CLBS14

Product Candidates for Coronary Microvascular Dysfunction and Refractory Angina

CLBS14 is a formulation of autologous G-CSF mobilized peripheral blood derived CD34+ cells designed to stimulate the growth of microvasculature in the hearts of patients with myocardial ischemia. Caladrius has two CBLS14 clinical programs targeting similar indications. These CD34+ cell therapies are designed to treat either coronary microvascular dysfunction (CLBS14-CMD) or refractory angina (CLBS-RfA) using the patient’s own cells to repair and regenerate the damaged cardiovascular tissue. CLBS14-CMD is being studied in the ongoing ESCaPE-CMD Phase 2 proof-of-concept clinical trial and CLBS14-RfA is currently in late-stage development and received RMAT designation from the FDA for treatment of refractory angina.

CLBS14-CMD

CLBS14-CMD is being studied in a 20-patient proof-of-concept ESCaPE-CMD Phase 2 study at two centers in the United States. The trial is financially supported by a grant awarded from the National Heart, Lung and Blood Institute of the National Institutes of Health. The first patient was enrolled in April 2018 and results are expected by the end of 2019.  

Coronary Microvascular Dysfunction

Coronary microvascular dysfunction (CMD), previously known as syndrome X, is a heart disease in which disease of the microcirculation results in severe myocardial ischemia in the absence of blockages in the large arteries. CLBS14-CMD is designed to reduce the serious adverse consequences caused by the damage to the inner walls of the heart’s blood vessels through CD34+ cells’ innate ability to repair small blood vessels or microcirculation. Nearly 50 percent of patients with coronary artery disease have CMD. Approximately 8.3 million people in the United States1, 6.0 million people in Europe2 and 1.0 million people in Japan3,4 have CMD and could be eligible for CLBS14-CMD. There is currently no available targeted therapy for CMD

CLBS14-RfA

CLBS14-RfA has been studied in Phase 1, Phase 2 and Phase 3 randomized, double-blind placebo-controlled clinical trials. [5][6][7] A recent publication in the European Heart Journal, entitled “Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials” combines the data from all three studies encompassing over 300 patients and reveals statistically significant improvements in mortality, exercise capacity and chest pain frequency. Under the terms of the RMAT designation, Caladrius is holding discussions with the FDA to determine the most expeditious regulatory pathway to bring this potentially restorative therapy to patients in need.

Refractory Angina

It is estimated that as many as 1 million people in the United States have chronic symptomatic coronary artery disease (often referred to as refractory angina, or RfA) that is recalcitrant to medical therapy and not amenable to conventional revascularization procedures. Patients have reproducible lifestyle-limiting symptoms such as chest pain and shortness of breath and are easily fatigued. These symptoms are often due to totally occluded coronary arteries or to diffuse coronary atherosclerosis that makes revascularization problematic. As the population ages and the incidence of diabetes mellitus increases, this clinical condition is expected to become more prevalent. Patients with this condition have significant morbidity and experience a lower quality of life.[8]

CD34 cell therapy is supported by a profound body of clinical evidence

CD34 cells have been investigated in clinical studies encompassing >700 patients

  • Pre-clinical studies document improved microcirculation9
  • Phase 2 clinical studies consistently show benefits in safety and function
    • Reduced amputation in critical limb ischemia10
    • Improved function in claudication11
    • Reduced angina and improved ETT in refractory angina12
    • Improved mortality and LVEF in dilated cardiomyopathy13

Opportunities exist across multiple underserved cardiovascular indications

  • Critical limb ischemia (CLI) in Japan
  • Coronary microvascular dysfunction (CMD)
  • Refractory angina

Phase 2 development program for coronary microvascular dysfunction

 
Design
  • Interventional, open label, exploratory trial
  • Men and women over 18 years of age with coronary microvascular dysfunction
Primary Endpoint
  • Adverse events (including SAEs); laboratory investigations; physical exams; MACE
Efficacy Endpoints
  • Change from baseline to 6 months in: coronary flow reserve; endothelial-dependent microvascular function; peripheral arterial tonometry measurements; time to angina; total exercise time; time to ST depression; activity recorded by Fitbit during one-week period
  • Change from baseline to 3 and 6 months in: angina frequency; nitroglycerin use; health-related quality of life
Study Size
  • 20 patients to be enrolled
Treatment
  • CLBS14 (G-CSF mobilized peripheral blood derived autologous CD34+ cells
Mode of Administration
  • Cell infusion into a coronary artery
Timing
  • First-patient-in targeted for late Q1/early Q2 2018 with preliminary data expected in late 2018
References   1. Cleveland Clinic/AHA (American Heart Association)   2. Townsend, N, et al.: Cardiovascular disease in Europe: epidemiological update 2016, European Heart Journal, Volume 37, Issue 42, 7 November 2016, Pages 3232–3245   3. Kita, T; Coronary heart disease risk in Japan – an East/West divide?, European Heart Journal Supplements, Volume 6, Issue suppl_A, 1 March 2004, Pages A8–A11   4. Ueshima, H, et al.; Cardiovascular Disease and Risk Factors in Asia, AHA Journal, December 16/23, 2008, Volume 118, Issue 25 5. Losordo, D.W., et al., Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation, 2007. 115(25): p. 3165-3172 6. Losordo, D.W., et al., Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res, 2011. 109(4): p. 428-36. 7. Povsic, T.J., et al., The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34(+) Cell Administration in Patients With Refractory Angina. JACC Cardiovasc Interv, 2016. 9(15): p. 1576-85. 8. Ochsner J. 2009 Winter; 9(4): 220–226.
9. Kalka, C., et al. (2000). Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proceedings of National Academy of Sciences of the United States. 97:3422–3427. http://www.pnas.org/content/97/7/3422.full; Schatteman GC, et al. (2000). Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. The Journal of Clinical Investigation. 106:571–578; Madeddu, P. et al. (2004). Transplantation of low dose CD34+KDR+ cells promotes vascular and muscular regeneration in ischemic limbs. The FASEB Journal. 18:1737-1739.10. Losordo, DW., et al. (2012). A Randomized, Controlled Pilot Study of Autologous CD34+ Cell Therapy for Critical Limb Ischemia. Circulation: Cardiovascular Interventions. 5: 821–830. 11. From US study (n=17); Not yet published 12. Losordo, DW. et al. (2011). Intramyocardial, Autologous CD34+ Cell Therapy for Refractory Angina. Circulation Research. ; Povsic, TJ. et al. (2016).The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34+ Cell Administration in Patients With Refractory Angina.  JACC Cardiovascular Interventions. . 13. Vrtovec, B., et al. (2013). Effects of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circulation Research. 112:165-173.