The disease burden and current treatment landscape
Atopic dermatitis (AD), or eczema, is the most common skin disorder in Singapore and is estimated to affect 20% of children and 11% of adults in Singapore. AD, a chronic condition that usually begins in childhood, is characterized by intense pruritus and recurrent eczematous lesions. It has considerable negative impact on patients’ and caregiver quality of life, creating large clinical, economic and humanistic burden.
Topical interventions are the mainstay treatment of AD and systemic therapy is recommended for patients with inadequate treatment response. However, the reality of patients living with the chronic inflammatory skin disease is that many experience debilitating symptoms that are poorly managed by current treatment options. Rapid advancements have been made in the armamentarium of systemic AD therapy owing to developments in the understanding of disease molecular mechanism. Innovative treatments targeting interleukin (IL) and Janus kinase (JAK) receptors have demonstrated therapeutic potential, especially for the severe recalcitrant population.
Among the slew of Health Science Authority (HSA) market approvals in early 2022 lies a new oral option for adults living with refractory, moderate-to-severe AD. In January 2022, local approval was granted to abrocitinib (Cibinqo), an oral small molecule JAK-1 inhibitor that inhibits signalling of IL-4, IL-13 and other cytokines involved in the pathogenesis of AD. It’s market authorisation follows hot on the heels of baricitinib’s (Olumiant) approval for the same indication in November 2021. While the two agents have not been compared head-to-head in the setting of AD, abrocitinib’s selectivity for JAK1 compared to other isoforms provides a degree of disease specificity that differentiates it from the first-generation baricitinib. The recommended dose of abrocitinib is 100mg once daily, which can be escalated to 200mg in patients that remain unresponsive. The 50mg dose is approved for patients with moderate renal impairment, in patients receiving concomitant CYP2C19 treatment or in patients who are considered poor metabolizers of CYP2C19.
The efficacy and safety of abrocitinib (Cibinqo)
Registry approval was based on results from the Cibinqo JAK1 Atopic Dermatitis Efficacy and Safety (JADE) global clinical program that recruited more than 1,600 patients. In each trial, more than 40% of patients had prior exposure to systemic therapy which include corticosteroids, cyclosporin and biologic therapy. Notably, the safety and efficacy of abrocitinib, measured by the Investigator Global Assessment (IGA; severity), Eczema Area and Severity Index (EASI; disease extent), and Peak Pruritus Numerical Ratings Scale (PP-NRS: severity), were evaluated across 12 weeks in three randomized, placebo controlled, Phase III trials – JADE MONO-1, JADE MONO-2 and JADE COMPARE. An overview of the three key Phase III studies are summarised in the table below. The co-primary endpoints assessed at Week 12 were:
- The proportion of patients who had achieved an IGA response of 0 (clear) or 1 (almost clear), with a ≥2-grade improvement from baseline
- The proportion of patients who achieved ≥ 75% improvement in EASI score from baseline (EASI-75)
| Study | Efficacy Endpoints | Safety Findings |
| JADE MONO-1
N=387, mean age 32.5%, 57% Male ≥ 12 years with moderate-to-severe AD Randomized 2:2:1 to AB 200mg (N=154) or 100mg (N=156) vs oral placebo (N=77) once daily monotherapy for 12 weeks |
|
|
| JADE MONO-2
N=391, mean age 35.1years, 58.6% male ≥ 12 years with moderate-to-severe AD Randomized 2:2:1 to AB 200mg (N=155) or 100mg (N=158) vs oral placebo (N=78) |
|
|
| JADE COMPARE
N=838, mean age 37.7 years, 48.9% male ≥18 years with moderate-to-severe AD in combination with topical medicated therapy Randomized 2:2:2:1 with matched placebo to
|
Week 12:
|
|
Abbreviations – AB: abrocitinib, AD: atopic dermatitis, AE: adverse events, TEAE: treatment-emergent adverse events, URTI: upper respiratory tract infection, IBD: inflammatory bowel disease, PP-NRS: Peak Pruritus Numerical Ratings Scale, SC: subcutaneous
Across the trials, abrocitinib demonstrated a consistent safety profile and yielded profound improvements in skin clearance, extent of disease, and severity, as well as rapid improvement in itch after two weeks, for some people living with AD versus placebo. From a safety perspective, an integrated safety analysis of the clinical trial program determined that the most common dose-related adverse events (AE) were nausea, headache, herpes simplex, vomiting and acne. Most AEs were mild to moderate in severity, self-limiting and seldom resulted in interruption or permanent treatment discontinuation. Of note, dose-related events of venous thromboembolism are a known occurrence in patients treated with abrocitinib and other JAK inhibitors. Critically, no dose-response relationship for serious infections or an excess of events compared with placebo were found with abrocitinib-treated patients.
Overall, the robust efficacy of abrocitinib 200mg must be balanced against the safety and tolerability profile seen across clinical trials. The 100mg dose may be a more appropriate starting dose for patients with a higher risk for or lower tolerance for adverse reactions.
Cost-efficacy considerations and treatment access
In the absence of local economic data, the overall US costs associated with AD estimated to be $5.3 billion including over $1 billion in healthcare costs, provides a sense of the enormity of disease burden. There is thus a high unmet need for effective and safe systemic therapies to treat moderate-to-severe AD to which JAK inhibitors may potentially address.
A preliminary post-hoc economic analysis of the JADE MONO-2 and JADE COMPARE trials determined that although an advantage was not witnessed in decreasing physician visits, abrocitinib was associated with greater improvements in overall work impairment and associated costs versus placebo. The estimated annualized total cost reduction from baseline in patients who received abrocitinib versus placebo was calculated to be US$12,937 and US$10,951, respectively.
The economic impact of abrocitinib has yet to be evaluated in the local context. More critically, targeted therapies for AD have yet to be considered for local reimbursement by the Agency for Care Effectiveness, Singapore (ACE) and local access to innovative targeted therapies (i.e. dupilumab, baricitinib, abrocitinib) remains a costly out-of-pocket expense for patients with severe refractory AD.
Manufacturers and payers have the responsibility to ensure that effective new treatments for patients with AD are introduced in a way that mitigates health inequities. Access and uptake of the promising new molecule remains to be seen in the face of budget impact uncertainties.
