Vitiligo, a "beauty killer" affecting 120 million people worldwide.
The legendary superstar Michael Jackson conquered millions of fans with his unique stage style and unparalleled musical talent. However, his dramatic skin color change became a focal point for public controversy and misunderstanding. As a Black man, his skin gradually turned white until nearly his entire body was pale. During that time, numerous false rumors spread, accusing him of "betraying his race" and using so-called "bleaching" techniques to deliberately change his skin color, transforming into a "white" person. The truth, however, was that Michael Jackson suffered from severe vitiligo, a condition that had plagued him since the 1970s, forcing him to rely on heavy makeup to cover the abnormality of his skin.
To this day, vitiligo remains an unsolved medical challenge, with a global incidence rate approaching 2%. In China alone, nearly 20 million people are affected. Particularly concerning is that this disease is prevalent among adolescents, who are in a critical period of growth. Vitiligo causes significant misunderstandings and discrimination in areas such as academics, social life, and emotions, severely impacting both their physical and mental health.
Whether in terms of patient numbers or the harm caused, overcoming vitiligo would bring great social value.
Vitiligo (Vitiligo) is a chronic, systemic, common skin disease caused by the reduced or absent activity of tyrosinase in melanocytes within the skin and hair follicles, leading to a reduction or disappearance of melanin granules, resulting in localized or generalized depigmentation.
Clinically, vitiligo is characterized by localized or generalized complete depigmentation of the skin and mucous membranes. It often begins with one or several patches of skin with unclear borders. Most patients experience no obvious symptoms, but as the condition progresses, lesions of various shapes and sizes gradually spread.
Vitiligo is painless and non-itching, not contagious, and does not affect lifespan, but it causes significant cosmetic concerns, making it a "disfiguring" skin disease. If vitiligo appears on exposed areas, it can have a significant psychological impact on the patient. According to the American Academy of Dermatology, the probability of depression in vitiligo patients is as high as 22% to 31%, much higher than the global average of 3.1%. Furthermore, vitiligo patients have a weakened ability to defend against ultraviolet rays, resulting in a higher incidence of skin cancer. As patients age, they are also more susceptible to autoimmune complications.
The global prevalence of vitiligo is close to 2%, and it is estimated that there are as many as 120 million vitiligo patients worldwide, with nearly 20 million in China. The incidence has been gradually increasing in recent years. Vitiligo does not show a gender difference, and it can occur at any age, although it is most common in adolescents under the age of 20. In China, for example, 63.4% of patients are under 20 years old.
Despite a strong desire for treatment, there is still no definitive method to completely cure vitiligo. The main reason is that the cause of vitiligo is not yet clear. Modern research indicates that the pathogenesis of vitiligo is complex, involving immune theories, oxidative stress theories, genetic theories, and more.
Among these hypotheses, the autoimmune theory has been the focus of recent studies. It suggests that vitiligo is caused by CD8+ T cells in the body attacking melanocytes. T lymphocytes, especially cytotoxic CD8+ T cells, infiltrate the epidermal-dermal junction and continuously attack melanocytes in healthy areas, leading to the continued expansion of depigmented regions.
Vitiligo immune circuit
The oxidative stress theory proposes that an imbalance between oxidation and antioxidation in melanocytes triggers vitiligo. In vitiligo patients, various endogenous or exogenous factors may reduce the activity of antioxidant enzymes or generate excessive reactive oxygen species, creating an oxidative stress state. This condition further damages the DNA, proteins, and lipids in melanocytes, leading to melanocyte apoptosis or dysfunction.
The more one learns, the more one realizes how little knowledge there is. As more studies are conducted, single theories are no longer sufficient to explain the full picture of melanocyte reduction or disappearance. More scholars tend to believe that vitiligo is the result of multiple factors working together. Among these, oxidative stress is considered a key initiating factor, which mediates intrinsic damage to melanocytes, activates the skin’s local innate immune response, and induces the release of chemotactic factors and cytokines from keratinocytes, thereby triggering a specific T cell immune response against melanocytes. This is a key mechanism leading to vitiligo.
Due to the complex pathogenesis of vitiligo, current treatment options are very limited. Traditional treatments mainly include topical medications (such as corticosteroids, immune modulators, etc.), systemic medications (such as corticosteroids, antioxidants, etc.), phototherapy, and surgical treatments (such as autologous epidermal transplantation, melanocyte transplantation), but none of these achieve ideal results.
Topical corticosteroids, such as halometasone cream and mometasone furoate cream, are suitable for early localized vitiligo and can play an anti-inflammatory, immunosuppressive, and anti-proliferative role in vitiligo treatment. They help suppress autoimmune damage to melanocytes, aiding their survival and functional recovery. However, long-term use is not recommended as it may cause side effects like skin atrophy and capillary dilation. Systemic corticosteroids, such as prednisone, are used for generalized progressive vitiligo, but they come with a range of side effects such as osteoporosis, hypertension, and diabetes.
Calcineurin inhibitors, such as tacrolimus ointment and pimecrolimus cream, can suppress T cell activation and cytokine production, thereby reducing autoimmune attacks on melanocytes. They can also modulate the local immune microenvironment of the skin, promote melanocyte function recovery, and enhance melanin synthesis. These drugs do not cause the skin atrophy side effects associated with corticosteroids, but they can still lead to or worsen local infections like folliculitis and acne.
Vitamin D3 derivatives, such as calcipotriene ointment and tacalcitol ointment, can regulate the local immune response of the skin and increase the activity of tyrosinase in melanocytes, promoting melanin synthesis. However, they need to be used in combination with other medications, as their effect is slow, and they may require weeks or even months of continuous use to show any noticeable improvement.
It is worth noting that although the above drugs are included in the vitiligo treatment guidelines of many countries, none have been approved specifically for vitiligo indications. Currently, the only biologic agent approved for vitiligo is ruxolitinib cream.
Ruxolitinib cream, developed by Incyte, is a topical JAK inhibitor that was approved by the FDA in July 2022 for the treatment of non-segmental vitiligo in patients aged 12 and above. Results from two key Phase III clinical trials showed that by week 24, 29.9% of patients in the ruxolitinib group achieved at least a 75% improvement in their facial vitiligo severity score (F-VASI75), compared to 7.5% in the placebo group (TRuE-V1) and 12.9% in the second trial (TRuE-V2). Additionally, by week 52, about 50% of patients in the ruxolitinib group achieved F-VASI75.
Results of Phase III clinical trial of ruxolitinib cream
In December 2022, Kangzhe Pharmaceuticals announced that it had obtained the exclusive rights to develop and commercialize ruxolitinib cream in Mainland China, Hong Kong, Macau, Taiwan, and eleven Southeast Asian countries. On September 24, 2024, ruxolitinib’s New Drug Application (NDA) for vitiligo indications was accepted by the National Medical Products Administration of China. It had previously been approved for clinical emergency importation in Hainan Province and successfully launched in Macau.
Vitiligo is difficult to cure, and patients face long treatment cycles and high relapse rates, making the market potential enormous. While ruxolitinib is the only drug approved for vitiligo, its current revenue share is still small, failing to meet the full market demand. After the approval for vitiligo indications, ruxolitinib’s sales soared from $50 million in 2021 to $129 million in 2022, and further climbed to $338 million in 2023, a 162% year-on-year growth. Despite the rapid growth, the overall scale remains limited.
Overall, vitiligo remains in a state where significant breakthroughs are urgently needed in the medical field, with a highly significant and large unmet clinical demand. The development of new drugs holds broad market prospects.
In recent years, the medical community has been working tirelessly to find effective treatments for vitiligo, and many major innovative pharmaceutical companies have also begun to invest in this area. According to incomplete statistics, there are currently more than 20 ongoing vitiligo research pipelines globally, with their target exploration mainly focusing on JAK inhibitors, PDE4 inhibitors, and interleukin inhibitors, among others.
Among these, JAK inhibitors have undoubtedly become the focus of research and development.
In the pathological process of vitiligo, cytotoxic CD8+ T cells that produce IFN-γ activate JAK, triggering its phosphorylation and further activating STAT, which then affects gene expression and leads to melanocyte damage. JAK inhibitors can suppress the activity of JAK kinases, interrupting the excessive activation of the JAK-STAT signaling pathway mediated by cytokines. When applied to the skin of vitiligo patients, JAK inhibitors can effectively reduce the signaling of inflammatory cytokines such as IFN-γ and interleukin-15 (IL-15), significantly reducing the number of CD8+ T cells in the affected skin areas, thereby greatly alleviating immune attacks on melanocytes.
The already approved Ruxolitinib cream is the first and only topical JAK inhibitor approved by the FDA. Currently, many of the most advanced vitiligo drug candidates in the pipeline are related to the JAK target.
Leflunomide is a new oral JAK3 inhibitor developed by Pfizer. It is currently in Phase III clinical trials for vitiligo indications in the United States and is the fastest advancing vitiligo drug globally, besides Ruxolitinib cream. In a Phase IIb study, it was found that taking a 50mg tablet once a day significantly improved the proportion of facial vitiligo lesions (compared to a placebo group, the F-VASI score in the Leflunomide group decreased by up to 75% at 24 weeks).
Povorcitinib is an oral JAK1 inhibitor developed by Incyte and is currently undergoing Phase III clinical trials for non-segmental vitiligo and HS in several countries. Results from Phase IIb trials showed that after 24 weeks of treatment, patients receiving Povorcitinib daily showed significant repigmentation of their skin lesions compared to those receiving a placebo. In April of this year, Kangzhe Pharmaceutical obtained exclusive rights to develop, register, and commercialize Povorcitinib in Mainland China, Hong Kong, Macau, Taiwan, and eleven Southeast Asian countries.
Emmaxtinib is the first domestic JAK1 inhibitor independently developed by Hengrui Pharmaceuticals. It is indicated for conditions such as atopic dermatitis, ulcerative colitis, alopecia areata, ankylosing spondylitis, and vitiligo. In December 2020, Hengrui launched Phase II/III clinical trials for Emmaxtinib cream in China for the treatment of vitiligo, making it the fastest progressing vitiligo drug in the country.
Additionally, a team led by Professor Wang Honglin from Tiankang Pharmaceutical has pioneered the development of Cyclic Boswellic Acid (CKBA), which targets ACC1 and MFE2 to regulate cellular lipid metabolism, thereby inhibiting CD8+ T cells from producing effector molecules and exerting their effector functions. Currently, CKBA ointment is undergoing Phase II clinical trials for vitiligo and is expected to become the first drug in this class, offering a new approach to vitiligo treatment.
Because of the complex pathogenic mechanisms of vitiligo, current innovative drugs still have a distance to go before achieving a complete cure. However, with the rapid development of cell therapy and regenerative medicine, stem cell therapy and gene therapy theoretically offer the potential for fundamentally curing vitiligo. Overall, the medical community has been deeply invested in the field of vitiligo for many years and has made significant progress. The emergence of more targeted drugs has opened a new chapter in vitiligo treatment. With the increasing number of vitiligo drugs coming to market in the future, it is only a matter of time before this century-old problem is solved.
