Michael Jackson’s skin lightened as he grew older. In 1983, he was diagnosed with vitiligo, an autoimmune disease that causes patches of skin discoloration due to the death of pigment cells. But the public at large, including Jackson’s own producer, Quincy Jones, was convinced that he lightened his own skin intentionally. After Jackson’s 2009 autopsy confirmed his diagnosis, critics went silent.

The 1% of the world’s population with vitiligo know too well the stigma that comes with the disease. People can start to see patches of skin discoloration as early as age one. David Rosmarin, a dermatologist from Tufts Medical Center, said that the patients he sees sometimes isolate themselves or become depressed. In an effort to better help these people, Rosmarin recently tested a drug used to treat atopic dermatitis, ruxolitinib, to see if it could improve symptoms and quality of life for adults and adolescents with vitiligo. 

Rosmarin presented data from a phase III clinical trial at the 2022 American Academy of Dermatology (AAD) Annual Meeting showing that applying ruxolitinib cream twice daily improved discoloration by almost 75% after 52 weeks in patients age 12 and older (1-2). He applied for a new drug application that is currently under priority review with the FDA.

Why are you interested in developing treatments for vitiligo?

There is a real opportunity to improve quality of life. Children are bullied and adults avoid being intimate with others. Recovering natural pigment gives people more confidence and makes them feel comfortable developing relationships. Vitiligo affects about a million people in the United States, and there isn’t a single FDA-approved medicine. There is a better understanding now about which part of the immune system is too active in vitiligo, and researchers can develop medications that target these pathways. 

How do you currently treat the disease?

Clinicians use off-label topical corticosteroids, calcineurin inhibitors — immunosuppressants often used to treat other autoimmune disorders such as lupus — or light treatment. Steroids have a lot of side effects when used long-term, and it often takes a while before patients see results. There are limitations in terms of using it in sensitive areas, and many patients with vitiligo have it on their face, genitals, or other sensitive areas. 

Calcineurin inhibitors work well, and they can be applied in sensitive areas such as the face, but sometimes they can burn. They also don't work quite as well on the body. 

Phototherapy where patients are treated with ultraviolet light — is certainly a mainstay of treatment, but it can be inconvenient for patients. Physicians try to do it two or three times per week. If patients don't have easy access to a phototherapy booth, that can be challenging. 

How does ruxolitnib work?

Ruxolitinib inhibits janus kinase 1 and 2 (JAK1/2), which are part of the pro-inflammatory immune signaling JAK/STAT (signal transducer and activator of transcription) pathway. The cytokine interferon-gamma (IFN-γ), which activates JAK/STAT, is overexpressed in people with vitiligo, resulting in a hyperactive JAK/STAT pathway that kills pigmented cells or melanocytes. 

When IFN-γ binds to its receptors on cells, it activates JAK1/2, which phosphorylates and activates STAT to promote transcription of pro-inflammatory genes such as other cytokines. The IFN-γ activating signal is blocked by inhibiting JAK1/2 with ruxolitinib cream. JAK inhibitors warn the immune system to calm down.

How did you design the clinical trial?

Patients first hear about the study from their physicians, an advertisement, or a support group. Once they enroll, we treat them with either ruxolitinib cream or the vehicle. The patients come in regularly over the course of 52 weeks so that a clinician can ensure that the patient does not experience severe side effects and evaluate how well the treatment is working. At the four-week mark, patients who were given the vehicle can swap to ruxolitinib cream to ensure that everyone gets some treatment.

How effective is ruxolitinib?

When we did the initial study, we started treating patients who had tried other treatments that did not work. All of a sudden, they started to repigment, and we thought, “Wow, we’re on to something.” In the phase II study, we checked different doses and found that the therapy worked in a vigorous way. We followed people from the phase II study beyond a year and saw that patients who continued to use the cream saw increased benefits. We anticipate that the longer patients use the cream, the more repigmentation they will see. We haven’t seen the effects plateau yet.

The phase III results at 52 weeks confirmed the results from phase II. I am surprised how consistent the results are between the different phases of the study. 75% of patients saw 50% improvement in pigmentation on their face, and 30% achieved more than 90% more facial pigmentation. It’s definitely exciting. Unfortunately, the treatment doesn’t work for everyone. We don’t know why it works for some but not others. It’s a caveat, but it’s nice that people have this option. It will benefit a lot of people with vitiligo.

Do you combine the treatment with current therapies?

It works as a monotherapy, but we hope that it will be synergistic when combined with other treatments, particularly light therapy. In order to repigment patients with vitiligo, we need to calm down the immune system and stimulate pigment cells to come back. The cream tells the immune system to calm down, while the light therapy stimulates the cells to come back. 

In the phase II program, patients were allowed to use light therapy for the last third of the study. Patients who used light benefited from the combination. We have studies planned to better characterize the combination of ruxolitinib cream and light therapy to see if we can get a greater response for patients. It may be synergistic, but we need more data to really prove it.

What are your next plans?

We need to duplicate the results and achieve FDA approval of ruxolitinib to treat vitiligo. We also want to better understand how this drug promotes repigmentation at a mechanistic level and maybe find out why some patients respond better than others. By understanding how the drug works, we can develop even better treatments.

This interview has been condensed and edited for clarity.

References

1. Rosmarin, D. et al. Efficacy and safety of ruxolitinib cream monotherapy for the treatment of vitiligo: Results from two 52-week phase 3 studies. Presented at: 2022 American Academy of Dermatology Annual Meeting. Session: S026–Late-Breaking Research: Clinical Trials.
2. Rosmarin, D. et al. Efficacy and safety of ruxolitinib cream for the treatment of vitiligo by patient demographics and baseline clinical characteristics: Pooled subgroup analysis from two randomized phase 3 studies. Presented at: 2022 American Academy of Dermatology Annual Meeting. Abstract: 35187.