A New Era in Treating the Chronic Severe Itch of Prurigo Nodularis
Until recently, there were no FDA-approved systemic therapies for the severe itch and resultant scratching and nodules of the chronic inflammatory skin disease prurigo nodularis (PN). Thanks to two studies led by a University of Miller School of Medicine researcher, the FDA has now approved the monoclonal antibody dupilumab to bring relief — in many cases, life-changing relief — to PN patients.
In addition, the study’s results helped break new ground in understanding how PN works in the body and how its pathways can be disrupted.
“The intensity and frequency of itch in PN is among the worst of all dermatologic or other itch-causing diseases,” said Gil Yosipovitch, M.D., professor, Stiefel Chair of Medical Dermatology and director of the Miami Itch Center at the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, who led the two studies. “The itching, pain, stinging and burning of this disease often impairs sleep and affects mental and emotional health.”
Dr. Yosipovitch was first author of a paper on the studies and their results, which appeared in the May 2023 issue of the journal Nature Medicine.
In both studies, which were randomized, placebo-controlled phase 3 trials for the use of dupilumab to treat PN, many patients receiving the medication experienced clinically significant improvements in itchiness, skin lesions and quality of life. Far fewer of those receiving the placebo experienced such improvements.
The positive effects of dupilumab were similar for atopic and non-atopic patients, and did not appear to be affected by the use of topical corticosteroids/topical calcineurin inhibitors during the studies. In addition, fewer dupilumab-treated patients required rescue medication compared with those given placebo. The medication was well-tolerated, with no treated patients discontinuing treatment. Its safety profile was consistent with its known profile, and patients treated with it had fewer skin infections than those receiving placebo.
“This study demonstrated that dupilumab is effective and safe for prurigo nodularis and led the FDA to approve the first systemic drug for treating this condition,” said Dr. Yosipovitch. “This study also opened a new era for research into other drugs to bring relief to PN sufferers.”
Relief from Itching, Reduction in Nodules
The two dupilumab studies, known as the LIBERTY-PN PRIME and PRIME2 phase 3 trials, included 311 total participants, randomized to receive a subcutaneous injection every two weeks of either 300 mg of dupilumab or a placebo. Participants represented a group that roughly corresponds to the makeup of PN sufferers worldwide in relation to sex, age, racial/ethnic background and associated comorbidities. All suffered from a high PN disease burden, and more than 60% had tried other systemic therapies. Individuals already on a stable regimen of low- to moderate-potency topical corticosteroids or topical calcineurin inhibitors could continue them during the trial.
Both studies were originally designed to last only 12 weeks, but researchers noticed that participants receiving dupilumab continued to improve after 12 weeks during the first of the two studies, PRIME2. Based on those observations, they amended the PRIME study to 24 weeks.
At the start of the studies, participants had at least 20 PN nodules and severe itch, neither of which were adequately controlled by topical prescription therapies. After 24 weeks in PRIME, 60% of participants receiving dupilumab saw a reduction of more than four points in their Worst Itch Numeric Rating Scale (WINRS), on which patients rate their level of itchiness. Only 18.4% of participants receiving the placebo saw such a reduction in itchiness. After 12 weeks in PRIME2, 37.2% of participants receiving the treatment saw a WINRS reduction of more than four points, compared to 22% of those receiving the placebo. Research has shown that a four-point reduction on this scale is clinically meaningful in PN.
Patients treated with dupilumab also saw significant reduction in nodules by week 24 of the studies. In PRIME, 48% had five or fewer nodules, compared to 18.4% of those on placebo. In PRIME2, 44.9% had five or fewer nodules, compared to 15.9% of those on placebo.
Improvements in itching and nodule count continued progressively during the studies without plateauing, so further treatment might lead to even more improvements.
Improvements in DLQI Scores
Participants receiving dupilumab also saw significant improvements in their Dermatology Life Quality Index (DLQI) scores by the end of each study. The mean scores of participants at the start of each study corresponded to PN having a “very large impact” on quality of life. By the end of each trial, dupilumab-treated patients had scores at the threshold between “small” and “moderate” impact, while those receiving the placebo maintained the “very large” impact.
By week 24, participants receiving treatment with dupilumab saw more positive changes in several areas in each study, compared with those receiving the placebo:
- WINRS down by more than four points: 60% versus 18.4%
- Five or fewer nodules: 48% versus 11.8%
- DLQI: Negative impact reduced by 12 points versus 5.8 points
- Skin Pain Numeric Rating Scale: Down by 4.3 points versus 2.2 points
- Required rescue medication: 6.7% versus 18.4%
- Development of skin infection: 2.7% versus 9.3%
- WINRS down by more than four points: 37.2% versus 22%
- Five or fewer nodules: 44.9% versus 15.9%
- DLQI: Negative impact reduced by 13.2 points, versus 6.8 points
- Skin Pain Numeric Rating Scale: Down by 4.4 points, versus 2.7 points
- Required rescue medication: 7.7%, versus 24.4%
- Development of skin infection: 5.2% versus 6.1%
These results were the first to replicate positive results from two phase 3, randomized, placebo-controlled, global trials of dupilumab to treat PN.
Dupilumab Blocks Cytokine Reception
Dupilumab is a fully human monoclonal antibody produced by genetically modified mice. It blocks the function of the interleukin-4 receptor alpha protein. Most relevant for PN, this prevents reception of interleukin-4 and interleukin-13. These two cytokines are believed to play roles in the development of itch, inflammation and fibrosis by producing and/or promoting histamine and other inflammatory mediators, excess collagen that leads to fibrosis, and Th2 white blood cells involved in allergic reactions and other immune responses.
PN sufferers’ chronic scratching releases interleukin-4 and interleukin-13, which promote further inflammation and can directly activate sensory neurons in the skin. This activation sensitizes neurons to the effects of other itch-producing chemicals, thereby amplifying the itch response; that leads to further scratching, which leads to more itching, and so on. Dupilumab blocks absorption of the two cytokines, potentially disrupting this itch-scratch cycle.
“The success of targeting of interleukin-4 and interleukin-13 to relieve PN symptoms offers a novel therapeutic approach to this condition,” Dr. Yosipovitch said.
Dr. Yosipovitch’s co-authors included colleagues from the Perelman School of Medicine at the University of Pennsylvania; University Hospital Münster in Germany; Johns Hopkins University School of Medicine; Icahn School of Medicine at Mount Sinai in New York; and Sanofi Biotechnology and Regeneron Pharmaceuticals, Inc. Both the research and the paper were funded by Sanofi and Regeneron, which sell dupilumab under the brand name Dupixent.