Insulin inhaled

Unassigned

New Medicines

AfrezzaType 1 and 2 diabetes mellitus

Information

Afrezza
New molecular entity
MannKind
MannKind

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Launched

May 17: Nil re: any new partnerships to further develop Afrezza. Mannkind has not yet identified all of the requirements that they need to satisfy to submit Afrezza for approval for other jurisdictions. This will require additional time, expertise and expense, including the potential need to conduct additional studies or development work for other jurisdictions beyond the work they have conducted to support the NDA for Afrezza [36].


Jun 16: MannKind intends to seek regional partnerships for development and commercialisation of AFREZZA in foreign jurisdictions where there are appropriate commercial opportunities. In order to commercially market AFREZZA in the US and elsewhere, MannKind also needs to develop an internal sales team and expand their marketing infrastructure, collaborate with third parties who have greater sales and marketing capabilities, and/or purchase services from a contract commercial organisation [35].


Jan 16: MannKind has promised to find another partner willing to market its inhaled insulin, but the company´s financial situation has led many investors to doubt whether it´ll be in business for much longer [34].


Jan 16: MannKind reported termination of worldwide licensing and collaboration agreement with Sanofi for the development and commercialisation of inhaled insulin. This termination will be completely effective as of July 16. Transition of the product fro Sanofi to MannKind is anticipate over three to nine months [33].


Feb 15: Launched in the US. Afrezza is priced at more than twice the price of Apidra ($7.54 per day, based on a daily dose of 12 units vs. $3.14 per day, respectively [30].


Aug 14: Sanofi and MannKind have entered into a worldwide licensing agreement for development and commercialization of Afrezza. The companies plan to launch in the US in Q1 2015 [29].


Jun 14: Approved by US FDA. Afrezza is a rapid-acting inhaled insulin that is administered at the beginning of each meal, or within 20 minutes after starting a meal. [28]


Apr 14: FDA has delayed the date by which it will make a decision on approval to 15 Jul [27]


Apr 14: An FDA advisory committee recommended approval of Afrezza voting by margins of 13-1 and 14-0 for approval in type 1 and type 2 diabetes, respectively. Committee members called for additional long-term study due to the lack of sufficient information about its potential link to lung cancer [26].


Mar 14: An FDA briefing states that although Afrezza has been shown to be better than placebo and non-inferior to injected insulins in lowering HbA1c levels at 24 weeks, comparative efficacy “was not compelling... because of missing data, the robustness of this analysis is an issue." It also raises serious safety concerns about risks of bronchial spasms and declining lung function [25].


Oct 13: The Prescription Drug User Fee Act (PDUFA) date for Afrezza is April 13 2014 [24].


Oct 13: Afrezza refiled in the US to improve glycaemic control in adults with type 1 or type 2 diabetes. The filing is based on the entire data set from the Afrezza clinical development programme including positive results from two recent PII trials [24].


Oct 12: MannKind has completed recruiting patients for two PIII studies 171 and 175 and results are expected in Q2 2013. The company plans to re-file in the US in 3Q 2013 [21].


Aug 11: MannKind has confirmed with the FDA the design of two studies of AFREZZA that the FDA had previously requested with the next-generation inhaler. Study 171 is an open-label study in patients with T1DM (which will have a head-to head comparison of the new inhaler vs the MedTone inhaler) and Study 174 is in patients with T2DM inadequately controlled on metformin ± other oral medication [19].


Jan 11: FDA issues a second complete response letter. This letter asks the company to run two news trials in T1 and T2DM to get more data on the new MedTone inhaler used to deliver the insulin formulation. They also want an update of safety information on Afrezza as well as information on proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap and cartons [18].


Dec 10: FDA decision delayed by another 4 weeks until end of Jan 11 [17].


Jul 10: The FDA has accepted a resubmission for market authorization and a decision is expected by Dec 29, 2010. MannKind has submitted clinical data from a recently-completed efficacy study in patients with type 1 diabetes, updated pooled safety data and information on the comparability of the ‘Dreamboat’ delivery system vs the MedTone device used in pivotal studies [14].


Mar 10: The FDA has issued a complete response letter. The FDA has requested updated safety information, available clinical data that support the clinical utility of Afrezza and the comparability of the commercial version of the MedTone inhaler to the earlier version of this device that was used in pivotal clinical trials [9].


Jan 10: The FDA will miss the January 16 deadline for approval decision as it needs more time to complete its inspection of the 3rd party manufacturing facilities. The company does not know when the inspection will be complete, or when the FDA will announce its ruling on Afrezza [8].


Jan 10: FDA due to make a decision by 16 Jan 10 [7]


Mar 09: filed in US (4)


US filing expected early 2009 (3)

Category

Ultra rapid acting human insulin using Technosphere® drug delivery technology; Technosphere particles loaded with insulin change from powder to liquid upon contact with the neutral pH of the alveoli surface deep in the lung.
Currently 3.8 million people in the UK are diagnosed with diabetes (90% type 2), and it is estimated that a further 1 million people with type 2 diabetes have not yet been diagnosed [38].
Type 1 and 2 diabetes mellitus
Inhalation

Trial or other data

01. Dec 08: Company report that the primary goal in its two final Phase 3 studies of Afresa, an ultra-rapid-acting, inhaled insulin product, has been met. The first study, comparing the drug to usual care, met its primary endpoint of no observable adverse effects on the lungs of patients taking the drug. The second study compared the efficacy of the drug combined with a long-acting basal insulin with twice-daily injections of pre-mixed insulin. It met its primary endpoint, showing comparable improvements in HbA1c levels over 52 weeks between the two treatment groups (1,2)
02. The findings of two 52-week studies, in patients with type 1 and 2 diabetes (HbA1C 7.0% -11.0%), were presented at the ADA 69th session. Patients with inadequately controlled T2D despite insulin with/ without oral anti-hyperglycaemic therapy, were given either AFRESA and bedtime glargine insulin (n=334) or premixed biaspart 70/30 insulin twice daily (n=343). HbA1C (primary endpoint) was reduced by -0.66% and -0.72% in the two groups, respectively, and the % of subjects achieving HbA1C <7.0% were comparable (22% vs 27%). A second study in patients with T1D compared AFRESA (n=301) with insulin aspart (n=288), both given at meals, plus insulin glargine. Reductions in HBA1C were comparable with no significant differences in insulin glarine doses. Afresa was also found comparable to standard of care therapies in controlling post-meal blood sugar levels, and resulted in significantly less weight gain and risk of hypoglycaemia. Results from a prospective, 2-year PIII study in patients with T1D and T2D , receiving AFRESA (n=730) or usual antidiabetic treatment (n=824), along with nondiabetic subjects (n=145), were also reported, and showed no difference in mean change in FEV(1) between those treated with AFRESA and those treated with standard insulin therapy (non inferiority margin of 50 ml/year)[5].
03. Oct 09: 4 year data presented at the 45th Annual Meeting of the European Association for the Study of Diabetes on pulmonary function tests and HbA1C levels in subjects with T2D receiving AFRESA who had completed any of the two 3-month, controlled, PII trials and continued open-label AFRESA as their exclusive prandial insulin regimen (n=229). Annualised change in FEV1 was -0.048±0.006 l/year, and in diffusing capacity of the lung for carbon monoxide was -0.332±0.085 ml/min/mmHg after 4 years of continued treatment. This is claimed to be similar to the changes expected in adults with T2D. Mean HbA1C levels were 7.97% at baseline and remained steady. Overall, hypoglycaemia rates remained stable at 0.31 events/subject-month during the first 6 months and 0.42 events/subject-month after 3 years, as measured over the final 12 months of AFRESA therapy [6].
04. Jan 10: As part of the ongoing discussions between MannKind and the FDA, the agency has accepted AFREZZA the trade name for the product, which was formerly known as AFRESA. The agency had requested that the name change in order to avoid confusion with another medication. MannKind and the FDA have also discussed the basis for obtaining a waiver and deferral for paediatric studies. MannKind agreed to conduct a PIV study in 500 paediatric patients at least four years of age [8].
05. Mar 10: Following the complete response letter from the FDA, the company are considering submiting an application for its next-generation inhaler, known as ‘Dreamboat’, saying that this will settle labelling question raised by the FDA. MannKind had originally planned to launch Afrezza with its existing MedTone devices and switch patients to the Dreamboat after securing a separate FDA approvel for the product [10].
06. Apr 10: Data presented from a follow-up study at the American Association of Clinical Endocrinologists 19th Annual Meeting suggest that results of pulmonary function test in patients treated with Afrezza were similar to those in patients receiving standard antidiabetic therapy [11].
07. Apr 10: Findings from a prospective, multisite parallel-group study comparing the efficacy and safety of AFREZZA vs usual diabetes care in 538 patients with Type 1 diabetes mellitus and inadequate glycaemic control (HbA1c >6.6% and <12.0%) despite sc insulin therapy were presented at the American Association of Clinical Endocrinologists 19th Annual Meeting (Poster #283). Patients were followed for 2 years and were randomly assigned to AFREZZA plus sc basal insulin or usual diabetes treatment regimens of any insulin. At 2-years, there was a comparable reduction in HbA1c levels (0.29% vs 0.31%, respectively). AFREZZA resulted in weight loss, while standard care resulted in weight gain (-0.59 vs +1.38kg; p=0.0007). There incidence of hypoglycaemic events was lower in the AFREZZA group (61.8% vs 66.05%) and there were 2.36 severe events per 100 subject-months in the AFREZZA group vs 3.76 for the usual care group [12].
08. June 10: Results of a new 16-week trial show that AFREZZA Inhalation Powder, combined with basal insulin, is non-inferior to standard therapy insulin lispro, combined with basal insulin, in reducing HbA1c levels in subjects with inadequately controlled Type 1 diabetes. In addition, patients treated with AFREZZA had statistically significant lower rates of hypoglycemia, post-prandial glucose (PPG) levels when measured at 30, 60, 90 and 120 minutes, and fasting blood glucose (FBG) levels when compared to subcutaneously injected insulin lispro. (13)
09. Jun 10: Results from a 52 week open-label PIII study comparing inhaled insulin plus insulin glargine (n=334) vs premixed biaspart insulin (n=343) in patients with type 2 diabetes have been published in the Lancet (2010:375:2244-53). Changes in HbA1c at 52 weeks with the inhaled insulin regimen (-0.68%) were similar and non-inferior to those with biaspart insulin (-0.76%). Patients on the inhaled insulin regimen had fewer hypglycaemic events and significantly lower weight gain, but a greater incidence of cough and change in pulmonary function.
10. Sep 10: NCT01196104 - A PIIIb, multicentre, open-label, randomized, forced-titration clinical trial evaluating the efficacy and safety of Technosphere® insulin inhalation powder, using the Gen2 inhaler, in combination with insulin glargine, vs insulin aspart in combination with insulin glargine in 360 subjects with type 2 diabetes who are suboptimally controlled with their current insulin regimens. Primary outcome: change in HbA1c from baseline to week 16. To start Sep 10 and due to complete Jun 11 [15].
11. Nov 10: A former MannKind director for regulatory affairs has alleged that the company hid "scientific misconduct" from regulators, including irregularities at Russian and Bulgarian trial sites that suggest fake patients in clinical trials of Afrezza. The FDA may extend the review tim, currently set for Dec 29, to examine the data. In a regulatory filing, MannKind says it conducted its own investigation of the charges and hired an outside firm to evaluate the situation; neither investigation uncovered misconduct [16].
12. Oct 11: NCT01451398 - A PIII multicentre, double-blind, placebo-controlled RCT evaluating prandial technosphere insulin inhalation powder vs technosphere inhalation powder (placebo) in 328 insulin naïve subjects with T2DM poorly controlled with oral antidiabetic agents over a 24 week treatment period. The primary outcome is efficacy as measured by change in HbA1c. Inclusion criteria include: an HbA1c ≥7.5% and ≤10.0% , a BMI of ≤ 45 kg/m2, non-smoker, T2DM for >12 months and on stable oral hypogycaemics. The study will start Nov 11 and is due to complete Feb 13. [20]
13. Oct 12: Recruitment for two PIII clinical studies of AFREZZA® has been completed. Study 171 is an open-label study in pts with type 1 diabetes. After a run-in period, during which all pts are optimized on their basal insulin regimen, at least 471 subjects are to be randomized to one of three arms for mealtime insulin: a control arm, in which pts utilize injected rapid-acting insulin, or one of two AFREZZA arms, one for the MedTone inhaler and the other for the next-generation inhaler. After the mealtime insulin is titrated, there is a 12-week observation period on stable doses of the mealtime insulin to assess HbA1c levels, which is the primary outcome parameter. Another objective of this study is to compare the safety profile of the two AFREZZA treatment groups [22].
14. Aug 13: Preliminary results from the PIII Study 175 reported. In the double-blind study, 353 patients with T2DM inadequately controlled on metformin with or without a 2nd or 3rd oral medicine were randomized to AFREZZA or Technosphere Inhalation Powder (placebo), both administered using the Gen2 inhaler. The treatment period consisted of 12 weeks of prandial insulin titration followed by 12 weeks of relatively stable dosing. The primary endpoint was mean change in A1c levels from baseline to week 24 between the two groups. Mean A1c levels decreased by 0.82% in the AFREZZA group vs a decrease of 0.42% in the placebo group (between-group difference p<0.0001). 37.7% vs 19% achieved A1c levels <7.0% (p=0.0005), and 15.9% vs 4.2% achieved A1c levels <6.5% (p=0.0021), respectively. Patients on AFREZZA gained an average of 0.49 kg vs an average loss of 1.13 kg in the placebo group (p<0.0001). The incidence of mild and moderate hypoglycemia was higher in the AFREZZA group (67.2% vs 30.1%); severe hypoglyacemia, which was reported in nine (5.1%) and three (1.7%) patients (p=0.0943), respectively [23].
15. Jul 15: Results of PIII trail (n=345), published in Diabetes Care, found that in patients with T1DM, HbA1c reduction with inhaled insulin (-0.21%) was noninferior to that of aspart (-0.4%), with less hypoglycaemia, less weight gain, but increased incidence of cough [31].
16. Aug 15: Results of PIII trial, published in Diabetes care, found that in patient with TIIDM and HbA1c levels over or equal to 7.5% but less than 10% despite metformin alone or two or more oral antidiabetics, add-on prandial Afrezza reduced HbA1c by -0.4% (95% CI -0.575 to -0.23%) compared to placebo (p<0.0001) [32].

Evidence based evaluations

31 March 2014FDA doc