[Translation] A Phase 2 Randomized Double-Blind Placebo-Controlled Study Evaluating the Safety, Efficacy, Pharmacodynamics, and Pharmacokinetics of Weekly Subcutaneous Injections of SAR339375 in Patients with Alport Syndrome

主要目的：在患有奥尔波特综合征的受试者中评估SAR339375在减缓肾功能下降方面的疗效以及评估其安全性和耐受性次要目的：评估血浆药代动力学 (PK) 参数，药物抗体(ADA)的潜在形成以及对 miR-21和肾损伤和功能生物标志物变化的药效学作用。

[Translation]

Primary Objective: To evaluate the efficacy of SAR339375 in slowing the decline of renal function and to assess its safety and tolerability in subjects with Alport syndrome Secondary Objectives: To evaluate plasma pharmacokinetic (PK) parameters, potential formation of drug antibodies (ADA), and pharmacodynamic effects on changes in miR-21 and biomarkers of renal injury and function.

Start Date22 Sep 2020

Sponsor / Collaborator

Sanofi (China) Investment Co. Ltd.

NCT02855268 / TerminatedPhase 2

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Efficacy, Pharmacodynamics, and Pharmacokinetics of Lademirsen (SAR339375) for Subcutaneous Injection Administered Every Week in Patients With Alport Syndrome

Primary Objectives:
To assess the efficacy of lademirsen (SAR339375) in reducing the decline in renal function.
To assess the safety and tolerability of lademirsen (SAR339375) in participants with Alport syndrome.
Secondary Objectives:
To assess plasma pharmacokinetic (PK) parameters of the parent compound and its active major metabolite.
To assess the potential formation of anti-drug antibodies (ADAs) following administration of lademirsen (SAR339375).
To assess the pharmacodynamic effect of lademirsen (SAR339375) on miR-21 and on changes in renal injury and function biomarkers.

Start Date02 Nov 2019

Sponsor / Collaborator

Genzyme Corp.

NCT03373786 / CompletedPhase 1

A Phase 1, Open-Label Study to Evaluate the Safety, Pharmacodynamics, and Pharmacokinetics of RG-012 for Injection, Including Its Effect on Renal microRNA-21, in Subjects With Alport Syndrome

This is a Phase 1, open-label, multi-center study of the safety, pharmacodynamics, and pharmacokinetics of RG-012 administered to subjects with Alport syndrome.

Start Date22 Dec 2017

Sponsor / Collaborator

Genzyme Corp.

100 Clinical Results associated with Lademirsen

100 Translational Medicine associated with Lademirsen

100 Patents (Medical) associated with Lademirsen

Literatures (Medical) associated with Lademirsen

01 Aug 2024·Clinical Journal of the American Society of Nephrology

A Randomized Controlled Clinical Trial Testing Effects of Lademirsen on Kidney Function Decline in Adults with Alport Syndrome

Article

Author: Esteban de la Rosa, Rafael José ; Liu, Shiguang ; Iqbal, Sajida ; Hariri, Ali ; Shen, Yuqian ; Kowthalam, Madhurima Uppara ; Gross, Oliver ; Maski, Manish ; Gale, Daniel P ; Lin, Julie ; Zhang, Qi ; Appel, Gerald ; Wang, Fang ; Sayer, John A ; Ding, Jie ; Hall, Matthew

Key Points

Lademirsen, an anti–microRNA-21 therapy, was generally well-tolerated in adults with Alport syndrome at risk of rapid disease progression.

There were no significant differences between lademirsen-treated and placebo-treated participants in eGFR at any timepoint.

The proportions of participants with prespecified reductions in eGFR at weeks 24 and 48 were not significantly different for lademirsen versus placebo.

BackgroundPreclinical models of disease have suggested that targeting microRNA-21 (miRNA-21) may slow the decline in kidney function in individuals with Alport syndrome (AS). The objective of this study was to investigate the effects of the anti–miRNA-21 oligonucleotide, lademirsen, on rate of eGFR decline in adults with AS at risk of rapid disease progression.MethodsThis study was a phase 2 trial of lademirsen, with a randomized, double-blind, placebo-controlled period followed by an open-label period. Adults with AS, eGFR >35 to <90 ml/min per 1.73 m2, and evidence of rapidly progressive kidney dysfunction were randomized 2:1 to lademirsen 110 mg subcutaneously once weekly or placebo for 48 weeks. After a planned interim analysis (after 24 of 43 randomized participants completed the week 48 study visit or discontinued before week 48), the trial was terminated for futility.ResultsForty-three adults with AS (26 men, 17 women) participated (mean age 34 years), and 28 (lademirsen: n=19; placebo: n=9) completed 48 weeks of double-blind treatment. All participants in both groups developed treatment-emergent adverse events, mainly respiratory tract infections, headache, dizziness, metabolic/electrolyte disturbances, and anemia. Treatment was discontinued in three lademirsen-treated participants in the double-blind period and one participant in the open-label period, owing to treatment-emergent adverse events. The least squares mean eGFR slope (95% confidence interval) over 48 weeks in the lademirsen and placebo groups was −5 (−8.7 to −1.1) and −5 (−10.2 to 0.8) ml/min per 1.73 m2 per year, respectively. No significant differences between groups were identified in eGFR at any timepoint or in proportion of participants with prespecified reductions in eGFR at week 24 or 48.ConclusionsWhile anti–miRNA-21 therapy with lademirsen was generally well-tolerated with an acceptable safety profile, no meaningful improvement in rate of kidney function decline in adults with AS at risk of rapidly progressive disease was observed.Clinical Trial registration number: NCT02855268.

26 Apr 2022·ACS OmegaQ3 · CHEMISTRY

Modeling of Textile Dye Removal from Wastewater Using Innovative Oxidation Technologies (Fe(II)/Chlorine and H₂O₂/Periodate Processes): Artificial Neural Network-Particle Swarm Optimization Hybrid Model

Q3 · CHEMISTRY

ArticleOA

Author: Jeon, Byong-Hun ; Khan, Mohd Shahnawaz ; Merouani, Slimane ; Kebiche-Senhadji, Ounissa ; Asghar, Muhammad Nadeem ; Hamachi, Mourad ; Yadav, Krishna Kumar ; Benguerba, Yacine ; Fetimi, Abdelhalim

An efficient optimization technique based on a metaheuristic and an artificial neural network (ANN) algorithm has been devised. Particle swarm optimization (PSO) and ANN were used to estimate the removal of two textile dyes from wastewater (reactive green 12, RG12, and toluidine blue, TB) using two unique oxidation processes: Fe(II)/chlorine and H₂O₂/periodate. A previous study has revealed that operating conditions substantially influence removal efficiency. Data points were gathered for the experimental studies that developed our ANN-PSO model. The PSO was used to determine the optimum ANN parameter values. Based on the two processes tested (Fe(II)/chlorine and H₂O₂/periodate), the proposed hybrid model (ANN-PSO) has been demonstrated to be the most successful in terms of establishing the optimal ANN parameters and brilliantly forecasting data for RG12 and TP elimination yield with the coefficient of determination (R2) topped 0.99 for three distinct ratio data sets.

08 Mar 2022·Environmental TechnologyQ4 · ENVIRONMENTAL SCIENCE & ECOLOGY

The multiple role of inorganic and organic additives in the degradation of reactive green 12 by UV/chlorine advanced oxidation process

Q4 · ENVIRONMENTAL SCIENCE & ECOLOGY

Article

Author: Belghit, Aouattef ; Hamdaoui, Oualid ; Al-Zahrani, Saeed ; Bouhelassa, Mohammed ; Merouani, Slimane

The impact of various mineral anions, diverse organic substrates and different environmental matrices on the removal of C.I. reactive green 12 (RG12), a refractory textile dye, by UV/chlorine emerging advanced oxidation process (AOP) was performed. The co-exposure of RG12 (20 mg L^-1) to UV and chlorine (0.5 mM) at pH 5 produced a strong synergism on the degradation rate. Radical probe technique showed that ^●OH and Cl₂^●- were the main source of the synergistic effect. Bromide, bicarbonate and chloride at small dosage, i.e. 1 mM, enhanced the rate of RG12 degradation, but higher concentrations of these anions quenched the degradation process. Sulphate anions did not alter the degradation rate of the dye, but nitrite quenched it at ∼ 90%. The inhibiting effect of nitrate appeared only at advanced reaction time (>1 min).On the other hand, natural organic matter (NOM) reduced effectively the degradation rate. Besides, SDS surfactant at only 1 µM accelerated the degradation efficiency by ∼12%. However, Tween 80 has shown an insignificant effect, whereas reductions of 10% and 30% were recorded by Triton X100 and Tween 20, respectively. The RG12-degradation rate was not affected in the mineral water, but it was drastically improved in seawater. Conversely, a huge drop in the RG12-degradation efficiency was obtained in the wastewater effluent. UV/chlorine process is highly viable for degrading pollutant in matrices free of NOM. However, the process losses its potential application in matrices riche of NOM.

News (Medical) associated with Lademirsen

20 Jul 2022

·www.biospace.com

Sanofi, Merck Shut Down Alport Syndrome, Colorectal Cancer Trials

Shares of Regulus Therapeutics plunged nearly 10% Monday after the company disclosed that its partner Sanofi has terminated a development agreement for a small RNA molecule inhibitor being developed for Alport syndrome. In a filing with the U.S. Securities and Exchange Commission, Regulus said Sanofi has opted to terminate the Phase II clinical development of lademirsen (previously known as RG-012) for the treatment of Alport syndrome, a genetic disease that causes kidneys to progressively lose the ability to filter waste products from the blood. Sanofi indicated that it intends to evaluate different opportunities for lademirsen. In February, Regulus announced that the Phase II HERA study for Alport syndrome had completed enrollment. The trial was designed to assess the safety and efficacy of the experimental drug. Results were expected in the second half of 2023. In the filing, Regulus said the termination was due to the trial’s “failure to meet Sanofi’s pre-defined futility criteria,” but did not elaborate further. Sanofi gained control of lademirsen’s development in 2018 following a restructuring of a collaboration agreement between the two companies. If the HERA study were completed, Regulus would have gained $25 million from a milestone payment. The California-based company remains eligible for other milestones from completion of a Phase II fibrosis proof of concept study, Regulus said in its filing. There are currently no specific therapies approved in the U.S. for Alport syndrome. Earlier this year, the U.S. Food and Drug Administration issued a Complete Response Letter to Reata Pharmaceuticals regarding its experimental treatment citing a “lack of proof of effectiveness.” The regulatory agency said Reata’s bardoxolone methyl (bardoxolone) failed to demonstrate the ability to reduce the risk of progression to kidney failure. Merck Reaches Futility in Phase III Colorectal Cancer Trial Sanofi wasn’t the only company to halt a clinical trial this week. On Monday, pharma giant Merck announced it has halted the Phase III LYNK-003 trial evaluating PARP inhibitor Lynparza for patients with unresectable or metastatic colorectal cancer who have not progressed following first-line induction. The decision was based on the recommendation of an independent Data Monitoring Committee following tis review of data at an interim analysis. The committee reviewed the data for progression-free survival. Following the review, the committee said Lynparza, as a monotherapy and in combination with Genentech’s Avastin (bevacizumab), “met the criteria for futility.” Lynparza, an immuno-oncology drug, is being co-developed and co-commercialized with AstraZeneca. Merck said it will inform patients and study investigators about the decision. The Phase III LYNK-003 study included 309 patients with unresectable or metastatic colorectal cancer. In addition to colorectal cancer, Merck and AstraZeneca are assessing Lynparza as both a monotherapy and in new combinations across a range of DNA damage response deficient tumor types, including metastatic prostate cancer, ovarian cancer, breast cancer and pancreatic cancer.

Collaborate

100 Deals associated with Lademirsen

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Nephritis, Hereditary	Phase 2	CN	Genzyme Corp.	02 Nov 2019
Nephritis, Hereditary	Phase 2	US	Genzyme Corp.	02 Nov 2019
Nephritis, Hereditary	Phase 2	ES	Genzyme Corp.	02 Nov 2019
Nephritis, Hereditary	Phase 2	GB	Genzyme Corp.	02 Nov 2019
Nephritis, Hereditary	Phase 2	FR	Genzyme Corp.	02 Nov 2019
Nephritis, Hereditary	Phase 2	AU	Genzyme Corp.	02 Nov 2019
Nephritis, Hereditary	Phase 2	DE	Genzyme Corp.	02 Nov 2019

Clinical Result

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02855268 (phase 2 trial, Pubmed)	Phase 2	Nephritis, Hereditary microRNA-21	43	Lademirsen 110 mg	tflyqeddsr(cjkgzmzjpn) = All participants in both groups developed treatment-emergent adverse events (TEAEs), mainly respiratory tract infections, headache, dizziness, metabolic/electrolyte disturbances, and anemia. Treatment was discontinued in three lademirsen-treated participants in the double-blind period, and one participant in the open-label period, owing to TEAEs. hbkpfyjuuu (gbjvbydbxw )	Negative	03 Jun 2024
				Placebo

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