Abstract
Contract No.: 601573; EU contribution: € 5,999,210; Total costs: € 21,358,069; Starting date: 01/06/2013; Duration: 36 months
Background and Objectives
The goal of the SCOPE-DMD project is to utilize health research outcomes from previous EU-funded projects to perform an innovative, pivotal pediatric clinical trial to obtain market authorization for an antisense oligonucleotide (AON) treating a subset of Duchenne muscular dystrophy (DMD) patients. The results of the project will lead to (1) validation and implementation of novel outcome measures and biomarkers developed in former 6th (TREAT-NMD) and 7th (BIO-NMD) European Union's Framework Programmes, (2) a novel accelerated clinical trial design and regulatory strategy, applicable to a wide range of rare diseases, and (3) patient- and healthcare provider-derived innovative commercial strategies. The project is further building on TREAT-NMD and Prosensa's interactions with regulatory agencies, progressing the acceptability of novel biomarkers and outcome measures in neuromuscular disease (NMD), and the positioning of 2′methylphosphorothioate (2′OMePS) AONs as a single drug class for expedited development programs benefitting other subset of DMD patients.
DMD is a progressive muscle wasting disease with a prevalence of 0.32–0.52 per 10,000 inhabitants. Worldwide around 240,000 patients suffer from DMD. The X-chromosome linked disease is caused by mutations, often deletions, in the DMD gene that result in the disruption of the open reading frame of the gene, leading to a loss of dystrophin protein expression. Dystrophin is assumed to have a scaffolding function in muscle fibers, where it links the subsarcolemmal actin cytoskeleton through a complex of transmembrane proteins to the extracellular matrix. Muscle fibers lacking functional dystrophin are more prone to contraction-induced damage, which over time leads to an increase of connective tissue, replacement of muscle fibers by fat, and eventually to progressive muscle weakness and wasting. DMD boys are in most cases diagnosed by 4–5 years of age, with subclinical symptoms prior to that time. Patients become generally wheelchair dependent by 12 years of age and require assisted ventilation around the age of 18. Young DMD men typically die in the second or third decade of their life from cardiac or respiratory failure, although death may also occur in the late teens. There is currently no effective disease-modifying treatment for DMD.
Many deletions in the DMD gene result in an out-of-frame dystrophin transcript and therefore a truncated and nonfunctional dystrophin. AONs are short nucleotide chains that can bind to a selected complementary nucleotide sequence of the pre-mRNA and can induce exon skipping by blocking splicing enhancer sequences present in the exon, leading to a lack of exon recognition by the RNA splicing machinery. This results in the restoration of the open reading frame of the dystrophin mRNA, such that a truncated but functional dystrophin protein, as seen in patients with Becker muscular dystrophy (BMD), is expressed in the muscles. Based on BMD clinical experience with typically improved prognosis, it is expected that AON-treated patients will have improved muscle function due to expression of this truncated but functional dystrophin. This RNA-based approach is not gene therapy, but rather RNA modulation, as it does not manipulate or insert genetic DNA code. AON therapy can be halted by stopping the systemic administration of the compound.
The clinical trial that is part of the SCOPE-DMD project is an exploratory, open-label, dose-escalation phase IIb study. It aims to assess the efficacy, safety, pharmacodynamics, and pharmacokinetics of weekly subcutaneous doses of PRO045 in subjects with DMD. PRO045 is a 2′OMePS RNA oligonucleotide, directed against exon 45. Nonclinical studies on PRO045 have shown its skipping efficiency and a favorable safety and pharmacokinetic profile. In patients with DMD, mutations cluster around exons 45–55, and therefore the skipping of one specific exon could potentially be beneficial for patients with different mutations. In the case of skipping of exon 45, about 8% of all DMD patients could be treated, including those with deletions of exons 44, 46, 46–47, 46–48, 46–49, or 46–51. 1
The study is of seamless design, which is driven by the need to maximize the data from an exceptionally small patient population and to provide continuity of care in this rapidly progressing disease. It is made up of two phases: a dose escalation phase with 15 patients and an extended pivotal phase with an additional 55 patients.
Approach and Methodology
The SCOPE-DMD project consortium consists of two SMEs, Prosensa and BioSpring, and three academic institutes, the Institut de Myologie in Paris, France, the Leiden University Medical Centre, The Netherlands, and Newcastle University, United Kingdom. The project is coordinated by Newcastle University.
The project consists of seven scientific work packages (WP), all of which are closely linked. WP1 is the main clinical trial and is closely aligned to a further three WPs, which will explore three types of outcome measures, namely, motor function (WP2), muscle magnetic resonance imaging (WP3), and molecular biomarkers (WP4). Further WPs focus on drug development and interaction with EU and U.S. regulatory authorities, as well as on aspects of communication, dissemination, and project management.
Main Findings
The SCOPE-DMD project has made considerable progress since the start of the project in June 2013. Excellent cooperation and collaboration has been achieved through partner and WP meetings. The main results from the first 18 months of the project are presented below.
WP1
During the dose-escalation phase of the study, the most optimal dose was planned to be identified for the extended phase of the clinical trial. A total of 15 patients were enrolled into the study, who were treated with escalating doses of PRO045, ranging from 0.15 to 9.0 mg/kg subcutaneous and single dose of intravenous from 1.0 to 9.0 mg/kg. In general, the drug was well tolerated. Preliminary detected tissue concentrations of PRO045 did not reach the levels, as measured for drisapersen. To allow potentially higher bioavailability and to mitigate potential local tolerability issues, the dose escalation phase will be extended to investigate repeat intravenous dosing.
WP2
The Neuromuscular Physiology and Evaluation lab team at the Institute of Myology, Paris, ensured training of all clinical evaluators involved in the study. The equipment of each center was checked once a year to ensure accuracy of the measurements, and tools presenting technical problems were repaired as soon as possible to avoid as much missing data as possible. The Performance of Upper Limb measure has been finalized. All partners perform muscle MRI scans according to an agreed standardized protocol.
WP3
The aim of WP3 is to work further on imaging as a valuable noninvasive outcome measure for monitoring the structural alterations of skeletal muscle in inherited muscular disorders. A number of NMR indices were selected as outcome measures and will be monitored during the SCOPE-DMD protocol to determine whether changes have slowed compared with natural history data.
WP4
Pharmacokinetic and pharmacodynamic analysis in the muscle biopsies has progressed with the determination of PRO045 levels in the tissue and ongoing measurements of exon skip in the dystrophin messenger RNA as well as the expression of dystrophin protein in the sarcolemma. Development of additional biomarkers in muscle tissue and serum is underway, while development for urine biomarkers is planned for 2015.
WP5
Within the first 18 months, the process and method transfer from Prosensa to BioSpring was finalized successfully. This transfer includes two parts: (1) process information to enable BioSpring to manufacture the drug substance and (2) analytical methods to analyze PRO045. Based on this information and two process adaptions, BioSpring could set up within the first 18 months the complete manufacturing and analytical process required for PRO045 production.
WP6
This period has focused on the organizing of a workshop on current challenges facing AON development for DMD, which took place in April 2015 in London. A steering committee has been established to take the organization of the workshop forward, and builds significantly on work already undertaken by SCOPE-DMD consortium partners as well as TREAT-NMD and BIO-NMD project partners.
WP7
The project manager and patient liaison officer have worked closely together in disseminating key messages to a range of audiences. With the website www.scope-dmd.eu and the various communication channels open to the consortium, the project has been able to reach a large audience.
Expected Outcome
The SCOPE-DMD project has made good progress, despite some delays in the initial timeline of the clinical trial. This has meant that the dose-escalation phase will be extended. This initial extension changes little to the overall aim of SCOPE-DMD, which was to provide quality data to apply for market authorization approval of PRO045, as well as further work on novel outcome measures. The additional data collected during this extension phase will significantly contribute to the gaining of market approval, which is the original aim of the SCOPE-DMD project.
