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July 2019 Progress in the Treatment of Muscular Dystrophies Progress in the Treatment of Muscular Dystrophies July 20191 ____________________________________________________________________________ With Vertex’s announcements last month that it is • expanding its collaboration with CRISPR Therapeutics on gene editing for Duchenne and myotonic dystrophy including an upfront payment of $175 million, and • acquiring all outstanding shares of Exonics Therapeutics, a gene editing company focused on Duchenne and other neuromuscular diseases for $245 million these rare diseases are getting the focused funding and attention from big pharma required to bring novel, effective treatments to the market (Genetic Engineering & Biotechnology News 2019). With a small patient population and a challenging breadth of disease types and underlying biological and genetic causes, the dystrophies have historically lacked attention from the biopharma industry as a value-driver for new drug development. New technical capabilities in gene therapy and gene editing, and seed funds from philanthropic organizations focused on de- risking early-stage drug development have changed the playing field. In this report, we provide an overview of the current state of funding, therapeutics in development and novel technical approaches towards treating this group of challenging diseases.2 Overview Muscular dystrophies are genetic disorders characterized by progressive muscle weakness and loss of muscle function. Duchenne and Becker muscular dystrophy (DMD & BMD) are the most prevalent forms with 300-600 affected male babies born in the US every year. Generally diagnosed when patients are between two to five years old, it is caused by absence or reduction of the muscle protein dystrophin. DMD is one of the most rapidly progressing dystrophies. Patients are typically wheelchair bound by 12 years old and die in the second to third decade of life. There is no cure for any of the dystrophies. Current standard of care is palliative and includes the use of steroids and ventilators. The cost to families and patients, and to the healthcare system for rare diseases like muscular dystrophy is significant. In 2016 the average annual cost per patient for treating orphan diseases was five times greater than other diseases, $140,000 compared to $27,750. DMD itself has a large economic impact. 1 Report by NelsenBiomedical.com; Primary Author: D’anna Nelson, PhD Candidate at the University of Minnesota. Contact: [email protected] 2 Companies included in this report are those with later stage clinical programs and are only a subset of the over 85 companies with a stated focus in muscular dystrophy therapeutics. Progress in the Treatment of Muscular Dystrophies ©2019 Nelsen Biomedical, LLC 1 In the US alone in 2012, DMD cost $1.21 billion including hospital stays, caregiver’s lost work, and lost productivity (Luxner 2018). While there are over 30 different types of muscular dystrophy, most can be classified into eight categories based on the specific muscle groups affected. Across categories, muscular dystrophies are very heterogeneous with differing age of onset, rates of disease progression, and incidence rates that vary by country and race (populations of European descent often have higher prevalence). In order of incidence these groups include: 1. Duchenne and Becker muscular dystrophy (DMD & BMD) is the most prevalent category. Global incidence rates of 4.78 and 1.53 per 100,000 males, respectively (Mah et al. 2014). The United States DMD/BMD diagnosis rate is roughly 15 out of every 100,000 males between the ages of 5-24 years (Emery 2002). 2. Myotonic muscular dystrophy is the second most prevalent affecting 11 out of 100,000 people [Northern England, (Norwood et al. 2009)]. 3. The remaining 6 categories—facioscapulohumeral (FSHD), limb-girdle (LGMD), congenital, distal, oculopharyngeal, and Emery-Dreifuss—cumulatively account for approximately another 11 out of 100,000 people [Northern England, (Norwood et al. 2009)]. Both young biotechnology companies and large players such as Roche and Pfizer are using a variety of approaches to develop therapeutics for these diseases. Progress is being made. However, finding a cure, even within a subset of dystrophies such as DMD, may be years into the future. Current activity is focused on targeting the most prevalent mutation types and therefore the larger patient populations. Clinical Trials There are limited numbers of new treatments in development for muscular dystrophies. There are 76 interventional studies currently listed as active or enrolling. Two-thirds are specific to Duchenne and Becker. Other dystrophies do have a few targeted trials but the numbers are drastically lower (Figure 1A)3. FSHD, with the most clinical trials after DMD/BMD, has only five active trials specific to its pathology. Dr. Mittal, former CEO and president of the Jain Foundation suggested that the focus on DMD is caused by two factors: the earlier discovery/study of the causative gene and the intense advocacy by parents of children afflicted with a lethal disease (personal communication, 2019). When assessed by trial phase, there are roughly an equivalent number of trials in all phases of development (Figure 1B). Sponsors are equally dispersed with 1/3 industry, 1/3 institutional and the remaining 1/3 a mix of industry, academic, government, and non-profit/advocacy groups (Figure 1C). 3 There are over 30 types of muscular dystrophy. Progress in the Treatment of Muscular Dystrophies ©2019 Nelsen Biomedical, LLC 2 Limited drug development is the norm for rare neuromuscular diseases. For example, amyotrophic lateral sclerosis (ALS/Lou Gehrig’s) has 86 active or recruiting interventional trials and Charcot-Marie-Tooth has only 51 (ClinicalTrials.gov). Other rare genetic disorders not affecting muscle have marginally more drug development activity. Cystic fibrosis has 128 currently active clinical trials and sickle cell disease has 156. When one considers that the clinical trials for muscular dystrophy cover multiple distinctive dystrophies caused by different genes, the number of trials per genetically distinct disease is significantly lower for the muscular dystrophies. Figure 1: Muscular dystrophy trials by dystrophy type, phase and funding source A. Clinical Trials: Type of B. Clinical Trials: Phase C. Clinical Trials: Muscular dystrophy Sponsor Phase I Phase I/II Academic/Hospital DMD/BMD FSHD Phase II Phase II/III Industry LGMD Other/Multiple Phase III N/A Mixed/Other 17 13 18 23 23 2 13 5 52 16 2 14 30 Source: clinicaltrials.gov Scientific Funding NIH funding is also disparate between muscular dystrophy and other rare genetic disorders and diseases. When one compares NIH funding of all 30+ muscular dystrophies to other rare diseases, muscular dystrophy comes up short. Cumulatively there was $145 million for muscular dystrophy research in FY20184. Sickle cell disease and Cystic fibrosis, both singular diseases, received $104 and $83 million in FY2018, respectively. Muscular dystrophy with $145 million may seem like a generous amount but when divided by 30 types of dystrophy, it is only $4.8 million per type, a figure much lower than Sickle cell and Cystic fibrosis. In Figure 2A, the 4 NIH categories of muscular dystrophy, DMD/BMD, FSHD, myotonic, and congenital. Progress in the Treatment of Muscular Dystrophies ©2019 Nelsen Biomedical, LLC 3 FY2018 NIH funding is divided by patient number within the USA. It is clear to see that funding for muscular dystrophy is incredibly low per patient while cystic fibrosis funding per patient is almost five times higher. Figure 2: NIH funding comparisons on three rare diseases Source: NIH RePORT report.nih.gov/categorical_spending.aspx In total NIH funding for 2018 • DMD/BMD received $32 million • Myotonic received $13 million • FSHD received $11 million • Congenital muscular dystrophy received $9 million. There was also additional $81 million given to muscular dystrophy research that was not classified by muscular dystrophy type (NIH, 2018). The Department of Defense (DoD) has also awarded $26.4 million to DMD research between FY2011-FY2018 as part of the Congressional Special Interest Medical Research Programs (CDMRP, 2019). DMD is the only muscular dystrophy type funded by this DoD program. While NIH funding for muscular dystrophy is increasing, it has a long way to go before it is similar to other rare diseases on a per disease or per patient basis. More funding is needed, especially to make progress on rare types of the disease that may be overshadowed by DMD/BMD. Fortunately many new therapeutic approaches being developed for DMD may have the potential to be modified to address other types of muscular dystrophies. DMD & BMD Therapeutic Approaches DMD/BMD represent a monogenic disease of differing severity. DMD is the result of a mutation within the dystrophin gene that leads to complete absence of the dystrophin protein. A Progress in the Treatment of Muscular Dystrophies ©2019 Nelsen Biomedical, LLC 4 shortened but still partially functional dystrophin protein resulting from a non-expressed exon(s) generally results in the milder BMD (Aartsma-Rus et al. 2006). The current standard of care for DMD boys is corticosteroid treatment. Steroids have been found to improve muscle strength, improve respiratory function, and prolong ambulation in multiple clinical trials (Goto et al. 2016; Biggar et al. 2006). Steroid therapy however will only slow disease progression and has multiple associated side effects such as

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