Dataset Information

Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients.

ABSTRACT:

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive and severe neurodegenerative disease caused by motor neuron death. There have as yet been no fundamental curative medicines, and the development of a medicine for ALS is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified an Src/c-Abl inhibitor, bosutinib, as a candidate molecular targeted therapy for ALS. The objectives of this study are to evaluate the safety and tolerability of bosutinib for the treatment of patients with ALS and to explore the efficacy of bosutinib on ALS. This study is the first clinical trial of administered bosutinib for patients with ALS.

Methods and analysis

An open-label, multicentre phase I dose escalation study has been designed. The study consists of a 12-week observation period, a 1-week transitional period, a 12-week study treatment period and a 4-week follow-up period. After completion of the transitional period, subjects whose total ALS Functional Rating Scale-Revised (ALSFRS-R) score decreased by 1-3 points during the 12-week observation period receive bosutinib for 12 weeks. Three to six patients with ALS are enrolled in each of the four bosutinib dose levels (100, 200, 300 or 400?mg/day) to evaluate the safety and tolerability under a 3+3?dose escalation study design. Dose escalation and maximum tolerated dose are determined by the safety assessment committee comprising oncologists/haematologists and neurologists based on the incidence of dose-limiting toxicity in the first 4 weeks of the treatment at each dose level. A recommended phase II dose is determined by the safety assessment committee on completion of the 12-week study treatment in all subjects at all dose levels. The efficacy of bosutinib is also evaluated exploratorily using ALS clinical scores and biomarkers.

Ethics and dissemination

This study received full ethical approval from the institutional review board of each participating site. The findings of the study will be disseminated in peer-reviewed journals and at scientific conferences.

Trial registration number

UMIN000036295; Pre-results, JMA-IIA00419; Pre-results.

SUBMITTER: Imamura K

PROVIDER: S-EPMC7003406 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients.

Imamura Keiko K Izumi Yuishin Y Banno Haruhiko H Uozumi Ryuji R Morita Satoshi S Egawa Naohiro N Ayaki Takashi T Nagai Makiko M Nishiyama Kazutoshi K Watanabe Yasuhiro Y Hanajima Ritsuko R Oki Ryosuke R Fujita Koji K Takahashi Naoto N Ikeda Takafumi T Shimizu Akira A Morinaga Akiko A Hirohashi Tomoko T Fujii Yosuke Y Takahashi Ryosuke R Inoue Haruhisa H

BMJ open 20191202 12

<h4>Introduction</h4>Amyotrophic lateral sclerosis (ALS) is a progressive and severe neurodegenerative disease caused by motor neuron death. There have as yet been no fundamental curative medicines, and the development of a medicine for ALS is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified an Src/c-Abl inhibitor, bosutinib, as a candidate molecular targeted therapy for ALS. The objectives of this study are to evaluate the safety and tolerability of bosu ...[more]

PMID: 31796494

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Project description:Summary Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of motor neurons, and development of effective medicines is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified the Src/c-Abl inhibitor bosutinib, which is approved for the treatment of chronic myelogenous leukemia (CML), as a candidate for the molecular targeted therapy of ALS. Methods An open-label, multicentre, dose-escalation phase 1 study using a 3 + 3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma neurofilament light chain (NFL) were explored, and single-cell RNA sequencing of iPSC-derived motor neurons was conducted. Patients, whose total ALSFRS-R scores decreased by 1–3 points during the 12-week, received escalating doses starting from 100 mg quaque die (QD) up to 400 mg QD based on dose-limiting toxicity (DLT) occurrence, and all participants who received one dose of the study drug were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT04744532, as Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic Lateral Sclerosis Medicine (iDReAM) study. Findings Between March 29, 2019 and May 7, 2021, 20 patients were enrolled, 13 of whom received bosutinib treatment and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300 mg QD, but DLTs were observed in 3/3 patients of the 400 mg QD cohort. In all patients receiving 100 mg–400 mg, the prevalent adverse events (AEs) were gastrointestinal AEs in 12 patients (92.3%), liver function related AEs in 7 patients (53.8%), and rash in 3 patients (23.1%). The safety profile was consistent with that known for CML treatment, and ALS-specific AEs were not observed. A subset of patients (5/9 patients) was found to respond well to bosutinib treatment over the 12-week treatment period. It was found that the treatment-responsive patients could be distinguished by their lower levels of plasma NFL. Furthermore, single-cell RNA sequencing of iPSC-derived motor neurons revealed the pathogenesis related molecular signature in patients with ALS showing responsiveness to bosutinib. Interpretation This is the first trial of a Src/c-Abl inhibitor, bosutinib, for patients with ALS. The safety and tolerability of bosutinib up to 300 mg, not 400 mg, in ALS were described, and responsiveness of patients on motor function was observed. Since this was an open-label trial within a short period with a limited number of patients, further clinical trials will be required. Funding AMED and iPS Cell Research Fund.

Project description:BackgroundThe primary objective was to demonstrate the safety and tolerability of monoclonal antibody against CD14 (IC14) (atibuclimab) in amyotrophic lateral sclerosis patients. The secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary effects on disease status and biomarkers.MethodsIn this open-label, dose-escalation trial, IC14 was administered at 2 mg/kg intravenous (IV) followed by 1 mg/kg/d IV × 3 (n = 3) and in subsequent patients at 4 mg/kg IV followed by 2 mg/kg/d IV × 3 (n = 7) (NCT03487263). Disease status was measured using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, Edinburgh Cognitive and Behavioural ALS Screen, and Revised ALS-Specific Quality-of-Life Score. Disease biomarkers included cerebrospinal fluid and serum levels of neurofilament light chain (NfL) and urinary p75 neurotrophin receptor.ResultsIC14 was safe and well tolerated. No antidrug antibodies were detected. The drug target saturation of monocyte CD14 receptors was rapid and sustained through day 8. There was no significant change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, or Revised ALS-Specific Quality-of-Life Score following a single cycle of treatment. Cerebrospinal fluid NfL levels decreased in 6 of 9 patients sampled with declines of 15% to 40% between baseline (not significant [ns]) and day 8 in 3 patients. Serum NfL modestly decreased in 5 of 10 patients (ns) at day 8 and was sustained in 4 (4%-37%, ns) over 33 days of follow up.ConclusionIC14 quickly and durably saturated its target in all patients. This study demonstrated safety and tolerability in patients with amyotrophic lateral sclerosis. Even though only a single cycle of treatment was given, there were promising beneficial trends in the neurofilament light chain, a disease biomarker. The emerging understanding of the role of systemic inflammation in neurodegenerative diseases, and the potential for IC14 to serve as a safe, potent, and broad-spectrum inhibitor of immune dysregulation merits further clinical study.Clinical trial registrationNCT03487263.

Dataset Information

Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients.

Introduction

Methods and analysis

Ethics and dissemination

Trial registration number

Publications

Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients.

Similar Datasets

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