Reimbursement Review

Upadacitinib (Rinvoq)

Sponsor: AbbVie Corporation

Therapeutic area: Giant cell arteritis

What Is Giant Cell Arteritis?

• Giant cell arteritis (GCA) is a type of vasculitis — a group of diseases whose main feature is inflammation of blood vessels. GCA most often affects arteries that carry blood to the head and typically occurs in adults aged older than 50 years. When it occurs, patients tend to present with loss of pulse, headache, jaw pain, and vision changes and/or loss. Untreated, GCA can lead to blindness and, rarely, strokes.

• The estimated standardized prevalence rate of GCA in Ontario between 2000 and 2018 was 235 (95% confidence interval, 231 to 239) per 100,000 people aged older than 50 years.

What Are the Treatment Goals and Current Treatment Options for GCA?

• Preserving vision, maintaining disease control and quality of life, and reducing treatment-related harms were identified as the most important outcomes in the patient group input. Other important outcomes identified by clinical input include minimizing cumulative corticosteroid (CS) exposure and offering ease of administration and monitoring.

• Current treatment for GCA typically involves a high-dose CS. Tocilizumab is increasingly used in combination with CS for the treatment of GCA either at initial presentation or relapse. Once disease control is achieved, CS should be tapered. The exact dosing and duration of treatment is dependent on the patient’s disease characteristics and comorbidities, and whether the use of a steroid-sparing drug was also initiated.

What Is Rinvoq and Why Did Canada’s Drug Agency Conduct This Review?

• Rinvoq is a drug that is available as an oral tablet. At the time this review was conducted, Health Canada was reviewing Rinvoq for the treatment of adult patients with GCA. Rinvoq is used in combination with a CS and as monotherapy following the discontinuation of a CS.

• Canada’s Drug Agency (CDA-AMC) reviewed Rinvoq to inform a recommendation to the participating public drug programs on whether it should be reimbursed for the indication under review by Health Canada.

How Did CDA-AMC Evaluate Rinvoq?

• CDA-AMC reviewed the clinical evidence on the beneficial and harmful effects, as well as the economic evidence, of Rinvoq versus other treatments used in Canada for the treatment of adult patients with GCA. CS and tocilizumab were considered as relevant treatments to compare with Rinvoq when reviewing the clinical evidence.

• CDA-AMC identified equity and ethical considerations relevant to Rinvoq and GCA.

• The review was informed by materials submitted by the sponsor, which included clinical and economic evidence.

• The review was also informed by 2 patient group submissions and 3 clinician group submissions in response to a call for input by CDA-AMC, and by input from the participating public drug programs around issues that may impact their ability to implement a recommendation.

• Two rheumatologists with representation from Ontario were consulted as part of the review process.

What Were the Findings?

Clinical Evidence

• CDA-AMC reviewed the following clinical evidence:

  • 1 randomized, controlled, phase III trial (the SELECT-GCA trial) comparing Rinvoq (n = 209) with placebo (n = 112)

  • 1 long-term extension study (Period 2 of the SELECT-GCA trial) comparing continuing (n = 68) versus discontinuing (n = 35) Rinvoq in patients with GCA

  • 1 matching-adjusted indirect comparison (MAIC) of Rinvoq versus tocilizumab.

• For the comparison of Rinvoq versus placebo based on the SELECT-GCA trial:

  • Treatment with Rinvoq likely results in a clinically important increase in the percentage of patients achieving sustained remission at 52 weeks compared to placebo, though there is some uncertainty due to imprecision. In patients who achieve remission for 24 consecutive weeks, continuing Rinvoq for 104 weeks likely results in a clinically important increase in the percentage of patients maintaining remission at 104 weeks compared to when treatment with Rinvoq is stopped after 52 weeks.

  • Treatment with Rinvoq likely results in a clinically important decrease in the cumulative CS exposure through 52 weeks compared to placebo, though there is some uncertainty due to a risk of bias because of patients being excluded from the analysis. In patients who achieve remission for 24 consecutive weeks, continuing Rinvoq for 104 weeks likely reduces the cumulative CS exposure over 104 weeks compared to when treatment with Rinvoq is stopped after 52 weeks.

  • Treatment with Rinvoq likely results in a clinically important increase in the probability of being flare-free at 6 months and 12 months compared to placebo, though there is some uncertainty due to imprecision. In patients who achieve remission for 24 consecutive weeks, continuing Rinvoq for 104 weeks appears to increase the duration of flare-free days compared to when treatment with Rinvoq is stopped after 52 weeks.

  • Treatment with Rinvoq may result in an increase in physical health-related quality of life and a reduction in fatigue compared to placebo, though there is uncertainty due to a serious risk of bias because a substantial number of patients were excluded from the analysis. Continuing treatment with Rinvoq for 104 weeks may improve physical health-related quality of life and may reduce fatigue compared to stopping treatment with Rinvoq after 52 weeks. The clinical importance of the estimated between-group differences is uncertain.

  • Treatment with Rinvoq likely results in little to no difference in serious treatment-emergent adverse events and treatment-emergent adverse events leading to treatment withdrawal compared to placebo, though there is some uncertainty due to imprecision. No new safety concerns were noted in patients who continued Rinvoq treatment for 104 weeks.

• For the comparison of Rinvoq versus tocilizumab based on the MAIC:

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  • Conclusions about the comparative harms and impact on health-related quality of life, which were deemed important by patient and clinician groups, cannot be made because these outcomes were not assessed in the sponsor-conducted MAIC.

• There is no evidence to inform the effects of Rinvoq beyond 104 weeks.

Economic Evidence

• Rinvoq is available as 15 mg, 30 mg, and 45 mg extended-release tablets. For the treatment of GCA, the use of Rinvoq 15 mg extended-release tablet is recommended. At the submitted price of $51.68 per 15 mg extended-release tablet, the annual cost of Rinvoq is expected to be $18,876 per patient, based on the Health Canada–recommended dosage.

• Clinical efficacy in the economic analysis for Rinvoq 15 mg with 26-week CS tapering compared to only 52-week CS tapering was derived from the SELECT-GCA trial. Evidence submitted by the sponsor indicates that treatment with Rinvoq likely results in a clinically important increase in the percentage of patients achieving sustained remission at 52 weeks and the probability of being flare-free at 6 months and 12 months compared with CS tapering alone among patients with GCA, though there is some uncertainty due to imprecision in the estimates.

• Clinical efficacy comparing Rinvoq with 26-week CS tapering and tocilizumab with 26-week CS tapering was informed by a sponsor-submitted unanchored MAIC. Due to the methodological limitations and imprecision associated with the MAIC, no definite conclusion can be drawn on the comparable efficacy of Rinvoq versus tocilizumab for patients with GCA (refer to the CDA-AMC clinical review). Conclusions about the comparative harms and impact on health-related quality of life, which were deemed important by patient and clinician groups, could not be made because these outcomes were not assessed in the sponsor-conducted MAIC.

• CDA-AMC estimates that the budget impact of reimbursing Rinvoq with 26-week CS tapering for the treatment of adult patients with GCA will be approximately $36.2 million to $50.4 million over the first 3 years of reimbursement compared to the amount currently spent on comparators, with an estimated expenditure of $78.0 million to $108.7 million on Rinvoq over this period. The range reflects uncertainty in the number of prevalent patients eligible for Rinvoq. The actual budget impact of reimbursing Rinvoq with 26-week CS tapering will depend on the proportion of prevalent and incident patients who are treated in clinical practice and the price of biosimilar tocilizumab. The magnitude of uncertainty in the budget impact must be addressed to ensure the feasibility of adoption, given the difference between the sponsor’s estimate and the CDA-AMC estimate.

• Based on evidence reviewed for this submission, there is no robust evidence to suggest that Rinvoq with 26-week CS tapering provides greater health benefit than tocilizumab with 26-week CS tapering. If there are no differences in health outcomes between Rinvoq and tocilizumab, then the cost of Rinvoq should not exceed that of tocilizumab for the treatment of adult patients with GCA to ensure cost-effectiveness. The cost-effectiveness of Rinvoq with 26-week CS tapering versus 52-week CS tapering alone is highly uncertain due to limitations with the submitted analysis. However, based on feedback from clinical experts and data presented by the sponsor, the use of 52-week CS tapering alone for this indication is anticipated to be small (approximately10%) and CS tapering would only be slightly affected should Rinvoq become available.

Background

Introduction

Context for the Review

The objectives of this report are as follows:

• Review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of upadacitinib 15 mg, oral, extended-release tablet in the treatment of giant cell arteritis (GCA) in adult patients. The focus will be placed on comparing upadacitinib to relevant comparators in clinical practice in Canada and identifying gaps in the current evidence; this focus is outlined in Table 1.

• Review and critically appraise the economic information submitted by the sponsor, including a cost-effectiveness analysis and budget impact analysis. The focus of the Economic Review is aligned with the scope of the Clinical Review, unless otherwise stated. For most reviews, a Canada’s Drug Agency (CDA-AMC) base case is developed, informed by clinical expert input, the available clinical evidence, and the best interpretation of the economic evidence based on the information provided by the sponsor.

Table 1: Information on the Application Submitted for Review and on the CDA-AMC Review

CDA-AMC = Canada’s Drug Agency; CS = corticosteroid; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; GCA = giant cell arteritis; HRQoL = health-related quality of life; JAK = Janus kinase; JAK1 = Janus kinase 1; NOC = Notice of Compliance; PCS = physical component score; SF-36 = Short Form (36) Health Survey; TEAE = treatment-emergent adverse event.

^aThe Economic Review aligns with the scope of the Clinical Review, unless otherwise stated.

^bCDA-AMC has previously issued a reimbursement recommendation for this drug for the same indication or a similar indication.

^cTEAEs of special interest in the clinical review included those listed in the upadacitinib product monograph and highlighted as important by clinical experts consulted for this review. They included serious infections (including tuberculosis), malignancies, thrombosis, and major adverse cardiovascular events.

Submission History for the Drug Under Review

CDA-AMC previously reviewed upadacitinib for the treatment of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, atopic dermatitis, and Crohn disease.

Sources of Information

The contents of the Reimbursement Review Report are informed by materials submitted by the sponsor, input received from interested parties (patient groups, clinician groups, and drug programs), and input from clinical experts consulted for this review.

Calls for patient group and clinician group input are issued for each reimbursement review. Two patient group submissions were received: 1 from Arthritis Consumer Experts and a joint submission from the Arthritis Society Canada, the Canadian Arthritis Patient Alliance, the Vasculitis Foundation Canada, and Vision Health Initiatives. Three clinician group submissions from CanVasc, the Canadian Rheumatology Association, and Rheumatologists of Newfoundland and Labrador and Prince Edward Island were received. The patient group submission from Arthritis Consumer Experts was informed by 2 patients completing surveys in 2021 while the joint submission was informed by 23 people living with GCA completing a survey in 2025. The full submissions received are available on the project landing page in the consolidated input document. The drug programs provide input on each drug being reviewed through the reimbursement review process by identifying issues that may impact their ability to implement a recommendation.

Input from patient and clinician groups is considered throughout the review, including in the selection of outcomes to include in the Clinical Review and in the interpretation of the clinical and economic evidence. Relevant patient and clinician group input is summarized in the Disease Background, Current Management, and Unmet Needs and Existing Challenges sections of this report.

Each review team includes at least 1 clinical expert 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. Two clinical experts with expertise in the diagnosis and management of GCA participated as part of the review team, with representation from Ontario.

Disease Background

GCA, also referred to as temporal arteritis, is a chronic, immune-mediated disease characterized by the inflammation of medium to large arteries.¹ GCA is a life-threatening medical emergency that carries a substantial risk of permanent blindness and visual impairment, as well as both ischemic complications (e.g., myocardial infarction, stroke) and vascular complications (e.g., aortic dissection, aortic aneurysm).^2-4 Approximately 80% of patients present with symptoms due to cranial ischemia, including loss of pulse, headache, jaw claudication and/or pain, and vision loss.^5-13 In most patients, symptoms resolve rapidly in response to treatment; however, approximately 55% to 77% of patients experience disease relapse or recurrence, called a GCA flare, within 2 years of starting glucocorticoid treatment.¹⁴ GCA is the most common form of vasculitis and almost exclusively affects adults aged older than 50 years.^9,15,16 It is more common in female patients than in male patients.^16,17

The sponsor-provided incidence and prevalence estimates were limited to 1 population-based study using 2000 to 2018 Ontario health administrative data. This study found the incidence rate of GCA was 25 per 100,000 people aged older than 50 years, and the standardized prevalence rate was 235 (95% confidence interval [CI], 231 to 239) per 100,000 people in the same age group.¹⁷ GCA is also associated with an increased all-cause mortality compared to a general population without vasculitis,^18,19 with 1 study using 2000 to 2018 Ontario health administrative data reporting mortality rates for people with GCA to be increasing over time (a standardized mortality ratio of 1.92 [95% CI, 1.81 to 2.03] in 2018).¹⁹

Patient group input: Patients providing input indicated that the onset of GCA symptoms is often sudden and alarming. The most common symptoms at disease onset included blurry or flashing vision (occurring in 41% of the 23 joint submission survey respondents), double vision (29%), scalp pain (22%), and persistent headaches (22%). The most commonly reported symptoms due to GCA were fatigue (reported by 83% of the 23 joint submission survey respondents), followed by persistent headaches (65%), pain and/or discomfort or fatigue when chewing (65%), and scalp pain or discomfort when touching the scalp (65%). Survey respondents also noted that GCA can affect the physical, emotional, and financial well-being of caregivers. This includes feelings of chronic anxiety and emotional fatigue due to the need to monitor for unpredictable flare-ups, feeling isolated due to the relative rarity of GCA, and requiring time off work to provide care.

Current Management

Treatment Goals

Patient group input: Patients reported the most important treatment goals were to preserve vision, maintain disease control (including experiencing fewer relapses), maintain quality of life (e.g., maintained vision, limited time spent receiving treatment), and reduce treatment-related harms. Due to the known burden associated with prolonged steroid use, reducing the cumulative steroid exposure was also noted as a top priority.

Clinician input: The clinical experts consulted for this review and clinician groups agreed the primary goals of GCA treatment are to prevent vascular complications such as blindness and stroke, control GCA signs and symptoms, and minimize treatment-related adverse effects. The clinical experts consulted for this review indicated additional treatment goals were to minimize cumulative glucocorticoid exposure and offer ease of administration and monitoring — a particularly important goal for patients who live in rural or remote areas or have economic disadvantages.

Current Treatment Options

Treatment for GCA should be initiated immediately to minimize the risk of disease complications. Patients presenting with GCA are recommended to initiate treatment with high-dose glucocorticoids whenever the disease is strongly suspected or confirmed to avoid vision loss.^4,10,20 Those without vision loss are typically recommended to initiate prednisone 40 mg to 60 mg orally daily to achieve rapid disease control and prevent vascular complications.^4,20 Those with vision loss at presentation or cerebrovascular manifestations should be treated with IV glucocorticoids followed by prednisone (methylprednisolone 500 mg to 1,000 mg daily for 3 days followed by prednisone 40 mg to 60 mg orally daily).^4,20 According to the American College of Rheumatology guidelines and the clinical experts consulted for this review, tocilizumab, the sole steroid-sparing advanced therapy approved in Canada for use in GCA, should be considered for initial treatment with glucocorticoids.^4,21,22 In contrast, the European Alliance of Associations for Rheumatology recommends an initial attempt of a successful steroid taper to 5 mg per day or less by 1 year with tocilizumab added if this approach is unsuccessful.¹⁰ Methotrexate, a nonsteroidal immunosuppressant, is recommended for use off-label in cases where patients have not experienced improvement with tocilizumab or where tocilizumab is not recommended for use.^5,23,24 The American College of Rheumatology guidelines note off-label use of abatacept with glucocorticoids may be considered if all other drugs are not effective.⁴

Once disease control is achieved, the glucocorticoid dose should be tapered to reduce toxicity. The dosing and duration of oral glucocorticoid therapy may vary depending on the patient’s manifestations and comorbidities and whether the use of a steroid-sparing drug was also initiated.⁴

For patients who experience relapse while on glucocorticoid therapy, other nonglucocorticoid immunosuppressive drugs are recommended by guidelines to be sequentially tried.^4,10 For patients who experience relapse upon glucocorticoid tapering (i.e., recurrence of active disease), glucocorticoid therapy should be reinitiated as recommended for new-onset disease.¹⁰

Key characteristics of upadacitinib are summarized with other treatments available for GCA in adult patients in the Supplemental Material document, in the Key Characteristics table in Appendix 1 (available on the project landing page).

Unmet Needs and Existing Challenges

Patient group input: According to the patient group inputs, while current treatment options for GCA can be effective in preventing vision loss and reducing inflammation, they come at a significant cost to patients’ quality of life (e.g., insomnia, mood swings, time burden associated with travel to clinics for infusions). The experience is marked by a heavy reliance on corticosteroids (CSs), prolonged uncertainty during tapering, and challenges accessing newer, potentially safer alternatives. There is an urgent need for expanded access to steroid-sparing therapies, better patient education, and a multidisciplinary approach to care that supports long-term well-being.

Clinician input: The clinical experts consulted for this review and clinician group input agreed that while CSs were effective at inducing clinical remission, there remains an unmet need for GCA treatments with an improved toxicity profile. Additionally, clinical experts consulted for this review and clinician group input noted that there remains a need for other drugs to treat patients with GCA who are refractory to tocilizumab, have contraindications to tocilizumab, or have prohibitive adverse effects that preclude the use of tocilizumab. One of the limitations associated with tocilizumab treatment is administration via subcutaneous injection, which may be difficult for patients to use or access due to storage safety concerns — possibly disproportionately affecting patients who live in rural or remote areas or have economic disadvantages. Clinician groups indicated that these difficulties may lead to poor adherence and, consequently, suboptimal clinical outcomes. These same clinician groups noted that oral tablets offer ease of administration to patients and reduced transportation barriers for rural or remote pharmacies.

Considerations for Using the Drug Under Review

Contents within this section have been informed by input from the clinical experts consulted for the purpose of this review and from clinician groups, as well as the reimbursement conditions proposed by the sponsor (refer to the Initiation, Renewal, Discontinuation, and Prescribing Conditions Proposed by the Sponsor table in Appendix 1). The implementation questions from the public drug programs and corresponding responses from the clinical experts consulted for this review are summarized in the Supplemental Material document, in the Summary of Drug Program Input and Clinical Expert Responses table in Appendix 1. The following has been summarized by the review team.

Place in Therapy

The clinical experts consulted for this review felt upadacitinib would offer an alternative first-line treatment option for patients deemed to not be suitable for tocilizumab treatment (i.e., those who have contraindications, have a needle phobia, or express a preference for the oral route) or as a second-line treatment in those who have not experienced improvement with tocilizumab. These experts believed that prescribing physicians would likely have greater experience with tocilizumab and therefore be more likely to use tocilizumab as the first-line treatment in the absence of a head-to-head trial comparing tocilizumab and upadacitinib. The clinical experts agreed that upadacitinib would be used with tapering steroids and/or methotrexate if needed.

In contrast, the CanVasc clinician group felt upadacitinib was likely to induce a practice change and be used as a first-line drug in patients with GCA in combination with an appropriate glucocorticoid taper as an alternative to tocilizumab. They agreed with the clinical experts that upadacitinib could also serve as a second-line drug in patients who are unable to tolerate tocilizumab, whose disease does not respond to tocilizumab, who have a needle phobia and prefer an oral medication, or who experience a relapse of their disease when treated with tocilizumab.

Patient Population

The clinical experts consulted for this review and all 3 clinician groups felt all patients with GCA should be eligible for treatment with upadacitinib. The clinical experts consulted for this review and the Canadian Rheumatology Association felt patients with various comorbidities, including a history of malignancy, a history of cardiovascular events, repeated episodes of shingles, repeated episodes of diverticulitis and/or gastrointestinal bleeding, and/or with venous thromboembolisms not on therapy, would be least suitable for treatment with upadacitinib.

The clinical experts consulted for this review indicated that while efforts should be made to obtain histologic or radiographic evidence of inflammatory large vessel vasculitis, approval for upadacitinib treatment should not be contingent on these tests being positive. Where there is no testing available, a diagnosis should be confirmed by someone with expertise in the diagnosis of GCA. The experts felt evidence of disease should include signs and/or symptoms compatible with GCA, a response to CS, and a reasonable interrogation to rule out other causes of GCA.

Assessing the Response to Treatment

The clinical experts consulted for this review and clinician groups indicated that, in clinical practice, a complete disease response is typically defined by the resolution of GCA signs and symptoms and tapering CS to a prednisone equivalent of 5 mg or less. The same clinical experts noted that GCA clinical trials generally use more stringent criteria for defining complete disease response. These criteria usually include the absence of GCA signs and symptoms, adherence to a prespecified CS-tapering regimen (i.e., typically achieving cessation of CS usage), and the normalization of inflammatory markers. According to clinical experts consulted for this review, response to treatment is initially assessed every 1 week to 2 weeks during the first 3 months, every 2 weeks to 4 weeks until 6 months, and monthly thereafter.

The clinical experts consulted for this review generally agreed with the sponsor’s proposed reimbursement renewal conditions (Appendix 1 of the Supplemental Material document), except for the proposed criteria related to severe disease involvement. While the clinical experts acknowledged evidence that patients with large vessel involvement are more likely to relapse, they noted a lack of data supporting the idea that all patients with severe disease are at increased risk of relapse. Therefore, the clinical experts felt renewal should be considered in patients who continue to receive a residual CS, patients with large vessel involvement or an organ-threatening event (e.g., amaurosis fugax), patients with ongoing residual disease activity or who experience disease relapse, or those who have sustained CS-free remission for less than 26 weeks.

Discontinuing Treatment

One of the clinical experts consulted for this review felt upadacitinib could be discontinued at 1 year of treatment provided that a patient had reached a steroid-free remission and had remained in this state for 6 months. The other clinical expert consulted for this review felt data were lacking to determine the exact duration at which upadacitinib should be discontinued. Both experts and the clinician groups felt patients who have disease refractory to upadacitinib or are unable to tolerate upadacitinib should be discontinued. Clinical experts and clinician groups noted that patients who could not tolerate alternative treatments (i.e., tocilizumab), wished to continue upadacitinib treatment, and for whom upadacitinib adverse events (AEs) were deemed manageable by their treating physician could continue being reimbursed for treatment despite refractory disease or AEs.

The sponsor proposed no discontinuation conditions, which the clinical experts consulted for this review felt would facilitate the work of the treating physician by allowing them to use their judgment in how and when to discontinue or reinitiate upadacitinib.

Prescribing Considerations

The clinical experts consulted for this review felt upadacitinib could be prescribed and managed in any setting (including inpatient, outpatient, and telemedicine visits) by a rheumatologist. In some instances, an ophthalmologist or internist with experience in GCA and the ability to provide long-term supervision could prescribe upadacitinib. Collaboration between a rheumatologist and another physician can be considered for patients living far from a centre. The prescribing conditions mentioned by clinical experts align with those proposed by the sponsor.

Clinical Review

Methods

The review team considered studies in the sponsor’s systematic review (pivotal studies and randomized controlled trials [RCTs]), sponsor-submitted long-term extensions (LTEs), indirect treatment comparisons (ITCs), and studies addressing gaps in the evidence for inclusion. Eligible studies for the systematic review included published and unpublished pivotal studies and phase III and phase IV RCTs. Relevant patients and interventions were defined by the indication or reimbursement request and the recommended dosage in the product monograph. Relevant comparators were drugs used in clinical practice in Canada to treat patients described in the indication under review. These included CS and tocilizumab. While methotrexate was identified as a potentially relevant comparator, the sponsor’s request to exclude methotrexate — due to low usage in current Canadian clinical practice, the availability of alternative therapies, precedent set by prior CDA-AMC submissions in GCA to exclude it as a comparator, and feasibility studies suggesting ITC comparisons across trials is unlikely — was accepted by CDA-AMC. LTEs of included pivotal studies and RCTs were included, regardless of whether there was a comparison group. ITCs and studies addressing gaps submitted by the sponsor were included when they filled an identified gap in the systematic review evidence (e.g., missing comparative evidence, longer follow-up time).

The review team selected outcomes (and follow-up times) for review considering the sponsor’s Summary of Clinical Evidence, clinical expert input, and patient and clinician group input. Included outcomes were those considered relevant to expert committee deliberations, and they were selected in consultation with committee members. Evidence from the systematic review for the most important outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Achieving sustained remission and reducing the cumulative CS exposure were assessed using GRADE because they were the most important clinical outcomes according to patient group input, clinician group input, and input from the clinical experts consulted for this review. Time to first disease flare was assessed in GRADE because it is a key input in the sponsor’s pharmacoeconomic model; according to the consulted clinical experts, 6 months and 12 months are the most clinically relevant time points for this outcome. Patient group input highlighted the importance of maintaining quality of life while receiving treatment. The 36-item Short Form (36) Health Survey (SF-36) physical component score (PCS) was selected for GRADE because it is a generic measure that provides a comprehensive picture of patients’ physical health. The Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) was appraised using GRADE to understand the effect of treatment on patients’ fatigue, an important aspect according to the clinical experts consulted for this review. Select harms outcomes considered important for expert committee deliberations were also assessed using GRADE: serious treatment-emergent adverse events (TEAEs) and TEAEs leading to treatment withdrawals.

Methods for data extraction, risk-of-bias appraisal, and certainty of evidence assessment are in the Supplemental Material document in Appendix 2.

Clinical Evidence

In this report, the following sources of evidence submitted by the sponsor have been reviewed and appraised:

• 1 RCT included in the systematic review, period 1 of the SELECT-GCA study

• 1 LTE study, period 2 of the SELECT-GCA study

• 1 ITC.

Systematic Review

Description of Studies

Study Characteristics

Characteristics of the included study are summarized in Table 2. Details pertaining to the eligibility criteria and relevant outcome measures are in the Supplemental Material document in Appendix 3.

The SELECT-GCA study investigated the efficacy and safety of 7.5 mg or 15 mg once daily upadacitinib compared to placebo once daily in adult patients aged 50 years and older with active new-onset or relapsing GCA. The study was conducted across 100 sites in 23 countries, including 3 sites in Canada. The study consisted of a 35-day maximum screening period followed by a 52-week randomized, double-blind, parallel-group period (period 1), a 52-week blinded extension period (period 2), and a 30-day follow-up period. The Systematic Review section of this report presents data from the initial 52-week randomized period (period 1). Data from the 52-week blinded extension period (period 2) is summarized in the LTE Studies section of this report.

All patients who met the inclusion criteria were randomized in a 2:1:1 ratio using interactive response technology to 1 of the following groups:

• upadacitinib 15 mg daily with a 26-week CS-tapering regimen (referred to as the upadacitinib group hereafter)

• upadacitinib 7.5 mg daily with a 26-week CS-tapering regimen

• placebo administered daily with a 52-week CS-tapering regimen (referred to as the placebo group hereafter).

For all patients other than those enrolled in Japan, randomization was stratified by baseline CS dose (prednisone or prednisolone > 30 mg or ≤ 30 mg), prior use of an interleukin-6 (IL-6) inhibitor (yes or no), and whether entering the study with new-onset or relapsing disease. While stratified randomization was not performed in Japan, characteristics on the stratification variables were still collected.

All patients received CS (prednisone or prednisolone) 20 mg, 30 mg, 40 mg, 50 mg, or 60 mg once daily at baseline. The initial dose was at the discretion of the investigator, based on disease severity and comorbid medical conditions, and was to be tapered according to a predefined schedule over a 26-week or 52-week period. Open-label prednisone or prednisolone was to be provided until the dose was tapered to 20 mg per day, after which blinded prednisone, prednisolone, or placebo was provided for the remaining blinded tapering regimen.

Efficacy and safety assessments occurred at screening, baseline, and week 2, week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 36, week 44, and week 52. The SF-36 and FACIT-F were assessed at baseline and week 8, week 12, week 24, and week 52. Data presented in this report are from the February 6, 2024, data cut-off. Relevant end points summarized in this report include:

• sustained remission (defined as an absence of GCA signs and symptoms assessed by the investigator and adherence to the protocol-defined CS-tapering regimen from week 12 to week 52)

• cumulative CS exposure from baseline to week 52 (defined as the total mg of CS received from baseline to week 52)

• time to first disease flare (disease flare was defined as an event determined by the investigator to represent recurrence of GCA signs or symptoms or an erythrocyte sedimentation rate [ESR] measurement greater than 30 mm per hour [attributable to GCA] and requiring an increase in CS dose)

• sustained complete remission (defined as an absence of GCA signs and symptoms assessed by the investigator, the normalization of ESR and high-sensitivity C-reactive protein [CRP], and adherence to the protocol-defined CS-tapering regimen from week 12 to week 52)

• the SF-36 PCS (a generic patient-reported health-related quality of life [HRQoL] instrument)

• FACIT-F (a patient-reported measure of fatigue)

• harms (TEAEs, serious TEAEs, treatment withdrawals due to TEAEs, and deaths due to TEAEs).

In line with the proposed Health Canada product monograph and reimbursement request under review, this report focuses on the upadacitinib 15 mg group.

Table 2: Characteristics of the Study Included in the Systematic Review

CRP = C-reactive protein; CS = corticosteroid; CYP3A = cytochrome P450 3A; ESR = erythrocyte sedimentation rate; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; GCA = giant cell arteritis; hs-CRP = high-sensitivity C-reactive protein; IL-6 = interleukin-6; JAK = Janus kinase; PCS = physical component score; PMR = polymyalgia rheumatica; RCT = randomized controlled trial; SF-36 = Short Form (36) Health Survey; TB = tuberculosis; TEAE = treatment-emergent adverse event.

^aGCA diagnosed according to the following: a history of ESR ≥ 50 mm per hour, or hs-CRP or CRP ≥ 1.0 mg/dL; a presence of unequivocal cranial symptoms of GCA or unequivocal symptoms of PMR; and a presence of temporal artery biopsy revealing features of GCA or evidence of large vessel vasculitis by angiography or cross-sectional imaging assessed by a qualified radiologist experienced in evaluating large vessel vasculitis, or an ultrasound of temporal arteries assessed by a qualified physician experienced in evaluating large vessel vasculitis.

^bDefined by the presence of an ESR ≥ 30 mm per hour, or hs-CRP or CRP ≥ 1 mg/dL and at least 1 of the following: unequivocal cranial symptoms of GCA, unequivocal symptoms of PMR, or other features judged by the investigator to be consistent with GCA or PMR flares.

^cIncluding, but not limited to, a cerebrovascular accident, a myocardial infarction, coronary stenting, and aortocoronary bypass surgery or other ischemic events unrelated to GCA, uncontrolled hypertension, and a history of any malignancy except for successfully treated nonmelanoma skin cancer or localized carcinoma in situ of the cervix.

Sources: The SELECT-GCA trial protocol and the SELECT-GCA trial Clinical Study Report.^25,26 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Statistical Testing and Analysis Populations

The SELECT-GCA study planned to randomize approximately 420 patients to have at least 90% power to detect a 20% difference in the sustained remission rate at week 52 between the upadacitinib 15 mg group and the placebo group (assuming 40% of patients in the placebo group experience a disease response), using the Fisher exact test, with an overall 2-sided alpha of 0.05.

All efficacy analyses were conducted using the full analysis set for period 1 based on treatment as randomized. All safety analyses were conducted using the safety analysis set in period 1, which included all patients who had received at least 1 dose of the study drug in period 1.

The following outcomes summarized in this report were controlled for multiplicity to ensure a strong control of familywise type I error rate at a 2-sided alpha of 0.05:

• the percentage of patients achieving sustained remission at week 52 (primary end point)

• the percentage of patients achieving sustained complete remission from week 12 through week 52

• cumulative CS exposure through week 52

• time to first disease flare through week 52

• change from baseline to week 52 in the SF-36 PCS

• change from baseline to week 52 in the FACIT-F score.

The order of the multiple testing procedure is detailed in Appendix 3 of the Supplemental Material document. Briefly, the SELECT-GCA trial began with testing the primary end point for the upadacitinib 15 mg dose group using an alpha of 0.05 and continued testing following a prespecified alpha transfer path, which included a downstream transfer along the end point sequence within each dose as well as a cross-dose transfer.

Patient Disposition

Patient disposition for the included study is summarized in the Supplemental Material document, Appendix 4.

In the SELECT-GCA trial, 633 patients were screened and 429 patients were randomized to 1 of the upadacitinib groups (n = 209 to the upadacitinib 15 mg group and n = 107 to the upadacitinib 7.5 mg group) or the placebo group (n = 112). There was 1 patient randomized to the upadacitinib 15 mg group who did not receive the study drug. During the 52-week study period, 23.2% of patients (26 of 112) in the placebo group and 15.3% of patients (32 of 209) in the upadacitinib 15 mg group discontinued from the study, mostly due to AEs (11.6% and 8.1%, respectively), withdrawal of consent (4.5% and 4.8%, respectively), and “other” reasons (4.5% and 2.4%, respectively). Similarly, a higher percentage of patients in the placebo group discontinued the study drug (36.6%) than in the upadacitinib group (25.8%). Common reasons for study drug discontinuation included AEs (20.5% and 15.3%, respectively) and lack of efficacy (7.1% and 3.3%, respectively).

Baseline Characteristics

Table 3: Summary of Baseline Characteristics From SELECT-GCA Study (FAS1)

CRP = C-reactive protein; CS = corticosteroid; ESR = erythrocyte sedimentation rate; FAS1 = full analysis set in period 1; IL-6 = interleukin-6; PMR = polymyalgia rheumatica; SD = standard deviation.

Note: Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Source: SELECT-GCA trial Clinical Study Report.²⁶ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Treatment Exposure and Concomitant Medications

Details of patients’ treatment exposure and adherence and use of concomitant medications in the SELECT-GCA study are in the Supplemental Material document, Appendix 4.

The median duration of treatment in both treatment arms was 364.0 days (range, 6 days to 372 days in the placebo group and 3 days to 373 days in the upadacitinib group). The mean treatment adherence was also similar across treatment groups, ranging from 97.4% (standard deviation = 4.4%) in the upadacitinib group to 98.1% (standard deviation = 6.8%) in the placebo group.

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Critical Appraisal

Internal Validity

Randomization and allocation concealment methods used in the SELECT-GCA study were deemed adequate by the CDA-AMC review team to limit the risk of bias in the randomization process.

Except for patients enrolled in Japan, randomization in the SELECT-GCA trial was stratified by baseline CS dose, prior use of an IL-6 inhibitor, and baseline disease status. These stratification factors were considered appropriate by the clinical experts consulted for this review and intended to balance known prognostic variables between treatment groups.

Notable differences in baseline characteristics between treatment groups included a higher percentage of female patients in the upadacitinib group (74.6% of patients [156 of 290]) than in the placebo group (68.8% of patients [77 of 112]), fewer patients in the upadacitinib group with a history of unequivocal symptoms of polymyalgia rheumatica (PMR) (52.2%) than in the placebo group (61.6%), and fewer patients in the upadacitinib group with ischemia-related vision loss (9.6%) than in the placebo group (19.6%). These differences may introduce confounding and bias the results, although the direction of the potential bias remains unclear and the clinical experts consulted for this review did not anticipate these differences would impact the results.

A higher percentage of patients in the placebo group discontinued the study drug, although the reasons for treatment discontinuation were similar across both treatment groups. Further, the analysis method for handling treatment discontinuation — counting patients as not having a disease response for binary remission-related outcomes or data collected regardless of treatment discontinuation for time-to-event and continuous outcomes — was considered appropriate, resulting in a low risk of bias. However, while overall protocol deviations were reported in a similar percentage across treatment groups ██████ ██████████ ██ ████████ ██ ███ ███████ █████ ████████ ███ █████ █████████ ██ █████████ ████ ████████ ██ ███ ████████████ █████ █████ ██████ ██████. Without any information on the actual treatment received, the resulting risk of bias due to deviations from the intended interventions remains uncertain.

All efficacy results deemed important by the clinician and patient input were included in the SELECT-GCA study’s hierarchical multiple testing procedure and the multiplicity control was deemed to be adequate by the CDA-AMC review team.

The SELECT-GCA study was a double-blinded trial, though treatment unblinding was permitted in the event of a medical situation requiring knowledge of the treatment received for appropriate management. The number of patients and investigators who were unblinded due to AEs was not reported and therefore, the magnitude of the resulting bias could not be assessed. Objectivity of the primary and most multiplicity-controlled secondary outcomes relied on the blinding of clinical assessors, who monitored GCA signs and symptoms and CS exposure. The assessors remained blinded to CRP and ESR levels and were only alerted when ESR levels were elevated. Therefore, the risk of bias in the measurement of relevant outcomes was deemed to be minimal.

Biases resulting from the self-reporting nature of HRQoL outcomes were deemed to be minimal because patients were blinded to the intervention received. No estimated minimal important difference in patients with GCA was identified in the literature for the SF‑36 PCS and FACIT-F score and the clinical experts could not inform on a clinically important between-group difference, so the null was used as the threshold. As such, there is uncertainty as to the clinical relevance of the between-group differences for these end points. Certainty of evidence for both scores was reduced owing to a risk of bias due to missing or excluded outcome data (only 39.3% to 58.9% of patients contributed to the analyses across groups and scores). HRQoL analyses used a mixed model of repeated measures, which assumes data are missing at random, an assumption that may not be plausible. Patients were mostly excluded from the analyses due to the use of escape therapy.

The primary approach for handling missing data for binary outcomes in the SELECT-GCA study was nonresponder imputation (wording of original source)²⁵ incorporating multiple imputation, except when missing at random could be reasonably assumed (according to the sponsor), which was handled by multiple imputations. For both sustained remission and sustained complete remission, because the percentages of patients with missing measurements were similar in the upadacitinib and placebo groups and CDA-AMC deemed the assumption of missing data indicating a lack of disease response to be appropriate, the risk of bias was deemed to be low. The use of as-observed analyses, which excluded patients who did not have an evaluation on scheduled visits, assumes that the missingness is not related to the outcome — that is, that the data are missing completely at random. The use of as-observed analyses for cumulative CS exposure led to the exclusion of approximately 14% of patients in the upadacitinib group and 20% in the placebo group due to missed evaluations or premature study discontinuation, raising concerns about potential bias due to missing data. For time to first disease flare, there was a high percentage of censoring at 52 weeks; however, censoring was primarily due to completing the study without a flare and reasons were evenly distributed across the 2 treatment arms. Therefore, the risk of bias due to informative censoring was deemed to be minimal.

The certainty of evidence for the between-group effect estimates for sustained remission, time to first disease flare, serious TEAEs, and TEAEs leading to treatment withdrawal were affected by imprecision. Although the point estimate for sustained remission and time to first disease flare at 6 months and 12 months suggest a clinically important increase, the 95% CIs include small differences that may not be considered clinically important. For serious TEAEs and TEAEs leading to treatment withdrawals, while the point estimates suggested little to no clinically important difference, the 95% CIs included the potential for a clinically important increase or decrease, respectively.

Results of the prespecified subgroup analyses of the primary end point were mostly aligned with those of the main analyses, with differences in the magnitude of the estimated effect in some subgroups. These analyses were limited by small sample sizes in the subgroups analyzed, wide CIs around the point estimates, and a lack of testing for subgroup by treatment interactions. As such, these analyses are of very low credibility and should not be used to draw conclusions about effect modification.²⁷

External Validity

Clinical experts felt the inclusion and exclusion criteria used in the SELECT-GCA trial were appropriate for a GCA trial and for informing the sponsor’s reimbursement request. Although the SELECT-GCA trial excluded patients who had previously experienced a disease flare while being treated with an IL-6 inhibitor, clinical experts felt upadacitinib would be just as effective in these patients as in those who had never received an IL-6 inhibitor. The same clinical experts felt that the percentage of patients completing and discontinuing treatment throughout the trial aligned with clinical practice in Canada.

While the majority of sites recruiting patients for the SELECT-GCA trial were not in Canada (only 3 of the 23 sites were in Canada), the clinical experts consulted for this review indicated the baseline characteristics of the study population were generally representative of patients seen in Canadian clinical practice.

The outcomes measured in the SELECT-GCA trial addressed the key treatment goals identified by patient and clinician group inputs submitted to CDA-AMC and were deemed to be relevant by the consulted clinical experts. Additionally, the clinical experts felt outcome definitions and the duration of follow-up were appropriate and in line with those used in Canadian clinical practice.

At the time that the SELECT-GCA study was initiated (2019), the clinical experts agreed the comparator used (CS alone) would have been the standard of care for GCA. The exact tapering regimen used in Canadian clinical practice varies by the treating physician and patient; however, the experts consulted did not feel alternative tapering regimens would impact the generalizability of results. Standard Canadian clinical practice now includes the use of tocilizumab in combination with CS tapering and it is of interest to understand how tocilizumab compares to upadacitinib.

Results

The key efficacy and harms results and findings from the GRADE assessment are presented in this section. Detailed efficacy and harms results can be found in Appendix 4 in the Supplemental Material document.

Efficacy

Key results include the following:

• The between-group difference in the percentage of patients achieving sustained remission was 17.1% (95% CI, 6.3% to 27.8%; P = 0.0019), favouring upadacitinib.

• The between-group difference in the mean cumulative CS exposure from baseline to week 52 was −1,267.0 mg (95% CI, −1,587.0 mg to −1,133.0 mg; P < 0.0001), favouring upadacitinib.

• The median time to first disease flare was not evaluable (NE) in the upadacitinib group and 323.0 days (95% CI, 249.0 days to NE) in the placebo group; the hazard ratio was 0.6 (95% CI, 0.4 to 0.8; P = 0.0028), favouring upadacitinib.

• The between-group difference in the percentage of patients achieving sustained complete remission was 21.0% (95% CI, 11.3% to 30.2%; P < 0.0001), favouring upadacitinib.

• The between-group difference in the SF-36 PCS least squares mean change from baseline to week 52 was 3.8 (95% CI, 1.4 to 6.1; P = 0.0019), favouring upadacitinib.

• From baseline to week 52, the between-group difference in the least squares mean change in FACIT-F score was 4.0 (95% CI, 1.3 to 6.8; P = 0.0036), favouring upadacitinib.

Harms

Key results include the following:

• Almost all patients experienced at least 1 TEAE (96.7% of patients [202 of 209] in the upadacitinib group and 94.6% of patients [106 of 112] in the placebo group). The 2 most common TEAEs in the upadacitinib group were headache (16.3% in the upadacitinib group versus 11.6% in the placebo group) and arthralgia (13.9% in the upadacitinib group versus 13.4% in the placebo group). The most common TEAEs in the placebo group were urinary tract infection (16.1% in the placebo group versus 10.0% in the upadacitinib group) and back pain (13.4% in the placebo group versus 12.0% in the upadacitinib group).

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• Serious TEAEs occurred in 23.0% of patients (48 of 209) in the upadacitinib group and 21.4% of patients (24 of 112) in the placebo group. Serious TEAEs that occurred in greater than ██ ██ ████████ ██ ██████ █████████ █████ ████ █████████ ███ ██ ███ ████████████ █████ ███ ████ ██ ███ ███████ ██████ ███ █████████ ████████ █████ ██ ███ ████████████ █████ ███ ████ ██ ███ ███████ ████████. More patients in the placebo group experienced a TEAE leading to withdrawal of the study drug (25.9% of patients [29 of 112]) than in the upadacitinib group (17.2% of patients [36 of 209 ███ █████ ████ ███ █████ ███████ ██ █████████ ██████████ ████ ████████ ██ ████ ████ ██ ██ █████████ █████ ████████ ███ █████ ███ ██████ █████████ █████ ███ ████ ███████████ ██████████ █████ ███ ████ ███ █████████ ████████ █████ ███ █████ ██ the placebo and upadacitinib groups, respectively.

• Two patients in each treatment group experienced a TEAE resulting in death. In the upadacitinib group, 1 patient experienced general disorders and administration site conditions and another had COVID-19 that resulted in death. In the placebo group, 1 patient had acute pancreatitis and another had sepsis that resulted in death.

• TEAEs of special interest occurred in a similar percentage of patients across both treatment arms. In the placebo and upadacitinib groups, respectively, AEs of special interest occurring in 5% of patients or more in either group included serious infections (10.7% and 5.7%), herpes zoster (2.7% and 5.3%), anemia (2.7% and 6.7%), and hepatic disorder (4.5% and 5.3%).

Summary of Findings and Certainty of the Evidence

In the absence of literature-based minimal important difference estimates, thresholds suggested by the clinical experts were used to inform the clinical meaningfulness of the between-group differences for the following outcomes: sustained remission to week 52 (threshold = 10), cumulative CS exposure through week 52 (threshold = 1,000 mg), time to first disease flare (threshold at 6 months and at 1 year = 10%), and serious TEAEs and TEAEs leading to treatment withdrawal (threshold = 10%). Because the clinical experts could not inform on a threshold for a clinically meaningful between-group difference in SF-36 PCS and FACIT-F scores, the null was used as the threshold.

Table 4: Summary of Findings for Upadacitinib vs. Placebo for Patients With GCA

CDA-AMC = Canada’s Drug Agency; CI = confidence interval; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; GCA = giant cell arteritis; GRADE = Grading of Recommendations Assessment, Development and Evaluation; LSM = least squares mean; MID = minimal important difference; NA = not applicable; NR = not reported; PCS = physical component score; RCT = randomized controlled trial; SF-36 = Short Form (36) Health Survey; TEAE = treatment-emergent adverse event; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aNo empirically derived and validated MID was identified. The clinical experts consulted for this review suggested that a 10% between-group difference would be clinically meaningful. Certainty was rated down 1 level for imprecision. The point estimate suggests a clinically meaningful effect, while the lower bound of the 95% CI includes the potential for little to no difference.

^bThis analysis was not part of the statistical analysis plan; CDA-AMC requested it from the sponsor to facilitate the GRADE assessment.

^cCertainty was rated down 1 level for risk of bias. Approximately 14% of patients in the upadacitinib arm and 20% in the placebo arm were excluded from this analysis due to premature study discontinuation and the use of as-observed analyses, which excluded patients with missing assessments. No empirically derived and validated MID was identified. The clinical experts consulted for this review suggested that a 1,000 mg between-group difference would be clinically meaningful.

^dCertainty was rated down 2 levels for risk of bias. Only about 40% of patients in the placebo group and 59% in the upadacitinib group had evaluable assessments and were included in the analyses. No empirically derived and validated MID was identified among patients with GCA. The clinical experts could not inform on a clinically important between-group difference, so the null was used as the threshold.

^eNo empirically derived MID was identified. The clinical experts consulted for this review suggested that a 10% between-group difference would be clinically meaningful. Certainty was rated down 1 level for imprecision. The point estimate suggested little to no difference; however, the upper and lower bounds of the 95% CIs suggested the potential for increased or decreased harm, respectively, for serious TEAEs and TEAEs leading to treatment withdrawal.

Source: The SELECT-GCA trial Clinical Study Report.²⁶ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

LTE Studies

Description of Studies

One LTE study — the SELECT-GCA trial, period 2 — has been summarized in this section. Period 2 of the SELECT-GCA trial was a double-blind extension study including patients in clinical remission (defined by the absence of GCA signs and symptoms and being CS-free) at the end of period 1 of the SELECT-GCA trial. The objective of period 2 was to evaluate the safety and efficacy of continuing versus withdrawing upadacitinib in patients who achieved remission in period 1 of the SELECT-GCA trial.²⁸

Populations

Patients assigned to upadacitinib who achieved sustained remission for at least 24 consecutive weeks before the week 52 visit (at the end of period 1) were rerandomized in a 2:1 ratio to either continue upadacitinib (the upadacitinib to upadacitinib group) or to switch to placebo (the upadacitinib to placebo group) in period 2. Rerandomization was stratified by baseline disease status (new-onset disease or relapsing disease). Only outcomes for patients who were rerandomized in period 2 are summarized in this section. Patients who were assigned to the placebo group in period 1 and achieved sustained remission for at least 24 consecutive weeks before week 52 continued to receive placebo in period 2 while patients whose disease was in remission for less than 24 weeks continued to receive their original treatment; all other patients were discontinued from the study drug.

Interventions

Interventions in period 2 included upadacitinib 15 mg once daily, upadacitinib 7.5 mg once daily, or placebo. In line with the proposed Health Canada product monograph and reimbursement request under review, this section focuses on the continuing upadacitinib 15 mg group (i.e., upadacitinib to upadacitinib) and the discontinuing upadacitinib 15 mg group (i.e., upadacitinib to placebo).

In period 2, patients who experienced a flare were to start open-label CS escape therapy with prednisone or prednisolone at the investigator's discretion. Patients with a flare returned within approximately 4 weeks after the visit in which the flare was determined for reassessment (either at a regularly scheduled or unscheduled visit). Patients were discontinued from the study drug if they were not flare-free (i.e., an absence of GCA signs and symptoms) within approximately 4 weeks. Patients who discontinued the study drug were to receive treatment at the investigator’s judgment in accordance with the local standard of care (which could include tocilizumab) and continue to follow the regular visit schedule for period 2 and adhere to the study procedures.

All sponsor-provided personnel with direct oversight of the conduct and management of the trial (with the exception of the Drug Supply Management Team), the investigator, study site personnel, and the patient remained blinded to each patient’s treatment throughout the study. The interactive response technology provided access to unblinded patient treatment information in the case of a medical emergency.²⁸

Outcomes

Efficacy end points for period 2 that are summarized in this section are as follows:

• time to first disease flare (defined as per period 1) from the onset of period 2 through week 104

• the percentage of patients maintaining remission from the onset of period 2 through week 104 (remission is defined as the absence of GCA signs and symptoms and being CS-free)

• the percentage of patients maintaining complete remission (defined as per period 1) from the onset of period 2 through week 104

• cumulative CS exposure (from baseline and from the onset of period 2) through week 104

• change from the onset of period 2 through week 104 in the SF-36 PCS

• change from the onset of period 2 through week 104 in the FACIT-F score.

For the end points in period 2, comparisons were performed to assess the effects of continuing upadacitinib treatment (i.e., upadacitinib to upadacitinib) versus discontinuing upadacitinib treatment (i.e., upadacitinib to placebo) using similar analysis methods and intercurrent events handling approaches as were used for the primary and secondary end points in period 1.

All efficacy analyses in period 2 were conducted using the full analysis set in period 2 (FAS2), which included all patients who received at least 1 dose of the study drug in period 2. Efficacy results summarized in this report are limited to the subset of patients in the FAS2 who were rerandomized (called the rerandomized FAS2 subset). For all safety analyses, patients are assigned to a treatment group based on the treatment received, regardless of the randomized treatment. All period 2 safety analyses were conducted using:

• the safety analysis set in period 2, which consisted of all patients who received at least 1 dose of the study drug in period 2, regardless of whether they were randomized or assigned

• the long-term safety analysis set, which consisted of all patients who had received at least 1 dose of study drug in period 1 and received the same study drug in period 2, regardless of whether they were randomized or assigned.²⁸

Patient Disposition

Patient disposition for the included study is summarized in the Supplemental Material document, Appendix 5.

A total of 223 patients who had received the randomized study drug in period 1 entered period 2. Of those, 181 patients had achieved sustained remission for 24 consecutive weeks before week 52 (at the end of period 1). This included 44 patients from the upadacitinib 7.5 mg group (not included in this section) and 103 patients from the upadacitinib 15 mg group who were rerandomized in a 2:1 ratio to either continue on upadacitinib or switch to placebo in period 2. Of those, 68 patients were included in the upadacitinib to upadacitinib group and 35 patients were included in the upadacitinib to placebo group. There were also 34 patients who achieved sustained remission for at least 24 consecutive weeks before the week 52 visit (at the end of period 1) who were assigned to placebo in period 1 and continued to receive placebo in period 2. The sponsor has not provided full patient disposition data for the patients who achieved sustained remission for 24 consecutive weeks before week 52, so the results included in this section are based on all patients (with and without sustained remission) who entered period 2.

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Baseline and Disease Characteristics

The baseline and disease characteristics in period 2 are presented in Table 5. There were some imbalances at baseline in the percentages of patients who were Asian or white, ESR, prior IL-6 use, ischemia-related vision loss, and baseline CS dose.

Table 5: Summary of Baseline Characteristics From SELECT-GCA Study, Period 2 — Rerandomized FAS2 Subset [Redacted]

CRP = C-reactive protein; CS = corticosteroid; ESR = erythrocyte sedimentation rate; FAS2 = full analysis set in period 2; PMR = polymyalgia rheumatica; SD = standard deviation.

Source: Sponsor data on file, 2025.²⁹

Exposure to Study Treatments

Study treatments: Data were not available.

Concomitant medications and cointerventions: Data were not available.

Subsequent treatment: This is not applicable.

Critical Appraisal

Internal Validity

Rerandomization and allocation concealment methods used in the SELECT-GCA study, period 2, were deemed adequate by the CDA-AMC review team to limit the risk of bias arising from the randomization process. Rerandomization was stratified by baseline disease status, which was considered appropriate by the clinical experts consulted for this review and intended to balance known prognostic variables between treatment groups. Efficacy results for the placebo to placebo group, who were not randomized in period 2, were not presented in this report because CDA-AMC cannot draw direct comparisons to the groups who were randomized. Harms results for the placebo to placebo group were presented in this report to inform the relative long-term safety of upadacitinib. As per the efficacy results, direct comparisons of harms results in the placebo to placebo group and the randomized groups cannot be drawn.

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Similar to period 1 of the SELECT-GCA trial, period 2 was a double-blinded trial, though treatment unblinding was permitted in the event of a medical situation requiring knowledge of the treatment received for appropriate management. The number of patients and investigators who were unblinded due to AEs was not reported and therefore the magnitude of the resulting bias could not be assessed. There is the possibility that patients assigned to the treatment groups could infer their treatment assignment owing to losses of the treatment effect (among patients assigned to placebo), biasing the measurement of subjective outcomes such as HRQoL, fatigue, and subjective harms. However, the presence of such bias cannot be confirmed.

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Among patients who were rerandomized in period 2, ████ ████████ ██ ███ ████████████████████ █████ ████████████ ███ █████ ████ ██████ ████████ ██ ██████ █ ██████ ████████ ████████ ██ █████ ██ ███ █████████████████████████ █████ ██████ ████████ █████ ███ ███████ ██████ ███ ███████████████ ███ ███ ██ ███ ██ ████ ███████ ███ ██████████ ███ ██████ ███ █████ ██ ███ ████████████████████ █████ ███████ ████ ███ █████ ██ ███ █████████████████████████ █████ ███████ ███████ ██████ ███ ███████████████ ███ ████ ██ █████████ █████ ███ ██████ ███ █████ ██ ███ ████████████████████ █████ ██████ ████ ███ █████ ██ ███ █████████████████████████ █████ ███████

Data on exposure to study treatments and concomitant medications and cointerventions were not available in period 2. As such, it is uncertain whether these were likely to affect the outcomes or be reflective of clinical practice. There might be potential biases related to withdrawals with true missing data and discontinuations from the study drug that were handled as intercurrent events. However, due to the lack of missing data, it was not possible to differentiate which data pertained to deviations from the intended interventions. Moreover, no data were provided for any important protocol deviations in the sponsor-provided report.

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External Validity

Given that the patients who took part in period 2 of the SELECT-GCA trial were originally from period 1 and the eligibility criteria remained the same, it is reasonable to expect that the same limitations to generalizability are relevant to period 2. Further, the results of period 2 apply only to patients in remission after period 1 — meaning those who tolerated the drug and initially experienced a positive outcome. This might have affected the overall generalizability of the study.

Results

As the complete Clinical Study Report for period 2 was not yet available, preliminary results have been provided by the sponsor and are summarized as follows.²⁸

Efficacy

Detailed results for outcomes relevant to this review are in Appendix 5 in the Supplemental Material document.

Key results include the following:

• The between-group difference in the percentage of patients maintaining remission from the onset of period 2 to week 104 was 38.9% (95% CI, 20.5% to 57.4%; P < 0.0001), favouring the upadacitinib to upadacitinib group.

• During period 2, the median cumulative CS exposure from week 52 to week 104 was 0 mg (95% CI, 0.0 mg to 0.0 mg) for the upadacitinib to upadacitinib group compared to 1,048 mg (95% CI, 50.0 mg to 2,716.0 mg) for the upadacitinib to placebo group (P < 0.0001).

• From baseline (onset of period 1) through week 104, the median cumulative CS exposure was 1,528.0 mg (95% CI, 1,150.0 mg to 1,615.0 mg) for the upadacitinib to upadacitinib group compared to 2,204.2 mg (95% CI, 1,230.0 mg to 3,896.25 mg) for the upadacitinib to placebo group (P = 0.0012).

• The median time to first disease flare (defined as the recurrence of GCA signs or symptoms or an ESR greater than or equal to 30 mm per hour and requiring an increase in CS dose) was NE in the upadacitinib to upadacitinib group and 129.0 days (95% CI, 57.0 days to NE) in the upadacitinib to placebo group; the hazard ratio was 0.10 (95% CI, 0.0 to 0.2; P < 0.0001), favouring the upadacitinib to upadacitinib group.

• The between-group difference in the percentage of patients in a maintained complete remission from the onset of period 2 to week 104 was 44.5% (95% CI, 28.3% to 60.7%; P < 0.0001), favouring the upadacitinib to upadacitinib group.

• The between-group difference in the SF-36 PCS least squares mean change from the onset of period 2 to week 104 was 4.2 (95% CI, 0.2 to 8.1; P = 0.0382), favouring the upadacitinib to upadacitinib group.

• From the onset of period 2 to week 104, the between-group difference in the change in the FACIT-F least squares mean score was 1.9 (95% CI, −2.1 to 6.0; P = 0.3467).²⁸

Harms

Detailed results for harms are presented in Appendix 5 in the Supplemental Material document. Key results include the following:

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Indirect Evidence

Direct comparative evidence exists between upadacitinib 15 mg and CS tapering from the SELECT-GCA trial, but there is a gap in the evidence comparing upadacitinib 15 mg with tocilizumab. Therefore, an indirect comparison was required to address this gap.

Description of Indirect Comparison

One matching-adjusted indirect comparison (MAIC) was submitted by the sponsor to determine the comparative effectiveness of upadacitinib 15 mg with tocilizumab for the treatment of GCA.

Study Selection and Review Methods

The MAIC was informed by a systematic literature review of evidence in patients with GCA. Published phase III or greater, randomized, and blinded studies comparing upadacitinib 15 mg daily (referred to as upadacitinib hereafter) or 162 mg weekly tocilizumab (referred to as tocilizumab hereafter) with placebo and/or CS tapering among adults aged 50 years and older with new-onset or relapsing GCA were eligible for inclusion. Single-arm, nonrandomized, open-label, or observational studies were excluded. Relevant outcomes assessed after 52 weeks of treatment included sustained complete remission with the normalization of CRP, sustained remission, patients experiencing disease flare, cumulative CS exposure, and time to first flare. These outcomes were evaluated across the overall population, and in populations with new onset and relapsing disease when data were available for these subpopulations.

The MAIC was informed by a sponsor-conducted systematic search executed on April 2, 2024, and updated in February 2025 to identify RCTs evaluating interventions as steroid-sparing drugs in GCA. Two independent researchers screened citations for inclusion and performed data extractions. Two RCTs, the SELECT-GCA study and the GiACTA study, were ultimately included in the MAIC. Both the SELECT-GCA and GiACTA studies are phase III, multicentre, randomized, double-blind, placebo-controlled trials. The SELECT-GCA study was aimed at evaluating the safety and efficacy of upadacitinib in patients with GCA. The GiACTA study was aimed at evaluating the safety and efficacy of tocilizumab in patients with GCA. Risk-of-bias assessment was conducted at the study level by 2 independent researchers using the revised Cochrane risk of bias tool for randomized trials (Version 2 of August 22, 2019).³⁰ In the event of any disagreement, arbitration was performed by a third researcher.

ITC Analysis Methods

The MAIC was conducted based on individual patient data from the SELECT-GCA study and aggregate data (baseline characteristics and outcomes) from the GiACTA study, obtained from publications. Both the SELECT-GCA and GiACTA trials included a placebo plus 52-week CS-tapering control arm, which was used as the comparator for the MAIC. The sponsor conducted literature reviews, evaluated the SELECT-GCA study’s clinical trial data, and consulted clinical experts to determine potential treatment-effect modifiers and confounders for the matching process of the MAIC. As a result, the following measures and baseline characteristics collected in the SELECT-GCA study and summary statistics from the GiACTA trial were considered for the matching process of the MAIC analyses: age (mean, years), sex (female or male, percentage), race (patients who are white or non-white [wording of original source],³¹ percentage), newly diagnosed versus relapsing GCA, the presence of cranial signs or symptoms, and symptoms of PMR.

Weights were obtained based on a logistic regression model for the propensity of enrolment in the SELECT-GCA study versus the GiACTA study, with all the matched-on baseline characteristics included as independent variables in the propensity score model.

After matching was performed, outcomes were compared in the weighted patient populations. The analyses were conducted as anchored MAICs (this included treatment-effect modifier adjustment), using placebo as the common comparator when possible. For outcomes where responses in the placebo arm did not exist or placebo response rates were quite different across studies after matching (i.e., a cumulative CS dose of 1,862 mg or greater based on the median cumulative CS dose in the tocilizumab group of the GiACTA study), an unanchored MAIC was used. Additionally, a sensitivity analysis using an unanchored MAIC for time to disease flare analysis was performed given the differences observed from preliminary analysis between the Kaplan-Meier curves in the placebo arms between the 2 trials.

For binary outcomes, missing data were handled by nonresponder imputation (wording of original source)³¹ where if there were no data at the visit or data after experiencing intercurrent events, the record was considered a treatment failure (or a lack of disease response).

Additional information on analysis methods of the sponsor’s MAIC can be found in Appendix 6 of the Supplemental Material document.

Summary of Included Studies

Study characteristics: In both the SELECT-GCA and GiACTA trials, patients were randomized to treatment for 52 weeks. In both trials, the comparator used for the MAIC was placebo plus a 52-week CS tapering and the baseline dose of CS was between 20 mg and 60 mg. Outcome definitions were generally consistent across the 2 trials, with results from a GiACTA trial sensitivity analysis used to inform the sustained complete remission end point.

Patient characteristics: Both trials enrolled patients aged 50 years or older with newly diagnosed or relapsing GCA. There were differences in inclusion criteria across the trials, including those used for GCA diagnoses (e.g., an ESR of 30 mm per hour or greater in the SELECT-GCA study versus greater than 50 mm per hour in the GiACTA study), the definition of newly diagnosed GCA (within 8 weeks of baseline in the SELECT-GCA study versus 6 weeks of baseline in the GiACTA study), and exclusion based on previous treatments (the GiACTA trial excluded patients receiving > 100 mg of daily IV methylprednisolone within 6 weeks of baseline whereas the SELECT-GCA trial did not). The SELECT-GCA trial enrolled a higher percentage of newly diagnosed patients (70.8% in the upadacitinib group and 67.9% in the placebo group compared to 47% in the tocilizumab group and 45% in the placebo group in the GiACTA study), a higher percentage of patients with cranial signs and symptoms (83.9% in the upadacitinib group and 92.8% in the placebo group compared to 78% in the tocilizumab group and 78% in the placebo group in the GiACTA study), and fewer patients with symptoms of PMR (52.2% in the upadacitinib group and 61.6% in the placebo group compared to 59% in the tocilizumab group and 69% in the placebo group in the GiACTA study; Table 6). These patient characteristics were balanced across the 2 trials after weighting.

Table 6: Summary of Baseline Characteristics Before and After Weighting

CS = corticosteroid; ESS = effective sample size; GCA = giant cell arteritis; PMR = polymyalgia rheumatica.

Source: Rinvoq GCA matching-adjusted indirect comparison technical report.³¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Both studies were deemed by the sponsor to have a low risk of bias.

Critical Appraisal of ITC

The methods for searching, study selection, and data extraction were deemed adequate by the CDA-AMC review team. However, given that it appears the systematic review and analyses were not preplanned (no protocol was available), there is a risk that the reported results were selected from multiple analyses of the data (i.e., based on a favourable direction and/or magnitude of effect).

Only 2 RCTs were available for inclusion, of which 1 had individual patient data from the sponsor and the other only had aggregate data available. The populations included in both RCTs align with the population of interest for this review. Heterogeneity across these 2 RCTs in patients’ baseline characteristics (e.g., the percentage of patients with newly diagnosed GCA, with cranial signs or symptoms, and with symptoms of PMR) precluded unbiased results from a Bucher ITC or network meta-analysis. Therefore, a MAIC was deemed to be a reasonable method for conducting an ITC.

The sponsor conducted risk-of-bias assessments at the study level and deemed the overall risk of bias to be low in both studies. Assessing risk of bias at the study level, rather than at the level of the reported effects, ignores that bias can vary depending on the effect estimate being evaluated, particularly for such domains as performance, detection, attrition, and reporting bias. As such, the risk of bias reported by the sponsor for each study may not universally apply to all end points reviewed.

To provide unbiased effect estimates, anchored MAICs should adjust for all treatment-effect modifiers. The sponsor conducted literature reviews, evaluated the SELECT-GCA trial data, and consulted clinical experts to identify treatment-effect modifiers and confounders. Given that no further details regarding the selection of the treatment-effect modifiers and confounders were provided, it is uncertain whether the identified variables comprised all treatment-effect modifiers (and prognostic variables, for the unanchored MAIC). As in all MAICs, the sponsor could only adjust for known and measured treatment-effect modifiers. Unknown and known but unmeasured treatment-effect modifiers could not be adjusted for, representing a source of residual confounding. The clinical experts consulted for this review considered the list of treatment-effect modifiers and confounders to be reasonable; however, no evidence was submitted to suggest that the list is comprehensive so there remains uncertainty as to whether the assumptions of the MAIC were upheld.

Patient characteristics before and after adjustment were provided only for the sponsor-identified treatment-effect modifiers. These patient characteristics were well balanced across trials after adjustment. However, after matching, the treatment groups in both trials had a lower percentage of patients with symptoms of PMR at baseline compared to the placebo groups. This might indicate the treatment groups in both trials had patients with less severe disease compared to the placebo groups, potentially biasing results. Before adjustment, patients in the SELECT-GCA trial had a shorter disease duration (a median of 41 days in the upadacitinib arm and 42 days in the placebo arm) than patients in the GiACTA trial (a mean of 307 days in the tocilizumab arm and 255 days in the placebo arm); however, the balance of these values after adjustment was not reported. Additionally, the GiACTA trial’s exclusion of patients recently treated with high-dose IV methylprednisolone may have led to the exclusion of patients with visual impairment whereas the SELECT-GCA trial included patients with ischemic vision loss; however, it remains unknown if this variable was balanced after adjustment. As such, it is uncertain if these were balanced after adjustment and they could be a source of bias if imbalanced. The balance of other baseline characteristics before and after adjustment were also not reported, which potentially represents a source of confounding if these remained imbalanced.

The effective sample size in the SELECT-GCA trial after matching was reduced by approximately ███ from the original sample size, which decreases the precision of estimates and raises concerns regarding the generalizability of results because these may be influenced by a smaller subset of patients from the index trial. The same limitation applies to subgroup analyses among patients with new-onset GCA and relapsing GCA, which had a reduction in effective sample size of about ███.

The outcomes selected for the MAIC aligned with those deemed important by patient and clinician groups. Notable outcomes deemed important that were not featured in the MAIC include measures of HRQoL and harms data.

Consistent definitions were used across both studies for all outcomes selected for inclusion in the MAIC. All outcomes included in the MAIC were assessed at 52 weeks and the comparative treatment effect beyond this time point remains unknown.

███████ ███ █████████ █████████ ██████████ █████████ ██████████ ████████ ███ ██████████ ██ █████ █ ██████ ███ ████ ██ █████ █████ ████ ██████████ ████ ███ ███ ███ ███ ████ ████ ███ ████████ ███ █████████ ████ ██████ ████████████ ██ ███████████ █████ ██ ████████ ████ ███████████ ████████ ███ ████ ████████████ ███ █████ █████████ Further, only relative effect estimates were reported, precluding a more nuanced appraisal of imprecision that would have been possible with the availability of absolute effect estimates.

Before matching, substantial differences were observed in the median cumulative CS exposure across the 2 placebo arms (3,818 mg [95% CI, 2,818 mg to 4,426 mg] in the GiACTA trial versus 2,882 mg [95% CI, 2,762 mg to 3,253 mg] in the SELECT‑GCA trial). While protocol-defined tapering regimens were similar across both trials, differences in investigator-preferred initial CS dose, the flexibility of tapering, the use of rescue CS, and the degree of investigator discretion may be driving the observed differences in CS cumulative exposure. Because large differences in cumulative CS exposure remained across the placebo arms after matching, an unanchored MAIC was conducted to determine the percentage of patients who had a cumulative CS dose of 1,862 mg or greater. The unanchored MAIC found fewer patients being given upadacitinib received 1,862 mg or more of CS compared to tocilizumab. Because no between-group effect estimates were reported, the precision of the observed effect could not be judged. Further, the randomization process cannot be preserved in an unanchored MAIC and therefore, results are at an increased risk of bias if any prognostic or treatment-effect modifying factors are not included in the matching process. Moreover, differences in CS dose across trials may influence other end points, potentially introducing bias.

Similarly, due to a substantial difference in the placebo response rate for time to first disease flare, an unanchored MAIC was conducted as a sensitivity analysis. Results from this sensitivity analysis were similar to those of the main analysis, albeit at an increased risk of bias due to the unanchored nature of the analysis. Nonetheless, the primary and sensitivity analyses are at an increased risk of bias and the certainty of results is low.

Efficacy Results of ITCs

Key results of the MAICs are in Table 7.

Anchored MAICs were run for sustained complete remission, sustained remission, patients who experienced at least 1 disease flare, and time to first disease flare. Given that the median CS dose in the GiACTA study’s placebo arm was nearly 1,000 mg higher than that of the SELECT-GCA study’s placebo group, an unanchored analysis was conducted to determine the percentage of patients who had a cumulative CS dose of 1,862 mg or greater for upadacitinib and tocilizumab.

Because time to first disease flare in the placebo arms of the GiACTA and SELECT-GCA studies remained different after matching, an unanchored time to first disease flare sensitivity analysis was run and results were similar to those of the main analysis (Appendix 6 in the Supplemental Material document).

Time to first disease flare subgroup analyses among new-onset patients and relapsing patients had results consistent with those of the main analysis (Appendix 6 in the Supplemental Material document).

Table 7: Summary of MAIC Efficacy Results for Upadacitinib vs. Tocilizumab at Week 52 [Redacted]

CRP = C-reactive protein; CS = corticosteroid; HR = hazard ratio; MAIC = matching-adjusted indirect comparison; NR = not reported; OR = odds ratio; vs. = versus.

Source: Rinvoq giant cell arteritis MAIC technical report.³¹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Studies Addressing Gaps in the Systematic Review Evidence

No additional studies to address gaps within the systematic review evidence were submitted.

Discussion

Efficacy

The patient group input collected for this review highlighted that the key treatment goals for patients with GCA are to achieve remission, reduce the reliance on CS, improve or maintain HRQoL, and reduce harms. The effect of upadacitinib compared with placebo was assessed in the SELECT-GCA trial through the assessment of sustained remission and sustained complete remission at 52 weeks, cumulative CS exposure, time to first disease flare, HRQoL (via SF-36 PCS), fatigue (via FACIT-F), and harms.

The clinical experts consulted for this review considered sustained remission at 52 weeks to be the most clinically important outcome. Results showed that at 52 weeks, the between-group difference in sustained remission was 17.1% (95% CI, 6.3% to 27.8%), indicating a clinically meaningful improvement compared to placebo. While differences in baseline characteristics were observed across the treatment groups, including sex, unequivocal symptoms of PMR, and ischemia-related vision loss, the clinical experts did not anticipate these imbalances to impact the observed results. The results of further prespecified sustained remission subgroup analyses were generally consistent with the primary results, albeit with small sample sizes, wide CIs, and a lack of testing for subgroup by treatment interactions. Results for sustained complete remission, which used a definition similar to that of sustained remission with the additional requirement for ESR and CRP normalization, also suggested a likely benefit with upadacitinib.

Reducing cumulative CS exposure was identified as an important outcome by both the patient group input and clinicians. At 52 weeks, patients in the upadacitinib group had 1,267.0 fewer mg (95% CI, −1,587.0 fewer mg to −1,133.0 fewer mg) than patients in the placebo group. The certainty of evidence was downgraded by 1 level (a moderate certainty of evidence per the GRADE assessment in Table 4) due to approximately 14% of patients in the upadacitinib arm and 20% of patients in the placebo arm being excluded from the analysis because of premature study discontinuation and the use of as-observed analyses, which excluded patients with missing assessments. The difference in CS exposure between groups was expected based on the different CS-tapering protocols across the treatment groups and may not reflect the real-world CS sparing effect of upadacitinib. Additionally, both treatment groups had high treatment adherence, which might not be replicated in routine clinical practice and could influence the real-world CS sparing effect. Nonetheless, the clinical experts consulted for this review felt the high treatment adherence rates and the observed CS dose differences in the SELECT-GCA trial support the steroid-tapering effect of upadacitinib.

The point estimate of the between-group difference for the duration of flare-free days was clinically meaningful at 6 months and 12 months; however, the certainty of evidence was rated as moderate at both time points due to wide CIs that include the potential for little to no difference.

Patient and clinician input highlighted that maintaining or improving HRQoL is an important treatment goal. HRQoL was measured in the SELECT-GCA trial using the SF-36 score and the impact of fatigue on daily activities was measured using the FACIT-F score. The clinical experts consulted for this review felt there lacked clarity on the construct and applicability of the mental component of the SF-36 and therefore believed the PCS was more clinically relevant for this setting. Results indicated that upadacitinib may lead to an increase in physical HRQoL and a reduction in fatigue compared to placebo (there was low certainty of evidence per the GRADE assessment); however, the clinical relevance of the differences is uncertain.

While data from period 1 of the SELECT-GCA trial were limited to a 52-week follow-up, the clinical experts consulted for this review felt this was sufficiently long to observe meaningful results in the identified outcomes. Due to the high risk of relapse in patients with GCA and the risk of CS-related toxicities, the experts supported the sponsor’s proposal of not imposing a time limit for reimbursement. The effect of continuing upadacitinib for 104 weeks versus discontinuing upadacitinib at 52 weeks was informed by measuring sustained remission, sustained complete remission, cumulative CS exposure, time to first disease flare, HRQoL outcomes, and harms from period 2 of the SELECT-GCA trial. The generalizability of results in period 2 is limited by the requirement for patients in the upadacitinib arm to have been in remission for 24 consecutive weeks before rerandomization. The clinical experts consulted for this review indicated that these patients likely have GCA that is more amenable to treatment and may systematically differ from those who do not achieve remission for 24 consecutive weeks. Due to the small sample sizes, and as evidenced by imbalances in baseline characteristics (e.g., baseline ESR, prior IL-6 use, baseline CS dose), it is possible that the treatment effects were influenced by prognostic imbalances between the 2 treatment groups. Nonetheless, results indicated that a higher percentage of patients who continued upadacitinib treatment maintained disease remission and complete remission. On average, patients who continued upadacitinib received less CS, had a longer period of flare-free days, and had improved physical HRQoL and reduced fatigue compared to patients who discontinued upadacitinib at week 52.

While the SELECT-GCA trial informed the comparison of upadacitinib to placebo, tocilizumab is now used in standard Canadian clinical practice and it is of interest to understand how tocilizumab compares to upadacitinib. The sponsor identified 1 trial of tocilizumab among patients with GCA (the GiACTA study). Given heterogeneity in patient characteristics between the GiACTA and SELECT-GCA trials, an MAIC was deemed to be a reasonable method for conducting an ITC. It remained uncertain whether the identified variables used for matching comprised all treatment-effect modifiers and, as in all MAICs, unknown and known but unmeasured treatment-effect modifiers could not be adjusted for, representing a source of residual confounding. Effect estimates from the sponsor-submitted MAIC comparing upadacitinib to tocilizumab were imprecise, with 95% CIs that included the potential that either treatment could be favoured for sustained complete remission, sustained remission, patients who experienced at least 1 flare, and time to first disease flare. This imprecision rendered the MAIC inconclusive for the outcomes, irrespective of other limitations of the analysis. While an unanchored MAIC found a lower percentage of patients being given upadacitinib received 1,862 mg or more of CS compared to patients receiving tocilizumab, the randomization process cannot be preserved in an unanchored MAIC and therefore, there is an increased risk of bias due to potentially failing to include prognostic or effect-modifying factors in the matching process. The effects of upadacitinib compared to tocilizumab on HRQoL — an outcome deemed important to patients — was not assessed in the MAIC submitted to CDA-AMC and therefore, no conclusions can be drawn for this outcome. In light of the inconclusive results from the MAIC and in the absence of a head-to-head trial comparing these 2 treatments, the clinical experts consulted for this review indicated that treating physicians would likely initiate GCA treatment with the more familiar option (i.e., tocilizumab). Upadacitinib may be used among patients for whom tocilizumab treatment is unsuitable (i.e., patients who have contraindications, those with a needle phobia, or those who express a preference for the oral route) or as a second-line treatment in those who have not experienced improvement with tocilizumab. Nonetheless, the clinical experts felt the order in which treatments are selected should be left up to the treating physician and patient.

Harms

Across the 2 treatment groups of the SELECT-GCA trial, period 1, there were generally similar percentages of patients experiencing harms outcomes. The 1 notable difference was a higher percentage of patients in the placebo group who experienced a TEAE leading to withdrawal compared to patients in the upadacitinib group (a between-group difference of 8.7%), although this difference was not clinically meaningful according to the clinical experts consulted for this review. No new safety signals were identified from the LTE phase (period 2) of the SELECT-GCA trial; however, long-term comparative data were not available. For the SELECT-GCA trial, the clinical experts consulted for this review felt the data presented did not raise any new concerns about the safety profile of upadacitinib and the observed events were consistent with what is expected with the drug.

In the MAIC comparing upadacitinib to tocilizumab, there were no comparisons of harms. Therefore, no conclusions can be drawn regarding the comparative harms of upadacitinib versus tocilizumab.

The product monograph indicates patients treated with upadacitinib should be monitored for serious infections, malignancies, thrombosis, and major adverse cardiovascular events.

Ethics and Equity Considerations

Previous studies have noted that GCA is more common in female patients than in male patients.^16,17 The SELECT-GCA trial, period 1, population was reflective of the distribution seen in clinical practice (in the upadacitinib group, 68.8% of patients [156 of 209] were female and 31.3% were male; in the placebo group, 74.6% of patients [77 of 112] were female and 25.4% were male). The SELECT-GCA trial enrolled a relatively high percentage of patients who are white (92.0% of patients in the upadacitinib group and 95.2% of patients in the placebo group). While previously published studies have reported a lower incidence of patients with GCA identifying as Asian or Black,³ these studies were not conducted in Canada and it remains unlikely that the high percentage of patients who are white enrolled in the SELECT-GCA trial is representative of the GCA population in Canada. Nonetheless, subgroup analyses stratified by sex and race showed similar results among female patients and male patients and among patients who are white and non-white patients (wording of original source);²⁶ however, these analyses were unlikely powered to detect subgroup differences.

One of the critical unmet needs highlighted by patient and clinician groups was the requirement for an alternative treatment option for patients who are refractory to tocilizumab, have contraindications to tocilizumab, or have prohibitive adverse effects that preclude the use of tocilizumab. It was noted that the availability of an additional steroid-sparing drug, such as upadacitinib, would offer these patients an alternative treatment option to CS alone, which is associated with substantial toxicity and impacts on patients’ quality of life. The patient group input highlighted that improved outcomes for people living with GCA mean fewer relapses, a better quality of life, reduced treatment-related harm, and more equitable access to comprehensive patient-centred care.

Patient groups noted the effects of GCA extend beyond the patients diagnosed with the condition. Caregivers play a vital role in supporting those living with GCA and face distinct challenges that can affect their physical, emotional, and financial well-being. These include feelings of chronic anxiety and emotional fatigue due to the need for monitoring for unpredictable flare-ups, feeling isolated due to the relative rarity of GCA, and requiring time off work to provide care. Improved outcomes for people living with GCA could also reduce the physical, emotional, and financial burden to caregivers.

The patient group noted that health equity is essential, particularly for patients in rural or underserved communities and for those from ethnically diverse backgrounds who may face barriers to recognition, referral, or culturally appropriate support. Clinician groups also felt the current standard of care, tocilizumab, poses transportation challenges for patients in rural or remote areas due to its storage requirements. As tocilizumab is administered via subcutaneous injection, clinician groups observed that some patients experience difficulties with administration. These experts believed an oral therapy would be preferred for patients with needle phobia or with difficulties self-administering subcutaneous injections, thereby addressing some of the access limitations.

Conclusion

Evidence from 1 double-blind, phase III RCT comparing the efficacy and safety of upadacitinib to placebo in adult patients with GCA — the SELECT-GCA study — showed a clinically meaningful benefit of upadacitinib in the percentage of patients achieving sustained remission and the probability of being flare-free at both 6 months and 12 months compared to placebo. The LTE phase of the same study also showed that a higher percentage of patients who continued upadacitinib treatment for 104 weeks maintained remission and experienced a longer period of flare-free days compared to those who discontinued upadacitinib at 52 weeks. While differences in CS exposure are reflective of differences in protocol-defined CS-tapering regimens — which might not reflect real-world practices — results showed that upadacitinib likely results in a clinically important reduction in cumulative CS exposure through 52 weeks compared to placebo. The observed benefit in reduced CS exposure was sustained in those who continued upadacitinib treatment for 104 weeks compared to those who discontinued upadacitinib treatment. Results showed that upadacitinib may increase physical HRQoL and reduce fatigue at 52 weeks; however, these results had a high degree of missing data and the clinical relevance of these effects is uncertain (there was low certainty of evidence). Patients continuing upadacitinib for 104 weeks had improved physical HRQoL and reduced fatigue compared to those who discontinued upadacitinib at 52 weeks. Compared to placebo, treatment with upadacitinib likely results in little to no difference in serious TEAEs and TEAEs leading to treatment withdrawal. Clinical experts consulted for this review deemed the overall harms profile of upadacitinib to be consistent with their expectations, based on upadacitinib’s known safety profile.

Due to methodological limitations and imprecision, ███ █████████████████ ████ █████████ ████████████ ██ ███████████ █████ ████████████ ███████ ███ █████████ ████████ ██████████ █████████ ██████████ ███ ████ ██ █████ ██████ █████ ██ ██████████ ████ █████ █ █████ ██████████ ██ ████████ █████████ ████████████ ████████ █████ ██ ██ ████ ██ ██ ████████ ██ ████████ █████████ ████████████ █████ ██ ██ █████████ ████ ██ ████ ███ ██ ███████████ ███████ ██ ███████ ██████████ █████████ ███ █████████ ██████ █████████ ███████ ██ ███ ████████ ████████ Harms and HRQoL outcomes were not investigated in the MAICs, so whether upadacitinib results in an increase or a decrease in HRQoL and harms compared to tocilizumab is unknown.

Economic Review

Methods

The review team appraised the pharmacoeconomic evidence submitted by the sponsor on the cost-effectiveness and budget impact of upadacitinib 15 mg with 26-week CS tapering compared to other relevant treatments for the treatment of adult patients with GCA.

Summary of the Submitted Economic Evaluation

The sponsor submitted a cost-utility analysis to estimate the cost-effectiveness of upadacitinib with 26-week CS tapering from the perspective of a public health care payer in Canada over a lifetime horizon (28.9 years). The modelled population comprised adult patients with GCA, which is aligned with the Health Canada indication and was based on the participants in the SELECT-GCA trial. The sponsor’s base-case analysis included costs related to drug acquisition, administration, monitoring, disease management, GCA-related complications, CS-related AEs, and AEs related to the use of upadacitinib.

In the sponsor’s base case, upadacitinib with 26-week CS tapering was dominated (i.e., more costly and less effective) by tocilizumab with 26-week CS tapering. Compared to 52-week CS tapering alone, upadacitinib was dominant (i.e., less costly and more effective). Additional information about the sponsor’s submission is summarized in the Supplemental Material document, Appendix 10.

CDA-AMC identified several key issues with the sponsor’s analysis (refer to Table 8; full details are provided in the Supplemental Material document, Appendix 11).

Table 8: Key Issues With the Sponsor’s Economic Submission

AE = adverse event; CDA-AMC = Canada’s Drug Agency; CS = corticosteroid; GCA = giant cell arteritis; MAIC = matching-adjusted indirect comparison; QALY = quality-adjusted life-year; vs. = versus.

Note: Full details of the issues that CDA-AMC identified are provided in the Supplemental Material document, Appendix 11.

CDA-AMC Assessment of Cost-Effectiveness

Based on the CDA-AMC clinical review of the sponsor-submitted MAIC comparing upadacitinib with 26-week CS tapering and tocilizumab with 26-week CS tapering, results for sustained complete remission, sustained remission, patients who experienced at least 1 flare, and time to first disease flare from the MAIC comparing upadacitinib with tocilizumab were inconclusive, owing to methodological limitations and imprecision. While the results of the unanchored MAIC suggested that patients receiving upadacitinib had a lower cumulative CS exposure than those receiving tocilizumab, the results were uncertain due to differences in study design. The precision of the effect cannot be judged due to the lack of a between-group effect estimate. Harms and HRQoL were not investigated in the sponsor-conducted MAIC, so whether upadacitinib results in an increase or decrease in HRQoL and harms compared to tocilizumab is unknown. Due to these limitations, no definitive conclusions could be drawn on the comparative efficacy and safety when comparing upadacitinib with 26-week CS tapering to tocilizumab with 26‑week tapering for the treatment of adult patients with GCA. As such, no reanalyses were performed. However, CDA-AMC notes that the sponsor’s assumptions on the treatment duration for upadacitinib (limited to 52 weeks) and using the branded price of tocilizumab in its model when a less costly biosimilar is available both impact the incremental treatment costs of upadacitinib compared to tocilizumab.

The results of the economic evaluation for the comparison of upadacitinib with 26-week CS tapering versus 52-week CS tapering alone are highly uncertain. Based on the CDA-AMC clinical review of the SELECT‑GCA trial, after 52 weeks of treatment, upadacitinib with 26-week CS tapering likely results in a clinically important increase in the percentage of patients achieving sustained remission at 52 weeks and likely results in a clinically important decrease in cumulative CS exposure compared to placebo with 52-week CS tapering. However, due to the lack of long-term comparative clinical evidence to support the treatment-effect duration assumptions made by the sponsor, as well as modelling issues with regard to the impact of CS-related AEs and GCA complications, the incremental costs and quality-adjusted life-years gained predicted by the submitted model are highly uncertain. Based on feedback from clinical experts and data presented by the sponsor, the use of 52-week CS tapering alone for this indication is anticipated to be small (approximately 10%) and CS tapering would only be slightly affected should upadacitinib become available.

Summary of the Budget Impact

The sponsor submitted a budget impact analysis to estimate the 3-year (2026 to 2028) budget impact of reimbursing upadacitinib with 26-week CS tapering for use in the treatment of adult patients with GCA. The sponsor assumed that the payer would be public drug plans participating in the CDA-AMC reimbursement review process and derived the size of the eligible population using an epidemiologic approach. The price of upadacitinib was aligned with the price included in the sponsor’s economic evaluation, while the prices of comparators were based on the publicly available list prices. Additional information pertaining to the sponsor’s submission is provided in Appendix 12 of the Supplemental Material document.

CDA-AMC was unable to generate budget impact estimates directly using the provided model due to conceptual and structural limitations. Instead, CDA-AMC conducted a reanalysis based closely on the sponsor’s assumptions, and by making changes in model parameter values and assumptions, in consultation with clinical experts (the Supplemental Material document, Appendix 12). CDA-AMC estimated that 6,371 newly diagnosed patients would be eligible for treatment with upadacitinib with 26-week CS tapering over a 3-year period (year 1 = 2,089 patients; year 2 = 2,123 patients; year 3 = 2,158 patients); of these, 1,281 patients are expected to receive upadacitinib with 26-week CS tapering (year 1 = 209 patients; year 2 = 425 patients; year 3 = 648 patients). CDA-AMC additionally estimated that from 9,589 to 15,856 prevalent patients would be eligible for treatment over a 3-year period, of whom 1,928 to 3,189 are expected to receive upadacitinib with 26-week CS tapering (year 1 = 314 patients to 520 patients; year 2 = 639 patients to 1,057 patients; year 3 = 975 patients to 1,612 patients). The estimated budget impact of reimbursing upadacitinib with 26-week CS tapering is predicted to be approximately $36.2 million to $50.4 million for the combined incident and prevalent populations over the first 3 years, with an expected expenditure of $78.0 million to $108.7 million on upadacitinib. The magnitude of uncertainty in the budget impact must be addressed to ensure the feasibility of adoption, given the difference between the sponsor’s estimate and the CDA-AMC estimate.

Conclusion

Based on the CDA-AMC clinical review of the SELECT-GCA trial, compared to placebo with 52-week CS tapering, upadacitinib with 26-week CS tapering likely results in a clinically important increase in the percentage of patients achieving sustained remission at 52 weeks and the probability of being flare-free at both 6 months and 12 months (with moderate certainty evidence), as well as a clinically important decrease in the cumulative CS exposure through 52 weeks of treatment. Evidence from the sponsor-submitted MAIC was insufficient to show a difference in efficacy of upadacitinib with 26-week CS tapering compared with tocilizumab with 26-week CS tapering. Conclusions about the comparative harms and impact on HRQoL, which were deemed important by patient and clinician groups, could not be made because these outcomes were not assessed in the sponsor-conducted MAIC. Given the uncertainty in the comparative clinical evidence, there is insufficient evidence to determine whether upadacitinib provides a greater health benefit than tocilizumab. To ensure cost-effectiveness, the costs of upadacitinib should not exceed those of tocilizumab for the treatment of adult patients with GCA.

The cost-effectiveness of upadacitinib with 26-week CS tapering versus 52-week CS tapering alone is highly uncertain due to limitations with the submitted analysis. However, based on feedback from clinical experts and data presented by the sponsor, the use of 52-week CS tapering alone for this indication is anticipated to be small (approximately 10%) and CS tapering would only be slightly affected should upadacitinib become available.

The budget impact of reimbursing upadacitinib with 26-week CS tapering to the public drug plans in the first 3 years is estimated to be approximately $36.2 million to $50.4 million. The 3-year expenditure on upadacitinib with 26-week CS tapering (i.e., not accounting for current expenditure on comparators) is estimated to be $78.0 million to $108.7 million. The estimated budget impact is uncertain due to difficulty in estimating the number of prevalent patients who would be considered eligible for treatment and uncertainty in the treatment duration of upadacitinib and tocilizumab.

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