It shouldn’t be that hard to develop pulmonary administered formulations of pharmaceuticals for the treatment of systemic conditions. For centuries a variety of active agents, notably tobacco, marijuana and opium, have been delivered via the pulmonary route with exceptional efficacy and, one could argue, relatively limited safety and tolerability issues in the absence of prolonged chronic use. Why does the delivery of prescription pharmaceuticals to the lung for systemic effect present such a challenge for the pharmaceutical industry? To use a baseball metaphor, do the well-reported business challenges of Mannkind’s Afrezza represent strike two, or a second out, in the development of meaningful inhaled pharmaceuticals for the treatment of systemic disease?

It’s not a new challenge
The challenges that have faced both Afrezza, and Exubera before it, are to some degree obscured by the too easy assumption that it is strictly a challenge of delivering macromolecules. While insulin, a protein of 51 amino acids and a molecular weight of 5,808 Daltons, is a relatively large molecule, many other products with much smaller molecular weights, easily delivered orally, have failed to gain approval. Among those few that have received approval, none have been widely adopted.

Local delivery for local and locoregional effect
There are dozens of approved pharmaceuticals administered to the lung by a variety of methods and devices. What the majority of these agents have in common is their use to treat local lung related conditions. These conditions range from asthma, to chronic obstructive pulmonary disease (COPD), to infectious disease, to lung cancer. The types of agents delivered by the pulmonary route to treat these conditions range from small molecule bronchodilators, antimuscarinics and steroids to the relatively larger antibiotics and much larger recombinant proteins. Common to these applications is the expectation that these inhaled pharmaceuticals will have only a local, rather than systemic, effect. In fact, any type of systemic exposure is generally looked upon with disfavor, especially with the use of corticosteroids for the management of asthma and COPD.

The pulmonary route is also used for the treatment of certain locoregional conditions impacting the lung and heart, most notably pulmonary hypertension where there is a complex interaction of pulmonary and cardiac dynamics. Delivery via the lung provides for somewhat selective delivery of relatively toxic agents to the heart and lung that would create safety and tolerability issues if delivered orally or intravenously where distribution is much wider and higher doses are required to achieve desired tissue levels in the lung and heart.

Why systemic delivery via the lung?
There are two major reasons underlying the development of inhalation formulations targeting systemic delivery: improved efficacy and convenience. The logic for the improving efficacy concerns the ability to provide a faster onset of action, something comparable to intravenous administration, without a needle. This seems to be the reasoning behind the ongoing and past development of a variety of pulmonary formulations of well-characterized CNS agents, notably fentanyl for the treatment of acute onset pain, and loxapine for agitation. The convenience benefit aims to improve patient acceptance by substituting inhalation for injection. This is certainly a desirable option with the chronic administration of macromolecules where injection, either subcutaneously or intravenously, is the only practical route of effective delivery.

Afrezza, MannKind’s inhaled insulin product, it seems was intended to deliver on both these needs by substituting inhalation for subcutaneous injection. More recently though, Mannkind in their reboot of Afrezza, has been touting the benefits of a more rapid onset of action, realizing perhaps that the simple subcutaneous injection of insulin, even multiple times a day, is not nearly as onerous as it once was.

A rapid onset of action with no need for an injection was also imagined for Alexza’s Adasuve, an inhaled formulation of loxapine intended for the treatment of agitation associated with schizophrenia. Approved in 2012 it has struggled to capture sales, despite having a reasonably elegant and effective delivery system.

A not too surprising relative success of systemic delivery via the lung has been nicotine inhalers. Approved for smoking cessation using a cartridge-based system, these inhalers actually deposit most of the nicotine in the buccal region with less than 5% reaching the lung. Formally pulmonary formulations, these nicotine inhalers might better be considered as buccal delivery systems.

Despite all of the interest and investment in developing inhaled analgesics for the management of breakthrough cancer pain and other acute pain indications, the only approved inhalation product for pain is Penthrox (methoxyflurane), a halogenated ether repurposed for acute pain management. Penthrox is used to treat pain in an acute trauma setting under the supervision of a medical professional using a proprietary inhalation device.

Considering the lack of approved inhalation products for systemic effect it may be that the challenges faced by Exubera and Afrezza are less related to the task of delivering effective doses of a larger molecule to the lung than the challenge of providing a meaningful competitive benefit. Different doesn’t qualify as better.

It should be mentioned that there are also a number of general anesthetic gases administered by the pulmonary route that have a profound systemic effect. These agents, though, are administered using sophisticated in-hospital devices that are unsuited for outpatient use.

Efficacy, safety, convenience and price
It’s possible to estimate the real-world potential of a pharmaceutical by considering its proposed competitive product profile in terms of its ESCP (efficacy, safety, convenience and pricing) attributes. Without efficacy it is unlikely that a product will receive regulatory approval, although products can vary in their degree of efficacy. With an assumption of efficacy, physicians and patients generally pay considerable attention to safety and tolerability. Beyond efficacy and safety, the next level of concern is convenience of administration, including dosing frequency and method of administration. This is where oral, transdermal and even inhaled products have a substantial advantage over injectables in the outpatient setting. Lastly, if all things are equal in terms of efficacy, safety and convenience, the prescribing decision is usually made on the basis of price.
These terms of reference may explain why inhaled pharmaceuticals intended for systemic treatment, especially inhaled insulin, have received little traction with patients, physicians and patients.

• Efficacy: We can safely assume by virtue of regulatory approvals that inhaled insulin is efficacious for the approved indications.
• Safety: While inhaled insulin may be safe by regulatory standards, it seems that physicians do not consistently believe that it is as safe as injectable. There are any number of arguments supporting and questioning the safety and tolerability of inhaled insulin, but any product that is to be administered chronically to the lung needs to have no questions in this area.
• Convenience: This should be an obvious advantage for Afrezza; no needles. But convenience comes at the expense of additional pulmonary testing, prior to starting therapy and then every few months to ensure that lung function is not being compromised. The testing, while not overly complex, is not an office procedure conducted in most general practitioner offices. Patient convenience, no needle, is balanced by physician and patient inconvenience, additional testing. Dosing with Afrezza also requires dose titration that is not simple or obvious with the available dosing packages. At the same, time injected insulin products are increasingly offering more sophisticated pen and delivery devices that reduce the sting, and the fear, of self-injection.
• Pricing: Insulin therapy is not inexpensive and it appears that Exubera at the time, and now Afrezza, are priced at a small premium to the injectables, including the pen formulations.

Adding it all up the balance doesn’t seem to sufficiently favor Afrezza enough to push patients to switch to inhaled insulin, or physicians to prescribe it more often.
A similar analysis can be performed for Alexza’s Adasuve. Although indicated for acute rather than chronic use in the inpatient setting, a higher price and a requirement for patient supervision seem to outweigh any benefit in terms of convenience and injection avoidance.

Pipelines past and pipelines future
So what does past performance mean for the development inhalation pipeline, especially products targeted to systemic and locoregional treatment?

In comparison with marketed products the development pipeline ratios for Local and systemic products (Table 2) pretty much parallel the ratio for Local products, with a somewhat greater emphasis on locoregional-inhaled products. Among registration stage products, the systemic product is a metered dose formulation of dihydroergotamine for migraine. The locoregional product is nebulized nitric oxide for pulmonary hypertension.

Examining the development pipeline in terms of targeted indications, Table 3 reveals that the majority of effort, is targeted to a small number of indications, notably respiratory—asthma, COPD, bronchospasm, and respiratory distress syndrome—and a variety of infectious lung diseases.

Neurological applications top the list of systemic indications in the pipeline and range from migraine to Parkinson’s to epilepsy. There is only a single product identified as being in development for diabetes, Dance-501, last reported as being Phase II testing.

Pulmonary hypertension is the top indication by far for product development using the lung to affect a locoregional therapeutic benefit.

Strike two, two outs or time out?
Do the challenges of inhaled insulin close the door on the opportunity for inhaled macromolecules, or the use of the lung as a portal for the delivery of any systemic acting pharmaceutical? The pipeline data, Table 4, seems to suggest that pulmonary delivery of macromolecules continue to be of significant interest, with almost a quarter of all pipeline products falling into the larger molecular weight class. But, the majority of these products are being developed for Local therapeutic benefit, not locoregional or systemic. Perhaps then the industry is taking a time out to rethink the potential of using the lung for the systemic delivery irrespective of molecular size. There may be better options that carry less risk. 

Given the relative lack of success of Exubera and Afrezza, along with their decade long development timelines and billion dollar costs, it is likely that the pharmaceutical industry is taking a time out to reconsider the opportunity of macromolecule delivery for systemic effect. None of the top selling macromolecules, all delivered in the outpatient setting by self-injection, are seen to be in development for pulmonary delivery. Nonetheless, there continues to be considerable interest in the delivery of macromolecules to the lung, but for local and locoregional applications. It may take the success of future small molecule products providing systemic benefits to lure the industry back to developing macromolecules anything more than local and locoregional applications.

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Tugrul Kararli is president and founder of PharmaCircle. Before founding the firm in 2003 Tugrul’s industry experience included 18 years at Searle/Pharmacia where he was involved with pharmaceutics, product development and drug delivery activities. As chairman of the global drug delivery technology team Dr. Kararli was responsible for the identification, planning and execution of drug delivery technology strategies for marketed and development products.

Kurt Sedo is vice president at PharmaCircle and responsible for product development and client services. Prior to joining PharmaCircle in 2003, Kurt held various positions and responsibilities within pharmaceutical sciences and analytical development departments at Searle/Pharmacia.

Josef Bossart serves as executive editor with PharmaCircle. Jo has decades of experience in the biopharmaceutical industry having held senior sales, marketing, operational and business development positions within Big Pharma and specialty pharma companies. More recently he has focused on analysis and strategy development related to drug delivery companies and products with numerous published articles and conference presentations.