Inquiries In Inhalation, Part 1: The Breadth Of Breath

By Tom von Gunden, Chief Editor, Drug Delivery Leader

As would an on-call physician, I have been making my rounds. In my case, the route is not mapped by hallways lined with patient rooms. Rather, my route, a familiar one I often travel, is one of routes of administration for delivering drugs and biologics.

Some recent investigative stops have found me back in the arena of delivery by inhalation, both orally and nasally. I have been especially eager to pause, exhale, and give myself time to look around at greater length and depth at what’s going on in inhalation these days. The impetus for this particular look-see is the trend toward transitioning therapy delivery from IV administration to other forms, including inhalation.

Of most interest to me now that I have begun to take a longer look around is the range of target indications for inhalation delivery. These include those historically addressed via inhalation, as well as any that might now be addressable or perhaps are on the horizon of becoming addressable, with inhalable formulations via oral and nasal routes.

Does or will that range include advanced, biologics-based therapies to the lungs for indications there? Does/will it include going through the lungs for indications beyond respiratory? What about advances in delivering to the nose for indications there? Or, going to/through the nose to reach targeted indications beyond olfactory, e.g., in the brain?

Airing The Hottest Topics In Inhalation Delivery

With that purpose and those questions in mind, as part of my deep dive I gathered a group of inhalation delivery experts, who graciously joined me for a Drug Delivery Leader Live online panel event, Just Breathe: Increasing Efficacy And Expanding Targets With Inhalation Delivery.

Even before the event, as I monitored the interests expressed by registrants during the sign-up process, I was able to confirm questions that echoed my own. These topics were front-of-mind for many in the audience:

• Transforming formerly IV- or injection-only administration to inhalation
  • Enabling non-clinical / at-home administration
• Delivering complex biologics via inhalation
  • Large molecule, high dose / high volume
  • Nebulizing LNPs / mRNA pay[oads
• Pros and cons of inhalation compared to other delivery methods
• Expansion of targets
  • Beyond respiratory (i.e., beyond asthma and COPD)
  • Unmet needs / novel therapies
  • Nasal to the brain
• Particle engineering
• Testing
  • Device design and usability
  • Formulation stability
  • Absorption and bioavailability

Heading into the discussion, I was also interested in determining audience members’ current levels of professional focus on and/or familiarity with inhalation delivery. Was anyone signing up just to “kick the tires,” so to speak? Put another way, what degree of persuasion would be required to move this audience to consider inhalation as a viable drug delivery option, particularly in the context of expanded therapeutic targets?

Well, our poll of the audience at the outset of the event suggested “not much.” When asked if inhalation delivery is, currently, a) their organization’s core competency, b), in the mix of current delivery offerings, or, at least, c) being considered as a delivery method for development, only about 18% of the respondents indicated that d) they were merely exploring and with no current or pressing “need to know.”

Based on those responses, I realized we would be addressing an audience of mostly “converts,” but that, nevertheless, here was an opportunity for all of us — moderator, panel, and audience — to see what boundaries of current thinking could be pushed and in which directions.

Tracing The Evolution Of Inhalation

Before inviting the Live event audience to gaze far out onto the horizon of the new, I asked panelist Nani Kadrichu to bring us up to date by tracing a brief history of inhalation drug delivery. Starting with the ancient world and landing on the present day, she remarkably did so in a segment we later published in video clip format as “A History Of Inhalation Drug Delivery In 8 Minutes.” For those in need of a tutorial or refresher on the historical range of targets for inhaled therapies — the traditional “breadth of breath,” if you will — I highly recommend Nani’s quick take.

As she outlined the milestones along the way, Kadrichu pinpointed 1956 and the emergence of the first MDI (metered dose inhaler), developed for the treatment of asthma, as the start of the modern era. From there, for the next several decades, the landscape of treatment was mostly covered by targeting respiratory and cardiopulmonary indications.

As Kadrichu related all this, I, for one, waited with bated breath (pun intended!) for her to tell us whether and how that “breadth of breath” can be further widened. Sure enough, by describing key characteristics of human physiology that make the lungs and the hose amenable as both therapy landing sites and delivery avenues, she helped frame our subsequent discussion on localized versus systemic treatments: i.e., to or through the lungs or nose.

Expanding Therapeutic Targets: To The Nose (Or Lungs) And Beyond

To illustrate the efficacy of local administration to the lungs, Kadrichu contrasted inhalation with IV- or infusion-based approaches to treating pulmonary arterial hypertension (PAH). “[The IV] works, but it dilates everything systemically and really also needs continuous infusion,” she explained. “But with the inhaled approach, you have vascular access to the entire cardiac output, which flows through the lung at every heartbeat.”

Using the same indication (PAH), Kadrichu also contrasted localized inhalation with systemic oral approaches to delivering steroidal treatments. “Inhalation really delivers small doses directly at the site,” she said. “A microgram of inhaled corticosteroid can outperform a milligram of oral dose because they land on the target site, which is the lung.”

About going through the lungs to target non-respiratory conditions, Kadrichu, while acknowledging technical challenges, underscored the promise of inhalation, even for delivering advanced, biologics-based therapies. “For systemic delivery, inhalation also makes sense because the lung offers 70 to 150 square meters of absorptive surface,” she explained. “And this area is highly profuse with blood, and the barrier is thin. So, it makes sense for systemic delivery for molecules with poor oral bioavailability when first pass metabolism is severe, rapid onset is required, and IV access is impractical. Also, the molecule could be unstable elsewhere. So that's why the [inhalation to the lungs] route is very attractive for delivery of biologics and fragile molecules.”

Kadrichu went on to tout the potential for nasal inhalation to also address difficult-to-treat targets. Most notable are CNS (central nervous system) diseases and disorders, which, from a therapy administration standpoint, have long been daunting because of the blood-brain barrier’s ability to limit, if not outright prevent, delivery. “It [the nose] has a different anatomy than the lungs, of course. The volumes are much smaller,” she explained. “But it can be used to allow treatment for neurological condition drugs via the olfactory and trigeminal routes. You bypass the blood-brain barrier. And then you basically reduce or minimize the systemic side effects and enable the drug to reach the CNS.”

Readying Inhalation Delivery For Biologics

So, we seem to have established that, across the expanding range of indications (respiratory and beyond) addressable via inhalation come opportunities and challenges for delivering increasingly complex, biologics-based therapies to and through the lungs and nose. What, then, are the key factors in supporting inhalation delivery of advanced therapies? Well, as the panel confirmed, it’s a matter of both the science (of drug formulation and of the body itself) and the delivery device technology.

Two of the Live event panelists, Stephen Stein and Geraldine Venthoye, both now consultants/advisors to the industry, had fairly recently joined me for episodes of my Supplier Horizons videocast series on Drug Delivery Leader when each were representing technology provider companies. So, I knew well that they knew well the current state of inhalation device capabilities and related formulation science. (Those episodes remain relevant and worth checking out: you can view Stein’s featured videocast appearance here, Venthoye’s featured appearance here, respectively.)

When I more recently asked panelist Stein about technology readiness to deliver advanced therapies and complex formulations for respiratory indications, he offered reassurance. “The good news is there are some mature delivery systems available for these different applications, whether those be metered dose inhalers, dry powder inhalers, or aqueous systems such as nebulizers or nasal sprays. So, there are well-established delivery systems that you can select from,” Stein confirmed before suggesting initial questions to guide selection of delivery route and device: “The first step is to really look at the specifics of your particular case, the dose size. That's something that you want to start out with. Is it going to be something used chronically or [is it] a one-off treatment? [In] what setting will the delivery occur?” (For the full context of Stein’s comments, see the Live event segment “Advancing Inhalation Delivery For Respiratory Indications.”)

A Boon For Bioavailability

As panelist Venthoye offered insights on the attractiveness of inhalation as an administration route for biologics, she concurred with Kadrichu on the expandable range of inhalation targets and with Stein on the readiness of inhalation device technology. “We're really at the cusp of a transition between being very good at delivering respiratory small molecules to now really opening up to more complex molecules and formulations and the ability to go beyond just respiratory,” Venthoye asserted. “About 40 percent of what we see in pipelines is going to be biologic molecules. Many of those will be immuno-therapeutics and vaccines. But some will be monoclonal antibodies and proteins and peptides that will be used for other, beyond-respiratory indications.”

In illustrating reasons for her enthusiasm, Venthoye pointed to increased bioavailability as among the attributes of biologics delivery via inhalation most likely to yield significant benefits in terms of patient outcomes. “We've got this very large mucosal surface area, which allows us to get good bioavailability for things that would otherwise be broken down or be prone to a very poor side effect profile from other routes of administration,” she explained. “We have the prospect of gene and cell therapy through mucus penetration and cell targeting of mRNA and other oligonucleotide types. So, this is really opening up what we can use the lung and the nose for.” (For Venthoye’s full take on the promise of inhalation for biologics delivery, see the Live event segment “Reaching Systemic Targets Via Oral And Nasal Inhalation.”)

Advancing Inhalation Innovation: What, How, And By Whom?

So, what will it take to move the dial of innovation in order to realize the benefits of inhalation delivery across an expanded range of therapies and targets? Well, high on the list of opportunities to leverage or of problems to solve or of challenges to overcome are aspects of inhalation science and technology related to molecule size, particle engineering, patient access, and device usability. Determining how those aspects will be addressed and by whom points to broader considerations about the contributions and interactions from various entities in the product development and distribution ecosystem.

I will take a deeper dive into all of that in an upcoming companion piece, “Inquiries In Inhalation, Part 2: Having A Nose For Innovation.” Hope you'll join me there.