Pharma & drug development

Waiting to inhale

When it comes to drug delivery, inhalation technologies have long proven a fertile ground of research. But with the conspicuous failure of inhalable insulin in 2007, some of the industry’s more ambitious projects may appear to have been canned. We ask Dr Andy Clark, chief technology officer at Novartis, what the latest developments mean for respiratory disorders and systemic delivery.

It seemed like the holy grail of diabetes treatment: an inhalable insulin product that would eliminate the need for multiple daily injections. Developed by Nektar Therapeutics, and guided to market by Pfizer, Exubera was launched in 2006 and attracted all the buzz expected of an industry first.

The forecasts were jubilant: Exubera would spawn a generation of copycat products, and draw in $2 billion a year in sales. Most excitingly, this would be the first time in the 85-year history of insulin that needles were rendered redundant.

Thus it came as a blow when, little more than a year later, Exubera was pulled. Amid quibbles at the price and disgruntlement at its bulkiness, there were also some more serious concerns – a perceived risk of lung problems, for example, plus confusions about appropriate dosage. The product had failed to live up to its market potential. As the hype subsided, a raft of similar products in development were quietly shelved.

“At the time, here were a lot of people interested in inhaling proteins and peptides, because it’s so much more convenient than injection,” explains Dr Andy Clark, site head and chief technology officer at Novartis’ San Carlo site. “But when Exubera went south, a lot of that potential evaporated with it. People were worried about safety, so the development time frame and costs went up.”

Inhalation innovation

Particularly in the context of the recession, pulmonary insulin looked set to be confined to history. But five years later, with research still ongoing, there shouldn’t be in any rush to write it off. After all, inhalation technologies have long proven a magnet for innovation.

Novartis’ San Carlo site (formerly Nektar therapeutics and acquired four years ago by Novartis) is one of the dominant players in the field. “We’ve got a site of about 250 people focused on pulmonary product development and commercial manufacture,” says Clark. “What we do is develop some fairly novel delivery and formulation technologies for respiratory medicine.”

Of the conditions being researched in the industry, the most obvious is surely asthma. For many years the mainstay of the industry, asthma has steadily increased in prevalence since the 1970s and now affects some 300 million people worldwide. Chronic obstructive pulmonary disease (COPD), associated with smoking damage, is also on the rise.

Smaller but equally important markets include the likes of pulmonary hypertension, idiopathic pulmonary fibrosis and cystic fibrosis. While these conditions cannot be cured, inhalation technologies can prove highly beneficial within the framework of palliative care.

“One of the main causes of death in cystic fibrosis is pulmonary complications, so there’s a focus on treating this part of the disease,” explains Clark. “There’s a great protein molecule, Pulmozyme, that I worked on that helps to clear mucus, and there are a number of antibiotic products delivered directly into the lungs.”

On target

With pulmonary disorders such as these, the case for using inhalers is self-evident. Because the lungs themselves are the locus of the problem, it makes sense to target them directly. This way, the patient can inhale a relatively high dose of the API, while minimising the side effects they would suffer with systemic delivery.

“If you were to take a drug systemically, about 5–10% of that drug would make it into the lung tissue,” says Clark. “But if you put it into the lungs, it all makes it there before it can go anywhere else in the body.”

The real challenge has less to do with targeting the appropriate area, and more to do with entering the lung at all. Inject a drug and it enters the body directly. Inhale that drug, however, and you are forced to bypass the body’s aerodynamic defences before the drug can be deposited in the lung.

Since the respiratory tract is lined with ciliated epithelial cells, air has to wend its way down tortuous paths to make it into the lungs. This barrier, evolved over millions of years precisely to prevent the intrusion of larger particles, is essential when it comes to the purity of what is breathed. Less fortuitously, it complicates drug inhalation. To avoid impaction in the oropharyngeal cavity, the particles need to be very small (less than a few microns in diameter).

“There’s quite a mishmash of formulation and device technologies out there, but the overarching principle is the same,” says Clark. “They’re all trying to make aerosols of less than three microns or so that will succeed in reaching the airways.”

Currently, this device technology comes in three main forms. The oldest is the nebuliser, which disperses atomised liquid medication into the mouth using compressed gas, a high frequency ultrasound or a vibrating mesh. While nebulisers have become smaller and more efficient in recent years, they were originally fairly crude devices, similar in operation to a bicycle pump.

A more sophisticated alternative was introduced in the 1950s. The metered dose inhaler (MDI) delivers a dose of drug suspended in a propellant, and is notable for its ease of use. Where it comes unstuck is in the matter of patient coordination. Because the spray is administered whenever the canister is pressed, the onus is on the user to inhale with perfect synchronicity.

The third key technology, the dry powder inhaler (DPI), eliminates this problem. Contained within a capsule or powder reservoir, the drug is delivered whenever the patient inhales on the device. Unfortunately, its upside is also its downside – some patients lack the respiratory force to attain good lung deposition.

None of these approaches provides a panacea, and there remains significant scope for improvement. The latest developments focus on heightening usability while minimising oral deposition, thus increasing the dose of API that actually reaches the airways.

“There are lots of variants these days,” says Clark. “There is a novel device technology that coordinates the firing of the MDI with the respiratory volumes. There are also novel DPI formulations that make the powder more dispersible and enhance the absorption of the drug. Alexza has a device where it vaporises the drug off a metal plate and it instantly recondenses to make an aerosol the patient can inhale. Then our site developed a formulation technology that makes what we call small porous, or ‘fluffy’ particles – very dispersible powders that will work efficiently even if the patient has a low inspiratory flow rate.”

Reaching potential

With technologies becoming more sophisticated, it is easy to see why researchers would wish to plumb the limits of their potential. The past few decades, in fact, have revolutionised thinking about aerosol delivery. At stake has been a central question: how well do inhalers function when the target is not the lungs but in the bloodstream?

Compared with other modes of delivery, the benefits are clear. Injections are the quickest route into the circulation, but they suffer from poor patient compliance. Pills are discreet and convenient, but risk being metabolised in the gastrointestinal tract or suffering first-pass losses in the liver.

Aerosol delivery, by contrast, provides minimal discomfort and excellent bioavailability. With a surface area of 75m² and a cell barrier of just 0.1mm, the alveolar region is ideally suited to quick and easy absorption of small molecules.

“If it’s a systemic delivery, one of the advantages is speed,” says Clark. “The molecules tend to look like they’ve been administered intravenously, because they’re delivered so rapidly. The lungs don’t really have any first pass metabolism for small molecules, so you get a fairly complete absorption in the systemic circulation.”

Even now, long after the R&D spike of the mid-2000s, there are several interesting products in development. MAP has a molecule, dihydroergotamine (DHE), that can be used to treat migraines, and Alexza is seeking approval for the panic-attack medication Alprazolam. If both products reach the market, they’ll be the first of their kind to be delivered through the airways.

Inhalable insulin is rather more complex, insofar as the lungs contain peptidases and proteases whose job it is to chew up proteins. Just 20–40% of the molecules inhaled will be absorbed into the rest of the body.

Efficient devices are therefore proving elusive, but several particularly determined players are refusing to lose heart.

“John Patton, who is the founder of Inhale, is still convinced in terms of inhaled insulin being a great product idea,” says Clark. “His company Dance Pharmaceuticals is still working on it and MannKind is in there, too.”

MannKind’s key product, Afrezza, has undergone 56 different clinical studies involving 5,300 patients. Despite some setbacks in the developmental pipeline, the researchers are fighting on. The perks are clear: Afrezza becomes effective within 12–14 minutes of inhalation, as compared with 30–60 minutes for injections, and its dry powder inhaler is smaller and less cumbersome than Exubera. The latest trials are due for completion in 2013.

Duration of activity

Elsewhere in the industry, a major point of focus has been increasing drugs’ duration of activity.

“When I first got involved in this industry, the molecules were fairly short-acting, lasting six to eight hours, so you had to administer them four times a day,” explains Clark. “The main push from a molecule perspective has been to try to bring this down to twice, and ultimately once a day. The thinking is that this will improve patient adherence.”

While the guidelines for asthma treatment are well-established, there have been shifts in the COPD arena in terms of which molecules are used at what stage of the disease. Novartis’ new long-acting bronchodilator molecule, Indacaterol, is poised to challenge GlaxoSmithKline’s Advair.

As pharma companies look out for new approaches, it is less about channelling the buzz of the Exubera period and more about resolving the evident challenges.

“We’ve gone through this huge peak of trying to use the lungs as a systemic portal,” says Clark. “As always, in most areas, while some product ideas have survived and are almost at the market, the reality is that a lot of them have got lost along the way.”

Realism, however, does not mean pessimism, and the current research field is no less thriving for being more low key. Inhalers for diabetes may yet prove to be surprisingly close at hand.

Dr Andy Clark

Dr Andy Clark is site head and chief technical officer for Novartis Pharmaceuticals. Prior to his role at Novartis, he was chief technical officer for Nektar Therapeutics from 1996 to 2008. During 1992–96, he led a pulmonary protein delivery group at Genentech in San Francisco. Before moving to the US he was the section head of respiratory physics for Fisons.


This article appears in the Autumn 2012 edition of World Pharmaceutical Frontiers

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