While cell therapies for heart disease have been long in development, none have been FDA-approved yet, which has created many skeptics. But one new treatment, CardiAMP, is available today through a clinical trial and may finally be the first cardiac cell therapy approved in the U.S. I caught up with Peter Altman, PhD, CEO at BioCardia to learn more about CardiAMP Heart Failure Trial and its best possible outcomes for patients.
CardiAMP involves 3 components: 1) pre-procedure screening assay for patient selection, 2) cell therapy, 3) minimally invasive delivery system. Explain CardiAMP in detail and how it is different from other biotherapeutic heart failure therapies.
Altman: CardiAMP cell therapy is different from other medications in that available data to date shows that patients improve in their heart function, quality of life, and exercise tolerance after treatment. All other therapies that we know of only slow the progression of the chronic disease, where patients using those therapies deteriorate more slowly than a control group, but do not show improvement in their symptoms. Outcomes from the CardiAMP Phase II TAC-HFT Trial1,2 and the Phase III CardiAMP Heart Failure Trial roll-in cohort3 were comparable, and for some endpoints, superior to those seen in pivotal trials for cardiac resynchronization therapy, an approved implantable electrical pacing therapy for the same patients.
The investigational CardiAMP cell therapy for heart failure has also been designed differently from other cardiac cell therapies based on learnings from trials that have come before it in the areas of mechanism of action, patient selection, dosing and delivery.
CardiAMP cells do not turn into heart cells, which we view as a significant advantage in that the creation of new heart cells present risks to patients that have not yet been solved. For years, researchers have been focused on creating new heart cells by either directly transplanting them, or inducing the growth of new myocardium. Rhythm abnormalities and rejection of these cells by the immune system remain significant challenges with this approach.
Rather than focusing on creating new myocardium, the CardiAMP mechanism of action hypothesis is based on observations that transplanted cells secrete stimulatory cytokines that instigate an innate regenerative response from resident stem cells. In other words, the cells may promote the heart’s natural healing response. Earlier cell therapies have been shown to provide paracrine mediators that promote a number of valuable mechanisms of action, including survival, contractility, neovascularization, differentiation and remodeling.
Biomarkers identified in previous BioCardia clinical work and in the scientific literature have been shown to correlate independently to the efficacy of cardiovascular cell therapy; one of the markers is the CD34+ cell titer in bone marrow. With that in mind, the investigational CardiAMP therapy uses a proprietary patient selection assay to identify and enroll those patients into the trial with potent bone marrow, i.e. those with a targeted amount of CD34+ cells, who are most likely to benefit from treatment. This therapy is the first cardiovascular cell therapy to use a pre-procedural assay to assist with patient selection, and we believe by targeting the therapy to patients with the right cell composition, we will improve patient outcomes.
CardiAMP therapy uses autologous cells and minimally processes them at a patient’s bedside, in the same procedure as delivery. The autologous dosage form eliminates the risk of cell rejection, and the processing approach results in a dosage form with both high cell viability and greatly reduced exposure of the therapeutic cells to biological contamination in remote processing. We use a high target dosage of 200 million cells, as literature has shown that higher dosages of cells have performed better in clinical study, and we are attempting to follow the results achieved in our positive Phase II experience.
Our Helix Biotherapeutic Delivery System for delivery of cell therapy into the myocardium has been shown in published literature to present the lowest risk to patients for biotherapeutic delivery compared to other delivery methods evaluated,4 and is three to six times more efficient at delivering cells to the heart muscle than other methods.5 We believe this performance will enable us to deliver a high effective dose of cells into the myocardium.
Our Phase II clinical trial showed that control patients deteriorated, while treated patients improved. The trial met its primary safety endpoint, with no treatment-emergent MACE at 30 days, and no death or MACE at 1 year. All secondary endpoints favored the therapy at 1 year, with functional capacity, quality of life and several other measures being statistically significantly improved. We are currently enrolling our Phase III clinical trial.
The CardiAMP Heart Failure Trial is studying an investigational stem cell-based therapy for heart failure that develops after a heart attack. Explain the study in detail.
Altman: The Phase III CardiAMP Heart Failure Trial is evaluating the cell therapy’s ability to improve patient survival, exercise capacity and quality of life, as well as its safety. The trial is the first multicenter clinical trial of an autologous cell therapy to prospectively select patients based on cell potency to maximize the probability of patient benefit. CMS currently reimburses the trial. All DSMB reviews to date have been positive.
The multi-center, double-blinded, randomized (3:2), controlled pivotal CardiAMP Heart Failure Trial is expected to enroll 260 patients at up to 40 centers nationwide – 88 patients have been enrolled to date. The trial’s primary endpoint is an outcomes composite score based on a three-tiered Finkelstein-Schoenfeld (FS) hierarchical analysis, an established outcomes design that has been used in other leading heart failure programs. The FS procedure is a ranked analysis that first compares each subject to each other subject for occurrence of first-tier events (time to death, in this case) and then compares patient outcomes for subsequent tiers. The tiers, starting with the most serious events, would be (1) all-cause death, including cardiac death equivalents such as heart transplant or left ventricular assist device placement, ordered by time to event; (2) non-fatal Major Adverse Coronary and Cerebrovascular Events (MACCE), excluding those deemed procedure-related occurring within the first seven days post-procedure (heart failure hospitalization, stroke or myocardial infarction), ordered by time to event; and (3) change from baseline in Six Minute Walk Distance at 12 months. The national co-principal investigators are Amish Raval, MD, of the University of Wisconsin and Carl Pepine, MD, of the University of Florida, Gainesville.
The CardiAMP HF Trial has 90+% power to demonstrate half the benefit shown in the Phase II trial, while most studies are typically powered at 80%. This means that if our Phase II results hold true, the CardiAMP Trial has a 90+% likelihood of meeting its primary endpoint and therefore having a successful trial outcome.
Twelvemonth results from the 10-patient roll-in cohort in the trial were published in the International Journal of Cardiology in 2020. Results showed that CardiAMP was well tolerated in heart failure patients, demonstrated improved activity levels via the Six Minute Walk Test at six months, saw a trend toward improvement in NYHA heart failure functional class and quality of life at one year, and no patients experienced serious adverse events related to bone marrow harvesting or cell delivery. Specifically, a 22% improvement in 6MWD was seen, with 8 or 10 patients improved. Seven of 10 patients improved in quality of life measures. Global LVEF was improved in 7 of 10 patients. Echocardiographic data showed that all 10 patients improved in wall motion score, 7 of 10 saw improved global LVEF, and 8 had significantly fewer akinetic myocardial segments.
BioCardia’s CardiAMP uses a patient’s own cells, rather than using donor cells, eliminating rejection and other concerns. Why is this the best possible option for patients?
Altman: CardiAMP is our lead autologous cell therapy candidate and has been shown to provide functional and quality of life benefits with few risks in patients who qualify for this therapy. As an autologous cell therapy, CardiAMP uses a patient’s own cells, so the patient is their own donor and there is no issue of rejection. The cell potency assay inclusion criteria also reduces problematic patient-to-patient variation in bone marrow cells and enriches the clinical investigation with patients most likely to respond to therapy. CardiAMP also enables point-of-care treatment, which is both convenient and offers enormous cost efficiencies to the health care system.
We feel that there is a place for both autologous and allogenic cell therapies. We are also pursuing allogenic cell therapy utilizing allogenic neurokinin 1 receptor positive (NK1R+) mesenchymal stem cells for various conditions, including ischemic heart failure. The initial cardiac indication for our allogenic therapy for ischemic heart failure is as an option for patients who would not qualify for CardiAMP due to the nature of their own bone marrow. This smaller population of NYHA Class II and III heart failure patients who are not eligible for CardiAMP may enable these allogenic cells to be advanced under an orphan indication for FDA approval for these no-option patients. Allogenic cells can be a good option because they are readily available, or “off-the-shelf.”
What is next for BioCardia?
Altman: We are very focused on completing enrollment in the CardiAMP Heart Failure Trial in the near term, but also recognize that there are additional opportunities for our cell therapies and enabling technologies. The FDA has approved a Phase III clinical trial for a second indication of our CardiAMP cell therapy in the treatment of chronic myocardial infarction, and we expect to begin enrolling patients in that study early in 2021.
We are also working toward IND acceptance this year for additional clinical trials that will study our NK1R+ allogenic cell therapy in ischemic heart failure and in acute respiratory distress developing from COVID-19. The emergence of new strains of COVID-19 may enhance the importance of this program.
We have partnerships with several companies who are using our Helix system for the delivery of biotherapeutic agents into the myocardium in their therapeutic development efforts, and it stands as the leading biotherapeutic delivery system for the heart. We are exploring additional access routes for Helix, and recently received a patent for catheter insertion through the small transradial artery in the wrist, which is growing in popularity as a delivery approach for percutaneous coronary interventions (PCI) to treat coronary artery disease.
We are encouraged by the clinical outcomes seen in our first patient cohort in the CardiAMP Heart Failure Trial and look forward to continuing to accelerate enrollment in the trial to completion. We are excited about the potential of this therapy to improve heart function, activity level and quality of life for the many people suffering from the effects of heart failure, and look forward to advancing our other cell therapy candidates down their clinical and regulatory paths.
Heldman, AW, DiFede, DL, Fishman, JE, et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: The TAC-HFT Randomized Trial JAMA 2014;311(1):62-73.
Wong Po Foo, C, Rouy, D, et al. The Transendocardial Autologous Cells in Ischemic Heart Failure Trial Bone Marrow Mononuclear Cells (TAC-HFT-BMC) Randomized Placebo Controlled Blinded Study. Poster presented at: World Conference for Regenerative Medicine; 2015 Oct 21-23; Leipzig, Germany.
Raval, AN, Johnston, PV, Duckers, HJ, et al. Point of care, bone marrow mononuclear cell therapy in ischemic heart failure patients personalized for cell potency: 12-month feasibility results from CardiAMP heart failure roll-in cohort. Int J Cardiol. 2020 Oct 20;S0167-5273(20)33996-6. doi: 10.1016/j.ijcard.2020.10.043.
Mitsutake, Y, Pyum, WB, Rouy, D, et al. Improvement of local cell delivery using Helix Transendocardial Delivery Catheter in a porcine heart. Int Heart J 2017;58(3):435-440.
Raval, AN, Pepine, CJ. Clinical safety profile of transendocardial catheter injection systems: A plea for uniform reporting. Cardiovasc Revasc Med 2020 Jun 30;S1553- 8389(20)30416-4.