Disease burden and current treatment landscape
Atopic dermatitis (AD) or atopic eczema is a common inflammatory skin condition that affects 20.8% of children aged 7 to 16 years in Singapore. While many children (about 70%) improve as they grow older, a significant proportion of patients in Singapore experience later onset (13.6%) after the age of 21 years. Further, it is estimated that up to a quarter of these adult cases manifest in the moderate to severe form which poses significant debilitating challenges for sufferers. Symptoms that include incessant itching, dry skin, excoriations and pain, can severely limit every day activities, psychological functioning, resulting in sleep disturbance and reduced quality of life. Individuals are also at an increased susceptibility to cutaneous and systemic bacterial and viral infections. While the local economic burden of adult AD is not well characterized, its impact is understood to be substantial and associated with high healthcare utilization. In 2006, the total cost of AD in the United States was estimated to be $1.6 billion, of which $1.0 billion were attributed to direct health care costs, and $600 million were attributed to lost productivity.
While therapy is often individualized in clinical practice, a typical treatment pathway involves emollients, topical corticosteroids, topical calcineurin inhibitors followed by phototherapy. Patients with unabating moderate to severe disease may require additional systemic therapy in the form of oral systemic immunomodulators such as azathioprine, cyclosporine, methotrexate or mycophenolate. The use of these agents however, are limited by their potential toxicities and side effects, highlighting an unmet need for effective and safer systemic therapies to treat moderate-to-severe AD. Encouragingly, advances in the molecular pathogenesis of AD and the identification of key cytokines, have led to the development of novel targeted treatments that provide additional therapeutic options for patients. Dupilumab, a monoclonal antibody directed against the α subunit of interleukin (IL)-13 and IL-4 receptors, was the first targeted molecule approved for the treatment of moderate-to-severe AD. However, AD does not always respond to dupilumab and some individuals eventually stop treatment due to adverse effects (AEs).
Updates in the treatment field for atopic eczema
Most recently, in November 2021, baricitinib (Olumiant) received market authorization by the Singapore Health Sciences Authority (HSA) for use in the ‘treatment of moderate to severe AD in adult patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable’. Baricitinib is the first Janus kinase (JAK) inhibitor approved for use in AD and works via a selective and reversible inhibition of JAK1 and JAK2.
JAK enzymes phosphorylate and activate signal transducers and activators of transcription (STATs), which promote pro-inflammatory signaling within the cell. Baricitinib modulates these signaling pathways by partially inhibiting JAK1 and JAK2 enzymatic activity, reducing the phosphorylation and activation of STATs. Baricitinib is available in Singapore as 2mg and 4mg film-coated tablets. The recommended dose is 2mg once daily and an escalation to 4mg once daily may be considered for patients who have not achieved control of disease activity. The drug is also approved for the treatment of adults with moderate to severe rheumatoid arthritis (RA) and is presently authorized for use in severe COVID-19.
Efficacy and safety of baricitinib in AD: an overview of the BREEZE trials
The evidence for baricitinib’s use in AD came from phase III trials within the global BREEZE AD program: 2 on baricitinib monotherapy i.e. BREEZE-AD1 and BREEZE-AD2; 2 on baricitinib on background of topical corticosteroids (TCS) i.e. BREEZE-AD4 and BREEZE-AD7; and a long-term extension (LTE) study i.e. BREEZE-AD3. BREEZE-AD5 and BREEZE-AD6 were limited to the US and Canada populations. Collectively, the results demonstrated the superiority of baricitinib 4mg in monotherapy or in association with TCS compared to placebo at week 16, measured by two main primary endpoints: the percentage of patients achieving an Investigator Global Assessment (IGA) score 0-1 (with a ≥ 2-point improvement over baseline) or an improvement of 75% of Eczema Area and Severity Index (EASI) score from baseline (EASI 75). Although not as effective as the 4mg dose, the 2mg dose similarly proved to be superior to placebo at week 16. The LTE further demonstrated baricitinib’s efficacy at sustaining these results with continuous treatment of up to 68 weeks. An overview of the BREEZE-AD 1, 2, 3, 4 and 7 primary endpoints are presented in Table 1.
| Trial | Design | Primary endpoint | Outcome |
| BREEZE-AD1
N=624 Baricitinib monotherapy in adults |
4mg vs 2mg vs 1mg vs placebo | IGA 0-1 at Week 16 |
|
| BREEZE-AD2
N=615 Baricitinib monotherapy in adults |
4mg vs 2mg vs 1mg vs placebo | IGA 0-1 at Week 16 |
|
| BREEZE-AD3
N=1,760 BREEZE-AD1, BREEZE-AD2 and BREEZE-AD7 patients continued treatment for 52 weeks (total 68 weeks of continuous therapy) |
Continued assigned treatments from originating studies | IGA 0-1 at Week 16, 36 and 52 |
|
| BREEZE-AD4
N=463 Baricitinib + TCS in adults who are intolerant/ contraindicated to/ experienced failure to cyclosporine |
4mg vs 2mg vs 1mg vs Placebo | EASI 75 at Week 16 |
|
| BREEZE-AD7
N=329 Baricitinib + low-moderate TCS in adults |
4mg vs 2mg vs placebo | IGA 0-1 at Week 16 |
|
Previous safety results from baricitinib in the treatment of RA had raised concerns over the occurrence of serious AEs pertaining to malignancies, thrombosis and serious infections. Encouragingly, this was not observed in the AD trials likely due to the characteristics of the study population. An integrated safety analysis of the phase II and phase III baricitinib RCTs determined that while treatment-emergent AEs (TEAEs) was higher for baricitinib 2mg (57.9%) versus placebo (51.6%), serious AEs, serious infections, and opportunistic infections were low in frequency and similar between the two arms. The results also confirmed the absence of cancer, gastrointestinal perforations, or major cardiovascular events (MACE) within the first 16 weeks of treatment. The long-term extension results of baricitinib 4-mg arms reported an overall low and similar incidence of serious infections between the treated and placebo arms, with 1 death, 2 cases of MACE and 2 venous thrombosis occurring. The most frequently reported TEAEs were mild infections that include nasopharyngitis, upper respiratory tract infections, and oral herpes.
Cost-efficacy considerations
Baricitinib in AD management has not been evaluated for cost-effectiveness or reimbursement within the Singapore context, and barriers to safe and effective AD therapy remain high. In March 2021, the UK NICE published a technology appraisal guidance highlighting that baricitinib’s cost-effectiveness estimates (ICER of GBP 27,037 to 28,396 per QALY gained compared to best supportive care) were considered an acceptable use of NHS resources when limited to moderate-to-severe AD in adults refractory to at least 1 systemic immunosuppressant and under the terms of a commercial price discount arrangement. BNF online (as of December 2020) lists the price of a 28-pack of 4-mg tablets at GBP 805.56 prior to manufacturer discounts. This constitutes a substantial cost especially in the absence of national reimbursement which may limit treatment access for a large majority of Singaporean patients. In face of an evolving AD therapy landscape, cost considerations remain a pertinent barrier to new therapies that address some of the most important symptoms that impact patient quality of life.
