Since our announcement last year that Clinuvel would commence a new program for SCENESSE® (afamelanotide) in nonsegmental vitiligo, the company has received vast interest in the application of the drug in this disease. Of the enquiries that best captured the essence of this program, one stood out: a US based analyst asked how the company intended to objectively measure the response to treatment, the repigmentation of vitiliginous lesions, in its trial.
Those acquainted with drug development will know this is the key question.
When evaluating a new therapy, one must be able to show the effects of that therapy first in isolation, then in comparison to the current standard of care (if it exists) and/or a placebo. The evaluation of the response to treatment must be objective and, importantly, should be done using a recognised method which allows third parties (initially regulators, but also the broader medical community) to compare the treatment to other therapies.
Vitiligo is a disorder where skin parts gradually lose pigment by the appearance of white lesions or ‘patches’. The pigment loss can be gradual or dramatic and can cease or recommence, spreading without warning. The medical community doesn’t quite yet know the reason for its onset. The goal of vitiligo therapy is to stop the spread of pigment loss and to return pigment to the lesions. One of the key issues in the evaluation of these therapies, however, has been how best to objectively measure the extent of repigmentation achieved and the time taken for the pigmentation to be restored.
Over the past decade, two methods of evaluation have been proposed and assessed in peer reviewed literature: the Vitiligo Area Scoring Index (VASI) and the Vitiligo European Task Force (VETF) system. Importantly, the two methods are recognised by the regulatory agencies EMA and FDA.
The VASI is a validated quantitative scale developed by a North American team (Hamzavi et al, see references below) with the goals of quantifying the total extent of depigmentation, allowing physicians to measure de/repigmentation over time and evaluating the effect of treatment on various body sites. Based on the Psoriasis Area Severity Index (PASI; a system for objectively measuring psoriasis), the VASI was initially developed to measure the response of vitiligo to narrowband ultraviolet-B (NB-UVB) treatment, but has since been used to evaluate various vitiligo therapies.
In the VASI assessment, the body is separated into five sites: hands, upper extremities, trunk, lower extremities and feet (subsequent studies have added a sixth site: the head/neck). Each site is clinically evaluated by visual assessment for the percentage of vitiligo involvement (depigmented skin) and the degree of skin depigmentation (using a visual scale of 0, 10, 25, 50, 75, 90 or 100%). The VASI score is then derived by multiplying the values assessed for the vitiligo involvement by the percentage of affected skin for each body site and summing the surface of the lesions of all body sites together.
Clinical evaluations of vitiligo therapies now use the VASI to assess initial levels of depigmentation then to monitor the levels of repigmentation achieved over a period of time and will often provide a percentage improvement of VASI seen (overall and/or at individual body sites). While criticisms have been leveled at the subjectivity of the VASI, it is generally accepted that the VASI allows for a more practical clinical workup than more time or resource intensive methods.
Based on SCORAD, a clinical evaluation system for atopic dermatitis, the VETF system has been developed over several years by a European group (see full list of the VETF team in Taïeb & Picardo reference below). The VETF evaluation system seeks to add more specific parameters to the quantitative measurement of depigmentation. Indeed, the VETF assesses the three dimensions of the disease (extent, staging and spreading/progression), and so provides three different values. Similar to the VASI assessment, the body is also separated into five different sites, specifically the head/neck, trunk, arms, legs and hands/feet.
Each site is clinically evaluated by visual and photographic assessment for the extent or percentage of vitiligo involvement (depigmented skin), the staging and the spreading of vitiligo. The staging and the spreading of vitiligo are assessed on the largest lesion within each specific body site. A specific UV light (a Wood’s lamp which allows the dermatologist to view pigment which is impossible to determine with the naked eye) is then used to illuminate the skin. Staging is assessed using grades from 0 (normal pigmentation) to 4 (complete hair whitening). Spreading is assessed using the following scores: 0 (stable disease), -1 (regressive disease) and +1 (progressive disease).
A clinical assessment form can also accompany the scoring in the VETF system to determine various factors within the given patient population, including the sex, age, duration of disease, age of onset, episodes of repigmentation, impact of vitiligo on quality of life, family history, additional medical conditions and the Fitzpatrick skin type of the patients involved. This allows for a greater clinical workup and for physicians to compare treatments based on reported factors beyond depigmentation; the downside being that this is a very labour intensive approach.
While the two systems differ in their approach and outcomes, both are widely recognised as validated standards for the comparative evaluation of vitiligo and vitiligo treatments under clinical conditions. Importantly, they also allow independent reviewers to objectively evaluate the efficacy of a treatment on an internationally recognised scale.
For more information on Clinuvel’s vitiligo program, go to www.clinuvel.com/vitiligo
Hamzavi I, et al (2004). “Parametric modeling of narrowband UV-B phototherapy for vitiligo using a novel quantitative tool: the Vitiligo Area Scoring Index.” Arch Dermatol. 140(6):677-83. Abstract online
Taïeb A, Picardo M & VETF Members (2007). “The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force.” Pigment Cell Res. 20(1):27-35. Abstract online
VETF, (2005). “Report on the 19th IPCC Satellite Symposium on Vitiligo, Reston Virginia”. Online: http://www.espcr.org/docs/Report_VETF_IPCC2005.pdf.