Duchenne Muscular Dystrophy (DMD) is a rare genetic disease characterized by progressive muscle degeneration and weakness. It is one of the most frequent genetic disorders, affecting approximately 1 of 3,600 (primarily) male children. The disease is caused by a mutation in the gene for dystrophin on the X chromosome that results in the absence of that protein, which helps keep muscle cells intact. Symptoms typically begin to manifest in early childhood, usually between the ages of 3-5. Until recently, boys with DMD did not typically survive much beyond their teen years. But thanks to advances in cardiac and respiratory care, life expectancy for those with DMD is increasing and survival into the early 30s has become more common.
No cure for DMD currently exists, and initial treatments have been aimed at controlling the symptoms of the disease to maximize the patient’s quality of life. Prednisone has been used in the United States to extend the ability of DMD affected boys to walk by two to five years. However treatment with that corticosteroid is associated with significant side-effects: weight gain, high blood pressure, behavioral changes, and delayed growth. The recently approved drug Emflaza (Deflazacort) — whose approval we wrote about in our last post — is also a corticosteroid, but offers a better side-effect profile than prednisone. Emflaza has been available outside of the United States for many years, but was only just approved by FDA in March.
Until very recently, there have been few marketed drugs to treat DMD — symptomatically or otherwise. However, much drug discovery and development is underway, following a number of different strategies including exon skipping, gene therapy, stop codon read-through, utrophin-modulation, and gene repair approaches like CRISPR.
Exondys 51 and Other Exon Skipping Approaches
Exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty sections of genetic code. This enables the production of a shortened but still functional form of dystrophin.
Researchers have identified over 1,800 mutations that can affect the dystrophin gene in people with DMD and Becker Muscular Dystrophy (BMD), a milder form of the condition, but the most common mutation in DMD is a deletion of one or more exons, which prevents the protein from being properly made. Genetic testing is needed to determine the particular mutation in a given patient, in order to understand whether he may be a candidate for treatment with an exon skipping therapy. Exon skipping is not a cure for DMD, but could potentially slow muscle degeneration and make DMD more like the much milder BMD.
In September 2016, Exondys 51 (eteplirsen), the first treatment for DMD aimed at the underlying cause of the disease received an accelerated approval from the US Food and Drug Administration for use in patients who have a confirmed mutation in the dystrophin gene that is amenable to exon skipping. That mutation, in exon 51, affects approximately 13% of patients with DMD. Sarepta Therapeutics, which developed and markets Exondys 51 has a variety of similar therapeutic candidates for DMD in development, addressing other specific mutations amenable to the exon skipping approach. Other companies with exon skipping therapies in development include AviBioPharma (exon 50) and ProSensa (exons 44, 45, 53, 52 and 55).
Gene Therapy Approaches to DMD
The aim of gene therapy is of gene replacement and a number of companies and academic institutions are focused on the development of gene therapies for DMD. However, the dystrophin gene itself is too large to deliver in such an approach. Research, therefore, has been generally focused on the delivery of a shorter, but still functional micro-dystrophin that can perform similarly to the native protein or perhaps the partially functional dystrophin protein made by patients with BMD. Companies preparing to enter human clinical testing with micro-dystrophin focused gene therapy approaches in 2017 include Solid Biosciences (SGT-001), Sarepta – which partnered in January with Nationwide Children’s Hospital to gain rights to their micro-dystrophin program, and Pfizer, which gained a similar program through its acquisition of Bamboo Therapeutics in August 2016.
Sarepta, in its deal with Nationwide Children’s Hospital, also gained access to another gene therapy program for DMD. This second, Galgt2 program is a potential surrogate approach — the aim is to induce a gene to modulate and increase the production of another muscle protein – utrophin. This protein is similar to dystrophin in function but produced during the early stages of muscle fiber development and switched off in maturing muscle fibers where dystrophin takes over the same role. Utrophin is also produced by damaged muscle cells during the earlier stages of muscle repair.
Stop Codon Read-through Strategies — Translarna (ataluren)
While most of the mutations responsible for DMD are due to large deletions or duplications in the genetic code of dystrophin gene, premature stop codons resulting from nonsense point mutations account for about 7% of DMD cases. Ataluren, PTC Therapeutics’ agent, interacts with the ribosomes involved in dystrophin production to reach through the premature stop signal on mRNA, allowing the production of a full length, functional dystrophin protein. As we mentioned in our last post, PTC Therapeutics has received conditional approval in Europe for Translarna and has filed for approval in the United States. A response from the US FDA is expected in October 2017.
Utrophin-Modulation via Small Molecule
Summit Pharmaceuticals is developing an oral, small molecule approach to utrophin modulation with the aim of maintaining its production. The company is currently conducting a Phase 2 trial with its drug candidate, ezutromid. If successfully developed, ezutromid would hold an advantage over other DMD treatment approaches, as it could potentially be used to treat all DMD patients regardless of their mutation. Moreover, it could potentially complement other approaches to treatment. In October 2016, Sarepta licensed the European rights to ezutromid.
CRISPR/Cas9 Approaches to Gene Repair
CRISPR/Cas9 is an approach to “genetic surgery” that enables targeted genetic sequences to be precisely removed and/or replaced. As such a number of academic research groups have been exploring its potential use for correcting the genetic problems that result in DMD. Active research efforts in this field are ongoing at Duke University, Harvard University, the University of California – Los Angeles, the Broad Institute of MIT and Harvard, and the University of Texas at Southwestern Medical Center.
CRISPR/Cas9 work led by Eric Olsen at that last institution was recently the focal point for the funding of a new start-up company, Exonics Therapeutics. In February 2017, Exonics received $5 million in funding from CureDuchenne Ventures, the investment arm of non-profit patient advocacy group, CureDuchenne. (In our final post in this three-part series, we’ll discuss the growing influence of patient advocacy organizations in funding Duchenne drug development — and more controversially, in influencing FDA decision-making.)
While several of the groups mentioned above have published preclinical research showing the expression of dystrophin in skeletal and cardiac muscle in mouse models of DMD, timing for clinical studies as yet remain unknown. There is yet no clinical evidence in any disease indication for the safety and efficacy of CRISPR therapeutic approaches in humans, and trials of the gene editing technology in cancer and blindness are only just slated to begin this year.