Translational development of a stressed allogeneic peripheral blood mononuclear cell secretome for diabetic foot ulcer, from the MARSYAS II trial (NCT04277598) to the APO2FOOT pivotal study design.
Year: 2026
Type: preprint
Abstract: Background. Chronic diabetic foot ulcer (DFU) is a major unmet need and no active wound-care product is standard of care. APOSEC is the cell-free secretome of irradiated, stress-conditioned allogeneic peripheral blood mononuclear cells (PBMC), a biological medicinal product that promotes angiogenesis and tissue repair in preclinical models. Two generations of APOSEC development are reported, the trial-grade prototype APO-2P used in the clinical study MARSYAS II and the optimised final product APO-2F developed thereafter.Methods. MARSYAS II was a randomised, double-blind, placebo-controlled phase I/II study with a safety lead-in (phase I part). The whole study was conducted at 12 sites in four European countries. 122 patients with DFU of Wagner grade I to II or Armstrong grade I-A or II-A received topical APO-2P at 12.5, 25.0 or 50.0 U/mL or placebo, three times weekly for 4 weeks; the study included a follow-up period of with 8 weeks. The primary endpoint was percentage reduction in centrally adjudicated wound area at week 4. Following MARSYAS II, APO-2F is being developed and evaluated through potency testing, comparability studies with APO-2P, and a db/db mouse wound-healing model.Results. At week 4 the mean wound-area reduction was 59%, 31% and 47% with APO-2P at 12.5, 25.0 and 50.0 U/mL against 29% with placebo in the full analysis set (n = 122). None of these results were significant, nor were those in the centrally adjudicated subgroup of 94 patients meeting the inclusion criteria defined in the study protocol. However, post-hoc responder analyses were directionally consistent. A reduction of at least 80% at week 4 occurred in 48% of patients in the 50.0 U/mL group against 20% with placebo, and complete closure rose through follow-up to 36% against 27% of patients. Placebo healing was unexpectedly high, possibly reflecting the hydrogel vehicle. APO-2P was well tolerated with one treatment-related adverse event and no treatment-related serious adverse events. In subsequent product-development studies, APO-2F met the predefined potency and identity specifications, showed angiogenic activity comparable to APO-2P, and, when delivered on an alginate fleece, accelerated early wound closure relative to gel-delivered APOSEC in db/db mice.Conclusions. APO-2P was safe and produced a dose-related healing signal that a 4-week percentage-reduction endpoint could not capture. These findings and the utilisation of APO-2F instead of APO-2 P define APO2FOOT, an observer-blind pivotal trial against standard of care with complete wound closure at 12 weeks as primary endpoint.Trial registration. ClinicalTrials.gov NCT04277598, prospectively registered 20 February 2020, before first enrolment on 11 November 2020. EudraCT 2018-001653-27.
Source: Figshare
Authors: Lisa Auer, Hannes Kühtreiber, Helmut Hofbauer, Michael Erb, Dirk Sorgenfrey, Anja Peterbauer-Scherb, Sylwia Gazda-Miarecka, Paul Felix Harbich, Lea Ann Dailey, Susanne Süssner, Nina Langoth-Fehringer, Matteo Watzka, Melanie Salek, Sophie Alexandra Röder, Bahar Golabi, Walter Wetzel Roth, Clemens Aigner, Wolfgang P Weninger, Michael Mildner, Hendrik Jan Ankersmit
Language: English
Topic: Wound Healing and Treatments
Subfield: Rehabilitation
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204467480