29/10/2014 Orphan Drug Development in Muscular Dystrophy: Update on Two Large Clinical Trials of Dystrophin Rescue Therapies - Eric

P Hoffman - Discovery

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Eric P Hoffman
Orphan Drug Development in Muscular Dystrophy: Update on Two Large Clinical Trials of
Dystrophin Rescue Therapies
Published on November 8, 2013
Author: Eric P. Hoffman
Specialty: Genetics, Gene Therapy, Neurology
Institution: Center for Genetic Medicine Research, Childrens National Medical Center
Address: Washington, DC, United States
Institution: Department of Integrative Systems Biology, George Washington University School of Medicine
Address: Washington, DC, United States
Author: Edward M. Connor
Specialty: Pediatrics, Microbiology, Immunology
Institution: Office of Innovation Development, Children's National Medical Center
Address: Washington, DC, United States
Institution: George Washington University School of Medicine
Address: Washington, DC, United States
Abstract: Duchenne muscular dystrophy is a relatively common 'rare disorder,' with an incidence of about 1/5,000 males
worldwide. The responsible gene and deficient protein (dystrophin) were identified in 1987, an early success of human
molecular genetics and emerging genome projects. A rational approach to therapeutics is to replace dystrophin in patient
muscle, thus addressing the primary biochemical defect. Fast forward 25 years, and two phase 2b/3 trials have been carried
out with agents designed to induce de novo dystrophin production in DMD patient's muscle; ataluren (stop codon read
through) with 174 patients, and drisapersen (exon skipping) with 186 patients. Both used a six minute walk test as the primary
outcome measure. Neither drisapersen nor high dose ataluren showed any significant improvement in this outcome, whereas
low dose ataluren is reported to show some possible improvement. Experience with ataluren and drisapersen has been
disappointing and this is a good time to ask: What can we learn from these programs and how can this inform further drug
development in DMD? At the times these two trials were started, there was a lack of existing data and infrastructure regarding
both clinical and biochemical outcome measures. The recent publications of more extensive natural history data in multiple
DMD cohorts, and ongoing efforts to define reliable and sensitive dystrophin assays are important. If the drisapersen and
ataluren programs were instead begun today, new progress in biochemical and clinical endpoints may have triggered a redesign, with better de-risking in phase 2 studies prior to resource-intensive phase 3 trials.

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Introduction
Some oft-quoted numbers regarding the cost and time typically needed to bring a single drug to market are intimidating: $500 million and 15 years. For the
traditional block buster drugs, this cost is distributed among millions of prescriptions. For orphan drug development in rare disorders, distributing the cost is more
challenging, so the cost per prescription can rise dramatically. Since the 1980s, orphan drug legislation has focused on incentives that make it more attractive to
enter the orphan drug development space (Pariser et al., 2011). These programs have been effective, with nearly 200 new orphan drug designations in the U.S. each
of the last few years, and over 420 orphan drug approvals to date. The rapidly increasing interest in orphan drug development, increased numbers of orphan drugs on
the market, and the very high cost of some of these drugs, have led to increasing efforts to develop cost effectiveness thresholds. Some national health insurance
organizations have begun to refuse to cover expensive orphan drugs that show only marginal improvement in patient quality of life (Gosain, 2013; Kanters et al.,
2013; Herder, 2013; Simoens et al., 2013).
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Incentive programs have been very effective in increasing interest in orphan drug development. However, much of the cost of drug development is concentrated late
in the clinical programs, particularly in phase 3 trials. Phase 3 trials are resource-intensive, not only in terms of financial cost, but also in terms of human resources
(patients, their families, and medical professionals, etc.) involved in the trials. Research on approaches to reducing the cost of drug development has found that
reducing the time of development is important (Trusheim et al., 2007; 2011). In response, both legislative and regulatory bodies of governments in the U.S. and
elsewhere have recently turned toward expediting drug development through accelerated approval processes and breakthrough therapy designation, with the use of
biomarkers to better inform decision-making (Connor and Cure, 2011; Dunoyer et al., 2011; Picavet et al., 2012; Forman et al., 2012).
Accelerated approval is a long-standing regulatory process designed to shorten drug development time and allow patient access to drugs for serious diseases (e.g.,
HIV). With FDASIA in 2012, FDA may base accelerated approval of drugs for serious conditions on either a surrogate endpoint or an intermediate clinical endpoint
for which there is scientific support (FDA, 2013a). More recently, Breakthrough Therapy Designation has also been added to the regulatory toolkit to enable faster
drug development for serious diseases where preliminary evidence suggests that a drug is a substantial improvement compared to available therapy on a clinically
significant endpoint (FDA, 2013b). Traditionally, accelerated approval has not been utilized often in rare and orphan drug development. However, this has changed
and recently greater emphasis has been placed on these mechanisms. Fundamental to accelerated approval and breakthrough therapy designation is the scientific
support for the importance of pharmacodynamic laboratory markers and intermediate clinical endpoints.
Accelerated approvals are considered provisional, with required follow-on studies (often inclusive of prospective phase 3 trials) to more clearly demonstrate safety
and clinical efficacy, but these are carried out simultaneously with marketing and sale of the drug. By providing accelerated approval prior to resource-intensive
phase 3 trials, these new approaches should enable faster and less expensive orphan drug development. As more common disorders are increasingly genetically
stratified into smaller subgroups, even common disorders may find themselves in the orphan drug space.
Non-profit foundation venture philanthropy programs have emerged as movers and shakers in orphan drug development, as have recent government funding
programs, such as the NIH TRND program (McKew and Pilon, 2013). Increasingly, these support programs focus on de-risking steps methods to increase the
confidence that a drug is worth taking forward into more and more expensive next steps. De-risking steps can include independent validations of key in vitro
mechanism of action assays, toxicology testing, and pre-clinical efficacy trials, as well as bringing experienced teams of drug developers to the table to provide
expert advice and guidance (McKew and Pilon, 2013). Another important step in de-risking is the emerging guidelines for more robust pre-clinical efficacy trials
(Landis et al., 2012). These steps are likely to have a strongly beneficial impact on future drug development, including the faster cheaper goal.
With this backdrop, we discuss the recent experience of the only two phase 2b/3 trials carried out in Duchenne muscular dystrophy to date, both focused on de novo
production of the dystrophin protein in patient muscle.
Ataluren
All Duchenne muscular dystrophy patients show mutations in the DMD (dystrophin) gene, the largest gene identified in any organism (Koenig et al., 1987). A subset
of mutations that cause DMD are single base changes that alter a triplet codon to a premature stop codon (nonsense mutations). A small molecule screen was carried
out to identify small molecule drugs that would modulate the translational machinery (ribosomes) so that they would read through the stop codons. In response to the
drug, the ribosomes ignore the mutation and continue translating dystrophin (Welsh et al., 2007). Ataluren was then developed to increase dystrophin in DMD
patient muscle in those ~10% of patients having stop codon mutations, and is also being tested in subsets of cystic fibrosis patients with stop codons (Karem et al.,
2008; Sermet-Gaudelus et al., 2010).
Multiple clinical studies of ataluren in DMD have been carried out since 2005 (clinicaltrials.gov, NCT00592553). There have been no published findings of drug
effects on either dystrophin production in muscle, or clinical outcomes. In the phase 2b/3 trial of 174 patients, baseline and placebo data are published (McDonald et
al., 2013a; 2013b), but these do not speak to drug efficacy. Clinical data on the phase 2b/3 trial has been publicly reported, including in a recent press release
regarding European Medicines Agency (EMA) validation of a Marketing Authorization Application (MAA) seeking conditional approval for ataluren including a
prospective phase 3 trial. The 48 week phase 2b/3 trial had two dose arms of ataluren, where the low dose (three doses per day at morning, noon, evening at 10, 10,
20 mg/kg, respectively) showed a 31 meter improvement in the six minute walk primary outcome measure compared to placebo that was marginally statistically
significant. The high dose arm did not show any improvement in six minute walk. The prospective phase 3 trial is underway at the lower dose with 220 patients
planned for recruitment (clinicaltrials.gov, NCT01826487).
Muscle biopsies were taken as part of phase 2a and 2b trials. The dystrophin measurements in these biopsies have not been reported. Dystrophin assays typically
involve antibody studies, using either immunostaining (optical visualization of dystrophin on histological frozen sections), or immunoblotting. Interpretation of
immunostaining is complicated by the requirement for well-preserved flash frozen biopsies, and such high quality specimens can be challenging to obtain and
transport in the context of a multi-site clinical trial. Immunostaining signals are also challenging to quantitate. Immunoblotting is technically challenging for a large
(427 kDa) relatively low abundance protein, and can suffer from variability upon repeat measures (poor reliability) and poor sensitivity. Challenges in measuring
dystrophin have been suggested as a factor that led to the drug moving to phase 3 trials, rather than seeking accelerated approval based upon dystrophin expression
as a surrogate biomarker. There have also been persistent questions regarding whether or not ataluren has sufficient stop codon read through activity to rescue
biochemical defects (Auld et al., 2009; 2010; McElroy et al., 2013).
Drisapersen
An alternative approach to increase dystrophin production in patient muscle is through exon skipping (Hoffman et al., 2011). This approach develops anti-sense
oligonucleotide drugs that are able to bind specifically to the dystrophin RNA while it is being transcribed and processed (spliced). The drugs are designed to bind to
an exon neighboring a patients deletion mutation, thereby modulating the splicing of the RNA to exclude an additional exon. In this manner, an out-of-frame mRNA
transcript that is unable to make dystrophin protein is converted to an in-frame transcript now capable of dystrophin production.
The initial drug development for exon skipping was targeted toward exon 51 of the dystrophin gene, as this neighbored the largest proportion of deletion mutations
(about 13% of boys with DMD). Two chemistries were taken to clinical trials. The drisapersen drug was developed by a partnership between Prosensa and GSK, and
was constructed of 2-O-methyl phosphorothioate (2OMePS) chemistry. This chemistry had the advantage of extensive clinical experience in other drug
development programs in other disorders (over 2,000 patients having received drugs consisting of some form of 2OMePS or closely related chemistries). Prosensa
was also the early developer of the exon skipping approach in DMD (established in 2002). Multiple phase 2 trials were carried out, and these included muscle
biopsies with dystrophin production as the primary endpoint (van Deutekom et al., 2007; Goemens et al., 2011). While evidence of de novo dystrophin is presented,
the levels appeared low and variable. However, as noted above, the assays traditionally used to quantitate dystrophin are problematic. The six minute walk test was
used as a secondary outcome measure, and a subset of patients in phase 2 extension trials showed stabilization of the disease progression (Goemens et al., 2011; and
data presented at meetings). A phase 3 trial with the six minute walk test as the primary outcome measure was carried out with 186 patients, and preliminary data
was provided in press releases in September 2013. Drisapersen treatment did not show statistically significant improvements in the primary outcome measure of the
6 minute walk test. The implications of these results for exon 51 directed products or new 2OMePS compounds directed at other exons are actively being discussed.

The second chemistry for exon 51 in clinical trials is the morpholino chemistry (Fletcher et al., 2006; Alter et al., 2006). This
chemistry appears to have advantages of lower toxicity and thus a considerably broader therapeutic window (Hoffman et al., 2011; Sazani et al., 2011). However,
there is relatively little previous clinical experience with this chemistry, it is more expensive to produce, and the drug is quickly removed from circulation by the
kidney. Pre-clinical mouse and dog studies from multiple laboratories have shown robust dystrophin expression in muscle, and the extent of dystrophin expression is
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clearly dose dependent (Malerba et al., 2009; Yokota et al., 2009; Wu et al., 2010; Yokota et al., 2012). Two phase 2 studies have been published for an exon 51
drug (etiplersen) similar to the GSK/Prosensa drug, but with a different chemistry (Table 1). Both phase 2 trials of the etiplersen morpholino chemistry had de novo
dystrophin production in patient muscle as the primary outcome measure (Cirak et al., 2011; 2012; Mendell et al., 2013). The amount of drug-induced de novo
dystrophin in patient muscle was variable in both studies, but the amount of expression appeared more robust than with 2OMePS chemistry, particularly in the initial
study (Cirak et al., 2011). Sarepta Therapeutics has issued a press release (Sarepta Therapeutics Announces Plans to Submit New Drug Application to FDA for
Eteplirsen for the Treatment of Duchenne Muscular Dystrophy in First Half of 2014, Jul. 24, 2013) providing information on its approach and interactions with the
FDA. In this release, Sarepta stated that it intends to seek accelerated approval based upon phase 2b de novo dystrophin expression in DMD patient muscle, and also
said that the FDA requested additional information related to the methodology and verification of dystrophin quantification.
To our knowledge, this represents the first attempt of any drug development company to seek accelerated approval from regulatory authorities based upon surrogate
biomarker data in DMD, but an interpretation of the communication reported by Sarepta could be that the FDA is seeking data regarding the sensitivity and
reliability of the dystrophin assays utilized, the robustness of the de novo dystrophin production, and/or correlation to clinical outcomes.
Analysis and Next Steps
The goal of both the ataluren and drisapersen phase 2b/3 trials was to increase dystrophin protein in muscle, thereby targeting the primary biochemical defect. This
mechanism of action enables the opportunity to use dystrophin expression as a critical surrogate biomarker in drug development, including potentially in accelerated
approval. While early studies of exon skipping demonstrated dystrophin expression in treated patients, development has been hampered by the paucity of published
reliable assays and SOPs for quantitating dystrophin. Moreover, the tissue requirements for existing methods often require repeated open muscle biopsies of patients
in clinical trials. Another primary issue for these initial dystrophin-specific drug programs was the relatively poor state of the art in understanding the natural history
and variability of clinical outcomes used as endpoint in DMD trials. Given the results from late stage studies with ataluren and drisapersen, it is now all the more
important to assure that going forward we are able to optimize dosing to maximize dystrophin production, qualify methods for dystrophin quantitation, and optimize
clinical outcomes as they relate to dystrophin expression.
Measurement/quantification of dystrophin expression and assessment of intermediate clinical endpoints are important elements for optimizing drug development in
DMD though accelerated approval and breakthrough designation. However, it is also clear that assays to measure dystrophin need to be made more sensitive and
reliable, and that the amount of drug-induced dystrophin should be robust in order to build a compelling case. International efforts are underway to identify the most
sensitive and reliable dystrophin assay methods, and provide publicly accessible standard operating procedures (SOPs) for these assays. These efforts have been
supported by TREAT-NMD and foundations, and are a critical step towards both de-risking drug programs earlier in the process, and enabling accelerated approvals.
A recently published mass spec assay for dystrophin measurements in muscle biopsies using stable isotope labeled control proteins has shown promise both with
regards to sensitivity and reliability (R2=0.99) (Hathout et al., 2013). Testing this method against more traditional antibody based methods is currently underway.
Were the ataluren and drisapersen programs de-risked adequately prior to moving to resource intensive phase 2b/3 trials? One increasingly utilized form of derisking by both NIH TRND and foundations is independent validations of key in vitro and in vivo pre-clinical assays. Once adequately de-risked, new drugs with a
solid mechanism of action and clear toxicology profile are increasingly likely to be successful in attaining accelerated approval, either through demonstration of
compelling biomarker studies, or clear clinical improvement in blinded proof-of-concept trials. Late-stage failures are expensive not only in monetary terms, but
most importantly in terms of emotional costs to patients and families, and in patient and clinical resources. Going forward, the increased traffic in the orphan drug
space should make us all better drivers, through adequate independent validations, compelling biomarker and/or clinical signals in phase 2 studies, and optimizing
the potential for accelerated approvals.
It could be argued that a sensitive and reliable dystrophin assay could have helped de-risk both ataluren and drisapersen clinical programs, prior to the resourceintensive phase 3 studies. Demonstration of robust dystrophin expression in a phase 2 trial may have led to accelerated approval, thus decreasing the time and cost of
the drug development. Alternatively, a robust assay that failed to show robust dystrophin in a phase 2 trial might have led the developers back to the drawing table,
to better optimize dose regimens, chemistry, or both. That said, muscle biopsies only sample a very minute part of the patients entire musculoskeletal system, and it
is expected that there is wide variation due to sampling error. Indeed, in multiple muscles studied in exon skipping in the dog model, quite variable dystrophin
production was seen from muscle to muscle in the same treated dog (Yokota et al., 2009; 2011). Thus, even with improved reliability and sensitivity of dystrophin
assays, dystrophin assessments from small muscle biopsies will remain only a crude estimate of what is happening in the entire patient. Regulators are certain to
recognize the intrinsic limitation of the sampling error when considering muscle biopsy surrogate biomarker data.
Dystrophin is only a surrogate biomarker for drugs whose mechanism of action is to increase dystrophin levels in DMD patient muscle, through stop codon read
through, exon skipping, or gene therapy. Other drugs being developed for DMD have different mechanisms of action, and may not have the luxury of the type of preexisting surrogate biomarkers as an early read-out of drug effects. Developing strong scientific support for intermediate clinical endpoints will be important in many
clinical development programs for DMD. To date, interpretation of clinical endpoints has been challenging. The 30 meter improvement in the six minute talk test
with the low dose PTC124 drug in their phase 2b/3 was felt to be adequately compelling for accelerated approval for the EMA, but not the FDA.
The clinical endpoint used by all trials to date, six minute walk test, also deserves further discussion and search for possible alternatives. The six minute walk test
involves a relatively long trounce up and down hospital hallways, done by disabled children, many with limited attention spans. Most parents and clinical evaluators
volunteer that verbal encouragement of the child is a key part of the test, and all will acknowledge that the six minute walk test measures central effort and
coordination, in addition to muscle strength and function. The drisapersen experience may be instructive here. The phase 2 extension trial showed impressive
stabilization of disease progression in a subset of treated patients over a multiple year time span, using serial measures of the six minute walk as the primary outcome
measure. But this was an unblinded study with no control group. The same drug (drisapersen) with the same six minute walk outcome measure then failed to show a
statistically significant drug response after 48 weeks of treatment in the recently announced results of a blinded phase 3 trial. Could the impressive stabilization of
the six minute walk have been influenced by a training effect of the outcome measure? Comparison of the phase 2 and phase 3 data for drisapersen data would seem
to suggest this. This lesson teaches that interpretation of unblinded six minute walk data in small numbers of patients should be interpreted with caution. There are
more acute measures of muscle function, such as time to stand from the floor, and 10 meter walk/run velocity, that show outstanding correlation with six minute
walk data, are certainly similar related to quality of life, and would seem to have a bit less central involvement (e.g., a sprint instead of a marathon) (McDonald et
al., 2013a). It can also be argued that younger DMD patients earlier in the progressive disease process should be used for clinical trials, where less skeletal muscle
has been lost to muscle wasting and gross motor scales show particular promise (Connolly et al., 2013).
Disclosure
E.P.H. is co-founder and member of the Board of both ReveraGen Biopharma and Agada Biosciences. The author has received consultancies from Guidepoint
Global on the topic of this review. The author has been and is currently the principle investigator of federal grants aiding the development of morpholino chemistry
for exon skipping.
E.M.C. is CEO/CMO of ReveraGen Biopharma, is principle investigator of Department of Defense grants on development of morpholino chemistry with Sarepta,
and has provided advice/consultancy to Sarepta, Prosensa in particular, and other companies in the orphan drug space.
Corresponding Author
Eric P. Hoffman, Ph.D., Director, Center for Genetic Medicine Research, Childrens National Medical Center and Chairman, Department of Integrative Systems
Biology, George Washington University School of Medicine, Washington DC, USA.
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 16(89):233-239, November 2013. Copyright Discovery Medicine. All rights reserved.]
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