The quest continues

Although Pfizer abandoned Exubera, and Novo Nordisk discontinued its development of AERx, respiratory delivery of biological therapies is still a live prospect. "The possibility of commercializing inhalation of long-acting insulin or combinations of long- and short-acting insulin exists," says Dalby. He adds that Exubera benefited from "a well-funded and sustained research effort that has allowed us to learn more about the strengths and weakness of inhaled biomolecules." Dalby notes that Pfizer's experience opens the door for manufacturers to develop respiratory delivery of other biologicals, particularly those with a wide therapeutic index.

Pfizer itself has apparently not abandoned its quest for inhaled insulin. In Feb. 2008, Reuters reported that Pfizer would invest EUR 130 million ($189 million) to build a facility that formulates and manufactures inhaled drugs. Pfizer chose to construct the unit at its Amboise, France, production plant.

Nektar is working on improvements to Exubera. The company simplified its insulin formulation by removing some excipients, Patton remarks. The new formulation can be delivered by a device "that you can hide in the palm of your hand," he says. Unlike the old device, the new inhaler is breath-activated. It "has a trigger that won't release air until you've achieved a certain pressure," Patton explains. He adds that the new device is less complicated and provides simpler dosing than the old device.

After discontinuing development of its fast-acting AERx medicine, Novo Nordisk decided to refocus its inhaled-insulin program. In a Jan. 14, 2008 press release, Lars Rebien Sørensen, the company's president and CEO, said, "We have concluded that fast-acting inhaled insulin in the form it is known today is unlikely to offer significant clinical or convenience benefits over injections of modern insulin."

The company announced it would increase its research and development activities to create inhalation systems for long-acting formulations of insulin and glucagon-like peptide-1 (GLP-1), which increases insulin secretion from the pancreas. An inhaled, long-acting insulin would eliminate the need for injections, which Exubera failed to do.

BioSante is pursuing the same goal as Novo Nordisk. Simes says BioSante has developed formulations for the delivery of long-acting proteins into the lungs. The company cooperated with the University of North Carolina on its "CaP" project to prolong the delivery and biologic effect of insulin (as the model protein) into the lungs. BioSante is now looking for a development partner for insulin as well as other proteins.

"The CaP approach uses calcium phosphate particles as the delivery system for insulin and other proteins," according to Simes. He thinks the approach has potential for controlled drug release. The technique would be easy to administer, compared with injections, and most likely acceptable to prescribers and patients, according to BioSante.

The CaP protein system can be delivered as a powder, which would enable the use of an inhaler. In contrast to Exubera, Simes explains, "CaP should result in better bioavailability, less frequent dosing, and a lower amount of protein per dose."

Alfred Mann, CEO of MannKind (Valencia, CA), expresses confidence that his company's "Technosphere Insulin" will succeed. Technosphere Insulin is a microparticle powder made from fumaryl diketopiperazine and insulin. A patient loads a powder-filled cartridge into the device and inhales to obtain a dose of insulin. The powder particles have an average diameter of 2 μm and a highly porous surface topography. The particles penetrate deep into the lungs. When they contact the lung surface, they instantly dissolve and release the insulin molecules in a monomer form. Technosphere Insulin is the only inhaled insulin that contains insulin monomer, the form that can readily be used by the body, according to MannKind.

Unlike Exubera, Technosphere Insulin has advantages over rapid-acting insulin analogs, MannKind says. The benefits include a reduction in postprandial glucose excursions, comparable levels of glucose control compared with HbA1c (which is considered the standard measure of a diabetes drug's effectiveness), and a lower risk of hypoglycemia.