Therapy Areas: Diabetes
Poxel Presents Complete PXL770 Phase 1 Results, Cardiac Safety Profile and Preclinical Efficacy Data in NASH at AMPK - From Mechanisms to New Therapies Scientific Congress
4 October 2018 - - French biopharmaceutical company Poxel SA (Euronext: POXEL - FR0012432516) PXL770 data at AMPK - From Mechanisms to New Therapies Scientific Congress held in Niagara-on-the-Lake, Ontario, Canada, September 30 - October 4, 2018, the company said.
The PXL770 results were presented in two poster presentations and an oral presentation. The data presented emphasized the favorable pharmacokinetic, tolerability and safety profile of PXL770 in the Phase 1 programme as well as a favorable cardiac and electrocardiography safety profile in both healthy subjects and animal models.
In addition, mechanistic and efficacy data in a diet-induced obese -NASH mouse model were also presented.
Poxel previously announced data results from the Phase 1b multiple ascending dose trial and a drug-drug interaction study of PXL770, a direct adenosine monophosphate-activated protein kinase activator, in a press release on July 18, 2018.
Based on these results, the company is advancing PXL770 into a Phase 2a proof-of-concept study in nonalcoholic fatty liver disease (NAFLD) patients who likely have NASH in early 2019.
In a poster presentation, results from the two Phase 1 studies including single and multiple ascending dose administrations of PXL770 investigated in healthy male subjects (n=124), were presented.
The safety profile was good across the dose range tested with no serious adverse events nor adverse effects leading to discontinuation.
A good tolerability profile was also observed up to the highest dose tested of 500 mg, both as single or multiple administrations, with no changes in the electrocardiogram observed. The maximum tolerated dose was not reached.
Pharmacokinetic assessment demonstrated that PXL770 plasma exposure (Cmax and AUC) increased in a dose dependent manner following single administration.
After multiple administrations, the pharmacokinetics (Cmax and AUC) of PXL770 were shown to be linear with a trend for saturation at the highest dose tested. These results suggest that PXL770 is well positioned to enter Phase 2 development.
In a second poster presentation, cardiac safety was evaluated in an extensive in vivo program. A pharmacological study performed in a rat model demonstrated that PXL770 administration (75 mg/kg bid) did not induce cardiac hypertrophy after 16 weeks of treatment in toxicological studies and no adverse effects of cardiac hypertrophy or accumulation of glycogen in the myocardium were detected at 1000 mg/kg dosing during 13 weeks of PXL770 treatment.
These results were replicated in the 13-week treatment study in dogs with no increase in cardiac glycogen content (Shiff periodic acid staining) observed.
A twenty-four-hour Holter-ECG recording performed in the 13-week study in dogs showed no rhythm or conduction disorders. Lastly, regulatory safety pharmacological studies (hERG binding assay, hERG voltage clamp assay and radiotelemetry in dogs) dedicated to cardiac assessment (cardiac repolarization and electrocardiographic parameters, blood pressure) did not raise any safety concerns.
The favorable cardiac safety is reinforced by the absence of adverse effects observed on extensive ECG recordings after a shorter period of PXL770 administration in healthy subjects evaluated in the Phase 1 program.
In addition, an oral presentation summarizing PXL770 and its preclinical profile as a direct AMPK activator, specifically in a diet-induced (high fat, fructose and cholesterol for 45 weeks) obesity NASH (DIO-NASH) mouse model, was presented.
The results highlighted the beneficial effect of AMPK activation in the NASH model and the potential of PXL770 as a promising novel treatment option in NAFLD and, in particular, NASH acting on the three main characteristics of the physiopathology: steatosis, inflammation and fibrosis.
The posters titled "PXL770, a direct AMPK activator, shows a favorable cardiac safety profile" and "PXL770, a direct AMPK activator for the treatment of NASH, shows a favorable PK, tolerability and safety profile in humans" are available on the company's website under "Posters" or by using the following link http://www.poxelpharma.com/en_us/product-pipeline/posters.
Non-alcoholic steatohepatitis is a metabolic disease with no clear disease origin that is quickly becoming a worldwide epidemic. It is characterised by the accumulation of fat in the liver causing inflammation and fibrosis.
The disease can be silent for a long period of time, but once it accelerates, severe damage and liver cirrhosis can occur, which can significantly impact liver function or can even result in liver failure or liver cancer.
Typical risk factors for NASH include obesity, elevated levels of blood lipids (such as cholesterol and triglycerides) and diabetes. Currently no curative or specific therapies are available.
PXL770 is a first-in-class direct adenosine monophosphate-activated protein kinase activator. 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, 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 non-alcoholic steatohepatitis.
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