Exubera – Inhaled Insulin

The product of a joint development programme between Aventis and Pfizer, Exubera is an inhaled short-acting insulin preparation indicated for the treatment of type 1 and type 2 diabetes.

In adult type 1 diabetics, Exubera was indicated for use in combination with long- or intermediate-acting insulin, while in type 2 adult patients it could be used in patients requiring insulin therapy and in those not adequately controlled on oral anti-diabetic medications alone.

The approval of the world’s first inhaled insulin marked an important advance in the treatment of diabetes that began with the discovery of insulin in the 1920s. However, the success of this innovative diabetes treatment has proved relatively short lived, as the company decided in October 2007 to withdraw the product from the market. Sales of Exubera had proved disappointing, as the product had failed to gain acceptance from both patients and clinicians.

Pfizer’s decision to withdraw Exubera now leaves the door open to other companies involved in the development of non-injectable insulins.

Non-invasive insulin delivery

At present, diabetics who require insulin to keep their blood sugar levels under tight control (target HbA1c levels of <7%) have to administer it by injection. The need for daily repeat injections is a major drawback for diabetics. It interferes with daily activities and can lead to patients developing needle phobia.

Although special self-injection pens, which are easier to use and deliver an accurate dose of insulin, are available they do not remove the need for regular injections. However, injections are considered the most efficient and reliable way to deliver insulin to the bloodstream at present.

Various alternatives to injectable insulin have been investigated:

• Insulin patches
• Insulin pumps
• Oral formulations designed to resist insulin digestion in the gastrointestinal tract
• Inhaled insulin

Of all the alternative delivery routes, pulmonary delivery of insulin looks the most promising.

Pulmonary delivery of Exubera

The concept of delivering insulin directly to the lungs (pulmonary insulin) was first advanced in 1925. However, the technical hurdles are high. Most insulin sprayed or inhaled through the mouth tends to become deposited in the pharynx and never reaches the lungs.

In developing Exubera, Pfizer and Aventis have collaborated with Nektar Therapeutics (formerly Inhale Therapeutics), a company that specialises in finding delivery solutions for oral, injectable and pulmonary drug administration. Exubera is a rapid-acting, fine dry-powder insulin which was developed using Nektar Therapeutics proprietary inhalation technology.

Apart from the benefit of needless administration, inhaled insulin enters the bloodstream more rapidly than by subcutaneous injection. This is likely to be especially beneficial when administering insulin just before meals and may aid treatment compliance.

Clinical trials suggest Exubera is effective

Over 2,000 patients have so far received Exubera in clinical trials worldwide, some for as long as five years. Results from the phase III clinical trials suggest that Exubera may be as effective as injected insulin and superior to oral agents in lowering blood glucose in patients with diabetes.

A phase III study involving 328 patients with type 1 diabetes, for example, showed that patients using Exubera before meals plus two daily insulin injections had glycaemic control comparable to patients on four insulin injections.

Compared with patients who received only insulin injections, patients receiving Exubera experienced significant reductions in both fasting plasma glucose levels (blood glucose measured before breakfast) and two-hour post-prandial glucose levels (blood glucose measured after meals). Patients also preferred using Exubera, were more satisfied with their overall treatment and showed greater improvements in symptoms and cognitive function (assessed by the Diabetes Quality of Life and Treatment Satisfaction questionnaire).

While Exubera appears efficacious, concerns have been raised about the safety of inhaled preparations and whether Exubera will compromise lung capacity or damage lung tissue in long-term use.

In the clinical trials the frequency and nature of adverse events were similar in the Exubera and control groups. However, mild to moderate cough occurred more frequently in Exubera-treated patients, which disappeared with increased exposure.

A small non-progressive difference in pulmonary function tests, but without clinical manifestation, was also observed between a limited group of Exubera and control patients. Additional studies are being conducted to address this safety concern and determine Exubera’s long-term pulmonary safety profile.

Marketing commentary

Diabetes is rapidly reaching epidemic proportions, affecting 150 million people worldwide and projected to double in prevalence by 2025. Since many cases go undiagnosed these figures are likely to be an underestimate of the true prevalence. Left uncontrolled, diabetes can lead to coronary heart disease, kidney failure, blindness, limb amputations and premature death. Compliance with insulin therapy is important in preventing the adverse clinical effects of the disease.

Exubera was described as a patient-friendly agent that was thought to be especially welcome to type 2 diabetic patients who are new to insulin therapy and reluctant to use injectable insulin. Among type 1 patients with diabetes, Exubera was seen as providing welcome relief from the need to give daily, meal-time insulin injections. However, these patients still needed injectable long-acting insulin therapy. It remains to be seen if patients will prove receptive to other non-injectable insulins once they become available.