Vitiligo topical treatment applying a potent, highly selective MC1R agonist

PROJECT SUMMARY
Vitiligo is the most common acquired hypopigmentary disorder that afflicts 0.5-2% of the world population, from
all ethnicities and skin color. It is characterized by loss of melanocytes, which is often progressive, resulting in
depigmented skin lesions. Vitiligo can be segmental (5-16% of all cases) or most commonly, non-segmental. It
is a disease of young adults, as 25% of all non-segmental vitiligo patients develop the disease by age 10, and
50% develop it by age 30. Vitiligo is erroneously perceived to be merely cosmetically disfiguring and not life-
threating. However, in addition to other pathologies, such as alopecia areata and Hashimoto’s thyroiditis, the
disease carries with it a tremendous psychological burden and social stigma, and a high rate of suicide,
particularly in patients with skin of color. Repigmentation of vitiligo skin is difficult, time-consuming, and
unpredictable. Even after successful repigmentation, there is 40% chance of recurrence of loss of pigmentation,
which adds to the patients’ anxiety and mental anguish. Multiple mechanisms have been proposed for
melanocyte destruction in vitiligo, including autoimmune response, generation of inflammatory mediators,
genetic factors, pro-oxidant state in skin, and intrinsic melanocyte abnormalities and detachment. The immune
response can be either the primary cause of melanocyte destruction or can be secondarily activated by neo-
antigens expressed on melanocytes. We hypothesize that persistent and more rapid repigmentation of
vitiligo skin will be achieved by targeting the melanocortin 1 receptor (MC1R) expressed on human
melanocytes by topical application of a superpotent and selective agonist. The PI has reported that
activation of MC1R expressed on human melanocytes by the physiological agonist α-melanocyte stimulating
hormone (α-MSH) promotes melanocyte proliferation, attachment, survival, normal redox state and
melanogenesis. These findings led her to develop potent tetrapeptide analogs of α-MSH that mimic its function
in human melanocytes. Her major goal is to develop one of these tetrapeptide analogs, LK 184, which is highly
selective for MC1R and 10-fold more potent than α-MSH, in a topical formulation to treat depigmented vitiligo
lesions. The Specific Aims are to develop LK 184 in an optimal topical formulation and provide preclinical ex vivo
and in vivo evidence of its efficacy and safety in stimulating long lasting pigmentation. The efficacy of LK 184 is
supported by her data, and by reported clinical trials showing that the full length α-MSH analog NDP- α-MSH
enhances repigmentation of vitiligo skin, when combined with narrow band UVB. However, NDP- α-MSH is not
selective to MC1R, has extracutaneous effects, and has to be administered systemically. The expectations are
that use of the first in class agent, LK 184, in combination with other existing treatments will have a huge positive
impact on the quality of life of vitiligo patients, and limit the use of potentially dangerous immunosuppressives.
The proposed studies will satisfy many requirements for regulatory approval of commercialization of LK 184 for
vitiligo treatment by MC1R Ventures LLC.

Grant Number: 1R41AR083311-01
NIH Institute/Center: NIH
Principal Investigator: ZALFA ABDEL-MALEK