DYNAMIC (Dilated cardiomYopathy iNtervention with Allogeneic MyocardIally-regenerative Cells) Trial: A randomized, double-blind, placebo-controlled Phase 1a/b multicenter study of allogeneic human cardiosphere-derived cells in patients with advanced heart
Disease Team Therapy Development III
$12 895 092
The proposed research will set out to demonstrate the safety and feasibility, in patients, of a novel treatment for heart failure based on heart-derived stem cells. The focus is on patients who have been diagnosed with a form of heart failure known as dilated cardiomyopathy (DCM). Currently, DCM is the most common type of heart failure, a disease which affects ~5 million Americans and which is one of the major causes of death and disability; it generally results from coronary atherosclerosis and multiple MIs, but can also be idiopathic in nature. The timing and course of the disease differs between individuals but ultimately the progression of disease leads to chronic heart failure. Medication and mechanical devices can be effective in slowing the progression of heart failure, but there is no known commercial therapy that can reverse the progression of the disease process. The heart remodels (i.e., dilates) to offset the loss of functional heart muscle. The remodeling process is ultimately maladaptive, with profound changes in cardiac structure and function as well as in the underlying molecular and cellular pathways. Conventional therapy relies largely on drugs that block secondary maladaptive signaling pathways; they slow the progression of heart failure, but do not reverse the disease. Once DCM becomes symptomatic, with shortness of breath and limited exercise capacity despite best current therapy, clinical outcomes are dismal. The one-year risk of death or hospitalization in such patients approximates 40%. Cell therapy has the potential to achieve myocardial regeneration and thus to improve, qualitatively, the prospects of these desperately ill patients. We will perform the DYNAMIC Phase 1 trial of allogeneic cardiosphere-derived cells in patients with DCM. DYNAMIC will study 42 patients (14 controls and 28 cell-treated). Functional testing will include cardiac imaging by echo and PET/CT in order to gain extensive information about perfusion, structure and function and how they may respond to therapy. Clinical events data will also be collected so as to better power follow-on studies seeking to reduce death and hospitalization. By the end of the project, we expect to have completed a clinical trial of a promising form of cell therapy in a highly-deserving patient population. The data collected will be vital in planning more advanced clinical studies that will determine, definitively, whether the treatment saves lives.
Statement of Benefit to California:
Cardiomyopathy is a group of heart-related diseases that affects heart muscle. This research focuses on dilated cardiomyopathy, which is the most common form and is typically characterized by the progressive, usually irreversible enlargement of heart muscle. Dilated cardiomyopathy is common, accounting for more than half of the ~5 million cases of heart failure in the USA today. Currently, the only treatment for dilated cardiomyopathy is management through optimal medication and lifestyle changes. Management of the disease focuses on reducing the symptoms and slowing disease progression. There is no known cure for dilated cardiomyopathy nor has there been a proven strategy to stop its progression, or to reverse established disease. This research is aimed at using heart-derived cell therapy, the only known intervention, to date, that has been proven clinically effective in regenerating the human heart. If our research is successful, we may offer a cost-effective way to reduce the tremendous damage to Californians inflicted by this type of heart disease. This in turn may also reduce the economic burden presently borne by taxpayers who support the health care systems in California. In addition to the public health benefits, spinoff technology developed by this disease team will benefit existing California-based biotechnology companies, leading to fuller employment and an enhanced tax base.
EXECUTIVE SUMMARY This proposal is aimed at developing a treatment for a form of heart failure known as dilated cardiomyopathy (DCM). The applicant proposes to test the safety and feasibility of an allogeneic cell therapy based on cardiac-derived stem cells in patients with established DCM, by conducting a Phase 1a/2b clinical trial which would be completed within the grant award period. The proposed clinical trial would include monitoring of clinical events together with functional testing and cardiac imaging to gain information about cardiac perfusion, structure and function and potential response to the therapy. Significance and Impact - Although extremely well written, this proposal had a serious major flaw that significantly impacted the score. The major serious criticism and flaw stems from the fact that the applicant is currently evaluating the same cellular product in a Phase 1/2 trial in a different subgroup of cardiac patients. Since the objectives of the proposed and currently enrolling trials are similar, reviewers agreed that the proposed Phase 1 trial does not add value and should be re-evaluated after completion and analysis of data from the current trial. - The economics of the proposed therapy for DCM was viewed as favorable given that this is an area of unmet medical need and of high patient care cost. - The target indication as defined in the TPP is extremely broad and includes a heterogeneous patient population with very diverse etiologies and physiologies. Reviewers commented that the target population should be better defined. Scientific Rationale and Risk/Benefit - The high one-year mortality for the target patient population may support a favorable risk/benefit ratio for trial participation. - Reviewers questioned the plausibility of a mechanism of action that would yield clinical benefit in the target indication. While there is reasonable expectation that the therapy will demonstrate short-term clinical benefit, the product was felt to be unlikely to result in reversal of fibrosis in the chronic fibrotic setting of DCM. - Although the ongoing trial with the same product candidate is in a different subgroup of cardiac patients and with a different cell delivery method, it was strongly felt by the reviewers that the risk/benefit ratio for the proposed trial would be better assessed following examination of the outcomes from the current trial. Therapeutic Development Readiness - This product is already in an early phase clinical trial and, therefore, from that perspective has achieved a level of development readiness for the proposed trial. - Regulatory issues (supported by preclinical data) were felt to have been sufficiently addressed in the IND filing. Design and Feasibility - There were several concerns raised about the trial design, such as the overly broad patient population, which reviewers believed would negatively impact whether meaningful information will be gained. The proposed composite endpoint was felt to be extremely optimistic for the proposed study size. - The project milestones seem to adequately capture key activities that are reliable indicators of the project's progress. At points throughout the clinical development pathway, clearly defined go/no-go decisions are proposed. The Plan to end-of-phase-2 is reasonable and builds upon the experience gained in phase 1. - The overall project plan is feasible and the proposed timeline appears to be realistic and achievable. - The investigators have made a good effort to compute the probability of detecting adverse outcomes. However their estimates may be overly optimistic, given the small sample size. Principal Investigator (PI), Development Team and Leadership Plan - The PI and development team appear to be strong. They have a good track record of advancing clinical trials. - Investigators are well trained with a great deal of scientific and clinical expertise making them well suited to lead the trial. Budget - Overall, the trial cost is high. Proposed patient care costs and CMC budget seem reasonable. Collaborations, Assets, Resources and Environment - The team is judged to be well positioned both with resources at their site and with external collaborators. - It was unclear if safety would be handled by an external CRO. Reviewers commented that it is critically important for safety to be handled by an independent safety vendor with access to a validated safety database and robust safety data collection processes.
- Joyce Frey-Vasconcells