POXEL SA , a clinical stage biopharmaceutical company developing innovative treatments for chronic serious diseases with metabolic pathophysiology, including non-alcoholic steatohepatitis (NASH) and rare metabolic disorders, today announces the publication of two preclinical articles on X-Linked Adrenoleukodystrophy (ALD) for PXL065 and PXL770. These molecules have separate and distinct mechanisms of action: PXL065 is a novel, proprietary deuterium-stabilized R-stereoisomer of pioglitazone which exerts effects via multiple non-genomic pathways engaged by thiazolidinedione molecules; PXL770 is a novel, first-in-class direct adenosine monophosphate-activated protein kinase (AMPK) activator. Both compounds are preparing to enter into Phase 2a clinical Proof-of-Concept (POC) biomarker studies in ALD patients with adrenomyeloneuropathy (AMN) as soon as possible, subject to financing.
“Therapeutic potential of deuterium-stabilized (R)-pioglitazone – PXL065 – for X-linked adrenoleukodystrophy”
An article on PXL065 has been published in The Journal of Inherited Metabolic Disease (“JIMD”) and is entitled “Therapeutic potential of deuterium-stabilized (R)-pioglitazone – PXL065 – for X-linked adrenoleukodystrophy”. It is available here: https://pubmed.ncbi.nlm.nih.gov/35510808/.
An article on PXL770 has been published in The Journal of Pharmacology and Experimental Therapeutics (“JPET”), and is entitled “Beneficial effects of the direct AMP-Kinase activator PXL770 in in vitro and in vivo models of X-Linked Adrenoleukodystrophy”.
These publications describe similar beneficial preclinical profiles of PXL770 and PXL065 in models of ALD. Elevated levels of toxic very long chain fatty acids (VLCFA) are a driver of ALD pathology. The published in vitro results show correction of this phenotype in ALD patient-derived cells. In a classical in vivo rodent model of ALD, elevated VLCFA levels were also suppressed by chronic treatment with both compounds (in plasma, brain and spinal cord). The two compounds also improved mitochondrial function and signs of inflammation in patient-derived cells.
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Importantly, improvements in neurologic deficits were also documented in the ALD mouse model (sciatic nerve morphology and locomotor function) with each of the two compounds. Given different mechanisms of action, it is anticipated that pursuit of the pending (identical design) Phase 2a clinical studies could yield results that will help determine diffentiation between these agents in this disease.
X-linked adrenoleukodystrophy (ALD) is an orphan neurometabolic disease caused by mutations in the ABCD1 gene which encodes for a key protein that is required for metabolism of very long chain fatty acids (VLCFA) by peroxisomes