Mannkinds’s third attempt was the charm in obtaining approval for Afrezza as a short-acting treatment to improve glycemic control in both type 1 and type 2 diabetes.
The company’s new drug application for the device was denied in 2011 for reasons including insufficient data on the latest “Gen2” version of the inhaler. The application also was rejected the previous year, with FDA requesting more clinical and labeling information.
MannKind has now submitted data from two new pivotal trials in type 1 and type 2 diabetes, respectively. For the noninferiority study evaluating Afrezza in type 1 diabetes, the new Gen 2 Dreamboat inhaler was compared with an older-generation inhaler (MedTone) and injected insulin.
Votes of the Endocrinologic and Metabolic Drugs Advisory Committee in favor of Afrezza were 13-1 for type 1 diabetes and 14-0 for type 2 diabetes. One panel member left early and did not vote.
Afrezza consists of a premeal insulin powder loaded into a cartridge for oral inhalation. The company is seeking an indication as an ultrarapid-acting insulin for adults with type 1 or 2 diabetes. In type 1 patients, the indication would be for use along with injected basal insulin.
Afrezza has a unique pharmacokinetic profile that mimics the early phase release of mealtime insulin observed in healthy individuals. Administered at the start of a meal, Afrezza dissolves in the lung immediately upon inhalation and delivers insulin quickly to the blood stream. Peak insulin levels are achieved within 12 to 14 minutes of administration.
Panel members cited the advantages of more rapid onset of insulin action and shorter duration, resulting in a lower risk for hypoglycemia, as well as the potential for greater acceptance of inhaled-insulin therapy for patients with type 2 diabetes who might otherwise refuse or be unable to self-inject insulin.
However, the panel did express concern about data suggesting lower glucose-lowering efficacy compared with injected short-acting insulin (aspart) in type 1 patients, and about lack of long-term lung-function data beyond 2 years, as well as a possible signal for lung cancer.
Panel members presented the agency with a long list of recommendations for postmarketing studies and labeling requirements to address those issues, among others.
The single panelist David Cooke, MD, associate professor of pediatrics at Johns Hopkins University School of Medicine, who voted against recommending approval of the device for the treatment of type 1 diabetes said his concerns over pulmonary and lung cancer risks with Afrezza use outweighed the proof of benefit of the drug-device combination. “My greatest concern is related to the cancer risk and I think the way I saw the data, the efficacy of this was not as good as injectable insulin,” adding that more preclinical data would reassure him against the cancer risk.
Because of the risk for bronchospasm in patients with underlying lung disease, including chronic obstructive pulmonary disease (COPD) and asthma, the product would be contraindicated in those groups, and the label would include recommendations for screening of patients for these conditions before starting them on Afrezza and possibly for periodic ongoing monitoring of lung function as well.
A total of 4 cases of lung cancer occurred in patients who had used Afrezza, 2 during the trial in smokers, and 2 others, both squamous-cell tumors, at 2.6 and 3.8 years after the end of the trial in nonsmokers. An oncologist on the panel, Liz Szabo, MD, from the National Cancer Institute, called that “unusual” and advised that more data be collected.
Panel members also considered whether there is a specific clinical setting and patient subgroup most appropriate for inhaled insulin in type 2 diabetes. The panel consensus was that there is not, at this point, an adequate treat-to-target trial, which would be “helpful and important” regardless of Afrezza’s approval, according to the summary given by panel chairman Robert Smith, MD, of Brown University in Providence, R.I.
Panel patient representative Rebecca Killion echoed the support heard from all 17 speakers during the open public hearing by voting Yes to approve Afrezza for use in both types 1 and 2 diabetics.
Another concern raised: MannKind’s new drug application for Afrezza cited cartridges containing up to three units of injected insulin, and double-strength cartridges with up to six units, when its clinical trial used cartridges with up to four units and double-strength cartridges of up to eight. The company cited an equivalency study that compared its inhaled insulin with injected insulin from other companies; Afrezza would compete with two injectable insulins, Humalog sold by Eli Lilly, and Novolog sold by Novo Nordisk.
FDA staff scientists, in a briefing document prepared for the meeting, raised concerns about possible inadequate dose titration in the type 1 diabetes study, stating, “It is not clear how to interpret the results of this noninferiority study.”
The reviewers also noted that study dropouts because of cough and other pulmonary problems did not appear to have changed meaningfully since the previous submission.
Noninferiority was achieved for the new inhaler, with HbA1c levels decreasing by 0.21 percentage points, compared with a decrease of 0.40 points for the older inhaler.
However, compared with injected aspart insulin, a decrease in FEV1 (forced expiratory volume in 1 second) was seen among patients using the new inhaler, and a higher rate of discontinuation because of cough was seen in the Dreamboat group.
The type 2 study compared the Afrezza insulin powder with Technosphere insulin powder, and found significantly greater decreases in HbA1c among patients using the Afrezza powder (-0.82 versus -0.42 percentage points, P<0.0001).
Mild and moderate hypoglycemia was more common in the Afrezza group, but fewer severe adverse events occurred. Cough was the most common side effect.
The committee, which met in Hyattsville, Md., was concerned that long-term exposure of the lungs to insulin could cause lung cancer. There were more cases of lung cancer among those who received Afrezza in clinical trials than in the control groups, but the numbers were small and far from definitive. MannKind is expected to undertake a long-term study to assess that risk.
The FDA is scheduled to decide whether to approve Afrezza by the middle of this month. The agency usually, but not always, follows the advice of its advisory committees.
MannKind, based in Valencia, Calif., is run by Alfred E. Mann, a highly successful aerospace and medical device entrepreneur still very active at age 88.
Even if it wins approval, Afrezza might not be a commercial success. MannKind has yet to find the larger pharmaceutical company partner it has said it will need to market and sell the product.
The reason for the skepticism stems in part from Pfizer’s experience. To much fanfare, it won approval for an inhaled insulin called Exubera in 2006. But Exubera flopped, and less than two years later, Pfizer said it would stop selling the product and take a charge of $2.8 billion. Two insulin giants, Novo Nordisk and Eli Lilly, subsequently abandoned their own efforts to develop inhaled insulin.
FDA advisory panel members are vetted for conflicts of interest and are given temporary waivers for participation if necessary. No waivers were issued for this meeting.
FDA News Release April 2, 2014, Afrezza Study Results, Mannkind.com