“The most fruitful basis for the discovery of a new drug is to start with an old drug”

Sir James Black

Nobel Prize in Physiology and Medicine, 1988

About Ambrisentan

Endothelin, a peptide hormone, is the most potent vasoconstrictor known today. Endothelin regulates primarily endothelial function and organ blood flow. In disease, increased activity of endothelin results in a decrease of blood flow, a decrease in organ oxygen delivery and fibrosis. Key organs, such as the lungs, kidney, skin and the liver are particularly sensitive to the effects of endothelin. By blocking the effects of endothelin, blood flow and oxygen delivery can be restored.

Ambrisentan, a small molecule, is a well-characterised endothelin receptor antagonist. Ambrisentan is currently approved/authorised for the treatment of some forms of Pulmonary Arterial Hypertension at doses of 5 and 10 mg. Given that ambrisentan is a potent drug, there is some indication that significantly smaller doses of ambrisentan may block the effects of endothelin. In addition, there is also an indication that significantly smaller doses of ambrisentan may result in fewer side effects.

Ambrisentan Structure

Why a Micro-dose Ambrisentan?

To elicit its effects, Endothelin binds to two receptors: the ETA receptor and the ETB receptor. When bound to the ETA receptor, Endothelin exerts a vasoconstrictive effect and reduction of blood flow. When bound to the ETB receptor, Endothelin exerts a vasodilatory effect, increases blood flow and promotes the formation of urine. To prevent the noxious effects of increased Endothelin in disease, selective blockade of the effects of Endothelin at the ETA receptor would be preferred. In addition, blockade of the ETB receptor may affect the ability of the kidney to produce urine, explaining in part the formation of fluid retention.

Ambrisentan has the ability to block the effects of endothelin on both the ETA and ETB receptors. However, the blockade of each receptor occurs at different concentrations of Ambrisentan in blood: Ambrisentan blocks the ETA receptor at significantly lower concentrations than those required to block the ETB receptor.

Given the potency of Ambrisentan, the current doses of commercially available Ambrisentan block both receptors. As such, the development of micro-dose Ambrisentan is a rationale approach to block the effects of endothelin selectively on the ETA receptor.

New Formulations of Ambrisentan

To address the requirements for a low dose and the clinical characteristics of the key indications, Noorik has developed novel formulations of ambrisentan for oral and parenteral administration.

Regulatory Pathway

Given that ambrisentan has been previously approved or authorised for commercialisation, Noorik plans to submit a New Drug Application (NDA) dossier for micro-dose Ambrisentan under the 505(b)(2) pathway in the US and as a hybrid application in Europe.

N-003 (micro-dose ambrisentan) is an investigational product and has not been approved or authorised for commercialization.

Intellectual Property

Noorik has been granted second medical use patents for our key target indications and for micro-dose ambrisentan in novel formulations in the United States and Europe (among others).