A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of the NOX1/4 Inhibitor Setanaxib in Patients With Alport Syndrome

The purpose of the study is to learn about the safety and tolerability of setanaxib in subjects with Alport syndrome, when added to their standard of care treatment. The study will assess how safe setanaxib is when compared to placebo. Study participants will be asked if they are experiencing any side effects at each study visit. In addition, tests in blood, urine and other examinations will be used to look at the safety of setanaxib. The study will also measure how well setanaxib works in comparison to a placebo, by measuring urine protein and certain markers in the blood and urine. The concentration of setanaxib in the blood will also be measured throughout the course of the study.
Setanaxib is planned for use together with the current standard of care to hopefully provide additional therapeutic benefits by preserving kidney function.
The study will be conducted at multiple research sites in the UK, Spain, and Czech Republic. Eligible participants will be randomly assigned to receive either setanaxib or placebo. Setanaxib dose level will depend on age and all participants will receive their standard of care in addition to setanaxib or placebo. The study consists of a Screening period of up to 4 weeks, a 24-week Treatment period and a 4- week Follow-up period.

Start Date27 Nov 2023

Sponsor / Collaborator

Calliditas Therapeutics AB

NCT05323656 / Active, not recruitingPhase 2

A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Setanaxib, When Administered With Pembrolizumab, in Patients With Recurrent or Metastatic SCCHN

The primary objective of this study is to compare the change in tumour size per Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1) in recurrent or metastatic SCCHN patients treated with setanaxib and pembrolizumab versus patients treated with placebo and pembrolizumab.

Start Date06 Apr 2022

Sponsor / Collaborator

Calliditas Therapeutics Suisse SA

EUCTR2021-004627-33-ES / Unknown statusPhase 2

A Phase 2, Randomised, Double-Blind, Placebo-Controlled, Proof-of-Concept Study to Evaluate the Efficacy, Safety, and Tolerability, and Effects on Tumour Biomarkers of the NOX1/4 Inhibitor Setanaxib, when Administered with the PD-1 Inhibitor Pembrolizumab, in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Start Date08 Mar 2022

Sponsor / Collaborator-

100 Clinical Results associated with Setanaxib

100 Translational Medicine associated with Setanaxib

100 Patents (Medical) associated with Setanaxib

153

Literatures (Medical) associated with Setanaxib

01 Jan 2024·Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

Setanaxib mitigates oxidative damage following retinal ischemia-reperfusion via NOX1 and NOX4 inhibition in retinal ganglion cells

Article

Author: Cheng, Qiaochu ; Zhong, Haibin ; Cui, Ling ; Jiang, Li ; Xu, Fan ; Hu, Yaguang ; Lai, Zhaoguang ; Huang, Guangyi ; Li, Min ; Wei, Yantao ; Qin, Yuanjun ; Huang, Wei ; Chen, Qi ; Lin, Jiali ; Liao, Jing

Glaucoma, a prevalent cause of permanent visual impairment worldwide, is characterized by the progressive degeneration of retinal ganglion cells (RGCs). NADPH oxidase (NOX) 1 and NOX4 are pivotal nodes in various retinal diseases. Setanaxib, a potent and highly selective inhibitor of NOX1 and NOX4, can impede the progression of various diseases. This study investigated the efficacy of setanaxib in ameliorating retinal ischemia-reperfusion (I/R) injury and elucidated its underlying mechanisms. The model of retinal I/R induced by acute intraocular hypertension and the oxygen-glucose deprivation/reoxygenation (OGD/R) model of primary RGCs were established. By suppressing NOX1 and NOX4 expression in RGCs, setanaxib mitigated I/R-induced retinal neuronal loss, structural disruption, and dysfunction. Setanaxib reduced TUNEL-positive cells, upregulated Bcl-2, and inhibited Bax, Bad, and cleaved-caspase-3 overexpression after I/R injury in vitro and in vivo. Moreover, setanaxib also significantly reduced cellular senescence, as demonstrated by downregulating SA-β-gal-positive and p16-INK4a expression. Furthermore, setanaxib significantly suppressed ROS production, Hif-1α and FOXO1 upregulation, and NRF2 downregulation in damaged RGCs. These findings highlight that the setanaxib effectively inhibited NOX1 and NOX4, thereby regulating ROS production and redox signal activation. This inhibition further prevents the activation of apoptosis and senescence related factors in RGCs, ultimately protecting them against retinal I/R injury. Consequently, setanaxib exhibits promising potential as a therapeutic intervention for glaucoma.

01 Jan 2024·Microcirculation (New York, N.Y. : 1994)

Advanced glycated end‐products inhibit dilation through constitutive endothelial RAGE and Nox1/4 in rat isolated skeletal muscle arteries

Article

Author: Murphy, Timothy V ; Rikard-Bell, Matthew ; Naser, Nadim ; Sandow, Shaun L ; Lonj, Chenchel K

Abstract:

Objective:

This study investigated the actions of advanced glycated end‐products (AGE), their receptors (RAGE), and NAD(P)H oxidase (Nox) subtypes 1, 2, and 4 on mechanisms of endothelium‐dependent dilation of the rat cremaster muscle artery (CMA).

Methods:

Immunofluorescence studies were used to examine expression of RAGE in rat arteries. ROS accumulation was measured using luminescence and fluorescence assays. Functional studies were performed using pressure myography.

Results:

High levels of RAGE expression were shown in the endothelial cells of the CMA, compared with low endothelial expression in middle cerebral and mesenteric arteries and the aorta. Exogenous AGE (in vitro glycated bovine serum albumin) stimulated H2O2 accumulation in CMA, which was prevented by the RAGE antagonist FPS‐ZM1, the NAD(P)H oxidase (Nox) inhibitor apocynin and inhibited by the Nox1/4 inhibitor setanaxib, but not the Nox2 inhibitor GSK2795039. In functional studies, AGE inhibited vasodilation of CMA stimulated by acetylcholine, sodium nitroprusside, and the BKCa activator NS1619, but not adenosine‐induced dilation. FPS‐ZM1, apocynin, and setanaxib prevented the inhibitory effects of AGE on responses to acetylcholine and NS‐1619.

Conclusion:

These observations suggest RAGE are constitutively expressed in the endothelium of the rat CMA and may be activated by AGE to stimulate Nox1/4 and ROS formation with resulting inhibition of NO and BKCa‐mediated endothelium‐dependent dilation.

01 Dec 2023·Placenta

Aspirin protects human trophoblast HTR-8/SVneo cells from H2O2-Induced oxidative stress via NADPH/ROS pathway

Article

Author: Guo, Xin ; Li, Wei ; Pei, Guizhen ; Ma, Xiaoqing ; Wang, Chunyan ; Sang, Fei ; Dilidaxi, Dinareer ; Li, Lihua

INTRODUCTION:

Pre-eclampsia (PE) is a pregnancy complication that can lead to maternal, fetal, and neonatal deaths in clinical practice. Accumulation of trophoblastic reactive oxygen species (ROS), which could result in oxidative stress and cell apoptosis, is considered to play an important role in PE pathology. It has been reported that aspirin has a positive effect on PE treatment in high-risk pregnant women.

METHODS:

In vitro, extravillous trophoblast cell line (HTR-8/SVneo) were treated with hydrogen peroxide (H₂O₂, 150 μM) after the presence of aspirin (90 and 120 μM) with or without GKT137831 (a Nox4 inhibitor, 20 μM). A series of experiments including CCK-8 assays, flow cytometry, biochemical testing, and Western Blotting etc. verified the protective effects and potential mechanisms of aspirin against oxidative stress-induced damage in PE.

RESULTS:

Our results demonstrated that H₂O₂ induces oxidative stress and apoptosis in HTR8/SVneo cells. However, aspirin pretreatment rescue cell viability and reduce LDH activity of HTR-8/SVneo cells. Aspirin can suppress the ROS overproduction and MDA level while increase SOD content and CAT activity. In addition, aspirin pretreatment significantly alleviated cell apoptosis and suppressed the expression of Nox4 and its subunits (p22phox and p47phox) at protein and mRNA levels. The above results were more obvious after the combination of aspirin with GKT137831.

DISCUSSION:

This study demonstrated that aspirin protects human trophoblasts against H₂O₂-induced oxidative stress and cell apoptosis via suppressing NADPH/ROS pathway. These findings provide novel insights for the application of aspirin as a protective and curative agent against PE.

News (Medical) associated with Setanaxib

18 Jun 2024

·www.prnewswire.com

Calliditas provides setanaxib patent update

STOCKHOLM, June 18, 2024 /PRNewswire/ -- Calliditas Therapeutics AB (Nasdaq: CALT) (Nasdaq Stockholm: CALTX) ("Calliditas") today announced that the United States Patent and Trademark Office (USPTO) has issued a patent for application no. 16/760,910 entitled "Use of NOX Inhibitors for Treatment of Cancer." The patent covers a method of treating a solid tumor presenting resistance to PD-1 inhibitor immunotherapy by administering setanaxib in combination with a PD-1 inhibitor. The patent will have an expiration date in 2039. Calliditas has corresponding applications and patents in several additional territories around the world, including a pending patent application in Europe. "We are delighted that the product protection of setanaxib in the area of oncology is extended by way of this patent, and we look forward to expanding this to other geographies", said Renee Aguiar-Lucander, CEO. Calliditas read out positive topline results of its Phase 2 head and neck cancer trial with setanaxib in May 2024. The analysis showed statistically significant improvements in progression-free survival (PFS), as well as in overall survival (OS), with statistically significant changes in tumor biology consistent with the mechanism of action of setanaxib. For further information, please contact: Åsa Hillsten, Head of IR & Sustainability, Calliditas Tel.: +46 76 403 35 43, Email: [email protected] The information was sent for publication, through the agency of the contact person set out above, on June 18, 2024 at 12:15 p.m. CET. About Calliditas Calliditas Therapeutics is a biopharma company headquartered in Stockholm, Sweden, focused on identifying, developing, and commercializing novel treatments in orphan indications with significant unmet medical needs. Calliditas' common shares are listed on Nasdaq Stockholm (ticker: CALTX) and its American Depositary Shares are listed on the Nasdaq Global Select Market (ticker: CALT). Visit Calliditas.com for further information. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding Calliditas' strategy, commercialization efforts, business plans, regulatory submissions, clinical development plans, revenue and product sales projections or forecasts and focus. The words "may," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "estimate," "predict," "project," "potential," "continue," "target," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties, and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, any related to Calliditas' business and operations, product protection for setanaxib, the safety and efficacy of setanaxib in SCCHN or other potential indications, anticipated timelines and other risks identified in the section entitled "Risk Factors" in Calliditas' reports filed with the Securities and Exchange Commission. Calliditas cautions you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made. Calliditas disclaims any obligation to publicly update or revise any such statements to reflect any change in expectations or in events, conditions, or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. Any forward-looking statements contained in this press release represent Calliditas' views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. This information was brought to you by Cision The following files are available for download: SOURCE Calliditas Therapeutics

Clinical ResultImmunotherapyPhase 2

28 May 2024

·firstwordpharma.com

Kidney disease drug maker Calliditas fields $1.1B bid from Asahi Kasei

Japanese conglomerate Asahi Kasei has launched a $1.1-billion cash bid to acquire Swedish biotech Calliditas Therapeutics as it looks to beef up its pharmaceuticals business.The offer of SEK 208 ($19.72) per share represents an 83% premium to Calliditas' closing stock price on Monday. The Calliditas board has unanimously recommended that shareholders accept the tender offer, noting that "with Asahi Kasei as its new strategic owner, the company aims to realise the benefits of being part of a larger platform."Calliditas' lead product is Tarpeyo (budesonide), the only fully-approved treatment shown to reduce the loss of kidney function in adults with primary IgA nephropathy (IgAN) who are at risk of disease progression. The drug was granted full FDA approval in December and has received conditional approval in Europe under the name Kinpeygo, while Calliditas plans to seek approval in Asia.The Swedish biotech's pipeline also includes setanaxib, a NOX1/4 inhibitor currently in Phase II development for fibrotic rare diseases and solid tumours.For Asahi Kasei, whose main products up to now have been in chemicals and materials, the acquisition aligns with its strategy to accelerate growth in its pharma division. The company said it "aims to expand its businesses globally through specialising in the areas of immunology, transplantation, and adjacent diseases."The tender offer period expected to begin around mid-July and expire at the end of August. Shareholders of Calliditas holding 45% of the shares have undertaken to accept the deal.Vertex Pharmaceuticals also broadened its kidney disease pipeline with an IgAN candidate earlier this year through the $4.9-billion buyout of Alpine Immune Sciences and its lead candidate povetacicept. For more on that, see – Vital Signs: Dissecting dealmaking at Vertex and its Alpine takeout.

Drug ApprovalAcquisitionPhase 2

07 May 2024

·www.fiercebiotech.com

Calliditas' survival data salvage midphase cancer trial after primary endpoint miss

Calliditas Therapeutics’ stock rose initially before falling back toward its opening price. Calliditas Therapeutics had a typical to-do list for its midphase head and neck cancer study. Step one, show the molecule shrinks tumors. Step two, look for early evidence of effect on survival. The Swedish biotech fell at the first obstacle on that timeworn path, seeing no change in tumor size, but bounced back up with early evidence of an effect on progression-free (PFS) and overall survival (OS). The double-blind, randomized phase 2 trial compared the effect of adding setanaxib or placebo to Merck & Co.’s PD-1 checkpoint inhibitor Keytruda. Setanaxib is designed to inhibit NOX1 and NOX4, enzymes expressed by cancer-associated fibroblasts (CAFs) in solid tumors. Researchers have linked high levels of CAFs to poor survival and resistance to immunotherapy. Calliditas identified setanaxib as a way to improve the penetration of immune cells into tumors and make checkpoint inhibitors effective in more patients. The biotech put that idea to the test in a phase 2 trial of 55 people with recurrent or metastatic head and neck cancer. Setanaxib was no better than placebo on the primary endpoint of best percentage change from baseline in tumor size. Calliditas is yet to share the response rates, a typical midphase endpoint, but did disclose that 70% of patients on setanaxib had at least stable disease, compared to 52% of people on placebo. The biotech focused on the PFS and OS results. Median PFS was five months in the setanaxib arm and 2.9 months in the placebo cohort. Similarly, the OS rate at nine months was 88% on setanaxib and 58% on the control. The biotech reported a similar divergence in OS rates after six months. Calliditas brushed over the failure to hit the primary endpoint—relegating the finding to a single line almost 300 words into its press release—but Chief Medical Officer Richard Philipson was clear about the importance of showing a reduction in tumor size on an earnings call in February. “We think this is an important endpoint in a study at this stage of development. It’s a little bit more sensitive than just looking at response rates,” Philipson said. “Clearly, what we want to see is a significant reduction in tumor size in patients who are receiving setanaxib on top of pembrolizumab versus patients who are receiving placebo on top of pembrolizumab.” Calliditas’ statement lacks an explanation for why patients may live longer on setanaxib if it has no effect on tumor size. The biotech plans to host an R&D day later this month to share more information on the phase 2 trial and other data supporting the mechanism of action of setanaxib. Investors appeared unsure what to make of the data, with Calliditas’ stock initially rising before falling back toward its opening price.

Phase 2Clinical ResultImmunotherapyADCASCO

100 Deals associated with Setanaxib

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Recurrent Squamous Cell Carcinoma of the Head and Neck	Phase 3	SE	Calliditas Therapeutics France SAS	30 Jan 2022
Nephritis, Hereditary	Phase 2	CZ	Calliditas Therapeutics AB	27 Nov 2023
Nephritis, Hereditary	Phase 2	ES	Calliditas Therapeutics AB	27 Nov 2023
Nephritis, Hereditary	Phase 2	GB	Calliditas Therapeutics AB	27 Nov 2023
Squamous cell carcinoma of head and neck metastatic	Phase 2	US	Calliditas Therapeutics Suisse SA	06 Apr 2022
Squamous cell carcinoma of head and neck metastatic	Phase 2	FR	Calliditas Therapeutics Suisse SA	06 Apr 2022
Squamous cell carcinoma of head and neck metastatic	Phase 2	DE	Calliditas Therapeutics Suisse SA	06 Apr 2022
Squamous cell carcinoma of head and neck metastatic	Phase 2	IT	Calliditas Therapeutics Suisse SA	06 Apr 2022
Squamous cell carcinoma of head and neck metastatic	Phase 2	PL	Calliditas Therapeutics Suisse SA	06 Apr 2022
Squamous cell carcinoma of head and neck metastatic	Phase 2	ES	Calliditas Therapeutics Suisse SA	06 Apr 2022

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05323656 (PRNewswire) Manual	Phase 2	Squamous Cell Carcinoma of Head and Neck	55	Setanaxib+Pembrolizumab	ohfukfhcbx(jeyidxvwjq) = zwvzitjdgc pajmfqepht (brrhulctwz ) View more	Positive	06 May 2024
				Pembrolizumab + Placebo	ohfukfhcbx(jeyidxvwjq) = twzkpnsdpb pajmfqepht (brrhulctwz ) View more
Pubmed	Phase 2	Primary Biliary Cholangitis Second line	111	Setanaxib 400 mg OD	ruptcfwinc(dyavskyxij) = ptdlxptbud yvjofaszmk (lfjelllyqw, 59.6) View more	Positive	15 May 2023
				Setanaxib 400 mg BID	ruptcfwinc(dyavskyxij) = tevmdwcguc yvjofaszmk (lfjelllyqw, 28.9) View more
NCT03226067 (CTgov)	Phase 2	Primary Biliary Cholangitis	111	Placebo oral capsule+GKT137831 (GKT137831 400mg Once Daily)	olegdmvkhf(xfbvafomng) = duqzypjrhx fpfatkdxmj (oktaiatjdm, oeqactbxsw - slmngmsjkq) View more	-	31 Mar 2022
				GKT137831 (GKT137831 400mg Twice Daily)	olegdmvkhf(xfbvafomng) = eulkudyuvg fpfatkdxmj (oktaiatjdm, uizzwgltdc - kjzevetina) View more
NCT03226067 (GlobeNewswire) Manual	Phase 2	Primary Biliary Cholangitis	111	Setanaxib	wqeumjtzkv(nbbchvrthx): P-Value = <0.002 View more	Positive	24 Jun 2019
				Placebo
BusinessWire Manual	Phase 2	Diabetic Nephropathies	155	Setanaxib	xnxfwqxgsn(nvnzfqmlrx) = not achieved within this timeframe toynhgqwol (uctncyxlmj ) View more	Positive	09 Sep 2015
				Placebo

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