SSAO inhibitor PXS-4728A

Novel SSAO/VAP-1 inhibitor (PXS-4728A) - for the treatment of inflammation

PXS-4728A is a very potent and highly selective compound in development for the treatment of cardiometabolic diseases like the liver-related disease Nonalcoholic Steatohepatitis (NASH). As a first-in-class, mechanism-based inhibitor of Semicarbazide-Sensitive Amine Oxidase (SSAO), also known as Vascular Adhesion Protein-1 (VAP-1), PXS-4728A provides >90% inhibition of its target enzyme for 24 hours after a single oral dose.

PXS-4728A is efficacious in various pre-clinical NASH and lung inflammation models, the inhibition of SSAO/VAP-1 can be easily measured with biomarkers and exhibits therapeutic potential across a range of chronic inflammatory conditions.

Clinical trials of PXS4728A

A phase I trial including a single ascending dose stage and a multiple ascending dose stage has recently been completed. In September the company announced positive results for all primary and secondary endpoints from the phase 1 clinical trial of PXS-4728A . Once daily oral dosing of PXS-4728A for 14 days at doses between 3 and 10 mg was found to be safe and well tolerated. The data confirmed the high oral bioavailability of PXS-4728A and most importantly, showed these low doses are efficacious in inhibiting the enzyme and cause a long lasting inhibition. PXS-4728A thus meets the ideal requirements for a drug intended for use in a chronic treatment; a once a day tablet that causes 24 hour inhibition of the target enzyme at low doses.

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Inflammation

Sale of PXS-4728A to Boehringer Ingelheim

In May 2015 Pharmaxis sold its anti-inflammatory drug candidate PXS4728A, the first drug developed from the amine oxidase platform, to leading global pharmaceutical company Boehringer Ingelheim.

With a total potential value in excess of $A750 million, the sale of Pharmaxis' investigational drug PXS4728A to Boehringer is a globally competitive deal. PXS4728A is being developed by Boehringer for the treatment of the diabetes and liver-related condition NASH, and has further potential in chronic obstructive pulmonary disease (COPD) and other diseases with high medical need.

Under the agreement, Boehringer is responsible for all development, regulatory, manufacturing and commercialisation activities. Pharmaxis received an upfront payment of €27.5 million (approximately A$39m) and, subject to the continuing successful development and commercialisation of the PXS4728A program:p to a total of €55 million in development milestone payments tied to the commencement of phase 2 and 3 clinical trials

  • Up to a total of €140 million in regulatory milestone payments upon filing of applications for marketing approval and receipt of regulatory and pricing approvals for a PXS4728A program product in the major pharmaceutical markets (i.e., USA, EU, and China or Japan) for the first indication
  • Additional milestone payments similar in total to those set forth above upon achievement of the same development and regulatory milestone events by a PXS4728A program product for a second indication
  • Earn-out payments on annual net sales of PXS4728A program products at tiered percentages starting in the high single digits
  • Commercialisation milestone payments upon achievement of specified levels of annual net sales of PXS4728A program products

In September the company announced positive results for all primary and secondary endpoints from the phase 1 clinical trial of PXS-4728A . Once daily oral dosing of PXS-4728A for 14 days at doses between 3 and 10 mg was found to be safe and well tolerated. The data confirmed the high oral bioavailability of PXS-4728A and showed these low doses are efficacious in inhibiting the enzyme and cause a long lasting inhibition suggesting PXS‐4728A can be dosed once a day.

Boehringer is currently designing and preparing for the phase 2 trial. While Pharmaxis is not involved in the program, based on usual drug development timeframes we would expect the phase 2 trial to commence by the first quarter of 2017.

NASH is commonly found in people who are overweight or obese. Given the increasing rate of obesity around the world, made worse by sedentary lifestyles and poor food choices, the condition is likely to become a major cause of liver disease and transplantations in coming years.

It’s estimated that one in three people have fatty liver disease and that up to 10% of those will have NASH. One of the main ways to manage NASH is for the sufferer to reduce fat in the liver by losing weight through exercise and healthy eating. However, with changes in behaviour notoriously difficult to achieve, drug therapies are needed. There are currently no approved therapies available to treat NASH and Deutsche Bank estimates that the global market could be worth in excess of US$35b by 2025.

It is not surprising that large Pharma companies are focussing their resources on developing and acquiring drug development programs in this area. In 2015, Gilead acquired Phenex a treatment for NASH in Phase 2 trials in a deal worth $470 million while AstraZeneca bought the rights for a pre-clinical drug candidate to treat NASH from Regulus. Companies like Genefit and Intercept who have drugs that have completed phase 2 trials in NASH have market values in excess of US$1b

For additional information on drugs being developed for NASH and the potential market please refer to the 2014 report by Deutsche Bank.

For additional information on NASH please refer to the September 2015 presentation "Clinical Perspective on NASH" by Prof Jacob George

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