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Indication: For the treatment of adults and adolescents 12 years of age and older with refractory moderate to severe atopic dermatitis who are not adequately controlled with a systemic treatment (e.g., steroid or biologic) or when use of those therapies is inadvisable. Upadacitinib can be used with or without topical corticosteroids
CADTH recommends that Rinvoq be reimbursed by public drug plans for the treatment of adults and adolescents 12 years of age and older with refractory moderate to severe atopic dermatitis (AD) if certain conditions are met.
Rinvoq should only be covered to treat patients who have previously tried and are refractory to, or who are ineligible or cannot tolerate, the highest tolerated dose of topical treatments for AD combined with phototherapy (where available), and at least 1 of methotrexate, cyclosporine, mycophenolate mofetil, or azathioprine.
Rinvoq should only be reimbursed if prescribed by a dermatologist, allergist, clinical immunologist, or pediatrician, and the cost of Rinvoq is reduced.
AD is a condition that affects the skin. People with AD have dry, red skin that is extremely itchy. Constant scratching can cause the skin to split and bleed, which can cause skin infections. Oozing and weeping sores can also occur in more severe forms of AD. Severe dermatitis can be physically disabling or incapacitating and cause anxiety or depression. The lifetime prevalence of AD is estimated to be up to 17% in the Canadian population.
There is no cure for AD, and treatment aims to provide symptom relief and control symptoms in the longer term. Although many treatments are approved in Canada to treat AD, symptoms may not be controlled with existing drugs in some patients. Other treatment options are needed for these patients.
Treatment with Rinvoq 15 mg is expected to cost approximately $17,768 per year. The 30 mg dose is expected to cost approximately $27,010 per year.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that upadacitinib be reimbursed 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., steroid or biologic) or when use of those therapies is inadvisable only if the conditions listed in Table 1 are met.
Four clinical studies evaluated the use of upadacitinib in patients with moderate to severe chronic AD and inadequate response to topical or systemic treatments. Three double-blind, placebo-controlled studies (Measure Up 1 [n = 847], Measure Up 2 [n = 836], and AD Up [n = 901]) in adults and adolescents (≥ 40 kg) demonstrated that upadacitinib 15 mg and 30 mg improved disease severity based on the Eczema Area and Severity Index (EASI) 75 score (i.e., a 75% or greater improvement from baseline in the EASI score) and the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) scores index when compared to placebo. Disease severity was improved whether upadacitinib was used as monotherapy (Measure Up 1 and 2 studies) or in addition to topical corticosteroids (AD Up study). The evidence from these studies also indicates that upadacitinib (15 mg and 30 mg) is likely to reduce AD symptoms (as assessed by the pruritus numeric rating scale [NRS], patient oriented eczema measure [POEM], and atopic dermatitis [ADerm] Impact Scale), improve health-related quality of life [HRQoL] (through the dermatology life quality index [DLQI]), and mood and productivity domains (hospital anxiety and depression scale and the work productivity and activity index). One comparative study (Heads Up, n = 692) demonstrated superior efficacy of upadacitinib 30 mg in reducing disease severity and symptoms (based on the EASI 75 and pruritus NRS) when compared to dupilumab 300 mg at week 16; however, after 24 weeks this difference was no longer observed. In all 4 studies, the subgroup of patients who previously used systemic therapies (e.g., steroid or biologic) showed similar results to the overall study populations for the primary end points of response based on the EASI 75 at week 16, and the vIGA-AD (except for the Heads Up study where no vIGA-AD was assessed). The subgroup analysis of patients who previously used systemic therapies was not defined a priori and may be underpowered; as a result, there was uncertainty about the generalizability of the results from the included studies to the approved indication. In addition, there was no evidence for dose escalation to 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 15 mg once daily in patients with adequate response on upadacitinib 30 mg once daily.
Patients identified a need for new AD treatment alternatives that are effective in reducing pruritus, pain, flares, and rashes, and improving sleep and HRQoL. CDEC concluded that the evidence for upadacitinib appears to address some of these outcomes.
Due to the lack of evidence evaluating dose escalation, de-escalation, and the proportions of patients taking either 15 mg or 30 mg at any time, the cost-effectiveness of upadacitinib is unable to be determined for the dosing strategy approved by Health Canada. CADTH exploratory cost-effectiveness estimates are highly uncertain, biased in favour of upadacitinib, and highly sensitive to assumptions about the price of both upadacitinib and dupilumab.
Reimbursement Conditions and Reasons.
AD (also known as atopic eczema) is an inflammatory, chronic skin disease affecting 20% of children and 2% to 8% of adults worldwide. In Canada, the lifetime prevalence of AD is up to 17% of the population. AD is characterized by severe pruritus, rash, and scratching. Secondary skin infections are common. AD usually develops before the age of 5 and may persist into adulthood. Symptoms can worsen through the night, resulting in sleep loss and affecting school or work activities, and HRQoL is also altered. The goals of AD treatments are to manage and prevent flares. The treatments include general skin care and topical anti-inflammatory medication (TCS). If these methods fail, patients may use off-label systemic therapy (i.e., immunosuppressant therapy) or phototherapy. Other options include topical calcineurin inhibitors (pimecrolimus and tacrolimus) and crisaborole. Systemic therapy involves antimicrobials, antihistamines, or immunomodulators — including methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine. 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 is used to treat patients with moderate to severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.
Upadacitinib is a small molecule, reversible, Janus kinase 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., steroid or biologic) or when use of those therapies is inadvisable. Upadacitinib can be used with or without TCS. The product monograph for upadacitinib contains black box warnings regarding the risk of serious infections, malignancies, and thrombosis. It is recommended that treatment with upadacitinib be interrupted if a patient develops a serious infection until the infection is controlled. Upadacitinib is available as 15 mg or 30 mg oral extended-release tablets. The Health Canada–recommended starting dose of upadacitinib for adult patients is 15 mg once daily. If an adequate response (e.g., EASI 75) is not achieved, an increase can be considered 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. In adolescents 12 to 17 years of age, the recommended dose is 15 mg once daily. Upadacitinib has not been studied in adolescents weighing less than 40 kg.
To make its recommendation, the committee considered the following information:
Three patient groups responded to CADTH’s call for patient input: the ESC, and the CSPA and Eczéma Québec, who provided a joint submission. ESC is a registered Canadian charity dedicated to improving the lives of people in Canada living with eczema with a mission of support, education, awareness, and research. CSPA is a national non-profit organization advocating, educating, and supporting people living in Canada who are impacted 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 the caregivers of children living with AD. Meanwhile, Eczéma Québec and CSPA developed and circulated a web-based survey that was distributed through both organizations’ newsletter and social media. There were 56 respondents to the survey.
The patient groups reported that AD negatively impacts the patient and their family and can lead to psychological distress. Patients frequently report that itch is the most burdensome symptom of AD, and more than half of adult respondents with severe AD reported rarely being able to control their urge to scratch. Itch also significantly impacts 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. A total of 41% of caregivers reported they feel like a failure when they cannot control their child’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, 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, sadly, 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 see these treatments as long-term options but rather “temporary.” Respondents also expressed concern over the financial impact of treatments.
Patients believe that the need for more treatment options for uncontrolled AD is critical. Overall, patients desire improvement in managing the itch, reducing flares and rashes, improved quality of life, and improved sleep. Patients also want to improve the appearance of their hands and eyes, less apparent eczema, and to obtain pain relief.
The clinical expert consulted by CADTH visualized the ideal treatment for AD as one 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 who are unresponsive to off-label immunosuppressive drugs. 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 from dupilumab, 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 on with emollients, TCS, and/or topical calcineurin inhibitors.
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 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 Janus kinase inhibitors such as severe active infections; malignancy, including ongoing treatment with chemotherapy (including checkpoint inhibitors); severe hepatic disease; severe renal disease; pregnancy or lactation; history of thromboembolic events; and pre-existing hematologic disease, as well as patients weighing less than 40 kg.
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 the response of 75% reduction in EASI score from baseline values 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 following initiation of drug.
According to the clinical expert, patients deemed to have severe symptoms would start on the 30 mg for 16 weeks dose and would get an assessment for response (e.g., EASI 75); if a response is reached, they would switch to the 15 mg dose. 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 the 30 mg dose. 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 clinically meaningful response at 16 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 (e.g., lymphopenia, neutropenia, arterial thrombosis, venous thromboembolism), 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 will include pediatric dermatologists, general dermatologists, or pediatricians with experience in treating patients with AD. Dermatologists are well-versed in appropriate dosing and duration of therapy and appropriate monitoring for potential toxicities.
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 managing 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, in which the main unmet need is lack of access to effective, convenient, and safe treatment that enables long-term disease control and remission, as 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 impact 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 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 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 indicated that upadacitinib should be used after a trial of systemic therapies currently used (even if off-label) for treating patients whose AD has failed to respond to TCS, such as methotrexate or cyclosporine.
The clinician group notes 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 TCS. These patients are in the most need of intervention as they lack long-term treatment options and are at high risk of disease progression.
The outcomes measured in clinical trials, such as the vIGA-AD, are also used in clinical practice, perhaps with the exception of EASI scores, which are relatively unknown in the day-to-day practice. The clinician group mentions that a clinically meaningful response to upadacitinib would include improvements in patient-reported itch (4 point reduction on the NRS or an NRS score of less than 3), DLQI score reduction of 4 or more (or an acceptable improvement), improved patient-reported sleep quality, fewer AD-related disruptions at school and work, and a Physician Global Assessment score of 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 a response to systemic therapy should be reassessed 12 to 16 weeks after initiation of treatment. According to input from the clinician group, the decision to discontinue treatment should be assessed based on lack of response, significant disease progression (i.e., lichenification, increased affected body surface area, and itching) and 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., 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]), 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 that they have access to, and 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.
Input was obtained from the drug programs that participate in the CADTH reimbursement review processes. The following were identified as key factors that could impact the implementation of a CADTH recommendation for upadacitinib:
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
Measure Up 1 and Measure Up 2 were 2 similar studies (n = 847 and 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 inadequate response to topical AD treatments or use of systemic treatment. Both studies randomized patients to upadacitinib 15 mg, 30 mg, or placebo. The studies evaluated co-primary outcomes, the proportion of responders based on EASI 75 score and a 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) but using TCS in combination therapy with upadacitinib 15 mg, 30 mg, or placebo, and also using 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 in adults (18 to 75 years old) with chronic AD and documented history of inadequate response to topical treatments or documented treatment with systemic therapies. This study’s primary end point includes the proportion of patients achieving an EASI 75 at week 16.
The clinical expert consulted by CADTH considered outcomes of disease severity such as EASI 75, vIGA-AD, and the SCORing Atopic Dermatitis scale (SCORAD) to be critical for decision-making and clinical practice. These were also mentioned in the patient input received from patient groups. Similarly, the outcome of symptoms — measured with the pruritus NRS, POEM, and ADerm Impact Scale — HRQoL, mood, and productivity were considered among the most important elements for measurement to be applied 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 an EASI 75 score in the upadacitinib 15 mg (196 [69.6%] of 281 patients) and upadacitinib 30 mg (227 [79.7%] of 285 patients) groups than in the placebo group (46 [16.3%] of 281 patients; adjusted difference versus placebo of 53.3% [95% confidence interval (CI), 46.4 to 60.2; P < 0.001] for the upadacitinib 15 mg group; 63·4% [95% CI, 57.1 to 69.8; P < 0.001] for the upadacitinib 30 mg group). When assessing EASI 90, more patients in the upadacitinib 30 mg (187 [65.8%]) and 15 mg (149 [53.1%]) groups were responders as compared to placebo (23 [8.1%]; adjusted difference of 57.8% [95% CI, 51.5 to 64.1] and 45.1% [95% CI, 38.6 to 51.7] respectively). In Measure Up 2, similarly, 166 [60.1%] of 276 patients in the upadacitinib 15 mg group and 206 [72.9%] of 282 patients in the upadacitinib 30 mg group versus 37 [13.3%] of 278 patients in the placebo group reached the EASI 75, with an adjusted difference in 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; 59.6% [95% CI, 53.1 to 66.2; P < 0.001] for the upadacitinib 30 mg group. When assessing EASI 90, more patients in the upadacitinib 30 mg (165 [58.5%]) and 15 mg (117 [42.4%]) groups were responders as compared to placebo (15 [5.4%]; adjusted difference of 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 (135 [48.1%] patients) and upadacitinib 30 mg (177 [62.0%] patients) groups than the placebo group (24 [8.4%] patients) (adjusted difference versus placebo of 39.8% [95% CI, 33.2 to 46.4; P < 0.001] for the upadacitinib 15 mg group; 53.6% [95% CI, 47.2 to 60.0; P < 0.001] for the upadacitinib 30 mg group) and in Measure Up 2 (107 [38.8%] patients in the upadacitinib 15 mg group and 147 [52.0%] patients in the upadacitinib 30 mg group versus 13 [4.7%] patients in the placebo group; adjusted difference in vIGA-AD response rate versus placebo of 34.0% [95% CI, 278 to 40.2; P < 0.001] for the upadacitinib 15 mg group; 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 upadacitinib 15 mg plus TCS group (194 [64.6%] of 300 patients) and the upadacitinib 30 mg plus TCS group (229 [77.1%] of 297 patients) than the placebo group (80 [26.4%] of 304 patients; adjusted difference in EASI 75 response rate versus placebo of 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 EASI 90, more patients in the upadacitinib 30 mg (187 [63.1%]) and 15 mg (128 [42.8%]) were responders as compared to placebo (40 [13.2%]; adjusted difference of 57.8% [95% CI, 51.5 to 64.1] and 45.1% [95% CI, 38.6 to 51.7] respectively). The proportion of patients who achieved a vIGA-AD response at week 16 was statistically significantly higher in the upadacitinib 15 mg plus TCS (119 [39.6%] patients) and upadacitinib 30 mg plus TCS (174 [58.6%] patients) groups than the placebo group (33 [10.9%] patients; adjusted difference of 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 showed statistically significantly higher rates of achieving EASI 75 scores (247 [71.0%]) than patients taking dupilumab 300 mg (210 [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 (59.5%) patients in the dupilumab group and 223 (64.2%) patients in the upadacitinib 30 mg group achieving an EASI 75 (adjusted difference of 4.6% [95% CI, -2.6 to 11.9]; P = 0.211). When assessing EASI 90 at week 16, more patients in the upadacitinib 30 mg (211 [60.6%]) group were responders as compared to the dupilumab (133 [38.8%] group; adjusted difference of 21.8% [14.5 to 29.1]), and this difference between groups was smaller at week 24 (adjusted difference of 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 (Measure Up1, Measure Up2, AD Up, and Heads Up trials) for the primary end points of response based on the EASI 75 at week 16, and the vIGA-AD (except for the Heads Up study where no vIGA-AD was assessed). In the subgroup of patients with prior use of a systemic treatment (e.g., steroid or biologic) for AD, the adjusted differences (95% CI) for upadacitinib 15 mg once daily and 30 mg once daily (respectively) compared with placebo for EASI 75 response at week 16 were: for Measure Up-1, 54.1% (44.1 to 64.0) and 67.6% (58.9 to 76.3); for Measure Up-2, 50.8% (41.8 to 59.9) and 61.5% (52.7 to 70.3); |||||||||||||||||||||||||||||||||| and ||||||||||||||||||||. For Heads Up, the proportion reaching EASI 75 at week 16 was ||||||| and ||||||| for dupilumab and upadacitinib, respectively; the adjusted difference of upadacitinib 30 mg against dupilumab 300 mg was ||||||||||||||||||||. For vIGA-AD response the results were: for Measure Up-1, |||||||||||||||||||||| and ||||||||||||||||||||; for Measure Up-2, |||||||||||||||||||| and||||||||||||||||||||||||||||||; for AD Up, |||||||||||||||||||| and ||||||||||||||||||||. Heads Up did not include a vIGA-AD assessment.
Symptoms of AD were also improved. In the Measure Up studies, the proportion of patients achieving a Pruritis NRS score of 4 or greater from baseline at week 16 was statistically significantly higher when compared to placebo for upadacitinib 15 mg (absolute risk difference from placebo [95%CI] of 40.5% [33.5 to 47.5] in Measure Up 1, and 32.6% [25.8 to 39.4] in Measure Up 2) and in the 30 mg group (48.2% [41.3 to 55.0] in Measure Up 1, and 50.4% [43.8 to 57.1] in Measure Up 2); P < 0.001 for all comparisons. The proportion of patients achieving POEM total score improvement (reduction) of at least 4 points from baseline at week 16 was also statistically significantly higher for upadacitinib 15 mg (absolute risk difference [95%CI] of 52.3% [45.2 to 59.4] in Measure Up 1, and 42.1% [34.5 to 49.8] in Measure Up 2) and 30 mg (58.6% [51.9 to 65.3] in Measure Up 1 and 54.7% [47.7 to 61.7] in Measure Up 2) against placebo (P < 0.001 for all comparisons). Improvements were also observed in ADerm Impact Scale 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 Measure Up, where the proportion of patients achieving a Pruritis NRS score of 4 or greater from baseline at week 16 was statistically significantly higher when compared to placebo for upadacitinib 15 mg (absolute risk difference from placebo of 36.8% [95% CI, 29.7 to 43.8]) and 30 mg (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 for upadacitinib 15 mg (absolute risk difference of 40.2% [95% CI, 33.0, 47.4]) and 30 mg (44.9% [95% CI, 37.9 to 51.8]) against placebo; P < 0.001 for all comparisons. Improvements were also observed in ADerm Impact Scale 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 Pruritis NRS score of 4 or greater at week 16 was statistically significantly higher in the upadacitinib 30 mg group (55.2%) as compared to dupilumab 300 mg (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 and 30 mg groups than in the placebo group in the Measure Up and the AD Up studies, but not when assessed with the generic EQ-5D 5-Levels index. Mood and work productivity were similarly improved in the upadacitinib groups versus placebo. Absenteeism domains were not significantly statistically different between groups. No subgroup analyses were performed on these outcomes.
Upadacitinib 15 mg and 30 mg doses in all studies were well tolerated as compared to placebo at week 16, and without significant increases in adverse events (AEs) or serious adverse events (SAEs) up to the latest follow-up of 52 weeks in the blinded extension studies. The incidence of SAEs and AEs leading to study drug discontinuation were similar among groups except for in the Heads Up study. The most frequently reported AEs were acne, upper respiratory tract infection, nasopharyngitis, headache, elevation in creatine phosphokinase 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 AEs.
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 creatine phosphokinase 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 placebo (2%) at week 16. No deaths were reported.
In the Heads Up study, the safety profile of upadacitinib was similar to the Measure Up and AD Up studies. The rates of SAEs 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 a patient treated with upadacitinib due to influenza-associated bronchopneumonia. The most frequently reported AE with upadacitinib was acne (15.8%), whereas this AE was only reported by 2.6% of patients receiving dupilumab. The most frequently reported AE with dupilumab was conjunctivitis (8.4%), whereas this AE was only reported by 1.4% of those receiving upadacitinib. Other AEs more common in the upadacitinib group were serious infection (1.1% versus 0.6%), eczema herpeticum (0.3% versus 0%), hepatic disorders (2.9% vs 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 creatinine phosphokinase elevations (6.6% versus 2.9%) were higher for upadacitinib than dupilumab.
Randomization and allocation concealment were properly completed, resulting in a similar distribution of baseline demographics and disease characteristics 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 patients may have been potentially unblinded or may have been aware of their assignments due to improvement or lack of improvement (placebo) in AD over the study period. There is the possibility that, in the Heads Up trial, certain adverse effects (injection site, hypersensitivity reactions, conjunctivitis) that would be known to be at higher risk with dupilumab may have also potentially 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-AD and EASI scores, both reliable and valid for the assessment of severity and extent of AD. The co-primary end points were appropriately analyzed using the intention-to-treat population. Secondary end points were analyzed based on complete case analyses. This is expected to introduce some risk of bias in favour of upadacitinib (as 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 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 by using a graphical multiple testing procedure. The greatest number of patients that 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 as more patients in the placebo group would have been imputed as nonresponders. However, sensitivity analyses were based on multiple imputation, the tipping point approach, and on the per-protocol population, with similar conclusions as 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, sex, among others) showing similar results.
The population in the included pivotal studies seem to be generalizable to adults and adolescents in the Canadian population who have 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, this is, data estimating the effects of upadacitinib in patients with AD who are switched from 15 mg to 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 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 results in the population for which the indication would be applicable.
In all pivotal trials included in this CADTH review, an assessment of the subgroup of patients with previous systemic therapies showed similar results to the base case for the primary end points of response based on the EASI 75 at week 16, and the vIGA-AD (except for the Heads Up study where no vIGA-AD was assessed). Although this implies that the beneficial effect of upadacitinib in the previously treated population is reflective of the overall base case population, this should be interpreted 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 in the rest of the studies. The rest of the baseline and demographic characteristics were overall similar between studies. The adolescent population analyzed in these included studies (except for the Heads Up trial) overall mirrored the results from the adult population; however, the adolescent population was relatively small in the included trials. More evidence will be needed in underrepresented population such as those who are Black, Indigenous, and Asian. Also, the duration of trials might not be long enough to assess long-term outcomes (harms), and as patients in the Measure Up and AD Up studies were “dupilumab naïve,” more evidence is needed to assess the response of upadacitinib in patients who are previously treated with dupilumab.
Three ITCs, 2 sponsor-submitted (ITC1, ITC2) and 1 obtained from the CADTH literature search (ITC3, conducted by the Institute for Clinical and Economic Review), 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 performed an analysis of upadacitinib and its efficacy against other common comparators using Bayesian network meta-analyses (NMAs).
The first is an NMA aiming at comparing upadacitinib 15 mg or 30 mg (with or without TCS) against dupilumab in adults or adolescents with moderate to severe AD whose disease has had an inadequate response to cyclosporine A or other systemic therapy (namely: ITC 1 – post cyclosporine). The second is an NMA on a comprehensive published RCT evidence base to determine the comparative effectiveness of upadacitinib 15 mg and 30 mg versus other immunomodulators in patients with moderate to severe AD as monotherapy (not concomitantly receiving TCS) and as combotherapy (concomitantly receiving TCS). The third is an NMA report from the Institute for Clinical and Economic Review evaluating systemic therapies (abrocitinib, baricitinib, upadacitinib, tralokinumab, dupilumab) with or without topical therapies in adults and children (≥ 12 years old) with moderate to severe AD.
Overall, the results from the 3 ITCs suggest that upadacitinib 30 mg and 15 mg are among the most effective systemic therapies for reducing the severity and symptoms of moderate to severe AD in adults and adolescents, either as monotherapy or in combination with TCS.
As monotherapy, based on results from ITC1, upadacitinib 30 mg and upadacitinib 15 mg demonstrated ||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. From the ITC2, 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 where no difference was detected in the EASI 75 scores and pruritus 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, and only inferior to upadacitinib 30 mg in both the EASI 75 and vIGA-AD scores. The ITC3 Institute for Clinical and Economic Review 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 the EASI 75 and vIGA-AD scores. Upadacitinib 15 mg was superior to abrocitinib 100 mg, baricitinib 1 mg, baricitinib 2 mg, and tralokinumab 300 mg; with no difference detected against abrocitinib 200 mg and dupilumab 300 mg, and only inferior to upadacitinib 30 mg in the EASI 75 and vIGA-AD scores.
When combination therapy with TCS was assessed, the ITC1 showed |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The ITC2 demonstrated that |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||. The 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 all EASI 75, vIGA-AD, and pruritus NRS scores. Only when evaluating the vIGA-AD score, no difference was detected between abrocitinib 200 mg and upadacitinib 30 mg. Upadacitinib 15 mg was only inferior to upadacitinib 30 mg, and superior to abrocitinib 100 mg, baricitinib 2 mg, and tralokinumab 300 mg, and no difference was detected when compared to dupilumab and abrocitinib 200 mg for all outcomes.
Effect estimates from ITC3 had, in general, lower odds ratio values when compared to ITC1 and ITC2, but overall, results were similar between the 3 ITCs, with superiority of upadacitinib 30 mg over upadacitinib 15 mg, dupilumab and the other comparators, and no difference detected against abrocitinib 200 mg.
No harm data were analyzed in any of the ITCs.
The limitations from the 3 ITCs stem from uncertainty in the effect estimates due to imprecision (wide and overlapping credible intervals 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 (ITC1) evaluated patients previously exposed to systemic therapies (cyclosporine). Although the comparison in this ITC is exclusively of upadacitinib versus dupilumab and it limits the scope (generalizability) to other comparisons, the dupilumab comparison is still relevant as it is a commonly prescribed and reimbursed AD treatment in Canada. Conclusions regarding the long-term efficacy of upadacitinib compared to the active comparators relevant to this review cannot be drawn as the NMA used study results collected over a relatively short duration compared to 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; consequently, results from the ITCs must be interpreted with caution. Moreover, no information was obtained regarding the comparative safety when comparing to other active comparators. In addition, no conclusion could be drawn on the HRQoL outcomes.
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 a phase III, randomized, double-blind, placebo-controlled multicenter studies in adolescents (12 to 17 years) and adults (18 to 75 years) with moderate to severe AD. The Measure Up studies included a 35-day screening period, a 16-week double-blind period, a blinded extension period of up to week 136, and a 30-day follow-up visit. AD Up (week 52 data cut-off was December 18, 2020) included a 35-day screening period, a 16-week double-blind period, a blinded extension period of up to week 136, and a 30-day follow-up visit. At week 16, patients in the placebo group were re-randomized in a 1:1 ratio to receive daily oral doses of upadacitinib 30 mg or upadacitinib 15 mg in a blinded fashion up to week 136 in the blinded extension period.
Patients in Measure Up 1 to 52, Measure Up 2 to 52, and AD Up 52 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 30 mg once daily, 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 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 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 30 mg once daily, respectively, maintained an EASI 75 response at week 52. In AD Up 52, 46.3% and 55.7% of the patients who started upadacitinib plus TCS 15 mg and 30 mg once daily, 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 plus TCS 15 mg and 30 mg once daily, respectively, maintained an EASI 75 response at week 52.
In Measure Up 1 to 52, a total of 648 patients had at least 1 AE during the study, most commonly related to acne (16.7%), upper respiratory tract infections (14.4%), and nasopharyngitis (13%). In Measure Up 2 to 52, a total of 606 patients (75.8%) had at least 1 AE during the study. The most common AE was acne (16.8%). In AD Up, a total of 731 patients had at least 1 treatment-emergent AE during the study, most commonly related to nasopharyngitis (20.9%) and acne (16.1%). No deaths were reported. SAEs included creatine phosphokinase elevations. The most common notable harms were hepatic disorder (6.1%), herpes zoster (5.3%), creatine phosphokinase elevation (8.2%), and serious infection (3.5%).
Summary of Economic Evaluation.
CADTH identified the following key limitations with the sponsor’s analysis: The estimated budget impact is not reflective of expected clinical use of upadacitinib; there is high uncertainty around assumptions on market share distributions of upadacitinib; the proportion of patients who receive upadacitinib 30 mg versus upadacitinib 15 mg is not reflective of clinical use; the number of individuals eligible for public drug plan coverage is underestimated; and adherence to treatment with subcutaneous injection is likely underestimated.
CADTH reanalysis included assuming a greater proportion of patients taking upadacitinib 30 mg, using the proportion of patients eligible for coverage to calculate market size, and assuming higher adherence for dupilumab. Based on CADTH reanalyses, the budget impact to the public drug plans of introducing upadacitinib for patients with moderate to severe AD is expected to yield cost savings of $12,321,887 in year 1; $19,926,427 in year 2; and $30,000,815 in year 3, for a 3-year total cost savings of $62,249,129. The estimated budget impact is sensitive to treatment adherence, the proportion of patients taking upadacitinib 15 mg versus upadacitinib 30 mg, and market share distribution.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Initial meeting date: February 24, 2022
Regrets: None
Conflicts of interest: None
Reconsideration meeting date: May 26, 2022
Regrets: One expert committee member did not attend.
Conflicts of interest: None
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Indication: For the treatment of adults and adolescents 12 years of age and older with refractory moderate to severe atopic dermatitis who are not adequately controlled with a systemic treatment (e.g., steroid or biologic) or when use of those therapies is inadvisable. Upadacitinib can be used with or without topical corticosteroids
Sponsor: AbbVie Corporation
Recommendation: Reimburse with conditions
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