SNT-4728 / Syntara - LARVOL DELTA

Effect of PXS-4728A on Microglia Activation in Participants With Isolated Rapid Eye Movement Sleep Behaviour Disorder (clinicaltrials.gov) - P2 | N=40 | Active, not recruiting | Sponsor: Syntara | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2025 ➔ Jan 2026

Enrollment closed • Trial completion date • CNS Disorders • Mental Retardation • Psychiatry • REM Sleep Behavior Disorder • Sleep Disorder

ROBIN: a randomised, double-masked, placebo-controlled Phase IIa study of the AOC3 inhibitor BI 1467335 in diabetic retinopathy. (PubMed, Eye (Lond)) - P2 | "BI 1467335 was well tolerated by patients with NPDR. There was a high variability in DRSS levels for individual patients over time, with no clear efficacy signal."

Journal • P2a data • Diabetic Macular Edema • Diabetic Retinopathy • Macular Edema • Ophthalmology • Retinal Disorders • AOC3

Effect of PXS-4728A on Microglia Activation in Participants With Isolated Rapid Eye Movement Sleep Behaviour Disorder (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Pharmaxis | Not yet recruiting ➔ Recruiting | Phase classification: P2a ➔ P2 | Initiation date: Jul 2023 ➔ Nov 2023

Enrollment open • Phase classification • Trial initiation date • Behavior Disorders • CNS Disorders • Mental Retardation • Psychiatry • REM Sleep Behavior Disorder • Sleep Disorder

A randomised Phase IIa trial of amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335 in adults with non-alcoholic steatohepatitis. (PubMed, Nat Commun) - P2 | "BI 1467335 strongly inhibited AOC3 in participants with NASH, with doses ≥3 mg dose-dependently reducing the levels of liver injury biomarkers, ALT and CK-18. This trial was registered with ClinicalTrials.gov (NCT03166735) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2016-000499-83)."

Journal • P2a data • Addiction (Opioid and Alcohol) • Hepatology • Inflammation • Liver Failure • Non-alcoholic Steatohepatitis • AOC3 • KRT18

Effect of PXS-4728A on Microglia Activation in Participants With Isolated Rapid Eye Movement Sleep Behaviour Disorder (clinicaltrials.gov) - P2a | N=40 | Not yet recruiting | Sponsor: Pharmaxis

New P2a trial • Behavior Disorders • CNS Disorders • Mental Retardation • Psychiatry • REM Sleep Behavior Disorder • Sleep Disorder

Pharmaxis to tackle Parkinson’s in “groundbreaking” clinical collaboration (Proactiveinvestors) - "Pharmaxis Ltd...is set to receive a £2.9 million (around A$5 million) cash injection from Parkinson’s UK to support a Phase 2 clinical trial. The leading charity will issue the funds from its drug discovery arm, the Parkinson’s Virtual Biotech program, with collaborators at the University of Sydney and the University of Oxford to lead the study. Essentially, the Phase 2 trial will investigate Pharmaxis drug candidate PXS-4728 in a bid to tackle Parkinson’s at the onset....Together, experts from Sydney and Oxford universities will recruit 40 patients with iRBD to participate in the placebo-controlled PXS-4728 trial. Recruitment is expected to begin in early 2023..."

Financing • New P2 trial • CNS Disorders • Parkinson's Disease

[VIRTUAL] ECC0509, A NOVEL PERIPHERALLY DISTRIBUTED AND SELECTIVE SEMICARBAZIDE-SENSITIVE AMINO OXIDASE (SSAO) INHIBITOR FOR NASH TREATMENT (AASLD 2021) - "The clinical development of SSAO inhibitor BI 1467335 for NASH was discontinued due to interference with brain monoamine oxidase B (MAO-B)...In addition, ECC0509 has less inhibition to DAO compared to TERN-201, suggesting unlikelihood of interference with histamine metabolism . ECC0509 is a potential best-in-class SSAO inhibitor and currently in phase I clinical trial ."

Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis • AOC3

ROBIN: A Study That Tests BI 1467335 in Patients With Diabetic Eye Disease (Diabetic Retinopathy). It Looks at the Way BI 1467335 is Taken up, the Effects it Has, and How Well it is Tolerated. (clinicaltrials.gov) - P2; N=79; Completed; Sponsor: Boehringer Ingelheim; Trial primary completion date: Feb 2020 ➔ May 2020

Clinical • Trial primary completion date • Diabetic Macular Edema • Diabetic Retinopathy • Ocular Infections • Ophthalmology • Retinal Disorders

A Study in Healthy People to Test How Combining BI 1467335 and Tyramine Affects Blood Pressure (clinicaltrials.gov) - P1; N=53; Terminated; Sponsor: Boehringer Ingelheim; N=37 ➔ 53

Clinical • Enrollment change

Semicarbazide-sensitive amine oxidase inhibition ameliorates albuminuria and glomerulosclerosis but does not improve tubulointerstitial fibrosis in diabetic nephropathy. (PubMed, PLoS One) - "We aimed to assess the effectiveness of a SSAO inhibitor (SSAOi; PXS-4728A) as an antifibrotic agent using a diabetic model of CKD. Diabetic mice were treated with SSAOi for 24 weeks and outcomes compared with untreated diabetic mice and telmisartan treated animals as a standard of care comparator...However, the effect of SSAO inhibition was less obvious in the tubulointerstitial compartment than in the glomeruli. Therefore, SSAO may be a potential target for diabetic glomerulosclerosis."

Journal • Chronic Kidney Disease • Diabetic Nephropathy • Fibrosis • Glomerulonephritis • Immunology • Nephrology • Renal Disease

Comparison of Inhibitor and Substrate Selectivity between Rodent and Human Vascular Adhesion Protein-1. (PubMed, Mediators Inflamm) - "Human VAP-1 was more sensitive compared to rat or mouse VAP-1 (lowest IC concentration) to semicarbazide but was least sensitive to hydralazine and LJP-1207...The larger hydrophobic compounds from Astellas (compound 35c) and Boehringer Ingelheim (PXS-4728A) were hypothesized to have higher binding affinity for human VAP-1 compared to rodent VAP-1 since the channel in human VAP-1 is larger and more hydrophobic than that in rodent VAP-1...Rat VAP-1 had the highest affinity for all three substrates and mouse VAP-1 had intermediate affinity for BA and phenylethylamine, but tyramine was not a substrate for mouse VAP-1 under these assay conditions. These results suggest that comparing oxidative deamination in mouse and rat VAP-1 may be important if using these species for preclinical efficacy models."

Journal • Preclinical • Immunology • AOC3

ROBIN: A Study That Tests BI 1467335 in Patients With Diabetic Eye Disease (Diabetic Retinopathy). It Looks at the Way BI 1467335 is Taken up, the Effects it Has, and How Well it is Tolerated. (clinicaltrials.gov) - P2; N=79; Completed; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Completed

Clinical • Trial completion • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Ophthalmology • Retinal Disorders

Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice. (PubMed, Transl Res) - "Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis."

Biomarker • Journal • Preclinical • Acute Coronary Syndrome • Atherosclerosis • Biosimilar • Cardiovascular • Dyslipidemia • Immunology

".@Boehringer 2nd @Pharmaxis PXS-4728A Trial Triggers $15m - subscribe to Biotech Daily https://t.co/4E9331THtC" (@biotech_daily)

Biosimilar

This Study Tests How BI 1467335 is Taken up in the Body of People With Normal Kidney Function and People With Reduced Kidney Function. The Study Also Looks at How Well the Participants Tolerate BI 1467335 (clinicaltrials.gov) - P1; N=20; Recruiting; Sponsor: Boehringer Ingelheim; Not yet recruiting ➔ Recruiting

Enrollment open • Biosimilar • Renal Disease

A Study in Healthy People to Test How Combining BI 1467335 and Tyramine Affects Blood Pressure (clinicaltrials.gov) - P1; N=37; Terminated; Sponsor: Boehringer Ingelheim; N=62 ➔ 37; Suspended ➔ Terminated; Due to the current COVID-19 pandemic, the recruitment of new subjects is temporarily discontinued. Ongoing, randomised patients are managed per Trial Protocol.

Clinical • Enrollment change • Trial termination

A Study in Healthy People to Test How Combining BI 1467335 and Tyramine Affects Blood Pressure (clinicaltrials.gov) - P1; N=62; Suspended; Sponsor: Boehringer Ingelheim; Recruiting ➔ Suspended

Trial suspension

Boehringer Ingelheim discontinues development of BI 1467335 for NASH (Boehringer Ingelheim Press Release) - "Boehringer Ingelheim and Pharmaxis Ltd today announced the discontinuation of the development of BI 1467335 for the treatment of NASH (non-alcoholic steatohepatitis). BI 1467335 was acquired from Pharmaxis in 2015."

Discontinued

ROBIN: A Study That Tests BI 1467335 in Patients With Diabetic Eye Disease (Diabetic Retinopathy). It Looks at the Way BI 1467335 is Taken up, the Effects it Has, and How Well it is Tolerated. (clinicaltrials.gov) - P2; N=100; Active, not recruiting; Sponsor: Boehringer Ingelheim; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A Study in Healthy Men to Test the Effects of Different Doses of BI 1467335 on MAO-B Activity in the Brain. (clinicaltrials.gov) - P1; N=10; Completed; Sponsor: Boehringer Ingelheim; Recruiting ➔ Completed

Clinical • Trial completion

Semicarbazide-Sensitive Amine Oxidase (SSAO) Inhibition Ameliorates Albuminuria and Glomerulosclerosis but Does Not Significantly Improve Tubulointerstitial Fibrosis in Diabetic Nephropathy (KIDNEY WEEK 2019) - "We aimed to determine the effectiveness of a SSAO inhibitor (PXS4728A) as an antifibrotic agent using a diabetic model of chronic kidney fibrosis...Therefore, SSAOi may be a potential target for diabetic glomerulosclerosis. Parameters of studied animalsSSAO inhibiton reduced glomerulosclerosis but not degree of tubulointerstitial fibrosis"

A Study in Healthy Men to Test the Effects of Different Doses of BI 1467335 on MAO-B Activity in the Brain. (clinicaltrials.gov) - P1; N=10; Recruiting; Sponsor: Boehringer Ingelheim; Active, not recruiting ➔ Recruiting

Clinical • Enrollment open

A Study in Healthy Men to Test the Effects of Different Doses of BI 1467335 on MAO-B Activity in the Brain. (clinicaltrials.gov) - P1; N=10; Active, not recruiting; Sponsor: Boehringer Ingelheim; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

Inhibition of Semicarbazide-sensitive Amine Oxidase Reduces Atherosclerosis in Cholesterol-fed New Zealand White Rabbits. (PubMed, Sci Rep) - "Treatment with PXS-4728A, a selective VAP-1/SSAO inhibitor, in cholesterol-fed rabbits significantly decreased SSAO-specific hydrogen peroxide generation in the aorta and reduced atherosclerotic plaques. VAP-1/SSAO inhibition also lowered blood low-density lipoprotein cholesterol, reduced the expression of adhesion molecules and inflammatory cytokines, suppressed recruitment and activation of macrophages, and decreased migration and proliferation of SMC. In conclusion, VAP-1/SSAO inhibition reduces atherosclerosis and may act through suppression of several important mechanisms for atherosclerosis."

Journal

ROBIN: A Study That Tests BI 1467335 in Patients With Diabetic Eye Disease (Diabetic Retinopathy). It Looks at the Way BI 1467335 is Taken up, the Effects it Has, and How Well it is Tolerated. (clinicaltrials.gov) - P2; N=100; Recruiting; Sponsor: Boehringer Ingelheim; Trial completion date: Jan 2020 ➔ May 2020; Trial primary completion date: Oct 2019 ➔ Feb 2020

Clinical • Trial completion date • Trial primary completion date