A US Meals and Drug Administration (FDA) advisory committee urged approval — though not devoid of some reservations — of a brand-new injectable knonwn generically as iGlarLixi that combines fixed doses of insulin glargine (Lantus, sanofi-aventis) along with lixisenatide (Lyxumia, sanofi-aventis), a glucagon-adore 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 Could 25 that the product, generically known as iGlarLixi, ought to be approved as an adjunct to diet regimen and physical exercise to boost glycemic regulate in adults along with type 2 diabetes mellitus.
The FDA generally follows its panel’s advice.
“This combination, delivered in this manner, meets clinical reason along 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 a lot more diabetes therapies were needed. “I believe choice is fairly essential for physicians and for patients,” said Dr Wilson.
Steven B. Meisel, PharmD, system director of patient safety, Fairview Healthiness Services, Minneapolis, Minnesota, voted versus approval, in section since he believed the pharmacokinetic data suggested that the drug may should be injected two times daily, not once a day, as sanofi-aventis was proposing.
Kenneth Burman, MD, director of the endocrinology section at MedStar Washington Hospital Center, Washington, DC, additionally voted versus the approval, primarily since he believed the delivery mechanism — a pen injector — required an overhaul.
Pen Injector Questioned
Even some committee members that backed approval said the device required improvements. “I feel fairly strongly you cannot usage 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-aventis is proposing to deliver iGlarLixi to patients via the SoloStar pen, a device that has actually been used for years for insulin glargine.
The company said it proposes two dosage pens for iGlarLixi. Pen A would certainly be used by insulin-naive patients and provides medications in a 2:1 ratio, along with 10 to 40 units of insulin glargine and 5 to twenty μg of lixisenatide. Pen B provides medications in a 3:1 ratio, along with 30 to 60 units of insulin glargine combined along with 10 to twenty μg of lixisenatide.
The company reported few errors in the discovering and usage of the pens by pharmacists, patients, and physicians in its studies, yet the FDA said it found that having two pens enhances the potential for mistakes. The pen design additionally means that some users could receive a reduced or better dose, said the agency.
Panelists were concerned concerning the notion that the pens would certainly be labeled in “units,” since the term did not refer to insulin units or units of lixisenatide.
“We’re not objecting to the notion of this construct altogether, yet there’s a challenge here in terms of exactly how to adequately label it, color it, structure it, and educate the people that will certainly be using this,” said Dr Smith.
Allergic Reactions Provide Pause
The safety of the combination was commensurate along with that of both drugs individually, yet sanofi-aventis’s studies revealed a adverse effect of potential concern: allergic reactions in patients that received lixisenatide alone.
Sanofi-aventis very first observed a better price 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 very first 5 to 6 weeks of starting lixisenatide. Urticaria was the most common reaction, affecting merely 0.2% of the 7300 patients that received lixisenatide.
Overall, the adjudication committee determined that 11 patients endured anaphylactic reactions or shock as a result of the drug. Seven cases resolved promptly along with antihistamines or steroids, yet four were a lot more severe. Even so, the reactions resolved along with treatment, said sanofi-aventis. The FDA pointed out that every one of 11 of those patients discontinued the drug.
The agency said that patients created antidrug antibodies that ultimately seemed to reduce the efficacy of lixisenatide. The antibodies additionally seemed to raise 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 could be a class effect that was not seen in smaller sized GLP-1 agonist development programs, said Dr Balakrishnan.
Dr Seely agreed. “I believe the company had in place a very, fairly sensitive detection system for choosing up allergic reactions that Could not have actually been as extensive for previous drugs in this class,” she said, adding that clinicians and the FDA required to watch for these types of reactions for every one of 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 about allergic reactions.
Efficacy Seemed Solid
Sanofi-aventis submitted two pivotal studies on iGlarLixi, too as some phase 2 and 3 data on lixisenatide alone as section of its approval application.
The FDA concluded that the company demonstrated iGlarLixi’s superiority to the 2 insulin glargine and lixisenatide alone in cutting down HbA1c, and that the 2 elements of the combination contributed to that reduction.
Sanofi-aventis said both pivotal iGlarLixi studies showed that the combination was a lot more powerful compared to both drugs used individually and that the combination significantly low HbA1c levels and attained much better fasting and postprandial glucose control.
The very 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 low HbA1c levels from a baseline of 8.1% to 6.5%, compared along with an endpoint of 7.3% for lixisenatide and 6.8% for insulin glargine. Seventy-four percent of iGlarLixi patients attained their HbA1c target, compared along with 59% of insulin glargine patients and 33% of lixisenatide patients.
The combination additionally was superior in cutting down fasting plasma glucose levels. Patients taking iGlarLixi lost 0.3 kg; those receiving insulin glargine endured a 1.1-kg increase; and those receiving lixisenatide had a 2.3-kg loss. Almost 10% of iGlarLixi patients endured nausea, yet that was considerably reduced compared to the 24% in the lixisenatide group that reported the adverse effect.
In the second pivotal trial, patients receiving insulin that required treatment intensification were randomly assigned to iGlarLixi plus metformin (367 patients) or insulin glargine plus metformin. Enrollees had been using insulin for concerning 3 years and could receive a optimum everyday dose of 60 units of insulin throughout the 30-week study.
The baseline HbA1c degree was 8.5%; iGlarLixi low levels to 6.9%, compared along with 7.5% for patients receiving insulin glargine.
Half of the iGlarLixi group met the HbA1c target, compared along with 30% of those receiving insulin. Weight obtain was mitigated by the combination: those taking iGlarLixi had a 0.7-kg loss, whereas those taking insulin glargine endured a 0.7-kg obtain throughout the study period.
In the 2 pivotal studies, the rates of hypoglycemia for iGlarLixi were similar to those seen along with insulin glargine, affecting a quarter of patients in one trial and 40% in the other.
Panelists were reassured concerning cardio safety, thanks in section 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 cardio risk margin of 1.3 or above,” in accordance along with previous FDA guidance.
iGlarLixi Second Combo Reviewed
Just the day prior to 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 actually been on the market for several years, whereas degludec is a newer product.
Both liraglutide and degludec are approved in the United States. Lixisenatide does not yet have actually FDA approval. It is sold as Lyxumia in 60 countries. Sanofi-aventis very first sought FDA approval for lixisenatide in 2012 yet withdrew the application a year later in the hopes of adding data from the ELIXA study. Sanofi-aventis resubmitted its application for lixisenatide in July 2015 and expects a decision on that application later this year.
The sanofi-aventis 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-aventis’ president of global research and development, said that the company was pleased along with the vote. “Sanofi will certainly keep on to job closely along with the FDA as it completes its reviews of these medicines, and we expect FDA decisions in the third quarter of 2016,” Zerhouni told Medscape Medical News.
