The clinical trials that Novo Nordisk AS and Sanofi conducted on their respective basal insulin/GLP-1 agonist products may have satisfied regulatory efficacy requirements for combination products, but they stopped short of answering some clinically important questions that could impact prospects for commercial adoption.

Specifically, the companies did not compare the effectiveness of their combination products against separate administration of the insulin component titrated to maximum effect and the maximum effective dose of the GLP-1 agent. They also did not conduct studies in which patients already on basal insulin and a GLP-1 agonist were converted to the combination product.

In addition, Sanofi's studies for iGlarLixi did not include patients who are already being treated with a GLP-1 agonist.

Such studies "were not required but would have answered clinically interesting questions," FDA clinical reviewer Suchitra Balakrishnan said in discussing the iGlarLixi clinical development program.

FDA's Fixed-Combination Product Rule

"Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug."

Both iGlarLixi and Novo Nordisk's IDegLira received overwhelming endorsements for approval from FDA's Endocrinologic and Metabolic Drugs Advisory Committee at a two-day meeting in May ([A#14160524004]).

However, panelists had concerns about the labeling for both products (see related story, [A#00160606013]).

They also expressed strong reservations about the design and coloring of the Sanofi device, suggesting it should be redesigned prior to approval ([A#14160525004]).

Although supportive of the products' efficacy, panelists questioned why certain types of studies that would have been informative to clinical practice were not performed. Such questions reflect the challenges that sponsors and FDA face with this new paradigm in combination products.

Choosing Between 'Artificial' Trial Designs

IDegLira and iGlarLixi represent a new breed of combination products, containing one component (basal insulin) that given on its own is titratable, and a second component (GLP-1 agonist) that is individually administered as a fixed dose.

Novo Nordisk conducted a total of five Phase III studies of IDegLira, which combines Tresiba (insulin degludec) with Victoza (liraglutide). Sanofi conducted two studies of iGlarLixi, a combination of Lantus (insulin glargine) with lixisenatide (see related story, [A#00160606002]).

At the iGlarLixi advisory committee meeting, Jean-Marc Guettier, director of the Division of Metabolism and Endocrinology Products, discussed the lack of precedent for applying the agency's regulations on fixed-combination dosage forms to a product that combines a titratable drug with a fixed-dose drug (see box).

Steven Meisel, system director of patient safety at Fairview Health Services in Minneapolis, noted Sanofi did not conduct a study looking at the administration of lixisenatide plus insulin glargine given independently, and he questioned whether FDA has ever approved a combination drug when the individual components were not studied in such a manner.

"For this particular product, the applicant basically has to meet the combination rule, which is to show that both components within the combination product contribute to the claimed effect," Guettier said. However, "this was a little tricky in this application because … most combination drugs combine the same type of active ingredient. So they'll combine a fixed dose with a fixed dose, so the fixed doses are easily studied as a factorial study."

When deciding on a clinical trial program to show contribution to the claimed effect, "we had to decide whether or not we were going to follow the paradigm of a titration product, comparing titration to titration, versus a completely artificial setting" in which the doses of the GLP-1 agonist and basal insulin are set for the duration of the study, Guettier said. However, setting a fixed dose of insulin "would not have been reflective of practice."

"We felt that it was reasonable to follow the titration approach," he said. "What the applicant really has to do is show contribution to the claimed effect. If they're able to do that, which is usually superiority on the primary outcome of the study, they meet the regulation."

FDA Reservations On Superiority

Novo Nordisk and Sanofi were able to demonstrate superior efficacy in HbA1c reduction from baseline. However, FDA expressed some reservations about superiority claims for both combinations in light of questions as to whether basal insulin in the comparator arms was used optimally due to titration algorithms and dose caps.

In briefing documents for the IDegLira meeting, FDA said that to reach a conclusion that the insulin degludec/liraglutide combination is superior to degludec alone, a trial "in which both arms were dosed and titrated in a maximally effective and balanced manner would be needed."

However, in pre-submission meetings "the agency agreed that an ‘artificial’ trial design limiting the maximal insulin degludec dose to 50 units once daily so that the superiority of IDegLira over IDeg could be tested would be acceptable. Demonstration of superiority of IDegLira over IDeg in a trial that studied the products the way that they would be used in clinical practice, i.e. with no dose cap, was not a requirement."

For FDA, the studies' design also raised questions as to whether the efficacy results were generalizable to clinical practice, where basal insulin doses can be increased without a limit. The agency's concern on this point reverberated with some panelists, although not enough to preclude an approval recommendation.

"The insulin cap in the comparator studies really limited my confidence in superiority over insulin," Susan Yanovski, co-director of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases, said at the iGlarLixi meeting.

Looking For GLP-1 Switching Data

Yanovski was among several panelists who said they were disappointed Sanofi did not study iGlarLixi as add-on therapy in patients already taking a GLP-1 agonist. Novo Nordisk did conduct such a study. Paul Chew, Sanofi's senior VP-R&D, said the company is about to start a trial in patients who are switched from GLP-1 agonists to the combination.

For both combination products, committee members generally said the most appropriate patient population would be type 2 diabetics already on at least one of the combination's components ([A#00160530013]). In the case of iGlarLixi, however, they acknowledged the dearth of data in GLP-1-experienced patients.

Endocrinologist Kenneth Burman, MedStar Washington Hospital Center, said that when recommending use of iGlarLixi in treatment-experienced patients "I don't know how appropriate it is to approve a drug when there are no studies showing that it works in that individual subgroup, although theoretically it should work."

"All of us want to see some further information especially on taking insulin or a GLP-1 agonist and then adding the combination," said Peter Wilson, a cardiologist and endocrinologist at Emory University. "I think that's where endocrinologists especially will want to see more science as we move forward."

Diabetes Combination Studies Leave Market Challenges Unresolved

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