N-003 (ambrisentan) is not approved for commercialisation
© — Noorik Biopharmaceuticals, Switzerland
“The most fruitful basis for the discovery of a new drug is to start with an old drug”
Ambrisentan is a receptor antagonist of endothelin, a potent vasoconstrictor. N-003 is a proprietary formulation of ambrisentan suitable for the administration of low doses to patients with advanced liver disease and cirrhosis.
Experimental and clinical data have shown that endothelin antagonism rapidly and significantly reduces portal pressure by reversing endothelin-induced intra-hepatic vasoconstriction, a key component of Portal Hypertension (Link). Endothelin antagonism is mechanistically different from current therapies such as terlipressin, midodrine and β-blockers which work by lowering blood flow to the liver. Endothelin antagonism reduces portal pressure by decreasing intra-hepatic resistance and increasing liver blood flow by decreasing hepatic sinusoidal resistance (Link).
Noorik has recently discovered that high-dose ambrisentan is less effective than low-dose ambrisentan in blocking the vasoconstrictive effects of endothelin. The doses currently used for Pulmonary Arterial Hypertension do not block the ETA receptor selectively. Human pharmacokinetic studies with N-003 have established that low-dose ambrisentan preferentially antagonise the effects of endothelin on the ETA receptor.
N-003 was recently evaluated in a Phase IIa study in patients with cirrhosis and a history of ascites. Currently, we are conducting a Phase IIb clinical study to confirm the sub-acute effect of N-003 on portal pressure as determined by Hepatic Vein Pressure Gradient (HVPG) and to evaluate the safety in this patient population. First results are expected in Q2.2019. If positive, N-003 may become the first therapy reducing portal pressure by modulating intra-hepatic sinusoidal resistance.
N-003 is an investigational product and has not been approved for commercialization. Noorik plans to submit a New Drug Application (NDA) dossier for N-003 under the 505(b)(2) pathway in the US and as a hybrid application in Europe. Ambrisentan is marketed since 2007 in the US as Letairis® and in Europe as Volibris®. Ambrisentan (5 and 10 mg) is currently used to treat some forms of Pulmonary Arterial Hypertension.
The focus of our studies is to determine the benefit of N-003 in decompensated cirrhosis, that is late-stage patients with the complications of Portal Hypertension. Other current drug development efforts focus on the etiology of cirrhosis. The evaluation of bombination regimens may be an important avenue to develop additional options for patients in early stage cirrhosis.
Patent applications on second medical uses and novel formulations for N-003 have been filed. If granted, this patent portfolio will confer market exclusivity up to 2037. Noorik is in the process of securing orphan designation for the complications of cirrhosis.