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Nemolizumab (Mitchga) is gearing up to be a potential new treatment for prurigo nodularis, with further phase 3 data supporting its efficacy and safety reported this month at the annual meeting of the European Academy of Dermatology and Venereology.
In the OLYMPIA 1 study, clinically significant improvements in both itch and skin lesions were seen after 16 weeks of treatment with nemolizumab compared with placebo (P < .0001).
Indeed, among the 286 patients who participated in the trial (190 on nemolizumab and 96 on placebo), 58.4% of those treated with nemolizumab and 16.7% of those who received placebo had an improvement of 4 points or more in the weekly average peak pruritus numeric rating scale (PP-NRS) at week 16 (P < .0001).
Skin lesions were assessed using an investigators general assessment (IGA) score, where IGA success was defined as a score of 0/1 indicating clear or almost clear skin or where there had been at least a 2-point change from baseline values. Over a quarter (26.3%) of nemolizumab-treated patients met these criteria vs 7.3% for those on placebo (P = .0001).
“These results confirm the results of the OLYMPIA 2 study, the other phase 3 study, and now I hope you understand why we are so excited,” lead investigator Sonja Ständer, effexor and pregnancy safety MD, of the Center for Chronic Pruritus, at University Hospital Münster, Germany, said at the meeting, where she presented the data.
The OLYMPIA 2 study included 274 patients and the results showed a weekly average PP-NRS score improvement of 56.3% vs 20.9% for placebo and IGA success in a 37.7% and 11% of patients, respectively, at 16 weeks.
“We know how difficult it is to treat patients; they are refractory to treatment, frustrated, and this really impacts them regarding their quality of life,” said Ständer. New options are needed to help patients, and nemolizumab, a first-in-class interleukin-31 (IL-31) receptor alpha antagonist, is one treatment that may answer this call.
Prurigo nodularis is a chronic neuroimmune skin condition characterized by severe itch and multiple nodular skin lesions, Ständer explained. She added that there is evidence that IL-31 has a key role to play in the development of itch, and in differentiation of keratinocytes, type 2 and type 17 immune responses, and fibrosis associated with the condition.
The OLYMPIA 1 and 2 trials are part of a large developmental program that includes two ongoing trials. One is assessing the durability of response over 24 weeks in 40 patients and the other is a long-term extension trial involving 450 patients from the OLYMPIA 1 and 2 trials.
Inclusion Criteria and Additional Results
For inclusion in the study, adults with prurigo nodularis for at least 6 months had to have 20 or more nodules on the body with a bilateral distribution, an IGA score of 3 or more, and an average PP-NRS of 7 or higher. The latter “was really a high bar for them to qualify for the trial,” said Ständer.
After an initial 4-week screening period, patients were randomly assigned to 24 weeks of treatment with nemolizumab or placebo given as a subcutaneous injection every 4 weeks. An 8-week ‘off-treatment’ period followed.
The nemolizumab dose was based on the patient’s body weight, with patients weighing less than 90 kg (198 lb) getting a loading dose of 60 mg followed by further doses of 30 mg; while patients weighing 90 kg or more receiving 50 mg of nemolizumab.
Ständer reported that nemolizumab met all of the trials’ secondary endpoints; this included at least a 4-point improvement in sleep disturbance. She noted that changes in itch and subsequent sleep disturbance occurred early, at 4 weeks of treatment — after just one injection of nemolizumab.
The response rates seen in the moderate-to-severe prurigo nodularis population studies are quite unique when compared with conventional therapies, Ständer maintained. “We’ve never seen something like this before.”
No Safety Concerns
No significant difference in tolerability was seen between the nemolizumab and placebo groups, Ständer observed. Any adverse event occurred in a respective 71.7% and 65.3% of patients, respectively, and serious adverse events in 8.6% and 10.5%.
There was a similar rate of adverse events leading to discontinuation, respectively (4.8% vs 4.2%).
Headache was seen more frequently among those on nemolizumab than those on placebo (7.0% vs 2.1%), and there was a higher number of eczema cases among those on nemolizumab (5.3% vs 1.1%). The latter is somewhat paradoxical because nemolizumab is also being studied as a treatment for atopic dermatitis, with good results seen in phase 3 trials. Asked about this finding after her presentation, Ständer said “we are following up on that to know exactly what is going on; this is a side effect of nemolizumab that is seen also with other biologics.”
JAK Inhibitor Trial for PN, CPUO
Nemolizumab is not the only promising new approach to treating prurigo nodularis. During a separate late-breaking news session at the meeting, Shawn Kwatra, MD, director of the Johns Hopkins Itch Center in Baltimore, presented “dramatic” data from a ‘proof-of-concept’ phase 2 study with the Janus kinase (JAK) inhibitor abrocitinib (Cibinqo), which is approved for atopic dermatitis in the United States and Europe.
The investigator-initiated trial took a different approach to most other trials, Kwatra said. The starting point was to look at studying multiple rather than single dermatologic diseases that were perhaps being left a little by the wayside but may potentially share some common ground. Those two diseases were prurigo nodularis and chronic pruritus of unknown origin (CPUO).
“They’re actually very analogous conditions in the way we treat, so I thought those would be a good pair,” Kwatra said, noting that there were several studies that made him think that JAK inhibition “would be an interesting concept to try.”
On that basis, 10 women with prurigo nodularis (mean age, 58 years) and two women and eight men with CPUO (mean age, 70 years) were recruited and all were treated with abrocitinib at a once-daily oral dose of 200 mg for 12 weeks.
“They all had really intense itch,” before treatment, Kwatra said. The mean baseline PP-NRS was 9.2 and 8.2 in the prurigo nodularis and CPUO groups, respectively. By the end of treatment, however, “the improvement in itch was pretty dramatic,” especially for prurigo nodularis, he said.
At 12 weeks, the PP-NRS score had fallen to 2.0 in the prurigo nodularis group, equating to a significant 78% change from baseline (P < .001). And, in the CPUO group, the 12-week PP-NRS score was 3.8, nearly a 54% drop from baseline (P = .01).
Sleep disturbance was improved for both conditions, and in the patients with prurigo nodularis, there were improvements in skin lesions. Looking at the patients who responded to treatment, Kwatra noted that “if you responded, you respond fast, and you respond almost entirely.”
Additional findings from cutaneous transcriptome analysis showed that JAK inhibition with abrocitinib was modulating Th1-, Th2-, Th17-, and Th22-mediated pathways in both groups of patients.
The overall frequency of adverse events was low, and no serious adverse events occurred.
Commenting on the potential use of abrocitinib in managing patients with PN and chronic pruritis of unknown origin, Tiago R. Matos, MD, PhD, MSc, Amsterdam University Medical Centers, Amsterdam, the Netherlands, told Medscape Medical News that JAK1 inhibitors “are showing promising results in treating several diseases.”
Matos, who was not involved in the study, added that JAK inhibition was “of special interest in prurigo nodularis and chronic pruritus, since these are some of the most difficult diseases to treat with limited therapeutic options.”
Kwatra observed: “Obviously, we need further development. But we also have clues here about how to design phase 3 trials.”
Galderma funded the OLYMPIA 1 and 2 studies. Ständer was an investigator for the trial and reported serving as a consultant, speaker, or investigator for multiple pharmaceutical companies, including Galderma.
Johns Hopkins University supported the abrocitinib study with funding from Pfizer. Kwatra is an advisory board member or consultant to several pharmaceutical companies and is an investigator for Galderma, Incyte, Pfizer, and Sanofi.
Matos was not involved in either study. He is a director of clinical research for Sanofi and a dermatology science consultant for Monasterium Laboratory Skin & Hair Research Solutions GmbH.
European Academy of Dermatology and Venereology (EADV) 2023 Annual Meeting:
Abstract 6707: Presented October 11, 2023
Abstract 6727: Presented October 13, 2023.
Sara Freeman is a medical journalist based in London, England.
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