Final Report Summary - SCOPE-DMD (Consortium for Products across Europe in Duchenne Muscular Dystrophy)
Executive Summary:
The SCOPE-DMD project has been a well-run EU FP7 funded project and has utilised health research outcomes from the TREAT-NMD FP6 project to perform an innovative, pivotal paediatric clinical trial by BioMarin for an antisense oligonucleotide (AON) treating a subset of Duchenne Muscular Dystrophy (DMD) patients.
The SCOPE – DMD consortium consisted of 2 companies, BioSpring and BioMarin and 3 academic institutes, Newcastle University, the Leiden University Medical Centre, the Institute of Myology and was coordinated by Newcastle University.
The key deliverable of the SCOPE-DMD project was an exploratory, open-label, dose-escalation phase IIb study; the efficacy, safety, pharmacodynamics and pharmacokinetics of weekly subcutaneous doses of PRO045 in subjects with DMD are assessed.
The clinical trial was of a seamless design which was driven by the need to maximise the data from an exceptionally small patient population and to provide continuity of care in this rapidly progressing disease. It was designed to be made up of two phases: a dose escalation phase with 15 patients and an extended treatment phase with an additional 55 patients.
For this trial, the SCOPE-DMD Consortium used an AON called BMN 045 (previously known as PRO045); BMN 045 is a chemically modified AON, complementary to sequences in exon 45 of the DMD gene. Patients with deletions in the DMD gene flanking exon 45 (8% of all DMD patients), including deletions of exons 44, 46, 46-47, 46-48, 46-49, 46-51, 46-53, 46-55 or 46-60 will be treatable by exon 45 skipping.
The SCOPE-DMD project consisted of 8 Work Packages (WP). Work Packages 1 to 4 included the Clinical Trial and supporting WPs that evaluated three different outcome measures: functional outcome measures (WP2), magnetic resonance imaging (WP3) and serum biomarkers (WP4). Other WPs focussed on drug development and production of the drug product, a chronic toxicity study, educating regulatory authorities and dissemination of project results.
The clinical trial around which the SCOPE-DMD project was set-up has encountered a number of delays which have affected the original timelines of the project and the achievability of a number of the objectives of the SCOPE-DMD project. Due to a number of external factors, the treatment phase of the trial was not started within the lifetime of the SCOPE-DMD project. These external factors included the corporate acquisition of Prosensa by BioMarin and emerging safety results that required further investigation before being able to start the treatment phase.
The consortium made every effort possible to keep the delays in the trial and the project to a minimum while work continued within the supporting WPs 2, 3 and 4. Whilst the trial has encountered delay, much of the work originally planned in the WP2 - 4 has continued, albeit on a smaller contingent of boys, and some additional analyses and work was undertaken as well in WP3 and WP4, respectively. The work on outcome measures, biomarkers and imaging undertaken within the SCOPE-DMD project resulted in two Stakeholder Workshops attended and hosted by the European Medicines Agency, as well as a publication in Lancet Neurology.
The objective of completing and reporting a dose finding and pivotal trial with BMN 045 within the lifetime of SCOPE-DMD project was not fully achieved. However, the further validation and implementation of novel outcome measures and biomarkers developed in former FP6 (TREATNMD) and FP7 (BIO-NMD) undertaken within the SCOPE-DMD project has influenced regulatory interactions progressing acceptability of novel biomarkers and outcome measures in Neuromuscular Disease (NMD), which will make a positive contribution to future trials undertaken.
Project Context and Objectives:
DMD is an inheritable, X-chromosome linked, lethal childhood disease with a prevalence between 0.32 and 0.52 per 10,000 inhabitants. Worldwide, around 240,000 boys suffer from DMD. DMD is caused by mutations, often deletions, in the DMD gene that result in the disruption of the open reading frame leading to a loss of dystrophin protein expression. Dystrophin has a regulatory function within the cell, which is still to be fully elucidated. Importantly, dystrophin also has a scaffolding function in muscle fibres where it links the actin cytoskeleton with the extracellular matrix and so absorbs force generated during muscle fibre contraction. Muscle fibres lacking functional dystrophin are damaged during normal activity and are unable to regenerate healthy tissue eventually leading to progressive muscle weakness and wasting. DMD boys have overt signs of the disease as early as 2 years of age, with subclinical symptoms prior to that time. DMD boys are generally wheelchair dependent by the age of 12 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 childhood. 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 non-functional 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 (Becker muscular dystrophin or BMD-like protein) 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.
Of note is that different AON therapies will be needed to treat different subpopulations of DMD patients. In this context, a subpopulation of DMD patients is defined by a group of different mutations that are correctable with one particular AON. This consortium will use an AON called BMN 045 (previously known as PRO045); BMN 045 is a chemically modified AON, complementary to sequences in exon 45 of the dystrophin gene (see above). Patients with dystrophin genotypic deletions flanking exon 45, including exons 44 , 46, 46-47, 46-48, 46-49, 46-51, 46-53, 46-55 or 46-60 will be treatable by exon 45 skipping; these patient represent 8% of the total DMD population.
The main goal of SCOPE-DMD is to restore expression of a functional dystrophin protein in a targeted subset of DMD patients using exon skipping technology with a chemically-modified AON.
Furthermore, by utilising health research outcomes from the TREAT-NMD FP6 project to perform an innovative, pivotal paediatric clinical trial, SCOPE-DMD will also further investigate the validation and implementation of novel outcome measures and biomarkers developed in former FP6 (TREATNMD) and FP7 (BIO-NMD) projects; use a novel accelerated clinical trial design and regulatory strategy applicable to future clinical trials in a wide range of (rare) diseases and build on TREAT-NMD and Prosensa’s/BioMarin’s groundwork in regulatory interactions progressing acceptability of novel biomarkers and outcome measures in Neuromuscular Disease (NMD).
Main objectives
The main activity in the work plan is the execution of an innovative, adaptive clinical trial of which the protocol has been positively evaluated by EMA in July 2012. In November 2012, the Belgian Competent Authorities approved the Clinical Trial Application (CTA), which contains the Investigational Medicinal Product Dossier (IMPD) and Investigator’s Brochure. The Belgian ethics committee (EC) approved the study in December 2012, and the French EC early 2013. EC approval by Netherlands is awaited. CTA and ethical submissions have also been initiated in Italy and the UK.
The SCOPE-DMD trial is an exploratory, open-label, dose-escalation phase IIb study; the efficacy, safety, pharmacodynamics and pharmacokinetics of weekly subcutaneous doses of PRO045 in subjects with DMD will be assessed. The study will not include a placebo arm and will be non powered due to anticipated low numbers of eligible DMD patients treatable with exon 45 skipping. Natural history data and placebo from other programmes will be used as an external control. It should be noted that BioMarin has heavily invested in an international contemporaneous natural history programme for this very purpose. Whilst beyond the scope of this FP7 application, the consortium is working closely together on this project as well.
The functional entry criterion is a 6MWD of 230 m or above for ambulant boys aged at least 5 years on the day of first dosing. Other inclusion criteria are defined, including confirmed dystrophin mutation correctable by treatment with BMN 045, adequate muscle quality for biopsy (confirmed by NMR), life expectancy of at least 3 years and stable glucocorticosteroid use for at least 3 months prior to first BMN 045 administration. In total, 14 exclusion criteria have been defined of which the following are the most important: known presence of dystrophin in ≥5% of fibers, current or history of liver disease or renal disease, aPTT or platelet abnormalities beyond normal limits.
The study is of a seamless design which is driven by the need to maximise the data from an exceptionally small patient population and to provide continuity of care in this rapidly progressing disease. It consists of two phases: a dose escalation phase with 15 patients and an extended pivotal phase with an additional 55 patients. This work will be undertaken in Work Package 1 (WP1). During the dose escalation phase, five cohorts of three subjects each are planned (0.15 1, 3, 6 and 9 mg/kg) during which the safety, tolerability and efficacy will be closely monitored. Each subject will receive a single IV dose followed by subcutaneous dosing in order to compare bioavailability. From the dose escalation phase data, it is expected to define an optimal dose of BMN 045 with clear pharmacodynamic effect within acceptable safety and tolerability profile. Six NMD (neuromuscular disease) clinical centres (NL, Be, Fr, It, UK) will be involved. A data safety monitoring board (DSMB) will be responsible to review data for acute toxicity before each cohort starts treatment at a higher dose level. The first subjects remain on the original dose for at least 12 weeks to assess for midterm sub-clinical toxicities, which will be strong indicators of viable long term dosing regimens. Once the second cohort has completed a minimum 12 weeks dosing and it is deemed safe to do so, the subjects from the first cohort will upwardly titrate. The same occurs for each subsequent cohort until a Maximum Tolerated Dose is reached, based on either acute or midterm reactions or feasibility associated with injection volumes. If dose-limiting toxicities occur, the design will be modified, depending on when the toxicities occur and the nature of the toxicities. Toxicities are likely to be identified earlier than with a classical design due to the ongoing administration at lower doses, enabling us to make an informed decision around the Maximum Tolerated Dose well before the subsequent cohorts reach that time-point, which would otherwise be unachievable in a short-term dose escalation study. First subject first visit has occurred in January 2013. Due to practical reasons, it is anticipated that the total duration of this phase will be approximately 1 year.
As explained above, the 6MWD test will be the primary outcome measure. Secondary outcome measures are the NSAA and other tests described previously. To be able to define the optimal dose from both a pharmacodynamic and clinical perspective, new and largely unexplored DMD outcome measures will be included in the study. Three types of outcome measures will be explored: functional outcome measures (WP2), imaging (WP3) and biomarkers (WP4).
For WP1 – seamless clinical trial - the main objectives are to define by M11 the optimal treatment dose, to determine by M34 safety and tolerability of drug product; to determine by M34 the efficacy of drug product, to determine the pharmacokinetic profile of drug product within the first 48 hours of dosing and through levels at multiple time points throughout the study and to determine the pharmacodynamic effect of drug product at 12 weeks post dose and during 48 weeks of continuous treatment.
The main objectives for WP2 – Functional outcome measures - are to characterise by M36 the effects of treatment with drug product on 4 exploratory functional outcome measures used to measure the progression of DMD and secondly to provide by M36 a set of meaningful and sensitive functional outcome measures for the assessment of DMD in the SCOPE-DMD clinical trial and in any future clinical trials using other compounds for the treatment of DMD.
The main objectives for WP3 – imaging outcomes - are to evaluate muscle degenerative changes qualitatively, using standard T1 weighted spin echo imaging at screening and week 48 (optional), to evaluate disease activity using T2 mapping at screening, week 12 and 48, to quantitatively evaluate fatty degenerative changes using 3 point DIXON at screening, 12 (optional) and 48 weeks, to assess pH, free ADP concentration, creatine pool, membrane phospholipid turnover, using 31P spectroscopy at screening, 12 and 48 weeks and to evaluate vascular reactivity after a short (2-5 min) ischemia using perfusion mapping by arterial spin labelling at 12 and 48 weeks. (Paris site only).
The main objectives of WP4 – biomarker analysis - are to determine the effect of treatment on muscle biomarkers (biopsy); dystrophin, dystrophin-glycoprotein complex and associated proteins, miRNAs, the number of infiltrating cells and muscle morphology and quality after 12 weeks of the dose escalation phase and 48 weeks of the treatment phase, to determine the effect of treatment on serum biomarkers; muscle specific microRNA and MMP-9 and to evaluate the utility of these biomarkers in correlating to phenotype and/or clinical response, predicting clinical response and as potential future surrogate markers for the benefit of the current study and future studies within the biopharmaceutical or academic field.
For WP5 – manufacturing of drug product - the main objective is to generate the drug product and obtain a drug product Certificate of Analysis (CoA) and Certificate of Compliance (CoC) for a DS batch previously produced by Girindus, for cGMP production by M11 of a first batch of 400g drug substance aiming at a purity of at least 92%, including a CoA, cGMP production by M16 of a second batch of 400g drug substance aiming at a purity of at least 92%, including a CoA and to generate drug product and obtaining a drug product CoA and CoC of the two batches manufactured by BioSpring by M21.
WP6 – non-clinical toxicity studies – will manufacture and formulate by M6 20g of drug substance with a purity of at least 85% and obtain by M14 the interim in-life report of the 13-week GLP i.v. toxicity study in monkeys.
WP7 – educating regulatory agencies - and WP8 – Dissemination and Communication – have as objectives engaging through two workshops a range of stakeholders including regulatory agencies, patient organisations, the scientific community as well as disseminating publications and outcomes from the trial and the project.
Finally, WP9 – Project Management - has as objective the overall management and coordination of the project, successful monitoring of completion of Deliverables and Milestones, reporting and financial management of the project.
Project Results:
The SCOPE-DMD project has met a considerable amount of the original objectives. The clinical trial (PRO045-CLIN-01) has not been completed as originally planned, but significant progress has been made in terms of further understanding of functional outcome measures and biomarkers and relevant data collected in the clinical trial so far have been described in an interim Clinical Study Report. The project has highlighted, through the stakeholder workshops and subsequent publication as part of WP7, the progress made within the Duchenne field, but also underlined the research still required to find an effective disease-modifying treatment. The consortium, along with many external stakeholders, has worked extremely well together to bring the SCOPE-DMD project to a successful conclusion and allow for lessons learned to be disseminated as widely as possible.
Brief overview of activities
WP1: During the dose-escalation phase of the study the most optimal dose was planned to be identified for the treatment phase of the clinical trial. A total of 15 patients were enrolled into the study, which were treated with escalating doses of BMN 045 (previously known as PRO045), ranging from 0.15 mg/kg to 9.0 mg/kg subcutaneous (SC) and single dose of intravenous (IV) from 1.0 mg/kg to 9.0 mg/kg. In general the drug was well tolerated. Prolonged dosing with 9.0 mg/kg resulted in emerging safety signals in 11 out of the 15 subjects resulting in the MTD for BMN 045 being set at 6.0 mg/kg SC. Preliminary detected tissue concentrations of BMN 045 did not reach the levels, as measured for drisapersen. Injection site reactions may limit long-term SC administration. Based on the data obtained so far from the study, an optimal dose and dosing route for the treatment phase of the study could not be identified.
WP2: All the tasks defined in the DOW has been completed in due time. Extra work also been completed in other DMD populations, particularly during various natural histories of the disease. Moreover reference values have been developed in health controls to define predictive equations for grip and pinch strength.
WP3: During the second part of the project, the NMR lab at the IoM, ensured follow-up for rescanning phantoms and volunteers at all sites. Since treatment was discontinued in the majority of the patients and an amendment for additional NMRI exams in the initially recruited 15 subjects was never validated, no new NMRI/S acquisitions were performed. Emphasis was put therefore on performing additional analyses on the existing data such as contractile muscle mass measurements, water T2 heterogeneity and alternative determination of water T2 based on the extended phase graph formalism (EPG), all of which are quantitative NMRI measures that can help in the understanding of the progression of the disease.
WP4: Following on from work undertaken in M1 – M18, serum proteomics analysis of DMD patients with 45 flanking deletion, BMD patients with relevant deletions and age matched controls has been performed at the LUMC. For BMD patients several parameters are available such as dystrophin levels in muscle, muscle gene expression, MRI and manual quantitative assessment. This will help to make the link between dystrophin levels in muscle, disease state and the value of a biomarker. Similarly, RNAseq analysis of muscle biopsies of the same BMD patients has been ongoing at the LUMC to correlate serum biomarkers levels to gene expression in muscle.
WP5: Within the second 18 month, the cGMP campaign at BioSpring (800 ± 80 gram) could be finalized successfully. After finalizing the manufacturing a new CoC and CoA was issued by BioSpring. This larger campaign is also a substitute for the originally planned two 400 ± 40 gram campaigns. All activities have been finalized in 2015.
WP6: The campaign of final lyophilised material for the 13-week toxicity monkey study using IV administration was completed in November 2014. However, since the treatment phase of the clinical trial had significantly been delayed the 13 week toxicity study has been postponed until further notice.
WP7: Two Stakeholder workshops were successfully delivered, both organised with cooperation from a range of stakeholders, including regulators, industry, patient organisations and clinicians. In total, more than 200 people attended.
WP8: Disseminating information about the clinical trial itself to patients has been undertaken predominantly by the clinical trial site clinicians, in close cooperation with BioMarin. The clinical trial hasn’t been completed yet and therefore the full data have not yet been analysed. Therefore, the dissemination to target audiences has focused on work undertaken in WP2, WP3 and WP4. The Stakeholder Workshops organised as part of WP7 have also contributed considerably.
WP9: UNEW has continued to work closely with BioMarin to manage the project. Three further partner meetings were held. The UNEW Project Coordinator and Project Manager worked closely with the EU Scientific Officer to make appropriate amendments and guide the consortium to successful completion of the reporting requirements.
Below is set out in more detail the main results from the scientific Work Packages along with key Deliverables and Milestones.
No new foreground was generated during the lifetime of the project.
Work Packages – in detail
WP1 – Seamless clinical trial
Summary of Achievement
The original protocol for this study was finalised on 02 August 2012. Changes to the protocol to collect data on IV administration of BMN 045have been included in amendment I, which was finalised on 18 December 2012. Protocol amendment II was finalised on 16 August 2013 to include the possibility for pre-planned treatment interruptions for the subjects in Group 1 and instruction on the process for resumption of dosing after the treatment interruption. The reason for this change was that the up-titration to 1.0 mg/kg was delayed due to a delay in the recruitment of Group 2 (1.0 mg/kg) and the continuing treatment for a prolonged time at 0.15 mg/kg was considered not significantly beneficial for the subjects in Group 1. The treatment interruption lasted until confirmation that the 12 week safety data from Group 2 was acceptable, allowing the subjects in Group 1 to be up-titrated to the Group 2 dose.
A total of 15 patients were enrolled into the study, which were treated with escalating doses of BMN 045, ranging from 0.15 mg/kg to 9.0 mg/kg subcutaneous (SC) and single dose of intravenous (IV) from 1.0 mg/kg to 9.0 mg/kg. In general the drug was well tolerated. Prolonged dosing with 9.0 mg/kg resulted in emerging safety information and an ad hoc Data Safety Monitoring Board (DSMB) meeting was convened.
The DSMB recommended to set the maximum tolerated dose (MTD) for BMN 045 at 6.0 mg/kg SC. Based upon the recommendations by the DSMB, BioMarin decided to halt dosing at 9.0 mg/kg. Subjects who tolerated the treatment well continued dosing at 6.0 mg/kg. The subjects with abnormal lab values remained off treatment. Additional assessments to better understand the mechanism of action of the emerging safety information have been included in the protocol by means of protocol amendment III, which was finalized on 07 January 2016. Following the approval of this amendment, subjects who had remained off treatment will join ongoing subjects at 6.0 mg/kg SC following normalisation of their lab values. Data will be reviewed by the DSMB and the Safety Review Team to determine further evaluation required and continued dosing strategy. In the absence of safety concerns subjects may continue dosing.
Key Deliverables and Milestones
Deliverable 1.2 – Identification of the optimal dose for the extended phase of the clinical trial (M19)
The optimal dose of the drug product has not been identified yet due to the dose escalation phase extended to investigate the emerging safety information.
The maximum tolerated dose for SC BMN 045 was determined to be at 6 mg/kg/per week.
Deliverable 1.3 – Summary of the Clinical Study Report (CSR) of the complete trial containing all relevant data on biopharmaceutical studies, human PK, human PD, efficacy and safety (M36)
As the trial is ongoing, an interim Clinical Study Report has been generated using a data cut off date of September 2015. The report contains all the relevant data from the clinical trial.
Milestone 2 – Define optimal dose of drug product (M11)
The optimal dose of the drug product has not been identified yet. The dose escalation phase was extended to investigate the emerging safety information.
WP2 – Functional outcome measures in the clinical trial
Summary of Achievements
During the first period of the project, the team from the Neuromuscular Physiology and Evaluation lab at the Institute of Myology ensured training of all clinical evaluators involved in the study. Quality control of the first measurements performed resulted in a retraining of all clinical evaluators, which was not originally planned in the Description of Work (DoW), to ensure quality of the data recorded. The equipment of each centre was checked once a year to ensure accuracy of the measurements as planned in the DoW. However tools presented technical problems, not anticipated in the DoW, and were repaired as soon as possible to avoid as much missing data as possible. Review of the first visits of each patient were originally planned in the DoW but all data collected were controlled (raw signals as well as operating procedures) to ensure accuracy of the database. Accelerometry signals were analyzed to compute gait parameters during the six-minute walk test and the 30 second walk test. Specific software for the automation of the analyses was developed. In addition, additional parameters were developed in order to find new parameters that would capture the walking pattern independently of gait speed. These extra analyses were not planned in the DoW and the software developed will enable to perform the analyses of remaining data more quickly for the remaining data.
In M19 – M36, all tasks as defined in the DOW has been completed in due time. Extra work also has been completed in other DMD populations, particularly during various natural histories of the disease. Moreover reference values have been developed in health controls to define predictive equations for grip and pinch strength.
The Performance of the Upper Limb Scale has been developed in an international collaboration with the SCOPE-DMD sites. Data analysis and interpretation of results has progressed the PUL with each iteration leading to the final Version PUL V2.0. The version was based on clinical interpretation of Rasch analysis with patient and advocacy input.
The introduction of a new outcome measure – The Active Seated Assessment in collaboration with Nationwide Children’s Hospital Columbus Ohio in 2015 has further expanded the breadth of outcome measures available in the SCOPE-DMD project.
Key Deliverables and Milestones
Deliverable 2.1 – report demonstrating the impact of treatment on muscle functionality: Report demonstrating the impact of treatment on muscle functionality for the complete trial including presentation of all performed statistical analyses of clinical/functional data (M36)
Deliverable 2.2 –Identification of which (set of) functional outcome measures is most optimal for the assessment of improvement of DMD in Duchenne boys treated with a curative therapy: Identification of which (set of) functional outcome measures is most optimal for the assessment of improvement of DMD in Duchenne boys treated with a curative therapy [month 36]
Deliverables D2.1 and D2.2 have been combined.
The Performance of the Upper Limb Scale developed within the SCOPE-DMD project resulted in a wealth of international collaborations outside of the SCOPE-DMD project as well as a number of publications on its development, reliability, validity, correlation with other outcome measures and its ability to detect change in clinical status as a result of treatment with steroids. The PUL has become a necessary part of the tool kit for assessment of boys and men with DMD in both therapeutic clinical trials and natural history studies. Furthermore the clinical meaningfulness of the PUL confirmed by the full participation of patients and advocacy groups has expanded the use of this scale out of the research arena and into clinics. The results of the PUL can direct professionals into targeting hands on therapies or aids and adaptations to assist patient function.
The PUL has been adopted for use in several clinical trials in DMD by different other companies including Eli Lilly, Sarepta, PTC, Bristol Squibb Myers, FibroGen and Capricor amongst others.
The process by which the PUL was developed has followed an iterative process. Items in Version 1.2 were clarified and some grading was simplified to make the scale more efficient. Some of the easier and some of the more difficult items were removed as there was duplication at these levels and fewer activities would deliver the same results reducing the burden of number of items for the patients. Many items simplified scoring to 0, 1 and 2 to better reflect progression rather than strategies. It was important though to understand that there were no construct differences between the two versions and therefore these adaptations were reviewed by comparing the individual item scores for the two similar tests on the same boy to assess if the final version (PUL2) reflects fully the construct as outlined and measured by version 1.2.
Fifty-two assessments from two centres within the SCOPE-DMD project were collected where dual data existed for the two versions. The two versions (PUL1.2 and PUL2) were entered into RUMM2030 as though they were one scale and the item locations for the original and the rescore were compared. Item fit, response categories, reliability and targeting were also reviewed for the two versions. When the two scales were combined into a single scale to see if the item location for individual items were comparable the results were highly similar with a similar range for both scales. Therefore a score as defined on the PUL1.2 relates to a score on the PUL2.
Milestone 5 – Update on the functional outcome data collected during the dose escalation phase of the trial (M19)
DMD is a multifaceted condition with changes occurring within muscle function at different rates over a prolonged time period. It was initially considered that upper limb and lower limb measures were compartmentalised into ambulant and non-ambulant disease stages. However the SCOPE-DMD project linking in with other natural history data sets from BMN 045-CLIN-01, North Star, Italian network and CINRGY groups have shown the relationship between ambulant and non-ambulant measures is more complex and not so simple as ambulant versus non-ambulant. This collaborative work within the SCOPE-DMD project has confirmed that upper-limb measures are relevant in the ambulant population. Use of the PUL has demonstrated that functional ability in ambulant boys is primarily proximal. There is a correlation with the PUL, active seated and Brooke scales as well as with the 6MWT. Although the PUL has a ceiling effect in high functioning boys, it is the most clinically meaningful outcome and other measures such as the active seated and Myotools with less ceiling effect may measure the more able boys longitudinally before functional weakness is perceived. Although we have not had sufficient data in the SCOPE-DMD project to identify Outcome Measures (OM) that determine improvement we have been able to determine meaningful measures to the families and which can detect deterioration over time which suggests that improvement would also be measurable.
Milestone 10 – Provide a set of meaningful and sensitive functional outcome measures (M36)
The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy however it is important to understand the relationship of the scale in DMD to typically developing children and ultimately develop normative values. A study by Pane et al looked at a cohort of typically developing children from the age of 3 years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. Normative data for the scale validation was collected on 277 typically developing subjects from 3 to 25 years old. A full score was consistently achieved by the age of 5 years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. This paper consolidated work begun within the SCOPE-DMD project and included evaluators trained by SCOPE-DMD physiotherapists.
Pane et al also published valuable data on the relationship between other OMs and the PUL and further developed the knowledge base of understanding when different OM are most efficacious. The first published data have shown that early signs of involvement can also be found in ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6 Minute Walk Test (6MWT) and the PUL in ambulant DMD boys. Both 6MWT and PUL were administered to 164 ambulant DMD boys of age between 5.0 and 16.17 years (mean 8.82). The 6 minute walk distance (6MWD) ranged between 118 and 557, the PUL total scores ranged between 52 and 74. The correlation between the two measures was 0.499. The scores on the PUL largely reflect the overall impairment observed on the 6MWT but the correlation was not linear. The use of the PUL appeared to be less relevant in the very strong patients with 6MWD above 400 meters, who, with few exceptions had near full scores. In patients with lower 6MWD the severity of upper limb involvement was more variable and could not always be predicted by the 6MWD value or by the use of steroids. Our results confirm that upper limb involvement can already be found in DMD boys even in the ambulant phase. Importantly although it correlates somewhat with the 6MWT it clearly measures a different dimension of the disease process.
The PUL has also been used to demonstrate the effectiveness of a successful treatment. Unfortunately this was not possible to show within the SCOPE-DMD trial but the work done on development of the PUL in this project has provided a suitable and meaningful outcome measure for use in other studies. The aim of the study performed by the Italian network was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naïve or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naïve group (p < 0.001).
The 12-month changes ranged between −20 and 4 (mean −4.4). The mean changes were −3.79 in the glucocorticoid group, −5.52 in those who stopped at loss of ambulation and −4.44 in the naïve group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels.
Their findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function.
WP3 – Imaging outcomes in the clinical trial
During the first period of the project, the team from the NMR lab at the Institute of Myology ensured training of all imaging technicians at the different centres involved in the study. This training was based on an imaging manual which was written for this study by the IoM with contributions from the LUMC and Prosensa. The qualification of each site included the acquisition of datasets in two phantoms (specifically designed/chosen for the imaging protocol to be used in the study) and two volunteers, an inter-site volunteer (visiting all centres involved) and an intra-site volunteer (who was scanned twice in a one to three week interval to check reproducibility). All data was analysed based on in-house matlab code (NMR Lab). Following the approval/validation of this data during the qualification period by the NMR Lab personnel, the centres were given the green light to start scanning patients. Quality control of all phantom, volunteer and patient data was performed upon acquisition and transfer of the data. Fifteen patients, divided over six different sites, received two MRI exams (V2 + V15). Preliminary analyses on the two first visits have been performed based on the Dixon, the T2 mapping and the 31P-MRS data (which corresponds with the milestones at M18 for WP3). No trends in the imaging outcomes have been found so far between V2-V15. Further analyses are ongoing.
During the second part of the project, the NMR lab at the IoM, ensured follow-up for rescanning phantoms and volunteers at all sites. Since treatment was discontinued in the majority of the patients and an amendment for additional NMRI exams in the initially recruited 15 subjects was never validated, no new NMRI/S acquisitions were performed.
However, during this second period, the emphasis was put on performing additional analyses on the existing data such as contractile muscle mass measurements, water T2 heterogeneity and alternative determination of water T2 based on the extended phase graph formalism (EPG), all of which are quantitative NMRI measures that can help in the understanding of the progression of the disease.
Additionally, as muscle perfusion might be used as a potential outcome measure in dystrophic muscle, a number of experiments were performed to optimize and validate this method for future protocols.
In conclusion, because the treatment was interrupted in most patients, the value of the different NMR outcome measures was impossible to compare. Based on data from other studies in Europe and in the US, muscle fat fraction as estimated from water-fat (Dixon) imaging is undoubtedly the most robust biomarker of muscle dystrophy progression.
Key Deliverables and Milestones
Deliverable 3.2 – Identification of which (set of) NMR indices is most optimal for the assessment of improvement of DMD in Duchenne boys treated with a curative therapy (M36)
Because the treatment was interrupted in most patients, again the value of the different NMR outcome measures was impossible to compare. Based on data from other studies in Europe and in the US, muscle fat fraction as estimated from water-fat (Dixon) imaging is undoubtedly the most robust biomarker of muscle dystrophy progression. It was shown to be able to monitor dystrophic muscle wasting (by the progressive increase in fat content from 20 to 60%) at an early stage of the disease, at a time the standard 6min walking distance remained stable and was non-informative.
WP4 – Biomarker analysis in the clinical trial
Summary of Achievements
Prior to initiation of dosing with BMN045, all patients underwent a skin biopsy and were screened for the applicability of an exon 45 skip. The screening has been completed and it is confirmed at the RNA sequence level that all screened patients carry the described mutations and that BMN 045 induces skipping of exon 45 in their cells.
In order to evaluate whether serum biomarkers can capture disease state and progression, serum proteomics analysis of DMD patients with 45 flanking deletion, BMD patients with relevant deletions and age matched controls has been performed at the LUMC. For BMD patients several parameters are available such as dystrophin levels in muscle, muscle gene expression, MRI and manual quantitative assessment. This will help to make the link between dystrophin levels in muscle, disease state and the value of a biomarker.
Similarly RNAseq analysis of muscle biopsies of healthy controls and the same BMD patients is ongoing at the LUMC to correlate serum biomarkers levels to gene expression in muscle.
Key Deliverables and Milestones
Deliverable 4.1 – report demonstrating the impact of treatment at molecular level and demonstrating a move towards Becker muscular dystrophy phenotype or healthy life characteristics (M36)
Muscle biopsies obtained from subjects participating in the trial were analysed for skip of exon 45 on RNA level, dystrophin intensity and concentrations of BMN 045. No clear increase in dystrophin or exon 45 skip transcripts was observed. Tissue concentrations of BMN 045 in muscle biopsies increased with increasing dose level.
Deliverable 4.2 – Identification of which (set of) biomarkers is most optimal for the assessment of improvement of DMD in Duchenne boys treated with a curative therapy (M36)
Exon skip and dystrophin protein levels remain the primary biomarkers for assessing the mechanism of action of a curative therapy aiming to induce exon skip in the DMD pre-mRNA and induction of dystrophin expression. DMD diagnostic serum biomarkers, muscle creatine kinase and lactate dehydrogenase, can serve as pharmacodynamic biomarkers that change upon drug treatment and different doses. The limitation is that the magnitude of change of these muscle biomarkers will also require a placebo treated group as these biomarkers tend to decrease also with age in the absence of drug treatment, in order to compare the magnitude of the reduction in the drug treatment and the placebo group.
Milestone 7 – Status update on the biomarker data collected during the dose escalation phase of the trial (M19)
Potential muscle tissue biomarkers;
To elucidate the primary mechanism of action of BMN 045, dystrophin levels of the muscle fibres were measured by immunofluorescence in pre and post treatment biopsies for 14 of the 15 subjects participating in the trial.
Exon 45 skip in pre-treatment and post treatment biopsies was also measured.
No clear increase in dystrophin or exon 45 skip transcripts was observed. Concentrations of BMN 045 in muscle increased with increasing dose.
Exploratory;
miRNAs in muscle were evaluated and no changes following drug treatment were observed in miRNA 133a and b, miRNA 1, miRNA 29c, miRNA 223, miRNA 146b, miRNA 21.
Potential serum biomarkers;
Creatine kinase and lactate dehydrogenase were measured and were found to be decreased upon dose escalation yet in the absence of a placebo arm the effects are difficult to interpret, as these muscle proteins decrease with age in DMD.
Milestone 12 – Provide a set of meaningful and sensitive biomarkers (M36)
Dystrophin assessed using a sensitive and reproducible immunofluorescence method remains a meaningful pharmacodynamics biomarker to measure in therapies aiming to induce dystrophin expression. Yet the choice of muscle group is critical and the time point of taking a muscle biopsy can affect the potential detection of dystrophin and the PK-PD response. Similarly exon skip is a biomarker that supports the mechanism of action.
Of the known serum muscle diagnostic DMD biomarkers CK and LDH can also serve as potential pharmacodynamic biomarkers yet are difficult to correlate to disease state as they are reduced with age and subsequent muscle loss and are affected by muscle activity such as exercise. Correlation of changes in CK and LDH and changes in 6MWD can help in the interpretation. Measurement of total activity of the patients during treatment (using methods such as ActiMyo) could elucidate whether reductions in CK and LDH are due to general reduction in activity.
The data analysis re correlation of DMD biomarkers and disease severity and comparison of biomarkers between DMD and BMD serum is currently ongoing.
WP5 - Manufacturing of drug product for the extended phase of the clinical trial
Summary of Achievements
Within the first 18 months, the process and method transfer from Prosensa to BioSpring was finalized successfully. This transfer includes two parts: a) process information to enable BioSpring to manufacture the drug substance and b) analytical methods to analyse BMN 045. Based on this information and two process adaptions, BioSpring were able to set-up within the first 18 months the complete manufacturing and analytical process required for BMN 045 production. Also the manufacturing process was transferred successfully within BioSpring from a lab-scale model (which was used first to prove successful method transfer between Sites) to BioSpring’s commercial manufacturing platform. Currently the cGMP campaign is running at BioSpring at 800 gram (± 80g). This larger campaign is also a substitute for the originally planned two 400 gram (± 40g) campaigns. Despite some delay within the project at the beginning of 2014, all activities planned for 2014 were completed by the end of 2014 or were close to being finalized Q1/Q2 2015. Task 5.3 Part I and Part II will be completed within 2015 (shifted from 2014 to 2015).
Within the second 18 month, the cGMP campaign at BioSpring (800 ± 80 gram) could be finalized successfully. After finalizing the manufacturing a new CoC and CoA was issued by BioSpring. This larger campaign is also a substitute for the originally planned two 400 ± 40 gram campaigns. All activities have been finalized 2015.
Key Deliverables and Milestones
Deliverable 5.1 – CoA and COC for the Drug Product originating from Girindus Drug Substance
Originally it was intended by BioMarin within this FP7 program to receive and update the CoC and CoA from the original Nitto Denko Avecia PS220 batch. In the meantime the technology transfer from Nitto Denko Avecia to BioSpring took place successfully. This successful transfer makes the CoA and CoC from BioSpring similar to the original CoA and CoC provided by Nitto Denko Avecia. The cGMP manufacturing campaign was finalized January 2015. After finalizing the manufacturing campaign, batch review and release a new CoC and CoA was issued by BioSpring 2015.
Deliverable 5.2 – CoA of two new 400g batches of Drug Substance
Originally it was intended by BioMarin within this FP7 program to run two 400 gram (± 40g) cGMP campaigns. However, due to some delay within the project and the accessibility of the new OligoProcess platform for cGMP manufacturing in March 2014, it was decided by BioMarin and BioSpring to run one 800 gram (± 80g) campaign instead of two 400 gram (± 40g) campaigns beginning of Q4 2014 (change of manufacturing strategy). The manufacturing campaign started beginning of November 2014 and finished January 2015. The material from BioSpring (approx. 920 gram) passed all specifications defined within the CoA. After batch record review and drug substance release a new CoC and CoA was issued by BioSpring (Q1 / 2015). 2015 the cGMP material was delivered to BioMarin as well.
Milestone 1 – Successful transfer of cGMP manufacturing to BioSpring
Within the first 18 months, the process and method transfer from Prosensa to BioSpring could be finalized successfully. This transfer includes two parts: a) process information to enable BioSpring to manufacture the drug substance and b) analytical methods to analyse PS220. 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 PS220 production. Also the manufacturing process could be transferred successfully within BioSpring from a lab-scale model (which was used first to prove successful method transfer between Sites) to BioSpring’s commercial manufacturing platform.
Milestone 8 – Produce 800g cGMP drug product
Originally it was intended by BioMarin within this FP7 program to run two 400 gram (± 40g) cGMP campaigns. However, due to some delay within the project and the accessibility of the new OligoProcess platform for cGMP manufacturing in March 2014, it was decided by Prosensa and BioSpring to run one 800 ± 80 gram campaign instead of two 400 ± 40 gram campaigns beginning of Q4 2014 (change of manufacturing strategy). The 800 gram manufacturing campaign started beginning of November 2014 and finished January 2015. The material from BioSpring (approx. 920 gram) passed all specifications defined within the CoA. After batch record review and drug substance release, a new CoC and CoA was issued by BioSpring (Q1 / 2015) and the cGMP material was delivered to BioMarin.
The drug substance was converted to drug product in February 2015 by Halix BV (Leiden, the Netherlands) with fill volumes of 0.7 and 1.0 mL. Both batches passed all specifications defined within the CoA. After batch record review and drug product release, a CoC and CoA was issued by BioMarin (Q4 / 2015).
WP6 – Non-clinical toxicity studies
Summary of Achievements
Task 6.1 – Manufacturing of 20g of formulated drug substance (BioSpring, BioMarin)
Final lyophilised material was shipped to BioMarin in January 2015. Since the 13 week toxicity study has been delayed, the drug substance has not been formulated yet.
Task 6.2 – 13-week IV study in monkeys
In the clinical study of this project, single IV administration was included in the dose escalation phase. Since the treatment phase of the clinical study has significantly been delayed and because of current discussions with authorities and ethical commissions, the 13 week toxicity study has been delayed, until further notice.
Key Deliverables and Milestones
Deliverable 6.1 – Non-cGMP Certificate of Analysis of drug substance (M19)
The final lyophilised non-GMP TOX material was shipped to BioMarin in January 2015. This included an issued CoA as well.
WP7 – Educating regulatory authorities
Summary of Achievements
The planning of the first Workshop started in June 2013. The meeting took place at the EMA on 29th April 2015 entitled “A forum discussion between stakeholders on current challenges that face antisense oligonucleotide therapy development for DMD” and was organised in collaboration with COST Action 1207. As reported in the Periodic Report for M1 – M18, a Steering Committee was set up specifically to organise and plan the April 2015 meeting. The EMA was represented on this Steering Committee.
The Steering Committee had a second teleconference in January 2015, and a face-to-face meeting was held in March 2015 in Leiden. Another Steering Committee teleconference was organised in April 2015.
It was attended by 120 stakeholders including clinicians, representatives from DMD parent organisations, senior representatives from the European Medicines Agency (EMA) and industry. A Briefing Document was produced by the Steering Committee, which comprised of clinicians and senior management of Prosensa/BioMarin as well as patient organisations. The outcome of these interactions has been published in the policy view in the Lancet Neurology and can be found following the link below:
http://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(16)30035-7.pdf
The Second workshop entitled “Making Outcomes Work” took place on the 26th May and was attended by approximately 80 people. The Workshop was chaired by Volker Straub and Andrew Blamire from Newcastle University and Maria Isaac from the EMA. WP Leads from SCOPE-DMD presented their latest interim biomarker and imaging findings from the SCOPE-DMD project.
Key Deliverables and Milestones
Deliverable 7.1 – First global workshop with all relevant stakeholders on the use of biomarkers in NMD clinical trials (M19)
The Stakeholder Workshop meeting on antisense oligonucleotide-mediated exon skipping therapy development for Duchenne muscular dystrophy (DMD) involved representatives from the Duchenne muscular dystrophy patient community, academia, industry and regulatory agencies. The meeting was organized by Cooperation of Science and Technology (COST) Action BM1207 and SCOPE-DMD (FP7, #601573) and hosted by the European Medicines Agencies (EMA, April 29, 2015) and was a follow up meeting of a previous meeting organized in 2009. The meeting was attended by 120 stakeholders. A Steering Committee was established for the organising the workshop as well as for the writing of a Briefing Document for those attending the workshop.
Deliverable 7.2 – Second global workshop with all relevant stakeholders (M36)
The second Global workshop was hosted at the British Library on the 26th May by Volker Straub and Andrew Blamire from Newcastle University. The objective of the workshop was to bring representatives of all the Consortium partners, the European Commission, EMA and patient organisations together to review the work undertaken as part of the SCOPE-DMD project and specifically discuss the progress on outcome measures for evaluation of DMD.
All key stakeholders were represented and there was a wide ranging debate on making outcomes work in the future for this disease.
Milestone 13 – Educate regulatory agencies (M36)
Interaction with the regulatory agencies played an important role at the two workshops. The first global workshop was hosted by the European Medicines Agency (EMA). There were regular contacts between the EMA, and the WP7 leads and senior representatives from the EMA both presented and attended.
At the second workshop, representatives from the EMA again played a key and active role, presenting the Agency view on answering questions posed by the Consortium members and patients groups. The forum facilitated the sharing of challenges when undertaking research in Duchenne Muscular Dystrophy with the entire audience, including the regulatory representatives.
A key achievement was the publication of the following paper: Stakeholder cooperation to overcome challenges in orphan medicine development: the example of Duchenne muscular dystrophy published in the Lancet Neurology - : http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)30035-7/fulltext. A podcast was also conducted prior to the launch of the paper. It can be listened to here: http://www.thelancet.com/pb/assets/raw/Lancet/stories/audio/laneur/2016/laneur_160606.mp3
Articles on the publication as well as the second Stakeholder Workshop were published in the June TREAT-NMD newsletter: http://www.treat-nmd.eu/newsletter/archive/email/29th_June_2016.html
Potential Impact:
Duchenne muscular dystrophy is a severe, progressive muscle disease affecting 1 in 5000 male births. The disease is characterized by continuous and irreversible loss of muscle tissue and function. Affected children are typically diagnosed at about four or five years of age, when it becomes apparent that their motor abilities are restricted, (e.g. repeated falling, difficulty with running and trouble climbing stairs). Without treatment most require the use of a wheelchair around the age of 9.5 years. Orthopaedic problems resulting from extreme muscle weakness, respiratory and cardiac complications emerge and death often occurs by the late teens or early adulthood, mostly due to respiratory or cardiac failure. With optimal care, including assisted ventilation patients can survive three decades, but older patients have profound weakness and require assistance with all activities of daily life, with a high emotional and financial burden to patients, families and society.
An innovative approach to DMD therapy: exon skipping
The exon skipping approach addresses the underlying cause of DMD, i.e. lack of functional dystrophin protein in muscle. Antisense oligonucleotides (AONs), which are modified pieces of DNA or RNA, allow the production of partially functional dystrophin proteins by re-establishing the open reading frame in the mutated dystrophin transcripts. Currently two different chemical modifications are being tested in clinical trials and more are undergoing pre-clinical evaluation. Exon skipping is a compelling example of a personalized/precision medicine approach, since the exon to be targeted depends on the individual mutation of the patient. While certain sizable groups of individuals would benefit from a single AON, the majority of AONs apply to smaller groups, each making up less than 2% of all patients.
Individuals affected by DMD and their families are aware of the challenges that need to be faced while attempting to provide effective therapies for this devastating disease. Research has shown that affected individuals and parents would welcome, for the time being, therapies that slow down disease progression, in line with what the therapeutic approaches currently in development aim to achieve. Furthermore, affected individuals and their parents are willing to accept a level of uncertainty inherent to the therapy development pathway and are willing to contribute to it at every step. Finally, patients and parents are keen to give input and advice at an earlier stage of drug development about trial design, choice of outcome measures, explaining what is clinically meaningful to them, how they see benefit risk, in- and exclusion criteria and on how to collect sufficient data in groups of patients not fitting these criteria in order to enhance the possibilities for extrapolation of trial results to these groups of patients.
The SCOPE-DMD study is an exploratory, open-label, dose-escalation phase IIb; to assess the efficacy, safety, pharmacodynamics and pharmacokinetics of weekly subcutaneous doses of BMN 045 (previously known as PRO045) in subjects with DMD. The study will not include a placebo arm and will be non-powered due to anticipated low numbers of eligible DMD patients treatable with exon 45 skipping. Natural History data and placebo data from other exon skip programmes will be used as an external control. Whilst beyond the scope of this FP7 application, the consortium is working closely together on the Natural History data and other exon skip programmes as well.
The SCOPE-DMD study highlighted the importance of safety monitoring. The start of the treatment phase of the clinical trial had to be delayed because of emerging safety signals during the prolonged dosing at 9.0 mg/kg SC. An ad hoc DSMB meeting was convened in February 2015 to discuss the emerging safety signals and the DSMB recommended to set the maximum tolerated dose for SC BMN 045 at 6.0 mg/kg/week. Based upon this recommendation, BioMarin decided to halt dosing at 9.0 mg/kg SC in all subjects and subjects who tolerated the treatment well continued dosing at 6.0 mg/kg. An Expert Panel meeting was convened to obtain advice and recommendations for the continuation of the clinical trial based on the emerging safety signals. This resulted in a protocol amendment to include additional safety monitoring to better understand the mechanism of action of the emerging safety signals.
At the time of writing BioMarin is discontinuing clinical and regulatory development of Kyndrisa as well as the three other first-generation follow-on products, BMN 044, BMN 045 and BMN 053. The efficacy and safety data generated from the BMN 045 study will have a significant benefit though on the further development of exon-skipping technology while BioMarin continues the development of next generation oligonucleotides.
Of note is also the innovative design used for this clinical trial. This trial consists of a dose escalation phase with 15 patients to determine a safe and efficacious dose followed by a pivotal treatment phase in which the same patients will be treated for 48 weeks together with an additional ~55 patients. In contrast to a classical design, this design ensured continuity of treatment for all patients enrolled in the study. It is not possible to conduct a statistically powered study due to the rarity of subjects with DMD correctable by exon 45 skipping, reflected by BMN 045 having orphan drug designation. The conduct of a single phase IIb registration pivotal study was therefore proposed, which has been discussed with the European Medicines Agency (EMA) Scientific Advice Working Party (SAWP).
Although the BMN 045 clinical trial did not progress as planned, the value created by the implementation of the innovative clinical trial design that allowed all enrolled patients to receive active treatment during the trial will not been lost and may support other compounds to be developed using a similar design.
Outcome measures & clinical benefit for DMD
Outcome measures that show correlation with slowing of disease progression would be appropriate endpoints in clinical trials given the importance of it to the patients and their families. Similarly, also outcome measures that predict disease milestones would be preferred. As an example, the time it takes to run 10 meters is predictive of when patients will lose ambulation, so a 2 second difference between treated and placebo groups in this test can indicate a delay of months or years in the decrease of motor function capabilities of the treated patients.
The DMD field has generated a huge amount of data on the use of outcome measures and their relevance. Consequently, the field is in need of clear and consistent guidance on what the regulators expect in terms of what outcome measures should be used in which DMD population (e.g. ambulant vs non-ambulant).
The SCOPE-DMD project has made a significant contribution to the research and development of outcome measures, as three Work Packages focused specifically on developing and validating new exploratory outcome measures. Work Package 2 focused on functional outcome measures, Work Package 3 focused on Imaging and Work Package 4 on biomarkers.
We would like to highlight the impact of the work undertaken in Work Package 2. The Performance of the Upper Limb Scale developed within the SCOPE-DMD project had led to a wealth of international collaborations outside of the SCOPE-DMD project as well as a number of publications on its development, reliability, validity, correlation with other outcome measures and its ability to detect change in clinical status as a result of treatment with steroids. The PUL has become a necessary part of the tool kit for assessment of boys and men with DMD in both therapeutic clinical trials and natural history studies.
Furthermore, the clinical meaningfulness of the PUL confirmed by the full participation of patients and advocacy groups has expanded the use of this scale out of the research arena and into clinics. The results of the PUL can direct professionals into targeting hands on therapies or aids and adaptations to assist patient function.
The PUL has been adopted for use in several clinical trials in DMD by other companies including Eli Lilly, Sarepta, PTC, Bristol Squibb Myers, FibroGen and Capricor amongst others. Evaluators working in other BioMarin studies have also been able to take advantage of the newly developed PUL V2. Clinical trial sites in Argentina, Australia, Belgium, Canada, Czech Republic, France, Germany, Israel, Hungary, Italy, Japan, Netherlands, Norway, Russia, Spain, Turkey and UK have all been trained by the SCOPE-DMD funded physiotherapists in PUL V2.0.
The need for innovative guidelines for development of DMD therapies
The process for development of DMD therapies would be greatly facilitated by publicly available up to date guidelines containing a direct input from the regulators. Furthermore, the introduction of novel trial designs that would allow inclusion of patients in different disease stages (e.g. ambulant and non-ambulant), with different mutations (e.g. the smaller groups for mutation specific approaches), and when possible trials without a placebo group, could contribute to a significant leap forward towards the offer of long awaited, sound therapeutic options for DMD patients.
Furthermore, the field asks for alignment and coherence in the scientific advice provided by the regulators (e.g. EMA, FDA) for clinical development plans. This alignment is not only needed for a single therapy, but also when different therapies are administered at the same time, since it is anticipated that in the future most DMD patients will receive a combination of treatments. Having guidelines on these aspects would be of paramount importance.
The dissemination undertaken during the lifetime of the SCOPE-DMD project has focused both on updating patients and the research community (directly by BioMarin as part of the study as well as at patient focused meetings and large international research meetings), as well as on a larger policy discussion in which patient organisations and regulatory agencies also participated.
Due to the encountered delays in the clinical trial, data generated from the clinical trial could not been published within the timeframe of the SCOPE-DMD project. News items therefore focused keeping the DMD community updated on the progress of the trial, on interactions with the regulatory agencies and on outcome measures.
For the first Stakeholder Workshop, early engagement with the EMA and the patient organisations was sought. The involvement of the EMA alongside companies involved in designing or undertaking clinical trials in DMD as well as patient organisations and clinicians in the organising of the workshop was paramount to its success. Furthermore, the development of a Briefing Document for the Stakeholder Workshop in April 2015 has led to a further request by the EMA for a similar format Briefing Document for an upcoming Stakeholder Workshop on Spinal muscular atrophy.
The Briefing Document produced for the Stakeholder Workshop was the basis for a Policy View published in Lancet Neurology: “Cooperation among stakeholders to overcome challenges in orphan medicine development: the example of Duchenne muscular dystrophy”. Among the authors of the Briefing Document and Policy View were several participants of the SCOPE-DMD project.
The discussion with regulators has started a productive dialogue with the EMA which will continue after the SCOPE-DMD project has ended. The discussions at both the Stakeholder Workshops, further strengthened by the publication of the Policy View in Lancet Neurology has brought the DMD community, industry and academic stakeholders together with the regulators to discuss the next steps in the development and acceptance of meaningful outcome measure, effective and innovative clinical trial design and above all the importance of early and continued patient engagement in all aspects of the development of an effective treatment for DMD. As the number of pharmaceutical companies that are undertaking clinical trials increases, the dialogue with the regulators and the patient organisations are important for an effective partnership. As many of the partners from the SCOPE-DMD project are also involved in other EU funded projects like SKIP-NMD, BIOIMAGE-NMD and two COST Action, namely COST Action BM1207: Networking towards clinical application of antisense-mediated exon skipping and COST Action BM1304 Applications of MR imaging and spectroscopy techniques in neuromuscular disease: collaboration on outcome measures and pattern recognition for diagnostics and therapy development, much of the work on MRI as an outcome measure and on exon-skipping will continue to be taken forward.
List of Websites:
www.scope-dmd.eu
The SCOPE-DMD project has been a well-run EU FP7 funded project and has utilised health research outcomes from the TREAT-NMD FP6 project to perform an innovative, pivotal paediatric clinical trial by BioMarin for an antisense oligonucleotide (AON) treating a subset of Duchenne Muscular Dystrophy (DMD) patients.
The SCOPE – DMD consortium consisted of 2 companies, BioSpring and BioMarin and 3 academic institutes, Newcastle University, the Leiden University Medical Centre, the Institute of Myology and was coordinated by Newcastle University.
The key deliverable of the SCOPE-DMD project was an exploratory, open-label, dose-escalation phase IIb study; the efficacy, safety, pharmacodynamics and pharmacokinetics of weekly subcutaneous doses of PRO045 in subjects with DMD are assessed.
The clinical trial was of a seamless design which was driven by the need to maximise the data from an exceptionally small patient population and to provide continuity of care in this rapidly progressing disease. It was designed to be made up of two phases: a dose escalation phase with 15 patients and an extended treatment phase with an additional 55 patients.
For this trial, the SCOPE-DMD Consortium used an AON called BMN 045 (previously known as PRO045); BMN 045 is a chemically modified AON, complementary to sequences in exon 45 of the DMD gene. Patients with deletions in the DMD gene flanking exon 45 (8% of all DMD patients), including deletions of exons 44, 46, 46-47, 46-48, 46-49, 46-51, 46-53, 46-55 or 46-60 will be treatable by exon 45 skipping.
The SCOPE-DMD project consisted of 8 Work Packages (WP). Work Packages 1 to 4 included the Clinical Trial and supporting WPs that evaluated three different outcome measures: functional outcome measures (WP2), magnetic resonance imaging (WP3) and serum biomarkers (WP4). Other WPs focussed on drug development and production of the drug product, a chronic toxicity study, educating regulatory authorities and dissemination of project results.
The clinical trial around which the SCOPE-DMD project was set-up has encountered a number of delays which have affected the original timelines of the project and the achievability of a number of the objectives of the SCOPE-DMD project. Due to a number of external factors, the treatment phase of the trial was not started within the lifetime of the SCOPE-DMD project. These external factors included the corporate acquisition of Prosensa by BioMarin and emerging safety results that required further investigation before being able to start the treatment phase.
The consortium made every effort possible to keep the delays in the trial and the project to a minimum while work continued within the supporting WPs 2, 3 and 4. Whilst the trial has encountered delay, much of the work originally planned in the WP2 - 4 has continued, albeit on a smaller contingent of boys, and some additional analyses and work was undertaken as well in WP3 and WP4, respectively. The work on outcome measures, biomarkers and imaging undertaken within the SCOPE-DMD project resulted in two Stakeholder Workshops attended and hosted by the European Medicines Agency, as well as a publication in Lancet Neurology.
The objective of completing and reporting a dose finding and pivotal trial with BMN 045 within the lifetime of SCOPE-DMD project was not fully achieved. However, the further validation and implementation of novel outcome measures and biomarkers developed in former FP6 (TREATNMD) and FP7 (BIO-NMD) undertaken within the SCOPE-DMD project has influenced regulatory interactions progressing acceptability of novel biomarkers and outcome measures in Neuromuscular Disease (NMD), which will make a positive contribution to future trials undertaken.
Project Context and Objectives:
DMD is an inheritable, X-chromosome linked, lethal childhood disease with a prevalence between 0.32 and 0.52 per 10,000 inhabitants. Worldwide, around 240,000 boys suffer from DMD. DMD is caused by mutations, often deletions, in the DMD gene that result in the disruption of the open reading frame leading to a loss of dystrophin protein expression. Dystrophin has a regulatory function within the cell, which is still to be fully elucidated. Importantly, dystrophin also has a scaffolding function in muscle fibres where it links the actin cytoskeleton with the extracellular matrix and so absorbs force generated during muscle fibre contraction. Muscle fibres lacking functional dystrophin are damaged during normal activity and are unable to regenerate healthy tissue eventually leading to progressive muscle weakness and wasting. DMD boys have overt signs of the disease as early as 2 years of age, with subclinical symptoms prior to that time. DMD boys are generally wheelchair dependent by the age of 12 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 childhood. 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 non-functional 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 (Becker muscular dystrophin or BMD-like protein) 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.
Of note is that different AON therapies will be needed to treat different subpopulations of DMD patients. In this context, a subpopulation of DMD patients is defined by a group of different mutations that are correctable with one particular AON. This consortium will use an AON called BMN 045 (previously known as PRO045); BMN 045 is a chemically modified AON, complementary to sequences in exon 45 of the dystrophin gene (see above). Patients with dystrophin genotypic deletions flanking exon 45, including exons 44 , 46, 46-47, 46-48, 46-49, 46-51, 46-53, 46-55 or 46-60 will be treatable by exon 45 skipping; these patient represent 8% of the total DMD population.
The main goal of SCOPE-DMD is to restore expression of a functional dystrophin protein in a targeted subset of DMD patients using exon skipping technology with a chemically-modified AON.
Furthermore, by utilising health research outcomes from the TREAT-NMD FP6 project to perform an innovative, pivotal paediatric clinical trial, SCOPE-DMD will also further investigate the validation and implementation of novel outcome measures and biomarkers developed in former FP6 (TREATNMD) and FP7 (BIO-NMD) projects; use a novel accelerated clinical trial design and regulatory strategy applicable to future clinical trials in a wide range of (rare) diseases and build on TREAT-NMD and Prosensa’s/BioMarin’s groundwork in regulatory interactions progressing acceptability of novel biomarkers and outcome measures in Neuromuscular Disease (NMD).
Main objectives
The main activity in the work plan is the execution of an innovative, adaptive clinical trial of which the protocol has been positively evaluated by EMA in July 2012. In November 2012, the Belgian Competent Authorities approved the Clinical Trial Application (CTA), which contains the Investigational Medicinal Product Dossier (IMPD) and Investigator’s Brochure. The Belgian ethics committee (EC) approved the study in December 2012, and the French EC early 2013. EC approval by Netherlands is awaited. CTA and ethical submissions have also been initiated in Italy and the UK.
The SCOPE-DMD trial is an exploratory, open-label, dose-escalation phase IIb study; the efficacy, safety, pharmacodynamics and pharmacokinetics of weekly subcutaneous doses of PRO045 in subjects with DMD will be assessed. The study will not include a placebo arm and will be non powered due to anticipated low numbers of eligible DMD patients treatable with exon 45 skipping. Natural history data and placebo from other programmes will be used as an external control. It should be noted that BioMarin has heavily invested in an international contemporaneous natural history programme for this very purpose. Whilst beyond the scope of this FP7 application, the consortium is working closely together on this project as well.
The functional entry criterion is a 6MWD of 230 m or above for ambulant boys aged at least 5 years on the day of first dosing. Other inclusion criteria are defined, including confirmed dystrophin mutation correctable by treatment with BMN 045, adequate muscle quality for biopsy (confirmed by NMR), life expectancy of at least 3 years and stable glucocorticosteroid use for at least 3 months prior to first BMN 045 administration. In total, 14 exclusion criteria have been defined of which the following are the most important: known presence of dystrophin in ≥5% of fibers, current or history of liver disease or renal disease, aPTT or platelet abnormalities beyond normal limits.
The study is of a seamless design which is driven by the need to maximise the data from an exceptionally small patient population and to provide continuity of care in this rapidly progressing disease. It consists of two phases: a dose escalation phase with 15 patients and an extended pivotal phase with an additional 55 patients. This work will be undertaken in Work Package 1 (WP1). During the dose escalation phase, five cohorts of three subjects each are planned (0.15 1, 3, 6 and 9 mg/kg) during which the safety, tolerability and efficacy will be closely monitored. Each subject will receive a single IV dose followed by subcutaneous dosing in order to compare bioavailability. From the dose escalation phase data, it is expected to define an optimal dose of BMN 045 with clear pharmacodynamic effect within acceptable safety and tolerability profile. Six NMD (neuromuscular disease) clinical centres (NL, Be, Fr, It, UK) will be involved. A data safety monitoring board (DSMB) will be responsible to review data for acute toxicity before each cohort starts treatment at a higher dose level. The first subjects remain on the original dose for at least 12 weeks to assess for midterm sub-clinical toxicities, which will be strong indicators of viable long term dosing regimens. Once the second cohort has completed a minimum 12 weeks dosing and it is deemed safe to do so, the subjects from the first cohort will upwardly titrate. The same occurs for each subsequent cohort until a Maximum Tolerated Dose is reached, based on either acute or midterm reactions or feasibility associated with injection volumes. If dose-limiting toxicities occur, the design will be modified, depending on when the toxicities occur and the nature of the toxicities. Toxicities are likely to be identified earlier than with a classical design due to the ongoing administration at lower doses, enabling us to make an informed decision around the Maximum Tolerated Dose well before the subsequent cohorts reach that time-point, which would otherwise be unachievable in a short-term dose escalation study. First subject first visit has occurred in January 2013. Due to practical reasons, it is anticipated that the total duration of this phase will be approximately 1 year.
As explained above, the 6MWD test will be the primary outcome measure. Secondary outcome measures are the NSAA and other tests described previously. To be able to define the optimal dose from both a pharmacodynamic and clinical perspective, new and largely unexplored DMD outcome measures will be included in the study. Three types of outcome measures will be explored: functional outcome measures (WP2), imaging (WP3) and biomarkers (WP4).
For WP1 – seamless clinical trial - the main objectives are to define by M11 the optimal treatment dose, to determine by M34 safety and tolerability of drug product; to determine by M34 the efficacy of drug product, to determine the pharmacokinetic profile of drug product within the first 48 hours of dosing and through levels at multiple time points throughout the study and to determine the pharmacodynamic effect of drug product at 12 weeks post dose and during 48 weeks of continuous treatment.
The main objectives for WP2 – Functional outcome measures - are to characterise by M36 the effects of treatment with drug product on 4 exploratory functional outcome measures used to measure the progression of DMD and secondly to provide by M36 a set of meaningful and sensitive functional outcome measures for the assessment of DMD in the SCOPE-DMD clinical trial and in any future clinical trials using other compounds for the treatment of DMD.
The main objectives for WP3 – imaging outcomes - are to evaluate muscle degenerative changes qualitatively, using standard T1 weighted spin echo imaging at screening and week 48 (optional), to evaluate disease activity using T2 mapping at screening, week 12 and 48, to quantitatively evaluate fatty degenerative changes using 3 point DIXON at screening, 12 (optional) and 48 weeks, to assess pH, free ADP concentration, creatine pool, membrane phospholipid turnover, using 31P spectroscopy at screening, 12 and 48 weeks and to evaluate vascular reactivity after a short (2-5 min) ischemia using perfusion mapping by arterial spin labelling at 12 and 48 weeks. (Paris site only).
The main objectives of WP4 – biomarker analysis - are to determine the effect of treatment on muscle biomarkers (biopsy); dystrophin, dystrophin-glycoprotein complex and associated proteins, miRNAs, the number of infiltrating cells and muscle morphology and quality after 12 weeks of the dose escalation phase and 48 weeks of the treatment phase, to determine the effect of treatment on serum biomarkers; muscle specific microRNA and MMP-9 and to evaluate the utility of these biomarkers in correlating to phenotype and/or clinical response, predicting clinical response and as potential future surrogate markers for the benefit of the current study and future studies within the biopharmaceutical or academic field.
For WP5 – manufacturing of drug product - the main objective is to generate the drug product and obtain a drug product Certificate of Analysis (CoA) and Certificate of Compliance (CoC) for a DS batch previously produced by Girindus, for cGMP production by M11 of a first batch of 400g drug substance aiming at a purity of at least 92%, including a CoA, cGMP production by M16 of a second batch of 400g drug substance aiming at a purity of at least 92%, including a CoA and to generate drug product and obtaining a drug product CoA and CoC of the two batches manufactured by BioSpring by M21.
WP6 – non-clinical toxicity studies – will manufacture and formulate by M6 20g of drug substance with a purity of at least 85% and obtain by M14 the interim in-life report of the 13-week GLP i.v. toxicity study in monkeys.
WP7 – educating regulatory agencies - and WP8 – Dissemination and Communication – have as objectives engaging through two workshops a range of stakeholders including regulatory agencies, patient organisations, the scientific community as well as disseminating publications and outcomes from the trial and the project.
Finally, WP9 – Project Management - has as objective the overall management and coordination of the project, successful monitoring of completion of Deliverables and Milestones, reporting and financial management of the project.
Project Results:
The SCOPE-DMD project has met a considerable amount of the original objectives. The clinical trial (PRO045-CLIN-01) has not been completed as originally planned, but significant progress has been made in terms of further understanding of functional outcome measures and biomarkers and relevant data collected in the clinical trial so far have been described in an interim Clinical Study Report. The project has highlighted, through the stakeholder workshops and subsequent publication as part of WP7, the progress made within the Duchenne field, but also underlined the research still required to find an effective disease-modifying treatment. The consortium, along with many external stakeholders, has worked extremely well together to bring the SCOPE-DMD project to a successful conclusion and allow for lessons learned to be disseminated as widely as possible.
Brief overview of activities
WP1: During the dose-escalation phase of the study the most optimal dose was planned to be identified for the treatment phase of the clinical trial. A total of 15 patients were enrolled into the study, which were treated with escalating doses of BMN 045 (previously known as PRO045), ranging from 0.15 mg/kg to 9.0 mg/kg subcutaneous (SC) and single dose of intravenous (IV) from 1.0 mg/kg to 9.0 mg/kg. In general the drug was well tolerated. Prolonged dosing with 9.0 mg/kg resulted in emerging safety signals in 11 out of the 15 subjects resulting in the MTD for BMN 045 being set at 6.0 mg/kg SC. Preliminary detected tissue concentrations of BMN 045 did not reach the levels, as measured for drisapersen. Injection site reactions may limit long-term SC administration. Based on the data obtained so far from the study, an optimal dose and dosing route for the treatment phase of the study could not be identified.
WP2: All the tasks defined in the DOW has been completed in due time. Extra work also been completed in other DMD populations, particularly during various natural histories of the disease. Moreover reference values have been developed in health controls to define predictive equations for grip and pinch strength.
WP3: During the second part of the project, the NMR lab at the IoM, ensured follow-up for rescanning phantoms and volunteers at all sites. Since treatment was discontinued in the majority of the patients and an amendment for additional NMRI exams in the initially recruited 15 subjects was never validated, no new NMRI/S acquisitions were performed. Emphasis was put therefore on performing additional analyses on the existing data such as contractile muscle mass measurements, water T2 heterogeneity and alternative determination of water T2 based on the extended phase graph formalism (EPG), all of which are quantitative NMRI measures that can help in the understanding of the progression of the disease.
WP4: Following on from work undertaken in M1 – M18, serum proteomics analysis of DMD patients with 45 flanking deletion, BMD patients with relevant deletions and age matched controls has been performed at the LUMC. For BMD patients several parameters are available such as dystrophin levels in muscle, muscle gene expression, MRI and manual quantitative assessment. This will help to make the link between dystrophin levels in muscle, disease state and the value of a biomarker. Similarly, RNAseq analysis of muscle biopsies of the same BMD patients has been ongoing at the LUMC to correlate serum biomarkers levels to gene expression in muscle.
WP5: Within the second 18 month, the cGMP campaign at BioSpring (800 ± 80 gram) could be finalized successfully. After finalizing the manufacturing a new CoC and CoA was issued by BioSpring. This larger campaign is also a substitute for the originally planned two 400 ± 40 gram campaigns. All activities have been finalized in 2015.
WP6: The campaign of final lyophilised material for the 13-week toxicity monkey study using IV administration was completed in November 2014. However, since the treatment phase of the clinical trial had significantly been delayed the 13 week toxicity study has been postponed until further notice.
WP7: Two Stakeholder workshops were successfully delivered, both organised with cooperation from a range of stakeholders, including regulators, industry, patient organisations and clinicians. In total, more than 200 people attended.
WP8: Disseminating information about the clinical trial itself to patients has been undertaken predominantly by the clinical trial site clinicians, in close cooperation with BioMarin. The clinical trial hasn’t been completed yet and therefore the full data have not yet been analysed. Therefore, the dissemination to target audiences has focused on work undertaken in WP2, WP3 and WP4. The Stakeholder Workshops organised as part of WP7 have also contributed considerably.
WP9: UNEW has continued to work closely with BioMarin to manage the project. Three further partner meetings were held. The UNEW Project Coordinator and Project Manager worked closely with the EU Scientific Officer to make appropriate amendments and guide the consortium to successful completion of the reporting requirements.
Below is set out in more detail the main results from the scientific Work Packages along with key Deliverables and Milestones.
No new foreground was generated during the lifetime of the project.
Work Packages – in detail
WP1 – Seamless clinical trial
Summary of Achievement
The original protocol for this study was finalised on 02 August 2012. Changes to the protocol to collect data on IV administration of BMN 045have been included in amendment I, which was finalised on 18 December 2012. Protocol amendment II was finalised on 16 August 2013 to include the possibility for pre-planned treatment interruptions for the subjects in Group 1 and instruction on the process for resumption of dosing after the treatment interruption. The reason for this change was that the up-titration to 1.0 mg/kg was delayed due to a delay in the recruitment of Group 2 (1.0 mg/kg) and the continuing treatment for a prolonged time at 0.15 mg/kg was considered not significantly beneficial for the subjects in Group 1. The treatment interruption lasted until confirmation that the 12 week safety data from Group 2 was acceptable, allowing the subjects in Group 1 to be up-titrated to the Group 2 dose.
A total of 15 patients were enrolled into the study, which were treated with escalating doses of BMN 045, ranging from 0.15 mg/kg to 9.0 mg/kg subcutaneous (SC) and single dose of intravenous (IV) from 1.0 mg/kg to 9.0 mg/kg. In general the drug was well tolerated. Prolonged dosing with 9.0 mg/kg resulted in emerging safety information and an ad hoc Data Safety Monitoring Board (DSMB) meeting was convened.
The DSMB recommended to set the maximum tolerated dose (MTD) for BMN 045 at 6.0 mg/kg SC. Based upon the recommendations by the DSMB, BioMarin decided to halt dosing at 9.0 mg/kg. Subjects who tolerated the treatment well continued dosing at 6.0 mg/kg. The subjects with abnormal lab values remained off treatment. Additional assessments to better understand the mechanism of action of the emerging safety information have been included in the protocol by means of protocol amendment III, which was finalized on 07 January 2016. Following the approval of this amendment, subjects who had remained off treatment will join ongoing subjects at 6.0 mg/kg SC following normalisation of their lab values. Data will be reviewed by the DSMB and the Safety Review Team to determine further evaluation required and continued dosing strategy. In the absence of safety concerns subjects may continue dosing.
Key Deliverables and Milestones
Deliverable 1.2 – Identification of the optimal dose for the extended phase of the clinical trial (M19)
The optimal dose of the drug product has not been identified yet due to the dose escalation phase extended to investigate the emerging safety information.
The maximum tolerated dose for SC BMN 045 was determined to be at 6 mg/kg/per week.
Deliverable 1.3 – Summary of the Clinical Study Report (CSR) of the complete trial containing all relevant data on biopharmaceutical studies, human PK, human PD, efficacy and safety (M36)
As the trial is ongoing, an interim Clinical Study Report has been generated using a data cut off date of September 2015. The report contains all the relevant data from the clinical trial.
Milestone 2 – Define optimal dose of drug product (M11)
The optimal dose of the drug product has not been identified yet. The dose escalation phase was extended to investigate the emerging safety information.
WP2 – Functional outcome measures in the clinical trial
Summary of Achievements
During the first period of the project, the team from the Neuromuscular Physiology and Evaluation lab at the Institute of Myology ensured training of all clinical evaluators involved in the study. Quality control of the first measurements performed resulted in a retraining of all clinical evaluators, which was not originally planned in the Description of Work (DoW), to ensure quality of the data recorded. The equipment of each centre was checked once a year to ensure accuracy of the measurements as planned in the DoW. However tools presented technical problems, not anticipated in the DoW, and were repaired as soon as possible to avoid as much missing data as possible. Review of the first visits of each patient were originally planned in the DoW but all data collected were controlled (raw signals as well as operating procedures) to ensure accuracy of the database. Accelerometry signals were analyzed to compute gait parameters during the six-minute walk test and the 30 second walk test. Specific software for the automation of the analyses was developed. In addition, additional parameters were developed in order to find new parameters that would capture the walking pattern independently of gait speed. These extra analyses were not planned in the DoW and the software developed will enable to perform the analyses of remaining data more quickly for the remaining data.
In M19 – M36, all tasks as defined in the DOW has been completed in due time. Extra work also has been completed in other DMD populations, particularly during various natural histories of the disease. Moreover reference values have been developed in health controls to define predictive equations for grip and pinch strength.
The Performance of the Upper Limb Scale has been developed in an international collaboration with the SCOPE-DMD sites. Data analysis and interpretation of results has progressed the PUL with each iteration leading to the final Version PUL V2.0. The version was based on clinical interpretation of Rasch analysis with patient and advocacy input.
The introduction of a new outcome measure – The Active Seated Assessment in collaboration with Nationwide Children’s Hospital Columbus Ohio in 2015 has further expanded the breadth of outcome measures available in the SCOPE-DMD project.
Key Deliverables and Milestones
Deliverable 2.1 – report demonstrating the impact of treatment on muscle functionality: Report demonstrating the impact of treatment on muscle functionality for the complete trial including presentation of all performed statistical analyses of clinical/functional data (M36)
Deliverable 2.2 –Identification of which (set of) functional outcome measures is most optimal for the assessment of improvement of DMD in Duchenne boys treated with a curative therapy: Identification of which (set of) functional outcome measures is most optimal for the assessment of improvement of DMD in Duchenne boys treated with a curative therapy [month 36]
Deliverables D2.1 and D2.2 have been combined.
The Performance of the Upper Limb Scale developed within the SCOPE-DMD project resulted in a wealth of international collaborations outside of the SCOPE-DMD project as well as a number of publications on its development, reliability, validity, correlation with other outcome measures and its ability to detect change in clinical status as a result of treatment with steroids. The PUL has become a necessary part of the tool kit for assessment of boys and men with DMD in both therapeutic clinical trials and natural history studies. Furthermore the clinical meaningfulness of the PUL confirmed by the full participation of patients and advocacy groups has expanded the use of this scale out of the research arena and into clinics. The results of the PUL can direct professionals into targeting hands on therapies or aids and adaptations to assist patient function.
The PUL has been adopted for use in several clinical trials in DMD by different other companies including Eli Lilly, Sarepta, PTC, Bristol Squibb Myers, FibroGen and Capricor amongst others.
The process by which the PUL was developed has followed an iterative process. Items in Version 1.2 were clarified and some grading was simplified to make the scale more efficient. Some of the easier and some of the more difficult items were removed as there was duplication at these levels and fewer activities would deliver the same results reducing the burden of number of items for the patients. Many items simplified scoring to 0, 1 and 2 to better reflect progression rather than strategies. It was important though to understand that there were no construct differences between the two versions and therefore these adaptations were reviewed by comparing the individual item scores for the two similar tests on the same boy to assess if the final version (PUL2) reflects fully the construct as outlined and measured by version 1.2.
Fifty-two assessments from two centres within the SCOPE-DMD project were collected where dual data existed for the two versions. The two versions (PUL1.2 and PUL2) were entered into RUMM2030 as though they were one scale and the item locations for the original and the rescore were compared. Item fit, response categories, reliability and targeting were also reviewed for the two versions. When the two scales were combined into a single scale to see if the item location for individual items were comparable the results were highly similar with a similar range for both scales. Therefore a score as defined on the PUL1.2 relates to a score on the PUL2.
Milestone 5 – Update on the functional outcome data collected during the dose escalation phase of the trial (M19)
DMD is a multifaceted condition with changes occurring within muscle function at different rates over a prolonged time period. It was initially considered that upper limb and lower limb measures were compartmentalised into ambulant and non-ambulant disease stages. However the SCOPE-DMD project linking in with other natural history data sets from BMN 045-CLIN-01, North Star, Italian network and CINRGY groups have shown the relationship between ambulant and non-ambulant measures is more complex and not so simple as ambulant versus non-ambulant. This collaborative work within the SCOPE-DMD project has confirmed that upper-limb measures are relevant in the ambulant population. Use of the PUL has demonstrated that functional ability in ambulant boys is primarily proximal. There is a correlation with the PUL, active seated and Brooke scales as well as with the 6MWT. Although the PUL has a ceiling effect in high functioning boys, it is the most clinically meaningful outcome and other measures such as the active seated and Myotools with less ceiling effect may measure the more able boys longitudinally before functional weakness is perceived. Although we have not had sufficient data in the SCOPE-DMD project to identify Outcome Measures (OM) that determine improvement we have been able to determine meaningful measures to the families and which can detect deterioration over time which suggests that improvement would also be measurable.
Milestone 10 – Provide a set of meaningful and sensitive functional outcome measures (M36)
The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy however it is important to understand the relationship of the scale in DMD to typically developing children and ultimately develop normative values. A study by Pane et al looked at a cohort of typically developing children from the age of 3 years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. Normative data for the scale validation was collected on 277 typically developing subjects from 3 to 25 years old. A full score was consistently achieved by the age of 5 years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. This paper consolidated work begun within the SCOPE-DMD project and included evaluators trained by SCOPE-DMD physiotherapists.
Pane et al also published valuable data on the relationship between other OMs and the PUL and further developed the knowledge base of understanding when different OM are most efficacious. The first published data have shown that early signs of involvement can also be found in ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6 Minute Walk Test (6MWT) and the PUL in ambulant DMD boys. Both 6MWT and PUL were administered to 164 ambulant DMD boys of age between 5.0 and 16.17 years (mean 8.82). The 6 minute walk distance (6MWD) ranged between 118 and 557, the PUL total scores ranged between 52 and 74. The correlation between the two measures was 0.499. The scores on the PUL largely reflect the overall impairment observed on the 6MWT but the correlation was not linear. The use of the PUL appeared to be less relevant in the very strong patients with 6MWD above 400 meters, who, with few exceptions had near full scores. In patients with lower 6MWD the severity of upper limb involvement was more variable and could not always be predicted by the 6MWD value or by the use of steroids. Our results confirm that upper limb involvement can already be found in DMD boys even in the ambulant phase. Importantly although it correlates somewhat with the 6MWT it clearly measures a different dimension of the disease process.
The PUL has also been used to demonstrate the effectiveness of a successful treatment. Unfortunately this was not possible to show within the SCOPE-DMD trial but the work done on development of the PUL in this project has provided a suitable and meaningful outcome measure for use in other studies. The aim of the study performed by the Italian network was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naïve or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naïve group (p < 0.001).
The 12-month changes ranged between −20 and 4 (mean −4.4). The mean changes were −3.79 in the glucocorticoid group, −5.52 in those who stopped at loss of ambulation and −4.44 in the naïve group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels.
Their findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function.
WP3 – Imaging outcomes in the clinical trial
During the first period of the project, the team from the NMR lab at the Institute of Myology ensured training of all imaging technicians at the different centres involved in the study. This training was based on an imaging manual which was written for this study by the IoM with contributions from the LUMC and Prosensa. The qualification of each site included the acquisition of datasets in two phantoms (specifically designed/chosen for the imaging protocol to be used in the study) and two volunteers, an inter-site volunteer (visiting all centres involved) and an intra-site volunteer (who was scanned twice in a one to three week interval to check reproducibility). All data was analysed based on in-house matlab code (NMR Lab). Following the approval/validation of this data during the qualification period by the NMR Lab personnel, the centres were given the green light to start scanning patients. Quality control of all phantom, volunteer and patient data was performed upon acquisition and transfer of the data. Fifteen patients, divided over six different sites, received two MRI exams (V2 + V15). Preliminary analyses on the two first visits have been performed based on the Dixon, the T2 mapping and the 31P-MRS data (which corresponds with the milestones at M18 for WP3). No trends in the imaging outcomes have been found so far between V2-V15. Further analyses are ongoing.
During the second part of the project, the NMR lab at the IoM, ensured follow-up for rescanning phantoms and volunteers at all sites. Since treatment was discontinued in the majority of the patients and an amendment for additional NMRI exams in the initially recruited 15 subjects was never validated, no new NMRI/S acquisitions were performed.
However, during this second period, the emphasis was put on performing additional analyses on the existing data such as contractile muscle mass measurements, water T2 heterogeneity and alternative determination of water T2 based on the extended phase graph formalism (EPG), all of which are quantitative NMRI measures that can help in the understanding of the progression of the disease.
Additionally, as muscle perfusion might be used as a potential outcome measure in dystrophic muscle, a number of experiments were performed to optimize and validate this method for future protocols.
In conclusion, because the treatment was interrupted in most patients, the value of the different NMR outcome measures was impossible to compare. Based on data from other studies in Europe and in the US, muscle fat fraction as estimated from water-fat (Dixon) imaging is undoubtedly the most robust biomarker of muscle dystrophy progression.
Key Deliverables and Milestones
Deliverable 3.2 – Identification of which (set of) NMR indices is most optimal for the assessment of improvement of DMD in Duchenne boys treated with a curative therapy (M36)
Because the treatment was interrupted in most patients, again the value of the different NMR outcome measures was impossible to compare. Based on data from other studies in Europe and in the US, muscle fat fraction as estimated from water-fat (Dixon) imaging is undoubtedly the most robust biomarker of muscle dystrophy progression. It was shown to be able to monitor dystrophic muscle wasting (by the progressive increase in fat content from 20 to 60%) at an early stage of the disease, at a time the standard 6min walking distance remained stable and was non-informative.
WP4 – Biomarker analysis in the clinical trial
Summary of Achievements
Prior to initiation of dosing with BMN045, all patients underwent a skin biopsy and were screened for the applicability of an exon 45 skip. The screening has been completed and it is confirmed at the RNA sequence level that all screened patients carry the described mutations and that BMN 045 induces skipping of exon 45 in their cells.
In order to evaluate whether serum biomarkers can capture disease state and progression, serum proteomics analysis of DMD patients with 45 flanking deletion, BMD patients with relevant deletions and age matched controls has been performed at the LUMC. For BMD patients several parameters are available such as dystrophin levels in muscle, muscle gene expression, MRI and manual quantitative assessment. This will help to make the link between dystrophin levels in muscle, disease state and the value of a biomarker.
Similarly RNAseq analysis of muscle biopsies of healthy controls and the same BMD patients is ongoing at the LUMC to correlate serum biomarkers levels to gene expression in muscle.
Key Deliverables and Milestones
Deliverable 4.1 – report demonstrating the impact of treatment at molecular level and demonstrating a move towards Becker muscular dystrophy phenotype or healthy life characteristics (M36)
Muscle biopsies obtained from subjects participating in the trial were analysed for skip of exon 45 on RNA level, dystrophin intensity and concentrations of BMN 045. No clear increase in dystrophin or exon 45 skip transcripts was observed. Tissue concentrations of BMN 045 in muscle biopsies increased with increasing dose level.
Deliverable 4.2 – Identification of which (set of) biomarkers is most optimal for the assessment of improvement of DMD in Duchenne boys treated with a curative therapy (M36)
Exon skip and dystrophin protein levels remain the primary biomarkers for assessing the mechanism of action of a curative therapy aiming to induce exon skip in the DMD pre-mRNA and induction of dystrophin expression. DMD diagnostic serum biomarkers, muscle creatine kinase and lactate dehydrogenase, can serve as pharmacodynamic biomarkers that change upon drug treatment and different doses. The limitation is that the magnitude of change of these muscle biomarkers will also require a placebo treated group as these biomarkers tend to decrease also with age in the absence of drug treatment, in order to compare the magnitude of the reduction in the drug treatment and the placebo group.
Milestone 7 – Status update on the biomarker data collected during the dose escalation phase of the trial (M19)
Potential muscle tissue biomarkers;
To elucidate the primary mechanism of action of BMN 045, dystrophin levels of the muscle fibres were measured by immunofluorescence in pre and post treatment biopsies for 14 of the 15 subjects participating in the trial.
Exon 45 skip in pre-treatment and post treatment biopsies was also measured.
No clear increase in dystrophin or exon 45 skip transcripts was observed. Concentrations of BMN 045 in muscle increased with increasing dose.
Exploratory;
miRNAs in muscle were evaluated and no changes following drug treatment were observed in miRNA 133a and b, miRNA 1, miRNA 29c, miRNA 223, miRNA 146b, miRNA 21.
Potential serum biomarkers;
Creatine kinase and lactate dehydrogenase were measured and were found to be decreased upon dose escalation yet in the absence of a placebo arm the effects are difficult to interpret, as these muscle proteins decrease with age in DMD.
Milestone 12 – Provide a set of meaningful and sensitive biomarkers (M36)
Dystrophin assessed using a sensitive and reproducible immunofluorescence method remains a meaningful pharmacodynamics biomarker to measure in therapies aiming to induce dystrophin expression. Yet the choice of muscle group is critical and the time point of taking a muscle biopsy can affect the potential detection of dystrophin and the PK-PD response. Similarly exon skip is a biomarker that supports the mechanism of action.
Of the known serum muscle diagnostic DMD biomarkers CK and LDH can also serve as potential pharmacodynamic biomarkers yet are difficult to correlate to disease state as they are reduced with age and subsequent muscle loss and are affected by muscle activity such as exercise. Correlation of changes in CK and LDH and changes in 6MWD can help in the interpretation. Measurement of total activity of the patients during treatment (using methods such as ActiMyo) could elucidate whether reductions in CK and LDH are due to general reduction in activity.
The data analysis re correlation of DMD biomarkers and disease severity and comparison of biomarkers between DMD and BMD serum is currently ongoing.
WP5 - Manufacturing of drug product for the extended phase of the clinical trial
Summary of Achievements
Within the first 18 months, the process and method transfer from Prosensa to BioSpring was finalized successfully. This transfer includes two parts: a) process information to enable BioSpring to manufacture the drug substance and b) analytical methods to analyse BMN 045. Based on this information and two process adaptions, BioSpring were able to set-up within the first 18 months the complete manufacturing and analytical process required for BMN 045 production. Also the manufacturing process was transferred successfully within BioSpring from a lab-scale model (which was used first to prove successful method transfer between Sites) to BioSpring’s commercial manufacturing platform. Currently the cGMP campaign is running at BioSpring at 800 gram (± 80g). This larger campaign is also a substitute for the originally planned two 400 gram (± 40g) campaigns. Despite some delay within the project at the beginning of 2014, all activities planned for 2014 were completed by the end of 2014 or were close to being finalized Q1/Q2 2015. Task 5.3 Part I and Part II will be completed within 2015 (shifted from 2014 to 2015).
Within the second 18 month, the cGMP campaign at BioSpring (800 ± 80 gram) could be finalized successfully. After finalizing the manufacturing a new CoC and CoA was issued by BioSpring. This larger campaign is also a substitute for the originally planned two 400 ± 40 gram campaigns. All activities have been finalized 2015.
Key Deliverables and Milestones
Deliverable 5.1 – CoA and COC for the Drug Product originating from Girindus Drug Substance
Originally it was intended by BioMarin within this FP7 program to receive and update the CoC and CoA from the original Nitto Denko Avecia PS220 batch. In the meantime the technology transfer from Nitto Denko Avecia to BioSpring took place successfully. This successful transfer makes the CoA and CoC from BioSpring similar to the original CoA and CoC provided by Nitto Denko Avecia. The cGMP manufacturing campaign was finalized January 2015. After finalizing the manufacturing campaign, batch review and release a new CoC and CoA was issued by BioSpring 2015.
Deliverable 5.2 – CoA of two new 400g batches of Drug Substance
Originally it was intended by BioMarin within this FP7 program to run two 400 gram (± 40g) cGMP campaigns. However, due to some delay within the project and the accessibility of the new OligoProcess platform for cGMP manufacturing in March 2014, it was decided by BioMarin and BioSpring to run one 800 gram (± 80g) campaign instead of two 400 gram (± 40g) campaigns beginning of Q4 2014 (change of manufacturing strategy). The manufacturing campaign started beginning of November 2014 and finished January 2015. The material from BioSpring (approx. 920 gram) passed all specifications defined within the CoA. After batch record review and drug substance release a new CoC and CoA was issued by BioSpring (Q1 / 2015). 2015 the cGMP material was delivered to BioMarin as well.
Milestone 1 – Successful transfer of cGMP manufacturing to BioSpring
Within the first 18 months, the process and method transfer from Prosensa to BioSpring could be finalized successfully. This transfer includes two parts: a) process information to enable BioSpring to manufacture the drug substance and b) analytical methods to analyse PS220. 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 PS220 production. Also the manufacturing process could be transferred successfully within BioSpring from a lab-scale model (which was used first to prove successful method transfer between Sites) to BioSpring’s commercial manufacturing platform.
Milestone 8 – Produce 800g cGMP drug product
Originally it was intended by BioMarin within this FP7 program to run two 400 gram (± 40g) cGMP campaigns. However, due to some delay within the project and the accessibility of the new OligoProcess platform for cGMP manufacturing in March 2014, it was decided by Prosensa and BioSpring to run one 800 ± 80 gram campaign instead of two 400 ± 40 gram campaigns beginning of Q4 2014 (change of manufacturing strategy). The 800 gram manufacturing campaign started beginning of November 2014 and finished January 2015. The material from BioSpring (approx. 920 gram) passed all specifications defined within the CoA. After batch record review and drug substance release, a new CoC and CoA was issued by BioSpring (Q1 / 2015) and the cGMP material was delivered to BioMarin.
The drug substance was converted to drug product in February 2015 by Halix BV (Leiden, the Netherlands) with fill volumes of 0.7 and 1.0 mL. Both batches passed all specifications defined within the CoA. After batch record review and drug product release, a CoC and CoA was issued by BioMarin (Q4 / 2015).
WP6 – Non-clinical toxicity studies
Summary of Achievements
Task 6.1 – Manufacturing of 20g of formulated drug substance (BioSpring, BioMarin)
Final lyophilised material was shipped to BioMarin in January 2015. Since the 13 week toxicity study has been delayed, the drug substance has not been formulated yet.
Task 6.2 – 13-week IV study in monkeys
In the clinical study of this project, single IV administration was included in the dose escalation phase. Since the treatment phase of the clinical study has significantly been delayed and because of current discussions with authorities and ethical commissions, the 13 week toxicity study has been delayed, until further notice.
Key Deliverables and Milestones
Deliverable 6.1 – Non-cGMP Certificate of Analysis of drug substance (M19)
The final lyophilised non-GMP TOX material was shipped to BioMarin in January 2015. This included an issued CoA as well.
WP7 – Educating regulatory authorities
Summary of Achievements
The planning of the first Workshop started in June 2013. The meeting took place at the EMA on 29th April 2015 entitled “A forum discussion between stakeholders on current challenges that face antisense oligonucleotide therapy development for DMD” and was organised in collaboration with COST Action 1207. As reported in the Periodic Report for M1 – M18, a Steering Committee was set up specifically to organise and plan the April 2015 meeting. The EMA was represented on this Steering Committee.
The Steering Committee had a second teleconference in January 2015, and a face-to-face meeting was held in March 2015 in Leiden. Another Steering Committee teleconference was organised in April 2015.
It was attended by 120 stakeholders including clinicians, representatives from DMD parent organisations, senior representatives from the European Medicines Agency (EMA) and industry. A Briefing Document was produced by the Steering Committee, which comprised of clinicians and senior management of Prosensa/BioMarin as well as patient organisations. The outcome of these interactions has been published in the policy view in the Lancet Neurology and can be found following the link below:
http://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(16)30035-7.pdf
The Second workshop entitled “Making Outcomes Work” took place on the 26th May and was attended by approximately 80 people. The Workshop was chaired by Volker Straub and Andrew Blamire from Newcastle University and Maria Isaac from the EMA. WP Leads from SCOPE-DMD presented their latest interim biomarker and imaging findings from the SCOPE-DMD project.
Key Deliverables and Milestones
Deliverable 7.1 – First global workshop with all relevant stakeholders on the use of biomarkers in NMD clinical trials (M19)
The Stakeholder Workshop meeting on antisense oligonucleotide-mediated exon skipping therapy development for Duchenne muscular dystrophy (DMD) involved representatives from the Duchenne muscular dystrophy patient community, academia, industry and regulatory agencies. The meeting was organized by Cooperation of Science and Technology (COST) Action BM1207 and SCOPE-DMD (FP7, #601573) and hosted by the European Medicines Agencies (EMA, April 29, 2015) and was a follow up meeting of a previous meeting organized in 2009. The meeting was attended by 120 stakeholders. A Steering Committee was established for the organising the workshop as well as for the writing of a Briefing Document for those attending the workshop.
Deliverable 7.2 – Second global workshop with all relevant stakeholders (M36)
The second Global workshop was hosted at the British Library on the 26th May by Volker Straub and Andrew Blamire from Newcastle University. The objective of the workshop was to bring representatives of all the Consortium partners, the European Commission, EMA and patient organisations together to review the work undertaken as part of the SCOPE-DMD project and specifically discuss the progress on outcome measures for evaluation of DMD.
All key stakeholders were represented and there was a wide ranging debate on making outcomes work in the future for this disease.
Milestone 13 – Educate regulatory agencies (M36)
Interaction with the regulatory agencies played an important role at the two workshops. The first global workshop was hosted by the European Medicines Agency (EMA). There were regular contacts between the EMA, and the WP7 leads and senior representatives from the EMA both presented and attended.
At the second workshop, representatives from the EMA again played a key and active role, presenting the Agency view on answering questions posed by the Consortium members and patients groups. The forum facilitated the sharing of challenges when undertaking research in Duchenne Muscular Dystrophy with the entire audience, including the regulatory representatives.
A key achievement was the publication of the following paper: Stakeholder cooperation to overcome challenges in orphan medicine development: the example of Duchenne muscular dystrophy published in the Lancet Neurology - : http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)30035-7/fulltext. A podcast was also conducted prior to the launch of the paper. It can be listened to here: http://www.thelancet.com/pb/assets/raw/Lancet/stories/audio/laneur/2016/laneur_160606.mp3
Articles on the publication as well as the second Stakeholder Workshop were published in the June TREAT-NMD newsletter: http://www.treat-nmd.eu/newsletter/archive/email/29th_June_2016.html
Potential Impact:
Duchenne muscular dystrophy is a severe, progressive muscle disease affecting 1 in 5000 male births. The disease is characterized by continuous and irreversible loss of muscle tissue and function. Affected children are typically diagnosed at about four or five years of age, when it becomes apparent that their motor abilities are restricted, (e.g. repeated falling, difficulty with running and trouble climbing stairs). Without treatment most require the use of a wheelchair around the age of 9.5 years. Orthopaedic problems resulting from extreme muscle weakness, respiratory and cardiac complications emerge and death often occurs by the late teens or early adulthood, mostly due to respiratory or cardiac failure. With optimal care, including assisted ventilation patients can survive three decades, but older patients have profound weakness and require assistance with all activities of daily life, with a high emotional and financial burden to patients, families and society.
An innovative approach to DMD therapy: exon skipping
The exon skipping approach addresses the underlying cause of DMD, i.e. lack of functional dystrophin protein in muscle. Antisense oligonucleotides (AONs), which are modified pieces of DNA or RNA, allow the production of partially functional dystrophin proteins by re-establishing the open reading frame in the mutated dystrophin transcripts. Currently two different chemical modifications are being tested in clinical trials and more are undergoing pre-clinical evaluation. Exon skipping is a compelling example of a personalized/precision medicine approach, since the exon to be targeted depends on the individual mutation of the patient. While certain sizable groups of individuals would benefit from a single AON, the majority of AONs apply to smaller groups, each making up less than 2% of all patients.
Individuals affected by DMD and their families are aware of the challenges that need to be faced while attempting to provide effective therapies for this devastating disease. Research has shown that affected individuals and parents would welcome, for the time being, therapies that slow down disease progression, in line with what the therapeutic approaches currently in development aim to achieve. Furthermore, affected individuals and their parents are willing to accept a level of uncertainty inherent to the therapy development pathway and are willing to contribute to it at every step. Finally, patients and parents are keen to give input and advice at an earlier stage of drug development about trial design, choice of outcome measures, explaining what is clinically meaningful to them, how they see benefit risk, in- and exclusion criteria and on how to collect sufficient data in groups of patients not fitting these criteria in order to enhance the possibilities for extrapolation of trial results to these groups of patients.
The SCOPE-DMD study is an exploratory, open-label, dose-escalation phase IIb; to assess the efficacy, safety, pharmacodynamics and pharmacokinetics of weekly subcutaneous doses of BMN 045 (previously known as PRO045) in subjects with DMD. The study will not include a placebo arm and will be non-powered due to anticipated low numbers of eligible DMD patients treatable with exon 45 skipping. Natural History data and placebo data from other exon skip programmes will be used as an external control. Whilst beyond the scope of this FP7 application, the consortium is working closely together on the Natural History data and other exon skip programmes as well.
The SCOPE-DMD study highlighted the importance of safety monitoring. The start of the treatment phase of the clinical trial had to be delayed because of emerging safety signals during the prolonged dosing at 9.0 mg/kg SC. An ad hoc DSMB meeting was convened in February 2015 to discuss the emerging safety signals and the DSMB recommended to set the maximum tolerated dose for SC BMN 045 at 6.0 mg/kg/week. Based upon this recommendation, BioMarin decided to halt dosing at 9.0 mg/kg SC in all subjects and subjects who tolerated the treatment well continued dosing at 6.0 mg/kg. An Expert Panel meeting was convened to obtain advice and recommendations for the continuation of the clinical trial based on the emerging safety signals. This resulted in a protocol amendment to include additional safety monitoring to better understand the mechanism of action of the emerging safety signals.
At the time of writing BioMarin is discontinuing clinical and regulatory development of Kyndrisa as well as the three other first-generation follow-on products, BMN 044, BMN 045 and BMN 053. The efficacy and safety data generated from the BMN 045 study will have a significant benefit though on the further development of exon-skipping technology while BioMarin continues the development of next generation oligonucleotides.
Of note is also the innovative design used for this clinical trial. This trial consists of a dose escalation phase with 15 patients to determine a safe and efficacious dose followed by a pivotal treatment phase in which the same patients will be treated for 48 weeks together with an additional ~55 patients. In contrast to a classical design, this design ensured continuity of treatment for all patients enrolled in the study. It is not possible to conduct a statistically powered study due to the rarity of subjects with DMD correctable by exon 45 skipping, reflected by BMN 045 having orphan drug designation. The conduct of a single phase IIb registration pivotal study was therefore proposed, which has been discussed with the European Medicines Agency (EMA) Scientific Advice Working Party (SAWP).
Although the BMN 045 clinical trial did not progress as planned, the value created by the implementation of the innovative clinical trial design that allowed all enrolled patients to receive active treatment during the trial will not been lost and may support other compounds to be developed using a similar design.
Outcome measures & clinical benefit for DMD
Outcome measures that show correlation with slowing of disease progression would be appropriate endpoints in clinical trials given the importance of it to the patients and their families. Similarly, also outcome measures that predict disease milestones would be preferred. As an example, the time it takes to run 10 meters is predictive of when patients will lose ambulation, so a 2 second difference between treated and placebo groups in this test can indicate a delay of months or years in the decrease of motor function capabilities of the treated patients.
The DMD field has generated a huge amount of data on the use of outcome measures and their relevance. Consequently, the field is in need of clear and consistent guidance on what the regulators expect in terms of what outcome measures should be used in which DMD population (e.g. ambulant vs non-ambulant).
The SCOPE-DMD project has made a significant contribution to the research and development of outcome measures, as three Work Packages focused specifically on developing and validating new exploratory outcome measures. Work Package 2 focused on functional outcome measures, Work Package 3 focused on Imaging and Work Package 4 on biomarkers.
We would like to highlight the impact of the work undertaken in Work Package 2. The Performance of the Upper Limb Scale developed within the SCOPE-DMD project had led to a wealth of international collaborations outside of the SCOPE-DMD project as well as a number of publications on its development, reliability, validity, correlation with other outcome measures and its ability to detect change in clinical status as a result of treatment with steroids. The PUL has become a necessary part of the tool kit for assessment of boys and men with DMD in both therapeutic clinical trials and natural history studies.
Furthermore, the clinical meaningfulness of the PUL confirmed by the full participation of patients and advocacy groups has expanded the use of this scale out of the research arena and into clinics. The results of the PUL can direct professionals into targeting hands on therapies or aids and adaptations to assist patient function.
The PUL has been adopted for use in several clinical trials in DMD by other companies including Eli Lilly, Sarepta, PTC, Bristol Squibb Myers, FibroGen and Capricor amongst others. Evaluators working in other BioMarin studies have also been able to take advantage of the newly developed PUL V2. Clinical trial sites in Argentina, Australia, Belgium, Canada, Czech Republic, France, Germany, Israel, Hungary, Italy, Japan, Netherlands, Norway, Russia, Spain, Turkey and UK have all been trained by the SCOPE-DMD funded physiotherapists in PUL V2.0.
The need for innovative guidelines for development of DMD therapies
The process for development of DMD therapies would be greatly facilitated by publicly available up to date guidelines containing a direct input from the regulators. Furthermore, the introduction of novel trial designs that would allow inclusion of patients in different disease stages (e.g. ambulant and non-ambulant), with different mutations (e.g. the smaller groups for mutation specific approaches), and when possible trials without a placebo group, could contribute to a significant leap forward towards the offer of long awaited, sound therapeutic options for DMD patients.
Furthermore, the field asks for alignment and coherence in the scientific advice provided by the regulators (e.g. EMA, FDA) for clinical development plans. This alignment is not only needed for a single therapy, but also when different therapies are administered at the same time, since it is anticipated that in the future most DMD patients will receive a combination of treatments. Having guidelines on these aspects would be of paramount importance.
The dissemination undertaken during the lifetime of the SCOPE-DMD project has focused both on updating patients and the research community (directly by BioMarin as part of the study as well as at patient focused meetings and large international research meetings), as well as on a larger policy discussion in which patient organisations and regulatory agencies also participated.
Due to the encountered delays in the clinical trial, data generated from the clinical trial could not been published within the timeframe of the SCOPE-DMD project. News items therefore focused keeping the DMD community updated on the progress of the trial, on interactions with the regulatory agencies and on outcome measures.
For the first Stakeholder Workshop, early engagement with the EMA and the patient organisations was sought. The involvement of the EMA alongside companies involved in designing or undertaking clinical trials in DMD as well as patient organisations and clinicians in the organising of the workshop was paramount to its success. Furthermore, the development of a Briefing Document for the Stakeholder Workshop in April 2015 has led to a further request by the EMA for a similar format Briefing Document for an upcoming Stakeholder Workshop on Spinal muscular atrophy.
The Briefing Document produced for the Stakeholder Workshop was the basis for a Policy View published in Lancet Neurology: “Cooperation among stakeholders to overcome challenges in orphan medicine development: the example of Duchenne muscular dystrophy”. Among the authors of the Briefing Document and Policy View were several participants of the SCOPE-DMD project.
The discussion with regulators has started a productive dialogue with the EMA which will continue after the SCOPE-DMD project has ended. The discussions at both the Stakeholder Workshops, further strengthened by the publication of the Policy View in Lancet Neurology has brought the DMD community, industry and academic stakeholders together with the regulators to discuss the next steps in the development and acceptance of meaningful outcome measure, effective and innovative clinical trial design and above all the importance of early and continued patient engagement in all aspects of the development of an effective treatment for DMD. As the number of pharmaceutical companies that are undertaking clinical trials increases, the dialogue with the regulators and the patient organisations are important for an effective partnership. As many of the partners from the SCOPE-DMD project are also involved in other EU funded projects like SKIP-NMD, BIOIMAGE-NMD and two COST Action, namely COST Action BM1207: Networking towards clinical application of antisense-mediated exon skipping and COST Action BM1304 Applications of MR imaging and spectroscopy techniques in neuromuscular disease: collaboration on outcome measures and pattern recognition for diagnostics and therapy development, much of the work on MRI as an outcome measure and on exon-skipping will continue to be taken forward.
List of Websites:
www.scope-dmd.eu