Vol. 20 No. 5, May 2010
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`Neuromuscular disorders : NMD.
`v. 20, no. 5 (May 2010)
`General Collection
`W1 NE337GB
`2010-05-19 06 :46:21
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`M
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`20 (5) 295-362
`ISSN 0960-8966
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`Neuromuscular Disorders 20 (20IO) 355-362
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`Contents lists available at ScienceDirect
`
`Neuromuscular Disorders
`
`ELSEVIER
`
`journal homepage: www.elsevier.com/locate/nmd
`
`Workshop report
`The development of antisense oligonucleotide therapies for Duchenne muscular
`dystrophy: Report on a TREAT-NMD workshop hosted by the European Medicines
`Agency (EMA), on September 25th 2009
`F. Muntoni ·, on behalf of the meeting steering committee, and of the TREAT-NMD Network
`The Dubowitz Neuromuscular Centre, University College Lo11do11. Institute of Child Health, 30 Guildford Street. London, WCJN /EH, UK
`
`1. Introduction
`
`A workshop entitled The Development of Antisense Oligonu(cid:173)
`cleotide Therapies for Duchenne Muscular Dystrophy. sponsored
`by the EU funded Clinical Network TREAT-NMD (Translational Re(cid:173)
`search in Europe for the Assessment and Treatment of Neuromus(cid:173)
`cular Diseases; www.treat-nmd.eu), Association Francaise contre
`les Myopathies, Duchenne Parent Project, European Medicines
`Agency, Muscular Dystrophy Association and Patient Project Mus(cid:173)
`cular Dystrophy, was held on 25th September 2009 at the Euro(cid:173)
`pean Medicines Agency (EMA), London, UK. The 40 active
`participants represented six countries and included scientists, cli(cid:173)
`nicians, patient representatives, industry and regulators from the
`EMA.
`The workshop opened with a welcome note from Agnes Saint(cid:173)
`Raymond (EMA) followed by the TREAT-NMD coordinator Volker
`Straub leading with an overview of what TREAT-NMD is and he
`emphasised it was created to relieve the schism impeding transla(cid:173)
`tional research for the development of new therapeutic strategies
`for rare neuromuscular diseases. Francesco Muntoni (chairman)
`then presented the background to and objectives of the workshop.
`Exon skipping represents a novel antisense oligonucleotide thera(cid:173)
`peutic approach for the treatment of Duchenne Muscular Dystro(cid:173)
`phy (DMD), which unlike existing treatments, directly addresses
`the lack of functional dystrophin protein that causes the disease.
`As there is currently no therapy addressing disease pathogenesis
`for DMD patients. exon skipping to convert the severe DMD disease
`into a condition analogous to the substantially milder Becker
`(BMD) is an appealing approach to stabilise disease progression.
`Recent pre-clinical and clinical trial results of exon 51 skipping
`antisense oligomers (AOs) as a therapeutic option to treat boys
`affected by DMD with deletions bordering exon 51, have fulfilled
`proof of principle suggesting that ultimately this approach could
`target >80% of DMD patients [I]. However, to achieve this aim, at
`least 30 novel /\Os will be required. Current regulations stipulate
`that each novel AO is classed as an individual medicinal product
`and thus each AO must undergo rigorous safety and efficacy stud(cid:173)
`ies prior to clinic,11 use or it must be justified why and how efficacy
`
`• TC'I. : +44 207 79052G0S: f,1x: +44 207 9052832.
`f- muil c,c/c/rcss: f.1m111to11i«Dich.ucl.,1e.uk
`
`0%0-8%6/$ - SC'l' front matter ~l 2010 Elsevier IJ.V. All rights reserved .
`doi: I0. I0I G/j .nmd.20 10.03.005
`
`and safety data can be extrapolated from one AO to another. Since
`DMD is a relatively rare disease, with only 100 new cases/year in
`the UI< from a range of different genetic mutations in the DMD
`gene, randomised controlled studies may not be feasible if most
`of the 30 candidate AOs have to be studied separately in such a
`small patient cohort. The aim of this workshop was thus to seek
`legislative guidance from both EMA and other regulatory represen(cid:173)
`tatives, to identify a rational strategy for developing a personalised
`AO therapeutic approach in a realistic time-frame for it to be of real
`benefit to DMD boys.
`
`2. The parent's perspective
`
`The first session opened with Elizabeth Vroom, a parent repre(cid:173)
`sentative for United Parent Project Muscular Dystrophy who pre(cid:173)
`sented the parent's and young individual's perspective of living
`with DMD. She showed videos of DMD boys aged between 4½ and
`19 to illustrate the clinical progression of the disease. These boys
`stated that what they want most in life is to be able to maintain
`the muscle function they have left, which demonstrates that the pa(cid:173)
`tients themselves see retardation of disease progression as a benefi(cid:173)
`cial outcome. She also highlighted the importance of including
`patients/carers in trial design, so as not to miss apparently minor
`non-clinical issues which are in fact of considerable burden to pa(cid:173)
`tients/carers. Her presentation is reproduced in part below:
`"15 years ago we came fo1ward to organise research meetings
`where we made it clear we were willing to shoulder responsibility
`and contribute towards advancing treatments and a cure. We
`asked for advice about how we might make a difference, for which
`the reply was to raise money for peer reviewed research and advo(cid:173)
`cate for government support. We achieved these aims in both Eur(cid:173)
`ope and the USA, contributing more than 40 million Euros. There
`are now a series of exon skipping clinical trials planned that pa(cid:173)
`tient group's support and we have helped develop new Duchenne
`patient registries. Parents and their families have enthusiastically
`embraced these trials and have come forward to work with clinical
`teams to test the new drugs. Today we again come as responsible,
`willing partners, asking you to understand what is at stake and
`hope to learn from you how we might expedite AOs as a potential
`therapy. Although there is great enthusiasm among the parent
`
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`356
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`F. Muntoni/Neuromuscular Disorders 20 (2010) 355-362
`
`community about these new possibilities we have the following
`concerns:
`
`tected. Could what we learn from the testing of one AO with a spe(cid:173)
`cific backbone be used for future AOs and reduce the potential risk,
`so that less pre-clinical work is required?
`What would be the benefits? It is important to consider care(cid:173)
`fully and clarify the definition of '13ENEFIT' in progressive debilitat(cid:173)
`ing conditions such as Duchenne. No further degeneration or
`steady state should be considered clinically relevant and as evi(cid:173)
`dence of benefit for DMD boys. Just slowing down the degeneration
`is already considered as benefici.il by the boys .incl their families."
`Eli zabeth concluded with an .inalogy: "In our country, .is in
`most European countries, we have speed limits on every ro.id
`and we consider this as very important for safety reasons. How(cid:173)
`ever, when somebody with a life-threatening illness is transported
`at high speed in an ambulance the outcome of the risk/benefit
`analysis is different and it is safer to drive faster. Similarly Duch(cid:173)
`enne is a life-threatening situation. Boys with Duchenne bear sig(cid:173)
`nificant risk, indeed to life itself. We recognize that your concern
`is about safety, protecting the patient. We ask that you consider
`the 'emergency' of Duchenne. We are not asking agencies to put
`safety aside, simply to understand the 'emergency', to help design
`a regulatory approach that fits the circumstances and to find the
`right process in order to rescue the patient(s) in the most efficient
`way possible."
`
`3. Clinical overview of DMD and exon skipping
`
`3.1. General overview: Wlrat is DMD, its natural history and standards
`of care available?
`
`(i) Living with such a progressive disorder is a race against the
`clock. We as parents are very worried that regulatory and
`administrative procedures are time consuming. For our sons'
`every year, month, day counts and we want to avoid wasting
`time.
`(ii) Families can see progress with one target exon, but are ask(cid:173)
`ing if drugs tailored to meet the other boys needs will be
`developed and if so when? We fear that pharmaceutical
`companies will be unable to fund expensive and repetitive
`animal testing over many months for new drugs before they
`can even begin clinical testing. Then, will the companies be
`obliged to repeat the same series of clinical trials for every
`possible gene variation, once the basic chemistry has been
`studied? Even the most prevalent group of genetic types that
`can be treated by a single AO, the ones to skip exon 51,
`consists of only a small subset of the Duchenne boys. All
`other AOs treat even smaller subsets, yet companies are
`eager to develop these treatments with the encouragement
`of patient advocacy groups. This, under the existing regula(cid:173)
`tions, each new AO might need to undergo several years
`and many millions of Euros in animal testing and then sev(cid:173)
`eral more years and tens of millions of Euros in clinical test(cid:173)
`ing. Even for the exons at the bottom half of the priority list,
`it will be difficult to find enough boys to fulfil all the regula(cid:173)
`tory obligations. What about the boys who need two differ(cid:173)
`ent AOs because 2 exons need to be skipped? Can the
`current regulatory requirements for assessing benefit/risk
`balance for new chemical entities, provide a framework to
`enable the timely assessment of AOs for the majority of
`patients?
`(iii) How can we make sure that boys of the full age range can
`profit from new medicines? We understand regulatory
`agencies as well as industry ,incl rese,1rchers consider walk(cid:173)
`ing tests as a good oulrnme me,1sure 10 show !he drug is
`effective in ambulant Iioys. But this should 1101 result in
`delay of developing prolornls for the other I,oys. The major(cid:173)
`ity of Duchenne palirnls ,ire 11011-amliulanl. They should not
`be the last ones to benefit from new clevelopmenls as they
`have less time left.
`(iv) The core mess,1ge of ,1ll l,1ws reg,rnling ,1pproval and lesling
`of new drugs and even more specific in children, ,ire
`focussed on "doing no h,mn", which we ,is parents embrace.
`No p.irent wants his child to suffer or die clue to the testing
`or use of new medicines. However in this disease, we as par(cid:173)
`ents worry that the strict regulatory issues may have lhe
`opposite effect and harm rather than protect the boys, since
`doing nothing is a fatal risk. When the letter of the law is
`appli ed instead of the concept of the law, our sons are in
`danger. Together we need to determine ways to streamline
`the process so that potential therapies are not delayed, while
`our sons lose function and die. Again, we are not desperate
`parents who want to take every possible risk, but we can't
`accept that regulatory systems do harm to our children. It
`is unacceptable when potential treatments are available,
`but have to sit on the shelf because of regulatory issues!!
`We are very happy to have the opportunity today to discuss
`with you the risk/benefit analysis for these boys and how
`this could be implemented in the next steps of development
`in the nearby future.
`
`The next session was opened by I<ate Bushby who outlined the
`clinical spectrum of patients with mutations in the DMD gene, its
`natural history and summarised the currently available treatment.
`DMD is one of the most common fatal genetic disorders to affect
`children on a global basis. Approximately one in every 3500 boys
`born worldwide is afflicted with DMD, with a global prevalence
`of ¼ million. Due to prenatal diagnostic screening in known fami(cid:173)
`lies the incidence is stable. However, at least one in three cases is
`due to a de novo mutation, so even if screening operates at maxi(cid:173)
`mum efficiency, new patients will still be born with high incidence.
`The social and emotional costs and burden of this disease are one
`of the highest for a childhood onset di sease for patients and their
`families . The economic costs have been estimated in an Australi,1n
`Access Economics report to be r257 million per year (2007 figures)
`for health care, or 05,000 per affected person, and the value of lost
`well being (disability and premature cle,1lh) estimated to cost a fur(cid:173)
`ther fGOO million annu;illy.
`The condition is life-limiting ;incl without supportive ventilation
`and cardiac therapies de.1th ocrnrs hy the early twenties. Interna(cid:173)
`tional guidelines for c.ire have recently been generated 12]. Life
`threatening complications of DMD include a decline in respir,1tory
`function and a progressive cardiomyopathy. Since these are
`predictable, they can be proactively treated. Steroid s in conjunc(cid:173)
`tion with physiotherapy can prolong ambul,1tion, preserve respira(cid:173)
`tory strength. cardiac protection and are offered when physical
`performance has reached a plateau. I lowever, steroids may have
`significant side effects; notably weight gain, height restriction
`and osteoporosis to name but a few. With such interventions it is
`possible to extend the life of m,1ny affected inclivicluals by at le.1st
`another decade. Despite this treatment p,ir,icligm, none of the cur(cid:173)
`rently recommended interventions for DMD h,1s ,111y effect on the
`underlying disease process and though they are cn;ci,11 to the p,1-
`tient and family, in essence most c,111 he regarded as p,11Ii,1tive. No(cid:173)
`vel therapeutic interventions are badly neeclecl for DMD p,llienls
`So what are the current risks? So far, widespread testing of the
`AOs in both normal and dystrophic animals, as well as in patients
`and that AO technology is currently ,1 vi,1ble ,1ppro,1ch 10 meet this
`suggests AOs are well tolerated with no adverse consequences de-
`aim.
`Th is m ater ia I w as copi.ed
`at the NLM and ma y :b-e
`:.ubject US Cacpcyright Law s
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`3.2. Outcome measures for the c/i11ical trials in DMD
`
`f. M1111roni/Nr11ro11111srn/ar Disorders 20 (2010) 355-362
`
`357
`
`pected that earlier treatment should conserve muscle mass and
`lead to an improved prognosis. As Francesco Muntoni reiterated,
`neonatal screening does not currently occur because there were
`no early treatment interventions available. However, such screen(cid:173)
`ing would be feasible and has been piloted in individual regions by
`studying serum creatine kinase, an inexpensive and effective test.
`If permission were granted for AO trials in neonates, then appropri(cid:173)
`ate OMs would be developed to take into account the higher per(cid:173)
`centage of functional muscle present. However, it will also be
`important to acquire information related to the natural history of
`the condition in this age group, something that has not been well
`described in the literature yet quite simply because most diagnoses
`are made very much later.
`
`3.3. The specific issues of personalised medicine in DMD
`
`Julaine florence presented an overview of outcome measures
`(OM) currently used in ambulant and non-ambulant DMD boys.
`Examples of OM for ambulatory DMD boys, which give high
`test-retest correlations, include the 6 min walk test (GMWf),
`timed functional tests ( 10 m walk/run, stair climb, stair descend
`and supine to stand, along with grading the quality of the perfor(cid:173)
`mance of these timed tests), muscle strength testing of shoulder
`abduction, elbow flexion and extension and knee flexion and
`extension with hand-held myometry, and StepWatch™ activity
`monitoring [3]. Intra-class correlation coefficient (ICC) for the
`GMwr was 0.91 [4,5 ]. The ICC values for the timed functional tests
`ranged from 0.74 to 0.93 [5,6] while myometry values ranged form
`0.74 to 0.91 [5].
`In regards to OM in non-ambulatory individuals a variety of
`tests await validation by regulators. These include a variety of
`Annemieke Aartsma-Rus described the genetics underlying
`functional scales measures of Qualify of Life (QoL), care-giver sur-
`DMD, the cellular function of dystrophin, the mechanics of exon
`veys, assessment of muscle strength with hand-held myometry or
`skipping and introduced AOs as a therapeutic strategy to treat
`fixed quantitative system [7] active and/or passive range of mo-
`DMD boys. DMD is caused by mutations in the DMD gene which
`tion, pulmonary function testing, and assessment of upper limb
`disrupt the open reading frame, completely abolishing the produc-
`and hand function looking at grip and pinch strength, nine hole
`tion of a functional muscle protein called dystrophin. Dystrophin
`peg and Jebsen timed tests [8,9]. In addition, studies are underway
`to validate outcome measures, previously shown reliable [7, 10] in
`cross-links the extracellular connective tissue to the internal cyto-
`plasmic actin filament network, via a collection of protein com-
`both ambulatory and non-ambulatory DMD to see if they are
`plexes at the sarcolemma. Its repeating spectrin-like structure
`appropriate proxy for survival.
`confers both elastic and rod-like features, which allow it to act as
`The EMA have previously recommended the use of QoL and
`a 'molecular shock-absorber' protecting the muscle cells from
`Care Giver Burden (CBG) scales in clinical trials of neuromuscular
`forces imposed during continual muscle contraction-relaxation
`disorders. There is only one muscle disease-specific QoL measure,
`forces. Loss of dystrophin, as seen in DMD, breaks this link and
`the PedsQL Neuromuscular Module (PedsQL NMM) which used to-
`the muscle cell is severely weakened. There is also secondary loss
`gether with the generic PedsQL Core thus combining the benefits of
`of other sarcolemma proteins. Without functional dystrophin-pro-
`a generic and a disease-specific QoL outcome measure [ 11 ]. The
`tein complexes, muscle fibres cannot withstand the continual
`relationships between QoL and disease severity show wide varia-
`forces imposed upon them during contraction and become cumu-
`tion and how QoL might change in a trial is not necessarily intui-
`latively damaged during normal exercise. Eventually, this results in
`tive. The PedsQL NMM and the Core have had limited use in
`the death of muscle fibres and replacement by connective and
`DMD, but its use is now being actively encouraged so that its use-
`adipose tissues, resulting in loss of muscle function. In-frame
`fulness can be documented. There is no CGB outcome measure that
`DMD mutations, generally deletions of single or multiple exons,
`has been devised for use in children with neuromuscular disease.
`Guidance is requested from the EMA as to their reasons for wishing
`clinically leads to the less severe BMD, where an internally short-
`ened dystrophin molecule is generated. Thus, protein-protein
`to include this as an OM.
`interactions at its termini are retained and so the structural
`Since newborn screening for DMD is currently not generally
`cross-link is maintained, allowing the shortened protein to func-
`available and DMD patients are clinically asymptomatic in the first
`several years with diagnosis in the majority delayed until the age
`tion, albeit with less strength. BMD is diagnosed in adolescence
`or adulthood, and the overall progression of the disease is slower.
`of 4 or 5 years, no great emphasis for the development of OM in
`the first years of life has yet been established.
`The majority of BMD patients do not become wheelchair depen-
`dent until 10-15 years after diagnosis, although some remain
`Various points were raised by the regulatory authorities on the
`ambulant until late in life. Importantly, BMD patients have a
`way ahead for developing more meaningful OM and also on youn-
`ger boys. One topic was how important are the changes in OM
`near-normal life expectancy. Therefore exon skipping to convert
`the severe DMD disease into a condition analogous to the substan-
`measured as the child ages and how does this translate into every
`tially milder BMD, it is an appealing approach to stabilise disease
`day life. The audience was reminded that in the context of a pro-
`progression.
`gressive condition such as DMD, 'no change over age' would qualify
`skipping modulates pre-mRNA
`Antisense-mediated exon
`as 'beneficial', since it implies no further deterioration. It was gen-
`splicing of DMD transcripts in such a way that the out-of-frame
`erally agreed that being able to stabilise the disease with AO ther-
`mutation is converted into its in-frame counterpart through the
`apy would be a significant advancement and should be considered
`skipping of one or more exons. The result is to convert the mRNA
`an achievable goal. Suggestions were made for additional OM to be
`unable to encode for dystrophin to one that produces an internally
`considered as this field develops, such as assessing the number of
`shortened form. Specific targeting by AOs can be used to skip most
`myofibres with functional dystrophin that translates to improve-
`of the 79 exons in the DMD gene, restoring the open reading frame
`men ts in muscle strength, as well as OM which examine enhanced
`for many different mutations (see Fig. 1 for an example [12]) and
`cardiac output and lung vital capacity. Finally, it was suggested
`theoretically restore the reading frame in 83% of all DMD patients
`that a goal attainment scale of OM could be compiled as utilized
`[ 1 ]. A low level of spontaneous exon skipping is found in many
`with Alzheimer patients. For this to be operative goals need to be
`DMD patients, generating a low percentage of so-called "revertant"
`defined and adhered to. The patients themselves can take an active
`dystrophin positive fibres. Therefore, this AO protocol mimics a
`role in what these goals are since they are the best judges of what
`naturally occurring phenomenon. /n vitro testing of AO technology
`enriches their lives. Several members of the regulatory authorities
`on DMD patient-derived cell cultures, and animal models for DMD
`expressed concern about the lack of neonatal screening and thus
`have confirmed this is a viable approach to treat patients [ 12, 13 ].
`appropriate OM in the early years, since obviously it would be ex-
`Th is materia I was oop,ied
`at the NLM and may be
`5,uhj ect US Co,pyright Laws
`
`

`

`Reading frame restoration by exon 51 skipping
`AON
`
`lntron 48/lntron 50
`
`"
`
`..
`! Exon 51 skipped ~ Open reading frame restored
`..
`
`lntron 52
`
`;.-
`
`mutation 'hotspot' located between exons 43 and 55 [ 14 ). Close
`to 20% of patients require clouble-exon skipping (notably exons
`51 and 45 which applies to 1.1% of patients) .:incl this procedure
`is effective in patient-derived cells and animal models [ 12, 13].
`It is understood by TREAT-NMD partners that current trial de(cid:173)
`sign for an RCT for one medicinal product in the ambulato1y
`DMD population using current OM would require recruitment of
`around 150 patients to trial one drug, in which case there would
`be only enough patients registered in the TREAT-NMD global reg(cid:173)
`istry who are suitable to perform clinical trials for the top 4 exons
`in Table 1. Even these are geographically dispersed .:ind of course
`not all patients are able or willing to participate in trials. The
`EMA representatives were thus asked whether smaller numbers
`of patients could be used to perform subsequent AO clinical trials.
`During the general discussion the regulatory authorities cor(cid:173)
`rected the widely held belief that each of these medicinal products
`would require a full development .:incl that a minimum of 150 pa(cid:173)
`tients would always be required to perform a clinical trial. There is
`a guideline available on clinical trials involving small populations
`and the EMA would be willing and strongly recommended to be
`engaged in further discussion for DMD clinical trials before they
`take place whether or not there are adequate patient numbers. This
`would mean seeking scientific advice at the EMA as early as possi(cid:173)
`ble. The FDA representative upheld this by making examples of
`randomised studies in USA performed on much smaller patient
`databases.
`
`4. Clinical applications of antisense oligonucleotides
`
`Art Levin presented a comprehensive study of the history of the
`development of AO technology, its efficacy in several medical sys(cid:173)
`tems, toxicology issues and proposed pathways for taking AO into
`the clinical setting to treat DMD boys. AO therapy has been in clin(cid:173)
`ical t