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

[+3]

NCT01777243 / Completed临床1期

A Single Dose First in Human Study of GSK2398852 Co-Administered With GSK2315698 in Patients With Systemic Amyloidosis

The study will be conducted in two parts. The first (Part A) will be an open label single dose escalation part beginning with the proposed starting dose level of GSK2398852 as 5 milligram (mg) [approximately equivalent to 0.1 mg/kilogram (kg)]. The next escalation dose levels are proposed as 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg. GSK2315698 will be administered at variable doses until the concentration of the serum amyloid P component monoclonal antibody (SAP mAb) has fallen below 100 nanogram/millilitre (ng/mL). Decisions about these next dose levels will be made following safety review of the prior subjects' data; dose levels may be changed (increased and lowered) and dose levels may be repeated depending on the observed safety such that Part A extension study may be performed. In addition, pharmacokinetics of GSK2315698 (SAP depleter) and GSK2398852 (anti-SAP mAb), and circulating SAP concentrations will be assessed. Dose escalation in Part A will continue to the highest well tolerated dose or the highest allowable dose. Subjects will be closely monitored and will undergo Equilibrium contrast Magnetic Resonance Imaging (EqMRI) including organ volume, Elastography and Liver Biopsy if required.
Part B will be a randomized partially blinded part with the principal objective of assessing the dose response of the GSK2398852 in more detail. Subjects will be assigned to one of approximately 5 dose groups from Part A. The precise selection of numbers of subjects and dose levels will be informed by the results from Part A.

开始日期2013-05-13

申办/合作机构

GSK Plc

[+3]

100 项与 Miridesap 相关的临床结果

登录后查看更多信息

100 项与 Miridesap 相关的转化医学

登录后查看更多信息

100 项与 Miridesap 相关的专利（医药）

登录后查看更多信息

项与 Miridesap 相关的文献（医药）

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).

2020-04-01·British journal of pharmacology2区 · 医学

Identification, preclinical profile, and clinical proof of concept of an orally bioavailable pro‐drug of miridesap

2区 · 医学

Article

作者: Thompson, Douglas ; Fernando, Disala ; Richards, Duncan ; Holmes, Duncan S. ; Storey, Jim ; Haque, Nazneen ; Bamford, Mark ; Liefaard, Lia ; Kumar, Subramanya ; Lewis, Gareth

Background and Purpose:

Miridesap, a depleter of serum amyloid P component (SAP), forms an essential component of a novel approach to remove systemic amyloid deposits; low oral bioavailability necessitates that it is given parenterally. We sought to identify and clinically characterise a pro‐drug that preserves the pharmacological properties of miridesap while having adequate oral bioavailability and physical stability.

Experimental Approach:

We utilised a preclinical screening cascade focused on appropriate physicochemical properties, physical and gut stability, and conversion to miridesap in liver microsomes and blood. GSK3039294 (GSK294) had the desired in vitro profile and progressed to preclinical in vivo pharmacokinetic and safety assessments. Based on a favourable profile, it was tested in healthy participants after single and repeat dosing.

Key Results:

GSK294 was highly soluble and stable in simulated gastric and intestinal fluids, stable in intestinal microsomes, and permeable in Madine Darby Canine Kidney type II cells. GSK294 was rapidly hydrolysed to miridesap and its mono pro‐drug ester in blood and liver microsomes. GSK294 showed good oral bioavailability of miridesap in rats and dogs. Following administration of GSK294 600 mg QD for 7 days in humans, pharmacodynamically active concentrations of miridesap were achieved with substantial and sustained depletion of plasma SAP. The study was terminated due to observations of arrhythmia, the relation of which to GSK294 remains unclear.

Conclusion and Implications:

Using a preclinical screening cascade, we identified a pro‐drug for a palindromic molecule with unique pharmacology (miridesap). The pro‐drug depleted circulating SAP with a time course and extent similar to that of parenterally administered miridesap.

100 项与 Miridesap 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D11464	-	-	DB13087

研发状态

10 条进展最快的记录,

后查看更多信息

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

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

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	遞餘網鑰選衊齋廠簾廠(窪鬱製蓋構鹹窪憲淵蓋) = 選觸醖鹹廠鑰糧獵鹽淵憲觸廠醖築衊築網餘鏇 (觸衊構構觸餘鑰艱鑰築 )	积极	2022-07-09
AAIC2008	N/A	阿尔茨海默症	5	CPHPC 60 mg	壓襯積鬱積衊繭鬱遞鏇(餘憲夢鏇選構鬱鹹膚願) = 繭窪廠餘顧網蓋鬱膚鹽壓壓襯製遞淵選憲壓鹹 (製鬱餘糧窪艱鹹窪願獵 ) 更多	-	2008-07-01