FDA Panel OKs Sanofi Insulin-GLP-1 Combo for Diabetes

Alicia Ault

May 26, 2016

A US Food and Drug Administration (FDA) advisory committee urged approval — though not without some reservations — of a new injectable known generically as iGlarLixi that combines fixed doses of insulin glargine (Lantus, Sanofi) with lixisenatide (Lyxumia, Sanofi), a glucagon-like peptide 1 (GLP-1) receptor agonist still pending FDA approval for type 2 diabetes.

The FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted 12-2 on May 25 that the product, generically known as iGlarLixi, should be approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

The FDA generally follows its panel's advice.

"This combination, delivered in this manner, meets clinical need with adequate efficacy," said committee chairman Robert Smith, MD, an endocrinologist at Warren Alpert School of Medicine, Brown University, Providence, Rhode Island.

Panelist Peter W. F. Wilson, MD, director of epidemiology and genomic medicine at the Atlanta Veterans Administration Medical Center, Georgia, said more diabetes therapies were needed. "I think choice is very important for physicians and for patients," said Dr Wilson.

Steven B. Meisel, PharmD, system director of patient safety, Fairview Health Services, Minneapolis, Minnesota, voted against approval, in part because he thought the pharmacokinetic data suggested that the drug might need to be injected twice daily, not once a day, as Sanofi was proposing.

Kenneth Burman, MD, director of the endocrinology section at MedStar Washington Hospital Center, Washington, DC, also voted against the approval, primarily because he thought the delivery mechanism — a pen injector — needed an overhaul.

Pen Injector Questioned

Even some committee members who backed approval said the device needed improvements. "I feel very strongly you cannot use the proposed pen," said Ellen W. Seely, MD, director of clinical research in endocrinology, diabetes, and hypertension at Brigham and Women's Hospital in Boston.

Sanofi is proposing to deliver iGlarLixi to patients via the SoloStar pen, a device that has been used for years for insulin glargine.

The company said it proposes two dosage pens for iGlarLixi. Pen A would be used by insulin-naive patients and provides medications in a 2:1 ratio, with 10 to 40 units of insulin glargine and 5 to 20 μg of lixisenatide. Pen B provides medications in a 3:1 ratio, with 30 to 60 units of insulin glargine combined with 10 to 20 μg of lixisenatide.

The company reported few errors in the understanding and use of the pens by pharmacists, patients, and physicians in its studies, but the FDA said it found that having two pens increases the potential for mistakes. The pen design also means that some users could receive a lower or higher dose, said the agency.

Panelists were concerned about the notion that the pens would be labeled in "units," because the term did not refer to insulin units or units of lixisenatide.

"We're not objecting to the notion of this construct altogether, but there's a challenge here in terms of how to adequately label it, color it, structure it, and educate the people who will be using this," said Dr Smith.

Allergic Reactions Give Pause

The safety of the combination was commensurate with that of the two drugs individually, but Sanofi's studies revealed a side effect of potential concern: allergic reactions in patients who received lixisenatide alone.

Sanofi first observed a higher rate of reactions in a phase 2 trial of the drug. The company decided to establish an Allergic Reaction Assessment Committee to adjudicate events. The majority of reactions occurred within the first 5 to 6 weeks of starting lixisenatide. Urticaria was the most common reaction, affecting just 0.2% of the 7300 patients who received lixisenatide.

Overall, the adjudication committee determined that 11 patients experienced anaphylactic reactions or shock because of the drug. Seven cases resolved quickly with antihistamines or steroids, but four were more severe. Even so, the reactions resolved with treatment, said Sanofi. The FDA pointed out that all 11 of those patients discontinued the drug.

The agency said that patients developed antidrug antibodies that ultimately seemed to reduce the efficacy of lixisenatide. The antibodies also seemed to increase injection site reactions and hypoglycemia in those patients, said Suchitra Balakrishnan, MD, PhD, a clinical reviewer in the FDA's Division of Metabolism and Endocrinology Products.

The hypersensitivity might be a class effect that was not seen in smaller GLP-1 agonist development programs, said Dr Balakrishnan.

Dr Seely agreed. "I think the company had in place a very, very sensitive detection system for picking up allergic reactions that may not have been as extensive for previous drugs in this class," she said, adding that clinicians and the FDA needed to watch for these types of reactions for all GLP-1 agonists.

The committee urged the agency to consider, in the event that iGlarLixi was approved, adding some sort of cautionary language to the label regarding allergic reactions.

Efficacy Seemed Solid

Sanofi submitted two pivotal studies on iGlarLixi, as well as some phase 2 and 3 data on lixisenatide alone as part of its approval application.

The FDA concluded that the company demonstrated iGlarLixi's superiority to both insulin glargine and lixisenatide alone in reducing HbA1c, and that both elements of the combination contributed to that reduction.

Sanofi said the two pivotal iGlarLixi studies showed that the combination was more powerful than the two drugs used individually and that the combination significantly reduced HbA1c levels and achieved better fasting and postprandial glucose control.

The first pivotal trial enrolled patients whose diabetes was not controlled using oral medications — 469 patients were randomly assigned to iGlarLixi, 467 to insulin glargine plus metformin, and 264 to lixisenatide plus metformin. Over 30 weeks, the combination significantly reduced HbA1c levels from a baseline of 8.1% to 6.5%, compared with an endpoint of 7.3% for lixisenatide and 6.8% for insulin glargine. Seventy-four percent of iGlarLixi patients achieved their HbA1c target, compared with 59% of insulin glargine patients and 33% of lixisenatide patients.

The combination also was superior in reducing fasting plasma glucose levels. Patients taking iGlarLixi lost 0.3 kg; those receiving insulin glargine experienced a 1.1-kg increase; and those receiving lixisenatide had a 2.3-kg loss. Almost 10% of iGlarLixi patients experienced nausea, but that was much lower than the 24% in the lixisenatide group who reported the side effect.

In the second pivotal trial, patients receiving insulin who needed treatment intensification were randomly assigned to iGlarLixi plus metformin (367 patients) or insulin glargine plus metformin. Enrollees had been using insulin for about 3 years and could receive a maximum daily dose of 60 units of insulin during the 30-week study.

The baseline HbA1c level was 8.5%; iGlarLixi reduced levels to 6.9%, compared with 7.5% for patients receiving insulin glargine.

Half of the iGlarLixi group met the HbA1c target, compared with 30% of those receiving insulin. Weight gain was mitigated by the combination: those taking iGlarLixi had a 0.7-kg loss, whereas those taking insulin glargine experienced a 0.7-kg gain during the study period.

In both pivotal studies, the rates of hypoglycemia for iGlarLixi were similar to those seen with insulin glargine, affecting a quarter of patients in one trial and 40% in the other.

Panelists were reassured about cardiovascular safety, thanks in part the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, which was last year. FDA reviewers called it a well-designed, well-conducted trial that "ruled out a cardiovascular risk margin of 1.3 or above," in accordance with previous FDA guidance.

iGlarLixi Second Combo Reviewed

Just the day before the iGlarLixi review, the Endocrinologic and Metabolic Drugs Advisory Committee backed Novo Nordisk's IDegLira, a similar product combining the GLP-1 agonist liraglutide (Victoza, Novo Nordisk A/S) and the long-acting insulin degludec (Tresiba, Novo Nordisk A/S).

Although the drugs combine similar agents, there are some differences. Insulin glargine has been on the market for many years, whereas degludec is a newer product.

Both liraglutide and degludec are approved in the United States. Lixisenatide does not yet have FDA approval. It is sold as Lyxumia in 60 countries. Sanofi first sought FDA approval for lixisenatide in 2012 but withdrew the application a year later in the hopes of adding data from the ELIXA study. Sanofi resubmitted its application for lixisenatide in July 2015 and expects a decision on that application later this year.

The Sanofi application for iGlarLixi was accepted by the FDA in February 2016 and is being reviewed on an accelerated 6-month time frame, according to the company. An FDA decision is expected in the next few months. An application was submitted to the European Union in March 2016.

After the meeting, Elias Zerhouni, Sanofi's president of global research and development, said that the company was pleased with the vote. "Sanofi will continue to work closely with the FDA as it completes its reviews of these medicines, and we look forward to FDA decisions in the third quarter of 2016," Zerhouni told Medscape Medical News.

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