deuterium-stabilized R-pioglitazone (PXL065) / Poxel SA - LARVOL DELTA

Poxel Announces Positive Preclinical Data for PXL065 in Hypertrophic Cardiomyopathy To Be Presented at the ESC Congress 2025 (Poxel Press Release) - "In connection with the mechanism of action of PXL065 on the inhibition of the mitochondrial pyruvate carrier (MPC) and on the inhibition of Acyl CoA Synthetase 4 (ACSL4) thus acting on oxidative stress, inflammation and fibrosis, PXL065 was successfully assessed in an established mouse model of hypertrophic cardiomyopathy."

Preclinical • Hypertrophic Cardiomyopathy

Therapeutic potential of pxl065 (deuterium-stabilized r-enantiomer of pioglitazone) in hypertrophic cardiomyopathy (ESC-WCC 2025) - No abstract available

Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy

Poxel Announces Positive Results from a Preclinical Study for PXL065, a Proprietary Deuterium-Stabilized R-Stereoisomer of Pioglitazone, in Hypertrophic Cardiomyopathy (Businesswire) - "The preclinical study was financed through a grant by DZHK and conducted at the TUM University Hospital German Heart Center under a research collaboration between Poxel and the TUM University Hospital German Heart Center. PXL065 demonstrated significant benefits in a HCM mouse model preventing pathological myocardial remodeling, including hypertrophy and fibrosis in the heart. The top-line results from this mouse model support the clinical development of PXL065 as a potential disease-modifying treatment for symptomatic and asymptomatic HCM."

Preclinical • Hypertrophic Cardiomyopathy

Study to Assess PXL065 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With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD) (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Poxel SA | Phase classification: P2a ➔ P2 | N=12 ➔ 0 | Not yet recruiting ➔ Withdrawn

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

Poxel Reports Financial Results for First Half 2023 and Provides a Corporate Update (Businesswire) - "R&D expenses totaled EUR 2.8 million for the first half of 2023, as compared to EUR 7.9 million for the corresponding period in 2022. The 2023 decrease primarily reflects the end, in 2022, of the Phase 2 DESTINY study evaluating PXL065 in NASH."

Commercial • Metabolic Disorders • Non-alcoholic Steatohepatitis

Study to Assess PXL065 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD) (clinicaltrials.gov) - P2a | N=12 | 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

Evaluation of PXL065 - Deuterium-Stabilized (R)-Pioglitazone in NASH Patients: a Phase 2 randomized placebo-controlled trial (DESTINY-1). (PubMed, J Hepatol) - "PXL065 is a novel molecule which retains an efficacy profile in NASH similar to Pio with reduced potential for PPARγ-driven side effects. Confirmation of histologic benefits by testing in a pivotal clinical trial is warranted."

Journal • P2 data • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis • PPARG

PLX065 reduces liver fat content, prevents worsening of fibrosis in NASH (Healio) - "'Pioglitazone has been extensively studied for many years. ... There have been at least six biopsy trials of varying durations, varying numbers of patients included in the trial, each showing histopathological and biochemical benefit,' Stephen A. Harrison, MD, FAASLD...said at The Liver Meeting."

Media quote

PXL065 (DEUTERIUM-STABILIZED R-ENANTIOMER OF PIOGLITAZONE) REDUCES LIVER FAT CONTENT AND IMPROVES LIVER HISTOLOGY WITHOUT PPARG -MEDIATED SIDE EFFECTS IN PATIENTS WITH NASH: ANALYSIS OF A 36 WEEK PLACEBO-CONTROLLED PHASE 2 TRIAL (DESTINY1) (AASLD 2022) - "DESTINY1 results support the concept that PXL065 is a novel PPARg sparing oral NCE which retains an efficacy profile in NASH similar to that reported with Pio without the side effects. PXL065 demonstrated statistically significant reductions in LFC and histology suggests an effect on fibrosis consistent with improvements in the biomarkers. Histological data need to be confirmed in larger, pivotal clinical trials."

Adverse events • Clinical • Late-breaking abstract • P2 data • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis • ACSL4 • PPARG

Study to Assess PXL065 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD) (clinicaltrials.gov) - P2a | N=12 | Not yet recruiting | Sponsor: Poxel SA | Initiation date: Jul 2022 ➔ Dec 2022

Trial initiation date • Genetic Disorders • Pain

Poxel Announces Positive Results from Phase 2 NASH Trial (DESTINY-1) for PXL065, A Novel, Proprietary Deuterium-Stabilized R-Stereoisomer of Pioglitazone (Poxel Press Release) - P2 | N=117 | DESTINY-1 (NCT04321343) | Sponsor: Poxel SA | "'Pioglitazone has a good record of efficacy in NASH with 6 clinical trials in NASH patients to-date having demonstrated substantial benefits on liver histology that compare favorably to other oral molecules in development,' said Stephen Harrison..."

P2 data

Study of PXL065 in Patients With Nonalcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P2 | N=123 | Completed | Sponsor: Poxel SA | Active, not recruiting ➔ Completed

Trial completion • Hepatology • Non-alcoholic Steatohepatitis • CRP

Deuterium-Stabilized (R)-Pioglitazone, PXL065, for Treatment of X-Linked Adrenoleukodystrophy (ALD) (EAN 2022) - "Despite reduced PPARγ activity, PXL065 showed substantial signs of efficacy and superior therapeutic potential vs. pioglitazone (in vivo) supporting clinical development for ALD. A Phase 2a study is planned in 2022."

Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • PPARG

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

Preclinical • Genetic Disorders

Therapeutic potential of deuterium-stabilized (R)-pioglitazone - PXL065 - for X-linked adrenoleukodystrophy. (PubMed, J Inherit Metab Dis) - "agonism but retained ACSL4 activity of pioglitazone. PXL065 has novel actions and mechanisms and exhibits a range of potential benefits in ALD models; further testing of this molecule in ALD patients is warranted."

Journal • CNS Disorders • Genetic Disorders • Immunology • Inflammation • Pain • ACSL4 • PPARG

BIOMARKERS, IMAGING AND SAFETY IN RESMETIROM 52 WEEK NON-CIRRHOTIC NASH PHASE 3 CLINICAL TRIAL, COMPLETED OPEN-LABEL ARM OF MAESTRO-NAFLD-1 (NASH-TAG 2022) - P3 | "No safety flags were identified; BP (systolic, diastolic) was reduced by ~2-4 mmHg, 20 • In vitro assays demonstrated that PXL065 lacks PPARγ agonism but retains the known non-genomic effects of Pio including inhibition of mitochondrial pyruvate carrier (MPC)4 and acyl-CoA synthetase long chain 4 (ACSL4). In this 52-week Phase 3 OL study, noninvasively identified NASH patients treated with 100 mg per day of resmetirom for up to 52 weeks demonstrated rapid and sustained reduction in 1) hepatic fat and liver volume 2) fibrosis as assessed by biomarkers, MRE and fibroscan; 3) LDL and atherogenic lipids, 4) liver enzymes and inflammatory biomarkers, providing support for the use of non-invasive tests to monitor individual NASH patient response to resmetirom treatment."

Biomarker • Clinical • P3 data • Diabetes • Dyslipidemia • Fibrosis • Hepatology • Hypertension • Immunology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • ACSL4 • APOB • PPARG

PRECLINICAL AND EARLY CLINICAL CHARACTERIZATION OF PXL065 - DEUTERIUM-STABILIZED (R)-PIOGLITAZONE – A POTENTIAL NOVEL ORAL THERAPY FOR NASH (NASH-TAG 2022) - "PXL065 is a novel NASH therapeutic candidate. Despite reduced PPARγ activity, it retains non-genomic target activity and preclinical efficacy that are similar to Pio. In preclinical models and humans, dosing of PXL065 results in significantly greater R- vs."

Preclinical • Diabetes • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • ACSL4 • PPARG

Study to Assess PXL065 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD) (clinicaltrials.gov) - P2a | N=12 | 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

Study to Assess PXL065 in Subjects With Adrenomyeloneuropathy (AMN) Form of X-linked Adrenoleukodystrophy (X-ALD or ALD) (clinicaltrials.gov) - P2a; N=12; Not yet recruiting; Sponsor: Poxel SA

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

[VIRTUAL] FIB-4 SCORE AS A PREDICTIVE FACTOR OF ADVANCED LIVER FIBROSIS SHOULD BE ADAPTED ACCORDING TO TYPE 2 DIABETES STATUS: SCREENING DATA FROM DESTINY-1 (PXL065) PHASE 2 STUDY (AASLD 2021) - "Diabetic patients have a higher risk of fibrosis compared to non-diabetic patients with similar characteristics . The use of similar threshold for Fib-4 in diabetic and non- diabetic patients results in different probabilities of fibrosis. Fib-4 criteria should be adapted according to the T2D status ."

Biomarker • P2 data • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • PPARG

Study of PXL065 in Patients With Nonalcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P2; N=123; Active, not recruiting; Sponsor: Poxel SA; Recruiting ➔ Active, not recruiting; Trial primary completion date: Mar 2022 ➔ Jun 2022

Clinical • Enrollment closed • Trial primary completion date • Hepatology • Non-alcoholic Steatohepatitis • CRP • MRI

Deuterium-Stabilized (R)-Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPARγ Activity. (PubMed, Hepatol Commun) - " PXL065 at a dose lower than 22.5 mg is predicted to exhibit efficacy for NASH equal to, or greater than, 45-mg pioglitazone without the potentially detrimental weight gain and edema. The development of PXL065 for NASH represents a unique opportunity to leverage the therapeutic benefits of pioglitazone, while reducing or eliminating PPARγ-related side effects."

Clinical • Journal • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Steatohepatitis • PPARG

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

NASH: A pandemic with an unmet need for pharmacotherapies (Healio) - "But to get FDA approval or conditional approval to use the drug, there needs to be improvements in fibrosis by at least 1 stage without worsening of NASH or NASH resolution without worsening fibrosis. Obeticholic acid met its primary endpoint on fibrosis improvement without worsening of NASH, however, the FDA did not approve the drug. The FDA noted concern with the risk-benefit ratio."

Online posting

HUMAN PHARMACOKINETICS AND NASH DEVELOPMENT STRATEGY FOR PXL065 – DEUTERIUM-STABILIZED (R)-PIOGLITAZONE (NASH-TAG 2021) - "Steady state exposure to R- vs. S-Pio with PXL065 is substantially shifted vs. Actos / Pio – in favor of the non-PPAR active R-Pio stereoisomer [R-Pio:S-Pio 80:20 for AUC, 90:10 for Cmax]."

PK/PD data • Cardiovascular • Diabetes • Hepatology • Non-alcoholic Steatohepatitis • CYP2C8 • CYP3A4 • MRI