PXL770 / Poxel SA - LARVOL DELTA

Study to Assess PXL770 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD) (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Poxel SA | Phase classification: P2a ➔ P2 | N=24 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Phase classification • Trial withdrawal • Genetic Disorders • Pain

Study to Assess PXL770 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD) (clinicaltrials.gov) - P2a | N=24 | Not yet recruiting | Sponsor: Poxel SA | Trial completion date: Mar 2023 ➔ Sep 2024 | Trial primary completion date: Mar 2023 ➔ Sep 2024

Trial completion date • Trial primary completion date • Genetic Disorders • Pain

A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease. (PubMed, Kidney Int) - "PXL770 induced AMPK activation and dose-dependently reduced cyst growth in principal-like Madin-Darby Canine Kidney cells stimulated with forskolin and kidney epithelial cells derived from patients with ADPKD stimulated with desmopressin. These effects were accompanied by a reduction of markers of cell proliferation (-48%), macrophage infiltration (-53%) and tissue fibrosis (-37%). Thus, our results show the potential of direct allosteric AMPK activation in the treatment of ADPKD and support the further development of PXL770 for this indication."

Journal • Preclinical • Autosomal Dominant Polycystic Kidney Disease • Chronic Kidney Disease • Fibrosis • Genetic Disorders • Immunology • Inflammation • Nephrology • Polycystic Kidney Disease • Renal Disease • PKD1 • PRKD1

Study to Assess PXL770 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD) (clinicaltrials.gov) - P2a | N=24 | Not yet recruiting | Sponsor: Poxel SA | Initiation date: Jul 2022 ➔ Dec 2022

Trial initiation date • Genetic Disorders • Pain

"Poxel Announces the Publication of Two Preclinical Articles on X-Linked Adrenoleukodystrophy for PXL065 and PXL770 https://t.co/oA1cOMTu9h" (@NewsFromBW)

Preclinical • Genetic Disorders

Study to Assess the Safety, Tolerability, and Pharmacokinetics of PXL770 in Healthy Subjects. (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Poxel SA

New P1 trial • Hepatology • Non-alcoholic Steatohepatitis

Beneficial effects of the direct AMP-Kinase activator PXL770 in in vitro and in vivo models of X-Linked Adrenoleukodystrophy . (PubMed, J Pharmacol Exp Ther) - "PXL770 is a novel clinical stage direct AMPK activator. In these studies, we used PXL770 to achieve preclinical validation of direct AMPK activation for this disease - based on correction of key biochemical and functional readouts in vitro and in vivo, thus supporting clinical development."

Journal • Preclinical • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders

Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis. (PubMed, Mol Metab) - "Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O-3O4 and PXL 770 for reducing atherosclerotic cardiovascular disease risks."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • AMPK • APOE

Preclinical Efficacy of Direct AMPK Activation with a Novel Small Molecule–PXL770–For the Treatment of Autosomal Dominant Polycystic Kidney Disease (ERA-EDTA 2022) - "In vivo , a kidney specific P18 tamoxifen induced Pkd1 KO mouse model (KspCad-CreERT2, Pkd1 lox, lox— ‘ADPKD mice’ [Lantinga-van Leeuwen IS, Hum Mol Genet 2007]) was used...These results were confirmed in human cysts where PXL770 inhibited desmopressin induced cyst swelling measured by cyst area, −67% at 15 µM compared with untreated control cysts (P < 0.001), and −115% at 50 µM (P < 0.0001)—below cyst area observed in solvent unstimulated condition. Similar result was achieved with tolvaptan...CONCLUSION Direct AMPK activation with PXL770 strongly reduced cyst growth and swelling in vitro in canine and human models and was shown to produce considerable efficacy in an orthologous genetic mouse model of ADPKD. These results show the potential of direct allosteric AMPK activation in ADPKD and support the further development of PXL770 in this indication."

Preclinical • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • PKD1 • PRKD1

Study to Assess PXL770 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD) (clinicaltrials.gov) - P2a | N=24 | Not yet recruiting | Sponsor: Poxel SA | Trial completion date: Nov 2022 ➔ Mar 2023 | Initiation date: Mar 2022 ➔ Jul 2022 | Trial primary completion date: Nov 2022 ➔ Mar 2023

Trial completion date • Trial initiation date • Trial primary completion date • Genetic Disorders • Pain

Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study. (PubMed, Cell Rep Med) - "PXL770 is a direct AMPK activator, inhibiting de novo lipogenesis (DNL) and producing efficacy in preclinical models...Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders."

Clinical • Journal • P1 data • PK/PD data • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity

Study to Assess PXL770 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD) (clinicaltrials.gov) - P2a; N=24; Not yet recruiting; Sponsor: Poxel SA

Clinical • New P2a trial • Genetic Disorders • Pain • MRI

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study. (PubMed, Lancet Gastroenterol Hepatol) - P2 | "PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis."

Clinical • Journal • P2a data • Diabetes • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • MRI

Direct AMPK Activation Corrects NASH in Rodents Through Metabolic Effects and Direct Action on Inflammation and Fibrogenesis. (PubMed, Hepatol Commun) - "A novel small-molecule direct AMPK activator, PXL770, was used...Novel properties of direct AMPK activation were also unveiled: improved insulin resistance and direct suppression of inflammation and fibrogenesis. Given effects also documented in human cells (reduced DNL, suppression of inflammation and stellate cell activation), these studies support the potential for direct AMPK activation to effectively treat patients with NASH."

Journal • Preclinical • Diabetes • Dyslipidemia • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Steatohepatitis

Poxel Provides Corporate Update and Reports Cash and Revenue for the Second Quarter and First Half 2021 (Poxel Press Release) - "Pr. Kenneth Cusi presented the results of the STAMP-NAFLD 12-week, randomized, controlled Phase 2a trial of PXL770 in 120 presumed NASH patients...PXL770 was observed to be safe and well tolerated."

Media quote

Poxel Presents Results of Two Clinical Studies on its Direct AMP Kinase Activator, the PXL770, at the International Liver Congress (ILC) 2021 (Yahoo News) - "Pr. Kenneth Cusi presented the results of the STAMP-NAFLD 12-week, randomized, controlled Phase 2a trial of PXL770 in 120 presumed NASH patients - selected as a 'Best of ILC' abstract...PXL770 was well tolerated with an acceptable safety profile."

Media quote

[VIRTUAL] Human proof-of-concept in non-alcoholic liver disease (NAFLD) patients with PXL770, a novel first-in-class direct AMP-kinase activator -- STAMP-NAFLD Phase 2a trial (EASL-ILC 2021) - "PXL770 is the first direct AMPK activator to be studied in patients with metabolic or liver disorders. These results support the potential utility of PXL770 in NASH-in particular for the large (≈ 45– 50%) subpopulation with coexisting T2DM where the severity and progression of disease is also associatedwith disproportionately high unmet medical need."

Clinical • P2a data • Diabetes • Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • MRI

[VIRTUAL] Target engagement and evidence of efficacy with PXL770, a novel direct AMP-Kinase activator, in a 4-week PK/PD trial in patients with NAFLD (EASL-ILC 2021) - "These results support the continued development of PXL770, the first direct AMPK activator to be studied in patients, and the potential utility of AMPK activation in NASH and other potential indications."

Clinical • PK/PD data • Addiction (Opioid and Alcohol) • Hepatology • Immunology • Inflammation • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus

[VIRTUAL] Chronic Treatment with the Direct AMPK Activator PXL770 Improves Cardiac, Vascular, and Renal Function in Rodents with Diabetes-Related Cardiorenal Disease (ADA 2021) - "In ZSF-1 rats, improvement of metabolic status induced by long-term treatment with the AMP kinase activator PXL770 is associated with an improved LV diastolic, vascular and renal function/structure. PXL770 could have therapeutic utility for the treatment of metabolic diseases and related co-morbid conditions."

Preclinical • Diabetes • Metabolic Disorders • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus

"In the #NAFLD therapy session, Kenneth Cusi presents a phase 2a trial of PXL770, a direct AMPK activator #ILC2021" (@LancetGastroHep)

P2a data • Hepatology • Non-alcoholic Fatty Liver Disease

A Study to Assess the Pharmacokinetics of PXL770 After 4 Weeks of Treatment in Subjects With NAFLD (clinicaltrials.gov) - P1; N=17; Completed; Sponsor: Poxel SA; Not yet recruiting ➔ Completed; N=32 ➔ 17

Enrollment change • Trial completion • Hepatology • Non-alcoholic Fatty Liver Disease

HUMAN PROOF-OF-CONCEPT IN NAFLD PATIENTS WITH PXL770, A NOVEL FIRST-IN-CLASS DIRECT AMP-KINASE ACTIVATOR (NASH-TAG 2021) - "PXL770 is the first direct AMPK activator to be studied in patients with metabolic disease; following oral daily dosing in patients with NAFLD, evidence of target engagement (suppression of DNL) was achieved. Treatment of patients with presumed NASH results in significant improvements in multiple NASH-related parameters; clinically meaningful and greater responses are seen in patients with coexisting T2DM – consistent with the hypothesis that greater metabolic dysfunction is associated with lower endogenous AMPK tone. Glycemic benefits also occurred in patients with T2DM along with evidence of insulin sensitization in both T2DM and non-diabetics."

Clinical • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus • MRI

A Study of the Efficacy and Safety of PXL770 Versus Placebo After 12 Weeks of Treatment in Patients With NAFLD (clinicaltrials.gov) - P2; N=120; Completed; Sponsor: Poxel SA; Recruiting ➔ Completed; Trial completion date: Feb 2020 ➔ Aug 2020; Trial primary completion date: Feb 2020 ➔ Aug 2020

Clinical • Trial completion • Trial completion date • Trial primary completion date • Hepatology • Non-alcoholic Fatty Liver Disease

[VIRTUAL] PXL770, A NEW DIRECT AMP KINASE ACTIVATOR AND POTENTIAL NASH THERAPEUTIC, PRODUCES ANTI-INFLAMMATORY EFFECTS IN MOUSE LIVER AND ADIPOSE TISSUE AND IN HUMAN IMMUNE CELLS (AASLD 2020) - "By directly activating AMPK, PXL770 reduced liver and AT inflammation in mice. PXL770 exerted direct anti-inflammatory effects on human immune cells and on the AT. These benefits demonstrate effects of AMPK activation that extend beyond metabolic modulation."

Hepatology • Immunology • Inflammation • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • IL10 • IL1B • IL6 • NFKB1 • TNFA

[VIRTUAL] PXL770, A NOVEL DIRECT AMP-ACTIVATED PROTEIN KINASE ACTIVATOR, IMPROVES HEPATIC MITOCHONDRIAL FUNCTION IN A RODENT NASH MODEL. (AASLD 2020) - "In the liver, PXL770 improved mitochondrial homeostasis, thereby increasing the pool of functional mitochondria. This improvement of mitochondrial function in the liver and the BAT may contribute to the beneficial effects of PXL770 on NASH hallmarks and particularly on liver steatosis."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis