Panel Embraces Sanofi Diabetes Combo, Shuns 'Pen' Devices

An FDA panel of advisors on May 25 voted 12-2 to back approval of Sanofi SA's experimental fixed-ratio combination (FRC) type 2 diabetes medicine, which marries the company's experimental glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide with its already marketed drug Lantus (basal insulin glargine).

Sanofi is seeking to market the combo drug, which has gone under the nickname "LixiLan," as iGlarLixi.

But most members of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) expressed concern over the two titratable pen devices Sanofi has proposed for commercial use to deliver the FRC product, which the panelists said were too complicated for patients and their health care providers.

While insulins are measured in units, GLP-1s are measured in milligrams or micrograms.

Sanofi wants to label the combo product's dose in units and reflect only the dosing on the insulin component alone in the labeling. It's also established a complicated dosing regimen.

For instance, a yellow color pen would be used for insulin-naïve patients to initiate treatment at a recommended daily insulin glargine (100U/mL) dose of 10 units, with a corresponding dose of 5mcg of lixisenatide.

But in patients switching from basal insulin to iGlarLixi, Sanofi wants to provide two different starting doses, which would be dependent on previous insulin need: the yellow pen with 20 U/10mcg or the green pen with 30U/10mcg.

The dose of iGlarLixi would be adjusted based on the need for basal insulin – primarily on the basis of fasting self-monitored plasma glucose levels.

After initiation of iGlarLixi and during titration, the yellow pen would be used for total daily insulin glargine doses of 10U to 40U, and the green pen for total daily doses of 41U to 60U, thereby not exceeding the maximum lixisenatide starting dose of 10mcg.

Patients using the yellow pen but require more than 40U could be switched to the green pen, Sanofi said.

The firm argued the flexibility of iGlarLixi dosing allows patients to titrate based on their individual responses to treatment.

But EMDAC panelist Ellen Seely, a professor of medicine at Harvard University, insisted the pen was "asking for trouble" and "really needs to be redesigned."

"I feel really strongly you cannot use the proposed pen," Seely declared, although she voted in favor of approving iGlarLixi for the US market.

Panelist Kenneth Burman, director of endocrinology at MedStar Washington Hospital Center, said he based his "no" vote "solely on the pen design," adding that "everything else was fine" with iGlarLixi.

He pointed out that in Sanofi's human factor study, one out of 15 pharmacists and one out of 45 nurses and patients had difficulties with the pens.

But other than the pen devices, "the advantages are worth the disadvantages" of the combo drug, Burman said.

Panelist Daniel Budnitz, director of the Medication Safety Program at the US Centers for Disease Control and Prevention, said that while he voted in favor of Sanofi's combination drug, that vote could have just as easily been against iGlarLixi – telling the FDA he was concerned about the potential doctors would put some patients on two drugs "when one would have been effective."

He also raised concerns about the pens and the proposed way in which Sanofi wants to label them.

Budnitz urged the FDA to ensure there is a standardized vocabulary for labeling injectable combination diabetes medicines – arguing that task should not be left to the prescribing community to develop.

EMDAC chair Robert Smith, a professor of endocrinology at Brown University in Providence, RI, said that while he was "swayed" to vote in favor of approval for iGlarLixi, that support came "contingent" on the FDA ensuring there was some type of guidance in place to address "special circumstances," like when patients are hospitalized with interrupted nutrition.

Smith also suggested the FDA require post-approval assessing of serious allergic reactions.

"I don't think that's adequately resolved," he said.

Smith also called for a post-approval study to examine how patients would transition from a GLP-1 to the iGlarLixi device – pointing out Sanofi lacked data on that.

Sagient Research's BioMedTracker, an affiliate of Scrip, noted there is time to work on the device issues, given the FDA is not expected to make a decision on iGlarLixi until Aug. 23, "though if major work needs to be done on the pens and testing for understanding of the device, it is conceivable there could be a delay."

Given the positive vote for iGlarLixi, the BioMedTracker analysts increased the likelihood of approval of the drug by 7% – from 91% to 98%.

Competition

Sanofi has been counting on iGlarLixi and the firm's single-agent lixisenatide, which the EMDAC also reviewed but didn't hold a vote on, to boost its diabetes product sales, given revenues from Lantus have been on a continued decline due to competition from biosimilars and the recent US approval of Eli Lilly & Co.'s and Boehringer Ingelheim GmbH's Basaglar (insulin glargine injection) (Also see "Lantus Follow-On Basaglar OK'd, But Can Lilly Sell It?" – Scrip, 16 Dec, 2016).

Sanofi also may soon face new competition from Novo Nordisk AS' fixed-dose combination diabetes medicine, which unites the active ingredients of Danish firm's GLP-1 receptor agonist Victoza (liraglutide) and Tresiba (insulin degludec), a basal insulin, into one single subcutaneous shot (Also see "Panel Back's Novo's Diabetes Combo, But Will The Market?" – Scrip, 24 May, 2016).

At a meeting a day earlier the EMDAC unanimously voted to approve Novo's combination medicine, which the company wants to market as Xultophy – the same name it uses in Europe.

Novo's combo medicine currently goes under the name IDegLira for the time being.

Both Sanofi and Novo will be up against the already marketed 18 combination antidiabetic drugs, the majority of which include metformin.

Analysts Andrew Frost and Natasha Boliter from Citeline, an affiliate of Scrip, said other companies with diabetes combination products in late-stage development include Pfizer Inc. and Merck & Co. Inc., which are collaborating on ertugliflozin plus metformin and ertugliflozin plus Januvia (sitagliptin) under a 2013 partnership.

They said other partnerships on diabetes combination drugs include Boehringer Ingelheim GMBH's and Eli Lilly & Co.'s development of an extended-release formulation of empagliflozin plus metformin; Johnson & Johnson subsidiary Janssen's pursuit of a once-daily fixed-dose combination formulation of canagliflozin and extended-release metformin, which is using Depomed Inc.'s Acuform technology; and AstraZeneca PLC's and Bristol-Myers Squibb Co.'s collaboration on a fixed-dose combination of saxagliptin and dapagliflozin.