A mini-review and implementation model for using ataluren to treat nonsense mutation Duchenne muscular dystrophy

Acta Pædiatrica ISSN 0803-5253 MINI REVIEW A mini-review and implementation model for using ataluren to treat nonsense mutation Duchenne muscular dystrophy Erik Landfeldt (erik.landfeldt@ki.se) 1,2, Thomas Sejersen 3,Mar Tulinius 4 1.Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 2.ICON plc, Stockholm, Sweden 3.The Department of Women s and Children s Health, Paediatric Neurology, Karolinska University Hospital, Astrid Lindgren Children s Hospital, Karolinska Institutet, Stockholm, Sweden 4.Department of Pediatrics, Queen Silvia Children s Hospital, University of Gothenburg, Gothenburg, Sweden Keywords Ataluren, Duchenne muscular dystrophy, Implementation model, Sweden, Treatment guidelines Correspondence E Landfeldt, PhD, Institute of Environmental Medicine, Karolinska Institutet, Nobels v ag 13, SE-17177 Stockholm, Sweden. Tel: +46 (0)70 37 95 280 Fax: +46 (0)8 33 69 81 Email: erik.landfeldt@ki.se Received 18 May 2018; revised 18 July 2018; accepted 4 September 2018. DOI:10.1111/apa.14568 ABSTRACT Aim: Ataluren has been approved for treating nonsense mutation Duchenne muscular dystrophy (nmdmd), and there are currently discussions concerning drug access and applications beyond the development programme. This study provides an overview of nmdmd and ataluren, stipulates clinical rules for treatment initiation and discontinuation and proposes a model for the implementation of orphan drugs in clinical practice in Sweden. Methods: This was a targeted mini-review of the literature from 1995 to 2018, which included cohort studies, guidelines, randomised clinical trials, clinical commentaries and reviews. The review covered the pathophysiology, epidemiology and burden of nmdmd and the clinical programme for ataluren. Results: Based on the current evidence, and our experiences, we recommend that patients with nmdmd should be given ataluren as soon as possible after diagnosis and this treatment should continue until they reach a forced vital capacity of <30%, and, or, a score of at least six on the Brooke upper extremity scale. We propose an implementation model that comprises a coordinating specialist physician and a national expert committee responsible for providing clinical intelligence to ensure appropriate use. Conclusion: Our clinical recommendations and proposed implementation model will inform the optimum medical management of nmdmd in Sweden and help ensure timely, equal access to ataluren and similar orphan drugs. BACKGROUND Duchenne muscular dystrophy (DMD) is a rare, X-linked recessive neuromuscular disease, which is severely disabling and ultimately fatal (1). The condition is named after Guillaume Benjamin Amand Duchenne (1806 1875), a French neurologist who established its basic clinical and pathological features (2). DMD is characterised by progressive muscle weakness caused by mutations in the gene that produces dystrophin, a cell membrane protein required to maintain muscle integrity. Deficiency or the complete absence of dystrophin causes plasma membrane leakage and muscle fibre degeneration, leading to progressive skeletal muscle weakening. Dystrophin is also deficient in cardiac and smooth muscles and in the central nervous system, resulting in cardiomyopathy and the increased incidence of bowel dysmotility, urinary bladder dysfunction, Abbreviations DMD, Duchenne muscular dystrophy; nmdmd, Nonsense mutation Duchenne muscular dystrophy. cognitive impairment, neuropsychological problems and neurobehavioural abnormalities (3). Approximately 10 15% of DMD cases are caused by a nonsense mutation in the dystrophin gene (nmdmd) (4), which is characterised by the presence of a premature stop codon in the messenger ribonucleic acid. This results in the translation of a truncated, non-functional protein. The natural history and health burden of nmdmd are thought to be similar to Key notes Ataluren has been approved for the treatment of nonsense mutation Duchenne muscular dystrophy (nmdmd). Following this mini literature review, we propose clinical recommendations for the initiation and discontinuation of ataluren for the treatment of nmdmd in Sweden. We also propose a model for the implementation of similar orphan drugs in clinical practice in Sweden. 224 2018 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2019 108, pp. 224 230

DMD from other causes, and this is relevant from a drug development perspective (5). THE MINI-REVIEW Ataluren has been approved for the treatment of nmdmd, and there are currently discussions concerning drug access and application beyond the development programme in many jurisdictions. This mini-review provides an overview of nmdmd and ataluren and stipulates clinical rules for the treatment initiation and discontinuation. It also proposes a model for the implementation of ataluren and other orphan drugs in clinical practice in Sweden. We carried out a targeted review of the literature concerning the pathophysiology, epidemiology and burden of nmdmd as well as the clinical programme for ataluren. This covered the period 1995 2018 and focused on papers published in English. It included randomised control trials, clinical commentaries and details of the legislation and regulations on the use of orphan drugs for diseases such as nmdmd. WHAT THE LITERATURE TELLS US Patients with DMD are diagnosed around the age of five years, but many boys show symptoms earlier due to proximal muscle weakness resulting in delayed physical milestones, for example walking, running and climbing stairs, a waddling gait and the use of Gowers manoeuvre when rising from the floor. Suspicions of DMD are further emphasised if there are also signs of speech delay or other problems with regard to cognition, behaviour and autism. Creatine kinase concentrations are markedly increased in patients with DMD, and the pathway to diagnosis typically starts with testing for these levels in blood. Since approximately 70% of individuals with DMD have a deletion or duplication of one or more exons of the dystrophin gene, initial molecular diagnostic analyses are usually aimed at finding such changes. If deletion duplication testing is negative, genetic sequencing should be performed to identify smaller mutations, including nonsense mutations, which account for approximately 25 30% of mutations in DMD (6). If genetic testing does not confirm the diagnosis, a muscle biopsy is recommended to detect the presence of dystrophin protein (7). The only medical therapy that is currently shown to be beneficial to all subtypes of DMD is corticosteroids (8). As the disease progresses, the patient s functional ability diminishes rapidly and children who are affected become non-ambulatory, usually in their early teens. However, the disease affects patients differently and recent research on the natural history of DMD has revealed significant heterogeneity with respect to progression as measured using the six-minute walk test, the most commonly employed measure to assess the efficacy of new treatments for DMD in randomised clinical trials. Specifically, a latent class analysis published in 2016 (9) showed that the mean change in the six-minute walk test results ranged from a decline of 117 m to an increase of almost 100 m per year when accounting for differences in age, baseline six-minute walk test results and corticosteroid use. In turn, these differences resulted in a mean adjusted difference in the observed age at loss of ambulation of more than five years. Despite these noteworthy variations, all patients lose their ability to walk independently during the second decade of their life. From a clinical point of view, loss of independent ambulation represents a critical disease milestone in DMD due to the relationship between loss of lower limb function, risk of scoliosis, upper limb muscle deterioration and the need for ventilation support for survival (10 14). In this sense, losing the ability to walk independently often marks the starting point of a more aggressive disease trajectory towards a life of complete dependency and an inevitable premature death. Moreover, delaying loss of ambulation is also of substantial importance to the individual patient as it enables patients to lead a close-to-normal life for as long as possible. This includes participating in social and sporting activities with their peers, spending more time with their family and friends, continuing their education and being able to live independently on a daily basis. From the patients perspective, preserving functional ability and maintaining independent ambulation during adolescence, a critical time for the development of selfidentity and self-confidence, would also be expected to be associated with long-term benefits in terms of general wellbeing and mental health. In the later, non-ambulatory stages of the disease, upper limb function deteriorates progressively and patients eventually need assistance to carry out the most basic activities of daily life, including feeding, dressing and toileting. Due to the involvement of the respiratory muscles, patients with DMD also rely on ventilatory assistance for survival from a mean age of about 23 years (15). In fact, in the natural history of DMD, the percentage of predicted forced vital capacity follows a near linear decline starting at around 10 years of age and eventually reaches a floor level of approximately 20% at more than 20 years of age (16). In addition, many patients also have some degree of mental impairment and learning difficulties, as well as mental health comorbidities, including autism-spectrum disorder and obsessive-compulsive disorder (3,17). If DMD is left untreated, the mean age at death is around 19 years, but the introduction of corticosteroid therapy, proactive cardiac management and nocturnal ventilatory support has prolonged life expectancy into the third and sometimes fourth decade of life (18,19). Respiratory failure and cardiomyopathy are the most common causes of death. EPIDEMIOLOGY OF DMD Data on the incidence and prevalence of DMD are scarce and vary across studies, depending on diagnostic criteria. Based on observations from newborn screening programmes that only included definite cases, the incidence of DMD has been estimated at between one in 3802 and 2018 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2019 108, pp. 224 230 225

6291 live male births (20) and the point prevalence has been estimated at 8.29 (95% confidence interval 6.90 9.88) per 100 000 male individuals (21). In Sweden, approximately 10 boys are diagnosed each year and the prevalence in children of <16 years old has been estimated at 16.80 (11.40 23.80) per 100 000 males (22). At the time of writing, there were approximately 250 patients in Sweden with nmdmd and approximately 170 were below the age of 18 years. STANDARD OF CARE OF DMD Duchenne muscular dystrophy is associated with extensive morbidity that necessitates a multidisciplinary approach to manage the disease. International clinical care guidelines were published in 2010 and updated in 2018 (7). They provide integrated treatment recommendations for both preventive and active interventions to address the manifestations and complications throughout the lifetime of the disease. In summary, optimum care encompasses regular visits to neuromuscular, cardiac and respiratory specialists, physiotherapy and routine monitoring of motor, cardiac and respiratory function. Patients with DMD also depend on medical devices and aids, such as orthoses and wheelchairs to manage the loss of muscle strength and function and thereby maintain independence for as long as possible. In addition, a significant proportion of patients with DMD need care from orthopaedists and speech and language therapists and, in many cases, psychologists. Corticosteroids, for example prednisolone and deflazacort, have been shown to slow the rate of deterioration of muscle strength in patients with DMD but do not correct the underlying cause of the disease (8) and were until recently the only pharmacological treatment option. Thus, in common with many neglected orphan diseases, the unmet medical need in DMD has been, and still is, substantial. However, several new therapeutic strategies have been developed in animal models and some of these interventions are now being used in clinical practice. Examples of treatment approaches currently under investigation include exon skipping, mutation suppression, utrophin upregulation, myostatin inhibition and insulin growth factors (23,24). In addition, several molecules that aim to restore dystrophin protein production have been explored. In 2014, ataluren, a first-in-class drug for patients with nmdmd, was granted conditional marketing authorisation by the European Commission for use in the European Union. ATALUREN FOR THE TREATMENT OF NMDMD Ataluren is an orally administered, small molecule compound (PTC Therapeutics, South Plainfield, NJ, USA) that promotes read-through of a nonsense mutation to produce full-length functional dystrophin protein. It thereby addresses the underlying cause of nmdmd (25 28). Specifically, the treatment interacts with the ribosome, which is the component of the cell that decodes messenger ribonucleic acid and manufactures proteins, to enable the ribosome to read through premature nonsense stop signals on messenger ribonucleic acid. This allows the cell to produce a full-length functional protein, although at lower than normal levels (26,27,29). Ataluren has been designated as an orphan drug by the European Medicines Agency and the US Food and Drug Administration. It has been approved for the treatment of ambulatory patients with nmdmd aged five years and older within the European Union Member States, Iceland, Liechtenstein, Norway, Israel and South Korea. However, the FDA refused approval for its use in this patient group in late 2017, stating that more research was needed. The efficacy and safety of ataluren for the treatment of nmdmd were evaluated in a comprehensive clinical programme comprising one phase IIA, one phase IIB, and one phase III trial involving 442 patients from 18 countries (27,28,30). In summary, randomised clinical trials have shown that, compared with current standards of care, ataluren is generally well-tolerated, improves dystrophin expression in the skeletal muscle and reduces the rate of muscle degeneration as measured using the six-minute walk test. In ambulatory patients, this is a baseline six-minute walk test distance of 300 m or more and less than 400 m across 48 weeks. Despite positive trends, the statistically significant benefits of the treatment have not been demonstrated in other patient subgroups, probably due to a lack of sensitivity of the outcome measures in those individuals (9) or a lack of study follow-up. However, additional studies are needed and PTC Therapeutics is currently carrying out a phase III randomised, double-blind placebo-controlled efficacy and safety study to confirm these findings (ClinicalTrials.gov identifier NCT03179631). In addition, the preliminary results are now available from an open-label phase III safety study sponsored by PTC Therapeutics and carried out at multiple sites in Europe, Israel, Canada and Australia (ClinicalTrials.gov identifier NCT01557400). These show that ataluren was associated with significant and clinically relevant reductions in the decline of pulmonary function, which are anticipated to delay the need for ventilation support and also potentially improve the prognosis for survival. Ataluren is available as 125, 250 and 1000 mg sachets of granules for oral suspension. The recommended dose is 10 mg/kg body weight in the morning, 10 mg/kg body weight at midday and 20 mg/kg body weight in the evening. This provides a total daily dose of 40 mg/kg body weight. IMPLEMENTATION OF ATALUREN IN CLINICAL PRACTICE IN SWEDEN The implementation of ataluren for the treatment of nmdmd in Sweden dates back to 2008. Two tertiary centres in Sweden took part in the clinical trial programme, including the pivotal phase IIb trial and the subsequent phase III trial. These were the Queen Silvia Children s Hospital at Sahlgrenska University Hospital in Gothenburg and the Astrid Lindgren Children s Hospital at Karolinska 226 2018 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2019 108, pp. 224 230

University Hospital in Stockholm. This means that ataluren has been used to treat nmdmd in Sweden for more than a decade covering more than 140 patient years. At the moment, there are no universal guidelines for the treatment of nmdmd with ataluren beyond the designated indications described in the marketing authorisation. Instead, different countries and, or, centres employ different criteria for treatment initiation, monitoring and termination and the rules governing these treatment algorithms are based on clinical data, as well as health economic evidence on estimated cost-effectiveness. For example, in the UK, patients will receive funding for ataluren for nmdmd until loss of independent ambulation (5). In contrast, a number of other countries within and outside the European Union initiate treatment both in boys of less than five years of age and also in older, non-ambulatory patients. In Sweden, to date, the medical management of nmdmd with ataluren has been dictated by the clinical trial protocols. However, as patients have started to transfer from clinical trials to healthcare settings, there is an urgent clinical need to define appropriate points when treatment should be started and stopped. CLINICAL RECOMMENDATIONS FOR THE TREATMENT OF NMDMD USING ATALUREN Based on the available clinical evidence and international experience, we propose that the treatment of nmdmd with ataluren should be initiated as early as possible after a confirmed diagnosis of nmdmd, usually between the ages of three and five years. This will maximise the potential to reduce muscle degeneration. This recommendation is in line with the approval of the Committee for Medicinal Products for Human Use of the European Medicines Agency in May 2018 to expand the indications for ataluren to include ambulatory children aged two to five years with nmdmd. Moreover, based on the available data, which suggests that ataluren would be expected to have a nontrivial, positive benefit on upper extremity and pulmonary functioning in patients with advanced disease (31), we propose that treatment with ataluren should continue until the patient has reached one of the following clinical milestones. These are a forced vital capacity below 30%, and, or, grade six on the Brooke upper extremity scale, for example if they cannot raise their hands to their mouth and their hands have no useful function. Beyond these milestones, the therapeutic effect of ataluren would be expected to be low as pulmonary function approaches the floor level of a predicted forced vital capacity of approximately 20% (16). Despite this, (7) we recommend that test outcomes other than the percentage of predicted forced vital capacity are used to appropriately define patients pulmonary functions and inform treatment decisions. With respect to drug management, all patients with nmdmd in Sweden are monitored directly or indirectly via specialised rare disease centres involving a multidisciplinary team of healthcare practitioners, typically coordinated by a neuromuscular specialist physician. In accordance with the international clinical care guidelines (7), care is organised to ensure that patients are evaluated by relevant expertise every three to 12 months depending on the disease stage. Treatment with ataluren requires some additional clinical tests, such as triglycerides, cholesterol and resting blood pressure, as well as renal functioning, blood urea nitrogen and serum creatinine, cystatin C monitoring. However, these are usually covered within the routine patient follow-up. COST-EFFECTIVENESS OF ATALUREN FOR THE TREATMENT OF NMDMD In most settings, resources are scarce and it is therefore important to make the best use of the money spent on health and health care. To this end, new pharmaceuticals, including orphan drugs, need to demonstrate evidence of cost-effectiveness. Indeed, a literature review (32) of orphan drug legislation, regulations and policies published in 2015 found that in 29 of the 35 countries examined, the health technology assessment of orphan drugs included evidence on cost-effectiveness from economic evaluations. However, the costs of orphan drugs are usually very high, frequently exceeding 100 000 per patient per year, and it takes years to recoup research and development costs from small patient populations. This means that these medicines are not typically found to be cost-effective. In addition, evidence of the efficacy for the treatment of rare diseases is often derived from small groups of patients and thus associated with greater uncertainty compared with data from trials of interventions for common illnesses. Therefore, a range of other factors also need to be taken into consideration in the health technology assessments of orphan drugs, including therapeutic value, budget impact, impact on clinical practice, global pricing and reimbursement practices, patient organisations, economic importance, ethical arguments and the political climate. In Sweden, for example, reimbursement decisions for all drugs are based on an ethical platform that comprises three main principles. These are the human dignity principle, where all individuals have equal value and rights, the needs solidarity principle, which dictates that resources should be allocated and used where the need is largest, and the cost-effectiveness principle. Thus, although harmonised legislation for drug development and marketing authorisation exists in the European Union, decisions regarding pricing and reimbursement are made at national levels. As a consequence, policies governing whether patients are reimbursed for the cost of orphan drugs differ substantially between health systems, creating inequality in access to, and the use of, orphan drugs between the citizens of different countries. For example, in 2009, Swedish patients were only reimbursed for 69% of all marketed orphan drugs, compared with 100% of patients in France (33). The cost-effectiveness of ataluren has been evaluated in various settings, including the UK (5) and discussions concerning reimbursement in Sweden started in 2015. In general, and as expected, ataluren does not adhere to 2018 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2019 108, pp. 224 230 227

conventional cost-effectiveness thresholds, due to the specific challenges noted above concerning uncertainty due to small patient populations and commercial returns. However, there are a couple of additional specific challenges with evaluating the cost-effectiveness of a treatment for a terminal disease such as nmdmd that warrant further discussion. Firstly, nmdmd is a disease that has been associated with extensive care requirements throughout the entire disease progression (34). For this reason, even substantial delays in progression would be expected to be associated with relatively modest cost reductions, particularly when combined with efficacy on mortality, as patients with the disease who are alive contribute with a considerable cost burden to society, especially in the more advanced stages of the disease (35). Despite the obvious clinical and humanistic value of prolonging life in patients with chronic progressive diseases with a high degree of morbidity, this may have a negative impact in terms of estimated costeffectiveness. Secondly, as nmdmd is an inherited, chronic disease, it has an extensive impact on families. In fact, nearly all patients with DMD receive most of their care at home, even in the more advanced stages of the disease (36). As a result, parents, siblings and other relatives are usually deeply involved in most aspects of the daily life of the patient, from providing emotional and social support to assisting them with daily life. This can include washing, dressing, toileting and helping them to get out of and into bed. It can also include helping them with formal health care, such as keeping track of appointments, following up on tests and assessments, filling prescriptions and accompanying them to appointments with physicians and other healthcare practitioners. Carers may face greater challenges looking after children rather than elderly relatives with diseases such as dementia or Parkinson s, as they normally live together and have no choice but to fully take on the caregiver role. The considerable involvement that family caregivers have in providing formal and informal care throughout the progression of DMD must be included in any economic evaluations of treatments for DMD, as well as the loss in caregiver quality of life. This is necessary if we are to accurately represent and appraise the total benefits of ataluren and avoid suboptimal policy decisions and the inefficient allocation of healthcare resources from a society perspective. A MODEL FOR THE IMPLEMENTATION OF AN ORPHAN DRUG IN SWEDEN We would like to propose an integrated set of recommendations for implementing an orphan drug such as ataluren, so that all of the regions in Sweden can have timely and equal access to existing and forthcoming health technologies that target life-threatening and severely debilitating rare diseases such as nmdmd. As a starting point, we suggest that specialised therapies, such as ataluren, should only be prescribed by healthcare practitioners with substantial neuromuscular experience and expertise. In addition, we feel that there needs to be a central source that provides clinical guidance and support and advice on the appropriate use of any treatment. We believe that a national expert committee should be established that comprises neuromuscular specialist physicians, covering both paediatric and adult care, together with physiotherapists and cardiac and respiratory specialists. The committee would be consulted for its expert opinion on specialised therapy prior to treatment with ataluren, as well as suggested criteria for the initiation of treatment with ataluren. Furthermore, the committee would be asked to evaluate each new patient put forward for treatment, as well as provided advice about when treatment should stop and how monitoring should be performed based on the existing indications. A good example of how this implementation model could work is the national committee on how to treat patients with spinal muscular atrophy with nusinersen. In addition, the committee would help collate clinical intelligence to negotiate reimbursement with the national reimbursement agencies. In Sweden, these are the Dental and Pharmaceutical Benefits Agency and the New Therapies Council, who are experts that advise Swedish county councils on questions Expert commi ee Define treatment start and stop criteria Diagnosis Planning of interven ons Ini a on of treatment Monitoring and recording of data Discon nua on of treatment Time Coordina ng physician Figure 1 Graphical representation of the proposed model for the implementation of an orphan drug in Sweden. 228 2018 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2019 108, pp. 224 230

about new drug therapies, to minimise regional variations and help inform value for money assessments on a case-bycase basis because of the rarity of the disease. A graphical representation of the proposed model is presented in Figure 1. CONCLUSION We believe that our clinical recommendations and proposed implementation model will inform the optimum medical management of nmdmd. One key aim is to ensure timely and equal access to ataluren and similar existing and forthcoming health technologies targeting life-threatening and debilitating rare diseases like nmdmd in Sweden. CONFLICT OF INTERESTS The authors have acted as consultants to PTC Therapeutics, which markets ataluren for the treatment of nmdmd. FINANCE PTC Therapeutics provided financial support for external medical writing, but had no role in any aspect of the review or paper. References 1. Emery AE. The muscular dystrophies. Lancet 2002; 359: 687 95. 2. Tyler KL. Origins and early descriptions of Duchenne muscular dystrophy. 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