A stomach-targeted drug delivery system
Oxford Medical Products (OMP) has developed OMPGEL, a novel and innovative hydrogel platform technology that is currently in early clinical trials for weight loss and is being developed as a stomach-targeted drug delivery platform. OMPGEL is taken as a pill and expands rapidly upon reaching the stomach where it remains in situ for several days before breaking down and passing naturally. With the stomach recently identified as an absorption site for macromolecules, OMP will use peptides to demonstrate OMPGEL’s potential as an oral drug delivery system.
OMP is looking for partners with early-stage, large-molecule, anti-obesity assets or small molecules where bioavailability and/or adherence is likely to be an issue. If interested in partnering, please get in touch here.
For many years, the pharmaceutical industry was reticent to invest in research and development (R&D) for weight-loss drugs. This was understandable, given that the anti-obesity drug landscape had been littered with failures that were, at best, moderately efficacious, and coupled with dangerous side effects. Indeed, 25 licensed anti-obesity drugs were withdrawn between 1964 and 2009 due to adverse reactions [1]. Despite these past failures, the substantial efficacy and comparative safety of a new class of anti-obesity drugs has stimulated a pharmaceutical R&D race to access a global market that is estimated to be worth more than $54 billion by 2030 [2].
This new class of peptide drugs, glucagon-like peptide-1 (GLP-1) agonists, were originally developed to treat type 2 diabetes. GLP-1 agonists achieve weight loss through several mechanisms including (1) reducing appetite, (2) slowing stomach emptying, (3) increasing both insulin secretion and insulin sensitivity, and (4) reducing glucagon production. While human GLP-1 has a very short plasma half-life of only 2 minutes, recent GLP-1 drugs developed have half-lives of several days. Consequently, they can exert a continuous, appetite-suppressing effect.
Novo Nordisk and Eli Lilly dominate the GLP-1 and related obesity therapy space. Novo has two drugs approved for weight loss – Wegovy® (semaglutide) and its less effective precursor Saxenda® (liraglutide) – and Lilly expects approval of tirzepatide as an obesity treatment later this year. While Novo and Lilly are initially expected to have a duopoly on the obesity drug market, their positions are expected to be challenged as other Big Pharma and biotech companies launch their own assets that are currently in early clinical development. As newer drugs enter the market, companies will be looking for methods to differentiate their assets from their competitors; one method could be delivery, since all GLP-1 drugs, except semaglutide, are only available as injections.
Oral administration predominates the drug delivery space due to administration ease, formulation flexibility, cost effectiveness, ease of storage and transport, and high patient compliance. However, most macromolecules – including peptides – are currently unsuitable for oral administration due to low oral bioavailability. This low bioavailability arises due to drug degradation prior to absorption and poor absorption across the gastric mucosa.
Permeation enhancers (PEs) have been developed to improve oral bioavailability of macromolecules. Salcaprozate sodium (SNAC) has been the most successful PE to date. SNAC was co-formulated with supplemental vitamin B12 (cyanocobalamin) to develop the oral treatment Eligen™ B12 [3]. While Eligen™ B12 demonstrated SNAC’s potential, it was Novo Nordisk’s successful use of SNAC to deliver the GLP-1 semaglutide orally that really captured the attention of the wider pharmaceutical industry. Oral semaglutide was approved by the FDA in 2019 for diabetes (Rybelsus®) and recent clinical data has demonstrated its effectiveness in weight-loss indications [4].
Clues as to how, mechanistically, SNAC increases oral bioavailability first came from Eligen™ B12. Excess water or food intake with the dosage form resulted in a loss of enhanced uptake, suggesting that the stomach was the absorption site. This was surprising since the stomach had not previously been considered an absorption site due to its small surface area, difficulty in ensuring sufficient residency time, and the potential for degradation. Later studies investigating the mechanism of oral semaglutide absorption provided substantial evidence that peptides co-formulated with SNAC are absorbed within the stomach [5].
While PEs facilitate oral peptide delivery, only very modest increases in oral bioavailability have been observed. Consequently, even if oral delivery is technically feasible, it may be commercially unviable to produce very high quantities of a drug to compensate for its poor bioavailability. Semaglutide’s oral bioavailability is significantly lower (0.4-1%) than when injected (87%). The increased semaglutide requirements are so great that the overall unit cost of the oral formulation is higher than the injectable formulation [6].
Novo has already struggled to supply Wegovy® in the face of exceptional demand. Despite clear benefits to launching an oral version of Wegovy®, its potential launch is partially contingent on “manufacturing capacity” [7] since it has very high semaglutide requirements. Further increasing oral semaglutide’s bioavailability would allow less semaglutide to be used, significantly lowering the cost of goods. While Novo had the resources to make oral semaglutide delivery economically feasible by dramatically scaling-up production [8], most companies lack the financial firepower to invest so heavily in manufacturing. Hence for now, the injectable route is likely to remain the preferred delivery route for companies developing therapeutic peptides.
To improve oral bioavailability of such peptides, three requirements must be fulfilled:
The drug must be stable in the stomach for a prolonged time period.
The drug must be able to be absorbed across the stomach mucosa.
The drug must be retained in the stomach for a sustained time period (at least hours or days).
Oxford Medical Products (OMP) has developed OMPGEL, an oral hydrogel platform technology that is currently in early clinical trials for weight loss and being developed as a stomach-targeted drug delivery platform. OMPGEL expands rapidly upon reaching the stomach where it remains in situ for several days (Figure 1) before breaking down and passing naturally.
Figure 1 – OMPGEL is a hydrogel-based gastroretentive platform technology. (A) OMPGEL is taken as a pill (A) and expands upon reaching the stomach (B). In-human magnetic resonance images (C and D) of OMPGEL expanded in the stomach. Arrows indicate the hydrogels within the stomach (white dashed outline).
With OMPGEL’s confirmed in-human stomach retention, we are now developing a delivery system to improve the oral bioavailability of both small- and large-molecule therapies. We believe that OMPGEL can be used to deliver large molecules, such as semaglutide and SNAC together, to their known absorption site in the stomach. This will increase drug exposure time, minimise dilutive effects and provide an opportunity to improve drug stability in the stomach.
While semaglutide’s stomach absorption makes it an obvious candidate to demonstrate OMPGEL’s potential as a stomach-specific delivery system, there is also the potential to improve semaglutide’s efficacy as a weight-loss treatment. By combining the mechanical weight-loss effects of the OMPGEL device (currently being investigated in clinical trials) with the pharmacological effects of the drug, there may be enhanced weight loss. Recent data from the gastric balloon company Allurion Technologies supports this hypothesis, with patients losing more weight when taking the balloon with Saxenda® (liraglutide), than either therapy alone [9].
Over the coming 12-18 months, OMP will demonstrate OMPGEL’s potential as a stomach-targeted drug delivery system. We are looking for partners with early-stage, large-molecule, anti-obesity assets, as well as companies developing small molecules where bioavailability and/or adherence is likely to be an issue. If interested in partnering, please get in touch here.
References
Onakpoya, I.J., Heneghan, C.J. & Aronson, J.K. Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review. BMC Med 14, 191 (2016). https://doi.org/10.1186/s12916-016-0735-y
https://www.morganstanley.com/ideas/obesity-drugs-investment-opportunity [accessed 31st May 2023]
Castelli MC, Friedman K, Sherry J, Brazzillo K, Genoble L, Bhargava P, Riley MG. Comparing the efficacy and tolerability of a new daily oral vitamin B12 formulation and intermittent intramuscular vitamin B12 in normalizing low cobalamin levels: a randomized, open-label, parallel-group study. Clin Ther. 2011 Mar;33(3):358-371.e2. doi: 10.1016/j.clinthera.2011.03.003. PMID: 21600388.
https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=166110 [accessed 31st May 2023]
Buckley ST, Bækdal TA, Vegge A, Maarbjerg SJ, Pyke C, Ahnfelt-Rønne J, Madsen KG, Schéele SG, Alanentalo T, Kirk RK, Pedersen BL, Skyggebjerg RB, Benie AJ, Strauss HM, Wahlund PO, Bjerregaard S, Farkas E, Fekete C, Søndergaard FL, Borregaard J, Hartoft-Nielsen ML, Knudsen LB. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med. 2018 Nov 14;10(467):eaar7047. doi: 10.1126/scitranslmed.aar7047. PMID: 30429357.
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