Disease Team Therapy Development - Research
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and one of the most common fatal genetic disorders. Approximately one in every 3,500 boys worldwide is affected with DMD. Extrapolating from population based studies, there are over 15,000 people currently living with DMD in the US. DMD is a devastating and incurable muscle-wasting disease caused by genetic mutations in the gene that codes for dystrophin, a protein that plays a key role in muscle cell health. Children are typically weaker than normal by age three, and progressive muscle weakness of the legs, pelvis, arms, neck and other areas result in most patients requiring full-time use of a wheelchair by age 11. Eventually, the disease progresses to complete paralysis and increasing difficulty in breathing due to respiratory muscle dysfunction and heart failure. The condition is terminal, and death usually occurs before the age of 25. While corticosteroids can slow disease progression and supportive care can extend lifespan and improve quality of life, no therapies exist that address the primary defect or dramatically alter the debilitating disease course. Exon-skipping is a promising therapy that aims to repair the expression of the dystrophin protein by altering the RNA, but it is unclear whether it will be effective enough to lead to clinical improvements. We have identified a combination therapy that improves the effectiveness of exon-skipping therapy in mouse muscle and in human DMD patient stem cell derived muscle cells in culture. Because the genetic defect is being directly repaired inside of each muscle cell, this therapy is predicted to lessen the disease severity. The early research and further development of the proposed combination therapy require screening for drug efficacy and toxicity using human DMD patient stem cells including: reprogrammed patient fibroblasts converted into muscle-like cells in culture or when transplanted in mice. These cells are necessary because each patient’s mutation in the dystrophin gene is different. In order to know who will or will not benefit from the exon-skipping therapy, individualized cell culture and mouse transplant models from a number of DMD patients must be created to effectively characterize the combination therapy. The proposed research program will complete necessary efficacy and toxicity studies to allow submission of appropriate material to the FDA to allow testing of this novel combined therapeutic in children with DMD. It will also involve a team of clinical trialists who will incorporate findings in planning optimal trial design and ensure clinical trial readiness by the grants end. Since exon-skipping therapy relies on knowing individual patients exact DNA mutation, this is a form of personalized genetic medicine. While the specific combination therapy being developed here will treat up to 13% of DMD patients, the strategy is likely to be generalized to be able to treat up to 70% of DMD patients.
Statement of Benefit to California:
Duchenne muscular dystrophy (DMD) is an incurable and inevitably fatal genetic disorder. It is caused by a defect in the gene that produces dystrophin, a protein critical to the function of normal skeletal muscle. DMD affects more than 1,000 patients in California, 15,000 nationwide, and 300,000 worldwide. Because the genetic mutation responsible for the disease occurs on the X chromosome, the overwhelming majority of patients are male. Children are typically diagnosed when they are toddlers. Muscle weakness first appears in the hips and legs and progressively extends to every muscle in the body, including the arms, neck, diaphragm and heart. By age 11, most patients require full-time use of a wheelchair . By their late teens, they have trouble feeding themselves. Inevitably, patients are completely paralyzed and cannot breathe without a ventilator. As their cardiac muscles fails, they develop heart failure. Patients usually die by age 25. Aside from the human suffering caused by DMD, the disease places a large economic burden on patients, their families and society as a whole. Patients require intensive medical care because they cannot perform the simplest activities of daily living. Eventually, each individual requires ventilation and 24/7 care due to progressive loss of all muscle function. The proposed combination therapy is intended to spare skeletal muscle by producing dystrophin. Specifically, the combination therapy will induce skipping of DMD exon 51 in skeletal muscle; a defect in exon 51 is responsbile for 13% of DMD cases. The therapy causes the dystrophin gene inside each muscle cell to express an internally deleted but partially functional dystrophin protein, lessening the severity of DMD. The approach has been well-validated in animal DMD models. A therapy that effectively slows or reverses disease will allow patients to lead longer, more productive lives and reduce the need for costly supportive services—progress that will benefit patients, their families and society.
This proposal is focused on the clinical development of a combination product, an antisense oligonucleotide (AO) together with an FDA-approved small molecule drug, for Duchenne Muscular Dystrophy (DMD). DMD is an X-linked genetic disorder in which mutations occur in the gene encoding dystrophin, a protein that plays a role in muscle health. The applicant claims that the AO promotes exon skipping, and the resulting protein can replace full length dystrophin. The concept is based on the applicant’s preclinical observation that an FDA-approved drug can enhance exon-skipping activity in a preclinical model of DMD, and in an assay of human skeletal muscle myotubes. Important activities will include confirmation of activity against multiple alleles of the dystrophin gene from human DMD patients using in vitro cell models. The goal of this project is to complete the preclinical dosing and efficacy studies, toxicity studies, and complete the regulatory and clinical activities to file an Investigational New Drug application (IND) within the four-year timeframe. Significance and Impact - DMD is one of most common lethal monogenic diseases, and no existing treatments significantly reduce the burden of disease. - The initial proposed therapeutic could possibly address an estimated 13% of the DMD population (approximately 10,000-15,000 cases); the applicant believes that the platform could eventually address 70% of DMD cases. - Exon skipping is an active area of therapeutics under investigation for this disease. This project focuses on one AO; another directly competitive AO is in clinical development by a second corporate entity. - At a minimum, a benefit would be a decrease in cost to treat with the single agent AO. - The Target Product Profile (TPP) was well laid out, although the optimal safety targets were not clear. - The project is responsive to the RFA as the team intends to use two forms of reprogramming to assess potential efficacy in samples from patients with various human dystrophin mutations. Project Rationale - A major flaw in the application was the absence of any data or discussion addressing whether this potential therapy would impact cardiac muscle, since most patients ultimately succumb to heart failure. - Recent Phase 2b data has been reported that showed increases in dystrophin levels with single agent AO treatment. No functional difference was observed between treated patients and those who received placebo. - One reviewer cited the Phase 2b results and recommended against funding this program until the absence of functional effect with the single AO agent is delineated. - The panel questioned the strength of the data supporting the argument that the candidate drug actually increases exon skipping. One reviewer noted the premise is based on unpublished data. - Data are included in the application showing a 2-3 fold increase in exon skipping at a low dose of AO, with the candidate drug. For one reviewer, methods and controls to quantify exon skipping in the human in vitro model system were not adequately described. - The application did not show data addressing the maximum level of muscle fibers the team can affect by increasing exon skipping; nor was a threshold demonstrated that might alter clinical outcomes. Therapeutic Development Readiness - Both components of the proposed combination therapy have been demonstrated to meet GMP manufacturing requirements; and therefore the panel anticipates no new manufacturing needs. - It was not clear to several reviewers whether the in vivo xenograft model is either ready or appropriate for efficacy and dose-finding studies. - Key proof-of-concept studies relied on a surrogate target gene in the preclinical model, and in vitro studies with human cells. - The applicant notes poor solubility of the small molecule, which may be suboptimal for oral administration. Replacement with more soluble compounds in the candidate combination product would be a major drawback and necessitate additional toxicology testing. - The observed variability in the Phase 2b clinical studies should be further evaluated in a preclinical setting. Feasibility of the Project Plan - Several reviewers commented that progression to IND submission is slow, and were unclear on the rationale for the full four years required to file an IND. - Several reviewers identified an excellent preclinical model that is often used for DMD, and noted that it is not introduced into this program. This is important because structural and physiologic endpoints should be assessed in a relevant weight-bearing model. - The safety data for the single AO was judged incomplete for the proposed combination. Several examples were discussed: off-target effects of the AO should be evaluated in combination with the proposed drug; immunogenicity should be evaluated with repeat administration of the AO. - The team should re-evaluate the rationale and design of the toxicology studies in the clinically relevant model, and integrate the discussion of design into the pre-IND meeting. Such studies are often costly and generally underpowered. - A robust pK/pD study should be included in this program, to address the very short half life of the AO in the context of the chronically administered small molecule. - The team should consider evaluation of a clinical biomarker which might reflect durability of response. Principal Investigator (PI) and Development Team - The PI has a strong background in genomics and gene expression, and has a track record that demonstrates a commitment to translational research. - The Co-PI’s primary expertise is immunology, with ample experience in translational research and clinical care for this condition. - The scientific leadership is augmented by individuals with experience with the preclinical model and human induced pluripotent stem cell development. In years three and four, a clinical expert who has conducted trials in DMD will join the team. - Product development and regulatory expertise is provided by two qualified industry partners. Collaborations, Resources and Environment - The applicant institution is well-suited to support the research components of the proposal, and appropriate industry partners have been enlisted to perform key IND-enabling and CMC activities. - The applicant should secure cooperation from the source(s) of the drug soon. It may be necessary to extend the labeling indication for drug in concert with approval for the single AO. Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding. ) - A significant amount of funds will be going to the industry partner in year 1. This partner should consider supplying the AO at either little or no cost, since this may be essential to success of their therapeutic. - Several reviewers identified financial redundancy with the partner’s corporate program. - Carcinogenicity for the single agent AO should not be funded by this project. Condition Applied by the Planning Award Grants Working Group (GWG) - The Planning Award GWG set a condition that “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.” - A letter included in the application from one of the AO providers agrees in principle, but raised concerns for reviewers.
- A motion was made to move this application into Tier 1, Recommended for Funding. Programmatic reasons cited were the devastating effects of the disease and the relatively fewer pediatric indications in the portfolio. The panel expressed general consensus about the desire to fund work in pediatric diseases. However, this application could not overcome the absence of clinical benefit for the single agent, and also the unknowns of the proposed combination product regarding immunogenicity, relevance of the proposed model, and whether the proposed therapeutic would target critical cardiac pathology. The motion was withdrawn.
- Bruce Montgomery
- Raj Chopra