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209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands
The utility and limitations of animal models in SMA is discussed.
•
Biomarkers that are potentially useful in a clinical trial setting are reviewed.
•
A detailed review of clinical outcome measures for use in a clinical trial is tabulated.
1. Introduction
Twenty-four researchers and industry representatives from 9 different countries (USA, Spain, Italy, France, Germany, Switzerland, Sweden, The Netherlands, United Kingdom), one patient and representatives of SMA Europe and from the SMA Foundation met in Holland on the weekend of the 7th–9th of November 2014 to update current knowledge on clinical trials and outcome measures for spinal muscular atrophy (SMA).
2. Background
Spinal muscular atrophy (SMA) is one of the most common neuromuscular diseases. While SMA is a monogenic disorder, there is a broad range of phenotypes from very weak infants unable to sit (type 1), non-ambulant children able to sit (type 2), to ambulant children (type 3). Further subtypes have also been suggested at the 2 ends of the clinical severity: SMA type 0, in which onset is in utero with reduced or absent movements, contractures, and requirement for mechanical ventilation support at birth, and cases of onset in adult life (type 4). Current classification of SMA is presented in Table 1. Since the last ENMC workshop on this condition held in 2007 [
Towards harmonisation of outcome measures for DMD and SMA within TREAT-NMD; report of three expert workshops: TREAT-NMD/ENMC workshop on outcome measures, 12th–13th May 2007, Naarden, The Netherlands; TREAT-NMD workshop on outcome measures in experimental trials for DMD, 30th June–1st July 2007, Naarden, The Netherlands; conjoint Institute of Myology TREAT-NMD meeting on physical activity monitoring in neuromuscular disorders, 11th July 2007, Paris, France.
] there have been noticeable improvements on the understanding of its pathogenesis and natural history. Recent appreciation of genetic and clinical nuances in SMA, as discussed here, highlights the need for a better definition of outcome measures and to improve clinical trial readiness. This is particularly relevant now that novel therapies are entering the clinic. The workshop concentrated on the following topics: diagnostic aspects, modifiers and biomarkers; pathophysiology including animal models; natural history studies; outcome measures; registries and standards of care.
Table 1Subtypes of SMA. SMA is a continuum. These subtypes summarize the typical age at diagnosis and clinical presentation. Sensation, facial expression and intellect are preserved in types 2, 3 and 4. Other organ system involvement is uncommonly seen clinically, even in type 0. Survival for type 1 is evolving with improved medical management of respiratory, nutritional and orthopaedic complications.
SMA type
Age at onset
Age at diagnosis
Defining clinical features at presentation
Maximal motor function achieved
0
Fetal
Birth
•
Paucity of movement in limbs, face, trunk, no suck
•
Muscle atrophy
•
Areflexia
•
Congenital contractures
•
Requirement for mechanical ventilation support at birth
Nil
1-A
Fetal
First 2 weeks of life
•
Hypotonia: severe, generalized
•
Weakness of limbs, neck
•
Areflexia, ±tongue fasiculation
•
Poor feeding, requiring support
•
Laboured breathing/requirement for mechanical ventilation may be needed since the neonatal period
]. Deletions or other mutations in the SMN1 gene cause SMA. An almost identical gene, SMN2, closely located on the same chromosome, is invariably present, as complete ablation of both SMN1 and SMN2 is considered to be lethal. Diagnostic testing for genetic confirmation of the diagnosis is now readily available in commercial and clinical labs around the world. The number of copies of the SMN2 gene is inversely related to severity but in individual cases is not entirely predictive of the extent of disability. Clinical trials are now utilizing the number of SMN2 copies carried by an individual as a means of enrolling a more homogeneous cohort of subjects, especially for an infantile onset (type 1) study (2 copy numbers in most current studies).
There are 2 issues that need to be considered when assessing SMN2 copy numbers in SMA. First, how robust is a technique to detect different copy numbers, especially when more than 4 are present? Secondly, are all SMN2 genes the same? Dr. Tiziano discussed current diagnostic methods for determination of the number of copies of the SMN2 gene. Both Multiplex Ligation-dependent Probe Amplification (MLPA) and quantitative PCR techniques are used commonly. No consensus, however, has been reached on how to best identify if the SMN2 gene is intact and whether this impacts the potential significance of copy number as a biomarker. Is determination of presence of exon 7 in the SMN2 gene sufficient or is it also necessary to determine the presence of all exons, the promotor and 3′UTR regions? This could be an issue in view of rare occurrences of truncated SMN2 versions and of other rare variants that can modify the level of SMN protein expression [
A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy.
The participants discussed that while the occurrence of truncated SMN2 genes (or other SMN2 variants) is believed to be rare, there is no current large study in which this issue has been addressed across multiple populations. Regarding the robustness of current techniques for screening, a proposal was accepted to determine the copy number on existing DNA samples from SMA patients in several labs using different techniques, to see if the results differ to a significant degree.
Additional modifier genes were also discussed by Dr. Wirth. PLS3 polymorphisms may be important, with a less severe phenotype in females, but are not commonly encountered. Other modifiers are also believed to exist and they are currently being characterized further [
The value of animal models in SMA was reviewed by Dr. Burghes. Several informative mouse models exist, with the most work done on the severe “delta 7” model that includes the human SMN2 transgene [
]. Involvement of other organ systems has been reported in these mice. However work from the DiDonato laboratory suggests that these two mouse lines do not necessarily overlap in the pathology of other organ system involvements [
]. It is currently unclear whether any of the peripheral organ pathologies reported in the SMA mice are relevant for SMA patients, and this is an area which requires more clinical studies. Nevertheless all these animal models contain the human SMN2 gene and thus are suitable for the study of SMN2 inducing compounds.
Therapeutic development for SMA has benefitted from screening small molecules, antisense oligonucleotides and AAV-mediated gene transfer strategies in the delta 7 mouse for improved survival, motor function and growth. Electrophysiological testing can also be performed on these mice, to examine the compound motor action potential (CMAP) and motor unit number estimate (MUNE) response to sciatic nerve stimulation, and provide a measure of functional restoration of the motor unit, which can also be performed in humans [
]. Delayed treatments become less effective but can result in substantial restoration of CMAP.
Electromyography (fibrillations) also appears to provide a useful readout on the extent of ongoing denervation. While mice are useful it is important to ensure that similar results can be obtained in a large animal model, which will more closely mimic SMA.
A pig model for SMA has been developed using a knock-down strategy. Interestingly, knockdown of SMN in motor neurons to levels found in SMA patients gave a marked phenotype with denervation and loss of motor neuron cell bodies, indicating the critical nature of SMN requirement for the motor neurons. This model was used as a pre-clinical model to investigate how the restoration of SMN levels affected phenotype and also to monitor the response to therapy using biomarkers. Due to its size and anatomy, the pig model better recapitulates human pathophysiology. In particular the pig, like SMA patients, shows fibrillations on EMG and reduced CMAP and MUNE. Early pre-symptomatic restoration of SMN resulted in CMAP and MUNE correction, whereas restoration of SMN in an early symptomatic stage resulted in increased CMAP but not restoration of MUNE. This indicates the powerful use of these biomarkers in determining that the motor neuron is functionally intact after treatment [
Dr. Muntoni presented data from the transgenic Taiwan SMA mouse model highlighting the presence of widespread vascular abnormalities in this model, confirming previous work of Simon Parson et al. [
]. Recent work performed by Zhou and Muntoni suggest that the administration of morpholino antisense oligonucleotides to modify SMN2 splicing improves this vascular phenotype. Furthermore, Dr. Muntoni reported that – in this model – the chronic administration of peripherally delivered antisense oligonucleotides contributes to the maintenance of muscle end-plates, to muscle innervation and motorneuron functional integrity, as demonstrated by reduced accumulation of neurofilaments at neuromuscular junctions and increased expression in motorneurons of neuronal markers which are typically depleted in SMA.
Important temporal and spatial questions remain incompletely answered. The critical period of irreversible motor neuron loss in SMA is undefined. How do these animal data relate to the human: when is the period of vulnerability for motor neuron loss in SMA types 1, 2 and 3 and when postnatally can meaningful rescue be achieved? How much SMN protein in motor neurons is needed and at which stages of development to have a meaningful effect? Will neuroprotective strategies provide an added benefit? Will these therapies result in tempering in the rate of decline, stabilize, or promote a gain in motor function? How long will such responses persist and how will future growth of the child potentially offset such gains? How limited is the capacity for future sprouting and reinnervation and will this result in a post-polio like situation months or years later? It will be important to determine the role of peripheral organs in patients with SMA, and, in particular, whether capillary alterations occur in man. How important is restoration of SMN protein in muscle? Investigation into each of these topics is currently in progress in animal model systems and early phase human studies.
3.3 Human pathology in SMA type 1
Dr. Sumner presented data on muscle pathology from SMA type 1 autopsy cases. Very small diameter muscle fibres are seen commonly in SMA-1, which varies among different muscles (diaphragm less so than intercostal muscles), and appear to be deficient in the ability to fuse [
] . This is separate from small fibres due to neurogenic grouped atrophy. The neuromuscular junction is also immature in morphology. Also, immature appearing proximal axons and dorsal root ganglia have been identified. Collectively, this suggests an element of developmental arrest in SMN deficient nerve and muscle and suggests that SMA is not purely a progressive neurodegenerative process [
]. Polyneuronal innervation of muscle in the early post-natal mouse differs from that in the human where one axon probably innervates one muscle fibre at birth. How this affects interpretation of the mouse data is still unclear.
Dr. Finkel presented neuropathological data that demonstrated thalamic changes, as initially reported in the 1980s, in all five cases studied, ranging from severe type 0 to mild type 1C. Chromatolysis was noted in motor cortex, cerebellum and Clark's column (Type 0 only), brainstem nuclei (XII in each case; III, V, VI, VII and X only in the type 0 cases) and dorsal root ganglia, in addition to motor neuron loss in the spinal cord in each case. Whether these changes are due to deficiency of SMN or are a secondary effect of motor neuron dysfunction is currently unknown. Delay in maturation of the acetylcholine receptor was described, as has also been published by other investigators [
In addition to the genetic modifiers described above, the role of serum biomarkers was discussed.
Dr. Chen presented assays for quantification of SMN protein. SMA results from a deficiency of full-length functional SMN protein. An ELISA assay for quantification of SMN protein in peripheral blood mononuclear cells (PBMCs) has been available the past several years. It demonstrated a limited association with severity of phenotype and high variability in SMN levels in PBMCs. A new assay to measure SMN protein in whole blood has been developed by PharmOptima in collaboration with the SMA Foundation. This assay is an electrochemiluminescence immunoassay (SMN-ECL), where a mouse monoclonal antibody functions as the capture antibody and a rabbit polyclonal anti-SMN antibody labelled with a SULFO-TAG™ is used for detection. The assay is highly sensitive (2–3 pg/ml), has a broad working range (9–20,000 pg/ml), and only requires 5 µl of whole blood. In contrast to the ELISA assay, SMN-ECL is able to detect SMN protein in highly diluted samples thus eliminating matrix effects. The SMN-ECL assay was qualified according to FDA guidelines and various conditions for blood collection/storage The assay has been used to measure SMN protein in human blood samples (healthy individuals and SMA patients), autopsy materials (spinal cord, muscles) and in a variety of mouse tissues (unpublished data). This SMN-ECL assay did not detect SMN protein in CSF samples uncontaminated with whole blood. A different, more sensitive CSF assay is under development and may prove informative as a response to therapy.
Dr. Chen also reviewed the SMA biomarker project (BforSMA and SMA-MAP), which developed an unbiased serum metabolomics panel. A panel of 27 non-SMN related biomarkers has been created (“SMA-MAP”), can be used in both humans and mice, and is commercially available [
]. Each biomarker has been demonstrated to associate with severity of the motor phenotype. In mice, several of these biomarkers relate to the level of SMN protein in spinal cord tissue. In addition a limited set of the markers used in mice responds to treatment with antisense oligonucleotide which restores SMN levels. This panel may be useful as an early readout of efficacy or in stratification of subjects in a clinical trial. Data from studies currently under analysis or in progress will indicate how responsive this panel of biomarkers is to a neuroprotective intervention in comparison to a placebo control (olesoxime, Trophos) or progression of disease (NeuroNEXT).
Dr. Swoboda discussed electophysiological biomarkers relevant to clinical trials in SMA. Reliably obtaining the CMAP and MUNE is challenging in a multicentre study. The technique used and rigorous training of the investigators are important considerations to ensure success and increase reliability in a multicentre trial setting. CMAP reflects the motor output of the nerve being stimulated, while MUNE estimates the number of functioning motor neurons in that nerve. Theoretically, both measures have value in a clinical trial, for example, if the MUNE remains low and the CMAP increases over time, this could be a reflection of effective neuronal sprouting and increased innervation. Alternately, an increasing MUNE with stable CMAP may reflect an increase in the pool of functional motor neurons [
]. Both CMAP and MUNE are uniformly low in symptomatic SMA type I and only CMAP is of practical utility in a multicentre clinical trial setting for type 1 subjects. Studying more than one nerve/muscle may be useful. Newborn screening for SMA is now technically feasible and will generate opportunities for pre-symptomatic intervention. For a pre-symptomatic type I study the CMAP will be highly informative.
In a study of SMA types 2 and 3, the CMAP correlates with motor function and might serve as a useful means of stratifying patients in a clinical trial. Nevertheless, in a recently completed large randomized placebo control conducted by Trophos, in which a therapeutic benefit of olexosime has been reported, electrophysiological results showed that with MUNE there was a statistically significant difference between the treated and the placebo groups measured as percent change from baseline. The difference was likely observed with the CMAP but did not reach statistical significance. The potential advantage of CMAP over simply measuring MUNE is that CMAP is both a measure of change in motor unit numbers as well as the physiological compensatory effect of motor unit sprouting. The reason why significant changes were observed with MUNE, presumably reflecting an increase in the number of motor units in a population with a chronic long lasting disease, needs more explanation. It will be relevant to verify that the most significant differences were detected in the youngest population. This study suggests the increased sensitivity of MUNE over CMAP, though both change in the same direction. Further analyses are still required to confirm the internal and external validity of the data and how these biomarkers can be used effectively in a clinical trial setting. Overall, analysis of the change in electrophysiological measures during this 2-year period provides important insights for monitoring SMA disease progression in a multicentre clinical trial.
Dr. Van der Pol reviewed his published data, which demonstrated a decremental response of the CMAP with low frequency repetitive stimulation in a proportion of SMA patients, suggestive of a post-synaptic physiological defect [
]. This may be relevant to muscle fatigue, a common symptom in SMA.
3.5 Natural history studies and relevant outcome measures
The aim of this session was to review existing outcome measures in SMA, and to discuss how each of them fits with a number of requirements including statistical robustness, clinical meaningfulness, and other criteria recently discussed with regulatory authorities for SMA and other neuromuscular disorders. For each measure published and unpublished data were reviewed trying to identify possible gaps and criticisms and to establish a roadmap of available outcome measures for future trials. Table 2A, Table 2B summarizes motor function scales currently used or in development.
Table 2AOutcome measures for clinical trials in SMA: motor function scales, electrophysiological biomarkers and strength testing.
HFMSE
MFM
6MWT
ULM
CHOP INTEND
TIMPSI
CMAP and MUNE
Myotools
Clinical utility: SMA subgroups
2 and weaker 3
2 and 3
3
2
1
1
✓
✓
Supports mechanisms of action
✓
✓
✓
✓
✓
✓
✓
✓
Conceptual framework for SMA
✓
✓
✓
✓
✓
✓
✓
✓
Reliability: Inter and intrarater
✓
✓
✓
✓
✓
✓
Protocol dependent
✓
Validation with other outcome measures
✓
✓
✓
✓
✓
✓
✓
✓
Normative ranges
✓
✓
✓
✓
✓
✓
✓
✓
Published natural history studies
✓
✓
✓
✓
✓
✓
✓
✓
Multicentre studies
✓
✓
✓
✓
✓
Protocol dependent
✓
Responsiveness to change
✓
✓
✓
In progress
✓
✓
✓
✓
Clinical meaningfulness
✓
✓
✓
✓
✓
✓
✓
MCID
Age-specific changes
✓
In progress
✓
In progress
✓
✓
Ambulant
✓
✓
✓
✓
✓
Non-ambulant
✓
✓
✓
✓
✓
✓
✓
HFMSE: Hammersmith Functional Motor Scale Expanded, MFM: Motor Function Measure, 6MWT: 6-minute walk test distance, ULM: upper limb module for SMA, CHOP INTEND: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders, TIMPSI: Test of Infant Motor Performance Screening Items, CMAP: compound motor action potential, MUNE: motor unit number estimate, MCID: minimal clinically important difference.
The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation.
Reliability and validity of outcome measures of in-hospital and at-home visits in a randomized, double-blind, placebo-controlled trial for spinal muscular atrophy.
First author [citation in references], n = number of subjects in cited reference. SMN2 # : number of copies of the SMN2 gene, DXA: dual-energy X-ray absorptiometry scan, MRI: magnetic resonance imaging scan, MRC: Medical Research Council (UK) scale of graded muscle strength, FIM: Functional Independence Measure, NM-Score: Neuromuscular Score, TUG: Timed Up-and-Go Test.
Dr. Finkel presented an overview of natural history studies in SMA type 1, focusing upon survival data, motor function scales, and CMAP within the context of clinical trial design. It is generally accepted that the primary outcome measure for a type 1 study will be survival, or the surrogate of permanent ventilation support. The latter has been defined as 16 hours or more of non-invasive or invasive ventilation for more than 14 days in the absence of an acute reversible illness or post-operatively. Nomenclature for type 1 subtypes was discussed and there was general agreement that type 0 refers to clear fetal onset (major contractures and need for ventilation support at birth), type 1A to clear onset of weakness, feeding difficulty and respiratory insufficiency within the first 2 weeks of life, type 1B to onset of weakness by 3 months of age and type 1C by 6 months of age. It is recognized that there may be occasional outliers to this classification, i.e. rarely, SMA patients with symptom onset less than 6 months of age will achieve independent sitting (hence, type 2) and these would likely have a SMN2 copy number of 3. Limiting a clinical trial to those with a copy number of 2 reduces this likelihood and will make the enrolled group of subjects more homogeneous. Standard of care issues are also a significant contributor to how these fragile SMA-1 babies fare. Close attention to weight gain and nutritional status is necessary as those who fail to gain or even lose weight fare poorly. This issue typically precedes the need for ventilation support unless an acute respiratory illness arises. Clinical trials in SMA-1 will need to consider carefully how to define nutritional and pulmonary/ventilation standards of care during the conduct of the trial if variability of survival due to progression of disease is to be minimized. Both the CHOP INTEND and TIMPSI motor function scales are being used in clinical trials (Table 2A, Table 2B). CMAPs are uniformly low in symptomatic patients at the time of diagnosis. CMAP may be informative as a supportive biomarker in SMA-1 clinical trials if the drug promotes sprouting, reinnervation and improved transmission at the neuromuscular junction, or possibly a more delayed response if the pool of functional motor neurons is increased.
Dr. Mercuri discussed the possible use of the Hammersmith Motor Function Scale Expanded (HFMSE) in the non-ambulant population. A review of published data patients confirms that the scale has been widely used in SMA patients (Table 2A, Table 2B). Several studies from different groups have reported its suitability for multicentric studies, validation and correlation with other measures in large cohorts of SMA patients. Large natural history data are also available showing longitudinal changes at 12 and 24 months. Data from a large collaborative project involving several large networks in the US and Europe of approximately 300 SMA patients were discussed. These provided further insight into multiple subsets of patients with differing trajectories of changes, emphasizing the need to consider age and baseline function in order to identify these trajectories effectively. Younger children (below 5 years) perform better overall than those assessed after the age of 5 and throughout puberty. Of note, the variance in the HFMSE becomes greater over time, especially for type 3.
The criticisms to the HFMSE were related to the paucity of items assessing upper limb function that can be relevant in weak non-ambulant SMA patients.
Dr. Montes discussed the ambulant population and reviewed the utility of the 6-minute walk test (6MWT), HFMSE, MFM, Northstar Ambulatory Assessment for SMA and the Timed Up and Go (TUG) scales. Physiological fatigue was also discussed and how this can be captured on the 6MWT [
]. Ms Main contributed 6MWT data that highlighted the variability that can be seen in individual patients over time.
Dr. Vuillerot presented a discussion on the MFM and highlighted how the items captured as part of the domains D1, D2 and D3 are relevant also for SMA patients with types 2 and 3 [
]. The MFM appears to be less appropriate for type 1. Data are available on the use of the MFM in SMA where it has also been validated. Longitudinal data are also available from the AFM database, where currently 61 and 89 SMA types 2 and 3, respectively, are registered (see http://www.motor-function-measure.org/data-bank.aspx.).
The MFM in its classic form (MFM32) is suitable for children older than 6 years and a modified version with 20 items (MFM20 version) has been validated for children less than 6 years of age. Although validated for children older than 6 years old, children between 4 and 5 years old were able to complete all items on the MFM32 [
]. The olesoxime (Trophos) MFM data were presented for type 2 and non-ambulant type 3 SMA patients from 3 to 25 years old (see below).
One criticism to the MFM highlighted by a recent paper was that although there are items in the MFM 20 that explore transfers and axial motor function, that are important in the stronger type 2 and weaker type 3 patients, there is a paucity of items that fill the gap between the non-ambulant and ambulant patients, with possible ceiling effect in non-ambulant patients [
]. This topic warrants further examination in a larger longitudinal cohort. Issues on the transition from MFM 20 to MFM 32 in young ambulant patients once they are older than 6 years were also discussed.
]. She highlighted where these scales had more robust areas of strength, where gaps need to be addressed and how rescoring selected items would optimize the linearity of the scales.
An international collaboration is currently working to improve outcome measures in SMA, which has led to the development of the Revised Hammersmith Scale for SMA (RHS). This scale aims to address the problems highlighted by the Rasch analysis with application of clinical sensibility. It includes addition of new items, removal of non-working items, and a revised scoring system to ensure it meets the rigorous demands required of clinically reported outcome measures by regulatory authorities. This scale is entering its third and final phase of testing and is likely to be reported on formally later in 2015.
Dr. Mercuri presented recent data showing how the HFMSE can be rescored, taking into account some points raised by the Rasch analysis. One of the concerns raised by the Rasch analysis and clinical sensibility was that there were several redundant items (e.g. rolling on right and rolling on left) and others in need of simplified scoring. As a result the existing HFMSE may overestimate the extent of longitudinal changes and the number of patients with changes outside the range of normal patient variation (+2 points) on the HFMSE. A large cohort of SMA patients was rescored according to these suggestions. The results of the new scoring indicates that the number of outliers is similar between the old and new scoring systems, suggesting that the concern that the HFMSE might overestimate changes is unlikely to be valid.
Dr. Yeh (Biogen Idec, Cambridge, USA) presented a fresh data analysis of the Pediatric Neuromuscular Clinical Research Network for SMA (PNCR, USA) network's HFMSE database. Items that were redundant were excluded and remaining items were rescored. It was quite apparent that the non-ambulant and ambulant populations segregated into a bimodal distribution with some overlap (Fig. 1). This observation raises the important question whether a clinical trial can feasibly enroll both non-ambulant and ambulant patients, and if so how to capture relevant motor function effectively with a single linear scale.
Fig. 1Distribution of HFMSE scores by type 2 and type 3 from the PNCR Network natural history study database (Wei-Shi Yeh, Biogen-Idec, with permission).
Dr. Khwaja added that items on these motor function scales need to be tethered to more general motor function so that the relevance of any changes can be intrinsically appreciated. Dr. Montes commented that the PNCRN is currently exploring how the HFMSE relates to clinically meaningful activities. The idea of composite scores or mathematically combining existing outcome measures was discussed. A composite broadens the spectrum of motor performance that can be captured in the weakest and strongest patients and may bridge potential gaps in assessment particularly in times of transition from ambulant to non-ambulant as well as from sitter to non-sitter [
]. A recently published paper confirms previously published results that the ULM can fill some gaps of the HFMSE and that the combination of the two scales can provide a wider range of activities [
]. The module is currently being revised to better address the functional repertoire relevant to SMA, expanding the number of items to include some that are more relevant for stronger SMA patients. Other upper limb measures have been reported recently [
] and are currently in progress (C McDonald, UC Davis, reachable space) but were not discussed here.
Dr. Hogrel reviewed the MyoTools that have been studied in SMA: the MyoGrip, the MyoPinch and the MoviPlate. Results differed according to the age of the patients, more specifically, whether they were younger or older than 14 years. At the one-year follow-up, the older group lost approximately 200 g of grip strength and 100 g of pinch strength. The confounding effect of growth, maturation and puberty can compensate the decrease of strength due to the disease in patients younger than 14. The relationship of grip and pinch strength to more general motor function as measured with the MFM also highlights the relevance of capturing strength with sensitive and reliable instruments.
Data on the ongoing NeuroNEXT biomarker study (clinicaltrials.gov ID NCT01736553) was shared by Dr. Kolb (Ohio State University, Columbus, USA) and will help define the longitudinal course of survival, motor function on the CHOP INTEND and TIMPSI, CMAP, Electrical Impedance Myometry, SMN protein levels in blood and the SMA-MAP biomarker panel [
Dr. Bertini presented unpublished data from the double-blind randomized olesoxime study (Trophos ClinicalTrials.gov Identifier: NCT01302600). Non-ambulant SMA patients age 3–25 years were studied for 104 weeks at 23 sites. The Motor Function Measure (MFM, sum of the D1 and D2 parts) after 24 months was the primary outcome measure and demonstrated a statistically significant reduction in the degree of change from baseline as compared to placebo. This apparent drug benefit in an obviously heterogeneous patient group was not statistically significant using the Hammersmith Motor Function Scale (not the expanded HFMS), which was assessed after 21 months, although a similar positive trend was found. The CGI (Clinical Global Impression) scale separately documented by investigators and parents/patients supported the positive study outcome. Lessons learned from this study include: taking great effort to ensure that the treatment and placebo arms are well-matched by age and functional level at baseline, although randomization with 2:1 allocation ratio can unavoidably lead to some imbalance, and the need to train the investigators rigorously in EMG performance if reliable data are to be obtained.
Dr. Burghes presented the study design and overview of the scAAV9 gene transfer study currently in progress at Nationwide Children's Hospital (Columbus, USA), sponsored by AveXis (ClinicalTrials.gov Identifier: NCT02122952). Pre-clinical data from intracerebroventricular administration in mice supported human administration. In this phase I safety and dose escalation study the vector is administered IV and is known in primates to cross the blood–brain barrier to allow targeting of motor neurons in the spinal cord, brain stem and cells in the cerebrum. A ubiquitous beta actin promotor will also target delivery to systemic tissues. Delivery into the CSF would require less vector and is being considered as a future step. To date, no major adverse effects have been noted.
Isis has several studies in SMA that are ongoing and new ones anticipated to start shortly. Data from the current clinical trials, where ASO is administered into the CSF via lumbar puncture, was recently presented at the World Muscle Society meeting in Berlin and were not otherwise discussed.
The Roche MOONFISH study (ClinicalTrials.gov Identifier: NCT02240355) will start shortly in SMA patients and was mentioned by Dr. Khwaja. This strategy uses an oral small molecule drug that alters splicing of the SMN2 transcript towards greater inclusion of exon 7.
Dr. Tseng announced the start of Novartis's small molecule drug programme for SMA (ClinicalTrials.gov Identifier: NCT02268552).
3.8 Additional clinical trial considerations
Dr. Tseng contributed the perspective that clinical trials in SMA will need to consider standards of care and uniform care, reproducibility of results, involving not only centres of excellence for trials and the risk of therapeutic misconception.
Dr. Finkel discussed the concepts of clinically significant versus clinically meaningful and how both are important considerations in a clinical trial. Defining the minimal clinically important difference (MCID) will be important for the type 1/non-sitters, non-ambulant and ambulant populations.
Dr. Montes then reviewed preliminary efforts by Amy Pasternak (Boston Children's Hospital) in using the PediCAT computer directed disability instrument in SMA. It has been found to be useful in the type 3 population, but not for type 2 and is not applicable for type 1. Future efforts will be directed to select new items that are more appropriate for type 2 patients.
Ms. Ramsey presented exploratory work using the PODCI in SMA.
Cure SMA (formerly Families of SMA) is currently undertaking a structured interview process to gain more information on quality of life and MCID topics from both the parent and patient perspectives. Pharmaceutical companies are also undertaking a similar effort.
Dr. Khwaja mentioned the concept of hierarchical outcome measures in a clinical trial. If the top outcome measure proves too difficult for a subject then the second, less demanding one is used, and so on, until the right fit is identified. It also gives room for the subject to move up or down to a neighbouring scale as the motor function changes.
The lack of defined respiratory outcome measures for types 2 and 3 was identified as an area needing more attention. Regulatory authorities would prefer to see supportive secondary outcome measures that are relevant to the disease under study, and not just focus on motor function.
The topic of registries for SMA was reviewed by Dr. Van der Pol and highlighted the challenges of developing an undated, genotype–phenotype registry for clinical trial readiness.
Dr. Sejersen reviewed standards of care for SMA and the need to update the 2007 guidelines.
Ms. de Lemus, representing SMA Europe, described the vital role that advocacy groups can play in clinical trial readiness: support implementation of standards of care, develop local and national registries, and disseminate information about and facilitate enrolment into clinical trials. The use of social media in connecting with families was emphasized.
Dr. Witchen provided an important perspective as an adult living with SMA and how clinical trials offer legitimate hope for patients.
Dr. Mercuri discussed the benefit of having qualification of outcome measures and biomarkers by regulatory authorities. This will harmonize and clarify efforts towards constructing efficient clinical trials that will meet with regulatory approval. A scorecard was constructed to summarize the status of current motor function scales and biomarkers. (Table 2A, Table 2B).
4. Conclusions
The workshop ended on Sunday morning with a discussion on future collaborative strategies. These ranged from the distribution of samples with known number of copy number to participating laboratories for quality control; to the work towards improved information that could help the regulatory authorities to better understand the content and concept behind the various functional scales; and to ensure there is a central repository of all scales used, under the TREAT-NMD domain (http://www.treat-nmd.eu/resources/outcome-measures/registry-of-outcome-measures/). Furthermore, additional work is planned to better link scales that capture different stages (or functional status) of the disease (for example links between scales for SMA1 and 2; and between SMA2 and 3). This will be important for capturing any possible improvements following experimental therapeutic interventions. The possibility to explore composite scores should also be discussed further. The participants also discussed that it would be helpful to approach regulatory authorities to present the state of the art in terms of knowledge and functional scales, similarly to what has been recently done both in Europe and USA for Duchenne muscular dystrophy, and informed guidelines for clinical trials in this condition. Finally, collaborative studies on how to best measure and capture respiratory function, orthopaedic topics of scoliosis and joint contractures, and adverse events were also discussed.
5. Participants – ENMC SMA Workshop Study Group*
Enrico Bertini, Rome, Italy
Alexandra Breukel, ENMC
Arthur Burghes, Columbus (Ohio), USA
Karen Chen, New York, USA
Richard Finkel, Orlando, USA
Mencia de Lemus, Madrid, Spain
Jean-Yves Hogrel, Paris, France
Omar Khwaja, Basil, Switzerland
Jan Kirschner, Freiburg, Germany
Marion Main, London, UK
Elena Mazzone, Rome, Italy
Eugenio Mercuri, Rome, Italy
Jacqueline Montes, New York, USA
Francesco Muntoni, London, UK
Danielle Ramsey, London, UK
Thomas Sejersen, Stockholm, Sweden
Charlotte Summer, Baltimore, USA
Kathryn Swoboda, Cambridge, USA
Danilo Tiziano, Rome, Italy
Brian Tseng, Cambridge, USA
Ludo Van der Pol, Amsterdam, The Netherlands
Carole Villerot, Lyon, France
Brunhilde Wirth, Bonn, Germany
Anna Witchen, Berlin, Germany
Wei-Shi Yeh, Cambridge, USA
Annelies Zittersteijn, ENMC
Acknowledgements
This Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors:
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Association Française contre les Myopathies (France)
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Deutsche Gesellschaft für Muskelkranke (Germany)
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Muscular Dystrophy Campaign (UK)
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Muskelsvindfonden (Denmark)
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Prinses Beatrix Spierfonds (The Netherlands)
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Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland)
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Telethon Foundation (Italy)
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Spierziekten Nederland (The Netherlands)
and Associated members:
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Finnish Neuromuscular Association (Finland)
With special thanks to the Dutch ZonMw, MDA USA, SMA Europe, SMA Trust, Genzyme Europe BV and GlaxoSmithKline Rare Diseases for their support to the ENMC activities. The generous support of Cure SMA and the SMA Foundation (USA) to sponsor the US participants to this workshop is gratefully acknowledged.
References
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Mayhew A.
Muntoni F.
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Towards harmonisation of outcome measures for DMD and SMA within TREAT-NMD; report of three expert workshops: TREAT-NMD/ENMC workshop on outcome measures, 12th–13th May 2007, Naarden, The Netherlands; TREAT-NMD workshop on outcome measures in experimental trials for DMD, 30th June–1st July 2007, Naarden, The Netherlands; conjoint Institute of Myology TREAT-NMD meeting on physical activity monitoring in neuromuscular disorders, 11th July 2007, Paris, France.
A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy.
The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation.
Reliability and validity of outcome measures of in-hospital and at-home visits in a randomized, double-blind, placebo-controlled trial for spinal muscular atrophy.
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