Funding opportunities

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.