SSAO Inhibitor BI 1467335

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 acquired from Pharmaxis in 2015 by Boehringer Ingelheim, initially to develop for the treatment of 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.

Access Pharmaxis Publications and Posters on SSAO inhibitors

Clinical trials of BI 1467335

In September 2015 the company announced positive results for all primary and secondary endpoints from a 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.

In August 2017 Boehringer Ingelheim commenced a phase 2a clinical trial in NASH [https://clinicaltrials.gov/show/NCT03166735]. This Phase IIa trial was a multi-centre, double-blind design in 108 patients with clinical evidence of NASH. The primary objectives were to establish proof of clinical principle, investigate suitable dosing, and to evaluate the safety of BI 1467335. In a 12 week Phase IIa trial investigating BI 1467335 in patients with clinical evidence of NASH, treatment was well tolerated and no related serious adverse events occurred. The study met the pre specified targets for inhibition of plasma amine oxidase copper‐containing 3 (AOC3) activity by BI 1467335 compared to placebo, as well as clinically relevant changes in NASH biomarkers. However, following assessment of another recently completed Phase I study, Boehringer Ingelheim decided not to further develop BI 1467335 in the NASH indication based on the potential risk of drug interactions in NASH patients.

In January 2018 Boehringer Ingelheim commenced a phase 2a clinical trial of BI 1467335 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 have been randomised to either BI 1467335 or to placebo for a 12-week treatment period[https://clinicaltrials.gov/ct2/show/NCT03238963].

NASH

Sale of PXS-4728A to Boehringer Ingelheim

In May 2015 Pharmaxis sold its anti-inflammatory drug candidate BI 1467335 (formerly known as 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 was initially developed by Boehringer for the treatment of the diabetes and liver-related condition NASH, and in January 2018 Boehringer commenced development of BI 1467335 for diabetic retinopathy (DR).

Under the agreement, Boehringer is responsible for all development, regulatory, manufacturing and commercialisation activities and pays milestone and other payments to Pharmaxis in relation to the development and approval of BI 1467335 in two (unspecified) indications. Pharmaxis received an upfront payment of €27.5 million (approximately A$39m) and a further  €28 upon commencement of phase 2a clinical trials in NASH and DR - a total of A$83 million received to date.

As a result of the discontinuation of BI's development of BI 1467335 in NASH announced in December 2019 (see above), Pharmaxis is eligible to receive payments in relation to BI's development and commercialisation of BI 1467335 in the one indication - DR. Subject to the continuing successful development and commercialisation of the BI 1467335 program this includes:

  • €37 million  tied to the commencement of a 3 clinical trial
  • 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
  • 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

 

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