A Phase 2a, Multi Centre, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Effect of 12 Weeks Treatment With Oral PXS-4728A on Microglia Activation, as Measured by Positron Emission Tomography, in Participants With Isolated Rapid Eye Movement Sleep Behavior Disorder

This study is to investigate the safety and efficacy of PXS-4728A as an intervention therapy in participants with iRBD. This study will be conducted in participants aged 50 to 80 years of age and will investigate a single dose level.

Start Date08 Nov 2023

Sponsor / Collaborator

Syntara Ltd.

NCT03979820 / TerminatedPhase 1

A Phase I Parallel Group Study in Healthy Subjects to Evaluate the Effect of Multiple Oral Doses of BI 1467335 and Phenelzine as Positive Control on Blood Pressure Response to Oral Tyramine (Double-blind, Randomised, Placebo-controlled Design for BI 1467335 Treatment Groups, Open Label for Phenelzine)

The main objective of the study is investigate the effect of escalating doses of oral tyramine on systolic blood pressure (SBP) at baseline and following an oral treatment with BI 1467335 up to 39 days at a low or high dose once daily compared to placebo and phenelzine (Nardil®) as positive control.

Start Date31 Jul 2019

Sponsor / Collaborator

Boehringer Ingelheim GmbH

NCT03927209 / CompletedPhase 1

A Phase I, Open-label, Positron Emission Tomography Study in Healthy Male Subjects to Explore the Inhibition of Monoamine Oxidase B in the Brain After Multiple Oral Doses of BI 1467335 (Non-randomized, Open-label, Parallel-group Study)

The main objective of this trial is to investigate the effect of multiple oral dosing of high dose BI 1467335 over 28 days and multiple oral dosing of low dose BI 1467335 over 42 days on MAO-B occupancy in the brain compared to baseline using [11C]-L-deprenyl-D2 PET tracer in healthy male subjects.

Start Date06 Jun 2019

Sponsor / Collaborator

Boehringer Ingelheim GmbH

100 Clinical Results associated with PXS-4728

100 Translational Medicine associated with PXS-4728

100 Patents (Medical) associated with PXS-4728

Literatures (Medical) associated with PXS-4728

01 Jul 2024·Eye

ROBIN: a randomised, double-masked, placebo-controlled Phase IIa study of the AOC3 inhibitor BI 1467335 in diabetic retinopathy

Article

Author: Dugel, Pravin ; Sivaprasad, Sobha ; Brucker, Alexander ; Jin, Xidong ; Berger, Brian ; Patel, Sunil ; Barranco, Jose Juan Escobar ; Figueira, João ; Silva, Rufino ; Habib, Maged ; Calvo, Pilar ; Bailey, Claire ; Hu, Allen ; Jhaveri, Chirag ; Boyer, David S. ; Ghanchi, Faruque ; Dong Nguyen, Quan ; Erke, Maja Gran ; Bandello, Francesco ; Kunimoto, Derek ; Donate Lopez, Juan ; Talks, James ; Giani, Andrea ; Pagliarini, Sergio ; Varano, Monica ; Menon, Geeta ; Maturi, Raj ; Sen, Harsha ; Rosen, Richard ; Androudi, Sofia ; Ehrlich, Michael S. ; Fawzi, Amani ; Weger, Martin ; Cunningham, Matthew ; Hahn, Paul ; Antoszyk, Andrew ; Manjunatha, Nonavinakere ; Ehlers, Justis P. ; Brown, David

AbstractObjectiveTo evaluate the safety and efficacy of BI 1467335 in patients with non-proliferative diabetic retinopathy (NPDR).MethodsROBIN is a Phase IIa, double-masked, randomised, placebo-controlled study (NCT03238963). Patients with NPDR and without centre-involved diabetic macular oedema were included; all had a best corrected visual acuity letter score of ≥70 Early Treatment Diabetic Retinopathy Study letters in the study eye at screening. Patients received oral BI 1467335 10 mg or placebo once daily for 12 weeks. Post-treatment follow-up was 12 weeks. The primary endpoint was the proportion of patients over the 24 weeks with ocular adverse events (AEs). Secondary endpoints were the proportion of patients with ≥2-step improvement from baseline in DRSS severity level at Week 12 and the proportion of patients with non-ocular AEs at 24 weeks.ResultsSeventy-nine patients entered the study (BI 1467335, n = 40; placebo, n = 39). The proportion of patients with ocular AEs over 24 weeks was greater in the BI 1467335 versus the placebo group (35.0% vs 23.1%, respectively). Treatment-related AEs were reported for similar numbers of patients in the placebo and BI 1467335 group (7.7% vs 7.5%, respectively). At Week 12, 5.7% (n = 2) of patients in the BI 1467335 group had a 2-step improvement in DRSS severity level from baseline, compared with 0% in the placebo group.ConclusionsBI 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.

20 Jan 2020·Mediators of InflammationQ3 · MEDICINE

Comparison of Inhibitor and Substrate Selectivity between Rodent and Human Vascular Adhesion Protein-1

Q3 · MEDICINE

ArticleOA

Author: Henry, Susan H. ; Lieu, Kuo Lee ; Diamond, Christine ; Tulberg, Niklas ; Kubota, Ryo ; Orme, Mark ; Reid, Michael J.

Vascular adhesion protein-1 (VAP-1) is an ectoenzyme that functions as a copper-containing amine oxidase and is involved in leukocyte adhesion at sites of inflammation. Inhibition of VAP-1 oxidative deamination has become an attractive target for anti-inflammatory therapy with demonstrated efficacy in rodent models of inflammation. A previous comparison of purified recombinant VAP-1 from mouse, rat, monkey, and human gene sequences predicted that rodent VAP-1 would have higher affinity for smaller hydrophilic substrates/inhibitors because of its narrower and more hydrophilic active site channel. An optimizedin vitrooxidative deamination fluorescence assay with benzylamine (BA) was used to compare inhibition of five known inhibitors in recombinant mouse, rat, and human VAP-1. Human VAP-1 was more sensitive compared to rat or mouse VAP-1 (lowest IC50concentration) to semicarbazide but was least sensitive to hydralazine and LJP-1207. Hydralazine had a lower IC50in rats compared to humans, although not significant. However, the IC50of hydralazine was significantly higher in the rat compared to mouse VAP-1. 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. Although the sensitivity of these two inhibitors was the lowest in the mouse enzyme, we found no significant differences between mouse, rat, and human VAP-1. Michaelis-Menten kinetics of the small primary amines phenylethylamine and tyramine were also compared to the common marker substrate BA demonstrating that BA had the highest affinity among the substrates. 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.

01 Jul 2018·Translational ResearchQ2 · MEDICINE

Inhibition of semicarbazide-sensitive amine oxidase reduces atherosclerosis in apolipoprotein E-deficient mice

Q2 · MEDICINE

Article

Author: Wang, Shu-Huei ; Kao, Hsien-Li ; Unzeta, Mercedes ; Weston, Chris J ; Solé, Montse ; Yu, Tse-Ya ; Li, Hung-Yuan ; Chen, Yuh-Lien ; Chuang, Lee-Ming ; Tsai, Feng-Chiao ; Lin, Mao-Shin ; Hung, Chi-Sheng ; Li, Yu-I

Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidation end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiography to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examined if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiography in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was positively associated with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion molecules, chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. 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.

News (Medical) associated with PXS-4728

24 May 2021

·www.biospace.com

NGM's Aldafermin Becomes Latest NASH Failure as it Misses Mark in Phase IIB

NGM Biopharmaceuticals’ aldafermin failed to hit its primary endpoint in the company’s Phase IIb ALPINE 2/3 trial for non-alcoholic steatohepatitis (NASH) with stage 2 or 3 liver fibrosis. NASH, a form of fatty liver disease in people who drink little or no alcohol, has been a tough nut to crack, with several high-pro in recent years. The ALPINE 2/3 study evaluated 171 patients with biopsy-confirmed NASH with stage 2 or 3 liver fibrosis (F2/F3). Patients received either 0.3 mg, 1 mg or 3 mg doses of aldafermin once a day via subcutaneous injections and were compared to placebo. The trial failed to hit the primary endpoint of a dose response showing improvement in liver fibrosis by greater than or equal to 1 stage with no worsening of NASH at week 24. It did achieve statistical significance compared to placebo on some secondary endpoints, including NASH resolution at the 3 mg dose and multiple non-invasive measures of NASH, including liver fat content reduction at the 1 mg and 3 mg doses. Aldafermin is an engineered analog of the human hormone FGF19. “These results are certainly disappointing, particularly given the dire unmet need in this patient population,” said David J. Woodhouse, chief executive officer of NGM. “The lack of significant fibrosis improvement was unexpected given the consistency of histology findings previously seen with aldafermin in our adaptive four-cohort Phase II study. "However, in line with the data from that study, ALPINE 2/3 achieved statistical significance on multiple non-invasive measures of NASH at the two higher doses," Woodhouse continued. "That said, given the failure to meet the primary endpoint, we have decided to shift resources that had previously been reserved for a Phase III F2/F3 NASH development program toward advancing our other programs.” That pipeline includes NGM621, an anti-complement C3 antibody in Phase II studies for geographic atrophy; NGM120, a GFRAL antagonistic antibody in Phase II for metastatic pancreatic cancer and cancer-related cachexia; and NGM707 and NGM438, anti-ILT2-ILT4 and LAIR1 myeloid checkpoint candidates, respectively. Both of those compounds are expected to start Phase I trials for advanced solid tumors this year. In addition, Merck is progressing its Phase IIb trial of MK-3655, an FGFR1c/KLB agonistic antibody for NASH, which NGM discovered via a collaboration with Merck. Woodhouse added, “NGM is a markedly different company than when we initiated ALPINE 2/3 in May 2019, when our clinical-stage pipeline consisted primarily of liver and metabolic programs. Over the past two years, we have steadily expanded that pipeline with programs generated from our productive in-house discovery engine, and today we are also an ophthalmology and oncology company with four Phase II programs underway. We look forward to advancing our clinical programs and moving additional programs into the clinic, supported by our cash balance that was in excess of $300 million at the end of the first quarter.” In mid-2020, France’s Genfit reported that its drug elafibranor failed a Phase III trial in NASH. The year before, Gilead Sciences’ selonsertib flunked a Phase III trial. Gilead’s firsocostat and cilofexor were also unsuccessful in NASH. Boehringer Ingelheim and Pharmaxis’ BI 1467335 also failed in trials. For quite some time, the leading company in the NASH race was Intercept Pharmaceuticals and its drug obeticholic acid (OCA). In June 2020, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) rejecting their application. The CRL stated that it could not be approved because of uncertainty about the efficacy of the treatment. There were also concerns over the risk-benefit pro the drug. NGM Bio took a hard hit at today’s news, with shares dropping 48.73% in premarket trading.

Antibody

13 Mar 2018

·www.bioportfolio.com

Pharmaxis Ltd PXS Financial and Strategic SWOT Analysis Review [Report Updated: 09032018] Prices from USD $300

Summary Pharmaxis Ltd Pharmaxis is a pharmaceutical research company that develops and commercialize healthcare products. The company offers products such as aridol which identify twitchy and assist in diagnosing and managing asthma, and bronchitol which restores normal lung hydration, improves lung function and relieves the mucus burden in the lungs of patients. Its products pipeline includes orbital dry powder inhaler, PXS4728A, LOXL2 and ASM8. The company offers solutions for cystic fibrosis, bronchiectasis, asthma and chronic obstructive pulmonary disease, and inflammatory and fibrotic diseases such as nonalcoholic steatohepatitis and pulmonary fibrosis, among others. Pharmaxis is headquartered in Sydney, New South Wales, Australia. Pharmaxis Ltd Key Recent Developments Oct 19,2017: Pharmaxis Strengthens Drug Discovery Capability as its Technology Platform Continues to Deliver Sep 27,2017: Synairgen: Interim results for the six months ended 30 June 2017 Jun 07,2017: Pharmaxis Appoints Former Head of Global Research at Merck to Board of Directors Mar 10,2017: Synairgen: Additional Positive Data in Lung Fibrosis This comprehensive SWOT profile of Pharmaxis Ltd provides you an indepth strategic analysis of the company's businesses and operations. The profile has been compiled by GlobalData to bring to you a clear and an unbiased view of the company's key strengths and weaknesses and the potential opportunities and threats. The profile helps you formulate strategies that augment your business by enabling you to understand your partners, customers and competitors better. This company report forms part of GlobalData's Profile on Demand' service, covering over 50,000 of the world's leading companies. Once purchased, GlobalData's highly qualified team of company analysts will comprehensively research and author a full financial and strategic analysis of Pharmaxis Ltd including a detailed SWOT analysis, and deliver this direct to you in pdf format within two business days. excluding weekends. The profile contains critical company information including*, Business description A detailed description of the company's operations and business divisions. Corporate strategy Analyst's summarization of the company's business strategy. SWOT Analysis A detailed analysis of the company's strengths, weakness, opportunities and threats. Company history Progression of key events associated with the company. Major products and services A list of major products, services and brands of the company. Key competitors A list of key competitors to the company. Key employees A list of the key executives of the company. Executive biographies A brief summary of the executives' employment history. Key operational heads A list of personnel heading key departments/functions. Important locations and subsidiaries A list and contact details of key locations and subsidiaries of the company. Key manufacturing facilities A list of key manufacturing facilities of the company. Detailed financial ratios for the past five years The latest financial ratios derived from the annual financial statements published by the company with 5 years history. Interim ratios for the last five interim periods The latest financial ratios derived from the quarterly/semiannual financial statements published by the company for 5 interims history. Note*: Some sections may be missing if data is unavailable for the company. Key benefits of buying this profile include, You get detailed information about the company and its operations to identify potential customers and suppliers. The profile analyzes the company's business structure, operations, major products and services, prospects, locations and subsidiaries, key executives and their biographies and key competitors. Understand and respond to your competitors' business structure and strategies, and capitalize on their weaknesses. Stay up to date on the major developments affecting the company. The company's core strengths and weaknesses and areas of development or decline are analyzed and presented in the profile objectively. Recent developments in the company covered in the profile help you track important events. Equip yourself with information that enables you to sharpen your strategies and transform your operations profitably. Opportunities that the company can explore and exploit are sized up and its growth potential assessed in the profile. Competitive and/or technological threats are highlighted. Scout for potential investments and acquisition targets, with detailed insight into the companies' strategic, financial and operational performance. Financial ratio presented for major public companies in the profile include the revenue trends, profitability, growth, margins and returns, liquidity and leverage, financial position and efficiency ratios. Gain key insights into the company for academic or business research. Key elements such as SWOT analysis, corporate strategy and financial ratios and charts are incorporated in the profile to assist your academic or business research needs.

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Phase 2	-	Syntara Ltd.	-
Nonalcoholic Steatohepatitis	Phase 1	BE	Boehringer Ingelheim GmbH	06 Jun 2017
Nonalcoholic Steatohepatitis	Phase 1	GB	Boehringer Ingelheim GmbH	06 Jun 2017
Nonalcoholic Steatohepatitis	Phase 1	CA	Boehringer Ingelheim GmbH	06 Jun 2017
Nonalcoholic Steatohepatitis	Phase 1	IE	Boehringer Ingelheim GmbH	06 Jun 2017
Nonalcoholic Steatohepatitis	Phase 1	US	Boehringer Ingelheim GmbH	06 Jun 2017
Nonalcoholic Steatohepatitis	Phase 1	NL	Boehringer Ingelheim GmbH	06 Jun 2017
Nonalcoholic Steatohepatitis	Phase 1	FR	Boehringer Ingelheim GmbH	06 Jun 2017
Nonalcoholic Steatohepatitis	Phase 1	DE	Boehringer Ingelheim GmbH	06 Jun 2017
Nonalcoholic Steatohepatitis	Phase 1	ES	Boehringer Ingelheim GmbH	06 Jun 2017

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02733627 (CTgov)	Phase 1	-	36	BI 1467335 (BI 1467335 10 mg (Low Dose))	bkgawhgprd(gmcjlgjlot) = skqcdxtwms agtdsnezli (lydvuxmnki, ckyblepnhm - xcgypbjbce) View more	-	07 Jun 2021
				BI 1467335 (BI 1467335 15 mg (Medium Dose))	bkgawhgprd(gmcjlgjlot) = wwoleauoos agtdsnezli (lydvuxmnki, hlpumdnfqe - hfdpmubctf) View more
NCT02999191 (CTgov)	Phase 1	-	18	BI 1467335 (BI 1467335: Tablets, Fed)	kbpbjarunh(iypcfmvvch) = cluyfxwewb obbabgrmje (uwyngvmgtu, jxtkzclbhz - uuhexdgoja) View more	-	07 Jun 2021
				BI 1467335 (BI 1467335: Tablets, Fasted)	kbpbjarunh(iypcfmvvch) = zwjzjqysuw obbabgrmje (uwyngvmgtu, yfipmlfafp - bjxgnlgkmz) View more
NCT03382509 (CTgov)	Phase 1	-	16	BI 1467335 (BI 1467335 10 Milligram (mg) (SD))	rahesrogsm(zmzwmwxhxj) = cakjjzocdu isjuknxinm (xcdzkemrkd, uextcbxuyk - yntobasmil) View more	-	07 Jun 2021
				BI 1467335 (BI 1467335 10 mg (MD))	rahesrogsm(zmzwmwxhxj) = eliwohtgty isjuknxinm (xcdzkemrkd, cznawcepyu - pbtaaronyv) View more
NCT03238963 (ROBIN, CTgov)	Phase 2	Diabetic macular oedema \| Nonproliferative diabetic retinopathy	79	Placebo	jophajzuxl(nxhlljwdyq) = qestokoekp vxofonwlab (xcucebhytu, eydflknxgh - wibzwmotcm) View more	-	04 Jun 2021
NCT03159455 (CTgov)	Phase 1	-	48	Placebo (Placebo (Japanese))	bmzkikdjho(fyaycukbyy) = fezkkuqfys xrtajnozzf (kcaydudbfd, wyjekiwccl - ysopciwujn) View more	-	04 Jun 2021
				BI 1467335 (BI 1467335 3 mg Tablet (Japanese))	bmzkikdjho(fyaycukbyy) = djdjgbinsv xrtajnozzf (kcaydudbfd, oxppkwalds - pxkekbsrdl) View more
NCT03927209 (CTgov)	Phase 1	-	10	BI 1467335 (BI 1467335 10 Milligram (mg))	rqeiunqqwr(rhladenjam) = ydbdszxkqo dfovoaikml (eykpuluzoq, sbtmkklbeq - jxzhweygzl) View more	-	04 Jun 2021
				BI 1467335 (BI 1467335 3 Milligram (mg))	rqeiunqqwr(rhladenjam) = osczpvwriu dfovoaikml (eykpuluzoq, mjoaoyeynv - rtzclejolv) View more
NCT03302091 (CTgov)	Phase 1	Renal Insufficiency	20	BI 1467335 (BI 1467335 Normal (R))	ajrdqiarjx(lchyuemzly) = tgoijahluj luehmprwpo (hwvkownjdi, spmnzidbfw - ystataiozy) View more	-	04 Jun 2021
				BI 1467335 (BI 1467335 Moderate (T))	ajrdqiarjx(lchyuemzly) = xsizmanllk luehmprwpo (hwvkownjdi, gsjrbxbhqc - lhskswemip) View more
NCT03483506 (CTgov)	Phase 1	-	12	BI 1467335 (BI 1467335 Tab)	qiatzebhas(oiskamraqg) = sokorfppbx okamlnscrt (yrwqsowojy, ngohpnrvtj - sasguhrtdn) View more	-	04 Jun 2021
				BI 1467335 (C-14)+BI 1467335 (BI 1467335 (C-14) iv)	qiatzebhas(oiskamraqg) = uajnizrgfc okamlnscrt (yrwqsowojy, lpogmczkfj - tujnpnhaun) View more
NCT03166735 (CTgov)	Phase 2	Nonalcoholic Steatohepatitis	114	Placebo	zljauoaxzy(yqpzmdtiqy) = qhswtrnpnc adiwblpijg (vkqrdbcvht, bylmsaxqmg - cfazcbaqbm) View more	-	11 Jun 2020

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