The Resurgence Of Fervor For Oral Delivery

By Tom von Gunden, Chief Editor, Drug Delivery Leader

At the outset of this article, it seems to me that a few seeming oxymorons are in order — formerly “seeming,” that is. Let’s start with these two: oral peptides and oral biologics. The first two, as descriptors of the current state of drug delivery capabilities, would have once been considered implausible, and not all that long ago. For most of drug delivery history, oral routes of administration were thought to be reserved for travel pretty much only by small molecule formulations.

However, the most notable countering example of boundary breaking in today’s delivery world — putting peptides in orally administered formulations for treating metabolic disorders — emboldens me to offer a third oxymoron. This time, it’s in the form of my own humble boast, stated as follows:  I am absolutely confident, in now employing the word seismic to describe it, that  I am not overstating the medical and cultural impact of  the rise in GLP-1s targeting diabetes and, especially, obesity.

But the impact is far from limited to metabolic disorders. Across the landscape of drug and biologics delivery, that volcanic explosion has helped not only to refocus significant attention on oral methods of delivery but also to stir hopes and dreams for the expansion of targetable indications and positive patient outcomes from leveraging those methods.

So, in positioning this article under a renewed spotlight on oral delivery, I will illuminate key challenges, aspirations, and advances I have encountered and explored with industry innovators and thought leaders over the past couple of years, including but well beyond the GLP-1 space. My editorial travels across the oral delivery landscape revealed fascinating efforts at advancing the science and technology, some of them jaw-dropping.

Getting There: Ensuring Arrival At Target Sites

As with any drug delivery route or method, a signficant challenge in oral administration is getting the therapeutic payload to its destination safely and efficiently, with as much bioavailability and as little unwanted toxicity and off-target effects as possible.

In several ways, innovation efforts outline below showed folks acknowledging and/or taking up those challenges via oral delivery.

Avoiding Gastric Pitfalls

One of my first looks was at a capsule/device combination platform in development at Biograil. For an episode of my Supplier Horizons videocast series, I spoke with Founder and CEO Karsten Lindhardt about challenges in delivering biologics, such as peptides, antibodies, and oligonucleotides, orally. Those challenges include degradation of the biologic substance by enzymes in the GI tract and low pH in the stomach.

To increase bioavailability through oral administration, the combination approach at Biograil leverages a microdevice embedded within a longstanding oral delivery vehicle – a dissolvable capsule. In this case, the cargo released when the capsule dissolves is a device that begins its therapy-enabling work upon arrival in the antrum (i.e., bottom) portion of the stomach.

Lindhardt described the device’s mechanism of action in this way: “When that [capsule] is dissolved or weakened enough, there is a trigger mechanism — a spring-loaded trigger mechanism — that triggers an insertion element that inserts into the stomach wall. It’s made of a bio-soluble material that dissolves in the tissue and then distributes the API that's embedded in the soluble insertion part. And that means that you're really getting a very effective distribution out into the general circulation and around the typical barrier there would be for absorption of a biologic drug.”

(For the full coverage of what I consider to be in the realm of “jaw-dropping,” view [and/or read the transcript from] the episode, “Expanding Biologics Delivery Options Via Oral Devices.”)

Preserving And Directing Payloads For Release

In a later conversation, this time for my Sit and Deliver videocast series, I caught up with Founder and CEO Ketan Mehta from pipeline and platform company Tris Pharma. We discussed oral delivery, in both solid dose and liquid dose formulations, of therapies for treating CNS (central nervous system) disorders, including ADHD, pain, and addiction. Among the challenges, or perhaps desires, we discussed were 1) adding flexibility to dosing (i.e., overcoming the limitations of fixed dose forms), and 2) supporting extended release (e.g., two release cycles from a single ingestion).

It was in that context that Mehta described the use of polymer coatings to prepare particles for flexible dosing, including for sustained release. While no scientist, even I could hang in there with Mehta as he described leveraging what he termed ionic chemistry. “You are coating them with the different kinds of polymers, and you achieve the desired release profile,” he explained, before illustrating with this delivery scenario: If you are delivering a liquid in a liquid environment, [the polymer coating] gives them a stable ionic profile. So, you're not releasing the drugs while they're in the bottles. They only start reacting, or rather, releasing the drug once you ingest them.”

I was most intrigued by a platform delivery approach being developed at Tris Pharma that Mehta described as rafting, that is, a payload-carrying “raft” of sorts that floats its way along the desired release route after oral administration. The sample scenario Mehta had me envisioning was a therapy that would otherwise require the administration of a second dose during the night. Yes, a “set the clock for 3 a.m.” kind of nightly experience.

As an alternative, Mehta described an extended, multi-part release occurring as the “raft” descends through the stomach. “So, we combined [the drug] with certain excipients, such that when you take this particular composition, it actually swells, expands, and forms something like a raft,”  he explained. Eventually, the floating results in staged disintegration of the raft.

In a helpful tutorial on how extended release actually works, chemically and physically, Mehta painted this picture of the mechanism of action: “What it is doing is slowly allowing initial release of the drug to be absorbed right in the upper intestine area, where it needs to be absorbed. And as time goes by, it eventually disintegrates and allows the bolus of drug to be administered at the end. So, you get a long duration, and the patient can sleep for the whole night.”

(For my complete conversation with Mehta, see the episode and its transcript, “Increasing Oral Delivery Precision For CNS Targets.”)

Identifying A Barrier-Busting Delivery Method

Given the relatively lengthy anatomical structure of the GI tract, there are a lot of potential stops along the way, post-ingestion, for an orally administered drug product to launch its campaign of therapeutic impact. To identify a particularly efficacious target area for absorption, depending on the indication being targeted, wouldn’t it be helpful to have a map of the landscape? According to Thomas von Erlach, co-founder and CEO at oral platform and pipeline company Vivtex, it sure would.

As I was exploring advances in oral peptide delivery, I spoke with von Erlach about the use of high-throughput screening and computational tools for assessing prime locations for generating maximum therapeutic uptick from oral delivery. We discussed numerous benefits from conducting such assessments, including the potential for avoiding or minimizing common obstacles to efficient oral delivery, including barriers to absorption.

Considering the  GI tract at the tissue level and the mucosal layer on top, von Erlach reflected on the complexity of coordinating delivery within a structure designed as much for prevention as for permeation. “[The GI tract] is a very interesting structure that evolved over many years to essentially enable us to absorb certain chemicals that the body needs, certain nutrients, but avoid harmful chemicals to reach systemic exposure,” he explained, then described an approach intended to outsmart this complex system: “To make sure that we can trick those barriers into absorbing a drug that would otherwise not be absorbed, we need to be able to capture the entire complexity we have in the GI tract.”

To that end, Vivtex is building and using screening tools designed to assess the entirety of the GI tract so as to determine delivery methods most likely to break through the body’s natural defenses. “A big motivation for that has been to be able to make sure that whatever we see in a well plate, in a screening assay, is ultimately going to be possible to be translated into a solid dosage formulation that basically ticks off all the boxes required to be clinically and commercially viable,” von Erlach said.

(We discussed that approach and more, including oral administration timing and adherence, in the videocast episode, “Enabling Oral Delivery Of Biologics.”)

Triggering Precise Therapeutic Responses

With advances in oral delivery precision comes the promise of oral options for addressing unmet needs in rare diseases. Often, those are in the realm of immunology, including conditions for which the therapeutic goal is to suppress or outright prevent unwanted immune responses.

My catch-up with Chief Commercial Officer Wim Souverijns and Chief Technical Operations Officer Stefan Abele from Pharvaris revealed admirable efforts underway to address the rare genetic condition Hereditary Angioedema (HEK). How rare? According to Souverijns, “There are about 7,000 patients in the U.S., about 15,000 in Europe, and, globally, there are probably around 100,000 patients.”

Disabling and potentially life-threatening, HEK causes serious attacks of swelling. Because the onset can be both recurring and unpredictable, Pharvaris is working on two kinds of treatments – one preventative; the other, for on-demand use.

Both are oral and both are delivered in capsule form. As a sufferer of occasional bouts of significant edema (in my case, a lingering side effect of surgery, not a genetic condition), I can certainly envision the attraction of an orally delivered option to reduce swelling, particularly in its most threatening manifestations.

That’s why I was both encouraged and fascinated to discover additional, emerging capabilities for oral administration in immunology. In the case of the approaches in development at Pharvaris, the intent is to suppress excess bradykinin binding to blood vessels and causing the swelling.

The on-demand approach leverages an immediate release capsule formulation; the preventative approach, extended release. As Abele described it, the on-demand version “reaches therapeutic threshold within about 15 to 30 minutes.”  In summarizing findings from Phase 2 studies, Abele stated that the on-demand use provided “symptom relief as well as resolution of symptoms with a single dose for the vast majority of attacks.”

About the preventative use case, Abele described the extended-release approach in this way: “The drug substance is embedded in an acid-stable polymer matrix. It passes the stomach and disintegrates in the gut resulting in a colonic absorption of the drug substance.”  As for the treatment regimen and its effects, Abele stated that the extended release “maintains a sustained therapeutic exposure over 24 hours, allowing for once-daily oral administration to prevent HAE attacks.”

(For the full episode and transcript about the approaches underway at Pharvaris, see “Halting HAE Attacks Via Oral Delivery.”)

Adding ‘Signaling’ As An Action

Back on the metabolic disease beat, I also caught up with Chief Scientific Officer Steffen-Sebastian Bolz from Aphaia Pharma. In the realm of precision targeting, Aphaia is taking what, from my perspective, seems to be a rather unique approach to managing hormones in the treatment of obesity and using oral delivery as the means. As is the case with GLP-1-based treatments currently on the market, it’s a matter of brain signaling. The differences come both in the carrier for oral administration and in the type of payload and its mechanism of action. The carrier is beads; the payload is glucose.

Sounds simple, right? A simple ‘device’ carrying an abundant, naturally occurring substance. Too simple to actually work? Skeptics beware because, according to Bolz, it does, and here’s how:

About the physiology: “The small intestine regulates metabolism and behavior. And this only works because we have cells down there — and this is what we home in on, the so-called L-cells, primarily — that can not only sense food but that also release hormones,” Bolz explained. “And those hormones are actually the agents who travel to those organs in the periphery to change their metabolism — liver, pancreas, and so on, to just name a few —but which are also hardwired to the brain.”

About the carrier: “We use beads — beads smaller than 1 millimeter — because they behave like fluids. They travel just alongside this bolus and get down there. And then we developed a coating, a polymer coating, that opens up exactly what we needed,” Bolz described.

About the payload, its mechanism of action, and the intended effect: “We bring the glucose down there. It triggers the cells. The cells send the endocrines to the hormonal signals and the nervous signals to the brain,” Bolz explained. “And when they do this — when these cells are being activated by glucose — we actually see the normalization of the metabolism. We see normalization of behavior.”

(For my complete conversation with Bolz, see the episode and transcript, “An Orally Delivered Alternative Approach To Obesity.”)

Getting In: Bolstering Bioavailability

Of course, delivering medications and therapies orally and achieving optimum bioavailability while doing so requires overcoming certain challenges that are foundational rather than advanced, as they would be with, say, precision targeting. These foundational challenges include product permeation, solubility, and stability, as well as, and, even more basic than formulation science, challenges related to patients’ ability to consume and process medications via the GI tract.

Promoting Permeability

For the Drug Delivery Leader Live online event, Advanced Oral Delivery: Maximizing Molecules, Targets, And Adherence, I gathered a panel of industry experts to discuss, well, advanced oral delivery. Panelist Eduardo Jule offered reminders and updates about the challenge throughout the history of oral delivery development to increase permeability, a challenge made even more significant with the formulation of  large molecule biologics delivered orally.

Jule began with the example of early attempts at delivering insulin orally and continued into today’s arena of biologics delivery through enteral routes: The common barrier along the way: product breakdown caused by enzymes. “Scientists realized that it was not just the environment. There were enzymes associated to quick degradation of insulin, and this is applicable to other large molecules,” Jule stated. “Of course, the role of proteases [enzyme inhibitors] cannot be neglected. We've come to realize that sometimes you need to add those inhibitors to make sure that you limit to some extent degradation by enzymes.”

His helpful tutorial reminders moved beyond enzyme-inhibiting materials to those designed to actively enhance drug permeability. In the current context of increasingly large molecules, the challenge remains, as Jule noted: “Even when we're talking about insulin, which is a relatively small peptide, talking about a molecular weight of around 6,000, it's not easy to have it permeate across any barrier, whether it's gastric or intestinal,” Jule explained. “So there has to be an adjuvant, a permeation enhancer. And here we have looked into many different options from bile cells to surfactants. And we talk about SNAC [salcaprozate sodium] these days as a permeation enhancer that basically facilitates mucosal motility.”  

While hopeful about efforts underway to address the challenge of large molecule permeation, Jule wove some cautionary realism into his generally optimistic take. “Of course, we need to look into the toxicology aspects, especially when talking about higher doses, when talking about chronic use,” he advised.

(For more from Jule on the current state of large molecule oral delivery, view the Live event segment, “Expanding The Range Of Oral Delivery Capabilities.”)

Supporting Stability And Solubility

Continuing the thematic thread introduced by Jule’s comments on permeation, I asked Live event panelist Jing Ling, a drug discovery and early development scientist at Merck, about formulation considerations related to oral delivery efficacy. In commenting on decisions around a drug product’s viability via oral administration, she emphasized the Target Product Profile (TPP). “It's baked in the TPP profile, starting from early discovery,” she asserted. (Coincidentally and gladly, Ling’s grounding of considerations in the TPP echoed recent commentary from me about its foundational importance in any drug and delivery development program. For that, see my article, “Need A Drug Delivery Conversation Starter? Try Target Product Profile.”)

Ling went on to outline key considerations during early formulation and product development, especially around testing: “One very key component is whether the drug can survive all the GI tract … testing the potential enzyme degradation and pH changes,” she explained. “Can the drug be absorbed in the GI, and can we achieve sufficient exposure to support, for example, the efficacy study, the safety study?”

Ling’s comments reiterated that permeation, solubility, and stability serve as a kind of reigning triumvirate of inputs into ‘go / no-go’ or ‘how to’ decisions. “Once a lead compound or molecular candidate is identified in the discovery phase and moves to more formulation development, there’s need to build a detailed understanding of the property of the molecule,” she offered. “Again, as we are talking about solubility, permeability, and stability solutions, the fundamental question is, ‘Can we formulate the drug as it is? Or, do we need some high tech or enabling technology to help to drive or making the drug druggable for oral delivery?’”

(For Ling’s full take on druggability and deliverability considerations, view the Live event segment, “Determining Formulation Suitability For Oral Drug Delivery.”

Staying There: Aiding Patient Capability And Compliance

Ultimately, the efficacy of any medicine or therapy is, of course, highly dependent upon the ability and willingness of patients to receive their treatments as designed. Can they do it? Will they do it? And with the accuracy, frequency, and timing required?

Pun way intended, answering all those questions can be a mouthful.

Accommodating Oral Administration Limitations

On the capability front, oral administration brings with it some unique challenges for certain patient populations. Over the course of conducting various videocast conversations about oral delivery, I encountered one particularly tricky condition to address: dysphagia.

Dysphagia is described as difficulty or pain in swallowing. It can also include blockage of food and drink further down the GI tract. Obviously, for those suffering from the condition, taking medications by mouth presents significant challenges, if not outright barriers. Common patient profiles are pediatric and geriatric populations, as well as those at any age with a disability or medical condition that brings on or exacerbates dysphagia.

The reality of dysphagia may seem to beg the question, “Why not just move to an alternative route of administration? Injection, for example?” Well, for several reasons — convenience, preference, targeting, mechanism of action, efficacy — oral administration may remain the ideal option, as long as the impact of dysphagia can be minimized or avoided.

Interested in learning what, if any, ways there may be to get around or through the limitations caused by dysphagia without abandoning oral delivery altogether, I spoke with Nathan Givoni, CEO and co-founder of Gelteq. As the company name suggests, Gelteq develops gel-based methods for oral administration.

As Givoni described to me, there are two key concepts involved in the gel technologies in development at Gelteq: texture and release point. About the former, Givoni explained, “There are actually different levels of thickness that patients require to avoid aspirating. People are generally put on those levels based on doctor or speech pathologist recommendations. We had to address the fact that we needed to have texture flexibility.”  

Givoni went on to describe ways in which the formulation and materials in the gel matrix provide flexibility. About the latter key concept — the therapeutic payload release point — Givoni said, “We can also play with the different aspects for the release profile. If it needs to be released higher up or lower down in the gut, that allows us to address the efficacy of the drug.”

(For more from Givoni on patient challenges and the science and technology of addressing them, see the episode and transcript, “Defying Dysphagia Via Gel-Based Delivery.”)

Enabling Patient Adherence

Of course, any treatment regimen administered by patients themselves, as orally delivered medications most commonly are, is highly dependent not only on patients’ physical capabilities but also on their willingness or mental acuity to do so consistently and compliantly.

In “Patient-Centric Considerations For Oral Drug Delivery,” a segment in the aforementioned Live online discussion, panelist Firouz Asgarzadeh mentioned technology that can help with patient adherence and accurate dosing: “If a bottle is opened or if the blister is open, [a device] sends a signal to the hospital or monitoring system to make sure that the patients who are in the clinical trial are taking it,” he explained.

Asgarzadeh went on tp describe additional characteristics of certain patient populations that must be addressed to help bolster oral administration success. Patients with Parkinson’s disease constitute one such group, he noted. “You have the hand that is shaking” he offered, before listing obvious product development considerations in response to that factor: “How you design that drug product, the bottle, the opening, but also even the shape of the drug.”

My memories of taking medicines as a child were brougnt to mind when Asgarzadeh offered reminders about preferences that can present challenges in oral treatmenl compliance in children. “Taste masking is a big and important factor to consider when we design products for children,” he stated. “If we are designing for a child, we have to come up with products that don't cause taste issues, or they don't have bad texture.”

Hearing that, for a brief moment I shuddered inside, recalling the dreaded spoonfuls of this or that foul-tasting liquid dose coming at me from the extended arm of my mother: “Here, take this!” Brrrr! Fortunately, none of what came into view across the landscape of oral delivery surveyed above was anything other than a tasty tidbit of welcomed update or insight.