FDA On Novo's Diabetes Combo: It's Complicated

Some concerns raised by the FDA about a fuzzy trial design used by Novo Nordisk AS for a fixed-dose formulation that unites two of its already marketed drugs – Victoza (liraglutide), a glucagon-like peptide 1 (GLP-1) receptor agonist, and Tresiba (insulin degludec), a basal insulin – may throw a wrench into the firm's hope of turning the combo product into what the Danish company is hoping will be a big moneymaker.

The FDA wants its Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) to help the agency grapple with various issues with the combo drug, which Novo wants to sell as a treatment for type 2 diabetes under the brand-name IDegLira – known in Europe as Xultophy.

The meeting is critical in Novo's effort to convince the FDA to approve IDegLira, which would be available in a pre-filled pen containing 100 units of insulin degludec and 3.6mg per mL of liraglutide.

One of its rivals, Sanofi, also has a combination product – insulin glargine and lixisenatide, which has been nicknamed "LixiLan" – going before the same committee a day later.

Leerink analyst Seamus Fernandez said the FDA's worries over IDegLira essentially was the agency dealing with its "existential struggle" with the positioning and use of a fixed-formulation injectable product that marries an agent that does not require titration, Victoza, with a titratable long-acting insulin, Tresiba.

Regulators noted that all of Novo's Phase III trials of IDegLira met their pre-specified primary endpoints and demonstrated superiority to the comparators.

But, they said in briefing documents released ahead of the May 24 EMDAC meeting, the interpretation of the efficacy findings in the Tresiba comparator studies was complicated by the protocol specified starting dose and titration algorithm used for the trials – declaring it was biased favoring IDegLira.

Because of those trial design concerns, regulators said they were not able to conclude IDegLira was superior to Tresiba.

"To reach such a conclusion, a trial in which both arms were dosed and titrated in a maximally effective and balanced manner would be needed," they said.

The FDA's drug reviewers pointed out, however, that in meetings with regulators before Novo had submitted its application, the agency had agreed that an "artificial" trial design limiting the maximal insulin degludec dose to 50 units once-daily, so that the superiority of IDegLira over Tresiba could be tested, would be acceptable.

And, they said, demonstration of superiority of IDegLira over Tresiba in a trial that studied the products the way they would be used in clinical practice – meaning with no dose cap – was not a requirement.

The FDA pointed out that combining two products into one dosage form can reduce daily pill or injection burden.

The agency said it does not require that potential benefits derived from enhanced convenience be demonstrated for combination product approval.

All antidiabetic combinations approved for the US market have combined either two individual fixed-dose oral products or two individual titratable mixed insulin products, the FDA's reviewers said, noting the majority of US marketed diabetes combos include metformin.

While regulators said there were no new safety issues identified for IDegLira that weren't already known for Tresiba and Victoza, they said it was, nonetheless, important to note that use of the combination product would expose patients to safety risks associated with both of the individual drugs, like hypoglycemia and adverse gastrointestinal effects, respectively.

The drug reviewers also said the use of IDegLira allows for doses of the Victoza component that are lower – less than 1.2mg – than what's approved in the US for glycemic lowering.

In addition, regulators said, the dose range proposed for the Victoza component for the combination product includes doses that were not effective when used alone.

Regulators said interpreting the clinical meaningfulness of the results of trials designed to demonstrate "contribution to the claimed effects" when one of the comparators is a titratable product was "problematic."

The drug reviewers also said the introduction of a non-insulin component to what traditionally has only been insulin-based combination products "presents a challenge" with the labeling in ensuring the pen injector is used appropriately.

Unlike insulin-insulin combination products, the two active ingredients in IDegLira are dosed using different terms of measure – units versus milligrams.

IDegLira's components also are not conventionally dosed in the same manner.

While insulin is dosed on a continuous scale, with adjustments unit-by-unit, depending on the patient's clinical need, GLP-1 agonists are dosed at fixed increments that provide the range of dosing intended to meet clinical needs, but not on a continuous scale.

Regulators said Novo was seeking to "simplify" the expression of dose for IDegLira in its labeling by focusing dosing on the insulin component alone.

But, they said, if the dosing in IDegLira's package insert and on the pen device were to express both active ingredients, "it may be cumbersome in labeling and practice."

Among the issues the FDA wants the EMDAC at the May 24 meeting to discuss are those related to the loss of dosing flexibility, including the use of potentially ineffective doses of one agent in populations with low insulin requirements, inability to dose the two drugs independently with the device presentation proposed, inability to increase the insulin dose beyond 50 units.

After mulling over a handful of discussion questions, the EMDAC is expected to vote on whether Novo's data backed approval of IDegLira as a treatment for adults with type-2 diabetes.