An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Indication: For the treatment of adult patients with moderately to severely active Crohn disease who have demonstrated prior treatment failure; that is., an inadequate response to, loss of response to, or intolerance to at least one conventional and/or biologic therapy
CADTH recommends that public drug plans reimburse Rinvoq for the treatment of moderately to severely active Crohn disease (CD) if certain conditions are met.
Rinvoq should only be covered to treat adult patients with moderately to severely active CD who do not respond to, stop responding to, or who cannot tolerate conventional or biologic therapies, provided that Rinvoq is covered for a similar patient population and in a similar way to biologic therapies currently reimbursed by public drug plans for the treatment of adult patients with moderately to severely active CD.
Rinvoq should only be reimbursed if prescribed by a physician experienced in the diagnosis and management of CD, if it is not used in combination with biologics for CD, and if the cost of Rinvoq is reduced so that it does not cost the drug programs more than the least costly biologic therapy reimbursed for the treatment of moderately to severely active CD. Patients must respond to treatment in the first 12 weeks of starting Rinvoq to continue receiving the drug.
CD is an inflammatory bowel disease that causes recurrent uncontrolled inflammation in any part of the gastrointestinal tract, but commonly affects the small intestine, colon, and rectum. For many patients with CD, symptoms are chronic and sporadic, and disease severity can vary widely over time. Common CD symptoms include diarrhea, abdominal pain, fatigue, fever, rectal bleeding, loss of appetite, weight loss, and malnutrition. There is no cure for CD, and patients usually have symptoms on and off for life. It was estimated in 2018 that CD affects more than 135,000 people in Canada.
Patients with CD expressed a need for effective treatments that reduce symptoms, achieve sustained remission or response, reduce corticosteroid use, and improve HRQoL.
Treatment with Rinvoq is expected to cost between $23,074 and $30,178 per patient in the first year and $18,864 to $28,090 per patient in subsequent years.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that upadacitinib be reimbursed for the treatment of adult patients with moderately to severely active CD who have demonstrated prior treatment failure, i.e., an inadequate response to, loss of response to, or intolerance to at least 1 of conventional and/or biologic therapy, only if the conditions listed in Table 1 are met.
Evidence from 3 phase III, double-blind, randomized, placebo-controlled trials (U-EXCEED, U-EXCEL, and U-ENDURE) showed that, compared with placebo, treatment with upadacitinib resulted in clinically meaningful improvements in the coprimary outcomes of clinical remission and endoscopic response after 12-week induction (45 mg daily, oral) and 52-week maintenance (15 mg or 30 mg daily, oral) in adult patients with moderately to severely active CD who have demonstrated prior treatment failure; that is, an inadequate response to, loss of response to, or intolerance to at least 1 conventional and/or biologic therapy. In induction trials, the difference compared to placebo in patients who achieved clinical remission based on patient-reported outcomes (PROs) was 25.9% (95% CI, 18.7% to 33.1%) in the U-EXCEED trial, and 28.7% (95% CI, 20.9% to 36.4%) in the U-EXCEL trial. For clinical remission based on the Crohn Disease Activity Index (CDAI), the differences compared to placebo were 17.9% (95% CI, 10.0% to 25.8%) in the U-EXCEED trial and 20.8% (95% CI, 12.7% to 28.8%) in the U-EXCEL trial. In patients who achieved clinical response in the induction trials and continued into the U-ENDURE maintenance trial, the between-group differences compared to placebo in clinical remission based on PROs at 52 weeks were 21.9% (95% CI, 13.7% to 30.0%) and 31.8% (95% CI, 23.2% to 40.3%) in the upadacitinib 15 mg group and upadacitinib 30 mg group, respectively, while the between-group differences compared to placebo in clinical remission based on CDAI, they were 23.7% (95% CI, 15.2% to 32.1%) and 32.8% (95% CI, 23.9% to 41.6%), respectively. Induction therapy with upadacitinib also resulted in clinical benefits in endoscopic remission, improvements in HRQoL, and the proportion with CR-100. In the induction trials, the difference in endoscopic response at 12 weeks compared to placebo was 31.2% (95% CI, 25.5% to 37.0%) in the U-EXCEED trial and 33.0% (95% CI, 26.2% to 39.9%) in the U-EXCEL trial, while in the U-ENDURE maintenance trial, the difference in endoscopic response at 52 weeks was 21.0% (95% CI 13.6%, 28.4%; P < 0.0001) and 33.7% (95% CI, 26.0% to 41.3%) in the upadacitinib 15 mg group and upadacitinib 30 mg group, respectively.
Patients and clinicians indicated that there is a need for effective treatments that reduce symptoms, achieve sustained remission or response using both clinical and endoscopic metrics, reduce corticosteroid use, and improve HRQoL. CDEC concluded that upadacitinib may address these needs, as it is effective in inducing and maintaining clinical remission and endoscopic response, reducing clinical symptoms, aiding in discontinuation of corticosteroids, and may improve HRQoL in adult patients who had an inadequate response, lost response, or experienced intolerance to other treatments.
At the sponsor-submitted price for upadacitinib and publicly listed prices for all relevant comparators, upadacitinib was more costly than several relevant comparator treatments used in moderately to severely active CD. As there is insufficient evidence to suggest that upadacitinib is more effective than biologic treatments for moderately to severely active CD, the total drug cost of upadacitinib should not exceed the total drug cost of the lowest-cost biologic treatment.
Reimbursement Conditions and Reasons.
CD is a chronic progressive form of inflammatory bowel disease (IBD) that leads to significant disability and has a negative impact on a patient’s HRQoL. It is characterized by recurrent, uncontrolled inflammation that can affect any part of the gastrointestinal (GI) tract from mouth to anus and mostly affects the ileum, colon, and rectum. Common CD symptoms include diarrhea, abdominal pain, fatigue, fever, rectal bleeding, loss of appetite, weight loss, and malnutrition. Complications associated with CD can include bowel obstructions, fistulas, anal fissures, intra-abdominal and other abscesses, and ulcers. For many patients with CD, symptoms are chronic and intermittent, and disease activity and severity can vary widely over time. The incidence of CD varies across the Canadian provinces, with the highest rate reported in Nova Scotia at 22.6 per 100,000 persons. In contrast, in Alberta, British Columbia, Manitoba, Ontario, Quebec, and Saskatchewan, rates range from 8.8 to 16.6 per 100,000 persons. The predicted prevalence of CD in 2018 was 368 per 100,000 population, which translates to approximately 135,000 people in Canada living with CD.
Currently, there is no cure for CD. Therapeutic goals include inducing and maintaining clinical and endoscopic remission and reducing corticosteroid dependence. There are 2 significant categories of pharmacotherapies used for treating CD: conventional therapies and biologic therapies. The conventional therapies include corticosteroids (e.g., prednisone), 5-aminosalicylates (5-ASA), and immunomodulators (e.g., azathioprine, cyclosporine, methotrexate, and 6-mercaptopurine). Medical management is based on a stepwise approach, with treatments used sequentially and escalated to either newer therapies or higher doses as patients fail to respond to each treatment step. Not all patients respond to available treatments, and their disease may become refractory to the current treatment regimens.
Upadacitinib is a selective and reversible Janus kinase (JAK) inhibitor engineered to have greater inhibitory potency for JAK1 versus JAK2, JAK3, and TYK2 in human cellular assays. Upadacitinib preferentially inhibits signalling by JAK1 or JAK1/3 with functional selectivity over cytokine receptors that signal via pairs of JAK2. Upadacitinib is administered orally. The recommended dosing schedule is in 2 phases: a 12-week induction phase consisting of 45 mg upadacitinib once daily, followed by an ongoing maintenance phase. The recommended dose of upadacitinib for maintenance treatment for patients who are in the age group 18 to 64 years of age is 15 mg or 30 mg once daily, based on patient presentation where the dose of 30 mg once daily may be appropriate for patients with high disease burden (such as refractory or severe disease) or those who do not show adequate therapeutic benefit with 15 mg once daily, and the lowest effective dose for maintenance should be used. For patients who are at least 65 years of age, the recommended maintenance dose is 15 mg once daily. In patients who are responding to induction or maintenance treatment with upadacitinib, corticosteroids may be reduced and/or discontinued following standard of care.
Upadacitinib is indicated for the treatment of adult patients with moderately to severely active CD who have demonstrated prior treatment failure; that is, an inadequate response to, loss of response to, or intolerance to at least 1 of conventional and/or biologic therapy.
To make its recommendation, CDEC considered the following information:
The information in this section is a summary of input provided by the patient and clinician groups who responded to CADTH’s call for input and from 1 clinical expert who CADTH consulted for this review.
Two patient groups, the CCC and the GI Society, provided input for this review. The CCC gathered the information from a report published in 2018 (Impact of IBD in Canada Report), a survey, and interviews with patients who participated in upadacitinib clinical trials. The patient input provided by the GI Society was based on surveys, interviews, a patient roundtable, and media interactions.
The 2 patient groups emphasized that CD has a tremendous impact on every aspect of a person’s life. The most frequent symptoms associated with CD reported by the patients are diarrhea, rectal bleeding, abdominal pain, and weight loss. Other symptoms included inflammation of the eyes or joints, ulcers of the mouth or skin, tender and inflamed nodules on the shins, anemia, anxiety, and stress. Both the CCC and GI Society stated that being unable to predict when the next urgency of bowel movements would occur and the inability to control the flare had a significant negative impact on the personal and social lives of patients with CD.
The GI Society described the treatment of CD as multifaceted as it involves managing symptoms and consequences of the disease and reducing inflammation. Patients also rely on medications to reduce the need for surgery. First-line treatments include 5-ASA and corticosteroids to reduce inflammation in moderate to severe cases of CD. When 1 medication fails, patients must try another one. According to the patient input, these treatments are inconvenient therapies that make it difficult for patients to keep a normal routine. As described by the GI input society, JAK inhibitors (such as the drug under review) are a newer class of medication. Unlike biologics, which are delivered by infusion therapy, JAK inhibitors are more accessible and more convenient to take since they are in pill form. Patients have difficulty achieving remission or adequate symptom relief despite available treatment options. Even after surgery to repair fistulas and fissures or the removal of diseased bowel tissue, CD symptoms tend to reoccur in most patients.
Improved outcomes noted as important by the patient groups included symptom mitigation and a reduction in preventable patient suffering. CCC respondents also noted that managing unpredictable and frequent bowel movements, pain, and fatigue was important. The CCC noted that unmet patient needs varied among individuals depending on their unique symptoms and life circumstances. Both patient groups emphasized the importance of a treatment option that is easy to administer and one that can provide symptom relief, achieve remission, and improve subsequent HRQoL.
Three patients from the CCC and 2 patients from the GI Society group had experience with upadacitinib and reported near-immediate improvements in their health, alleviation of the disease symptoms, and symptoms of their CD with no side-effects or few mild side-effects such as weight gain. Patients noted the convenience of pill-based administration and no need to refrigerate the medication or visit a clinic for infusions.
The clinical expert indicated there are profound treatment gaps in the management of IBD, including CD. Transmural damage results over time, leading to complications (e.g., stenosis and penetrating complications that often require surgery). Early treatment initiation is key to limit the disease activity and stop progression. Although there are a number of effective drugs available for the treatment of moderate to severe CD, there are significant limitations in efficacy, in addition to the frequency of loss of response over time and the reduced efficacy with the introduction of each subsequent biologic after failure. This was described as the greatest treatment challenge in the management of CD.
The clinical expert described that primary nonresponse and secondary loss of response are common in treating CD with advanced therapies, and therefore, therapies that remain efficacious in biologic-experienced patients are needed.
Clinical trial design historically focused on clinical symptoms of response and remission, which may not always correlate with objective measures such as endoscopic remission and mucosal healing. The clinical expert noted that long-term longitudinal studies to evaluate the modification of bowel damage are lacking as most clinical trials are up to 2 years in duration.
The clinical expert described that some treatments are particularly inconvenient and impact a patient’s lifestyle due to the need to go to an infusion clinic for a few hours every 4 to 8 weeks. Therapies given by subcutaneous (SC) injection are more convenient, but patients may find them painful. There are currently no available orally-administered advanced therapies for CD.
The clinical expert noted that the current treatment paradigm for adults with moderately to severely active CD is complex and is dictated by disease phenotype. Conventional therapies (e.g., steroids and immune suppressants) are not typically used in isolation long-term, and most patients with moderate to severe active disease would go on to receive advanced therapy such as biologic therapy. The clinical expert noted that the first-prescribed therapy has the best chance for improvement and healing due to the aforementioned pattern of lower likelihood of robust response with subsequent advanced therapies. Selecting the most optimal therapy from the start is a challenge and is based on disease phenotype, disease severity, and the risks and expected onset of action of each available therapy; for instance, particularly severe disease would warrant the selection of a therapy with rapid onset, high efficacy, and steroid-sparing effects (e.g., antiTNFs or anti IL 23 and 12/23).
Nearly half of patients have EIMs of CD, which can be disabling, and only a select few currently available medications address them, with a preference for the antiTNF category. Approximately a quarter of CD patients have fistulizing perianal disease, which is a marker of severe disease, and again antiTNFs are the preferred therapeutic option for this subpopulation. Other options for patients with these disease phenotypes are needed.
The clinical expert indicated that upadacitinib would be used as a first drug for patients receiving advanced therapies for CD, and that there is no mechanistic, efficacy, or sequencing-based argument to require the failure of other advanced drugs before initiating upadacitinib.
The clinical expert also noted that there is increasing off-label use of combination therapies with complementary mechanisms of effect in particularly severe, high-risk patients with prior drug failures, surgeries, or other markers of disabilities. The expert described that combinations would typically include a low-risk, safe drug such as an anti-integrin with other more systemically active drugs. This may become relevant in the case of upadacitinib. However, it was emphasized that this is limited to dire situations where there is a risk of extensive surgery or disability.
The clinical expert described that patients with confirmed pathologic or histologic diagnosis of moderate to severe CD are typically diagnosed by a gastroenterologist. Misdiagnosis is rare, but diagnosis may be delayed as previously described. Patients with EIMs (e.g., inflammatory arthropathy, peripheral or axial) are a priority for treatment. Although there are no clear stages of CD, objective measures such as endoscopic activity and the requirement or dependence on corticosteroids are important while the presence of clinical symptoms is not as critical. There are no established predictors of disease response.
The clinical expert noted that assessment of response in clinical practice differs from clinical trials due to logistics and patient preference. The most easily accessed marker of response is improvement in clinical symptoms (especially abdominal pain and frequency of soft or liquid stools), but this is poorly correlated with objective markers of disease activity and may be very heterogeneous according to disease phenotype. For instance, patients with bowel stricture may experience constipation instead of diarrhea, and patients with prior surgeries may have differing symptoms caused by anatomic alteration rather than inflammation. Objective measures of disease activity are important, especially endoscopy (i.e., ileocolonoscopy). The clinical expert described that although the clinical trials assessed endoscopic outcomes at 12 weeks, endoscopy is rarely performed at 12 weeks in clinical practice, and instead is typically performed at 6 to 9 months and can be challenging to repeat. Other objective measures may include biomarkers (c-reactive protein [CRP] and fecal calprotectin) as well as noninvasive intestinal ultrasound.
The clinical expert indicated the treatment discontinuation should be considered similarly to other advanced therapies for adults with CD, a combination of clinical symptoms and objective data to support primary nonresponse or loss of response:
Prescription of upadacitinib should not be limited to IBD specialists, as general gastroenterologists would have the expertise required to initiate therapy. General internists with a special interest in IBD/GI may have sufficient experience and training to prescribe upadacitinib, which may be important for accessibility in rural regions of Canada.
The clinical expert noted that initiation criteria should be similar to that of biologics currently reimbursed for the treatment of adult patients with moderately to severely active CD. However, the expert emphasized that the current requirements for previously failed therapies are not up-to-date with clinical practice. In particular, the current requirements for prior drug failures in prescribing advanced therapies includes 5-ASA, which is considered by the clinical expert to be out-of-date due to its known lack of efficacy in this population. The clinical expert noted that in clinical practice, this results in short prescriptions of 5-ASA to meet the requirements when it is not expected to have patient benefit, and the expert recommended that this is not included as a requirement for prior treatment failures when prescribing upadacitinib. The expert noted that if treatment is interrupted for at least 2 weeks, the patient may need to undergo induction therapy again.
One clinician group, the Canadian IBD Specialist Group, responded to CADTH’s call for input. The input was based on a discussion held by the Canadian IBD Specialist Group in March 2023.
The clinician group emphasized that CD tremendously impacts the physical, emotional and social aspects of those living with the disease, affecting the HRQoL and causing a significant economic burden. The current treatment paradigm for CD includes 5-ASA, corticosteroids, immune modifiers, and biologics that include antiTNF, anti-integrin, and anti-IL 12/23 and anti-IL 23 drugs.
The input from the clinician groups identified the same unmet medical needs for CD patients and potential place in therapy for the drug under review as the clinical experts consulted by CADTH.
The clinician group noted that there are significant unmet therapeutic needs for patients living with moderate to severe CD. There is a lack of safe and effective treatments that could rapidly improve the endoscopic appearance, maintain long-term improvement and remission, and reduce the risk of complications and the need for surgery.
In addition to relieving clinical symptoms, the clinician group emphasized that the goal of treatment should focus on changing the course of disease for CD patients, preventing further intestinal damage, avoiding disability, and reducing the overall cost of care.
The clinician groups noted that upadacitinib has a new mechanism of action, and it is the first oral therapy for CD that has ever been evaluated to meet the treatment goals. According to the clinician group, any patient with inadequate response or intolerance to corticosteroids or multiple advanced therapies and those with 1 or more extraintestinal IBD manifestations could benefit from upadacitinib.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially have an impact on the implementation of a CADTH recommendation for upadacitinib:
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
Three phase III, double-blind, placebo-controlled, multicentre, international RCTs were included in this review. Two of the RCTs were induction studies in adult patients with moderately to severely active CD and a history of biologic failure (U-EXCEED) or history of biologic and/or conventional therapy failure (U-EXCEL). Patients in both induction studies were randomized in a 2:1 ratio to receive upadacitinib 45 mg once daily or placebo. The primary results for randomized cohorts were evaluated at 12 weeks (part 1). However, patients who did not achieve an adequate response could carry on to part 2 or 3 for extended induction, where adequate response was defined as at least a 30% decrease in average daily very soft or liquid stool frequency and/or at least 30% decrease in average daily abdominal pain score (both not worse than baseline). The third RCT was a maintenance study of upadacitinib 15 mg or 30 mg once daily versus placebo in patients who had achieved adequate response in either the U-EXCEED or U-EXCEL trial, and the primary results were evaluated at 52 weeks among re-randomized patients from part 1 of the induction studies. Patients who had carried on to extended induction therapy in either of the induction study and thereafter achieved a response could also enrol into cohort 2 or 3 of the U-ENDURE trial, which were not randomized. The coprimary outcomes in all trials included clinical remission (based on patient-reported outcomes [PROs] or the Crohn Disease Activity Index [CDAI]), and endoscopic response (based on the Simple Endoscopic Score for Crohn Disease [SES-CD]). Other important outcomes included endoscopic remission, proportion of patients who discontinued corticosteroid use for CD and achieved clinical remission (among patients taking corticosteroids at induction baseline), proportion of patients who achieved both clinical remission and endoscopic remission, change in HRQoL (using the IBDQ), clinical response [CR]-100, resolution of EIMs in patients who had EIMs at induction baseline, the proportion who experienced CD-related hospitalizations or surgeries, and the proportion who experienced harms including serious adverse events (SAEs) or adverse events of special interest (AESIs).
U-EXCEED enrolled 624 patients across 229 sites in 39 countries; U-EXCEL enrolled 526 patients across 209 sites in 42 countries; and U-ENDURE enrolled 901 patients across 277 sites in 43 countries. In the double-blind cohorts of U-EXCEED, U-EXCEL, and U-ENDURE, there were slightly more male than female patients (53.5%, 53.8%, and 55.4%), and the mean ages were 38.1, 39.6, and 37.0 years, respectively. Most enrolled patients were white (approximately 70% in each trial, followed by Asian, Black, multiple races (unspecified in the study), and American Indian or Alaska Native). The mean duration of CD was 9.4 years in U-EXCEED, 6.1 years in U-EXCEL, and 7.2 years in U-ENDURE; the differences were expected given that U-EXCEL included patients who may not have failure with biologics, indicating an earlier point in treatment history on average. Overall, most enrolled patients in the randomized cohorts had a history of biologic failure (100% in U-EXCEED by design, 45.4% in U-EXCEL, and 75.6% in U-ENDURE).
In U-EXCEED and U-EXCEL, there was a higher percentage of patients who achieved clinical remission per PROs among those treated with upadacitinib 45 mg than placebo. In U-EXCEED, the response rate difference compared to placebo was 25.9% (95% CD: 18.7% to 33.1%), and in U-EXCEL it was 28.7% (95% CI, 20.9% to 36.4%).
Results were consistent across subgroups based on number of prior biologics failed and the analysis for clinical remission per PROs at 12 weeks.
In U-EXCEED and U-EXCEL, there was a higher percentage of patients who achieved clinical remission per CDAI among patients treated with upadacitinib 45 mg than placebo. In U-EXCEED, the response rate difference compared to placebo was 17.9% (95% CI, 10.0% to 25.8%) and in U-EXCEL it was 20.8% (95% CI, 12.7% to 28.8%).
Results were consistent across subgroups based on number of prior biologics failed and the analysis for clinical remission per CDAI at 12 weeks.
In U-EXCEED and U-EXCEL, there was a higher percentage of patients who achieved endoscopic response among patients treated with upadacitinib 45 mg compared to placebo. In U-EXCEED, the response rate difference compared to placebo was 31.2% (95% CI, 25.5% to 37.0%) and in U-EXCEL it was 33.0% (95% CI, 26.2% to 39.9%).
Results were consistent across subgroups based on number of prior biologics failed and the analysis for endoscopic response at 12 weeks.
In U-EXCEED and U-EXCEL, there was a higher percentage of patients who achieved endoscopic remission among patients treated with upadacitinib 45 mg than placebo. In U-EXCEED, the difference compared to placebo was 16.8% (95% CI, 12.0% to 21.6%) and in U-EXCEL it was 21.8% (95% CI, 15.8% to 27.8%).
In U-EXCEED and U-EXCEL, a higher proportion of patients treated with upadacitinib 45 mg discontinued corticosteroid use and had CDAI clinical remission at week 12 compared to the placebo group. In U-EXCEED, the difference compared to placebo was 22.5% (95% CI, 11.1% to 34.0%) and in U-EXCEL it was 27.7% (95% CI, 15.7% to 39.8%).
Results were similar for discontinuation of corticosteroid use and clinical remission per PROs at 12 weeks.
In U-EXCEED and U-EXCEL, a higher proportion of patients treated with upadacitinib 45 mg had clinical remission per CDAI and endoscopic remission at 12 weeks. The adjusted difference compared to placebo was ||||| |||| ||| |||| || |||||| and ||||| |||| ||| |||| || ||||||, in U-EXCEED and U-EXCEL, respectively.
Results were similar for clinical remission per PROs and endoscopic remission at 12 weeks.
In U-EXCEED and U-EXCEL, there was a larger within-group change from baseline in IBDQ total score in patients treated with upadacitinib 45 mg than patients treated with placebo. The between-group difference compared to placebo (least squared mean) was 24.3 (95% CI, 17.2 to 31.5) in U-EXCEED and 21.8 (95% CI, 15.6 to 28.1) in U-EXCEL.
In U-EXCEED and U-EXCEL, there was a higher percentage of patients who achieved CR-100 among patients treated with upadacitinib 45 mg than placebo. In U-EXCEED, the difference compared to placebo was 22.8% (95% CI, 14.4% to 31.2%), and in U-EXCEL it was 19.8% (95% CI, 11.3% to 28.4%).
In U-EXCEED, resolution of EIMs at week 12 in patients with any EIMs at baseline was 32.8% for upadacitinib 45 mg versus 21.7% for PBO (between-group difference 11.5%; 95% CI, −1.5% to 24.4%). In U-EXCEL, resolution of EIMs at week 12 in patients with any EIMs at baseline was 28.5% for upadacitinib 45 mg versus 20.9% for PBO (between-group difference 9.0%; 95% CI, −1.9% to 19.9%). In both cases, the 95% CI crossed the threshold between potential benefit and potential harm (i.e., null).
There were no substantial differences observed in the proportion of patients with CD-related hospitalizations between patients treated with upadacitinib 45 mg in U-EXCEED (20/324) and U-EXCEL (13/350) compared to patients treated with placebo (15/171 and 9/176), respectively. The difference compared to placebo was −2.6% (95% CI, −7.6% to 2.4%) in U-EXCEED and −1.4% (95% CI, −5.2% to 2.4%) in U-EXCEL, respectively. In both cases, the 95% CI crossed the threshold between potential benefit and potential harm (i.e., null).
|||||| ||||||||| ||||||| ||| ||||||||||| ||| ||||||||||| |||||||||| ||||||||| |||| |||||||| ||| |||||||||| || ||| |||||||||||| || || ||||| |||||||| || ||| ||||||| ||||| ||| |||| |||| ||| ||||| || ||||| || |||||||| ||| |||| |||||| || ||||| || |||||||| || |||| |||||| ||| ||| || ||||||| ||| ||||||||| ||||||| ||||||||| ||||||| ||| ||||||||| |||| |||||| ||||||
In U-ENDURE, the upadacitinib 15 mg group and 30 mg group had higher percentages of patients who achieved response rates in clinical remission per PROs compared to the placebo group. The differences between upadacitinib 15 mg group and placebo, and between upadacitinib 30 mg group and placebo were 21.9% (95% CI, 13.7% to 30.0%) and 31.8% (95% CI, 23.2% to 40.3%), respectively.
The results were similar for the subgroups of at least 1 prior biologic failed, 1 prior biologic failed, and 0 prior biologics failed in the 30 mg group. However, for the subgroup of 0 prior biologics failed in the 15 mg group, the difference (versus placebo) was smaller and the 95% CI crossed the null value (11.7% [-9.1% to 32.5%]).
The upadacitinib 15 mg group and 30 mg group had higher percentages of patients who achieved clinical remission per CDAI compared to the placebo group. The differences between upadacitinib 15 mg group and placebo, and between upadacitinib 30 mg group and placebo were 23.7% (95% CI, 15.2% to 32.1%) and 32.8% (95% CI, 23.9% to 41.6%), respectively.
Results in the subgroups based on number of prior biologics failed were consistent with the analysis for both dosage groups.
The upadacitinib 15 mg group and 30 mg group had higher percentages of patients who achieved endoscopic response compared to the placebo group. The differences between upadacitinib 15 mg group and placebo, and between upadacitinib 30 mg group and placebo were 21.0% (95% CI, 13.6% to 28.4%) and 33.7% (95% CI, 26.0% to 41.3%), respectively.
Results in the subgroups based on number of prior biologics failed were consistent with the analysis for both dosage groups.
The upadacitinib 15 mg group and 30 mg group had higher percentages of patients who achieved endoscopic remission compared to the placebo group. The differences between upadacitinib 15 mg group and placebo, and between upadacitinib 30 mg group and placebo were 14.4% (95% CI, 7.7% to 21.0%) and 23.6% (16.1% to 31.0%), respectively.
Among patients taking corticosteroids for CD at induction baseline, a higher proportion of patients in the upadacitinib 15 mg group and 30 mg group discontinued corticosteroid use and had CDAI clinical remission at week 52 compared to the placebo group. The differences between upadacitinib 15 mg group and placebo, and between upadacitinib 30 mg group and placebo were 35.4% (95% CI, 23.3% to 47.5%) and 32.3% (95% CI, 20.1% to 44.5%), respectively. Among all patients (i.e., not limited to those taking corticosteroids at induction baseline), the differences between upadacitinib 15 mg group and placebo, and between upadacitinib 30 mg group and placebo were 23.8% (95% CI, 15.5% to 32.1%) and 32.2% (95% CI, 23.4% to 40.9%), respectively.
A higher proportion of patients in the upadacitinib 15 mg group and 30 mg group had both CDAI clinical remission and endoscopic remission at week 52 compared to the placebo group. The differences between upadacitinib 15 mg group and placebo, and between upadacitinib 30 mg group and placebo were 12.2% (95% CI, 6.3% to 18.1%) and 19.8% (95% CI, 13.0% to 26.6%), respectively.
There was a larger within-group change from baseline in IBDQ total score in upadacitinib-treated patients (15 mg or 30 mg) than placebo-treated patients. The between-group difference (least squared mean) was 12.9 (95% CI, 4.3 to 21.4) when upadacitinib 15 mg group was compared to placebo and 18.1 (95% CI, 9.8, 26.4) when upadacitinib 30 mg group was compared to placebo. Only the between-group difference in the latter comparison (i.e., 30 mg upadacitinib versus placebo) was greater than the minimally important difference (MID) of 16 points in the IBDQ total score for patients with CD; the 95% CIs of both comparisons include values both greater than and less than this MID.
There was a higher percentage of patients who achieved CR-100 among patients treated with upadacitinib 30 mg or 15 mg than placebo. The differences between upadacitinib 15 mg group and placebo, and between upadacitinib 30 mg group and placebo were 27.1% (95% CI, 18.3% to 35.8%), and 36.4% (95% CI, 27.5% to 45.2%), respectively.
The proportion who achieved resolution of EIMs at week 52 in patients with any EIMs at induction baseline was 24.6% (upadacitinib 15 mg), 35.6% (upadacitinib 30 mg), and 15.2% (placebo). The difference versus placebo was 9.6% (95% CI, −3.4% to 22.6%) for upadacitinib 15 mg and 22.0% (95% CI, 9.3% to 34.8%) for upadacitinib 30 mg. For the 15 mg dose but not the 30 mg dose, the 95% CI crossed the threshold between potential benefit and potential harm (i.e., null).
There were no substantial differences observed in the percentages of patients experienced CD-related hospitalizations across the upadacitinib 30 mg group, 15 mg group, and placebo group. The differences between upadacitinib 15 mg group and placebo, and between upadacitinib 30 mg group and were −0.78% (95% CI, −10.4% to 8.8%) and −4.17 (95% CI, −13.1% to 4.7%), respectively. In both cases, the 95% CI was wide and crossed the threshold between potential benefit and potential harm (i.e., null).
|||||| ||| ||||||||| ||||||| ||||| |||||| ||||||||| |||| || |||||||||| ||||||||| ||| ||| ||||||||||||| |||| || |||||| ||| |||| |||||||||| |||||| |||||||||||||| || ||| |||||||||||| || || ||| || || |||||| |||||||| || ||| ||||||| ||||| |||| |||| |||| ||| ||||| || ||||| ||| |||| |||||| || |||||| ||||||||||||| || |||| |||||| ||| ||| || ||| |||| ||| ||||||| ||| ||||||||| ||||||| ||||||||| ||||||| ||| ||||||||| |||| |||||| ||||||
Across the trials, AEs were common and were experienced by approximately 58% to 76% of patients. In the placebo-controlled parts of the trials, the rate of AEs and withdrawal due to AEs were generally similar between treatment arms. SAEs occurred to approximately 7% to 15% of patients across the different treatment arms and cohorts of the included trials and were approximately similar between upadacitinib-treated and placebo-treated patients in the comparative cohorts. Some of the most frequently reported SAEs among all trials were GI disorders and infections and infestations.
SAEs were evaluated using GRADE, and it was determined that upadacitinib induction or maintenance may result in little to no difference in the incidence of SAEs compared to placebo in a 12-week or 52-week time period.
AESIs were selected based on safety concerns reported for other JAK inhibitors, upadacitinib data obtained from preclinical studies, the upadacitinib development program, as well as customary regulatory concerns for novel small molecule drugs. Across the trials, AESIs of serious infection, opportunistic infection, herpes zoster, adjudicated gastrointestinal perforation, anemia, neutropenia, lymphopenia, creatine phosphokinase (CPK) elevation, hepatic disorder, renal dysfunction, and adjudicated venous thromboembolic events were observed. The most commonly reported AESIs (≥ 4% in any part or cohort of any included trial) included anemia, lymphopenia, serious infections, infections and infestations, herpes zoster, hepatic disorder, and CPK elevation. One adjudicated cardiovascular event was observed in U-EXCEL in a placebo-treated patient from part 1. Malignancies (all types), malignancies (excluding non-melanoma skin cancer), and non-melanoma skin cancer occurred rarely in U-ENDURE and were not observed in the induction trials (i.e., U-EXCEED and U-EXCEL). No events of lymphoma or active tuberculosis were observed in any included trial.
All 3 trials were phase III, double-blind, placebo-controlled, multicentre studies that assessed several important clinical, endoscopic, and HRQoL-related outcomes. There were no concerns about internal validity related to study design (e.g., method of randomization, concealment of allocation, maintenance of blinding, balance of patient characteristics between treatment arms, etc.). The U-ENDURE maintenance study included an enriched population given that only patients with response and adequate tolerance of study drug during induction could enrol, but this is representative of the reality of clinical practice. The trials all included nonrandomized cohorts to accommodate for patients who needed greater than 12 weeks of induction to reach an adequate response; although not represented in the primary analysis, these patients do also reflect a minority of real-world practice. Only the randomized data are discussed in detail herein. In U-ENDURE, patients who enrolled after achieving a response at 12 weeks of induction were re-randomized, which preserved the strength of the randomized study design. Additionally, the use of separate induction and maintenance studies is consistent with European Medicines Agency guidance for developing drugs for treating CD. Discontinuation rates were potentially imbalanced with a greater number of placebo-arm withdrawals due to the lack of efficacy in U-EXCEL and were generally high during U-ENDURE (20% to 28% across cohorts and treatment arms).
The clinical expert consulted by CADTH indicated that the study populations were wholly representative of the target population of adults with moderate to severe CD and a history of treatment failure. The dose of the intervention, upadacitinib, was 45 mg once daily during the induction studies and either 15 mg or 30 mg once daily during the maintenance study. The clinical expert consulted by CADTH described that clinical practice in moderate to severe CD would lean more commonly toward a 30 mg once daily maintenance dose due to evidence of higher efficacy and reluctance to potentially under-treat, due to the irreversible nature of bowel damage that can occur. However, the clinical expert and the product monograph also note that patients should be treated with the lowest effective dose in the interest of safety, and the approach to dosing may vary by the treating physician and severity of disease. All 3 RCTs were placebo-controlled trials, and there is a lack of direct evidence comparing active therapies head-to-head. The 3 RCTs were relatively unique among CD trials in that there was a mandatory taper of corticosteroids, which was considered to be reasonably similar to clinical practice. Overall, the outcomes selected as primary and key secondary outcomes were relevant to decision-making and/or clinical practice, and adequately reflected measures of both efficacies and harms. The duration of follow-up was appropriate for the induction and maintenance phase of treatment. However, when measuring the proportion of patients who experienced events such as hospitalizations or surgeries related to CD, both a 12-week and 52-week time frame were considered to be inadequate to witness a difference between arms, which contributed to uncertainty in interpreting these outcomes. Additionally, the clinical expert noted that endoscopy is not typically conducted at 12 weeks in clinical practice, but rather after 6 to 9 months of initiating treatment due to practical limitations and the invasiveness of the procedure. This logistical limitation was also considered by the expert to be a factor in decision-making around dosing, as patients without symptoms may be experiencing endoscopic activity that would not be seen until the procedure could be completed.
For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group. Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.
The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: clinical remission per PROs, clinical remission per CDAI, endoscopic response, endoscopic remission, discontinuation of corticosteroid use for CD and CDAI clinical remission in patients taking corticosteroids at induction baseline, endoscopic remission and CDAI clinical remission, change in IBDQ, CR-100, resolution of EIMs among patients who had EIMs at induction baseline, CD-related hospitalization, CD-related surgery, and SAEs.
The induction studies (U-EXCEED and U-EXCEL) were assessed together due to their similarities in population and study design and are reported in Table 3. The maintenance study (U-ENDURE) is reported separately in Table 4 and GRADE assessment was conducted independently for the 2 doses of upadacitinib maintenance therapy (15 mg or 30 mg once daily).
Summary of Findings for Upadacitinib Induction Versus Placebo for Patients With Moderately to Severely Active CD and History of Treatment Failure.
Summary of Findings for Upadacitinib Maintenance Versus Placebo for Patients With Moderately to Severely Active CD and History of Treatment Failure.
One indirect treatment comparison (ITC) was submitted by the sponsor to estimate the relative efficacy and safety of upadacitinib versus advanced therapies for the treatment of adult patients with moderately to severely active CD.
Studies included in the ITC enrolled adult and adolescent patients with moderately to severely active CD and advanced treatments for CD, namely upadacitinib, vedolizumab (VDZ), ustekinumab (UST), risankizumab (RZB), adalimumab (ADA), and infliximab (IFX). Efficacy outcomes included clinical outcomes (remission and response), endoscopic outcomes (remission and response), and safety outcomes (any AE, SAE, serious infection, and AEs leading to discontinuation), which generally aligned with the outcomes that were important to patients and clinicians.
||| ||||||| || ||| ||| ||||||||| |||| |||||||||||| ||| ||| |||||||||||| ||||||||| |||| ||||| |||||||| ||||||||| ||| |||||||| ||||||||| ||| |||||||| |||||||||| ||| |||||||||| |||||||| |||||||| |||| |||||| |||| ||||||||||||||| |||||| || ||||||||||| || |||| |||||| ||||||||||| |||| ||| ||||| ||||||||| ||| |||| ||| |||| |||||||||| |||| ||||| |||||||||| ||||||||| ||||| |||| |||||||| ||| ||||| |||| |||||||||| |||| |||||||||| ||||||||| ||||||||| |||||| |||||||||| ||||| |||| |||||||||| ||||||||||||| |||||| |||||||||| ||| |||| |||||||||||| ||| ||| ||||||||||| |||||| |||||||||| |||||||||| ||||||||||| ||||||| |||||||||||| || |||| || |||| ||||||||||| |||| ||| ||||||||||| |||| ||||| |||||
||||||||| ||||| |||||| ||||||| ||| |||| |||| ||| ||| ||||||| ||| |||| ||| ||||||||||| || |||||||||||| |||||| ||||| |||||||| ||||||||||| ||||||||| ||||||||||||| ||| |||||||||| |||| |||| ||||||||| ||||||||||| |||||| ||||||||||| |||| ||||| |||| |||| |||||||||||
||| |||||||| ||| |||||||||| ||| |||||| ||||||||||| ||||||| |||||| |||||||||| || |||| ||||| |||||| |||||||||| |||||||||| || |||||||| ||||| || ||| |||||||| ||||||| |||||||||||||||| ||| |||||||| |||||| ||| || ||| ||||||| |||| ||| |||||||| || ||| ||||||| |||| ||||||| ||| ||||||||||||| || ||||| ||| ||||| ||||||| |||||||||||| || |||||||| |||||||| ||||||||| |||||||| ||||| ||| ||||||||||| || ||||||| ||||||||||||||| ||||| ||||||||| ||||||||| |||||| |||||||||| |||||| ||| |||||||| |||| || ||| ||||||| ||||||||| ||| ||| ||||| |||||||||||| ||||||| ||||||||||| |||||||||| |||| ||| || || |||| |||||| |||| ||||| |||| ||||||||||| || ||||||||| |||||||||| |||| |||||||| |||||||||| ||||||| ||| ||||| ||||||| ||||||||||| |||| |||| ||| ||||||||| ||||| ||| ||||||||||||| || ||| |||||||| || ||||||||| ||| ||||||||||| ||||||| || ||| |||||||||| || ||||||||| |||||||| |||||| |||||||| ||||| || ||| ||||||||||| ||||||| ||||||||||||||| |||| ||| ||||||||||| ||||| ||||||||||| ||| |||||||||| |||||||| ||||||| ||||||||||| ||| ||||||| |||| ||||||||| ||||||||||| ||| |||||| |||||||| |||||||| |||||| |||| ||||||||| ||||| |||||||| ||| ||||||||||||| ||||| ||||||||| ||||||||| ||||||||||||| |||||| |||||||| ||| |||| |||| |||| || ||||||||||| || |||| |||||||||| |||||||| ||| |||||| ||||||||||| ||||||| |||||||||||| ||| |||||| || ||||| |||| ||||| |||||||| || |||||||||| || |||| |||||||||||
Cost and Cost-Effectiveness.
CADTH identified the following key limitation with the sponsor’s analysis: market size was estimated using a claims-based approach, which was not specific to the Health Canada-indicated population (i.e., moderately to severely active CD and prior failure of at least 1 conventional or biologic treatment). Using a claims-based approach to estimate the number of eligible patients introduces uncertainty with the anticipated budget impact of upadacitinib that could not be resolved. Additional limitations include uncertainty in the proportion of patients eligible for public drug plan coverage, the omission of risankizumab as a comparator in the sponsor’s base case, uncertainty in the annual cost of UPA, uncertainty in the market uptake of upadacitinib, and the presence of confidential prices for most comparators. Without more reliable input values to estimate the eligible population size, the sponsor’s base case was maintained.
The net budget impact of reimbursing upadacitinib for the treatment of moderate to severe CD among patients with a prior treatment failure was estimated by the sponsor to be $7,325,987 in year 1, $20,226,831 in year 2, and $39,587,222 in year 3. The net budget impact over the 3-year time horizon was $67,140,041.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Edward Xie, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Peter Jamieson, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Trudy Huyghebaert, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Meeting date: October 25, 2023
Regrets: Two expert committee members did not attend.
Conflicts of interest: None
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third-party supplier of information.
This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.
This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for noncommercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
Redactions: Confidential information in this document may be redacted at the request of the sponsor in accordance with the CADTH Drug Reimbursement Review Confidentiality Guidelines.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Indication: For the treatment of adult patients with moderately to severely active Crohn disease who have demonstrated prior treatment failure; that is., an inadequate response to, loss of response to, or intolerance to at least one conventional and/or biologic therapy.
Sponsor: AbbVie Corporation
Final recommendation: Reimburse with conditions
Copyright © 2024 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
Your browsing activity is empty.
Activity recording is turned off.
See more...
