Development of a Unique Crosslinked Glycosaminoglycan for Soft Tissue Repair: Treatment of Interstitial Cystitis/Bladder Pain Syndrome

There are only two approved treatments for Interstitial Cystitis/Bladder Pain Syndrome (IC/PBS) in the US, with the last approval nearly 30 years ago. There are several reasons for this situation. First, the etiology remains elusive; no traditional drug targets have been identified. Second, the diagnosis is one of exclusion based on clinical symptoms with overlap to other conditions. Lastly, the population is heterogeneous and may contain patients who are a priori non-responders to targeted therapies.

The normal barrier function of the urothelium is compromised in the majority of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) patients. The permeability barrier is complex, and the first line of defense seems to be a layer of glycosaminoglycans carried on proteoglycans. The relative contributions of the GAG layer, the hydrophobic uroplakins on the bladder surface and the tight junctions are unclear, but digestion of this GAG layer alone with Chondroitinase enzymes (and other agents) leads to significantly increased permeability of the urothelium in animal models. Intra-vesical replenishment of the GAG layer with instillations of chondroitin sulfate (CS) and/or hyaluronan (HA) have been used clinically outside the United States, but with less success than might be expected from preclinical models.

Chondroitin sulfate is a linear polymer of limited molecular weight (MW), whereas the natural GAG layer is very large and three dimensional. These relatively small linear polymers may not adhere to the damaged bladder surface long enough to maintain impermeability between treatments. Based on these hypotheses, we sought to optimize CS by synthesizing a cross-linked CS that would produce a deeper 3-dimensional structure. In an earlier paper, we showed that in animal models of permeabilized bladder, although these SuperGAGs and CS both restored the permeable rat bladder to normal impermeability, the crosslinked polymer maintained normal impermeability longer than CS and was more effective than CS in abrogating a pelvic pain response.

Optimization in an animal model of the disease led to a polymer denoted as GLX-100. This paper describes efficacy in the animal model and describes the synthesis of other useful CS derivatives. Biotinylated derivatives show that the GLX-100 is retained on the bladder surface for much longer than CS. GLX-100 has also passed standard preclinical safety criteria needed to initiate a clinical trial.

Glycologix recently completed an open label, first in human Phase I clinical trial of GLX-100 in Australia, and the results will be presented at a podium session of the upcoming American Urological Association (UA) Annual Meeting in April 2025. Based on the promising Phase 1 safety and efficacy data, the company is currently planning a multi-center Phase 2 GLX-100 clinical trial in the USA.

Written by: Richard W. Heidebrecht Jr.,¹ Thomas H. Jozefiak,¹ Harrison C. Shain,¹ Eugene M. Skrabut,¹ Debra Saunders,² Nataliya Smith,² Rheal A. Towner,^2,3 Robert Hurst¹

Glycologix, Inc., Beverly, Massachusetts, United States of America.
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada.

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