitus?" asked panel member Kenneth Burman, MD, director of the endocrinology section at MedStar Washington Hospital Center, Washington, DC. "The answer is yes."

Committee member Marie C Gelato, MD, PhD, professor of medicine at Stony Brook University, New York, agreed. "Diabetes is a tough disease, and we need all of the things we can muster to get it under control," she said.

Dr Burman said the combination offered advantages in patient compliance, decreased patient costs, and fewer injections. But many issues remain unresolved, including the potential for medication errors with the two-drug combination and the difficulty of incremental dosing in a fixed-ratio product.

Committee chair Robert J Smith, MD, an endocrinologist at Warren Alpert School of Medicine, Brown University, Providence, Rhode Island, said that an insulin-containing combination might overcome what he called "insulin inertia" — the reluctance to prescribe insulin when needed. Another part of the attraction is that patients on IDegLira lost weight when compared with insulin.

Liraglutide has been marketed as Victoza for the treatment of type 2 diabetes for a number of years and was recently approved at a higher dose, as Saxenda, for the treatment of obesity. Approval of the long-acting insulin degludec (Tresiba, Novo Nordisk) was delayed in the US for a number of years, but it was finally approved last September.

Lower Starting Doses, Fewer Side Effects?

Novo Nordisk sought approval based on the theory that the two drugs together will allow patients to intensify treatment at lower starting doses of each medication separately and therefore with fewer side effects. The panel members agreed that the company met its safety and efficacy end points, although most were concerned about dropouts that led to missing data.

And panelists said they'd like to have more reassurance that prescribers and patients would understand how to use the pen injector device, which will be labeled with simple numbers.

The committee also was uncertain about patient selection for IDegLira. "We need some better guidelines, and I'd rather see them before the drug would be marketed, said Steven B Meisel, PharmD, system director of patient safety, Fairview Health Services, Minneapolis, Minnesota.

Peter WF Wilson, MD, director of epidemiology and genomic medicine at Atlanta Veterans Administration Medical Center, Georgia, said he saw a role for treating patients with HbA1c levels in the 7% to 8% range who had not gotten a good response to a GLP-1 agonist alone.

Most panelists concurred that the combination was probably most beneficial to patients who had already been on either a GLP-1 agonist or insulin. But it would be harder to select patients who had previously been on insulin, depending on which type of insulin they had taken, the doctors said.

FDA Questions Some Efficacy Conclusions

Novo Nordisk submitted five phase 3 clinical studies to the agency. The FDA said that although the primary end point was met for all the trials, it was concerned that insulin titration may have resulted in an overstatement of the treatment effect on HbA1c in the insulin-comparator trials.

Titration affects the timing of the maximally effective dose, said Tania Condarco, MD, a clinical reviewer for the agency. She suggested that Novo Nordisk may have based conclusions on incomplete data in those insulin-comparator trials.

Panel member Brendan M Everett, MD, MPH, director of the general cardiology inpatient service at Brigham and Women's Hospital, Boston, Massachusetts, said this apprehension about titration constituted "very real concerns." But, he added, "They didn't trump for me overall evidence of efficacy."

Two trials were conducted in patients not previously treated with a GLP-1 agonist or basal insulin. In both, patients were poorly controlled on oral medications. The first — one of the two pivotal trials — randomized patients to IDegLira, liraglutide, or insulin degludec (at an uncapped dose). The second trial compared IDegLira with placebo.

In the first study, at 26 weeks, IDegLira reduced HbA1c levels by 1.91% points compared with 1.28% for liraglutide and 1.44% for insulin degludec alone.

The second pivotal trial enrolled patients uncontrolled on basal insulin and tested IDegLira against insulin degludec alone. An additional study pitted IDegLira against insulin glargine (Lantus, Sanofi), a competitor product.

In both pivotal studies, the combination was superior to the elements alone. IDegLira was more effective in reducing postprandial glucose than basal insulin and at a lower dose. The combo also gave superior reductions in fasting plasma glucose when compared with liraglutide alone.

A final study was conducted in patients who were uncontrolled on a GLP-1 agonist. They either continued the GLP-1 agonist or received IDegLira.

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Weight gain was a mixed bag, but overall, patients taking IDegLira lost pounds when compared with those on basal insulin, and the weight was unchanged when compared with those on the GLP-1 agonist alone.

No new safety concerns were uncovered. The rates of hypoglycemia were lower with the combination than with basal insulin, and gastrointestinal adverse events were lower than with the GLP-1 agonist alone. There were no cases of pancreatitis or medulloblastoma thyroid cancer.

Novo Nordisk said it would have more information on cardiovascular outcomes when it issues final data from the Liraglutide Effect and Action in Diabetes, Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial.

Top-line results for LEADER, reported in May, indicate that this trial was a big success, with liraglutide significantly reducing the risk of major adverse cardiovascular events compared with placebo but on top of standard treatment for diabetes. The full results, which are highly anticipated, will be presented at the American Diabetes Association's Annual Scientific Sessions next month.

Patients, Clinicians, Urge Approval

A handful of patients and clinicians urged the agency to approve IDegLira during a public-hearing portion of the meeting.

They said a single injection would increase compliance and reduce out-of-pocket costs. "It's one injection, it's one copay," said Kelly Close, founder of the nonprofit diaTribe Foundation.

"Improving adherence is where the rubber meets the road in clinical practice," said Steven Edelman, MD, director of the Diabetes Care Clinic at the Veterans Affairs (VA) Healthcare System of San Diego, California.

While the doses included in IDegLira might not be right for all patients, "this combination is by far the most potent, yet safe and easy to administer class of agents that we've seen in the clinic in a long time," he added.

And Stanley Schwartz, MD, FACE, who spoke on behalf of the American Association of Clinical Endocrinologists (AACE), said that "patients and physicians need more choices to control the burdens of diabetes."

IDegLira offers the potential to decrease the required dose of basal insulin, decrease hypoglycemia, avoid weight gain, and decrease glycemic variability and gets more patients to goal with fewer medications, he said. That "reduces the medication burden and likely the cost as well, we hope."

A decision on the IDegLira approval is expected by August, according to Washington Analysis, a Washington, DC-based investment advisor.

Todd Hobbs, MD, US chief medical officer for Novo Nordisk, said the company was "extremely pleased" with the advisory committee vote and that it "look[s] forward to working with the FDA to advance the IDegLira NDA toward approval."

Dr Edelman disclosed that he is a consultant for a number of diabetes drug makers, including Novo Nordisk and Sanofi.

References
SOURCE:

FDA Panel Backs Novo Nordisk Insulin–GLP-1 Combination IDegLira. Medscape. May 25, 2016.

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