PXL065 in ALD
Preclinical and clinical results obtained with pioglitazone and a related molecule, leriglitazone (Minoryx), support the potential utility of PXL065 in ALD. PXL065 was observed to ameliorate key features of ALD in preclinical models, including both patient-derived cells and a classical rodent disease model. PXL065 has open IND for ALD in the U.S. PXL065 differentiates from pioglitazone and leriglitazone in several ways including its potential for greater efficacy and reduced side effects.
A Phase 2a clinical POC biomarker study of PXL065 is planned to initiate in early 2022, with data expected by year end 2022. The initial focus will be on ALD patients with adrenomyeloneuropathy (AMN), the largest subtype of ALD. The study will enroll adult male AMN patients and assess the effect of PXL065 over 12 weeks of treatment on pharmacokinetics, safety, and efficacy using relevant biomarkers, including the impact on elevated very long-chain fatty acids (VLCFA), the hallmark plasma marker of disease.
PXL770 in ALD
PXL770 is a first-in-class direct AMPK activator. Clinical Phase 1 and 2a development to-date has demonstrated target engagement and translation of several metabolic efficacy parameters to humans which suggests the likelihood of broader translation for this mechanism. PXL770 was observed to ameliorate key features of ALD in preclinical models, including both patient-derived cells and a classical rodent disease model.
A Phase 2a clinical POC biomarker study is planned to initiate in early 2022, with data expected by year end 2022. The initial focus will be on ALD patients with adrenomyeloneuropathy (AMN), the largest subtype of ALD. The study will enroll adult male AMN patients and assess the effect of PXL770 over 12 weeks of treatment on pharmacokinetics, safety, and efficacy using relevant biomarkers, including the impact on elevated very long-chain fatty acids (VLCFA), the hallmark plasma marker of disease.
PXL065 is deuterium-modified R-pioglitazone, currently in a streamlined Phase 2 trial (DESTINY1). Although pioglitazone is not approved by the FDA for the treatment of NASH, it is the most extensively studied drug for NASH and has demonstrated NASH resolution and improvements in fibrosis in multiple clinical trials. Pioglitazone is the only drug recommended for biopsy-proven NASH patients by the Practice Guidelines published by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL). Pioglitazone’s off-label use for NASH, however, has been limited due to the PPARγ-related side effects, which include weight gain, bone fractures and fluid retention.
Pioglitazone is a 1:1 mixture of two mirror-image compounds (R- and S-stereoisomers) that interconvert in vivo. Using deuterium, we stabilized each stereoisomer and characterized their different pharmacological properties. PXL065 is the R-pioglitazone isomer stabilized by deuterium. In in vitro studies, PXL065 has been shown to lack PPARγ activity while retaining non-genomic TZD actions. In preclinical animal models, PXL065 exhibits similar anti-inflammatory and NASH activity as pioglitazone with little or no weight gain or fluid retention, side effects which are associated with the S-stereoisomer. Based upon preclinical and Phase 1 results to date, we believe that PXL065 may have a better therapeutic profile than pioglitazone for NASH.
PXL770 is a first-in-class direct AMPK activator that has completed Phase 2a in NASH. AMPK is a central regulator of multiple metabolic pathways leading to the control of lipid metabolism, glucose homeostasis and inflammation. Based on its central metabolic role, directly targeting AMPK offers the opportunity to pursue a wide range of indications to treat chronic metabolic diseases, including diseases that affect the liver, such as NASH.
The STAMP NAFLD Phase 2a trial of PXL770 results demonstrated efficacy– both with respect to NASH-related parameters (liver fat content, liver enzymes) and metabolic status (insulin sensitivity, glycemia). PXL770 was observed to be generally safe and well tolerated.
Further development in NASH is awaiting strategic decisions based on PXL065 and PXL770 Phase 2a readouts in ALD and PXL065 Phase 2 results in NASH.
Imeglimin is a first-in-class novel medicine that is now approved as TWYMEEG in Japan for the treatment of Type 2 diabetes. It has a dual mode of action which corrects hyperglycemia by improving insulin secretion in response to glucose from pancreatic b-cells and ameliorating insulin resistance in key tissues (muscle and liver). Imeglimin also has the potential to exert cardiorenal disease modifying benefits and protective effects on pancreatic islet b-cell survival. This unique profile supports Imeglimin's use for the treatment of Type 2 diabetes in almost all stages of the current treatment paradigm.
In Japan, China, Taiwan, Korea and 9 other Southeast Asian countries, Sumitomo Dainippon Pharma is our strategic partner for Imeglimin. A new drug application for TWYMEEG Tablets 500mg1 (International Nonproprietary Name (INN): Imeglimin hydrochloride), for the treatment of type 2 diabetes, was approved in Japan on June 23, 2021. Japan is the first country in the world to approve Imeglimin. Sumitomo Dainippon Pharma, the diabetes market leader in Japan, anticipates launching TWYMEEG in 2021.
The TWYMEEG approval in Japan is supported by numerous preclinical and clinical studies, including the Phase 3 TIMES (Trials of IMeglimin for Efficacy and Safety) program managed jointly by Poxel and Sumitomo Dainippon Pharma, which included three pivotal trials to evaluate TWYMEEG’s efficacy and safety in over 1,100 patients. In all three trials, TWYMEEG met its primary endpoints and objectives and was observed to exhibit a favorable safety and tolerability profile when used alone or in combination with standard of care.
In China, Taiwan, South Korea, Indonesia, Vietnam, Thailand, Malaysia, the Philippines, Singapore, Myanmar, Cambodia, and Laos, Sumitomo Dainippon Pharma will be solely responsible for the development and commercialization of Imeglimin.
1Dosage and administration: In general, for adults, 1,000 mg of Imeglimin hydrochloride is orally administered twice daily in the morning and evening.
U.S. and Europe
In the US, Europe, and other countries not covered by the partnership with Sumitomo Dainippon Pharma, Poxel is considering various options to advance Imeglimin in those countries.
Additional Pipeline Opportunities
Preclinical studies are ongoing to evaluate our adenosine monophosphate-activated protein kinase (AMPK) activation and dTZD platforms in additional chronic and rare-orphan metabolic diseases.