CLBS12

Product Candidate for Critical Limb Ischemia (CLI)

Caladrius plans to develop its product candidate, CLBS12, in Japan under Japan’s regenerative medicine law. This law enables an expedited path to conditional approval for regenerative medicine products that show sufficient safety evidence and signals of efficacy in a phase 2 study. Our Clinical Trial Notification for a pivotal Phase 2 trial investigating CLBS12 was submitted to the Japanese Pharmaceutical and Medical Device Agency ("PMDA") and was cleared to proceed. The protocol design was agreed with PMDA and if successful, could provide the basis for conditional approval under Japan's favorable regenerative medicine law. We are seeking to collaborate on CLBS12 with development and/or manufacturing partners.

No-Option Critical Limb Ischemia

The goal of CLBS12 is to prevent the serious adverse consequences of no-option CLI (cases where there is no longer the potential for other treatment beyond amputation) by extending the time of continuous CLI free status through improved blood flow in the affected limb. We also believe a CD34 product would have potential in treating chronic heart failure ("CHF"). Published reports have provided evidence that CD34 cells administered into the coronary arteries of patients with CHF can improve survival compared to patients treated with standard medical therapy.

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 microcirculation1
  • Phase 2 clinical studies consistently show benefits in safety and function
    • Reduced amputation in critical limb ischemia2
    • Improved function in claudication3
    • Reduced angina and improved ETT in refractory angina4
    • Improved mortality and LVEF in dilated cardiomyopathy5
Opportunities exist across multiple underserved cardiovascular indications
  • Critical limb ischemia (CLI) in Japan
  • Coronary microvascular dysfunction (CMD)
  • Refractory angina

Japanese development program for critical limb ischemia

Phase 2 protocol and CMC strategy completed in consultation with Japanese PMDA

Design
  • Prospective, open label, controlled, randomized trial
  • Patients with no-option CLI
Advantageous Primary Endpoint
  • Time to continuous CLI-free status (defined as 2 consecutive monthly visits)
Study Size
  • 35 patients enrolled across multiple centers in Japan
Treatment
  • Up to 106 autologousG-CSF-mobilized peripheral blood-derived CD34+ cells/kg per affected limb
Control/comparator
  • SOC pharmacotherapy with drugs approved in Japan (e.g. antiplatelets, anticoagulants and vasodilators)
  • The choice of pharmacotherapy will be made by the investigators
Mode of Administration
  • Intramuscular, 20 injections in affected lower limb in single administration
Timing
  • First-patient-in targeted for 4Q17/1Q18 with preliminary data expected within 6 months of initiation

References

1. 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.

2. 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.

3. From US study (n=17); Not yet published

4. 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. .

5. 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.