SSAO inhibitor BI 1467335 (formerly known as PXS-4728A)
Novel SSAO/VAP-1 inhibitor BI 1467335( formerly known as PXS-4728A) - for the treatment of inflammation
BI 1467335 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), BI 1467335 provides >90% inhibition of its target enzyme for 24 hours after a single oral dose.
BI 1467335 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 BI 1467335
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 BI 1467335. Once daily oral dosing of BI 1467335 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 BI 1467335 and most importantly, showed these low doses are efficacious in inhibiting the enzyme and cause a long lasting inhibition. BI 1467335 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.
In August 2017 Boehringer Ingelheim commenced a phase 2 clinical trial in NASH. This Phase IIa trial is a multi-centre, double-blind design in 150 patients with clinical evidence of NASH. The primary objectives are to establish proof of clinical principle, investigate suitable dosing, and to evaluate the safety of BI 1467335. Patients will be randomized to either one of four dosages of BI 1467335 or to placebo for a 12-week treatment period[https://clinicaltrials.gov/show/NCT03166735]. A subsequent Phase IIb study will seek to confirm and extend these findings.
In September 2017 Boehringer Ingelheim initiated a phase 2 clinical trial in diabetic retinopathy. This Phase IIa trial is a multi-centre, double-blind design in 100 patients with moderately severs non-proliferative diabetic retinopathy without centre involved diabetic macular oedema. The primary objectives are to establish proof of mechanism and support dose findings, and to evaluate the safety of BI 1467335. Patients will be randomized to either BI 1467335 or to placebo for a 12-week treatment period[https://clinicaltrials.gov/ct2/show/NCT03238963]. A subsequent Phase IIb study will seek to confirm and extend these findings.
|Description||Phase 2a NASH study|
|Sites||USA, Canada, The Netherlands|
|Description||Phase 2a Study in Diabetic Retinopathy|
Sale of PXS-4728A to Boehringer Ingelheim
In May 2015 Pharmaxis sold its anti-inflammatory drug candidate BI 1467335 (PXS-4728A), 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 BI 1467335 to Boehringer is a globally competitive deal. BI 1467335 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 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 BI 1467335 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 BI 1467335 program product for a second indication
- Earn-out payments on annual net sales of BI 1467335 program products at tiered percentages starting in the high single digits
- Commercialisation milestone payments upon achievement of specified levels of annual net sales of BI 1467335 program products
In September 2015 the company announced positive results for all primary and secondary endpoints from the phase 1 clinical trial of BI 1467335. Once daily oral dosing of BI 1467335for 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 BI 1467335 and showed these low doses are efficacious in inhibiting the enzyme and cause a long lasting inhibition suggesting BI 1467335 can be dosed once a day.
In August 2017 Boehringer commenced a Phase 2a study in NASH. 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
In September 2017 Boehringer initiated a Phase 2a study in diabetic retinopathy. Diabetic retinopathy (DR) is the leading cause of vision-loss in adults aged 20-74. It progresses from mild nonproliferative diabetic retinopathy to moderate and severe nonproliferative diabetic retinopathy (NPDR), characterized by retinal hemorrhages and vascular changes in the retina, to proliferative diabetic retinopathy (PDR), characterized by the growth of new blood vessels on the retina. Diabetic Macular Edema (DME), characterized by retinal thickening from leaky blood vessels, can develop at all stages of retinopathy. Of an estimated 285 million people with diabetes mellitus worldwide, approximately one third have signs of DR and of these, a further one third of DR is vision-threatening DR (severe NPDR, PDR and DME)
* ClinicalTrials.gov is a service provided by the U.S. National Institutes of Health, Department of Health and Human Services, through its National Library of Medicine. ClinicalTrials.gov provides patients, family members, and members of the public easy and free access to information on clinical studies for a wide range of diseases and conditions. Pharmaxis chooses to publish all Pivotal Trials on the ClinicalTrials.gov website.