A drug was identified through the use of muscle stem cells that can enhance the effectiveness of exon skipping by antisense oligonucleotides to the DMD gene to restore dystrophin expression and at least partially correct the defect responsible for loss of muscle function in Duchenne. We propose to test the effectiveness of this drug in combination with antisense oligonucleotides as a novel therapeutic strategy for Duchenne muscular dystrophy (DMD). DMD is the most common muscular dystrophy and leads to progressive muscle loss in boys resulting in severe weakness, and is caused by mutations in the DMD gene. DMD generally leads to death in the teens or early 20’s, making Duchenne one of the most severe disorders in humans. Further, Duchenne occurs in 1/3500 boys, making it one of the most common genetic disorders. There are no highly effective therapies. Thus, there is an urgent need to develop new and highly effective therapies. We propose to perform the necessary studies using DMD patient-derived iPS and animal models to perform safety studies that will permit regulatory approval to test the safety and efficacy of the combination therapy in Duchenne muscular dystrophy. The goal of the treatment is to make a functional dystrophin protein the patient’s body by altering the RNA in each muscle cell. Preliminary results indicate that the process is relevant to about 70% of those afflicted by Duchenne.
Since Duchenne muscular dystrophy is the most common lethal genetic disorder, there are over 1,000 patients affected in the state of California alone, 15,000 nationwide, and 300,000 worldwide. Duchenne muscular dystrophy has a large direct economic impact with intensive medical care with substantial disability. There is an obvious huge impact on the family as well. More effective therapies will directly benefit these families, lead to increased productivity. Further, a California based company will have developed a key therapy for an otherwise lethal genetic disorder further demonstrating California’s leadership in medical science, and generating novel business opportunities within the Biotechnology industry in California.
This proposal focuses on a combination small molecule therapy for Duchenne Muscular Dystrophy (DMD). DMD is a pediatric, genetic disorder, caused by mutations in the dystrophin gene, which lead to production of a nonfunctional dystrophin protein, muscle degeneration and early death. A promising class of experimental drugs, called antisense oligonucleotides (AONs), are currently in clinical trials for DMD and work by causing the DNA-reading machinery of the cell to skip over mutated regions (called exons) of the dystrophin gene. This exon skipping allows the cell to produce a partially functional dystrophin protein and could greatly reduce the severity of DMD. The applicant has identified a drug that enhances the efficiency of exon skipping AONs and characterized it in induced pluripotent stem cell (iPSC)-derived muscle cells from DMD patients. The applicant proposes to conduct preclinical studies to develop the combination therapy of this drug with AONs and file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) by the end of 4 years.
Significance and Impact
- DMD is a significant unmet medical need and there are no currently approved therapies, although several are being tested in clinical trials.
- If successful, the proposed therapy could have a major impact on the treatment of DMD, as the exon skipping approach would apply to approximately 65% of patients.
- The application lacks a clearly defined Target Product Profile (TPP). The TPP describes the therapy as if it will be the drug alone, rather than in combination with an AON. The applicant should consult the FDA guidance document (Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool for instructions on how to prepare a TPP) in preparing the TPP should a full application be submitted.
- Reviewers expressed mixed opinions about the responsiveness of this application to the RFA. Some noted that iPSCs were used to characterize the drug candidate and will continue to be used. Others questioned whether iPSCs were necessary for the project.
Project Rationale and Feasibility
- It is not clear from the application that the applicant has agreements in place with the companies developing the proposed AONs to permit clinical development of the proposed combination drug. Reviewers described this as a potentially fatal flaw.
- Reviewers were not convinced that the applicant appreciates the regulatory challenges of developing a combination product. They noted that regulatory agencies will likely insist on the usual rules for combination therapies. For example, each agent will need be studied for toxicity independently and in combination.
- The rationale for developing a drug to increase the efficiency of AON treatment is excellent.
- The proposal is based on strong preclinical and clinical data.
- The proposed activities and timeline are reasonable and can be accomplished in four years. However, the development of a combination drug is not described, and reviewers noted that it is unlikely the FDA would support the path outlined in the applicant’s Gantt chart.
- The mechanism by which the drug candidate enhances exon skipping is not known and this is a weakness. Understanding mechanism would increase the rationale for clinical trials and potentially allow the identification of even more effective therapeutic strategies.
Principal Investigator (PI) and Planning Leader
- The PI is a productive and experienced investigator in the areas of human genetics and pediatric medicine. However, reviewers did raise concerns about the extent of his/her expertise in DMD.
- The Planning Leader is an expert in immunology, biochemistry and cell biology and is involved in active DMD drug discovery efforts. It is not clear if s/he has experience in the development of human therapeutics.
- PROGRAMMATIC REVIEW
- A motion was made to move this application into Tier 1, Recommended for Funding, with a condition. To be eligible for the Disease Team Research Award competition, the applicant must provide at the time of Full Application written assurance from the companies that own the intellectual property surrounding the two antisense oligonucleotides that the applicant has access to the drugs and permission to file an IND for clinical testing. Reviewers agreed that this condition addresses a potentially fatal flaw in an otherwise exciting proposal. The motion carried.