Background & Aim No-Option Refractory Disabling Angina (NORDA) is an orphan-sized population with an estimated prevalence between 18,194 and 94,338 persons in the US. CLBS14 has previously been studied for the treatment of NORDA in phase 1 proof of concept, phase 2 dose-defining, and partially completed 3 studies. These studies enrolled up to 1.9% of the prevalent population. The Phase 2 study demonstrated statistically significant improvements in key outcome measures including angina frequency, exercise time, and mortality and is considered pivotal evidence of efficacy. Two independent analyses of combined data from all three studies further support the conclusion of efficacy. Thus, existing evidence may support accelerated or conditional approval in some regions. In the event that additional evidence is required, confirmatory investigations including post-marketing commitments to be potentially completed during the review of a marketing authorization application were designed. Methods, Results & Conclusion We describe a Phase 3 pivotal study to meet regulatory requirements as a confirmatory study in subjects with NORDA, defined as 1) experiencing ongoing angina despite use of maximally tolerated doses of anti-anginal medications, 2) limited by angina after at least 3 minutes but no more than 10 minutes on a modified Bruce-protocol exercise tolerance test, 3) experiencing a minimum of 7 episodes of angina per week during a 2-week lead-in period, 4) with objective evidence of inducible ischemia, 5) not having gained relief from or not being eligible for revascularization procedures, and 6) being assessed by an independent committee as CCS angina class III or IV. Approximately 400 subjects representing up to 2.2% of the prevalent population will be randomized 4:3:1 to receive double-blind intramyocardial CLBS14, double-blind intramyocardial placebo or open-label standard of care (SOC). The primary endpoint will be total exercise time at 6 months, with secondary endpoints of angina frequency and change in CCS angina class. Mortality will be followed for 2 years. SOC subjects will have the option to receive CLBS14 treatment after an initial 6-month observation. A favorable outcome in conjunction with previous data has regulatory support for submission and review of a BLA for CLBS14 for this orphan-sized indication. Considerations around study design and regulatory implications for this first potentially approvable cardiovascular cell therapy, including pathways to conditional approval, will be discussed. No-Option Refractory Disabling Angina (NORDA) is an orphan-sized population with an estimated prevalence between 18,194 and 94,338 persons in the US. CLBS14 has previously been studied for the treatment of NORDA in phase 1 proof of concept, phase 2 dose-defining, and partially completed 3 studies. These studies enrolled up to 1.9% of the prevalent population. The Phase 2 study demonstrated statistically significant improvements in key outcome measures including angina frequency, exercise time, and mortality and is considered pivotal evidence of efficacy. Two independent analyses of combined data from all three studies further support the conclusion of efficacy. Thus, existing evidence may support accelerated or conditional approval in some regions. In the event that additional evidence is required, confirmatory investigations including post-marketing commitments to be potentially completed during the review of a marketing authorization application were designed. We describe a Phase 3 pivotal study to meet regulatory requirements as a confirmatory study in subjects with NORDA, defined as 1) experiencing ongoing angina despite use of maximally tolerated doses of anti-anginal medications, 2) limited by angina after at least 3 minutes but no more than 10 minutes on a modified Bruce-protocol exercise tolerance test, 3) experiencing a minimum of 7 episodes of angina per week during a 2-week lead-in period, 4) with objective evidence of inducible ischemia, 5) not having gained relief from or not being eligible for revascularization procedures, and 6) being assessed by an independent committee as CCS angina class III or IV. Approximately 400 subjects representing up to 2.2% of the prevalent population will be randomized 4:3:1 to receive double-blind intramyocardial CLBS14, double-blind intramyocardial placebo or open-label standard of care (SOC). The primary endpoint will be total exercise time at 6 months, with secondary endpoints of angina frequency and change in CCS angina class. Mortality will be followed for 2 years. SOC subjects will have the option to receive CLBS14 treatment after an initial 6-month observation. A favorable outcome in conjunction with previous data has regulatory support for submission and review of a BLA for CLBS14 for this orphan-sized indication. Considerations around study design and regulatory implications for this first potentially approvable cardiovascular cell therapy, including pathways to conditional approval, will be discussed.

Background & Aim CLBS12 (autologous, mobilized peripheral blood derived selected CD34 cells) has previously been studied for the treatment of No-Option Critical Limb Ischemia (NOCLI) in Phase 1 and 2 studies in Japan and the United States. These studies demonstrated statistically significant improvement in key outcome measures including reduced Rutherford category, improved walking distance, reduction in pain, improvement in blood flow and tissue oxygenation, reduction in size and number of ulcers, and improved amputation-free survival. In one of the Japan studies, more than 80% of subjects treated with a single administration of CD34 cells became CLI-free and maintained this status through 4 years of observation. The promising results of these studies led to discussions with the PMDA regarding the design of a confirmatory study that, with a favorable outcome, could support registration of CLBS12 in Japan for NOCLI under the new regenerative medicine regulations. Methods, Results & Conclusion The study is a prospective, randomized clinical trial in subjects with arteriosclerosis obliterans (ASO; n=30) or Buerger's Disease (BD; n=5). All patients receive standard-of-care treatment (SOC). The study calls for randomization of 30 subjects with ASO to receive either CLBS12 or to continue with SOC alone. Additionally, 5 subjects with BD were to be allocated to a sub-study and receive CLBS12 while continuing SOC treatment. The primary endpoint for the study is ability to achieve a continuous CLI-free state. Other key measures include progression-free, amputation-free, and overall survival; Rutherford category; tissue oxygenation; blood flow; ulcer size, depth, and infection; pain; and quality-of-life. For preparation of CLBS12, subjects are mobilized with GCSF 5 µg/day for 5 days, then undergo apheresis to collect a mononuclear cell fraction. CD34 cells are separated using a magnetic separation method. CLBS12 is formulated as a cell suspension in proprietary media in a 10 mL volume for administration as a series of 20 intramuscular injections in one affected limb. The study was initiated in December 2017 and is expected to be completed in 2020. The BD sub-study has enrolled 6 subjects and half have achieved a continuous CLI-free state. Interim data from the trial will be presented. CLBS12 (autologous, mobilized peripheral blood derived selected CD34 cells) has previously been studied for the treatment of No-Option Critical Limb Ischemia (NOCLI) in Phase 1 and 2 studies in Japan and the United States. These studies demonstrated statistically significant improvement in key outcome measures including reduced Rutherford category, improved walking distance, reduction in pain, improvement in blood flow and tissue oxygenation, reduction in size and number of ulcers, and improved amputation-free survival. In one of the Japan studies, more than 80% of subjects treated with a single administration of CD34 cells became CLI-free and maintained this status through 4 years of observation. The promising results of these studies led to discussions with the PMDA regarding the design of a confirmatory study that, with a favorable outcome, could support registration of CLBS12 in Japan for NOCLI under the new regenerative medicine regulations. The study is a prospective, randomized clinical trial in subjects with arteriosclerosis obliterans (ASO; n=30) or Buerger's Disease (BD; n=5). All patients receive standard-of-care treatment (SOC). The study calls for randomization of 30 subjects with ASO to receive either CLBS12 or to continue with SOC alone. Additionally, 5 subjects with BD were to be allocated to a sub-study and receive CLBS12 while continuing SOC treatment. The primary endpoint for the study is ability to achieve a continuous CLI-free state. Other key measures include progression-free, amputation-free, and overall survival; Rutherford category; tissue oxygenation; blood flow; ulcer size, depth, and infection; pain; and quality-of-life. For preparation of CLBS12, subjects are mobilized with GCSF 5 µg/day for 5 days, then undergo apheresis to collect a mononuclear cell fraction. CD34 cells are separated using a magnetic separation method. CLBS12 is formulated as a cell suspension in proprietary media in a 10 mL volume for administration as a series of 20 intramuscular injections in one affected limb. The study was initiated in December 2017 and is expected to be completed in 2020. The BD sub-study has enrolled 6 subjects and half have achieved a continuous CLI-free state. Interim data from the trial will be presented.

Early evidence from COVID-19 patients and autopsy series indicates that moderate to severe cases are accompanied by damage to the pulmonary endothelium and microcirculation. These data indicate that SARS-CoV-2 infection is particularly avid for lung microvascular endothelium, reflecting endothelial cell infection, inflammation, and focal thrombi occluding the pulmonary circulation leading to progressive fibrosis reminiscent of endothelial-mesenchymal transition. This appears to be a potential mechanism by which COVID-19 causes progressive fibrotic changes, impairment in the pulmonary vasculature, and loss of lung function that persists after acute recovery. Early data from the SARS-CoV-1 epidemic indicated that CD34+ cells in the lung could also be a target of infection and that destruction of lung CD34+ progenitors could account for persistence of pulmonary manifestations. Preclinical studies reveal that restoration of microvasculature in the lung can trigger and sustain regeneration of lung tissue. The microvascular repair function of CD34+ has been documented in preclinical models and multiple human trials in ischemic tissue repair. Accordingly, we designed a clinical trial to evaluate autologous CD34+ cells (CLBS119) for amelioration/repair of COVID-19 lung damage. Subjects must be hospitalized for COVID-19 and have ongoing pulmonary involvement based on room air hypoxia. The study will include approximately 50% of subjects who cannot be liberated from ventilatory support. CD34+ cells will be mobilized with plerixafor and selected from the mononuclear fraction following apheresis. Doses up to 500 x 10 6 cells will be administered IV. Subjects will receive a single administration of cells. Key measures will include assessment of oxygenation, need for supplemental oxygen, pulmonary function assessments, radiographic assessments, and biomarkers. Subjects will be followed for 6 months following administration. Interim findings will be presented.