Nektar
Therapeutics (formerly Inhale Therapeutic Systems) has developed a pulmonary drug delivery system for
insulin [HMR 4006,
Exubera]. The rationale behind developing a pulmonary drug delivery system is to ensure that
insulin powder is delivered deep into the lungs, where it is easily absorbed into the bloodstream, in a hand-held
inhalation device. The device converts the
insulin powder particles into an
aerosol cloud for the patient to inhale. No propellants are used. The
inhaler requires no
power source and the clear chamber ensures that the patient knows immediately when all the
insulin has been inhaled. Nektar
Therapeutics, developers of the
inhalation device and formulation process, has licensed the system to Pfizer. Under the terms of the agreement, Pfizer will lead the clinical development of inhaled
insulin, while working with Nektar
Therapeutics to develop the technology required for packaging the product. Pfizer has an agreement with Hoechst Marion Roussel (now Aventis Pharma) for developing, manufacturing and promoting inhaled
insulin. Under the terms of the collaboration, Aventis Pharma will supply recombinant
insulin to Nektar
Therapeutics to process it into dry
powder for incorporation into the
inhaler device. Nektar
Therapeutics will receive royalties on sales of inhaled
insulin marketed by Pfizer and Aventis Pharma, and milestone payments and research support from Pfizer. Aventis Pharma's codename for the product is HMR 4006.
Profil, a CRO in Germany, is cooperating with Pfizer/Aventis Pharma in the development of inhaled
insulin. In March 2004, Pfizer and Aventis announced that the European Medicines Evaluation Agency (EMEA) accepted the filing of the MAA for inhaled
insulin (
Exubera) for the treatment of type 1 and
type 2 diabetes mellitus. The two companies are working with the US FDA to determine the timing for the submission of the NDA in the US. Pfizer completed five pivotal phase III clinical trials with inhaled
insulin in patients with type 1 and
type 2 diabetes mellitus in 120 centres worldwide, and will use a fourth prototype
inhaler device that is half the size of the first prototype, and has reduced manufacturing costs. Pfizer and its partner, Aventis Pharma, are conducting additional long-term pulmonary safety data studies in patients with type 1 and
type 2 diabetes. Pfizer is also conducting phase III clinical trials with inhaled
insulin in paediatric patients aged 6-17 years. Nektar
Therapeutics is using its Advanced PEGylation technology to develop a dry
powder-inhaled
polyethylene glycol (PEG) formulation for delivering
peptides efficiently across the lungs and to promote prolonged serum concentration of the
peptide. PEG is a neutral, water-soluble, nontoxic
polymer comprising any number of repeating units of
ethylene oxide. PEGylation is designed to increase the size of the active molecule and ultimately improve
drug performance by optimising pharmacokinetics, increasing bioavailability, and decreasing immunogenicity and dosing frequency. The investigation has begun with inhaled, long-acting (
PEGylated) insulin [inhaled
PEG-insulin,
PEGylated insulin--Nektar], and is funded by Pfizer. Preclinical results of a dry
powder formulation of inhaled
PEG-insulin presented at the 63rd Scientific Sessions of the American Diabetes Association (ADA-2003) [June 2003, New Orleans, LA, USA] demonstrated prolonged systemic activity of
insulin in dogs. Nektar
Therapeutics was granted US patent 5,997,848 on a method for delivering inhalable
insulin. The patent covers a method for delivering of 0.5-15 mg of
aerosol dry
powder insulin per dosing session in 1-4 individual dosages into the deep lung for systemic absorption. The patent does not specify the formulation of
insulin or
aerosol delivery device. Nektar
Therapeutics estimated in June 2002 that
Exubera could earn the company potential revenues of >200 million US dollars.