Topical JAK Inhibitor Active in Itchy Prurigo Nodularis

ORLANDO — More than 40% of patients with longstanding prurigo nodularis (PN) had significant improvement within 3 months of starting topical ruxolitinib (Opzelura), according to a study reported here.

After 12 weeks of treatment, 44.6% of patients had at least a 4-point improvement in severe itching, the major symptom of PN. Half of the responding patients met the study’s primary endpoint within the first week. Significantly more patients had clear or almost clear skin at 12 weeks with the cream formulation of the Janus kinase (JAK) inhibitor as compared with a non-therapeutic cream.

No patient reported treatment-related adverse events or application-site reactions with topical ruxolitinib, reported Shawn G. Kwatra, MD, of the University of Maryland in Baltimore, at the American Academy of Dermatology meeting.

“There was statistical significance at week 12 in the primary endpoint and two secondary endpoints, and significant itch improvement occurred early,” said Kwatra. “The overall safety profile is very similar to what’s known about ruxolitinib in other studies in the real world. Overall, it looks like [topical ruxolitinib] may be a novel approach for the treatment of PN.”

Preliminary data from an ongoing trial of ruxolitinib cream in PN did not show a significant difference in itch from the vehicle control group, which had an increased placebo response.

“That’s been common throughout many itch studies, something that’s very important to keep in mind for trial design,” Kwatra added. “We’re going to be looking into that.”

During a discussion that followed the presentation, co-moderator Kenneth Gordon, MD, of the Medical College of Wisconsin in Milwaukee, asked whether the presence of background atopic dermatitis (AD) affected the results and whether investigators had considered diffuse treatment to prevent formation of new lesions.

The AD data have yet to be analyzed, “but we would expect that it would be effective for both groups [with and without AD],” said Kwatra. With regard to preventive treatment, “it boils down to how much cream we can get on the body. We made a decision for one centimeter around each of the lesions because we know that very lesional skin also has a little bit of inflammatory infiltrate. We didn’t try [broad application] but it is a good suggestion.”

Co-moderator Joel Gelfand, MD, of the University of Pennsylvania in Philadelphia, asked whether the medication is “getting where it needs to be” in patients with thick prurigo nodules. Would longer treatment be required, which could raise questions about adherence?

“That’s why we’re exploring various subgroups,” said Kwatra. “We know that some subgroups have a significant amount of fibrosis, and other groups have fairly shallow lesions. We’re exploring that but I think our results show that if you get to areas where peripheral neurons are active, you can still shut it down.”

An unidentified member of the audience asked about duration of treatment effect. Kwatra said investigators intend to explore that, including the potential to stop therapy, during a long-term extension phase of the study.

The rationale for evaluating topical ruxolitinib in PN comes from evidence linking the disease’s pathogenesis to proinflammatory cytokine and chemokine signaling through the JAK/STAT pathway. Ruxolitinib cream is a selective JAK1/2 inhibitor currently approved for AD and non-segmental vitiligo. The FDA has recently approved two injectable therapies for PN, dupilumab (Dupixent) and nemolizumab (Nemluvio).

Kwatra reported findings from the primary analysis of the phase III, multicenter, randomized, vehicle-controlled TRuE-PN1 trial. The study involved adults with a PN diagnosis of at least 3 months’ duration, at least six PN lesions on two or more areas of the body, an investigator global assessment (IGA-CPG-S) score ≥2, itch score (WI-NRS) ≥7, and body surface area (BSA) ≤20%.

Patients were randomized to 1.5% ruxolitinib cream applied twice daily for 12 weeks or a vehicle cream. The primary endpoint was the proportion of patients achieving at least a 4-point improvement in itch score (WI-NRS4).

Data analysis included 204 patients, who had a median disease duration of 4-4.7 years, mean WI-NRS score of 8.4, skin pain score of 7-7.5, and mean BSA of 8.8%. A majority of patients had a treatment history of potent or very potent topical corticosteroids.

The primary analysis showed that more than twice as many patients in the ruxolitinib arm achieved the primary endpoint at 12 weeks (44.6% vs 20.6%, P<0.001). A statistically significant difference in response rates emerged within the first week of treatment (22.4% vs 8.0%, P<0.01). A difference in the proportion of patients achieving an IGA-CPG-S score of 0/1 (clear/nearly clear) emerged within the first 2 weeks and achieved statistical significance by week 12 (15.8% vs 3.9%, P<0.01).

Treatment-emergent adverse events (TEAEs) occurred in a similar proportion of the ruxolitinib and vehicle treatment arms, as did grade ≥3 TEAEs and serious TEAEs. Rates of TEAE-related discontinuation were 3-4%.

Whereas TRuE-PN1 met the primary and all secondary endpoints, preliminary data from TRuE-PN2 (N=189) showed no significant difference in the primary endpoint. Kwatra noted that the vehicle arm in TRuE-PN2 had a much larger placebo effect as compared with TRuE-PN1 (36.2% vs 20.6%). A pooled analysis of both trials showed a significant difference in the primary endpoint in favor of ruxolitinib cream (42.3% vs 28.1%, P=0.0029).

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