Status: NDA pending

Organizations involved:

Mannkind Corp. - Manuf.; R&D; Tech.; World mark.

Pharmaceutical Discovery Corp. – R&D; Tech.

Cross ref.: See the Insulin Products entry.

Description: Afrezza is a powder formulation of "ultra rapid acting mealtime" recombinant pH-sensitive (for dissolution) powdered insulin, mostlhy in monomeric form within Technosphere particles, administered by inhalation. Afrezza is a drug-device combination product, consisting of Afrezza Inhalation Powder pre-metered into single unit dose cartridges and the Afrezza Inhaler as the delivery device for oral inhalation.

In most insulin products, regular human insulin exists as a hexamer, a complex of six associated insulin molecules (See the Insulin Products entry). In order to exert a pharmacological effect, the hexamer must first dissociate into three dimers — complexes of two insulin molecules — which then further dissociate into individual insulin molecules, or monomers. Only these monomers exert a physiological effect. Rapid-acting insulin analogs are generallly designed to be fragile hexamers that dissociate more quickly than regular insulin, thereby reducing the time required to achieve an effect, but this is still far slower than insulin that is released from a healthy pancreas. The insulin released from Technosphere particles in Afrezza is already largely in monomeric form. During the manufacture of Technosphere Insulin, hexameric insulin is dissociated into insulin monomers before being loaded onto Technosphere particles..

Nomenclature: Insulin, rDNA, inhaled/MannKind [BIO]; Afrezza [TR]; Afresa Inhalation Powder [TR former]; Technosphere insulin [TR; SY]; insulin human [rDNA origin] [FDA]

Biological.: The feature that distinguishes Afrezza from all other insulin products is not the route of administration - it is its pharmacokinetic profile. The large surface area of the lung provides unique access to the circulatory system. The pH-sensitive Afrezza particles immediately dissolve upon contact with the lung surface, releasing insulin monomers that rapidly enter the bloodstream. This time-action profile approximates the insulin secretion profile normally seen in healthy individuals immediately following the beginning of a meal.

Afrezza achieves peak insulin levels within 12-14 minutes of administration, effectively mimicking the release of meal-time insulin observed in healthy individuals, but which is absent or impaired in patients with diabetes. Administered at the start of a meal, Afrezza dissolves immediately upon inhalation and delivers insulin quickly to the blood stream. The metabolic effect of Afrezza peaks approximately 1 hour after administration, substantially earlier than what has been reported for other insulins. The majority of its glucose-lowering activity is delivered in the first 3 hours, which is generally the period during which glucose becomes available from a meal — instead of the much longer duration of action observed when insulin is injected subcutaneously. Peak insulin levels are achieved within 12 to 14 minutes of administration, effectively mimicking the release of meal-time insulin observed in healthy individuals.

To administer Afrezza, a patient loads a cartridge into its palm-sized inhaler. By inhaling through the inhaler, air is pulled through the cartridge, which aerosolizes the powder and pulls the particles into the air current and out through the mouthpiece. The particles are small and have aerodynamic properties that enable them to travel deep into the lungs. When the particles contact the moist lung surface with its neutral pH, the Technosphere particles dissolve immediately. This releases the insulin molecules, which then diffuse across a thin layer of cells into the bloodstream. Studies indicate that this insulin absorption is a passive process that occurs without disruption of either the cell membranes or the tight junctions between cells..

Companies.: Afrezza is being developed by Mannkind Inc. It will be manufactured (formulated product) by Mannkind and marketed worldwide by Mannkind and its licensees.

Technosphere technology was originally developed by Dr Solomon Steiner. Al Mann formed Mannkind Corp. around 2001 by merging Pharmaceutical Discovery Corp. (which Dr Steiner headed) and other companies.

In Sept. 2008, after the failure of Exubera, Mannkind entered into collaboration with Pfizer through which MannKind will transition certain Exubera patients with a continuing need for inhaled insulin to Afrezza (open trial). Thin included patients with severe needle-phobia or a very poor response to subcutaneous insulin.

In June 2009, Mannkind purchased Pfizer's insulin-related assets [(after failure of its inhaled insulin product, Exubera (see related entry)]. This included a quantity of bulk insulin and Pfizer's FDA license (NDA) to manufacture bulk insulin for use in pulmonary delivery. MannKind and Pfizer also entered into an agreement pursuant to which MannKind agreed to maintain and store the remainder of Pfizer's bulk insulin inventory and acquired an option to purchase the remaining insulin, in whole or in part, at a specified price, to the extent that Pfizer has not otherwise disposed of or used the remaining insulin. The total purchase price for this transaction, including consideration payable to MannKind for its storage and maintenance obligations, was $3 million, which MannKind paid in cash.

MannKind had entered into a sale and purchase agreement with Pfizer relating to Pfizer's insulin manufacturing facility in Frankfurt, Germany. MannKind's rights and obligations under this latter agreement had been subject to a right of first refusal in favor of Sanofi-Aventis. On June 8, 2009, Sanofi-Aventis exercised its right of first refusal, thereby releasing MannKind from its obligations under this agreement.

Mannkind is expected to partner with one or more other companies for the marketing and distribution of Afrezza. In Oct. 2009, Mannkind reported that it did not expect to find a partner(s) in 2009, and probably will not conclude a deal until Afrezza approval, leading to speculation that the company may receive a complete response letter or otherwise expects to encounter problems in approval of its NDA.

FDA class: Drug NDA

Status: On March 16, 2009, Mannkind filed an NDA seeking approval of Afrezza (insulin monomer human [rDNA origin]) Inhalation Powder and the Afrezza Inhaler for the treatment of adults with type 1 or type 2 diabetes mellitus for the control of hyperglycemia. The NDA was accepted for filing on May 18, 2009.

In March 2010, MannKind received a Complete Response letter to its NDA for Afrezza (renamed) from the FDA requesting additional information. In response, MannKind submitted clinical data from a recently completed efficacy study in patients with type 1 diabetes as well as updated pooled safety data related to Afrezza and information on the comparability of MannKind’s next-generation delivery system to the device that was used in pivotal clinical studies.

On July 20, 2010, MannKind resubmitted an NDA and classified it as a Class 2 resubmission. On July 30, 2010, the NDA was refined and classified as a Class 2 resubmission. The FDA set a corresponding Prescription Drug User Fee Act (PDUFA) action date of December 29, 2010.

In Nov. 2010, John Arditi, MannKind’s former senior director of regulatory affairs, filed a lawsuit in a New Jersey state court against MannKind and several executives alleging he was fired in retaliation for his insistence that MannKind alert the FDA to improprieties in Afrezza’s clinical trials. The suit was disclosed in a company quarterly SEC filing.

In Jan. 2011, Mannkind reported that FDA would not complete its review by a delayed PDUFA action date of Jan. 16, 2011. The company asserted that the only problem seemed to be that the FDA had not completed the inspection of the insulin manufacturing facility of Organon, a subsidiary of Merck which is a third-party supplier to MannKind.

In Jan. 2011, FDA sent a second complete response letter to MannKind noting that it needed to conduct two new trials for Type I and Type II diabetes to get a closer look at the performance of the next-generation inhaler used to deliver the insulin formulation. FDA wants to see more data on the "performance characteristics, usage, handling, shipment and storage of the next-generation device, an update of safety information related to Afrezza as well as information on proposed user training and changes to the proposed labeling of the device, blister pack, foil wrap and cartons." Analysts noted that the new trial demands would likely add another year or two of work for a program that has already been dogged by one delay after another

Tech. transfer: Technosphere powder particle technology was developed and licensed from Pharmaceutical Discovery Corp. Technosphere-related patents apparently include: 4,925,673, "Delivery systems for pharmacological agents encapsulated with proteinoids," expired May 15, 2007; 4,976,968, "Anhydrous delivery systems for pharmacological agents," expired Feb 24, 2009; 5,352,461, "Self assembling diketopiperazine drug delivery system, expiring Mar 11, 2012; 5,503,852, "Method for making self-assembling diketopiperazine drug delivery system, " expiring Apr 2, 2013; 7,279,457, "Rapid acting drug delivery compositions, expiring Mar 11, 2025; 7,648,960, "Method for delivery of monomeric or dimeric insulin complexed to diketopiperazine microparticles," expiring Jun 29, 2020. 7,713,929 and 7,718,609, "Rapid acting and long acting insulin combination formulations," expiring April 2, 2027; 7,943,178, "Methods and compositions for delivering peptides." expiring Jun 29, 2020.

EP2209528 - RAPID ACTING INJECTABLE INSULIN COMPOSITIONS," expires in 2028. EP2280021, "Pharmaceutical formulations comprising insulin complexed with a diketopiperazine, expires in 2020. EP2280004, "Pharmaceutique formulations comprising insulin complexed with a diketopiperazine," expires in 2020. EP2403520, "INSULIN FORMULATIONS FOR RAPID UPTAKE," expires in 2030. Trials: The Afrezza Phase II/IIII clinical program included over 4,500 adult patients. With Exubera associated with lung problems, the association of Afrezza with lung problems has been a major concern in clinical trials.

In June 2009, results were reported from two 52-week (1 year) trials comparing Afrezza to conventional basal insulin. Afrezza wa shown comparable to standard of care therapies in controlling post-meal blood sugar levels, and also resulted in significantly less weight gain and risk of hypoglycemia for adult patients with diabetes.

In Oct. 2009, Mannkind reported that Afrezza had shown no significant changes in pulmonary function and had sustained glycemic control in adult patients with type 2 diabetes over four years of continuous treatment. These results were from an open-label, controlled study conducted with patients who had previously completed two three-month, randomized Phase II clinical trials. Minimal mean change was observed in forced expiratory volume in one second (FEV1) over a four-year period for those treated with Afrezza. Additionally, patients using Afrezza therapy experienced glycemic control for at least four years.

Market: Note that a prior inhaled insulin product, Exubera (see related entry), from Pfizer failed in the marketplace and was withdrawn.