Targeted Antibody Provides Significant Relief From Itchy Nodular Condition

BOSTON -- In the first-ever phase III trial for prurigo nodularis, dupilumab (Dupixent) significantly reduced itching after as little as 12 weeks of treatment.

The results showed that 37.2% of patients in the dupilumab arm had at least a 4-point improvement in the patient-reported Worst-Itch Numerical Rating Scale (WI-NRS) at 12 weeks as compared with 22% of patients randomized to placebo plus standard topical therapy. By week 24, WI-NRS response had increased to 57.7% in the dupilumab arm, but decreased to 19.5% in the control group.

After 24 weeks, almost three times as many patients in the dupilumab arm met the Investigator Global Assessment (IGA) criteria for disease response, reported Gil Yosipovitch, MD, of the University of Miami in Florida, at the American Academy of Dermatology annual meeting.

"These were patients with severe itch, high lesion count, and impaired quality of life," said Yosipovitch. "The condition was inadequately controlled by topical prescription therapies. Nearly two-thirds of these patients had previously used systemic therapies."

"A significantly greater proportion of dupilumab-treated patients achieved clinically meaningful improvements in itch and skin lesions compared with placebo-treated patients. The safety profile of dupilumab was good and was consistent with the known safety profile in its approved indications," he added.

Despite advancements in other inflammatory skin conditions, prurigo nodularis remains a therapeutic challenge, as neither the FDA nor its European counterpart have approved a systemic therapy specifically for the condition. Dermatologists have used a variety of steroid, immunomodulatory, and immunosuppressive therapies, as well as topical treatments and phototherapy, with limited success, Yosipovitch noted in his introductory comments. The current standard of care includes non-approved treatments that lack supporting evidence and carry a risk of multiple side effects and toxicities.

Exact pathogenic mechanisms of the disease remain unknown, although evidence suggests neural and immune dysregulation. Recent studies have implicated both interleukin (IL)-4 and IL-31 in prurigo nodularis pathogenesis, providing a rationale for clinical evaluation of dupilumab, which inhibits IL-4 and IL-13. Several case series showed favorable symptomatic results with dupilumab, providing support for formal clinical evaluation.

Yosipovitch reported findings from the phase III PRIME-2 trial involving patients with moderate to severe prurigo nodularis, defined as a WI-NRS score ≥7, ≥20 lesions, and lack of response to a 2-week course of topical corticosteroids. All patients could continue standard topical corticosteroids/immunomodulators and were randomized to placebo or dupilumab (600 mg loading dose followed by 300 mg every 2 weeks). Treatment continued for 24 weeks with an additional 12 weeks of follow-up.

The primary endpoint was the proportion of patients who achieved at least 4-point improvement in WI-NRS from baseline to week 12. Secondary endpoints included ≥4-point improvement in WI-NRS and IGA rating of 0 or 1, both at week 24.

Investigators randomized 160 patients; mean age was 49, and about two-thirds were women. Almost half of the study population had a history of atopy, about 60% had an IGA score of 3, and the mean baseline WI-NRS score was 8.5. All of the patients had received prior topical therapy for prurigo nodularis, and 63% had received systemic treatment for the condition.

The primary analysis showed that significantly more patients in the dupilumab arm met criteria for WI-NRS response (P<0.0216) at 12 weeks. The 24-week data showed even greater increase in WI-NRS response with dupilumab versus placebo (P<0.0001), and IGA response rates were 44.9% with dupilumab versus 15.9% with placebo (P<0.0001).

Treatment-emergent adverse events (TEAEs) occurred in a similar proportion of patients in the two treatment arms. Headache was the most common TEAE in both groups (5% to 6%). With respect to TEAEs of special interest, herpes viral infections occurred more often with dupilumab (6.5% vs 0%), skin infections occurred more often in the placebo group (8.5% vs 5.2%), and conjunctivitis occurred more often with dupilumab (3.9% vs 0%). No severe TEAEs occurred in either group.

Earlier this year, Sanofi and Regeneron announced completion of a second positive phase III trial of dupilumab for prurigo nodularis. The top-line results showed that 60% of patients treated with dupilumab met the trial's itch-response endpoint at 24 weeks as compared with 18% of placebo-treated patients. Additionally, IGA response rates were 48% versus 18%. Complete results will be reported at an upcoming conference, according to the company statement.

Yosipovitch predicted that improved understanding of prurigo nodularis pathogenesis will lead to development of additional therapies that more specifically address the disease origin and provide better symptomatic relief for patients. Toward that end, a recent phase II study of the IL-31 receptor antagonist nemolizumab showed significant improvement in WI-NRS and lesion status with the monoclonal antibody versus placebo.

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