About Non-Alcoholic Steatohepatitis (NASH)
Non-alcoholic steatohepatitis (NASH) is a metabolic liver disease that is quickly becoming a worldwide epidemic. It is characterized by the accumulation of fat in the liver causing inflammation, cell death and fibrosis. The disease can be silent for a long period of time, but may progress towards severe damage and liver fibrosis, which ultimately can even result in liver failure and/or liver cancer. Typical risk factors for NASH include insulin resistance, obesity, elevated levels of blood lipids (such as cholesterol and triglycerides) and diabetes. Currently no curative or specific therapies are available.
According to analyses conducted by the National Institute of Diabetes and Digestive and Kidney Diseases, NAFLD, which results in an accumulation of fat in the liver, is one of the most common liver diseases in the United States. It affects approximately 20% of the world’s population and up to 70% of type 2 diabetes patients.
NASH is a more severe form of non-alcoholic fatty liver disease (NAFLD). These liver diseases result in cases of cirrhosis and hepatocellular carcinoma. According to published estimates, about 10% to 30% of NAFLD patients also suffer from NASH and approximately 40-50% of patients with NASH have co-existing type 2 diabetes.
Both PXL065 and PXL770 are novel first-in-class oral agents with potential therapeutic utility for the treatment of NASH.
PXL065, a New Approach for the Treatment of NASH
PXL065 offers a new approach for the treatment of NASH. PXL065 is the R stereoisomer (deuterium modified single R-isomer) of pioglitazone. Its parent molecule, pioglitazone (Actos®) has been marketed since 1999 for the treatment of type 2 diabetes. Pioglitazone is a mixture, in equal proportions, of two mirror molecules (R and S stereoisomers) that interconvert in vivo. Like other thiazolidinedione (TZD) molecules, pioglitazone targets activation of PPARγ and also mediates non-genomic actions with pathways that include modulating the mitochondrial pyruvate carrier (MPC). Pioglitazone has been the subject of a large number of Phase 2, .3 and 4 clinical trials for the treatment of NASH, which have demonstrated its ability to target disease resolution and reduce the progression of fibrosis. It 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).
However, its use is restricted due to the adverse effects caused by the activation of PPARγ receptors, such as weight gain, bone fractures and fluid retention (edema). PXL065, the deuterium-modified R stereoisomer, has little or no observed PPARγ activity or associated adverse effects that appear to be related to the S stereoisomer of pioglitazone. In preclinical models, PXL065 retains the NASH efficacy of pioglitazone via non-genomic pathway actions and was observed to produce little or no weight gain or fluid retention. PXL065 is a new chemical entity (NCE) with composition of matter IP.
Clinical Development – PXL065
PXL065 is being developed using the 505(b)(2) new drug approval path, an expedited FDA pathway that allows sponsors to cite and leverage pre-existing public data of a closely related reference molecule – in this case pioglitazone (including preclinical and clinical safety).
In September 2020, we initiated a streamlined Phase 2 trial (DESTINY1). This Phase 2 36-week trial in noncirrhotic biopsy-proven NASH patients will assess three doses of PXL065 compared to placebo in at least 120 patients. The results of this trial are anticipated in the third quarter of 2022 and will be used to help identify the dose or doses for a Phase 3 registration trial.
The Phase 2 trial design for PLX065 is shown below:
The previous Phase 1 program for PXL065 consisted of several trials in healthy subjects that were designed to assess safety and pharmacokinetics. The Phase 1 program also included pioglitazone as an active comparator. In addition, exposure to known metabolites was compared with equivalent doses of PXL065 and pioglitazone. Based on these Phase 1 results, a PK model was generated to predict the dose of PXL065 that would produce the same exposure to R-pioglitazone as the 45 mg dose of pioglitazone, as well as the number of days of use of the drug required to achieve this equilibrium. The PK results and simulations in humans, associated with preclinical animal studies, also suggest that PXL065 (at approximately 15 mg daily) could potentially have the same efficacy in NASH as pioglitazone, but with fewer PPARγ receptor-related adverse effects, such as weight gain and fluid retention. In the Phase 1 program, PXL065 was well-tolerated, with no serious adverse events.
As displayed in the charts below from a multiple dose Phase 1 study, the PK assessment showed that PXL065 plasma exposure increased in a dose-proportional manner up to 30mg, the highest dose tested, when using a tablet formulation. Stabilization of R-pioglitazone (R-pio) with deuterium was observed at all doses tested; thus there was minimal exposure to the PPARγ-active S-stereoisomer with relatively greater exposure to the R-isomer.
PXL770, a Potential Breakthrough Therapy for Chronic Metabolic Disorders, Including NASH
PXL770 is a novel drug candidate that directly activates adenosine monophosphate-activated protein kinase (AMPK). AMPK is major cellular energy sensor which is activated by exercise or caloric restriction and inhibited by over-nutrition. It is a central regulator of multiple metabolic pathways; activation leads to the control of lipid metabolism, glucose homeostasis and inflammation. Based on its central metabolic role, we believe that 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 and rare metabolic disorders (e.g. adrenoleukodystrophy).
Direct activation of the AMPK enzyme has the potential to treat the root causes of NASH by triggering benefits on the main pathophysiologic processes occurring in the liver and leading to NASH: steatosis, inflammation, ballooning and fibrosis.
By directly targeting a primary regulator of cellular energy metabolism, we believe that PXL770 is well positioned for the treatment of NASH. Based on results from multiple preclinical models for PXL770 and published literature that are consistent with potential clinical beneficial effects, we believe that AMPK activation could play a beneficial role in the metabolic and inflammatory pathways that lead to liver injury and NASH. Based on clinical trials and preclinical studies to date, PXL770 has been observed to:
- improve sensitivity to insulin;
- inhibit the two main sources of steatosis, de novo lipogenesis (DNL) and lipolysis;
- reduce inflammation in the liver and fat tissue;
- reduce profibrogenic pathways leading to fibrosis; and
- reduce CV risk factors.
Clinical Development – PXL770
In October 2020, we announced results from our Phase 2a trial of PXL770. The STAMP-NAFLD was a 12-week randomized, placebo-controlled, parallel group trial in 120 presumed NASH patients, with or without diabetes, which evaluated three dosing regimens of PXL770 versus placebo. The Phase 2a trial met its objectives by demonstrating safety and evidence of efficacy.
PXL770 was observed to be generally safe and well tolerated. The number of patients with treatment-emergent adverse events in each group were similar to placebo and these events were mainly mild-to-moderate. The safety results from the Phase 2a trial are consistent with the PXL770 PK/PD trial and Phase 1 program.
Effects of PXL770 to reduce liver fat content and liver enzymes were observed with greater efficacy demonstrated in patients with co-existing type 2 diabetes. This observation is consistent with published literature showing that endogenous AMPK activity in various tissues is reduced in states of metabolic dysfunction including hyperglycemia. In addition, clinically meaningful improvements in glucose levels (HbA1c and fasting glycemia) were observed in the type 2 diabetes sub-population.
As the first direct AMPK activator studied in human disease, these results support progression of development in NASH, including key high-risk subgroups (patients with type 2 diabetes) and other chronic and rare metabolic diseases.
In June 2020, we announced results from our Phase 1b PK-PD trial of PXL770. This trial examined the effects of a single dose level (500 mg QD for 4 weeks) of PXL770 in 12 patients with insulin resistance and NAFLD. Four placebo-treated subjects were included for comparison. AMPK target engagement was demonstrated via an effect of PXL770 to suppress DNL. Additional signs of efficacy were also observed in this trial including improvements in insulin sensitivity scores and in glucose levels during a glucose tolerance test. The PK profile was also consistent with prior Phase I studies. PXL770 was observed to have a favorable safety and tolerability profile in this study.
In previous Phase I studies that were conducted in healthy subjects, PXL770 was observed to be well tolerated with an acceptable adverse event profile. Based on careful ECG monitoring, PXL770 was not associated with any prolongation of the QT interval, which is a cardiac safety measurement, or any changes in other ECG parameters. The PK parameters of PXL770 were predictive of once daily oral dosing and were linear with a saturation tendency at the highest dose tested. In addition, a specific drug interaction trial with rosuvastatin showed no potential for unfavorable PK interactions.
Further development of PXL770 in NASH will await 2022 data readouts from the Phase 2a studies of PXL770 and PXL065 in adrenoleukodystrophy and from the ongoing DESTINY1 Phase 2 study with PXL065.
Given the mechanistic heterogeneity of NASH, we believe there is a need for combination approaches that target multiple pathways in the disease’s progression. Our two lead products in NASH target distinct pathways, and we believe that the differentiated profiles of PXL770, which allosterically activates AMPK to mitigate metabolic overload in liver cells, and of PXL065, which functions via non-genomic TZD-driven pathways to prevent liver inflammation and fibrosis, are well-suited for use as a combination therapy. To this end, we are currently conducting preclinical studies for PXL770 and PXL065 in combination together and with other therapies using other mechanisms of action that we believe could have additive or synergistic benefits for the treatment of NASH.