PNQ 103 from Advinus for the potential treatment of COPD & sickle cell disease (SCD)

PNQ 103

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for the potential treatment of COPD & sickle cell disease (SCD)

Adenosine A2b receptor antagonist

Advinus Therapeutics Ltd

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PNQ-103 is a proprietary A2B Adenosine receptor (A2BAdoR antagonist), currently in the pre-clinical development stage for the potential treatment of COPD & sickle cell disease (SCD). Advinus is looking for partnering/co-development opportunities.

COPD

Chronic Obstructive Pulmonary Disease (COPD) is a disease that damages lung tissue or restricts airflow through the bronchioles and bronchi, and commonly leads to chronic bronchitis and emphysema. COPD, along with asthma, forms the third leading cause of death in both developed and developing countries and an annual direct and indirect cost of healthcare of more than $50 billion in the US alone. Current therapies suffer from lack of long term efficacy, patient compliance and a narrow therapeutic index.

Adenosine is a powerful bronchoconstrictor and pro-inflammatory agent in COPD and asthma. Adenosine regulates tissue function by activating its receptors: A₁AdoR and A_2AAdoR are high affinity receptors and A_2BAdoR and A₃AdoR are low affinity receptors. During pathological conditions in lung, local adenosine concentrations rise to high levels and activate A_2BAdoR. A_2BAdoR agonized by adenosine induces both bronchoconstriction and pro-inflammatory effects in lung by acting on multiple cell types that lead to airway hyperreactivity and chronic inflammation. Therefore, A_2BAdoR antagonists are expected to be beneficial in COPD and asthma.

PNQ-103 is a proprietary A_2BAdoR antagonist, currently in the pre-clinical development stage for the potential treatment of COPD.  It is a potent, selective, orally bio-available agent with low clearance and small volume of distribution. PNQ-103 is efficacious in standard rodent asthma and lung fibrosis models. PNQ-103 was found to be safe in exploratory safety studies including a Drug Matrix Screen, mini-AMES test, and a test for cardiovascular liability in dog telemetry as well as a 30- day repeat dose study in rats.

SCD

Sickle Cell Disease (SCD) affects millions of people worldwide. It is caused by an autosomal mutation in the hemoglobin gene (substitution of amino-acid valine [Hb A] for glutamic acid [Hb S]. Hb S in low O2 condition polymerizes, leading to distortion of the cell membrane of red blood cells (RBC) into an elongated sickle shape. Sickled RBCs accumulate in capillaries causing occlusions, impair circulation and cause tissue damage and severe disabilities. Unfortunately, there is no targeted therapy for SCD.

Adenosine levels are elevated in SCD patients. Activation of the A_2BAdoR by adenosine increases 2,3-DPG levels in RBCs, which reduces Hb S affinity to O2 and promotes its polymerization leading to RBC sickling. A recent study published in Nature Medicine (2011; 17:79-86) demonstrated potential utility of an A_2BAdoR antagonist for the treatment of SCD, through selective inhibition of 2,3-DPG production in RBCs.  Therefore, PNQ-103, a selective A_2BAdoR antagonist, is expected to be useful for the treatment of SCD.  In support, ex vivo PoC (selective inhibition of 2,3-DPG production) has been established for PNQ-103 in RBCs from normal and SCD patients.

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