Background: Mesenchymal stem/stromal cells are self-renewing, multi-potent stromal cells which act as modulators of immune responses. Umbilical cord-derived mesenchymal stromal cells, a classification of cells that includes umbilical cord lining stem cells (ULSC) may be associated with a younger cellular phenotype with minimal expression of HLA-DR after activation, which is expected to correlate with reduced immunogenic potential. Dermatomyositis/Polymyositis (DM/PM) is a heterogeneous disease with complex pathophysiology that may be efficiently counteracted by USLC therapy at various levels, including inhibition of plasmacytoid dendritic cell production of type-1 interferon, regulation of B cell maturation, and enhancement of T regulatory cell development. Here we describe the rationale for use of ULSC based on results of a phase I trial in patients with idiopathic inflammatory myopathy (IIM) and we outline the study design for a phase 2 trial.

Objectives: The overall objectives are to evaluate the potential efficacy of umbilical cord lining stem cells (ULSC) to ameliorate the manifestations of disease and to promote a pre-specified down-titration of steroids as well as other standard immunosuppressive agents in participants with idiopathic inflammatory myopathy (IIM).

Methods: The phase I trial was a first in human, open-label, non-controlled, dose-escalation trial that investigated a single intravenous infusion of ULSC in patients with IIM. This trial was registered prospectively with ClinicalTrials.gov (NCT04723303). Subjects had definite or probable dermatomyositis or polymyositis, with a characteristic muscle biopsy that excluded features of muscular dystrophy, metabolic myopathies, drug-induced myopathy, inclusion body myopathy, and necrotizing myopathy. Patients with IIM were recruited with active disease on treatment or in remission on treatment. A total of nine subjects were enrolled with 3 participants in each of 3 dose groups, consisting of an intravenous Infusion of 50, 100, or 200 million ULSC, with follow up of 12 months. In the Phase 2, double-blinded, randomized, dose-repeating, cross-over trial, efficacy and safety will be assessed based on the effects of ULSC on change in disease activity from baseline (evaluated as the standard weighted sum of 6 core set measures of improvement), at repeating doses of 1 x 108 cells per doses provided on Day 0 and Month 4 (Cohort 1; 40 subjects), in comparison with Cohort 2 (40 subjects), which will receive placebo carrier solution on Day 0 and Month 4. With a true cross-over design, participants in Cohort 1 will switch to Placebo for the infusions at Months 8 and 12. Participants in Cohort 2 will switch to ULSC (1 x 108 cells per dose) for the infusions at Months 8 and 12. For participants undergoing steroid therapy (Prednisone), a prescribed steroid tapering schedule will be initiated 2 weeks after the baseline infusion. The steroid tapering schedule will target reduction from baseline to ≤5 mg. The primary endpoint evaluation will be at 8 months. A target will be the Total Improvement Score (TIS) in the 6 core set measures, of TIS>20 points. Secondary endpoints will include changes from baseline in pain, activity, and quality of life in participants with IIM, evaluated at 7 and 30 days following each infusion. Efficacy will be be evaluated from baseline to 8 months, and again at 16 months, comparing the feasibility of steroid dose reduction (steroid-sparing effect) between Cohorts 1 and 2.

Results: Nine subjects completed the Phase 1. Safety and Tolerability outcomes included one Adverse Event attributed to the study product by both the Principal Investigator and the independent IDMC, a flushing reaction occurring during the infusion for the first subject. The infusion was temporarily paused, 150 mg intravenous hydrocortisone administered, and the infusion re-initiated with no recurrence. Exploratory efficacy data showed that 6 of 9 subjects met criteria for moderate improvement with total improvement score (TIS) of ≥40% – a composite outcome of six core measures of myositis activity – within 6 months of the infusion. Criteria for significant improvement, TIS of ≥20, was met by 7 of 9 subjects. Manual Muscle Testing (MMT8) showed a significant improvement in strength between baseline and Month 6 of nearly 10 points on the scale, 59 ± 4 at baseline and 68 ± 4 at Month 6 (mean ± SEM), p< 0.001. Average prednisone dosage decreased by 35% at 6 months, when excluding data from one subject (a non-responder by TIS) who had a flare treated with corticosteroids at that time point.

Conclusion: Taken together, the overall human experience with the intravenous infusion of ULSC has demonstrated an absence of adverse outcomes attributable to this investigational product, and in the context of DM/PM, has demonstrated early evidence of clinical improvement in multiple participants using complementary outcome measures, in the context of progressive reduction in steroid dosing. A phase 2 trial has been designed that will further evaluate safety and efficacy endpoints.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Michael Bubb AbbVie/Abbott, Alexion, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKlein, Priovant, Restem, UCB, Eileen Handberg Restem, Rafael Gonzalez Restem, Blas Betancourt: None declared, Keith March Restem, Restem, Carl Pepine Restem.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.