Background: Necrobiosis lipoidica (NL) is a rare, chronic granulomatous skin condition with no FDA- approved therapies. PCS499, an oral deuterated analog of pentoxifylline, has anti-inflammatory and antifibrotic properties that may offer therapeutic benefit. This Phase II open-label study (NCT03698864) evaluated the safety and exploratory efficacy of PCS499 in adults with NL.

Methods: Twelve adults with biopsy-confirmed NL were enrolled to receive PCS499 (900 mg orally, twice daily) for 6 months, with an optional 6-month extension. Safety was assessed by adverse event (AE) monitoring, labs, and ECGs. Exploratory efficacy endpoints included lesion characteristics, photography, and validated clinician-and patient-reported outcomes such as Investigator Global Assessment (IGA), NL Color and Ulcer Scale (NLCUS), Physician and Patient Global Assessments (PGA, PtGA), Dermatology Life Quality Index (DLQI), and Skindex-29. Ten subjects completed treatment and were included in the efficacy analysis. Clinical outcomes were summarized descriptively; changes from baseline to month 6 were evaluated using Wilcoxon signed-rank tests (p < 0.05 significant).

Results: All subjects were female with a median age of 41; 80% had diabetes mellitus, 20% had ulcerated NL, and mean disease duration was 12.7 years. PCS499 was generally well tolerated. The most common AEs were mild gastrointestinal symptoms. One subject discontinued during the optional extension period due to a treatment-emergent AE of alopecia that was mild and assessed as probably related to the study drug. No serious AEs or clinically significant lab or ECG changes occurred.

Among the two subjects with ulcerated NL, one achieved complete wound healing by day 85 and the other by day 351, with no recurrence through 12 months. Reference ulcer area decreased >75% by month 6 in both cases, and continued treatment through the extension period led to the closure of all remaining ulcers.

In the full cohort, five of ten subjects achieved “clear” or “almost clear” status on the IGA, with a mean time to response of 111 days (range: 54–166). Significant improvements were seen in IGA Activity (Δ −1.3, p = 0.026), PGA (Δ −1.4, p = 0.038), NLCUS inflammation/color (Δ −0.9, p = 0.024), and induration (Δ −0.9, p = 0.037). PtGA and DLQI improved without reaching statistical significance. Skindex-29 scores improved in all domains, with a significant change in the function domain (Δ −10.8, p = 0.045) and trends in symptom and emotion domains.

Conclusion: PCS499 was safe and well tolerated, with evidence of clinical response and improved quality of life, especially in the ulcerated group. Findings support further investigation in larger controlled trials.