Afrezza Approval FDA Adcom Briefing Document
Question re lung toxicity
“The pharmacokinetic profile of Afresa sets it apart from all other insulin products. The large surface area of the lung provides unique access to the circulatory system. The pH-sensitive Afresa particles immediately dissolve upon contact with the lung surface, releasing insulin monomers that rapidly enter the bloodstream.”
“We are encouraged by this long-term study which demonstrates that over four years, AFRESA maintained glycemic control with changes in lung function comparable to that seen in diabetic patients treated with injectable and oral therapies,” said Peter Richardson, Corporate Vice President and Chief Scientific Officer, MannKind Corporation. “These findings add to the growing body of clinical evidence that AFRESA is a promising therapeutic option for this patient population.”
“It seems to me that the concern about lung cancer should have ended by now since there is no factual basis for such concern. Even for Exubera, there was no conclusion as to causality or acceleration and AFRESA is so very, very different. In relation with AFRESA, it is certainly less risky than for some other chronically entailed drugs and even less so than breathing in a large city. An advisory committee has dismissed any risk of lung cancer from AFRESA. While we are seriously concerned about this risk, all of the data gives us confidence that any concern about lung cancer with AFRESA is without foundation and is bogus. Nevertheless, we must address some perceptions that have been created.”
MannKind has also undertaken a more comprehensive examination of the toxicology profile of Technosphere(R) Insulin than has been reported for any other inhaled insulin. Last year, MannKind completed a two-year carcinogenicity study in rats in which Technosphere(R) Insulin, and large doses of Technosphere(R) particles alone, were well tolerated after daily inhalations for 104 consecutive weeks. There were no indications in these studies that either Technosphere(R) Insulin or Technosphere(R) particles alone had any carcinogenic potential or caused any cellular proliferation in the lungs. MannKind also recently completed a six-month carcinogenicity study in transgenic mice, finding no macroscopic indications of carcinogenicity in animals given daily subcutaneous injections of Technosphere(R) Insulin or Technosphere(R) particles for 26 consecutive weeks. In addition, MannKind plans to submit data from over 100 preclinical studies supporting the safety of our product, the vast majority of which have already been completed.
“We also did high-definition CT scans on the 600 patients in our study. That’s the best you can do with people. We saw no change in their lungs, and some of them have been using the product for up to 5 years now.”
Pulmonary function over 2 years in diabetic patients treated with prandial inhaled Technosphere Insulin or usual antidiabetes treatment: a randomized trial
Aims: Development of inhaled insulin has increased the need to understand its pulmonary safety. This study evaluated pulmonary function changes in diabetes patients receiving inhaled Technosphere Insulin (TI) or usual antidiabetes treatment (usual care).
Methods: This randomized, open-label study was conducted at 220 sites (25 July 2005 to 29 August 2008). Pulmonary function tests [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and lung diffusion capacity for carbon monoxide (DLCO)]were prospectively followed over 2 years in patients with type 1 or type 2 diabetes receiving TI (n = 730) or usual care (n = 824), along with a cohort without diabetes not receiving any special therapy (n = 145).
Results: Baseline demographics and pulmonary function were similar between diabetes treatment groups. Lung function declined frombaseline in all groups. TI was non-inferior to usual care for mean change in FEV1from baseline to month 24 [mean (s.e.m.) 0.037 (0.0119) l;95% CI 0.014 to 0.060] using mixed-model repeated-measure with a pre-speci?ed non-inferiority margin of 50 ml/year. After a greater initialdecline at month 3 with TI, rate of change (slope) in FEV1, FVC and DLCO(months 3–24) was not statistically different between treatment groups. TI was well tolerated; no serious safety concerns emerged. The most common respiratory event associated with TI was mild, transient cough, occurring within minutes of inhalation.
Conclusions: Observed changes in lung function with TI were small, occurred early after therapy initiation, remained non-progressive over 2 years and were unlikely to be clinically meaningful.
Keywords: diabetes, inhaled insulin, pulmonary function, Technosphere Insulin, usual antidiabetes treatment
Date submitted 30 June 2011; date of first decision 2 August 2011; date of final acceptance 20 September 2011
Safety of Technosphere Insulin as an Ultra-Rapid-Acting Prandial Insulin
The safety of TI has been studied extensively, both preclinically and in a clinical program involving more than 5600 subjects. The most common treatment-emergent adverse events were hypoglycemia, cough, and upper respiratory tract infection.17 Cough occurred in approxi-mately 32% of patients administering TI but tended to be mild and transient, occurring within minutes of inhalation.17 Furthermore, cough diminished over time and rarely led to study discontinuation.
A pooled analysis of cardiovascular events from nine clinical studies comprising 4467 patients who administered TI or usual diabetes care showed that the incidence of cardiovascular or cerebrovascular events was similar between the TI and usual diabetes care groups (relative risk, 1.01; 95% CI, 0.84 to 1.20).23
Lung function was examined in a 2-year prospective, multicenter, randomized, open-label study in patients with type 1 or type 2 diabetes administering TI (n = 730) or usual diabetes care (n = 824) and a cohort without diabetes who did not receive any specific therapy (n = 145).24 Lung function declined from baseline in all treatment groups, in line with normal age-related changes and as seen in diabetes in general. Compared with usual diabetes care, TI showed a small reduction in forced expiratory volume in 1 s (FEV1) from baseline to month 24 (-0.037 ± 0.0119 liter; 95% CI, 0.014 to 0.060). After a greater initial decline by month 3 with TI, the rate of change (slope) in FEV1, forced vital capacity, and diffusing capacity of the lung for carbon monoxide over months 3 to 24 was not statistically different between treatment groups. This observed treatment group difference was small, occurred early after therapy initiation, did not progress over 2 years, and resolved after discontinuation of therapy.
Two cases of cancer involving the lung have been reported during clinical trials, both in ex-smokers. The incidence does not exceed what would be expected in a similar, nontreated population.25 A 2-year carcinogenicity study in rats26 and a 6-month study in transgenic mice (data on file, MannKind Corporation) did not indicate a carcinogenic potential.
Technosphere® Insulin: Defining the Role of Technosphere Particles at the Cellular Level
Insulin Lung Deposition and Clearance Following Technosphere® Insulin Inhalation Powder Administration
To determine distribution and deposition of Technosphere® Insulin (TI) inhalation powder and the rate of clearance of fumaryl diketopiperazine (FDKP; major component of Technosphere particles) and insulin from the lungs.
Deposition and distribution of 99mpertechnetate adsorbed onto TI immediately after administration using the MedTone® inhaler was quantified by gamma-scintigraphy. Clearance from the lungs was studied in a second experiment by serial bronchoalveolar lavage (BAL) after administration of TI inhalation powder and assay of the recovered fluid for FDKP and insulin.
Following inhalation, ~60% of radioactivity (adsorbed on TI) emitted from the inhaler was delivered to the lungs; the remainder of the emitted dose was swallowed. Clearance from the lung epithelial lining fluid (ELF) of FDKP and insulin have a half-life of ~1 hour.
TI inhalation powder administered via the MedTone inhaler was uniformly distributed throughout the lungs; ~40% of the initial cartridge load reached the lungs. Insulin and FDKP are quickly cleared from the lungs, mainly by absorption into the systemic circulation. The terminal clearance half-life from the lung ELF, estimated from sequential BAL fluid measurements for both components, was ~1 hour. Since there is an overnight washout period, the potential for accumulation on chronic administration is minimal.
INNOVATION IN DRUG DELIVERY BY INHALATION
TECHNOSPHERE® TECHNOLOGY: A PLATFORM FOR INHALED PROTEIN THERAPEUTICS