CADTH Reimbursement Review

Upadacitinib (Rinvoq)

Sponsor: AbbVie Corporation

Therapeutic area: Atopic dermatitis

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

Atopic dermatitis (AD), also known as atopic eczema, is an inflammatory, chronic skin disease commonly occurring in families with other allergic conditions. AD is considered among the most common non-communicable skin diseases, affecting 20% of children and 2% to 8% of adults worldwide.¹ In Canada, the lifetime prevalence of AD is up to 17% of the population. There is evidence to suggest that the prevalence has increased over the past 30 years.^2,3

AD is characterized by severe pruritus and rash as well as scratching that may result in lichenification.⁴ Secondary skin infections are common due to a compromised skin barrier function and scratching.^1,4 AD usually develops before the age of 5 and may persist into adulthood.⁴ The majority of children outgrow the condition, but it is common for children with AD to develop asthma and/or hay fever — a process commonly referred to as the “atopic march.”⁵ Symptoms can worsen through the night, resulting in sleep loss and affecting school or work activities. Health-related quality of life (HRQoL) is also altered. Stigma can affect patients physically and mentally. Health care utilization and costs are also affected and usually associated with the severity of the disease.⁶

The goals of AD management are to prevent flares — and to manage flares effectively when they do occur — by preventing the disease’s progression. While there is no cure for AD, there are several therapeutic options available to patients to manage the condition. The majority of patients treat AD by using general skin care methods and topical anti-inflammatory therapy and by avoiding skin irritants. If these common methods fail to improve AD, patients may use off-label systemic therapy (i.e., immunosuppressant therapy) or other therapies, such as phototherapy.^1,4,7

The most common pharmaceutical topical therapies include topical corticosteroid (TCS) and topical calcineurin inhibitors (TCIs).¹ In Canada, hydrocortisone 1% (low potency) is the most commonly prescribed type of TCS, followed by triamcinolone or betamethasone valerate (moderate potency).^1,4 TCIs are steroid-free, anti-inflammatory, immunosuppressant drugs that can be used long-term. In Canada, the 2 drugs available are pimecrolimus and tacrolimus.^4,7 The most common adverse event (AE) associated with TCIs is application site–specific burning and irritation. Crisaborole, a topical phosphodiesterase type 4 inhibitor, is also available. The advantage of the TCIs and crisaborole is that both can be safely applied to the face and in creases, whereas TCS therapies that are more potent than 1% hydrocortisone are inappropriate. Systemic therapy involves the use of antimicrobials, antihistamines, or immunomodulators.^2,7 Immunomodulatory drugs include methotrexate, cyclosporine A, mycophenolate mofetil, and azathioprine. These can be used in patients who are not responsive to other treatments.^2,4,7 However, these commonly used off-label treatments are administered in the lowest dose and for the shortest duration possible due to the possibility of side effects. Dupilumab (Dupixent) is an interleukin (IL)-4 and IL-13 inhibitor indicated for use in adults and the pediatric population with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. CADTH has recommended that dupilumab be reimbursed with conditions, and it is currently reimbursed by participating drug programs for patients whose AD is inadequately controlled with topical prescription therapies and who have demonstrated failure on or intolerance to an adequate trial of phototherapy (where available), methotrexate, and cyclosporine A.⁸ Phototherapy is another second-line therapy that is commonly used after failure of TCS therapies and TCIs. Phototherapy requires 2 or 3 treatments per week for a duration of 8 weeks and is guided by a number of factors, including patient skin type and skin cancer history.⁹

Upadacitinib is a small-molecule, reversible, Janus kinase (JAK) inhibitor indicated for the treatment of adults and adolescents 12 years of age and older with refractory, moderate to severe AD who are not adequately controlled with a systemic treatment (e.g., a steroid or biologic) or when use of those therapies is inadvisable. Upadacitinib can be used with or without TCS. Upadacitinib is available as 15 mg or 30 mg oral extended-release tablets. The recommended starting dose of upadacitinib for adult patients is 15 mg once daily. If an adequate response (e.g., at least 75% improvement in the Eczema Area and Severity Index score from baseline [EASI 75]) is not achieved, physicians can consider increasing the dosage to 30 mg once daily. For some patients, such as those with severe disease, a starting dose of 30 mg once daily may be appropriate. Upadacitinib should be discontinued if an adequate response is not achieved with the 30 mg dose after 16 weeks of treatment. Patients should use the lowest effective dose needed to maintain response. For patients older than 65 years of age, the 30 mg dose once daily is not recommended. The recommended dosage of upadacitinib is 15 mg once daily for adolescents (from 12 years to 17 years of age) weighing at least 40 kg. Upadacitinib has not been studied in adolescents weighing less than 40 kg.¹⁰

The objective of this review is to perform a systematic review of the beneficial and harmful effects of upadacitinib for the treatment of adults and adolescents 12 years and older with moderate to severe AD who are candidates for systemic therapy.

Stakeholder Perspectives

The information in this section is a summary of the input provided by the patient groups who responded to CADTH’s call for patient input and from 1 clinical expert consulted by CADTH for the purpose of this review.

Patient Input

Three patient groups responded to CADTH’s call for patient input: the Eczema Society of Canada (ESC), the Canadian Skin Patient Alliance (CSPA), and Eczéma Québec. The latter 2 organizations provided a joint submission. ESC is a registered Canadian charity dedicated to improving the lives of Canadians living with eczema, and has a mission of support, education, awareness, and research. CSPA is a national, non-profit organization that educates, supports, and advocates for Canadians affected by skin, hair, and nail disorders. Eczéma Québec is a patient advisory committee and registered non-profit organization.

ESC gathered survey data from more than 3,000 adults living with AD and caregivers of children living with AD. Meanwhile, Eczéma Québec and CSPA developed a web-based survey that was distributed through both organizations’ newsletters and social media. There were 56 survey respondents.

The patient groups reported that AD negatively affects patients and their families and can lead to psychological distress. Patients frequently report that itch is their most burdensome symptom; more than half of adult respondents with severe AD reported rarely being able to control their urge to scratch. Itch also significantly affects sleep; patients report being woken frequently and having trouble falling and staying asleep due to their itch. The severity of AD correlates with impacts on HRQoL as well as lost productivity at school and burden on health systems. AD also has significant impacts in terms of the psychosocial burden of symptoms. All respondents experienced itching because of their condition. According to the CSPA survey, other symptoms included redness of the skin (87.88%), repeated rashes (84.85%), frequent scratching (84.85%), cracked skin (84.85%), dry and rough skin (78.79%), disrupted sleep (75.76%), bleeding (69.70%), flaking of the skin (69.70%), pain (69.70%), thickening of the skin (60.61%), oozing (48.48%), swelling (42.42%), lichenification (39.39%), and blistering (36.36%). From the ESC survey, 32% of adult respondents with moderate or severe AD have missed work events due to their condition, and 30% have had to change careers or give up certain activities. Caregivers noted that AD places a significant emotional toll on the entire family, and feelings of guilt, frustration, anger, and sadness are common. Forty-one percent of caregivers reported feeling like failures when they cannot control their children’s flares. Patients and caregivers reported that the mental health impact of AD is a significant aspect of the condition and is often not understood by others or prioritized by health care providers. Uncontrolled chronic AD can lead to feelings of depression and anxiety as well as poor self-esteem, low energy, and — in some extreme cases — suicidal thoughts.

Most patients expressed their dissatisfaction with the treatment options currently available to them. Another source of frustration for these participants was that they didn’t view these treatments as long-term options, but rather as temporary. Respondents also expressed concern about the financial impacts of treatments.

Overall, patients desire a treatment that will help them to manage itch, reduce flares and rashes, and enjoy an improved quality of life and sleep. Patients also want to improve the appearance of their hands and eyes (i.e., with less apparent eczema) and to have better pain relief.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

The clinical expert consulted by CADTH visualizes the ideal treatment for AD as 1 that is available to all Canadians, is cost-effective in the context of a publicly funded health care system, has a proven long-term safety record, and completely reverses the barrier dysfunction and immunologic abnormalities that constitute AD.

Upadacitinib was considered by the clinical expert as a potentially useful addition to the currently available therapeutic options for AD, especially in patients who have contraindications to, experience adverse effects from, or are unresponsive to off-label immunosuppressive drugs. Upadacitinib could also be of value in patients treated with dupilumab who have a suboptimal response, develop severe conjunctivitis or other ocular side effects, or are intolerant to injections (e.g., due to severe injection-site reactions) and prefer an oral drug. Furthermore, the clinical expert noted that all patients with AD treated with upadacitinib would be expected to continue with emollients, TCSs, and/or TCIs.

According to the clinical expert, upadacitinib can be another effective treatment option in the Canadian clinical landscape. Off-label immunosuppressives or dupilumab are not expected to be used in combination with upadacitinib; however, the clinical expert believed that many practitioners would still consider a trial of methotrexate and cyclosporine A before initiating treatment with upadacitinib. The clinical expert suggested that patients less suitable for treatment with upadacitinib would be those with AD who are well controlled with topical therapy, phototherapy, and/or intermittent off-label immunosuppressive therapy, as well as patients well controlled with dupilumab. Upadacitinib should be avoided in patients with potential contraindications to JAK inhibitors, such as those with severe active infections, malignancies, ongoing chemotherapy treatment (including checkpoint inhibitors), severe hepatic disease, severe renal disease, a history of thromboembolic events, or pre-existing hematologic disease. Patients who are pregnant or lactating, or who weigh less than 40 kg, should also avoid upadacitinib.

In general, the outcomes used in clinical practice are aligned with the outcomes typically used in clinical trials of AD treatments. Of these outcome measurements, a rational benchmark was a 75% reduction from baseline in the EASI score at 16 weeks. In the opinion of the clinical expert, patients placed on upadacitinib would be re-evaluated at 16 weeks after initiating treatment. Those who are judged to be responders at this visit would be seen subsequently at 6-month intervals. Those who have not reached response targets at 16 weeks would be re-evaluated at 20 weeks.

According to the clinical expert, patients deemed to have severe symptoms would start on 30 mg for 16 weeks and be assessed for response (e.g., EASI 75); if a response is reached, they would switch to 15 mg. The product monograph approved by Health Canada states that patients who are receiving 15 mg and do not achieve a response after 16 weeks of treatment would be switched to 30 mg. The product monograph also states that if patients do not achieve adequate response (e.g., EASI 75) after 16 weeks of treatment on the 30 mg dose, upadacitinib should be discontinued.

The factors anticipated by the clinical expert to be used as criteria for discontinuation included failure to achieve a clinically meaningful response at 16 weeks to 20 weeks, failure to maintain an adequate response on long-term maintenance, development of a hypersensitivity response judged to be due to upadacitinib, treatment-emergent adverse effects (TEAEs) (e.g., lymphopenia, neutropenia, arterial thrombosis, venous thromboembolism [VTE]), and treatment-emergent severe infections or malignancies.

There are no special challenges for the administration of the drug. However, a specialist would still be required to diagnose, treat, and monitor patients taking upadacitinib. Appropriate specialists include pediatric dermatologists, general dermatologists, or pediatricians with experience in treating patients with AD. Dermatologists are well versed in the appropriate dosing and duration of therapy and appropriate monitoring for potential toxicities.

Clinician Group Input

One clinician group provided input on the reimbursement review of upadacitinib for the treatment of adult and adolescents with moderate to severe AD: the Atlantic Specialist Group Managing Atopic Dermatitis is a group of physicians, including general practitioners, dermatology, and allergy and immunology specialists, who manage patients with AD. The members of the group are located in various clinical settings across Atlantic Canada.

The clinician group indicated that the greatest unmet need is in the subset of patients with moderate to severe AD, who lack access to an effective, convenient, and safe treatment that enables long-term disease control and remission, given that many patients experience flares as soon as they stop their current medication. This cycle of recurrence leads to disease progression, ending in chronic severe AD and severe impacts on HRQoL.

According to the clinician group, the place in therapy for upadacitinib would be after initial treatments for mild AD (e.g., lifestyle measures and topical steroids). In such a case, upadacitinib would replace systemic therapies that are currently used off-label to treat AD, as well as phototherapy. In the clinician group’s opinion, dupilumab addresses some of the concerns and needs of some patients, but upadacitinib may shift the paradigm due to its efficacy and ease of administration. This place-in-therapy judgment differs from the opinion of the clinical expert consulted by CADTH, who considered that upadacitinib should be used after a trial of systemic therapies that are currently used (even if off-label) to treat patients who fail to respond to TCSs, such as methotrexate or cyclosporine A.

The clinician group noted that upadacitinib would be best suited to treat patients with moderate to severe AD who have not responded, are not expected to respond, or have had adverse reactions to long-term use of TCSs. These patients have the greatest need for intervention because they lack long-term treatment options and are at high risk of disease progression.

The outcomes measured in clinical trials, such as the Investigator Global Assessment (IGA), are also used in clinical practice, perhaps with the exception of EASI scores, which are relatively unknown in day-to-day practice. The group mentioned that a clinically meaningful response to upadacitinib would include improvement in patient-reported itch (a 4-point reduction on the numerical rating scale [NRS] or an NRS score of less than 3), a Dermatology Life Quality Index (DLQI) score reduction of greater than or equal to 4 (or an acceptable improvement), patient-reported improvement in sleep quality, fewer AD-related disruptions at school and work, and a Physician Global Assessment (PGA) score 0 or 1. Importantly, a patient should not experience any severe side effects, including over sustained time periods, in order for the response to upadacitinib to be clinically meaningful.

The group suggests that the response to systemic therapy should be reassessed in 12 weeks to 16 weeks after the initiation of treatment. According to input from the clinician group, the decision to discontinue treatment should be assessed if there is a lack of response, significant disease progression (i.e., lichenification, increased affected body surface area [BSA], or increased itching), or deterioration in quality of life, or if the patient experiences adverse reactions or intolerance to the medication that are deemed to be unacceptable by the patient-physician team. Treatment with upadacitinib should be interrupted if a patient develops a serious infection or presents serious abnormal laboratory results (e.g., an absolute lymphocyte count of less than 500 cells/mm³, an absolute neutrophil count of less than 1,000 cells/mm³, or hemoglobin less than 8 g/dL), or if drug-induced liver injury is suspected (based on hepatic transaminases); treatment with upadacitinib may be resumed once levels return to normal. Patients with AD receiving upadacitinib would ideally be managed in any non-emergent setting to which they have access and that has a dermatologist or allergist who is well versed in managing moderate to severe AD. Referring family physicians, nurse practitioners, or other health care providers should be counselled on the appropriate referral process.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review processes. The following were identified as key factors that could affect the implementation of a CADTH recommendation for upadacitinib:

• Access to phototherapy may be limited in some areas of Canada. The clinical expert consulted by CADTH noted that phototherapy is typically accessible in urban areas, but that access may be limited in rural areas. The expert noted that this barrier to phototherapy access should be considered in the reimbursement review decision-making process.

• As to whether upadacitinib should be initiated in patients who have failed previous treatment with a biologic drug, the clinical expert’s perspective was that patients who have failed dupilumab plus 1 of the immunomodulators would be candidates to receive upadacitinib, but that this also would apply for those who have failed dupilumab alone. The clinical expert noted that there is limited evidence for the sequential use of upadacitinib after an adequate trial of dupilumab in patients with moderate to severe AD.

• On the question of whether patients would require a previous trial of (or be ineligible for) cyclosporine A, methotrexate, and/or phototherapy before initiating upadacitinib, the expert’s opinion was that a trial of at least 2 of the 4 immunomodulators (i.e., methotrexate, cyclosporine A, mycophenolate mofetil, or azathioprine) should be considered before initiating upadacitinib.

• On the question of whether the reimbursement criteria that were recommended for dupilumab would be applicable to upadacitinib (e.g., the initiation and renewal criteria), the clinical expert consulted by CADTH noted that the criteria for dupilumab could be applicable for upadacitinib and could be implemented in clinical practice. Dupilumab as prior therapy should not be an initiation criterion. Both drugs would have the same place in therapy in the population for this indication.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

Four clinical studies were included in this report evaluating the use of upadacitinib in patients with moderate to severe AD.

Measure Up 1 and Measure Up 2 were 2 similar studies (n = 847 and n = 836, respectively) with a double-blind, placebo-controlled parallel design. Eligible patients were adults and adolescents (≥ 40 kg) with chronic AD and a documented history of systemic treatment or inadequate response to topical AD treatments. Both studies randomized patients to upadacitinib 15 mg, upadacitinib 30 mg, or placebo. The studies evaluated co-primary outcomes, the proportion of responders based on the EASI score (where 75 indicates an improvement of 75% from baseline), and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 or 1 at week 16.

The AD Up study had a similar design to the Measure Up 1 and Measure Up 2 studies, with the same inclusion criteria and population (n = 901). However, it used TCSs in combination with upadacitinib 15 mg, upadacitinib 30 mg, or placebo. It used the same co-primary end points at 16 weeks.

The Heads Up study was a double-blind, double-dummy, active-controlled, randomized study (n = 692) comparing upadacitinib 30 mg to dupilumab 300 mg subcutaneous (SC) in adults (18 years to 75 years old) with chronic AD and a documented history of inadequate response to topical treatments or documented treatment with systemic therapies. This study’s primary end point included the proportion of patients achieving EASI 75 at week 16.

The eligibility criteria for the included randomized controlled trials (RCTs) were similar except for the differences in the age range for the study comparing upadacitinib to dupilumab (i.e., the Heads Up study was limited to adults, while the others included adolescents). All of the trials enrolled patients with moderate to severe AD and an inadequate response to topical AD therapies. This is reflective of the indication that was initially submitted to Health Canada and CADTH; however, the approved Health Canada indication reflects a more restrictive population (i.e., those with refractory, moderate to severe AD and an inadequate response to other systemic drugs). The proportion of patients with prior exposure to at least 1 systemic therapy for AD in the included trials were: Measure Up 1 = 46.4%; Measure Up 2 = 54.5%; AD Up = 66.6%; and Heads Up = |||||.

Efficacy Results

Outcomes of disease severity, such as EASI 75, the vIGA-AD, and the Scoring Atopic Dermatitis (SCORAD) scale, were considered by the clinical expert consulted by CADTH critical for decision-making and clinical practice and mentioned in the patient input received from patient groups. Similarly, among the outcomes of symptoms — as measured with the Worst Pruritus Numerical Rating Scale (WP-NRS), Patient-Oriented Eczema Measure (POEM), and the Atopic Dermatitis Impact Scale (ADerm-IS) and Atopic Dermatitis Symptom Scale (ADerm-SS) — HRQoL, mood, and productivity were considered among the most important across different domains of decision-making.

At 16 weeks of follow-up, upadacitinib showed statistically significant improvements in the co-primary end points of disease severity in the Measure Up, AD Up, and Heads Up studies. In Measure Up 1, more patients reached EASI 75 in the upadacitinib 15 mg group (196 patients of 281 patients [69.6%]) and in the upadacitinib 30 mg group (227 patients of 285 patients [79.7%]) than in the placebo group (46 patients of 281 patients [16.3%]); the adjusted differences versus placebo were 53.3% (95% confidence interval [CI], 46.4 to 60.2; P < 0.001) for the upadacitinib 15 mg group and 63.4% (95% CI, 57.1 to 69.8; P < 0.001) for the upadacitinib 30 mg group.

When assessing for an EASI score of 90, more patients in the upadacitinib 30 mg group (187 patients [65.8%]) and the upadacitinib 15 mg group (149 patients [53.1%]) were responders compared to placebo (23 [8.1%]); the adjusted differences were 57.8% (95% CI, 51.5 to 64.1) and 45.1% (95% CI, 38.6 to 51.7), respectively. Similarly, in Measure Up 2, 166 patients out of 276 patients (60.1%) in the upadacitinib 15 mg group and 206 patients out of 282 patients (2.9%) in the upadacitinib 30 mg group versus 37 patients out of 278 patients (13.3%) in the placebo group reached EASI 75, with adjusted differences in the EASI 75 response rate versus placebo of 46.9% (95% CI, 39.9 to 53.9; P < 0.001) for the upadacitinib 15 mg group and 59.6% (95% CI, 53.1 to 66.2; P < 0.001) for the upadacitinib 30 mg group. When assessing for an EASI score of 90, more patients in the upadacitinib 30 mg group (165 patients [58.5%]) and the upadacitinib 15 mg group (117 patients [42.4%]) were responders compared to placebo (15 patients [5.4%]); the adjusted differences were 53.1% (95% CI, 46.7 to 59.4) and 36.9% (95% CI, 30.6 to 43.3), respectively.

Likewise, in Measure Up 1, a larger proportion of patients achieved a vIGA-AD response at week 16 in the upadacitinib 15 mg group (135 patients [48.1%]) and the upadacitinib 30 mg group (177 patients [62.0%]) than in the placebo group (24 patients [8.4%]); the adjusted differences versus placebo were 39.8% (95% CI, 33.2 to 46.4; P < 0.001) for the upadacitinib 15 mg group and 53.6% (95% CI, 47·2 to 60·0; P < 0.001) for the upadacitinib 30 mg group. In Measure Up 2, 107 patients (38.8%) in the upadacitinib 15 mg group and 147 patients (52.0%) in the upadacitinib 30 mg group achieved a vIGA-AD response at week 16 versus 13 patients (4.7%) in the placebo group; the adjusted differences in vIGA-AD response rate versus placebo were 34.0% (95% CI, 278 to 40.2; P < 0.001) for the upadacitinib 15 mg group and 47.4% (95% CI, 41.0 to 53.7; P < 0.001) for the upadacitinib 30 mg group.

In the AD Up study, at week 16, the proportion of patients who had achieved EASI 75 was statistically significantly higher in the group receiving upadacitinib 15 mg plus TCS (194 out of 300 patients [64.6%]) and in the group receiving upadacitinib 30 mg plus TCS (229 of 297 patients [77.1%]) than in the placebo group (80 of 304 patients [26.4%]); the adjusted differences in the EASI 75 response rate versus placebo were 38.1% (95% CI, 30.8 to 45.4; P < 0.001) for the upadacitinib 15 mg group and 50.6% (95% CI, 43.8 to 57.4; P < 0.001) for the upadacitinib 30 mg group. When assessing for an EASI score of 90, more patients in the upadacitinib 30 mg group (187 patients [63.1%]) and upadacitinib 15 mg group (128 patients [42.8%]) were responders compared to placebo (40 patients [13.2%]); the adjusted differences were 57.8% (95% CI, 51.5 to 64.1) and 45.1% (95% CI, 38.6 to 51.7), respectively. The proportions of patients who achieved a vIGA-AD response at week 16 were statistically significantly higher in the group receiving upadacitinib 15 mg plus TCS (119 patients [39.6%]) and in the group receiving upadacitinib 30 mg plus TCS (174 patients [58.6%]) than in the placebo group (33 patients [10.9%]); the adjusted differences were 28.5% (95% CI, 22.1 to 34.9) for the upadacitinib 15 mg group and 47.6% (95% CI, 41.1 to 54.0) for the upadacitinib 30 mg group (P < 0.0001 for both doses).

In the Heads Up trial, patients in the upadacitinib 30 mg group showed statistically significantly higher rates of achieving EASI 75 (247 patients [71.0%]) than those on dupilumab 300 mg (210 patients [61.1%]) at week 16; the adjusted difference between groups was 10.0% (95% CI, 2.9 to 17.0; P = 0.006). This difference was no longer statistically significant at week 24, with 205 patients in the dupilumab group (59.5%) and 223 patients in the upadacitinib 30 mg group (64.2%) achieving EASI 75 (adjusted difference = 4.6%; 95% CI, –2.6 to 11.9; P = 0.211). When assessing for an EASI score of 90 at week 16, more patients in the upadacitinib 30 mg group (211 patients [60.6%]) were responders compared to those in the dupilumab group (133 patients [38.8%]; the adjusted difference was 21.8% (95% CI, 14.5 to 29.1), and this difference between groups was smaller at week 24, at 4.6% (95% CI, 0.5 to 15.4; P = 0.036).

An assessment of patients with previous systemic therapies showed similar results to the base case in all studies (i.e., the Measure Up 1, Measure Up 2, AD Up, and Heads Up trials) for the primary end points of response based on EASI 75 at week 16 and on the vIGA (except in the Heads Up study, which did not assess vIGA). In the subgroup of patients with prior use of a systemic treatment for AD (e.g., a steroid or biologic), the adjusted differences (95% CI) for upadacitinib 15 mg once daily and upadacitinib 30 mg once daily (respectively) compared with placebo for EASI 75 at week 16 were: for Measure Up 1, |||||||||||||||||| and |||||||||||||||||||||||||||; for Measure Up 2, ||||||||||||||||||||||||||||||||||||||||||||||||||||||; for AD Up, |||||||||||||||||||||||||||||||||||||||||||||. For Heads Up, the proportions of patients reaching EASI 75 at week 16 were ||||||||| and ||||||||| for dupilumab and upadacitinib, respectively; the adjusted difference for upadacitinib 30 mg versus dupilumab 300 mg was |||||||||||||||||||||||||||. For IGA response, the results were: Measure Up 1, ||||||||||||||||||||||||||| and ||||||||||||||||||; Measure Up 2, |||||||||||||||||| and ||||||||||||||||||; AD Up, |||||||||||||||||| and ||||||||||||||||||. Heads Up did not include a vIGA assessment.

Symptoms of AD were also improved. In the Measure Up studies, the proportion of patients achieving a WP-NRS score of greater than or equal to 4 from baseline at week 16 was statistically significantly higher compared to placebo in the upadacitinib 15 mg group (i.e., the absolute risk differences from placebo were 40.5% [95% CI, 33.5 to 47.5] in Measure Up 1 and 32.6% [95% CI, 25.8 to 39.4] in Measure Up 2) and in the upadacitinib 30 mg group (48.2% [95% CI, 41.3 to 55.0] in Measure Up 1 and 50.4% [95% CI, 43.8 to 57.1] in Measure Up 2; P < 0.001) for all comparisons. The proportion of patients achieving a POEM total score improvement (reduction) of at least 4 points from baseline at week 16 was also statistically significantly higher in the upadacitinib 15 mg group, with an absolute risk difference of 52.3% (95% CI, 45.2 to 59.4) in Measure Up 1 and 42.1% (95% CI, 34.5 to 49.8) in Measure Up 2 and in the 30 mg group, with absolute risk differences of 58.6% (95% CI, 51.9 to 65.3) in Measure Up 1 and 54.7% (95% CI, 47.7 to 61.7) in Measure Up 2 versus placebo (P < 0.001 for all comparisons). Improvements were also observed in the ADerm skin pain, sleep, emotional, and daily activities domains (P < 0.001 for all comparisons). No subgroup analyses were performed on symptoms outcomes.

In AD Up, the results were similar to those of Measure Up, in which the proportion of patients achieving a WP-NRS score of greater than or equal to 4 from baseline at week 16 was statistically significantly higher when compared to placebo in the upadacitinib 15 mg group (absolute risk difference from placebo = 36.8% [95% CI, 29.7 to 43.8]) and in the upadacitinib 30 mg group (absolute risk difference from placebo = 48.8% [95% CI, 41.9 to 55.7]); P < 0.001 for all comparisons. The POEM total score improvement of at least 4 points from baseline was also statistically significantly higher in the upadacitinib 15 mg group (absolute risk difference of ||||||||||||||||||||||||||| and 30 mg [|||||||||||||||||||||||||||] against placebo; P < 0.001 for all comparisons). Improvements were also observed in the ADerm skin pain, sleep, emotional, and daily activities domains (P < 0.001 for all comparisons).

When compared to dupilumab (Heads Up study), the proportion of patients achieving a WP-NRS of greater than or equal to 4 at week 16 was statistically significantly higher in the upadacitinib 30 mg group (55.2%) compared to the dupilumab 300 mg group (35.9%), with an absolute risk difference of 19.3% (95% CI, 11.9 to 26.7; P < 0.001). The risk difference decreased at week 24 to 8.3% (95% CI, 0.8 to 15.8), although it was still statistically significant (P = 0.030).

HRQoL, assessed by the DLQI score, was also improved more frequently in the upadacitinib 15 mg and upadacitinib 30 mg groups than in the placebo group in the Measure Up and AD Up studies, but not when assessed using the generic EQ-5D Five-Level (EQ-5D-5L) questionnaire. Mood and work productivity were similarly improved in the upadacitinib groups versus placebo. The absenteeism domains were not significantly statistically different between groups. No subgroup analyses were performed on these outcomes.

Harms Results

Upadacitinib 15 mg and upadacitinib 30 mg doses in all studies were well tolerated compared to placebo at week 16, without significant increases in AEs or serious adverse events (SAEs) up to the latest follow-up of 52 weeks in the blinded extension (BE) studies. The incidence of SAEs and AEs leading to study drug discontinuation were similar among groups except in the Heads Up study. The most frequently reported AEs were acne, upper respiratory tract infection, nasopharyngitis, headache, elevation in creatine phosphokinase (CPK) levels, and AD. No deaths were reported. No subgroup analyses based on prior exposure to systemic treatment (e.g., steroid or biologic) for AD were performed for AE.

In the AD Up study, the most frequently reported AEs (≥ 5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood CPK levels, headache, and AD. Acne was more frequent in the upadacitinib groups (10% to 14% in the 15 mg and 30 mg groups, respectively) than in the placebo group (2%) at week 16. No deaths were reported.

In the Heads Up study, the safety profile of upadacitinib was similar to those of the Measure Up and AD Up studies. The rates of serious AEs and AEs leading to study drug discontinuation were 2.9% and 1.2% for upadacitinib and 1.2% and 1.2% for dupilumab, respectively. One death was reported in an upadacitinib-treated patient due to influenza-associated bronchopneumonia. The most frequently reported AE among patients receiving upadacitinib was acne (15.8%); this AE was reported by only 2.6% of patients receiving dupilumab. The most frequently reported AE with dupilumab was conjunctivitis (8.4%); this AE was reported by only 1.4% of patients on upadacitinib. Other AEs that were more common in the upadacitinib groups were serious infections (1.1% versus 0.6%), eczema herpeticum (0.3% versus 0%), hepatic disorders (2.9% versus 1.2%), and herpes zoster (2.0% versus 0.9%). Also, rates of anemia (2.0% versus 0.3%), neutropenia (1.7% versus 0.6%), and CPK elevations (6.6% versus 2.9%) were higher for upadacitinib than dupilumab.

In the Japan study, through week 16, the rates of AEs observed in the upadacitinib 15 mg and 30 mg groups were higher than those observed in the placebo group overall.

Table 2: Summary of Key Results — Pivotal and Protocol Selected Monotherapy Studies

CI = confidence interval; CPK = creatine phosphokinase; EASI = Eczema Area and Severity Index; ITT = intention to treat; q.d. = once daily; SAE = serious adverse event; UPA = upadacitinib; vIGA-AD = validated Investigator Global Assessment for Atopic Dermatitis; vs. = versus; WP-NRS = Worst Pruritus Numerical Rating Scale.

^aAssessed in the ITT population with nonresponder imputation incorporating multiple imputation to handle data missing due to COVID-19.

^b95% CI for adjusted difference and P values are calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline vIGA-AD score categories and age [adolescent vs. adult]) for the comparison of 2 treatment groups.

^cSafety population.

Source: Clinical Study Reports for Measure Up 1 and Measure Up 2.^11,12

Table 3: Summary of Key Results — Pivotal and Protocol Selected Combination Therapy Studies

CI = confidence interval; EASI = Eczema Area and Severity Index; ITT = intention to treat; q.d. = once daily; SAE = serious adverse event; TCS = topical corticosteroid; UPA = upadacitinib; vIGA-AD = validated Investigator Global Assessment for Atopic Dermatitis; vs. = versus; WP-NRS = Worst Pruritus Numerical Rating Scale.

^aAssessed in the ITT population with nonresponder imputation incorporating multiple imputation to handle data missing due to COVID-19.

^b95% CIs for adjusted difference and P values are calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline vIGA-AD score categories and age [adolescent vs. adult]) for the comparison of 2 treatment groups.

^cSafety population.

Source: Clinical Study Report: AD Up.¹³

Table 4: Summary of Key Results — Pivotal and Protocol Selected Head-to-Head Studies

2.q.w. = every 2 weeks; CI = confidence interval; CPK = creatine phosphokinase; DUP = dupilumab; EASI = Eczema Area and Severity Index; ITT = intention to treat; q.d. = once daily; SAE = serious adverse event; UPA = upadacitinib; vIGA-AD = validated Investigator Global Assessment for Atopic Dermatitis; vs. = versus; WP-NRS = Worst Pruritus Numerical Rating Scale.

^aAssessed in the ITT population with nonresponder imputation incorporating multiple imputation to handle data missing due to COVID-19.

^b95% CI for adjusted difference and P values are calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (baseline vIGA-AD score categories and age [adolescent vs. adult]) for the comparison of 2 treatment groups.

^cSafety population.

Source: Clinical Study Report: Heads Up.¹⁴

Critical Appraisal

Randomization and allocation concealment were properly completed, resulting in a similar distribution of baseline demographics and disease characteristic variables between the treatment groups in each trial, without important imbalances.

Blinding of patients and study personnel was appropriately maintained. However, given that a placebo was used in several studies, it is possible that patients may have potentially become unblinded or aware of their assignments through improvement or lack of improvement (placebo) in their AD symptoms over the study period. There is the possibility that, in the Heads Up trial, certain adverse events (such as injection-site reactions, hypersensitivity reactions, or conjunctivitis) known to be potential risks associated with dupilumab could have resulted in unblinding, which could have biased the results of patient-reported outcomes, such as HRQoL. However, the co-primary end points are relatively objective, and risk of bias would be small.

The co-primary outcomes were based on the vIGA and EASI scores, both of which are reliable and valid for the assessment of the severity and extent of AD. The co-primary end points were analyzed appropriately using the intention-to-treat (ITT) population. Secondary end points were analyzed based on complete case analyses. This is expected to introduce some risk of bias in favour of upadacitinib (given that more complete data were available for upadacitinib due to lower discontinuations and drop-outs) because the groups may no longer be balanced in characteristics, and the data observed from the incomplete cases are discarded (i.e., patients who are responding to treatment and have limited AEs may be more likely to stay in the study and contribute data to the end points). Controlling for multiplicity was appropriate for the primary and secondary end points of all trials; a graphical multiple testing procedure was used. The greatest number of patients who discontinued the intervention were within the placebo groups in the Measure Up and AD Up trials. This introduces the potential for bias against the null (i.e., toward an inflated efficacy of upadacitinib) due to the analytical approaches used because more placebo patients would have been imputed as nonresponders. However, sensitivity analyses were based on multiple imputation, the tipping point approach, and the per-protocol population, with similar conclusions to those reached in the primary analyses. Several subgroup analyses were properly specified a priori and conducted across the trials (e.g., based on baseline vIGA-AD, baseline EASI, previous systemic therapy, age, and sex, among other factors), showing similar results.

The population in the included pivotal studies seems to be generalizable to adults and adolescents in the Canadian population having AD. However, when considering the applicability of the results for the population of patients previously treated with systemic therapies (i.e., the approved indication for upadacitinib), only a proportion of the patients included in the pivotal studies was similar to the approved Health Canada indication. Furthermore, the information from the pivotal studies for the 30 mg dose also represents a proportion of the population, and data to inform the approved indication are lacking — that is, data estimating the effects of upadacitinib in patients with AD who are switched from upadacitinib 15 mg to upadacitinib 30 mg if an adequate response (e.g., EASI 75) is not achieved. In addition, there were no clinical studies that studied a dose de-escalation to upadacitinib 15 mg once daily in patients who achieved a response to upadacitinib 30 mg once daily. This lack of evidence adds uncertainty to the generalizability of the results in the population for whom the indication would be applicable.

In all of the pivotal trials included in this CADTH review, an assessment of the subgroup of patients who had taken previous systemic therapies showed similar results to the base case for the primary end points of response based on EASI 75 at week 16 and vIGA score (except for the Heads Up study, in which no vIGA score was assessed). Although this implies that the beneficial effect of upadacitinib in the previously treated population is reflective of the overall base-case population, such a conclusion should be drawn with caution because it was not an a priori specification for this subgroup analysis and can be underpowered for drawing conclusions. The clinical expert consulted by CADTH suggested that the response to upadacitinib would likely be similar for those with and without prior exposure to a systemic therapy for AD.

The population in Measure Up 1 appeared to have slightly less severe AD than the populations in the rest of the studies. The rest of the baseline and demographic characteristics were similar overall between studies. The results for the adolescent populations analyzed in these included studies (except in the Heads Up trial) mirrored those for the adult populations; however, the adolescent populations were relatively small in the included trials. More evidence will be needed in under-represented populations, such as people of Black/African, First Nations, and Asian descent, compared to the White population. Also, the trial durations might not have been long enough to assess long-term outcomes (harms); and given that patients in the Measure Up and AD Up studies were dupilumab-naive, more evidence is needed to assess the response to upadacitinib in patients who were previously treated with dupilumab.

Indirect Comparisons

Description of Studies

Three indirect treatment comparisons (ITCs) — 2 sponsor-submitted (ITC 1 and ITC 2) and 1 obtained from the CADTH literature search (ITC 3, conducted by the Institute for Clinical and Economic Review [ICER]) — were included to provide an increased perspective on the body of evidence by including indirect comparisons of upadacitinib against dupilumab and other systemic therapies. All ITCs analyzed upadacitinib and its efficacy against other common comparators using Bayesian network meta-analyses (NMAs).

The first is an NMA comparing upadacitinib 15 mg or upadacitinib 30 mg (with or without TCS) versus dupilumab in adults or adolescents with moderate to severe AD with an inadequate response to cyclosporine A or other systemic therapy (i.e., ITC 1, a post-cyclosporine A NMA). The second is an NMA of a comprehensive published RCT evidence base conducted to determine the comparative effectiveness of upadacitinib 15 mg and upadacitinib 30 mg versus other immunomodulators in patients with moderate to severe AD as monotherapy (i.e., in patients not concomitantly receiving TCS) and as combination therapy (i.e., concomitantly receiving TCS). The third is an NMA report from ICER evaluating systemic therapies (abrocitinib, baricitinib, upadacitinib, tralokinumab, and dupilumab) with or without topical therapies in adults and children (≥ 12 years old) with moderate to severe AD.

Efficacy Results

Overall, the results from the 3 ITCs suggest that upadacitinib 30 mg and upadacitinib 15 mg are among the most effective systemic therapies for reducing the severity and symptoms of moderate to severe AD in adults and adolescents, whether as monotherapy or in combination with TCS.

As monotherapy, based on the results from ITC 1, upadacitinib 30 mg and upadacitinib 15 mg demonstrated |||||||||||||||||| against dupilumab 300 mg in improving EASI 75 scores; the NMA detected |||||||||||||||||| between upadacitinib 30 mg and upadacitinib 15 mg. In ITC 2, upadacitinib 30 mg was superior to all comparators (abrocitinib 100 mg, dupilumab 300 mg, baricitinib 2 mg, baricitinib 4 mg, tralokinumab 300 mg) on all outcomes except against abrocitinib 200 mg, versus which no difference was detected in EASI 75 scores and WP-NRS. Upadacitinib 15 mg was superior to abrocitinib 100 mg, dupilumab 300 mg, baricitinib 2 mg, baricitinib 4 mg, and tralokinumab 300 mg, with no difference detected against abrocitinib 200 mg; it was inferior only to upadacitinib 30 mg in both the EASI 75 and IGA scores. The ITC 3 ICER report showed that upadacitinib 30 mg was superior to upadacitinib 15 mg, abrocitinib 100 mg, dupilumab 300 mg, baricitinib 1 mg, baricitinib 2 mg, and tralokinumab 300 mg, with no difference detected against abrocitinib 200 mg when assessing EASI 75 and IGA scores. Upadacitinib 15 mg was superior to abrocitinib 100 mg, baricitinib 1 mg, baricitinib 2 mg, and tralokinumab 300 mg; there was no difference detected against abrocitinib 200 mg and dupilumab 300 mg; and it was inferior only to upadacitinib 30 mg in EASI 75 and IGA scores.

When combination therapy with TCS was assessed, ITC 1 showed no difference between upadacitinib 30 mg and upadacitinib 15 mg or against dupilumab 300 mg in EASI 75 scores. ITC 2 demonstrated that upadacitinib 30 mg was superior to all comparators (upadacitinib 15 mg, baricitinib 2 mg, baricitinib 4 mg, and tralokinumab 300 mg) in EASI 75, IGA, and WP-NRS except dupilumab 300 mg, versus which no difference was detected when evaluating the EASI 75 score. Upadacitinib 15 mg demonstrated superiority only to baricitinib (2 mg and 4 mg) and tralokinumab 300 mg; it was no different from dupilumab 300 mg, and inferior only to upadacitinib 15 mg in terms of EASI 75, IGA, and WP-NRS. ITC 3 demonstrated superiority of upadacitinib 30 mg against upadacitinib 15 mg, abrocitinib 200 mg, abrocitinib 100 mg, dupilumab 300 mg, baricitinib 2 mg, and tralokinumab 300 mg in EASI 75, IGA, and WP-NRS. Only when evaluating the IGA score was no difference detected between abrocitinib 200 mg and upadacitinib 30 mg. Upadacitinib 15 mg was inferior only to upadacitinib 30 mg. It was superior to abrocitinib 100 mg, baricitinib 2 mg, and tralokinumab 300 mg. No difference was detected when compared to dupilumab 200 mg and abrocitinib 200 mg for all outcomes.

Effect estimates from ITC 3 had generally lower OR values when compared to ITC 1 and ITC 2. However, overall, results were similar between the 3 ITCs, demonstrating superiority of upadacitinib 30 mg over upadacitinib 15 mg, dupilumab, and the other comparators, with no difference detected against abrocitinib 200 mg.

Harms Results

No harms data were analyzed in any of the ITCs.

Critical Appraisal

The limitations from the 3 ITCs stem from uncertainty in the effect estimates due to imprecision (wide and overlapping credible intervals [CrIs] among comparisons) and baseline heterogeneity. It is uncertain how upadacitinib relates to other relevant comparators in the population previously treated with systemic therapies (i.e., the approved indication for upadacitinib). Only 1 ITC (ITC 1) evaluated patients previously exposed to systemic therapies (cyclosporine A). Although the comparison in this ITC is exclusively of upadacitinib versus dupilumab, which limits the ITC’s generalizability to other comparisons, the dupilumab comparison is still relevant because that drug is commonly prescribed and reimbursed for AD treatment in Canada. Conclusions regarding the long-term efficacy of upadacitinib compared to the active comparators relevant to this review cannot be drawn because the NMA used study results that were collected over a relatively short time frame, considering the chronic nature of AD. There is also uncertainty due to the inherent heterogeneity across trials in the networks. The robustness of the comparative efficacy was further compromised by the lack of precision in the findings; therefore, results from the ITCs must be interpreted with caution. Moreover, no information was obtained regarding the comparative safety of upadacitinib versus other active comparators. In addition, no conclusion could be drawn regarding the HRQoL outcomes.

Other Relevant Evidence

Description of Studies

Three extension studies of the included studies were reported in the submission. Measure Up 1 to 52, Measure Up 2 to 52, and AD Up 52 are phase III, randomized, double-blind, placebo-controlled, multi-centre studies in adolescents (12 years to 17 years) and adults (18 years to 75 years) with moderate to severe atopic dermatitis. The Measure Up studies included a 35-day screening period, a 16-week double-blind period, a BE period up to week 136, and a 30-day follow-up visit. AD Up (for which the week 52 data cut-off was December 18, 2020) included a 35-day screening period, a 16-week double-blind period, a BE period up to week 136, and a 30-day follow-up visit. At week 16, patients in the placebo group were re-randomized in a 1 to 1 ratio to receive daily oral doses of upadacitinib 30 mg or upadacitinib 15 mg in a blinded fashion up to week 136 in the BE period.

Efficacy Results

Patients in the Measure Up 1 to 52, Measure Up 2 to 52, and AD Up 52 studies maintained response in the co-primary end points. For instance, in Measure Up 1 to 52, 59.2% and 62.5% of the patients who started upadacitinib 15 mg and upadacitinib 30 mg every day, respectively, maintained a vIGA-AD response of 0 or 1 at week 52; and 82% and 84.9% of the patients who started upadacitinib 15 mg and upadacitinib 30 mg once daily, respectively, maintained an EASI 75 response at week 52. In Measure Up 2 to 52, 52.6% and 65.1% of the patients who started upadacitinib 15 mg and upadacitinib 30 mg once daily, respectively, maintained a vIGA-AD response of 0 or 1 at week 52; and 79.1% and 84.3% of the patients who started upadacitinib 15 mg and upadacitinib 30 mg once daily, respectively, maintained a EASI 75 response at week 52. In AD Up 52, 46.3% and 55.7% of the patients who started upadacitinib 15 mg and 30 mg once daily plus TCS, respectively, maintained a vIGA-AD response of 0 or 1 at week 52; and 70.8% and 83.5% of the patients who started upadacitinib 15 mg and 30 mg once daily plus TCS, respectively, maintained an EASI 75 response at week 52.

Harms Results

In Measure Up 1 to 52, a total of ||||| patients had at least 1 AE during the study. The most common AEs (per 100 patient-years) were related to acne (|||||), upper respiratory tract infections (|||||), and nasopharyngitis (|||||). In Measure Up 2 to 52, a total of 606 patients (||||| per 100 patient-years) had at least 1 AE during the study. The most common AE was acne (|||||). In AD Up, a total of ||||| patients had at least 1 TEAE during the study, most commonly related to nasopharyngitis (|||||) or acne (|||||). No deaths were reported. SAEs included CPK elevations. The most common notable harms were hepatic disorder (|||||), herpes zoster (|||||), CPK elevation (|||||), and serious infection (|||||).

Conclusions

Evidence from 3 double-blind, placebo-controlled studies (Measure Up 1, Measure Up 2, and AD Up) shows that compared to placebo, both upadacitinib 15 mg and upadacitinib 30 mg improve disease severity end points in adults with moderate to severe AD, based on EASI 75 and vIGA-AD scores, whether as monotherapy (as in the Measure Up 1 and 2 studies) or in addition to TCS (as in the AD Up study). The evidence from these studies also indicates that upadacitinib 15 mg and upadacitinib 30 mg would likely reduce AD symptoms (WP-NRS, POEM, ADerm-IS), improve HRQoL (DLQI), and improve mood and productivity domains (Hospital Anxiety and Depression Scale – Anxiety [HADS-A] and Work Productivity and Activity Impairment Index: Atopic Dermatitis [WPAI:AD]). The evidence suggests that these effect estimates are similar in the adolescent subpopulation. These results were considered clinically relevant by both clinical experts and patients. Results from 1 head-to-head study (Heads Up) demonstrated superiority of upadacitinib 30 mg in reducing disease severity and symptoms (based on the EASI 75 and WP-NRS) compared to dupilumab at week 16; however, after 24 weeks, this difference was no longer observed, and beyond this time point, the evidence is still uncertain.

Three ITCs support the notion that upadacitinib 15 mg and upadacitinib 30 mg are effective when compared to dupilumab and other systemic immunomodulators, and that upadacitinib may be among the most effective systemic therapies for reducing severity and symptoms in patients with moderate to severe AD, either as monotherapy or in combination with TCS. However, conclusions regarding the long-term efficacy of upadacitinib compared to the active comparators relevant to this review cannot be drawn because the ITCs used study results collected over a relatively short duration, whereas AD is chronic in nature. There is also uncertainty due to the inherent heterogeneity across trials in the networks. The robustness of the comparative efficacy was further compromised by the lack of precision in the findings; therefore, the results from the ITCs must be interpreted with caution. Moreover, no information was obtained regarding comparative safety versus other active comparators. In addition, no conclusion could be drawn on HRQoL outcomes.

All of the trials enrolled patients with moderate to severe AD and an inadequate response to topical and systemic AD therapies. This is reflective of the indication that was initially submitted to Health Canada and CADTH; however, the approved indication reflects a more restrictive population (i.e., patients who are not adequately controlled with a systemic treatment, such as a steroid or biologic, or when use of those therapies is inadvisable). Although there is some similarity in the results between the overall populations and the proportion of patients with prior exposure to a systemic therapy (indicating that prior exposure had little to no effect on benefits and harms compared to the overall population), generalizability of the results from the included studies to the approved indication is uncertain because only a proportion of the populations from the pivotal studies is relevant to the current indication of patients with previous systemic therapies; in addition, there was no evidence for dose escalation to upadacitinib 30 mg once daily in patients with an inadequate response to upadacitinib 15 mg once daily, and there was no clinical evidence for dose de-escalation to upadacitinib 15 mg once daily in patients who achieved a response to upadacitinib 30 mg once daily. The clinical expert consulted by CADTH indicated that the subgroup analyses suggested that the response to upadacitinib would likely be similar for those with and without prior exposure to a systemic therapy for AD.

Overall, upadacitinib was safe and tolerated in all studies. AEs that were more common with upadacitinib included acne and respiratory tract infections. The safety profile of upadacitinib once daily over 52 weeks was consistent with that observed during the 16-week double-blind period, with no unexpected safety signals reported. However, longer-term data will help better characterize the efficacy and safety of upadacitinib in the treatment of this chronic condition.

Introduction

Disease Background

AD, also known as atopic eczema, is an inflammatory, pruritic, chronic or chronically relapsing skin disease commonly occurring in families with other allergic conditions, such as asthma and rhino-conjunctivitis. AD is considered among the most common non-communicable skin diseases, affecting up to 20% of children and 2% to 8% of adults worldwide.¹ In Canada, the lifetime prevalence of AD is up to 17% of the population, and there is evidence to suggest that the prevalence has increased over the past 30 years.^2,3

AD is characterized by severe pruritus that results in red and swollen skin (a rash). The resulting lesions may appear as fluid-filled vesicles that ooze, crack, and crust. Frequent scratching may result in lichenification (thickening of the skin).⁴ AD typically affects body creases or flexural areas, such as the popliteal and antecubital fossa, but may also appear on the face, neck, and hands. In patients with AD, secondary skin infections are common due to a compromised skin barrier function plus frequent scratching. Furthermore, the reduced water-holding capacity of the skin produces dryness that requires treatment with specific bathing, cleansing, and moisturizing practices.^1,4

AD usually develops in childhood (most cases begin before the age of 5 years) and may persist into adulthood; less frequently, it starts in mid-life or late life.⁴ The majority of children will outgrow the condition by adolescence. However, it is common for children with AD to develop asthma and/or hay fever — a process commonly referred to as the “atopic march.” AD is often the first step in this sequence of the development of atopic conditions.⁵

Patients often experience worse itching throughout the night, which may result in sleep loss and ensuing detrimental effects pertaining to school or work. Individuals with AD may also suffer from the social stigma of having a highly visible skin condition. Overall, these patients describe a physically and mentally exhausting condition that can result in anxiety, depression, and decreased quality of life. Health care utilization and costs are also affected and usually associated with the severity of the disease.⁶

The goals of AD management are to prevent flares and to manage flares effectively when they do occur by preventing AD from progressing. While there is no cure for AD, there are several therapeutic options available to patients to manage the condition. The majority of patients treat AD using general skin care methods, such as by avoiding skin irritants, and by using topical anti-inflammatory therapy. If these common methods fail to improve AD, patients may use off-label systemic therapy (i.e., immunosuppressant therapy) or other therapies, such as phototherapy.⁴

Standards of Therapy

General Skin Care

General skin care practices for patients with AD include avoiding irritants and managing dry skin. The symptoms of AD may be reduced or prevented by avoiding known skin irritants or triggers.^1,4,7 Some common irritants include temperature, humidity, dust, pets (animal dander), smoke, and grass. Using mild detergents to wash clothing (with no bleach or fabric softener) and double-rinsing clothing during laundering have been recommended for those with AD. Dry skin associated with AD can be countered through specific bathing, cleansing, and moisturizing practices. Baths using lukewarm water and emulsifying oil followed by the use of moisturizers is recommended. Limiting the use of soap and fragranced products may also help to reduce symptoms.^1,7

Topical Therapy

While a number of non-pharmacological topical therapies exist for treating the symptoms of AD, the most common therapy is the use of moisturizers to combat dry skin through hydration and the prevention of trans-epidermal water loss. Moisturizers are routinely used to provide some barrier protection for the skin from irritants or allergens and can act to soften, reduce itching, and minimize cracking, fissuring, and lichenification. Moisturizers are routinely used frequently throughout the day, preferably after bathing, and can contain a combination of emollients, humectants, and occlusive drugs.^2,4,7 Emollients (e.g., glycol and glyceryl stearate, soy sterols) lubricate and soften the skin by smoothing out its surface and filling spaces with droplets. Humectants (e.g., glycerol, lactic acid, urea) attract water and increase the skin’s water-holding capacity. However, humectants sting open skin and are not useful in children with AD. Occlusive drugs (e.g., petrolatum, dimethicone, mineral oil) provide a layer of oil on the surface of the skin to slow trans-epidermal water loss and prevent water loss though evapouration, thereby increasing the moisture content of the skin. The choice of moisturizer depends on the area of the body and the degree of dryness of the skin.^2,4,7

The most common pharmaceutical topical therapies include TCSs and TCIs. TCSs act as anti-inflammatory therapies and are considered to be the first-line treatment for AD.¹ There are more than 30 different types of TCSs that can take the form of lotions, creams, oily creams, ointments, or gels. These may be combined with other drugs, such as antibiotics. TCSs vary in potency. In Canada, hydrocortisone 1% (low potency) is the most commonly prescribed type for use on the face. For the rest of the body, triamcinolone or betamethasone valerate (moderate potency) are most commonly prescribed. TCSs are applied directly to the area of affected skin before the use of emollients. A response is typically seen within 10 days to 14 days. Side effects associated with the long-term use of TCSs include striae (stretch marks), petechiae (small red or purple spots), telangiectasia (small, dilated blood vessels on the surface of the skin), skin thinning, atrophy, and acne.^1,2,4,7 TCSs can also be recommended for use in children, according to the American Academy of Dermatology (AAD), with cautions regarding dosing, given that children have a larger surface area to body mass ratio and that there are mixed results from various studies suggesting that systemic absorption may have an impact on growth.^1,4

TCIs are steroid-free, anti-inflammatory, immunosuppressant drugs that can be used over the long-term. In Canada, the 2 second-line drugs available are pimecrolimus and tacrolimus. Pimecrolimus 1% cream can be used for short-term and intermittent long-term therapy for mild to moderate AD and is effective in controlling pruritus.^4,7 Topical tacrolimus is an ointment that can be used for short-term and intermittent long-term therapy in moderate to severe AD and demonstrates rapid and sustained AD symptom control. The most common AE associated with TCIs is site-specific burning and irritation. There remains a black box warning for the TCIs regarding lymphoma; however, long-term (10-year) surveillance studies have not found an increased risk of lymphoma versus that of the general pediatric population. Other topical therapies for AD include treatments with diluted bleach baths, which can help reduce the occurrence of secondary skin infections.^1,4

Crisaborole, a topical phosphodiesterase type 4 inhibitor, is also available. The advantage of the calcineurin inhibitors and crisaborole is that both can be safely applied to the face and to creases. TCSs more potent than hydrocortisone 1% are inappropriate.

Systemic Therapy

Systemic therapy for the treatment of AD typically involves the use of antimicrobials, antihistamines, or immunomodulators.^2,7 Systemic antibiotic treatments can be used to counter widespread secondary bacterial infections. Many patients encounter infection with Staphylococcus aureus, which may cause new inflammation and exacerbate AD symptoms. The choice of systemic antibiotic drug depends upon the skin culture and sensitivity profile. Sedating antihistamines have been used in cases where patients are not achieving adequate sleep due to itching.⁴

Immunomodulatory drugs include methotrexate, cyclosporine A, mycophenolate mofetil, and azathioprine. These can be used in patients who are not responsive to other treatments.^2,4,7 However, these commonly used, off-label treatments are administered in the lowest doses and for the shortest durations possible due to the possibility of side effects. There is limited evidence for the use of methotrexate and azathioprine in the pediatric population; however, a recent 12-week study showed that while methotrexate had a slower onset than low-dose cyclosporine A, it had an increased time before relapse after discontinuation.¹⁵ Regarding azathioprine, there is evidence of efficacy in children; however, its use is recommended to be reserved for recalcitrant cases of AD, or in cases where AD is having a significant psychosocial impact.¹⁶ The AAD states that mycophenolate mofetil is a relatively safe systemic therapy in all ages; however, its long-term (> 24 months) efficacy and safety in the pediatric population have not been studied.⁷ With respect to corticosteroids, there is a longstanding understanding that chronic use can affect growth in children.

Dupilumab (Dupixent) is an IL-4 and IL-13 inhibitor indicated for use in adults and pediatrics with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. CADTH recommended that dupilumab be reimbursed with conditions; it is currently reimbursed by the participating drug programs for patients whose AD is inadequately controlled with topical prescription therapies and who have demonstrated failure on or intolerance to an adequate trial of phototherapy (where available), methotrexate, and cyclosporine A.⁸

Other Therapy

Phototherapy is another second-line therapy that is commonly used after the failure of TCSs, TCIs, and crisaborole. This therapy is offered over several sessions and its use is guided by a number of factors, including patient skin type and skin cancer history. According to the AAD guidelines, phototherapy is considered to be a safe and effective treatment for AD in children. There are no studies that address its long-term use in children or adults.⁹

Drug

Upadacitinib is a small-molecule, reversible JAK inhibitor. JAKs are intracellular enzymes that transmit signals arising from cytokine or growth factor receptor interactions on the cellular membrane to influence the cellular processes of hematopoiesis and immune cell function. Upadacitinib is indicated for the treatment of adults and adolescents 12 years of age and older with refractory, moderate to severe AD who are not adequately controlled with a systemic treatment (e.g., a steroid or biologic) or when the use of such therapies is inadvisable. Upadacitinib can be used with or without TCSs. The sponsor’s reimbursement request is for the treatment of patients aged 12 years and older with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies and/or who are refractory to or ineligible for systemic immunosuppressant therapies (i.e., due to contraindications, intolerance, or need for long-term treatment).¹⁰

Upadacitinib is available as 15 mg or 30 mg oral extended-release tablets. The recommended starting dose for adult patients is 15 mg once daily. If an adequate response (e.g., EASI 75) is not achieved, the dosage can be increased to 30 mg once daily. For some patients, such as those with severe disease, a starting dose of 30 mg once daily may be appropriate. Upadacitinib should be discontinued if an adequate response is not achieved with the 30 mg dose after 16 weeks of treatment. The lowest effective dose needed to maintain response should be used. For patients older than 65 years, the 30 mg dose once daily is not recommended. The recommended dosage of upadacitinib is 15 mg once daily for adolescents (from 12 years to 17 years of age) weighing at least 40 kg. Upadacitinib has not been studied in adolescents weighing less than 40 kg. The product monograph indicated that treatment should be interrupted if a patient develops a serious infection, and should also be interrupted if laboratory abnormalities (such as in absolute neutrophil count, absolute lymphocyte count, hemoglobin, and hepatic transaminases) are present or develop during treatment.¹⁰

Upadacitinib was previously reviewed by CADTH on February 4, 2020, for the indication of adults with moderate to severely active rheumatoid arthritis, after which a final recommendation was issued that it be reimbursed with conditions. Upadacitinib has also been reviewed recently (June 16, 2021) for the indication of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs.

The characteristics of upadacitinib and its most common comparators for the purpose of this review are presented in Table 5.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

About the Patient Groups and Information Gathered

Three patient groups responded to CADTH’s call for patient input: ESC, CSPA, and Eczéma Québec. The latter 2 organizations provided a joint submission.

ESC is a registered Canadian charity dedicated to improving the lives of Canadians living with eczema with a mission of support, education, awareness, and research.

CSPA is a national non-profit organization advocating, educating, and supporting Canadians affected by skin, hair, and nail disorders. Its mission is to promote skin health and improve the quality of life of Canadians living with skin disorders through advocacy, education, and awareness, and by supporting research and working with affiliate member organizations that serve specific communities of patient such as those with eczema, melanoma, and psoriasis.

Eczéma Québec was created as a branch of the McGill University Hospital Network Center of Excellence for Atopic Dermatitis. It is a patient advisory committee and registered non-profit organization. It established a network of adult patients with AD and health care practitioners in the field of AD (encompassing specialist clinician dermatologists, general practitioners, nurse practitioners, and more), with a goal of building resources based on international best-practice guidelines. Eczéma Québec works with McGill’s Center of Excellence on knowledge translation tools to improve patient education and care as well as awareness.

ESC gathered survey data from more than 3,000 adults living with AD and from the caregivers of children living with AD. Topics included quality of life impact, experience with systemic treatments, the patient journey, and experience with itch related to AD. Information was also gathered through questionnaires and 1-on-one interviews.

Eczéma Québec and CSPA developed and circulated a web-based survey in English and French using the Survey Monkey platform. The survey was distributed through both organizations’ newsletters, social media, and websites. Eczéma Québec held 30- to 60-minute individual interviews through the Microsoft Teams platform with 3 adult respondents living with moderate to severe AD. There were 56 respondents to the survey. Of the respondents, 91% resided in Quebec, 3.6% in Ontario, 3.6% in New Brunswick, and 1.9% in Manitoba; 76.8% were patients and 12.5% were parents of patients. Most (80.4%) reported their gender assigned at birth as female, and 19.6% reported their assigned gender as male. Of these respondents, 11 identified as male, 43 as female, and 2 as non-binary. The age groups of the respondents were divided as follows: 18 years to 24 years (3.6%), 25 years to 34 years (23.2%), 35 years to 44 years (26.8%), 45 years to 54 years (21.4%), 55 years to 64 years (5.4%), and 65 years and older (16.1%).

Disease Experience

According to the patient input received for this review, AD negatively affects individuals and their families and can lead to psychological distress. Patients frequently report that itch is the most burdensome symptom of AD; more than half of adult respondents with severe AD reported rarely being able to control their urge to scratch. Itch also significantly affects sleep; patients report being woken frequently, and have trouble falling and staying asleep due to their itch.

The severity of AD correlates with impacts on HRQoL as well as lost productivity at school and burden on health systems. Among adult respondents, 54% reported rarely being able to control their urge to scratch. One noted that, “All my life, I have struggled with itch. The constant, debilitating itch that would never leave me alone.” AD also has significant impacts in terms of the psychosocial burden of symptoms, as 1 respondent reflected: “If flaring, [it is] hard to do some things physically and [I’m] self-conscious so tend to stay home.”

One respondent reported “Work stoppage, repeated depression, lack of sleep. It’s hard to participate in social or seasonal activities.” AD can negatively affect mood, work, school, and social interactions. Thirty-two percent of adult survey respondents with moderate or severe AD have missed work events due to their condition, and 30% have had to change careers or give up certain activities. Among the respondents, 18.2% noted that they would miss 1 or 2 days of work per month; 6.1% would miss more than 7 days each month because of their condition.

The respondents noted that the most prevalent areas where they experienced AD were the backs of their hands (63.64%), thighs and/or legs (54.55%), neck (51.52%), the insides of their arms and/or the elbow folds (51.52%), the outsides of their arms and/or the exterior parts of their elbows (51.52%), scalp (48.48%), face (45.45%), ears (45.45%), abdomen (45.45%), the area around the eyes (39.39%), breasts, under breasts, and/or nipples (39.39%), back (39.39%), backs of the knees (36.36%), tops of the feet (30.30%), palms (30.30%), groin area and/or genitalia (24.24%), buttocks (21.21%), front of the knees (21.21%), soles of the feet (21.21%), and armpits (18.18%).

All respondents experienced itching because of their condition. Other symptoms included redness of the skin (87.88%), repeated rashes (84.85%), frequent scratching (84.85%), cracked skin (84.85%), dry and rough skin (78.79%), disrupted sleep (75.76%), bleeding (69.70%), flaking of the skin (69.70%), pain (69.70%), thickening of the skin (60.61%), oozing (48.48%), swelling (42.42%), lichenification (39.39%), and blistering (36.36%). In the ESC survey, 32% of adult respondents with moderate or severe AD said they had missed work events due to their condition, and 30% had to change careers or give up certain activities.

One respondent recounted that, “When I was younger, my mom would wrap my hands so I couldn’t scratch myself in my sleep. My AD was so bad my clothes would stick to my skin during the day, and I had to take a bath in oil just to get clothing, like my tights, off my body.”

Caregivers noted that AD places a significant emotional toll on the entire family, and feelings of guilt, frustration, anger, and sadness are common. Forty-one percent of caregivers reported feeling like a failure when they cannot control their child’s flares. “As a parent, you question everything when your child is suffering, and you are trying to find a solution. You wonder if you are doing enough, or if you are doing something wrong. There needs to be a better way — lives are being destroyed by this condition.” Patients and caregivers reported that the mental health impact of AD is a significant aspect of the condition and is often neither understood by others nor prioritized by health care providers. Uncontrolled chronic AD can lead to feelings of depression and anxiety as well as poor self-esteem, low energy, and — in some extreme cases — suicidal thoughts: “AD is not only exhausting, it is hard on mental health and self-confidence. It is all-consuming for those that suffer from it and for their families.”

Experience With Currently Available Treatments

Patients generally use frequent moisturizing, trigger avoidance, and topical treatments to control their AD flares. Respondents with uncontrolled AD have used systemic treatments that include off-label immunosuppressant medications (such as methotrexate and cyclosporine A), oral corticosteroids (e.g., prednisone), and phototherapy. Oral corticosteroids were the most frequently used systemic treatments. Respondents also noted that they had limited experience with targeted treatments for AD (14.3% had experience with dupilumab and TCIs and 28.6% had experience with cyclosporine A). Respondents mentioned the hurdles associated with the trial-and-error method that many experience before they find an appropriate treatment. One respondent noted that, “I haven’t found the right treatment for me yet. I use diprosone and it doesn’t do much for me unless I am in a major outbreak.” Another mentioned “A lot of trial and error. Now, it's better after looking for 30 years.”

Most patients expressed dissatisfaction with the treatment options available to them and how these addressed the most important symptom of their disease. One respondent stated: “Nothing works,” while another respondent said, “Nothing has stopped the itch.” Another source of frustration for these participants was that they did not view these treatments as long-term options, but rather “temporary.”

Some of the respondents also mentioned the side effects associated with certain treatments. For example, 1 said it was “Alright for a while but had side [e]ffects so discontinued.” Another said, “I started Dupixent a week ago. It's working well so far. It’s unbelievable. I, however, have an intense conjunctivitis in my eyes (side effect of treatment).”

Respondents expressed concern over the financial impact of treatments, with 1 noting, “I had to suspend the use of Protopic until I was on my spouse's insurance. I also needed the Freedom Dupixent program AND my spouse's private insurance. Again, I have a deadline for my [when coverage for my] prescription [ends]. Who can pay $2,500 a month for ONE drug? Not to mention that I must pay for other medications (antidepressants for example).”

Improved Outcomes

Overall, patients desire improvement in managing itch, reducing flares and rashes, and improving their quality of life and sleep. Respondents expressed that they would like a new medication to result in manageable AD in the summer without the use of hydrocortisone, “to improve the appearance of [their] hands and eyes,” to have “less apparent eczema” and more “freedom,” and to provide pain relief. Caregivers want a treatment that will permit them or their child to have a good life, free of itchy skin and painful rashes. Of the respondents, 67.9% preferred daily pills taken by mouth, 50% preferred daily topical medications, and 42.9% preferred injections every other week they could do themselves or with help. The trial-and-error process of cycling through currently available treatments is a common experience among patients, and for those who have experienced repeated failed treatments, the experience is demoralizing, tiring, and causes significant distress, including mental health deterioration. This significant challenge highlights the need for improved treatments for this small population of patients who do not respond to topical treatments.

One respondent noted that, “If you knew how many layers of creams, I had to slather on my body with help.... It was just inhumane.”

On the subject of tolerating side effects, respondents were generally unwilling to accept serious side effects. However, across the spectrum of AD severity, patients and caregivers consistently reported carefully weighing the risks and benefits of any medication, from topical to systemic medications. The willingness of a patient to accept potential serious adverse effects correlates to the severity of their disease and the impact it has on their quality of life. The trial participants who were interviewed reported having had painful and debilitating symptoms of uncontrolled AD. They also shared that they were willing to accept some level of side effects associated with a new treatment and a clinical trial if it meant it would bring them relief from their symptoms.

“[T]he inability to sleep due to the symptoms of eczema is a serious problem in the medium and long term, it must serve as a comparison to the side effects of the drug.”

Experience With Drug Under Review

Respondents who participated in the clinical trial of upadacitinib reported positive experiences, including relief from itch as well as significant and rapid improvement in skin rashes and lesions. One patient reported experiencing significant relief from the itch within days of starting the treatment, and improvement in their skin condition within weeks. A caregiver shared that their child’s rash, which once covered the child’s entire body, was finally able to heal for the first time in their lives. The child no longer had to struggle with constant infections, open sores, and raw, inflamed skin.

One respondent said, “Upadacitinib was extremely helpful in managing my AD. When I think back to where I started, I don’t know where I would be if I hadn’t tried it.” Patients and caregivers also shared that the once-a-day oral pill was an improvement compared to the time-consuming and uncomfortable nature of their previous skin care and topical treatment routines.

Patients and caregivers who had experience with upadacitinib noted that the medication rapidly improved their symptoms and significantly improved their quality of life. It also allowed patients a variety of opportunities, such as regained self-confidence and ability to exercise, better work productivity, improved personal relationships, and the ability to better care for themselves or their loved ones.

Additional Information

Uncontrolled moderate to severe AD can be debilitating and life-altering, and there are significant gaps in treatment for this patient population. The need for more treatment options for uncontrolled AD is critical. The patient groups mention that those living with skin disorders deserve to be treated with respect and dignity by the health care system, which includes embracing new and tailored treatment options.

All respondents noted that the treatment needs to be accessible, with 1 stating that, “Treatments need to be accessible to everyone who needs them and who qualify (i.e., if a doctor deems it helpful). This is not just a skin rash. It is an all-consuming issue that can really affect an individuals’ quality of life — physical and mental. There needs to be knowledge, empathy, and medical support for the physical, mental, and emotional aspects of AD.”

Clinician Input

Input From the Clinical Expert Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol; assisting in the critical appraisal of clinical evidence; interpreting the clinical relevance of the results; and providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of AD.

Treatment Goals

The clinical expert consulted by CADTH visualizes the ideal treatment for AD as 1 that is available to all Canadians, is cost-effective in the context of a publicly funded health care system, has a proven long-term safety record, and completely reverses the barrier dysfunction and immunologic abnormalities that constitute AD. The ideal treatment goal would aim at maintaining complete clearance of AD without additional therapy and would result in a complete elimination of pruritus and resolution of all visible signs of skin inflammation.

Unmet Needs

According to the clinical expert, off-label immunosuppressive drugs are commonly offered to patients who are achieving suboptimal disease control with appropriate disease-specific skin care measures (i.e., irritant avoidance, emollients, and bleach baths), TCSs, calcineurin inhibitors or crisaborole, and phototherapy. In Canada, the most commonly used immunosuppressive drug is methotrexate, followed by cyclosporine A, azathioprine, and mycophenolate mofetil. Because of their potential toxicities, these drugs are generally prescribed as intermittent courses for patients with AD. New drugs could fill this potential treatment gap when toxicities are a concern. There are also patients who do not respond to these drugs. Dupilumab is offered as a second-line systemic therapy alternative to immunosuppressive drugs, but reimbursement for it remains problematic in Canada.

Place in Therapy

Upadacitinib was considered by the clinical expert as a potentially useful addition to the currently available therapeutic options for AD, with special consideration in patients who have contraindications to, or who experience adverse effects from off-label immunosuppressive drugs or who are unresponsive to these. It could also be useful in a subset of patients who respond to off-label immunosuppressive drugs, but still require continuous long-term therapy to control AD.

Upadacitinib could also be of value in patients treated with dupilumab who have a suboptimal response, who develop severe conjunctivitis or other ocular side effects, or who are intolerant to injections (e.g., due to severe injection-site reactions) and prefer an oral drug.

The clinical expert noted that all patients with AD treated with upadacitinib would be expected to continue on emollients, TCSs, and/or TCIs. It is expected that upadacitinib would not be combined with other systemic treatments.

According to the clinical expert consulted by CADTH, upadacitinib is unlikely to cause a significant shift in the current treatment paradigm for AD beyond its inclusion as another effective treatment option in the Canadian clinical landscape. Off-label immunosuppressives or dupilumab (or the new biologics, such as tralokinumab, that are emerging in AD) are not expected to be used in combination with upadacitinib; however, the clinical expert believed that many practitioners would still consider a trial of methotrexate and cyclosporine A before initiating upadacitinib. Dermatologists are well versed in the appropriate dosing and duration of therapy and appropriate monitoring for potential toxicities.

Patient Population

In the opinion of the clinical expert, any patient with moderate to severe AD could respond to treatment with upadacitinib. However, it is still unclear whether this drug can effectively treat patients who have failed methotrexate and/or cyclosporine A. The efficacy of upadacitinib in patients who have failed dupilumab must also be assessed.

AD is, in general, not a diagnostic challenge for a dermatologist. However, there are some differential diagnoses to consider (e.g., psoriasis, ichthyoses, allergic contact dermatitis, irritant contact dermatitis, and cutaneous T-cell lymphoma). Biopsy would usually be reserved for patients recalcitrant to all therapy — for instance, to rule out cutaneous T-cell lymphoma or to differentiate AD from psoriasis.

The clinical expert suggested that patients less suitable for treatment with upadacitinib would be those with AD who are well controlled with topical therapy, phototherapy, and/or intermittent, off-label immunosuppressive therapy, as well as those who are well controlled with dupilumab. Patients with potential contraindications to JAK inhibitors, such as severe active infections (acute or chronic, including latent tuberculosis, deep fungal infections, and opportunistic infections), potential malignancy (including ongoing treatment with chemotherapy, including checkpoint inhibitors), severe hepatic disease, severe renal disease, pregnancy or lactation, a history of thromboembolic events, pre-existing hematologic disease (i.e., lymphopenia and neutropenia), or a weight of less than 40 kg.

Assessing Response to Treatment

In general, the outcomes used in clinical practice are aligned with the outcomes typically used in clinical trials of AD treatments. The clinical expert anticipates that the EASI score could be used as the benchmark for decision-makers. As such, this will be calculated and recorded at each patient visit. Reduction in pruritus will also be noted by clinicians, but perhaps not formally scored. The patient’s impression of their overall improvement will also be important and recorded.

Of these outcome measurements, a rational benchmark response will be EASI 75 at 16 weeks. However, EASI score reductions of 50% to 75% could also be considered clinically meaningful to patients, particularly those who have had severe disease recalcitrant to all previous therapies.

In the opinion of the clinical expert, patients placed on upadacitinib would be re-evaluated 16 weeks after initiating treatment. Those judged to be responders at this visit would be seen subsequently at 6-month intervals. Those who have not reached response targets at 16 weeks would be re-evaluated at 20 weeks following initiation of the drug. The decision to stop upadacitinib or continue on it would be made at the 20-week visit. Bloodwork, including complete blood count and differential, liver function tests, creatinine, lipids, and CPK, would be done monthly before the first follow-up visit and every 3 months thereafter if there are no concerns.

Discontinuing Treatment

The factors anticipated by the clinical expert to be used as criteria for discontinuation included failure to achieve a clinically meaningful response at 16 weeks to 20 weeks, failure to maintain an adequate response on long-term maintenance, development of a hypersensitivity response judged to be due to upadacitinib, TEAEs (e.g., lymphopenia, neutropenia, arterial thrombosis, VTE), and treatment-emergent severe infections or malignancies.

Prescribing Conditions

Because this is an orally administered drug, the clinical expert consulted by CADTH indicated that there are no special administration challenges. However, a specialist would still be required to diagnose, treat, and monitor patients taking upadacitinib. Appropriate specialists will include pediatric dermatologists, general dermatologists, or pediatricians with experience and interest in AD.

According to the clinical expert, patients deemed to have severe symptoms would start on 30 mg for 16 weeks and then be assessed for their response (e.g., EASI 75); if a response is reached, they would switch to a 15 mg dose. The product monograph approved by Health Canada states that patients who are receiving upadacitinib 15 mg and do not achieve a response after 16 weeks of treatment should be switched to upadacitinib 30 mg. The product monograph also states that if patients do not achieve an adequate response (e.g., EASI 75) after 16 weeks of treatment on the 30 mg dose, upadacitinib should be discontinued.

Additional Considerations

The clinical expert considered that some of the comparators included in this review, such as apremilast, retinoids (acitretin, alitretinoin), and ustekinumab, are unlikely to be prescribed in Canada for patients with AD.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

One clinician group provided input on the reimbursement review of upadacitinib for the treatment of adults and adolescents with moderate to severe AD. The Atlantic Specialist Group Managing Atopic Dermatitis is a group of physicians, including general practitioners, dermatologists, and allergy and immunology specialists, who manage patients with AD. The members of the group are located in various clinical settings across Atlantic Canada.

Unmet Needs

The clinician group considers that improving AD symptoms — such as chronic itch, dry and inflamed skin, and sleep disturbances — and improving quality of life and patient satisfaction (i.e., better sleep and less work or school disruption) are top priorities for treatment goals. Other priorities include flare reduction and disease control, as reflected by the DLQI and PGA scores of clear or almost clear.

The group considers that the greatest unmet need is in the subset of patients with moderate to severe AD, among whom the main unmet need is for an effective, convenient, safe treatment that enables long-term disease control and remission, given that many experience flares as soon as they stop their current medications. This cycle of recurrence leads to disease progression, ending in chronic, severe AD and severe impact on quality of life. Available off-label treatments have poor efficacy and safety profiles that are unacceptable for long-term use. Phototherapy, which is often used in conjunction with systemic therapies, is associated with issues such as poor accessibility, long wait times, low efficacy, and exposure to UV radiation. Suboptimal care of patients with AD commonly leads them to access drugs that are neither effective nor approved for AD and that can be harmful to their health.

According to the clinician group, upadacitinib would allow rapid disease control in patients with moderate to severe AD, addressing the unmet needs that lead to many of the problems experienced by these patients.

Place in Therapy

Upadacitinib would be the first JAK inhibitor approved for AD. The first biologic drug approved for AD, dupilumab, targets IL 14 and IL 13 signalling; therefore, it targets the underlying disease mechanisms of AD through a different mode of action. In the clinician’s opinion, dupilumab addresses some concerns and needs of some patients, but upadacitinib may shift the paradigm due to its efficacy and ease of administration.

The clinician group states that upadacitinib would be used after initial treatments for AD have been implemented, such as lifestyle measures and topical steroids, and after the patient has been diagnosed with moderate to severe AD. In the group’s opinion, upadacitinib would replace both phototherapy and systemic therapies that are currently used off-label to treat moderate to severe AD. If patients fail on or have a contraindication or intolerance to upadacitinib, their treating physician may consider dupilumab as the next therapeutic option. This place-in-therapy judgment differs from that of the clinical expert consulted by CADTH, who considers that upadacitinib should be used after a trial of currently used (even if off-label) systemic therapies, such as methotrexate or cyclosporine A.

Patient Population

According to the clinician group, upadacitinib would be best suited to treat patients with moderate to severe AD who have not responded, are not expected to respond, or have had adverse reactions to long-term use of TCSs. These patients have the greatest need for intervention because they lack long-term treatment options and are at high risk of disease progression. The patients suited for treatment would be treated by a specialist initially, but there are no diagnostic challenges once the patient reaches specialized care; nor are there drug administration challenges. On occasion, a patient with AD will insist on allergy testing due to misperceptions about the link between their condition and allergic reactions. This often leads to an inconclusive diagnosis (with rash or eruption as the descriptor) and patient frustration. Patient and physician education about the pathophysiology of AD is crucial to treatment success. Upadacitinib would be least suitable for patients with mild AD or whose symptoms are well controlled with initial treatments (e.g., TCSs).

Assessing Response to Treatment

The clinician group considers that the outcomes measured in clinical trials, such as the IGA and the proportion of participants achieving a 75% or 90% to 100% improvement on the EASI, are also used in clinical practice (in which the equivalent PGA is used instead of IGA) and are similarly aligned with additional measures, including BSA affected and WP-NRS score (which ranges from 0 [“no itch”] to 10 [“worst imaginable itch”]). EASI scoring is not routinely used in clinical practice. The group mentions that a clinically meaningful response to upadacitinib would include improvement in patient-reported itch (i.e., a 4-point reduction on the WP-NRS or a WP-NRS score of less than 3), a DLQI score reduction of greater than or equal to 4 (or an acceptable improvement), patient-reported improved sleep quality, fewer AD-related disruptions at school and work, and a PGA score of 0 or 1. Importantly, for the response to upadacitinib to be clinically meaningful, a patient should not experience any severe side effects, including over sustained time periods.

The group also suggests that a response to systemic therapy should be reassessed 12 weeks to 16 weeks after the initiation of treatment.

Discontinuing Treatment

According to the clinician group, the decision to discontinue treatment should be assessed based on lack of response, significant disease progression (i.e., lichenification, increased affected BSA and itching) and deterioration in quality of life. Treatment should also be discontinued if the patient experiences adverse reactions or intolerances to the medication that are deemed unacceptable by the patient-physician team.

Treatment with upadacitinib should be interrupted if a patient develops a serious infection, until the infection is controlled. Treatment should also be interrupted to address abnormal laboratory results (i.e., absolute lymphocyte count less than 500 cells/mm³, absolute neutrophil count less than 1,000 cells/mm³, hemoglobin less than 8 g/dL) or if drug-induced liver injury is suspected (based on hepatic transaminases). It may be resumed once levels return to normal.

Prescribing Conditions

Patients with AD who are receiving upadacitinib would ideally be managed in any non-emergent setting to which they have access to that has a dermatologist or allergist well versed in managing moderate to severe AD. Referring family physicians, nurse practitioners, or other health care providers should be counselled on the appropriate referral process.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 6.

Table 6: Summary of Drug Plan Input and Clinical Expert Responses

AD = atopic dermatitis; CDEC = CADTH Canadian Drug Expert Committee; DMARD = disease-modifying antirheumatic drug; EASI = Eczema Area and Severity Index; EASI 75 = at least 75% improvement in EASI total score from baseline; JAK = Janus kinase; RCT = randomized controlled trial.

Clinical Evidence

The clinical evidence included in the review of upadacitinib is presented in 3 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of upadacitinib for the treatment of adults and adolescents 12 years and older with moderate to severe AD who are candidates for systemic therapy.

Methods

Studies selected for inclusion in the systematic review will include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada as well as those meeting the selection criteria presented in Table 7. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Of note, the systematic review protocol presented here was established before the granting of a Notice of Compliance from Health Canada.

Table 7: Inclusion Criteria for the Systematic Review

AE = adverse event; CPK = creatine phosphokinase; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; IGA = Investigator Global Assessment; MACE = major adverse cardiovascular event; RCT = randomized controlled trial; SAE = serious adverse event; SCORAD = Scoring Atopic Dermatitis; vs. = versus; WDAE = withdrawal due to adverse event.

The literature search was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²²

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) through Ovid and Embase (1974–) through Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Rinvoq (upadacitinib). Clinical trial registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies. The initial search was completed on May 11, 2021. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on February 23, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the CADTH checklist, Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.²³ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to include in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 5 unique studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 8 and Table 9. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 8: Details of Included Studies — Part 1

AD = atopic dermatitis; ADerm-IS = Atopic Dermatitis Impact Scale; ADerm-SS = Atopic Dermatitis Symptom Scale; BE = blinded extension; DB = double blind; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; HADS-A = Hospital Anxiety and Depression Scale – Anxiety; HADS-D = Hospital Anxiety and Depression Scale – Depression; MCID = minimal clinically important difference; POEM = Patient-Oriented Eczema Measure; RCT = randomized controlled trial; SCORAD = Scoring Atopic Dermatitis; TCI = topical calcineurin inhibitor; TCS = topical corticosteroid; TSS-7 = 7-Item Total Symptom Score; vIGA-AD = validated Investigator Global Assessment for Atopic Dermatitis; vs. = versus; WP-NRS = Worst Pruritis Numerical Rating Scale.

Source: Clinical Study Reports for Measure Up 1 and Measure Up 2.^11,12

Table 9: Details of Included Studies — Part 2

AD = atopic dermatitis; BE = blinded extension; BSA = body surface area; DB = double blind; EASI = Eczema Area and Severity Index; EASI 75 = at least 75% improvement in EASI total score from baseline; EASI 90 = at least 90% improvement in EASI total score from baseline; EASI 100 = at least 100% improvement in EASI total score from baseline; PDE 4 = phosphodiesterase 4; RCT = randomized controlled trial; SC = subcutaneous; TCI = topical calcineurin inhibitor; TCS = topical corticosteroid; vIGA-AD = validated Investigator Global Assessment for Atopic Dermatitis; WP-NRS = Worst Pruritis Numerical Rating Scale.

Source: Clinical Study Reports for AD Up, Heads Up, and Japan studies.^13,14,25

Description of Studies

Table 10 provides an overview of the studies that were summarized and appraised by CADTH in the current review of upadacitinib.

There were 5 double-blind, phase III RCTs included in the CADTH systematic review: 2 similar multi-centre, placebo-controlled trials conducted with upadacitinib used as monotherapy for AD (Measure Up 1 and Measure Up 2); 1 double-blind, placebo-controlled trial conducted with upadacitinib used as combination therapy with TCSs for AD (AD Up study); 1 double-blind, double-dummy, active-controlled trial comparing upadacitinib versus dupilumab (Heads Up study); and 1 phase III, double-blind, placebo-controlled trial conducted with upadacitinib used as combination therapy with TCSs in a Japanese setting (Japan study) assessing the safety of upadacitinib as the main end point.

Monotherapy Studies

Measure Up 1 and Measure Up 2 were both phase III, double-blind RCTs aimed at evaluating the efficacy and safety of upadacitinib as monotherapy in adolescents (12 years to 17 years of age at the time of the screening visit and body weight ≥ 40 kg) and adults (18 years to 75 years of age) with moderate to severe AD. Both studies included patients with AD whose onset of symptoms was at least 3 years before the baseline screening date. Both studies consisted of a 5-week screening period, a 16-week double-blind treatment phase, and a BE study of a duration of up to 136 weeks and a 30-day follow-up visit.^11,12 Eligible patients were randomized in a 1 to 1 to 1 ratio to receive a daily oral dose of upadacitinib 30 mg, upadacitinib 15 mg, or matching placebo every day. Randomization was stratified by baseline disease severity (moderate [vIGA-AD score of 3] versus severe [vIGA-AD score of 4]), by geographic region (US, Puerto Rico, and Canada; Japan; China; and other), and by age (adolescent [ages 12 years to 17 years] versus adult [ages 18 years to 75 years]). At week 16, patients in the placebo group were re-randomized in a 1 to 1 ratio (stratified by week 16 reduction of at least 50% in EASI from baseline [EASI 50], responder status [yes or no], geographic region [US, Puerto Rico, Canada, China, Japan, and other], and age group [adolescent or adult]) to receive daily oral doses of upadacitinib 30 mg or upadacitinib 15 mg in the BE period. Patients originally randomized to upadacitinib were to continue on upadacitinib in the extension period at the same dose. Rescue treatment for AD was permitted at the week 4 visit at the discretion of the investigator if medically necessary and if specified parameters were met. The overall designs of the Measure Up 1 and Measure Up 2 studies are presented in Figure 2.

Measure Up 1 was conducted from August 2018 to December 2020 at 151 sites in 24 countries (US, Canada, China, and countries in Latin America and Europe), while Measure Up 2 was conducted from July 2018 to January 2021 at 154 study sites across 23 countries, including Australia, Canada, the US, and countries in Europe and Asia.

Figure 2: Study Design Schematic of the Measure Up 1 and Measure Up 2 Studies

DB = double blind; QD = once daily.

Source: Clinical Study Reports for Measure Up 1 and Measure Up 2.^11,12

Combination Therapy

The AD Up study was a phase III, double-blind RCT aimed at evaluating the efficacy and safety of upadacitinib as combination therapy with TCSs in adolescents (12 years to 17 years of age at the time of the screening visit, with body weight ≥ 40 kg) and adults (18 years to 75 years of age) with moderate to severe chronic AD (i.e., the onset of symptoms was at least 3 years before baseline screening). The study consisted of a 5-week screening period, a 16-week double-blind treatment phase, and a BE study lasting up to 136 weeks plus a 30-day follow-up visit. Eligible patients were randomized in a 1 to 1 to 1 ratio to receive a daily oral dose of upadacitinib 30 mg plus TCS, upadacitinib 15 mg plus TCS, or a matching placebo plus TCS. Randomization was stratified by baseline disease severity (moderate [vIGA-AD score of 3] versus severe [vIGA-AD score of 4]), by geographic region (US, Puerto Rico, Canada; Japan; mainland China; other), and by age (adolescent [ages 12 years to 17 years] versus adult [ages 18 years to 75 years]). At week 16, patients in the placebo group were re-randomized in a 1 to 1 ratio (stratified by week16 EASI 50, responder status [yes or no], geographic region [US, Puerto Rico, Canada; mainland China; Japan; other], and age group [adolescent or adult]) to receive daily oral doses of upadacitinib 30 mg plus TCS or upadacitinib 15 mg plus TCS in the BE period. Patients originally randomized to upadacitinib were to continue upadacitinib in the extension period at the same dose. Rescue treatment for AD was permitted from the week 4 visit through week 24, if medically necessary and with an < EASI 50 response at 2 consecutive visits. After week 24, rescue therapy was permitted if medically necessary and with an < EASI 50 response at any visit. The overall design of the AD Up study is presented in Figure 3.

The AD Up study was conducted from August 2018 to December 2020 at 170 sites in 22 countries (including the US, Canada, China, and countries in Europe).

Figure 3: Study Design Schematic of the AD Up Study

EASI 75 = at least 75% improvement in EASI total score from baseline; IGA = Investigator Global Assessment; QD = every day; TCS = topical corticosteroid.

Source: Clinical Study Report: AD Up.¹³

Head-to-Head Studies

The Heads Up study was a phase III, double-blind, double-dummy, active-controlled, randomized trial aimed at evaluating the efficacy and safety of upadacitinib versus dupilumab for the treatment of adult patients (18 years to 75 years of age) with moderate to severe chronic AD (i.e., with onset of symptoms at least 3 years before baseline screening) who are candidates for systemic therapy.

The Heads Up study compared the safety and efficacy of upadacitinib 30 mg given once daily as an extended-release tablet until week 24 versus dupilumab 600 mg as an SC injection administered at baseline followed by dupilumab 300 mg as an SC injection every other week from week 2 to week 22. At the end of the double-blind period, patients either entered an open-label upadacitinib extension in which patients were to be treated for an additional 52 weeks or had an end-of-treatment follow-up visit (12 weeks from the last injection). This study consisted of a 5-week screening period, a 24-week double-blind treatment phase, and an end-of-treatment follow-up visit at 12 weeks after the last injection for patients who did not enrol in the open-label study. Eligible patients were randomized in a 1 to 1 ratio and stratified by baseline disease severity (moderate [vIGA-AD = 3] versus severe [vIGA-AD = 4]) and age (< 40 years, ≥ 40 years to < 65 years, ≥ 65 years). Prior use of dupilumab or JAK inhibitors was not allowed. Patients required a documented history of inadequate response to TCSs or TCIs, a documented history of systemic treatment for AD within 6 months, or had to have been medically advised not to use topical AD treatment. Rescue treatment for AD was permitted from the week 4 visit through week 16 if medically necessary.

The overall design of the Heads Up study is presented in Figure 4. The Heads Up study was conducted from February 2019 to December 2020 at 129 sites in 22 countries (including the US, Canada, and countries in Asia and Europe).

Figure 4: Study Design Schematic of the Heads Up Study

BL = baseline; SC = subcutaneous.

Source: Clinical Study Report: Heads Up.¹⁴

Populations

Inclusion and Exclusion Criteria

Monotherapy Studies

Measure Up 1 and Measure Up 2 had similar inclusion criteria among them except with regards to the time since AD diagnosis: the Measure Up 2 study included patients with chronic AD (defined as AD with onset of symptoms at least 3 years before baseline, with patients meeting the Hanifin and Rajka criteria),²⁶ while the Measure Up 1 study included patients with more recent onset of symptoms. Both studies included patients with a documented history of inadequate response to treatment with topical AD treatments or use of systemic treatment for AD who met the following disease activity criteria: EASI score greater than or equal to 16; vIGA-AD score greater than or equal to 3; greater than or equal to 10% BSA of AD involvement at the screening and baseline visits; and a baseline weekly average of daily WP-NRS greater than or equal to 4. Both studies required adolescent patients (≥ 12 years and < 18 years of age) to have a body weight greater than or equal to 40 kg at the baseline visit.

Both studies excluded patients with prior exposure to JAK inhibitors; patients using systemic treatments for AD (e.g., corticosteroids, methotrexate, cyclosporine A, azathioprine, mycophenolate mofetil), phototherapy, laser therapy, tanning, or Chinese medicine within 4 weeks from screening; and those who had used targeted biologic treatments within 12 weeks.

Combination Studies

The AD Up study main difference was the addition of a TCS to each arm of the study, whether in the double-blind or BE period. The AD Up study included patients with characteristics that were similar to those of patients in the Measure Up 2 study: i.e., those with chronic AD (defined as AD with onset of symptoms at least 3 years before baseline) who met the Hanifin and Rajka criteria,²⁶ had a documented history of systemic treatment or inadequate response to topical AD treatments and met the following disease activity criteria: EASI score greater than or equal to 16; vIGA-AD score greater than or equal to 3; greater than or equal to 10% BSA of AD involvement at the screening and baseline visits; and a baseline weekly average of daily WP-NRS greater than or equal to 4. The study required adolescent patients (≥ 12 years and < 18 years of age) to have a body weight greater than or equal to 40 kg at the baseline visit. This study excluded patients with prior exposure to a JAK inhibitor or dupilumab and those with greater than or equal to 30% of AD surface involvement at baseline that could not be treated with a medium- or high-potency TCS. Investigators also excluded patients using any of the following AD treatments within the specified time frame before the baseline visit: systemic therapy for AD, including but not limited to corticosteroids, methotrexate, cyclosporine A, azathioprine, and phosphodiesterase 4 (PDE 4) inhibitors; mycophenolate mofetil within 4 weeks; and oral or parenteral Chinese medicine within 4 weeks.

Head-to-Head Studies

As with the Measure Up 2 and AD Up studies, the Heads Up study (comparing upadacitinib versus dupilumab) inclusion criteria included patients greater than or equal to 18 years old and less than or equal to 75 years old at the screening visit who were in general good health (other than AD) as determined by the principal investigator based on results of medical history, laboratory profile, and physical examination. Patients with chronic AD had an onset of symptoms at least 3 years before baseline and met Hanifin and Rajka criteria. At screening and baseline, they met the following disease activity criteria: EASI score greater than or equal to 16; vIGA-AD score greater than or equal to 3; greater than or equal to 10% BSA of AD involvement; and a baseline weekly average of daily WP-NRS ≥ 4.

Prior use of dupilumab or JAK inhibitors was not allowed. Patients were required to have a documented history of inadequate response to TCSs or TCIs, a documented history of systemic treatment for AD within 6 months, or past medical advice against the use of topical AD treatment.

Baseline Characteristics

The main demographic information, disease characteristics, medical history, and prior medications for the Measure Up 1, Measure Up 2, AD Up, and Heads Up studies included in this review are presented in Table 11, Table 12, Table 13, and Table 14, respectively.

No major differences were observed in any of the demographic or baseline characteristics between the intervention and placebo arms in or among any of the included studies. All 4 studies involved young adult patients (with median ages from 32 years to 37 years) with similar median disease durations since diagnosis, varying from 17 years in the Measure Up studies to 23 years in the Heads Up study. The baseline median EASI scores (ranging from 24 to 27) and the proportions of patients with vIGA-AD scores indicating severe AD (ranging from 44% to 55% of included patients) were also similar within and among the included pivotal studies.

Approximately half of the included patients in the 4 studies had tried a previous systemic therapy (range = 42.7% to 58%) at baseline. Nearly all patients (99% to 100%) had any type of AD therapy before the study, with TCS as the most frequent previous therapy; the use of TCIs ranged from 32% to 47% of patients. While the number of patients who had previously tried immunomodulating drugs ranged from 50% to 57%, previous use of biologics was rare (from 0.6% to 4%).

Table 11: Summary of Baseline Characteristics — Measure Up 1

AD = atopic dermatitis; ADerm-SS = Atopic Dermatitis Symptom Scale; BMI = body mass index; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; HADS = Hospital Anxiety and Depression Scale; HADS-A = Hospital Anxiety and Depression Scale – Anxiety; HADS-D = Hospital Anxiety and Depression Scale – Depression; max = maximum; min = minimum; POEM = Patient-Oriented Eczema Measure; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation; TSS-7 = 7-Item Total Symptom Score; UPA = upadacitinib; vIGA-AD = validated Investigator Global Assessment for Atopic Dermatitis; WP-NRS = Worst Pruritus Numerical Rating Scale.

Note: Redacted rows have been deleted.

Source: Clinical Study Report: Measure Up 1.¹²

Table 12: Summary of Baseline Characteristics — Measure Up 2

AD = atopic dermatitis; ADerm-SS = Atopic Dermatitis Symptom Scale; BMI = body mass index; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; HADS = Hospital Anxiety and Depression Scale; HADS-A = Hospital Anxiety and Depression Scale – Anxiety; HADS-D = Hospital Anxiety and Depression Scale – Depression; max = maximum; min = minimum; POEM = Patient-Oriented Eczema Measure; SCORAD = Scoring Atopic Dermatitis; SD = standard deviation; TSS-7 = 7-Item Total Symptom Score; UPA = upadacitinib; vIGA-AD = validated Investigator Global Assessment for Atopic Dermatitis; WP-NRS = Worst Pruritus Numerical Rating Scale.

Note: Redacted rows have been deleted.

Source: Clinical Study Report: Measure Up 2.¹¹

Table 13: Summary of Baseline Characteristics — AD Up