FDA Reviewers Question Sanofi Diabetes Combination
FDA reviewers have serious questions about a Sanofi NDA for its combination insulin glargine and lixisenatide injection, a fixed ratio drug product consisting of insulin and a GLP-1 receptor agonist for treating Type 2 diabetes. On 5/25, the agency’s Endocrinologic and Metabolic Drugs Advisory Committee will meet to review the NDA, along with a separate NDA for lixisenatide as a monotherapy.
One concern held by reviewers is that the proposed combination “combines a product that, when administered alone, is a fixed dose product (the GLP-1 agonist) with another product that is a titratable product dosed on a close to continuous scale (the insulin),” a review briefing document says. “All antidiabetic combinations approved and marketed to date have combined either two individual fixed dose products (.e.g., two oral anti-diabetics) or two individual titratable products (e.g., mixed insulin products).” They add that the proposed dosage for the GLP-1 component is not the dosage recommended and established as effective when the GLP-1 product is used alone. The reviewers further say that “it is possible that specific patient populations (i.e., insulin sensitive individuals who require low doses of the combination for control) could be exposed to one component that provides no therapeutic benefit and causes specific adverse reactions. ”
The reviewers also say that interpreting “the clinical meaningfulness of the results of a study designed to demonstrate ‘contribution to the claimed effects’ when one of the comparators is a titratable product is problematic. Factorial studies generally compare fixed doses and some comparisons generally include the maximally effective doses of all products. In this application one of the comparators (i.e., the insulin) has no maximally effective dose and insulin dosing in the trial is artificially constrained compared to the clinical care setting (i.e., starting dose of the insulin is standardized to that the combination product, the dose adjustment for the insulin is fixed and standardized to that of the combination, the maximum allowable dose of the insulin is capped in some studies and the final determination of benefit is fixed and made at 6 months).”
Another concern is the combination product’s practical utility. The reviewers say that “patients currently treated with one of the two products in the proposed combination cannot be easily switched to the combination product without a significant reduction in dose of the component they were previously on. This is a unique problem inherent to this specific antidiabetic combination. For other marketed fixed dose combinations, no dose reduction in either component is needed when making the switch. In the combination proposed in this application, a patient who is inadequately controlled on a maximally effective dose of the GLP-1 agonist, for example, would be receiving a substantially lower dose of the GLP-1 agonist (perhaps an ineffective dose) when initiating use of the combination because of the risk of hypoglycemia associated with starting insulin at a high dose.”
Additionally, the reviewers are questioning the recommended increments in product strength for the proposed commercial pen presentations, which they say are complicated and not intuitive. “Use of two pens for two purposes adds complexity to the use of this combination,” the briefing document says. “It is unclear why it is clinically desirable to lower the dose of lixisenatide in all patients when increasing the dose of the combination in a patient not adequately controlled on doses offered by the low dose pen. A patient receiving 40 units of insulin and 20 micrograms of lixisenatide with the ‘low dose’ pen will receive 40 units of insulin and 13 micrograms of lixisenatide (a 35% reduction in lixisenatide dose) when switched to the ‘high dose’ pen.”