Design of a confirmatory pivotal study with intramyocardial GCSF-mobilized autologous CD34 cells (CLBS14) for the treatment of an orphan-sized population with no-option refractory disabling angina

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.