PureTech Meets Milestone of Achieving Oral Bioavailability of Allopregnanolone in Healthy Adults Dosed with LYT-300
PureTech Health plc,a clinical-stage biotherapeutics company dedicated to discovering, developing and commercializing highly differentiated medicines for devastating diseases, announced the achievement of proof-of-principle for its Glyph platform in a healthy adult study of LYT-300 (oral allopregnanolone), PureTech’s wholly-owned therapeutic candidate for the potential treatment of a range of neurological and neuropsychological conditions. This is a key milestone for the candidate, which is designed to overcome the normally poor oral bioavailability of allopregnanolone to deliver its proven efficacy via simple, convenient oral dosing. This is also the first mechanistic proof-of-principle in the clinic for PureTech’s Glyph lymphatic targeting platform, which is designed to bypass first-pass metabolism to help maximize the therapeutic potential of validated targets and drugs where oral bioavailability has been a barrier. The Glyph platform is also designed to have additional applications through its ability to selectively traffic therapeutics into the lymphatic system, potentially enabling more direct targeting of the immune system.
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“I am excited by the data generated with PureTech’s LYT-300 and believe it could represent an exciting step towards enabling bioavailability for this and other classes of therapeutics.”
“Natural allopregnanolone has demonstrated efficacy for the treatment of postpartum depression (PPD) and other neuropsychological conditions, but up to now has required IV delivery due to high first-pass liver metabolism. LYT-300 is designed to unlock the validated pharmacology of natural allopregnanolone with a potential oral treatment option for PPD and a range of other neurological and neuropsychological conditions,” said Julie Krop, M.D., Chief Medical Officer of PureTech. “Achieving significant systemic exposure of allopregnanolone with orally administered LYT-300 is also a key validation for our Glyph lymphatic targeting platform and represents proof-of-principle for being able to administer drugs orally that currently require IV administration due to first-pass liver metabolism.”
PureTech has previously presented data in non-human primates with LYT-300 demonstrating significantly greater oral bioavailability than orally administered allopregnanolone. Data from this Phase 1 program reaffirmed this finding in humans, showing bioavailability of allopregnanolone that was approximately nine-fold greater than that of orally administered allopregnanolone, based on previously published data.1 In the PureTech 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
Allopregnanolone is a natural neurosteroid with well-established biology that has demonstrated efficacy for the treatment of epilepsy, depression and other neurological indications, but its poor oral bioavailability has limited its development as a therapeutic. The United States Food and Drug Administration (FDA) has approved a 60-hour intravenous infusion formulation of allopregnanolone for the treatment of PPD, though this method of administration has inherent limitations. The Glyph platform is designed to leverage the body’s natural lipid absorption and transport process to overcome these limitations to enable oral administration. Demonstrating oral bioavailability with the Glyph platform opens up the possibility of developing other natural neurosteroids and a number of bioactive molecules as oral therapies to treat a range of serious diseases.
“Due to a relative paucity of newly FDA-approved molecules in recent decades, significant patient needs exist, and we are experiencing a national mental health crisis that makes these needs even greater. Achieving an orally bioavailable prodrug of allopregnanolone may prove promising in the treatment of mood disorders such as postpartum depression – and potentially a range of related neurological and neuropsychiatric conditions,” said Maurizio Fava, M.D., Psychiatrist-in-Chief at Massachusetts General Hospital.
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“Given the proven efficacy of allopregnanolone in postpartum depression and its potential in a range of other conditions, significant effort has been put into delivering oral formulations for the molecule, without success. This has led to synthetic approaches that may not capture the full therapeutic potential of natural allopregnanolone,” said Scott Reines, M.D., Ph.D., former Senior Vice President, J&J Pharmaceutical Research & Development. “I am excited by the data generated with PureTech’s LYT-300 and believe it could represent an exciting step towards enabling bioavailability for this and other classes of therapeutics.”
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 identify a dose to take forward. With the achievement of the first objective, additional dose exploration and the effect of food on oral absorption of the prodrug are progressing, and assessments of safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) will be measured. Dose escalation continues as no dose-limiting toxicities have been observed to date.
As allopregnanolone is a modulator of the GABAA receptor, the Phase 1 program will also explore the impact of LYT-300 on b-EEG, and other markers of GABAA target engagement, thus potentially providing further early insights into the mechanistic effects of LYT-300 and its potential in a range of indications where GABAA receptors play a key biological role. Completion of the rest of the Phase 1 program is expected by the end of 2022, and – if data are favorable – a Phase 1b/2a study is planned to initiate in 2023.
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