Monash University and Seaport Therapeutics have developed a new approach to delivering drug molecules that piggybacks onto natural fat absorption pathways to allow oral delivery of some drugs previously requiring injection.
The research, published today in Science Translational Medicine, describes the first clinical evidence that a fat, or lipid, modified version of the naturally occurring neurosteroid allopregnanolone (GlyphAllo™) can result in high enough levels of the substance in the human bloodstream to be potentially effective.
The endogenous neurosteroid allopregnanolone is a well-established molecule known for its clinically validated antidepressant, anti-anxiety and sleep-promoting effects – but to this point had to be given by IV infusion.
This study provides the first evidence that chemically linking a drug to dietary fat can re-route drug absorption pathways in humans and shows oral administration of Seaport’s GlyphAllo is able to effectively blunt the human stress response in a human clinical trial – significantly lowering salivary cortisol levels compared to a placebo.
Senior author, Professor Christopher Porter, Director of the Monash Institute of Pharmaceutical Sciences (MIPS) and leader of the team at MIPS that initially developed the Glyph™ platform, which is now exclusively licensed to Seaport, said the findings represent a major step forward for oral drug delivery.
“For many years, the therapeutic potential of allopregnanolone has been restricted by the need to administer as a long 60-hour intravenous infusion, but this technology finally unlocks its potential as an accessible daily treatment,” Professor Porter said.
Oral delivery of allopregnanolone has been limited by a process called first pass metabolism, where the liver breaks down the drug as it is transported through the blood stream from the gut to the general circulation.
“The liver acts in many ways like a master security guard for the body, assessing anything that enters from the gut. Some drugs are let through, but for others, like allopregnanolone, the liver breaks them down before they can ever reach the brain,” Professor Porter said.
To bypass this, researchers chemically attached the drug to a fat molecule. The gut then registers the medicine as dietary fat like oil or butter, rerouting it away from the liver’s security checkpoint and instead transporting it through the gut’s lymphatic system, allowing the medication to empty directly into the bloodstream.
Scientists also engineered a specialised chemical bridge to hold the drug and fat together, carefully balancing the right properties so that the drug molecules remained stable in the gut fluids, but ultimately released once in the bloodstream.
“The lymphatic system is a remarkably efficient conduit for absorbing and transporting dietary fats. By altering drugs to mimic these materials, we effectively trick the digestive system into treating the drug like a key nutrient, allowing it to skirt the metabolic processes in the liver and enter the bloodstream through a back door,” Professor Porter said.
Translation of these findings into humans was confirmed in Phase 1 and Phase 2a clinical trials, which demonstrated dose-dependent, therapeutically relevant allopregnanolone levels and pharmacodynamic effects in healthy volunteers. In Phase 1, GlyphAllo was generally well tolerated following single and multiple-ascending oral doses ranging from 70–1000 mg and provided therapeutically relevant plasma exposures of allopregnanolone.
In the Phase 2a initial proof-of-concept trial using the Trier Social Stress Test, a validated clinical model of anxiety, a single 375 mg dose of GlyphAllo significantly reduced levels of salivary cortisol versus placebo (p=0.0001), demonstrating that GlyphAllo can potently blunt the acute physiological stress response.
The results have also positioned the drug as a compelling candidate to treat major depressive disorder (MDD). A global, randomised, double blind, placebo-controlled Phase 2b trial, called BUOY-1, was launched in July last year which is currently evaluating GlyphAllo in adults living with MDD, with or without anxious distress.
Dr Michael Chen, Co-Founder and Chief Scientific Officer at Seaport Therapeutics, and senior author of the paper added: “Importantly, these findings also further validate the broad compatibility of the Glyph platform to transform promising small molecules with pharmacokinetic limitations into prodrugs with the right properties to address those challenges with potential applications extending beyond neuropsychiatry into oncology, immunology and inflammation, metabolic disease, and obesity.”
The research team at Monash was led by Professor Chris Porter with co-authors Professor Natalie Trevaskis, Dr Sifei Han, Dr Luojuan Hu, Dr Nathania Leong, Dr Garima Sharma, and Dr Dan Zheng from the Drug Delivery, Disposition and Dynamics Theme at MIPS in collaboration with Seaport Therapeutics’ Dr Jamie Simpson, and co-authors Dr Daniel Bonner, Dr Steven Paul, Dr Michael Chen, and Dr Tim Quach.
Read the research paper: doi.org/10.1126
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