Igor V. Korobko,1 Konstantin M. Lomonosov1,2

1 VR Foundation, New York, NY, USA (i.korobko@vrfoundation.org) 2 Department of skin and venereal diseases, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

ABSTRACT INTRODUCTION & OBJECTIVES Vitiligo is a pigmentary disorder affecting around 0.5% of the world population. Recent vitiligo treatment armory is quite scanty, and little efforts are undertaking to bring novel treatment options to patients, most likely due to a non-life threatening nature of the disease. Yet vitiligo often results in a social repulsion and psychological burden thus demanding for novel treatments to cope with this condition. Stopping depigmentation progression is a prerequisite for subsequent successful repigmentation when dealing with active vitiligo. Although mechanisms of vitiligo pathogenesis are far from being completely understood, disease progression is most likely linked to autoimmune processes. Sodium oxodihydroacridinylacetate (ODHAA) is a substance with immunomodulatory activity which is used to normalize impaired immune system functions under various conditions. The aim of the study was to investigate efficacy of ODHAA in stabilizing active vitiligo. MATERIALS & METHODS Sixty patients with active non-segmental vitiligo were treated with ODHAA (10 intramuscular injections every other day). Vitiligo progression was assessed in 1, 3, 6 and 12 months after treatment. Serum tumor necrosis factor a (TNFa) and interleukin-6 (IL-6) levels were measured prior and after treatment by IVD-certified ELISA.

ABSTRACT (continued) RESULTS After treatment with ODHAA, in 44 out of 60 patients (73.3%), cessation of vitiligo activity has been observed, with disease remaining stable in 12 month follow-up. In 4 patients, some repigmentation of depigmented lesions was seen. The treatment was well tolerated by the patients, and no side effects were observed. Absence of other autoimmune diseases, younger age and shorter disease duration correlated with favorable treatment outcome. In addition, serum IL-6 level prior the treatment emerges as a prognostic factor to predict successful arresting disease progression by ODHAA. CONCLUSIONS Our results enlighten ODHAA as a novel efficient agent for active vitiligo treatment and warrant its further investigation in a larger study.

Stop disease progression

Induce repigmentation

Prevent recurrence

Systemically acting treatments: Phototherapy – lengthy treatment with strict schedule Steroids – side effects Experimental treatments – side effects, incomplete efficacy

Stop disease progression

Induce repigmentation

Prevent recurrence

? Need for convenient side effect free treatments

N-acridone acetic acid: sodium or N-methylglucamine salt

•Long-term officially approved use in medicine •Excellent safety profile

Mode of action: •Immunomodulating compound, interferon inducer

Official indications:

•Viral infections •Immunodeficiency •Oncological diseases •Multiple sclerosis

•Long-term officially approved use in medicine •Excellent safety profile

Mode of action: •Immunomodulating compound, interferon inducer

Official indications:

•Viral and bacterial infections •Rheumatoid and systemic connection tissue diseases – suppressing autoimmune reactions, anti-inflammatory

• alterations in blood immunophenotype (CD3+, CD4+, CD8+, CD19+; CD4+/CD8+) • positive results in experimental treatment of diseases with autoimmune etiology: - rheumatoid arthritis; - lupus erythematosus; - psoriasis, which were accompanied by normalization of immunophenotype in peripheral blood

Autoimmune reaction

Vitiligo activity

Acridone acetic acid

Normalizing immune system functions, including autoimmune processes

Acridone acetic acid Active vitiligo ?

Aim: to evaluate efficiency of acridone acetic acid, sodium salt, in stopping active nonsegmental vitiligo progression

Study design: • pilot uncontrolled study; • 60 patients with nonsegmental vitiligo were treated by

10 i.m. injections (250 mg each) every 48 hrs; • serum IL-6, IL-8, TNFa and serum, spontaneous and

induced IFNa and IFNg levels were determined prior to and after the treatment;

• disease activity was assessed in 1, 3, 6 and 12 months after treatment.

Gender: females – 38 (63.3%); males - 22 (36.7%) Age: 34.3±10.2 years (range 18 – 64) Disease duration: 13.6±8.7 years (range 1 – 36) Vitiligo type: localized – 46 (76.7%), generalized – 14 (23.3%) Leukotrichia: 6 patients (10%) Family history: 7 patients (11.7%) Co-morbid autoimmune diseases: 6 patients (10%)

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44 out of 60 patients (73.3%)

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disease stabilization

Presence of other autoimmune pathologies Р=0.038, OR=7.0, 95% CI 1.14-42.97; n=6

Lower age 32.5±10.1 years, n=44 versus 39.2±8.8 years, n=16, Р=0.0219 Age under 35: Р=0.0189, OR=5.2, 95% CI 1.30-20.84 Age under 40: Р=0.0039, OR=6.48, 95% CI 1.86-22.61

Shorter disease duration 12.1±8.0 years, n=44 versus 13.6±8.7 years, n=16, Р=0.0234

High IL-6 level before treatment

Serum IL-6 above normal level (>5.9 pg/ml) Р=0.0009, OR=25.8, 95% CI 2.8-239

Detectable (>2 pg/ml) serum IL-6 Р=0.0005, OR=13.7, 95% CI 2.97-63

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In the preliminary study, sodium oxodihydroacridinylacetate showed high efficiency in achieving long-term stabilization of nonsegmental vitiligo Lower age, shorter disease duration, lack of other autoimmune diseases, and low serum IL-6 level are predictors of good response Further controlled studies are required to prove it efficiency and further validate prognostic factors

Sodium oxodihydroacridinylacetate (and other salts of acridone acetic acid) emerges as novel treatment for vitiligo

•efficient and long-term cessation of disease activity; •excellent safety profile

Identified clinical parameters permit prediction of response:

• rational selection of treatment; •personalized approach

Potential to apply for vitiligo recurrence prevention:

•none presently exists.

I.M. Sechenov First Moscow State Medical University

Vitiligo Research Foundation (VR Foundation)