Trial offers hope to children with hypoplastic left heart syndrome

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Mesenchymal stromal cells (MSCs) have been the subject of intense study for decades, and their potency as a biological therapeutic agent has been demonstrated in a variety of animal models of disease and in numerous human phase 1/2 clinical trials. Nevertheless, few phase 3 clinical trials have unequivocally confirmed their ability to mediate their expected medical benefit. It is likely the lack of standards regarding MSCs’ critical quality attributes and of harmonized practices regarding tissue sources, isolation, and culture methods have all contributed to these conflicting outcomes. In addition, differences in the route of administration and lack of patient stratification data to allow identification of those who can unequivocally benefit from this type of biological treatment have further confounded interpreting data about the true therapeutic potential of these cells.

Recently, the FDA granted rare pediatric disease (RPD) designation to a well-characterized, off-the-shelf, proprietary MSC-based product—Stro-3-selected mesenchymal progenitor cells (MPCs/Rexlemestrocel-L)—for the treatment of hypoplastic left heart syndrome (HLHS), a rare (∼1 in every 4,000 births) but severe congenital heart defect in which structures of the left heart are underdeveloped, including the left ventricle (LV).¹ This designation represents a major step, as it will allow the product to receive a priority review voucher, thereby accelerating and streamlining the regulatory process to ensure this potentially life-saving product can reach patients with HLHS, a disease for which such a therapy is direly needed. Infants with HLHS may have lifelong complications, and cardiac dysfunction and, ultimately, heart failure (HF) remain the most common causes of death and indications for transplantation in this population.² Current treatments are palliative, with a series of three surgeries to increase blood flow and bypass the underdeveloped left side of the heart. Cell therapy for these patients has mainly focused on preventing the deterioration of cardiac function into HF.^3,4 In patients with HLHS and borderline LV after single-ventricle palliation, staged LV recruitment is feasible to gradually promote volume loading of the hypoplastic LV and encourage growth.

Building off the DREAM-HF phase 3 trial in adults,⁵ the recent study⁶ that led the FDA to assign RPD designation to Rexlemestrocel-L aimed to investigate the safety and feasibility of administering MPCs to pediatric patients, during the LV recruitment phase, to stimulate growth and allow for biventricular conversion. Adverse events were reported in both MPC recipients and controls with similar frequency and severity, leading to the conclusion that they were unrelated to the MPCs. Of some concern was that, of the 24 patients planned for enrollment, the total number of randomized subjects was ultimately limited to 19 when the manufacturer curtailed release of MPCs. Importantly, although this trial was not powered to detect efficacy (n = 19), more than 50% of subjects underwent biventricular conversion within 2 years (n = 12), with 100% success (5/5) in MPC-treated patients.

With safety and feasibility demonstrated, larger human trials can be undertaken to investigate dosage, examine mechanisms, and establish the therapeutic potential of MPCs, and perhaps other promising cell populations,⁷ in this fragile patient population. Therefore, the RPD designation for this product is propitious, as it could mean that more patients with this rare disease could be treated, the definitive therapeutic efficacy determined, and lives saved.