Medical Device Daily

Diabetes is a tough disease to manage – primarily because it requires a heavy dose of self-management – so anything that makes that management simpler is likely to get significant uptake. That concept is emerging as an overriding theme, perhaps even more so than in the past, at this year's 66th annual scientific sessions of the America Diabetes Association (Alexandria, Virginia) ongoing in Washington.

Thus, Eli Lilly (Indianapolis) and Alkermes (Cambridge, Massachusetts) are riding the main wave as they rolled out at the meeting new studies which push forward the potential commercialization of their combined work: administration of a Lilly insulin product delivered by Alkermes' AIR Inhaled System.

Additionally, Lilly was demonstrating its HumaPen Memoir, an electronic pen injection device with a feature that “remembers” previous doses of insulin.

Lily and Alkermes are hoping that they can be the second to offer an inhaled insulin product, following the approval, this past January (Medical Device Daily; Jan. 31, 2006), of Exubera, the first inhaled insulin product developed jointly by Pfizer (New York) and Nektar Therapeutics (San Carlos, California), with analysts saying that together, and perhaps even separately, inhaled insulin will reach the high ground of “blockbuster” sales status.

The new safety studies position Lilly and Alkermes to develop a product that can be used by those with both diabetes and breathing problems – asthma and chronic obstructive pulmonary disease (COPD), an application that was recommended against by the FDA panel reviewing Exubera, according to Doug Muchmore, senior medical scientist, Medical Fellow II, for Lilly.

He told Medical Device Daily that Pfizer and Nektar had supplied some study information to the FDA panel concerning safe use of Exubera in cases of COPD, but that the studies by Lilly and Alkermes are the first to be published and showing safety in these uses. Continued positive results, he said, would likely be used to seek the broader indications for the AIR system.

Thus, the studies reported on at this year's ADA meeting were not broad-based but focused narrowly on the use of the system in COPD.

Muchmore told MDD that the company also has just completed enrollment of pivotal Phase II safety study, noting this as a “major milestone” in the companies' clinical development programs for the AIR/insulin combination.

He declined offering timelines for regulatory filings or potential commercialization of the product given “the complexities and interactions” of what is required.

In the collaboration, Muchmore said Lilly is supplying the bulk insulin product – an unmodified human insulin, chemically identical to human insulin – and then providing a range of expertise for the trials.

The role of Alkermes has been to reformulate the insulin for the inhaler device and do the packaging into blister packs and foil pouches.

He described the special formulation as having two key characteristics: large particle composition of the insulin, but with low density, so as to need low energy to get into the lungs. Together, these features enable, for the insulin product, “a high level of consistent dose delivery [requiring only] regular breathing.”

The studies reported at the ADA meeting take into account that 10 million people in the U.S. – according to the National Heart, Lung, and Blood Institute (Bethesda, Maryland) – have COPD and that it may be a risk factor, particularly among women, for developing Type 2 diabetes.

Klaus Rave, MD, of Profil Institute for Metabolic Research (Neuss, Germany), said, “Because of COPD's prevalence and its potential correlation with Type 2 diabetes, particularly in women, it's important to study the safety, efficacy and predictability of AIR insulin in many patient populations, including in people with compromised lung function.”

Specifically, the studies analyzed the effect, in Type 1 and Type 2 diabetes, of these patients' COPD on inhaled insulin absorption and action; the importance to patients of simple, patient-directed training of an inhaled insulin system; and dosing flexibility with the AIR insulin system.

The company's Phase I study, “Pharmacokinetics (PK) and Glucodynamics (GD) of Human Insulin Inhalation Powder (HIIP) in Subjects with Chronic Obstructive Pulmonary Disease (COPD),” is, according to Lilly and Alkermes, the first published analysis of the effect of COPD on inhaled insulin absorption and action. Designed to evaluate the impact of compromised lung function on inhaled insulin dose delivery, the study found that the absorption and action of AIR insulin was reduced by a consistent amount in the presence of COPD.

The results also demonstrate that AIR insulin was able to deliver similar results on different days in patients with or without COPD and was “generally well-tolerated.”

In this open-label, randomized, three-period crossover trial, pharmacokinetic and glucodynamic responses to AIR insulin were compared with subcutaneous insulin lispro in 15 non-smoking healthy subjects (mean age 38) and 30 non-smoking subjects with moderate COPD – 15 each with chronic bronchitis (mean age 53) and emphysema (mean age 58) – using standard glucose clamp methodology, a process for measuring the absorption of and an individual's response to insulin.

Subjects received two single doses of AIR insulin and one dose of subcutaneous insulin lispro. Pharmacokinetic and glucodynamic measures were assessed using blood tests, and safety was assessed using pulmonary function tests (PFTs) before and after each clamp and by spirometry, performed four times during clamps.

Key results: Total insulin exposure and metabolic effect after subcutaneous insulin lispro were comparable in all three groups. Compared with healthy subjects, AIR insulin absorption was reduced by 22% in subjects with emphysema and by 44% in those with chronic bronchitis. The metabolic effect of the AIR insulin dose was reduced in emphysema subjects and chronic bronchitis subjects.

AIR insulin was well-tolerated by these patients, measurements showing no difference between AIR insulin and subcutaneous insulin lispro treatments, with modest decreases in forced expiratory volume and forced vital capacity in both COPD groups.

A poster presentation, “A Comparison of Standard vs. Intensive Training on Usage of the Human Insulin Inhalation Powder (HIIP) Delivery System in Type 2 Diabetes (T2D) Patients,” reported on a Phase II trial in people with Type 2 diabetes, designed to compare two levels of training intensity, either standard/patient-directed training, or intensive/provider-coached training for the AIR insulin system on overall blood glucose levels.

Key results: the AIR insulin system is easy to use and can be supported by simple, patient-driven training while helping patients manage blood sugar levels. Both training methods had similar rates of compliance with training directions, and similar safety profiles. AIR insulin exposure was also similar between groups.

Besides other studies focusing on key attributes of the AIR insulin system, Lilly was demonstrating its HumaPen Memoir device, the term “memoir” referring to the device's ability to provide the time, date and amount of the last 16 insulin doses delivered. Looking very much like a standard fountain pen, the device features a small clear viewing window at one end providing the information via digital display.

The HumaPen can inject from one to 60 doses of Humalog from a small cartridge. Humalog is the flagship insulin from Eli Lilly, introduced by Lilly as the world's first insulin analog. Humalog can be taken within 15 minutes before or immediately after a meal, enabling patients to adjust the dose according to when they eat, what they eat and how much they eat.

FDA-approved – and in use in Europe for several years – the HumaPen will get commercial rollout in the U.S. this fall, according to Lily.