AbbVie's RINVOQ Demonstrates Superior Efficacy Over Dupixent in Phase 3b Head-to-Head Trial for Moderate-to-Severe Atopic Dermatitis

AbbVie recently announced that the results of the Phase 3b head-to-head Heads Up study (NCT03738397), evaluating the oral JAK1 inhibitor Rinvoq (upadacitinib) versus the subcutaneous formulation Dupixent (dupilumab) for the treatment of moderate-to-severe atopic dermatitis (AD) in adult patients, have been published in the international medical journal 《JAMA Dermatology》.

Results demonstrated that Rinvoq exhibited superior efficacy compared to Dupixent across both the primary endpoint and all secondary endpoints. Compared with Dupixent, Rinvoq demonstrated a faster onset of action, with patients experiencing pruritus reduction within 1 week of treatment, improved skin clearance at 2 weeks, and a higher proportion of patients achieving high-level skin clearance at 16 weeks. For details, see: Efficacy and Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial.

Rinvoq is an oral, once-daily, selective and reversible JAK inhibitor, and its new indication for the treatment of moderate-to-severe AD is currently under regulatory review in the United States and the European Union. Dupixent is an IL-4/IL-13 inhibitor from Sanofi/Regeneron and is the world's first targeted biologic approved for the treatment of moderate-to-severe AD. It can rapidly, significantly, and sustainably improve skin lesions and pruritus in patients with AD. In China, Dupixent was approved in June 2020 for the treatment of adult patients with moderate-to-severe AD.

The Heads Up study was conducted in adult patients with moderate-to-severe AD who were eligible for systemic therapy, and evaluated the efficacy and safety of Rinvoq (30 mg orally once daily) versus Dupixent (300 mg subcutaneously once weekly) as monotherapy. In the study, both agents were administered as monotherapy for 24 weeks.

Results published in *JAMA Dermatology* expand upon previously announced topline results, demonstrating that Rinvoq showed superior efficacy to Dupixent at the primary endpoint: at Week 16 of treatment, a higher proportion of patients in the Rinvoq group achieved EASI75 (≥75% improvement in the Eczema Area and Severity Index) compared with the Dupixent group (71% vs 61%).

Furthermore, during the 16-week treatment period, Rinvoq demonstrated statistically significant superiority over Dupixent across all secondary endpoints, including additional measures of skin clearance and itch reduction. The specific data were as follows: (1) At Week 1, the Rinvoq group showed a 31% reduction in itch (measured by the Worst Itch Numeric Rating Scale [NRS]), compared with a 9% reduction in the Dupixent group; (2) At Week 2, 44% of patients in the Rinvoq group achieved an EASI 75 response, versus 18% in the Dupixent group (p < 0.001); (3) At Week 16, 28% of patients in the Rinvoq group achieved complete skin clearance (EASI 100; p < 0.001) and 61% achieved near-complete skin clearance (EASI 90; p < 0.001), compared with 8% and 39%, respectively, in the Dupixent group.

In this study, the safety profile of Rinvoq was consistent with that observed in three pivotal Phase 3 studies (Measure Up 1, Measure Up 2, and AD Up). During the 16-week treatment period, the most common adverse events were acne in the Rinvoq group and conjunctivitis in the Dupixent group. The incidence of serious adverse events was 2.9% in the Rinvoq group and 1.2% in the Dupixent group. Serious infections were rarely reported in both groups (occurring in 1.1% of patients in the Rinvoq group and 0.6% in the Dupixent group). One death occurred in the Rinvoq group due to bronchopneumonia associated with influenza A. No malignancies were reported in the Rinvoq group, whereas one case of non-melanoma skin cancer was reported in the Dupixent group. Neither group reported any major adverse cardiac events or venous thromboembolism events.

Heads Up Study Results

Atopic dermatitis (AD) is a common, chronic, relapsing, inflammatory skin disease characterized by a recurrent cycle of itching and scratching, leading to painful, broken skin. It is estimated that up to 25% of adolescents and 10% of adults will be affected by AD at some point in their lives. 20%–46% of adults with AD will experience moderate-to-severe disease. The symptoms of the disease impose a significant physical, psychological, and economic burden on patients.

Rinvoq is an oral, once-daily, selective, reversible JAK inhibitor. In the United States, Rinvoq is approved only for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX), with an approved dosage of 15 mg for this indication. In the European Union, Rinvoq has been approved for three indications: (1) treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs); (2) treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to one or more DMARDs; (3) treatment of adult patients with active ankylosing spondylitis (AS) who have had an inadequate response to conventional therapy. For these indications, the approved dosage of Rinvoq is 15 mg.

Currently, the new indication applications for Rinvoq for the treatment of AD are under review by the U.S. FDA and the EU EMA, specifically for: the treatment of moderate to severe AD in adult patients (15 mg and 30 mg once daily) and adolescent patients (15 mg once daily). Additionally, new indication applications for Rinvoq for the treatment of PsA and AS are also under review by the U.S. FDA.

In the United States, the FDA has delayed the review timeline for Rinvoq in the treatment of PsA, AS, and AD, as the agency is currently investigating the safety of the JAK inhibitor drug class. In the European Union, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending the approval of Rinvoq for AD this June. The European Commission (EC) is expected to issue its regulatory decision this August. If approved, this will mark the fourth indication for Rinvoq in the EU, and Rinvoq will also become the first JAK inhibitor approved in the EU for adult and adolescent (aged ≥12 years) patients with moderate-to-severe AD.

Chemical structure of upadacitinib (Image source: medchemexpress.com)

The active pharmaceutical ingredient of Rinvoq is upadacitinib, an oral, selective, and reversible JAK1 inhibitor discovered and developed by AbbVie, which is being developed for the treatment of several immune-mediated inflammatory diseases. JAK1 is a kinase that plays a critical role in the pathophysiology of various inflammatory diseases.

Currently, Phase III clinical trials of Rinvoq for the treatment of ulcerative colitis (UC), rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), Crohn's disease (CD), atopic dermatitis (AD), and giant cell arteritis (GCA) are ongoing.

The industry is highly optimistic about the commercial prospects of Rinvoq. UBS Group analysts previously projected that the peak sales of Rinvoq and Skyrizi, AbbVie's other monoclonal antibody anti-inflammatory drug, would reach $11 billion. These two new products are expected to offset the sales losses incurred by AbbVie's flagship product, Humira (adalimumab), due to biosimilar competition.

Humira is the world's first approved anti-tumor necrosis factor-alpha (TNF-α) drug and the best-selling anti-inflammatory medication globally, with worldwide sales in 2020 reaching nearly USD 20 billion (USD 19.832 billion). In the European Union, multiple adalimumab biosimilars have already been launched and are commercially available. In the US market, however, Humira will face significant biosimilar competition in 2023.

Source: JAMA Dermatology Publishes Data Showing RINVOQ (upadacitinib) Achieved Superiority Versus DUPIXENT (dupilumab) for Primary and All Ranked Secondary Endpoints in Phase 3b Head-to-Head Study in Adults with Atopic Dermatitis

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