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Mannkind’s struggle to continue at FDA advisory committee for inhaled insulin

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By Jennifer Boggs
Managing Editor

Briefing documents released ahead of the Endocrinologic and Metabolic Drugs Advisory Committee meeting Tuesday for Mannkind Corp.’s regulatory-plagued inhaled insulin candidate, Afrezza, indicate that executives of the Valencia, Calif.-based firm have their work cut out for them.

But that’s nothing new.

Mannkind’s dogged pursuit of a successful inhaled insulin goes back more than seven years and has continued in the wake of the spectacular commercial failure of Pfizer Inc.’s Exubera, the first – and only – inhaled insulin to hit the market, and despite two previous complete response letters (CRLs). And it has consumed considerable investment, with nearly $1 billion committed by founder and CEO Alfred Mann, who voiced continued optimism during a presentation at the J.P. Morgan Healthcare Conference in January and said he looked forward to communicating in a public forum the benefits of Afrezza in diabetes treatment. (See BioWorld Today, Jan. 16, 2014.)

Based on the briefing docs, Mann and his company will get that chance. The adcom members will have two voting questions, deciding separately whether data in the new drug application (NDA) are sufficient to demonstrate Afrezza’s safety and efficacy in type 1 diabetics and type 2 diabetics.

Type 1 might prove the larger hurdle. Data included in the NDA package came from two phase III studies completed last year, both designed to address FDA concerns raised in the second CRL regarding the switch to the next-generation inhaler. Both met their primary endpoints, with data showing that Afrezza was noninferior to insulin aspart – Novo Nordisk A/S’ Novolog – in type 1 patients and superior to oral therapy in type 2 patients. (See BioWorld Today, Aug. 15, 2013.)

But, while reviewers acknowledged that treatment with Afrezza met endpoints, they pointed to weaknesses in the efficacy data, stating in their conclusion that “because of missing data, the robustness of this analysis is an issue. Since there was only one confirmatory study submitted for the indication of type 1 diabetes mellitus, this makes drawing a solid conclusion regarding efficacy for this type of diabetes mellitis problematic.”

Cowen and Co. analyst Simos Simeonidis didn’t view the briefing docs as encouraging. Based on a preliminary read, he wrote in a research note that Afrezza “looks non-approvable” in type 1 diabetes “based on its marginal efficacy vs. sc insulin.” While the odds are higher in type 2 diabetes, “a lot of questions around efficacy remain.”

Reviewers also raised safety concerns, primarily the risk of bronchial spasms and effects on lung function, though also noted in the briefing docs was an imbalance in the number of lung cancer cases.

“These seemingly unresolved issues may require more data,” noted J.P. Morgan’s Cory Kasimov in a research report. But those could be addressed in postmarketing studies, he added. “Regarding other safety issues, we saw no smoking gun.”

Kasimov stops short of predicting an outcome for the adcom meeting. “In the end,” he wrote, “we believe one or two vocal panelists on Tuesday could still sway sentiment one way or the other, and we also note that some old regulatory baggage, as well as data for Pfizer’s Exubera has been brought up.”

Reviewers also remarked on the “complex regulatory history” of Afrezza. The product has been through three inhaler devices and is on its second proposed brand name – now known as Afrezza (Technosphere insulin inhalation system).

Its first CRL came in 2010, with the FDA asking for additional clinical utility and comparator data, though no new trials were specifically requested. The second letter required the two additional phase III studies with the new device. (See BioWorld Today, March 16, 2010, and Jan. 21, 2011.)

More battles ahead?

But for Mannkind, the adcom is just the first of many battles. Even if it succeeds in earning a thumbs-up from the panel, it still needs FDA approval. While the FDA usually follows the recommendations of its adcoms, it’s not bound by those opinions.

Afrezza’s PDUFA date is April 15, just two weeks after the adcom, though more than one analyst has surmised that the agency could delay a decision to give it more review time.

Assuming approval, Mannkind will have to find a partner. During his J.P. Morgan presentation, Mann conceded that a few firms were in discussions but others clearly were waiting for approval and labeling. He also told investors that his company wanted to maintain a U.S. co-promotion option.

Then there’s commercialization, a prospect over which Exubera’s shadow has loomed large.

Approved in early 2006, Exubera had been hailed a likely blockbuster. But its ramp-up was saddled with manufacturing problems followed by difficulty winning patient acceptance, attributed to the unwieldy inhaler device. Pfizer even attempted a direct-to-consumer campaign, though that effort was viewed by many as being too little, too late. After second quarter 2007 sales totaled a measly $4 million, Pfizer dropped the product. (See BioWorld Today, Oct. 19, 2007.)

Pfizer’s exit prompted nearly all others in the inhaled insulin field to follow suit. Mannkind was the only late-stage player that remained and, in the years since, Mann and his team have invested in market studies to gauge interest in inhaled insulin and worked to create the small, next-generation inhaler – previously dubbed Dreamboat – that would better appeal to patients.

About the size of a toy whistle, the breath-powered inhaler comes with disposable, single-use cartridges containing clearly marked pre-metered doses of inhalation powder, so that patients always get the precise dosage of insulin. And Mannkind has claimed that once patients become accustomed to the proper dosing of Afrezza, the product could prove superior to existing prandial insulin, reducing the chances of hypoglycemia and weight gain.

If it gains approval this time around, Afrezza could nab a portion of the large – and growing – diabetes market. But if a third CRL is forthcoming, the drug-device product’s future is uncertain. Already the CRLs and regulatory delays have taken their toll on the company, which has posted a cumulative net loss of $2.3 billion since its 1991 inception and been largely funded by Mann himself, who has invested $575 million and provided a $350 million owner’s loan to get Afrezza to the finish line.

Shares of Mannkind (NASDAQ:MNKD) fell 37 cents Friday to close at $4.83.