A spray formulation of allogeneic neonatal keratinocytes and fibroblasts significantly improved wound healing in a multicenter, randomized, placebo-controlled phase II study of more than 200 patients with venous leg ulcers.
The mean reduction in wound area was significantly greater among 177 patients who received 12 weeks of active treatment with the novel cell therapy, known as HP802-247, than among 50 patients who were treated with application vehicle of a modified fibrin spray alone. HP802-247 consists of cryopreserved, allogenic, growth-arrested fibroblasts and keratinocytes derived from neonatal foreskin. The largest improvement (16% on average over placebo) was seen in 44 patients assigned to treatment with 5.0x106 cells per mL every 14 days, Dr. Robert S. Kirsner of the University of Miami and his colleagues reported. The study was published online in the Aug. 3 issue of The Lancet.
Reduction in wound area was between 8% and 12% over that seen with placebo in 45 patients treated with 5.0x106 cells per mL every 7 days, 44 patients treated with 5.0x106 cells per mL every 14 days, and 43 patients treated with 0.5x106 cells per mL every 7 days, the investigators said (Lancet 2012 Aug. 3 [doi:10.1016/S0140-6736(12)60644-8]).
The study investigators included vascular surgeons, dermatologists, and podiatrists at universities and in private practice. All patients were treated with standard compression bandaging as well as the study treatment.
"Wound area began to decrease rapidly after initiation of treatment. After one application of the 0.5x106/mL every 14 days dose, the mean reduction in wound area was 40%, compared with 23% for the vehicle group. This effect persisted with the maximum difference in mean reduction between the group assigned [0.5x106 cells per mL] every 14 days and the vehicle group occurring at week 7 of treatment (87% vs. 65%)," they wrote.
At week 12 of treatment, the mean wound area in the group treated with 0.5x106 cells per mL every 14 days was reduced by 91%, compared with 80% with vehicle, and for the other treatment groups, the mean wound area was reduced by between 84% and 87%.
"Overall, patients treated with cells had higher proportions of healed wounds than did those assigned vehicle alone, but only the group assigned [0.5x106 cells per mL] every 14 days differed significantly compared with control," they noted.
Adverse events were similar across all groups, and most were nonserious, mild to moderate events that resolved. Only new skin ulcers and cellulitis occurred at a frequency of greater than 5%. Immunotoxicity testing showed that there was no treatment-induced alloantibody formation or induction of autoimmunity.
Included in this study were adult outpatients enrolled from 28 centers in the United States and Canada between 2009 and 2011. All had venous reflux confirmed by duplex Doppler ultrasonography, and up to three venous leg ulcers. Those assigned to the placebo group received vehicle alone applied every 7 days for the 12 weeks of the trial.
The findings may have important implications for the treatment of venous leg ulcers, which affect an estimated 1.65% to 1.74% of adults aged 65 years and older. Standard treatment with infection control, primary dressings, and high-strength compressions heal between 30% and 75% of such ulcers, compared with the 84%-91% healing seen with HP802-247 in this study, with the remainder becoming "chronic, with unresolved inflammatory processes within the extracellular matrix of the wound bed and dysfunction of wound fibroblasts and keratinocytes," the investigators noted.
"The results are sufficiently promising that larger randomized trials comparing HP802-247 to standard treatment for venous leg ulcers are now warranted," they concluded.
The researchers reported that their study was limited by the wound upper end boundary of 12 cm3, which represents 80% of all venous leg ulcers, but a smaller proportion of chronic venous ulcers.
The research trial is registered with ClinicalTrials.gov as NCT00852995.
Dr. Kirsner received consulting fees for his assistance with protocol design and data interpretation. Two of his coauthors also received such consulting fees, and other authors on the study disclosed that they are employed by Healthpoint, and/or hold adjunct academic appointments at the University of North Texas Health Sciences Center in Fort Worth, Tex.