Glyph Technology Platform

Lymphatic-targeting chemistry platform leveraging the body's natural lipid absorption and transport process to orally administer drugs via the lymphatic system

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Lymphatic-targeting chemistry platform leveraging the body's natural lipid absorption and transport process to orally administer drugs via the lymphatic system

We are advancing a synthetic lymphatic-targeting chemistry platform called Glyph, which is designed to employ the lymphatic system’s natural lipid absorption and transport process. We have now generated seven programs based on our Glyph platform including LYT-300, LYT-310 and LYT-320. Consumed nutrients and most orally administered pharmaceuticals are initially absorbed by the small intestine mucosa, distributed to the liver by the portal vein before entering systemic circulation. Importantly, many consumed dietary lipids, particularly triglycerides, enter systemic circulation by an alternate route. Triglycerides, which are composed of three fatty acid chains tethered to a 3-carbon glycerol molecule, are absorbed by small intestine mucosal enterocytes where they are incorporated into large lipid-protein complexes (chylomicrons) and released into the submucosa. Chylomicrons are too large to enter blood vessels and are instead taken up by submucosal lymphatic vessels. Once in the lymphatic vessels, they are transported to mesenteric lymph nodes associated with the gastrointestinal (GI) tract where they pass into larger lymphatic vessels connected to the thoracic duct, then merge with systemic circulation. This is in contrast to conventional systemic circulation via the gut and liver.

Our proprietary Glyph technology platform takes advantage of the fact that one of the triglyceride-associated fatty acids remains bound to dietary lipids during intestinal absorption, chylomicron conversion, lymphatic vessel uptake and eventual transport into the circulatory system. Using a modular set of proprietary chemical entities, small molecule pharmaceutical compounds can be attached to triglycerides where, following oral administration, the small molecule is directed into the mesenteric lymphatic system and on to systemic circulation. The process of drug release from the triglyceride is governed by self-cleaving chemical structures, with different release-timing features, that tether the small molecule to the module connected to the triglyceride.

Key Points of Innovation & Differentiation
- We believe this platform provides the following capabilities:
  - Targeting the mesenteric lymphatics: This lymphatic targeting technology has important features that offer potential advantages in the creation of orally-administered medicines, especially those that need to reach immune system drug targets present in the GI tract mucosa and submucosa, such as intestine-associated immune cells, or in the mesenteric lymphatic vasculature, such as circulating immune cells, and mesenteric lymph nodes, such as lymph node stromal cells, antigen-presenting cells and lymph node-associated immune cells.
  - Enabling and enhancing oral bioavailability by bypassing first-pass metabolism: We believe this technology could provide a broadly applicable modular means to potentially enable oral administration of a range of bio-active natural molecules, such as neurosteroids, cannabinoids, and a large number of parenterally administered drugs, that are otherwise not orally bioavailable. This technology also has the potential to significantly enhance the bioavailability of orally-administered drugs that suffer from substantial first-pass hepatic metabolism, especially those utilized in combination therapies, that act as modulators (inducers and/or inhibitors) of drug-metabolizing systems in the liver.
- To demonstrate the utility of our Glyph lipid prodrug platform, we chose a natural bio-active neurosteroid allopregnanolone as the subject of our inquiry, which has resulted in the LYT-300 program (see here). However, we believe that this benefit has the potential to be widely applied to nearly any natural molecules or therapeutic compatible with the synthetic approach which suffers from hepatic first-pass metabolism as has been evaluated by us and our collaborators.
Program Discovery Process by the PureTech Team
- We sought out different approaches that could selectively traffic therapeutic molecules through the lymphatic system to target immune cells in the lymph nodes. Based on insights gained internally and via unpublished findings through our network of collaborators, we became aware of certain technology being developed at Monash University that had the potential to selectively target the lymphatic system. We obtained an exclusive license to this technology and the related intellectual property from Monash University. We have since further developed the platform and have generated our own intellectual property associated with the Glyph technology platform.
- We have developed an oral lipid prodrug of natural allopregnanolone, LYT-300 (see here), which is our most advanced therapeutic candidate derived from our Glyph platform in development for the treatment of both neuropsychiatric & rare central nervous system (CNS) conditions.
Milestones Achieved & Development Status
- In June 2022, we achieved proof-of-principle for the Glyph platform in a healthy adult study of LYT-300. This was the first mechanistic proof-of-principle in the clinic for the Glyph lymphatic targeting platform.
  - Data from this Phase 1 program of LYT-300 showed bioavailability of allopregnanolone that was approximately nine-fold greater than that of orally administered allopregnanolone, based on previously published data.¹ In the study, fasted healthy adults were given LYT-300 containing the equivalent of 53 mg of allopregnanolone, achieving plasma exposure levels with an AUCinf of 352 ng*hr/mL. This represents a nine-fold increase in dose-adjusted exposure when compared to a previously published study in fasted healthy adults in which 30 mg of allopregnanolone was orally dosed, resulting in an AUCinf of 21 ng*hr/mL.¹
  - The multi-part Phase 1 program of LYT-300 has three primary objectives – to demonstrate oral bioavailability, evaluate safety and tolerability across a range of doses, and to inform dose selection moving forward.
- In December 2023, we announced the nomination of a new therapeutic candidate powered by the Glyph platform, LYT-320, which is a novel prodrug of agomelatine in development for the treatment of anxiety and mood disorders
- In April 2022, the U.S. Patent Office granted two patents covering our Glyph technology platform. One patent is directed to Glyph and broadly covers lipid chemistries used in our prodrug compounds with a patent term that extends to September 2037. A second patent was issued and covers a variety of prodrug chemistries exemplified with the immunosuppressant mycophenolic acid with a patent term that extends to December 2038.
- In September 2021, preclinical proof-of-concept research was published in Nature Metabolism, which provides further support for the therapeutic potential of our Glyph technology platform². The study showed for the first time that restoring normal function of the mesenteric lymphatics may reverse insulin resistance and modify obesity-associated metabolic disease. The study also found that inhibition of COX-2 and VEGF-C signaling within the mesenteric lymphatics resulted in a repatterning of the lymphatic vasculature, which in turn led to reduced branching and significantly less leakage of lymphatic fluids rich in lipids and pro-inflammatory mediators. Targeted inhibition of COX-2 function with a celecoxib prodrug developed using our lymphatic targeting Glyph technology platform led to a normalization of multiple biomarkers, including VEGF-C concentrations specifically within mesenteric lymph and surrounding adipose tissue, and to levels observed in control animals that were not fed a high-fat diet. This correlated with reduced lymphatic vessel branching and leakage as well as restoration of glycemic control, and weight gain was blocked in the animals fed a high-fat diet. In fact, targeted administration of the celecoxib Glyph prodrug led to a 10-fold greater uptake of celecoxib in mesenteric lymph and more effective restoration of lymphatic function and glycemic control compared to the administration of unmodified celecoxib, which is commercially available.
- In February 2021, preclinical proof-of-concept for our Glyph technology platform was published in the Journal of Controlled Release³. The additional results highlighted in the publication support the ability of the platform to target administration of drugs such as mycophenolic acid (MPA), an immunosuppressant, into lymph and directly into gut-draining mesenteric lymph nodes (MLNs). As a key nexus of immune cell trafficking, MLNs play major roles in the pathophysiology of a range of conditions including inflammatory and autoimmune diseases, cancer and metabolic diseases. As published, oral administration of a Glyph-based prodrug of MPA (Glyph-MPA) resulted in a >80-fold increase in uptake of total MPA into the lymphatic system and a >20-fold increase in MPA concentrations in MLNs relative to what was achieved with oral dosing of free MPA. Furthermore, MPA administered orally as Glyph-MPA was significantly more potent than free MPA in inhibiting T cell proliferation in mice challenged with antigen. Plasma levels were similar with Glyph-MPA and MPA, indicating low potential for the emergence of new systemic side effects. Additionally, a prodrug of a fluorescent tracer was shown to rapidly accumulate in MLNs following administration. Together, these findings provide further support of the potential of our Glyph technology for oral administration of small molecule drugs directly to the lymphatic system, including drugs with immunomodulatory properties.
- In April 2022, preclinical proof-of-concept research was published in Frontiers in Pharmacology, which demonstrated our Glyph platform can enhance the oral bioavailability of buprenorphine, a clinically-validated opioid replacement therapy, further expanding the range of clinically-validated drug classes shown to be amendable to the Glyph technology.
- We have successfully extended our lymphatic targeting platform to encompass more than 20 molecules as well as a range of novel linker chemistries that have demonstrated promising lymphatic targeting in preclinical studies. We expect to select therapeutic candidates from this and ongoing discovery work.
- In April 2019, we announced an alliance with Boehringer Ingelheim, which is initially focused on evaluating the feasibility of applying our Glyph technology platform to one of its immuno-oncology therapeutic candidates⁴.
Intellectual Property
- We have broad intellectual property coverage for our proprietary Glyph technology platform, which includes exclusively licensed and co-owned patent applications, as well as company-owned patent applications. These patent applications cover compositions of matter, methods of use and methods of treatment encompassing specific chemical modifications, including a wide range of novel linker chemistries, as well as various classes of lymphatic targeting therapeutics, which include prodrugs for a large number of APIs, for use in the treatment of a wide range of diseases and disorders. The most advanced of these is LYT-300, which is an oral form of FDA-approved allopregnanolone, a natural neurosteroid, that we believe may be applicable to a range of neurological conditions.
- As of December 31, 2021, our Glyph technology platform intellectual property portfolio consists of 17 patent families comprising 19 U.S. patent applications, 20 foreign patent applications and three foreign patents. Of these, company-owned intellectual property consists of nine U.S. patent applications in nine patent families. We exclusively licensed and co-own a patent portfolio of eight patent families comprising 33 U.S. and foreign patent applications and three foreign patents from Monash University. Any patents to issue from the in-licensed patent applications are expected to expire in 2035-2036 and any issued patents from the co-owned and company-owned patent applications are expected to expire in 2038-2042, exclusive of possible patent term adjustments or extensions or other forms of exclusivity.

¹ Brexanolone NDA 211371 Multi-disciplinary Review and Evaluation, FDA CDER, 2018.

² Cao, E., Watt, M.J., Nowell, C.J. et al. Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity. Nat Metab 3, 1175–1188 (2021). https://doi.org/10.1038/s42255-021-00457-w

³ Kochappan, R., Cao, E., Han, S., Hu, L., Quach, T., Senyschyn, D., Ferreira, V. I., Lee, G., Leong, N., Sharma, G., Lim, S. F., Nowell, C. J., Chen, Z., von Andrian, U. H., Bonner, D., Mintern, J. D., Simpson, J. S., Trevaskis, N. L., & Porter, C. J. H. (2021). Targeted delivery of mycophenolic acid to the mesenteric lymph node using a triglyceride mimetic prodrug approach enhances gut-specific immunomodulation in mice. Journal of Controlled Release, 332, 636–651. https://doi.org/10.1016/j.jconrel.2021.02.008

⁴ PureTech retains rights to all other applications of this technology outside of the specific Boehringer Ingelheim candidates being studied.