ARAMCHOL



NAME OF DRUG : ARAMCHOL

LABORATORY : GALMED

STATUS AND ADVANCEMENT

Type of drug : FABACs

Clinical trials advancement : Ongoing Phase 2b

The drug got the Fast Track Status granted by the FDA

Estimated time to market : 72 months.

LABORATORY ABSTRACT ON THE DRUG

Aramchol (arachidyl amido cholanoic acid) is a novel fatty acid bile acid conjugate, causing beneficial modulation of intra-hepatic lipid metabolism. Aramchol's ability to modulate hepatic lipid metabolism was discovered and validated in numerous animal species and models by leading Israeli and European research groups led by the Company's founder, the late Prof. Tuvia Gilat. Recently, anti-inflammatory and anti- fibrotic effects were observed in mice treated with Aramchol using a methionine-choline deficient (MCD) diet treatment model and rats' prevention thioacetamide (TAA) model.

Mechanism of Action

Aramchol’s mechanism of action has been studied in-vitro and in-vivo. Aramchol has been shown to work by two parallel pathways, leading to synergistic effects:

The SCD1 Pathway

Aramchol partially inhibits the activity of Stearoyl Coenzyme A Desaturase 1 (SCD1) in the liver. This is likely a direct effect since the mRNA of this and other lipogenic genes or the activities of nuclear receptors are not affected. The physiologic effects of SCD1 inhibition include a reduced synthesis of fatty acids, which results in a decrease in storage of triglycerides and other esters of fatty acids. This effect diminishes liver fat (including triglycerides and free fatty acids), and results in an improvement in insulin resistance1. The partial inhibition of the SCD1 enzyme has been confirmed in human liver microsomes2and in animal studies by showing a reduction of the SCD1 activity marker, the fatty acid ratio 16:1/16:0, following aramchol treatment1. These studies showed that the SCD1 inhibition effect of aramchol is partial (between 70% and 83% inhibition).

Unlike other SCD1 inhibitors, studies have demonstrated that aramchol’s effects are non- atherogenic 1. Currently, there are no known inhibitors of SCD1 with the established safety and efficacy profile comparable to that of aramachol.

SCD13

REVERSE CHOLESTEROL TRANSPORT

In addition to the partial inhibition of SCD1, aramchol activates cholesterol efflux by stimulating the ABCA1 transporter by a factor of 2- to 4-fold). ABCA1 is known to be a universal cholesterol export pump present in all cells2,3. In animal models, Galmed established that the down regulation of ABCA1 leads to a significant reduction of blood and body cholesterol and an increase in fecal sterol output, mostly neutral sterols4.

Aramchol induces apolipoprotein-independent reverse cholesterol transport, which enables a more efficient cholesterol clearance from the liver.

Aramchol increases cholesterol efflux from human skin fibroblasts in a dose-dependent manner in the absence of known efflux mediators such as apoA-I (apolipoprotein A-I), but has little effect on phospholipid efflux. Although there is no effect on ABCA1 expression, plasma membrane levels of the transporter increase 2-fold.

Aramchol is the first small molecule that was shown to induce ABCA1-dependent cholesterol efflux without affecting transcriptional control2.

MOA2b

[1] Leikin-Frenkel A., Goldiner I., et al., “Treatment of preestablished diet-induced fatty liver by oral fatty acid-bile acid conjugates in rodents“, Eur J Gastroenterol Hepatol. 2008 Dec;20(12):1205-13

[2] Leikin-Frenkel A, Gonen A et al., “Fatty Acid Bile Acid Conjugate Inhibits hepatic Stearoyl Coenzyme A Desaturase and is not –Atherogenic“, Arch Med Res. 2010 Aug;41(6):397-404

[3] Goldiner I, van der Velde AE et al., “ABCA1-dependent but apoA-I-independent cholesterol efflux mediated by fatty acid-bile acid conjugates (FABACs)“, Biochem J. 2006 Jun 15;396(3):529-36

[4] Brown J.M.,and Rudel L.L., “Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery“, Curr Opin Lipidol. 2010 Jun;21(3):192-7

HISTORY AND ANALYSIS

Their drug candidate, the ARAMCHOL,  is a FABACs is synthetic combination:

  • cholic acid which is one of two major bile acids produced by the liver, where it is synthesized from cholesterol.
  • arachidic (eicosanoic) is a saturated fatty acid present in the peanut oil and other vegetable oils, and fish oils. It acts on liver metabolism

The Fabac's were originally approached to prevent the crystallization of cholesterol.

It has been tested in a Phase 2a

In a sample of 60 patients and three arms (20 patients per arm)

  • An arm dosed at 300 mg / day
  • An arm dosed at 100 mg / day
  • Placebo arm 

Inclusion criteria for this study were :

  • Patients with NAFLD or NASH (based on biopsy)
  • Elevated ALT
  • Steatosis and a lower fibrosis score of 4 (no cirrhosis)
  • A BMI <35.

All the centers wich have conducted the study are located in Israel were the GALMED company is located.

The criteria for the study were the change in triglyceride levels, metabolic and endothelial measures

No histological measures were planned in this study

 

Results

The study only demonstrated a reduction of lipids in the liver

  • For arm 100 mg (-2.89%) and not statistically significant
  • For arm 300 mg (-12.57%)

 

And GALMED also announces a trend of improvement (not statistically significant) in other parameters such as ALT, HOMA, endothelial function and adiponectin.

They do not mention the evolution of the lipid yet emphasized in preclinical testing in mice.

 

To summarize this phase 2a:

The ARAMCHOL in its clinical testing phase 2a, has demonstrated an ability to lower the fat (measured by MRI) in the liver by 12% with a 300 mg / day dose. No histological measure has been performed, so it is impossible to know whether this improvement of steatosis measured by MRI has a measurable effect on the liver histology.

Based on this study, GALMED initiated a Phase 2b targeting NASH:

 

This study (NCT02279524) includes a sample of 240 patients in 3 arms

  • An arm dosed at 600 mg / day
  • An arm 400 mg / day
  • Placebo arm

 

 The main inclusion criteria are as follows

  • BMI> 25 and <40
  • Type 2 Diabetes
  • NASH based on biopsy confirmed by centralized reading
  • NAS score> 4
  • Fat liver> 5.5% measured by MRI
  • No Cirrhosis 

This study takes place over 75 sites in 9 countries

USA, France, Italy, Peru, Mexico, Romania, Israel, Germany, Chile.

It should be noted that 75 sites and 240 patients three arms will make it difficult or virtually impossible to have some balanced sites which can be problematic.

Primary measures are:

  • Measurement of rate of change of triglycerides in the liver by MRI measurement
  • Secondary measures are numerous but has noted the two main histological measures are :
  • The improvement in NAS score a minimum of 2 points
  • The resolution of NASH (not defined)
  • The study duration is 52 weeks and will end in June 2017

 

RECENT NEWS ON ARAMCHOL

2017-01-09 : Galmed Pharmaceuticals Completes Patient Recruitment for ARREST Phase IIb NASH study

2016-03-30 : Aramchol™ Demonstrates Significant Anti-Fibrotic Effect in a Pre-clinical Model of Fatty Liver Disease

SOME PUBLICATIONS RELATED WITH ARAMCHOL

July 2017 : Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

December 2014 : The Fatty Acid–Bile Acid Conjugate Aramchol Reduces Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease

SOME NASHBIOTECHS POINTS OF VIEW RELATED WITH ARAMCHOL

October 2016 : NASH COMBOs ARE THE WAY

August 2016 : STATUS REPORT ON NASH (August 2016)

May 2016 : UPDATE ON THE RACE TO NASH MARKET (May 2016)

November 2015 : GILEADs POSSIBLES STRATEGIES IN NASH

October 2015 : THE NEW DEFINITION OF NASH STRIKE THE NASH PLAYERS

September 2015 : NASH ! TREATMENT’S STRATEGIES AND COMPETITION


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