A Multiple Treatment Session, Open Label Phase 2 Clinical Study of GSK2398852 Administered Following and Together With GSK2315698 in Cohorts of Patients With Cardiac Amyloidosis

The study is intended to evaluate whether monthly repeated courses of administration of GSK2315698 followed by GSK2398852 is associated with a reduction in cardiac amyloid load in patients with cardiac amyloidosis, monitored by cardiac magnetic resonance imaging (CMR) and echocardiography (ECHO), and whether this is associated with an improvement in cardiac function. Cohort 1 is transthyretin cardiomyopathy (ATTR-CM) , cohort 2 is patients with immunoglobulin light chain (AL) systemic amyloidosis at greater than 6 months post chemotherapy, cohort 3 newly diagnosed AL systemic amyloidosis undergoing chemotherapy. Primary objectives for the study are assessment of reduction in cardiac amyloid load after repeated administrations of Anti-SAP treatment as evaluated by CMR in all study groups and assessment of safety & tolerability of repeated administration of Anti-SAP treatment, including compatibility with chemotherapy treatment in patients with AL systemic amyloidosis. This is an open label, non-randomised, three-group, monthly repeat Anti-SAP treatment study in systemic amyloidosis patients with cardiac dysfunction caused by cardiac amyloidosis. Subjects will receive up to 6 courses of Anti-SAP treatment. Maximum total duration for a subject in the study is approximately 18 months.

开始日期2017-07-10

申办/合作机构

GSK Plc

NCT02953808 / Completed临床1期

A Single Centre, Double-blind, Randomised, Placebo-controlled, and Single Dose-ascending Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics, of Single Intravenous Doses of GSK2315698 in Healthy Japanese Subjects

This is the first study in which GSK2315698 will be administered in Japanese population. The primary objective of the study is to investigate safety and tolerability, pharmacokinetics, and pharmacodynamics after single intravenous infusion in healthy subjects. This will be a single center, double-blind, randomized, placebo-controlled, dose-ascending study.
Subjects in Cohort 1 will attend 3 dosing sessions, and will be randomized to one of the 3 groups. Each group will receive GSK2315698 and Placebo in a defined sequence. The dose levels of GSK2315698 are set to 10 milligrams (mg) per hour (hr), 20 mg/hr, and 40 mg/hr, to be administered over 1 hour. Dosing sessions 1 and 2, and dosing sessions 2 and 3, will be separated by a washout period of at least 8 and 10 days, respectively.
Subjects in Cohort 2 will attend a single dosing session, and will be randomized to receive either GSK2315698 20 mg/hr or Placebo, over a period of 15 hours.
A sufficient number of subjects will be randomized such that 18 subjects (9 in each cohort) complete the study. The duration of participation for any subject in this study will be approximately 59 days.

开始日期2016-11-01

申办/合作机构

GSK Plc

NCT02425241 / Completed临床1/2期IIT

A Randomised Double-blind, Placebo-controlled Phase I/IIa Trial to Investigate the Effect of Depletion of Serum Amyloid P Component (SAP) on the Immune Response to DNA Vaccination in Healthy Male Volunteers

This is a clinical proof-of-concept (PoC) study of DNA vaccination after SAP depletion. The investigators will measure the immune responses to DNA vaccination against HIV-1 in healthy adult male volunteers, comparing a group in whom SAP has been completely depleted at the time of DNA vaccination and a control group vaccinated without SAP depletion.

开始日期2013-10-01

申办/合作机构

University College London

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100 项与 Miridesap 相关的临床结果

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100 项与 Miridesap 相关的转化医学

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100 项与 Miridesap 相关的专利（医药）

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项与 Miridesap 相关的文献（医药）

2024-07-01·Open Biology

Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders

Article

作者: Schmidt, A Floriaan ; Chopade, Sandesh ; Rossor, Martin N ; Finan, Chris ; Ellmerich, Stephan ; Pepys, Mark B ; Hingorani, Aroon D

The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral A β amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis -Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10 −3 ), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10 −5 ) and plasma tau concentration (0.06 log 2 (ng l −1 ) 95%CI 0.03; 0.08, p = 4.55 × 10 −6 ). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.

2022-12-01·Orphanet journal of rare diseases

An observational, non-interventional study for the follow-up of patients with amyloidosis who received miridesap followed by dezamizumab in a phase 1 study

Article

作者: Lukas, Mary Ann ; Richards, Duncan ; Millns, Helen ; Cookson, Louise

Abstract:

Background:

Miridesap depletes circulating serum amyloid P (SAP) and dezamizumab (anti-SAP monoclonal antibody) targets SAP on amyloid deposits, triggering amyloid removal. In a phase 1, first-in-human study (FIHS), progressive amyloid removal was observed in some patients after ≤ 3 cycles of miridesap/dezamizumab.

Methods:

This observational, non-interventional study in patients who received miridesap/dezamizumab during the FIHS (planned follow-up: 5 years) evaluated response to treatment based on routine assessments of disease status and key organ function. In a post hoc analysis, patients responding to treatment in the FIHS during follow-up were identified as responders and further categorized as sustained or declining responders.

Results:

In the FIHS, 17/23 patients were treatment responders. Of these patients, seven (immunoglobulin light chain [AL], n = 6; serum amyloid A, n = 1) were considered sustained responders and ten (fibrinogen-a alpha chain [AFib], n = 5; AL, n = 4; apolipoprotein A-I, n = 1) were considered declining responders. We primarily present responder patient-level data for functional, cardiac, laboratory and imaging assessments conducted during the follow-up period, with non-responder data presented as supplementary.

Conclusion:

No further development of miridesap/dezamizumab is planned in amyloidosis. However, long-term follow-up of these patients may provide insight into whether active removal of amyloid deposits has an impact on disease progression.

Trial registration:

ClinicalTrials.gov, NCT01777243. Registered 28 January 2013, https://clinicaltrials.gov/ct2/show/study/NCT01777243.

2022-12-01·BMC Cardiovascular Disorders4区 · 医学

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study

4区 · 医学

ArticleOA

作者: Al Azzam, Wasfi ; Antoni, Gunnar ; Biswas, Swethajit ; Wechalekar, Ashutosh ; Wall, Anders ; Sörensen, Jens ; Schneider, Ian ; Janiczek, Robert L ; Lukas, Mary Ann ; Bergström, Mats ; Cleveland, Matthew ; Cheriyan, Joseph ; Cookson, Louise ; Solomon, Scott D ; Richards, Duncan ; Wikström, Gerhard ; Storey, James ; Thompson, Douglas ; Millns, Helen ; Falk, Rodney H ; Galette, Paul ; Vugts, Danielle J ; Kwong, Raymond Y ; van Dongen, Guus ; Chen, Chao

Abstract:

Background:

In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis.

Methods:

Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET.

Results:

Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks.

Conclusions:

Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated.Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).

100 项与 Miridesap 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11464	Miridesap	-	DB13087

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
老年性心脏淀粉样变性	临床2期	美国	GSK Plc	2017-07-10
老年性心脏淀粉样变性	临床2期	英国	GSK Plc	2017-07-10
淀粉样变性	临床2期	-	Pentraxin Therapeutics Ltd.	-
淀粉样变性	临床2期	-	F. Hoffmann-La Roche Ltd.	-
系统性淀粉样变性	临床1期	英国	GSK Plc	2011-10-13

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分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01777243 (FIHS, Pubmed) 人工标引	临床1期	淀粉样变性	23	Dezamizumab+Miridesap	淵鏇憲繭艱艱廠糧醖積(簾餘窪鹹繭顧淵鬱製範) = 繭選獵壓餘蓋鹹顧糧鏇夢製廠築構夢願築鑰鏇 (簾壓夢窪膚夢窪鬱簾憲 )	积极	2022-07-09
AAIC2008	N/A	阿尔茨海默症	5	CPHPC 60 mg	淵膚觸膚鹽壓構範遞餘(選構構鏇餘積願網鹽憲) = 鹹鬱憲獵窪遞鏇鬱憲鬱築鑰蓋繭壓窪齋夢憲鹽 (築蓋積鏇網壓觸醖壓築 ) 更多	-	2008-07-01