Summary of Evidence Considered by CDEC
The committee considered the following information prepared by the CADTH Common Drug Review (CDR): a systematic review that included three RCTs of CZP, one ITC, and a critique of the manufacturer’s pharmacoeconomic evaluation. The committee also considered input from a clinical expert with experience in treating patients with plaque psoriasis, and patient group–submitted information about outcomes and issues important to patients.
Summary of Patient Input
Two patient input submissions were received for this CDR review: one from the Psoriasis Society of Canada, and another submission jointly provided by the Canadian Skin Patient Alliance, the Canadian Association of Psoriasis Patients, and the Canadian Psoriasis Network. Patient perspectives were obtained through patient phone calls, online surveys, and a previous submission used for risankizumab. None of the submitting organizations declared any conflicts of interest or received any assistance in preparing their submissions. All four organizations disclosed financial support from a number of pharmaceuticals within the past two years; the Psoriasis Society of Canada and the Canadian Association of Psoriasis Patients received donations from UCB Canada Inc. The following is a summary of key input from the perspective of the patient groups:
In the Canadian Psoriasis Network, Canadian Skin Patient Alliance, and Canadian Association of Psoriasis Patients patient input survey, 74% of respondents described their condition as “uncontrolled.” The most prominent physical symptoms of psoriasis include plaques, scales, flaking, and itching of the skin and scalp. Some these symptoms represented a “nuisance” while for some they are painful and disabling. The symptoms affect patients physically (pain and discomfort) and psychologically (anxiety, depression, embarrassment, social isolation, and lack of self-confidence). Caregivers’ personal, social, and financial well-being are also negatively affected. Better symptom control (reductions in itching, scaling, pain, and flaking) and a better experience in living with the disease were the top improvements patients and caregivers would like in new treatments.
Patients receive a range of different therapies including topical treatments, phototherapy, oral systemic drugs, and biologics. Some characteristics of current treatments mentioned in both of the patient group submissions include switching therapies as one stops working or in the hope of finding something more effective, varying success from patient to patient (and a consequent desire for more and alternative treatment options), and variable experience with side effects. Patients were concerned about tiredness, dry face, dry lips, redness, soreness, thinning skin, painful burns, hair loss, and weight gain associated with long-term use of currently available treatments.
Patients expressed a desire for additional treatment options that adequately control or stop symptoms, such as itchiness, scaling, pain, bleeding, and flaking, without side effects. Treatment responses vary among patients and what works for one may not work for another, even when the symptoms are similar. Therefore, the availability of more treatment options would provide patients with choices to manage the disease. Female patients indicated a need for new treatments that are safe to use during pregnancy.
Clinical Trials
A total of three phase III, multi-centre, double-blind RCTs that evaluated the efficacy and safety of CZP were included in this systematic review: CIMPASI (N = 234), CIMPASI-2 (N = 227), and CIMPACT (N = 559). All three trials enrolled patients with moderate-to-severe plaque psoriasis, defined as body surface area involvement of 10% or more, PASI score of 12 or higher, and static PGA score of 3 or higher. The trials used both CZP 200 mg and 400 mg doses every two weeks and were separated into five similarly designed periods: screening (five weeks), initial treatment period (week zero to 16), maintenance treatment period (week 16 to 48), open-label treatment (week 48 to 144), and safety follow-up period. The CIMPASI trials differed from the CIMPACT trial in the treatment assignment and schedule during the initial and maintenance treatment period, described as follows.
CIMPASI-1 and CIMPASI-2 were two identically designed RCTs with a double-blind placebo-controlled initial treatment period, followed by a dose-blind maintenance treatment period. During the initial treatment period, patients were randomized in a 2:2:1 ratio to receive CZP 200 mg or 400 mg every two weeks, and placebo. The treatment received during the maintenance period was blinded or open-label based on the randomized treatment and the response to treatment at week 16. Patients initially randomized to CZP doses who achieved PASI 50 continued on the same dose; placebo-treated patients who achieved PASI 50 but not PASI 75 started CZP 200 mg every two weeks or continued to receive placebo if they achieved PASI 75.
CIMPACT was a double-blind, parallel-group RCT with a double-blind placebo but open-label active-controlled initial treatment period, followed by a double-blind placebo-controlled maintenance period. During the initial treatment period, patients were randomized in a 3:3:3:1 ratio to receive CZP 200 or CZP 400 mg every two weeks (through week 14), etanercept (ETN) 50 mg twice weekly (through week 11.5), and placebo (through week 14). At the subsequent maintenance treatment period, the treatment assignment was blinded or open-label based on the treatment received and response shown at week 16. Among patients who achieved PASI 75 at week 16, those initially randomized to ETN were re-randomized (2:1) to either CZP 200 mg every two weeks or placebo; those initially randomized to CZP 200 mg every two weeks were re-randomized (2:2:1) to CZP 200 mg every two weeks, CZP 400 mg every four weeks, or placebo; those initially randomized to CZP 400 mg every two weeks were re-randomized (2:2:1) to CZP 200 mg every two weeks, CZP 400 mg every two weeks, or placebo; and those in the placebo group continued to receive placebo. Patients who did not achieve PASI 75 at week 16 started escape treatment.
Following the maintenance period, patients in all three trials received an additional 96 weeks of open-label CZP treatment (currently ongoing, data not available), with dose determined and adjusted through this period depending on each patient’s PASI response. All patients started CZP 200 mg every two weeks with a CZP 400 mg loading dose (i.e., CZP 400 mg every two weeks for the first four weeks) followed by CZP 200 mg every two weeks thereafter, regardless of treatment period or week. Patients who did not achieve PASI 50 (in CIMPASI-1 and CIMPASI-2) or PASI 75 (in CIMPACT) at week 16 underwent escape treatment (i.e., open-label CZP 400 mg at the loading dose followed by CZP 200 mg every two weeks). In all trials, those who failed to achieve PASI 50 from week 32 through week 48 were withdrawn from the study. All patients who underwent escape treatment at week 48 continued to receive CZP 400 mg every two weeks or had their dose reduced to 200 mg if they achieved PASI 75. Finally, all patients, including those who discontinued the treatment, were followed up for an additional 10 weeks after the final dose of study medication.
The trials had a number of methodological limitations, including potentially unblinded treatment administration and risk of disclosure of treatment allocation, unblinded comparison between CZP and ETN, notable imbalances across treatment groups within trials for a number of variables, compromise of original randomization in the maintenance period, a higher dropout rate during the maintenance period relative to the initial treatment period, the use of an enriched sample in the maintenance period, and the lack of statistical comparisons between any treatment groups during the maintenance period. All three trials presented data through week 48 (limited long-term data beyond week 48 are available); however, much of the data from week 16 to week 48 (maintenance period) did not provide useful comparative information for the aforementioned reasons. An absence of long-term comparative treatment response limited the extrapolation of findings during the initial treatment period into the maintenance period. Although a 12- to 16-week period is adequate to determine patient response, given that psoriasis is a chronic condition requiring lifelong treatment, the available 48-week trial data are insufficient to determine whether CZP will be efficacious and safe over the long term. More long-term data are required to understand the prolonged efficacy and safety of CZP for moderate-to-severe plaque psoriasis. Further, there is a lack of direct evidence comparing CZP with newer biologics for the treatment of plaque psoriasis.
Outcomes
Outcomes were defined a priori in the CDR systematic review protocol. Of these, the committee discussed the following: HRQoL, as measured by the Dermatology Life Quality Index (DLQI), Hospital Anxiety and Depression Scale (HADS-A and HADS-D), the EuroQol 5-Dimensions 3-Level (EQ-5D-3L), and the Short Form-36 version 2 (SF-36); and skin clearance measures, as measured by PASI 75, 90, and 100 scores, and static PGA response. HRQoL and skin clearance were identified as being of particular importance to patients in the input received by CADTH from patient groups.
In CIMPASI-1 and CIMPASI-2, the following co-primary and secondary outcomes were measured at week 16 to evaluate the superiority of CZP 200 mg and 400 mg every two weeks against placebo parallelly, in the following sequence: 75% reduction in the PASI score from baseline (PASI 75), PGA response (defined as clear or almost clear, with a corresponding score of 0 or 1), PASI 90 score, and change from baseline in DLQI score. In CIMPACT, the following co-primary and secondary outcomes were assessed first at week 12 and then at week 16 to evaluate the superiority of CZP 400 mg and 200 mg every two weeks against placebo sequentially, in the following order: PASI 75 score, PGA response, and PASI 90 score. If the null hypotheses were rejected at that point, PASI 75 response at week 12 was evaluated between CZP 400 mg and ETN first, followed by CZP 200 mg and ETN, for noninferiority and superiority. None of the other outcomes were adjusted for multiplicity.
Efficacy
CIMPASI-1 and CIMPASI-2 found CZP 200 mg and 400 mg every two weeks were superior to placebo for the primary and secondary efficacy outcomes at week 16: achievement of PASI 75 response, PGA response (clear or almost clear; i.e., a score of 0 or 1), PASI 90 response, and improvements in DLQI score from baseline. At week 16, statistically significantly higher PASI 75 rates were observed for CZP 400 mg (CIMPASI-1 and CIMPASI-2: 75.8% and 82.6%) and CZP 200 mg (66.5% and 81.4%) compared with placebo (6.5% and 11.6%; P < 0.0001 for all). There were statistically significantly higher PGA responder rates for CZP 400 mg (CIMPASI-1 and CIMPASI-2: 57.9% and 71.6%) and CZP 200 mg (47.0% and 66.8%) compared with placebo (4.2% and 2.0%; P < 0.0001 for all).
In the CIMPACT study, 61.3% and 66.7% of patients of patients in the CZP 200 mg and 400 mg groups, respectively, achieved PASI 75 response at week 12 compared with 53.3% of patients who received ETN and 5.0% who received placebo. The odds ratio for being a PASI 75 responder were statistically significantly higher for both CZP groups versus placebo (P < 0.0001). CZP 400 mg was found to be superior to ETN (odds ratio, 1.76; 95% CI, 1.11 to 2.77; P = 0.015) and CZP 200 mg was found to be noninferior to ETN. Noninferiority was based on a −10% noninferiority margin for the difference in proportions (mean difference, 8%; 95% CI, −2.9% to 18.9%). CIMPACT found that 39.8% and 50.3% of patients in the CZP 200 mg and 400 mg group achieved PGA response at week 12, respectively, compared with 1.9% of patients in the placebo group (P = 0.0004 and P < 0.0001, respectively). PGA response was achieved by 39.2% of patients in the ETN group at week 12; however, no statistical comparison was made between CZP and ETN or between ETN and placebo.
In all three trials, data through week 48 suggest that patients who responded to CZP treatment (either dose) at week 12 or 16 continued to have good response to treatment, as shown by PASI and PGA scores, as well as a number of HRQoL measures. However, week 48 results may overstate the effect of CZP due to the focus on the enriched population of responders. In addition, no statistical comparisons between treatment groups were made post week 16 (CIMPASI-1 and -2) or week 12 (CIMPACT) end points; therefore, results for the maintenance period should be interpreted descriptively.
Of the subgroups identified as relevant by the review team, data were available only for previous systemic treatment experience. Analysis of primary outcomes (PASI 75 and PGA responder rate) by previous systemic treatment experience showed no consistent pattern, although a statistical comparison was not done.
Assessment of the disease-specific DLQI instrument and generic EQ-5D-3L, HADS-A and HADS-D, and SF-36 suggest that improvements in the symptoms of plaque psoriasis (demonstrated by PASI and PGA score) resulted in improvements in HRQoL for patients treated with CZP compared with placebo at week 12 or 16. However, statistical comparisons for these outcomes were not adjusted for multiplicity, with the exception of DLQI score change from baseline in CIMPASI-1 and CIMPASI-2. No statistical comparisons for HRQoL measures were made between CZP and ETN.
Two pharmacokinetic studies designed to assess the impact of CZP in pregnant and lactating women and their infants showed suggested limited fetal exposure and exposure to the newborn with continued use of CZP.
Harms (Safety)
The percentage of patients who experienced treatment-emergent adverse events (AEs) during the first 16 weeks ranged from 46% to 70% across the trials, with a balanced incidence between treatment groups within each trial. Infection was the most frequent AE associated with CZP, which is known with anti–TNF alpha medications. The overall frequency of serious AEs and events leading to study discontinuation were low (less than 10%) across treatment groups. The safety profile remained largely similar through the maintenance period, indicating that the AE profile of CZP remained similar with longer exposure. The incidence of neoplasm was infrequent, and no cases of hypersensitivity reaction or inflammatory bowel disease were reported. Overall, the safety profile of CZP in patients with psoriasis was consistent with that observed in other inflammatory conditions the drug is approved for.
Indirect Treatment Comparisons
CDR reviewed and critically appraised the manufacturer’s submitted ITC in order to address the lack of direct comparative evidence from other drug treatments for psoriasis. The systematic review for the network meta-analysis (NMA) identified 83 phase II to IV RCTs comparing interventions for moderate or severe psoriasis that had received regulatory approval in the US and the European Union prior to 2018, of which 65 studies were included in an NMA. The network was star-shaped, centred on placebo, with only eight studies of active comparisons. The primary analysis used a Bayesian multinomial random-effects model, adjusted for placebo risk of response, to calculate probabilities of improvement according to PASI score. Studies frequently report response according to various thresholds (PASI 50, PASI 75, and PASI 90), and the multinomial model is intended to accommodate variable thresholds and has previously been used in NMAs of other psoriasis therapies. Sensitivity analyses using binomial models to estimate probabilities of improvement and treatment comparisons for individual thresholds were also run to provide a check on model assumptions.
Sources of heterogeneity were investigated by comparison of study and baseline characteristics, and planned subgroup analyses of effect of exposure to biologicals. Data were available for NMAs of patients who are biologic naive (31 patients), but not for those who are biologic experienced. The models in the primary analysis were adjusted for risk of response in the placebo group as a means of adjusting for other factors influencing response, although details and a descriptive summary were not provided, and it is not possible to determine if this is an appropriate strategy. Other potential sources of heterogeneity were evaluated qualitatively; pairwise meta-analyses were not reported. Data were not available on the use of corticosteroids or number of previous treatments.
It is not possible to reach conclusions regarding the comparability of CZP with other biological drugs from the analysis due to concerns about model fit, convergence, and precision. The results of the sensitivity analysis suggest that the underlying assumptions of the multinomial model (proportional odds) may not have been satisfied, although some of the models failed to converge, producing inflated, variable results. In conclusion, biological drugs (including CZP) appear to have a higher predicted probability of response than non-biological drugs or placebo and indirect comparisons of effect suggested that CZP was favoured over non-biological drugs; however, the indirect comparison with methotrexate, which was representative of standard of care, was not reported. Data for treatment beyond 16 weeks, HRQoL, and safety and harms, were not available.
Cost and Cost-Effectiveness
CZP is available as a 200 mg/mL solution for subcutaneous injection in a single-use, pre-filled syringe or single-use pre-filled autoinjector. The recommended dose is 200 mg or 400 mg every two weeks. When initiating treatment, a dose of 400 mg is administered at week zero and week four, followed by 200 mg or 400 mg every two weeks thereafter. At the sponsor’s submitted price of $664.51 per pre-filled syringe or autoinjector, the annual cost of CZP is $19,271 to $34,555 in the first year and $17,277 to $34,555 thereafter.
The sponsor submitted a cost-utility analysis in patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy, based on a Markov state-transition model comparing CZP 200 mg and 400 mg with best supportive care (BSC) and the following biologic therapies reimbursed in Canada for moderate-to-severe plaque psoriasis: adalimumab, brodalumab, etanercept, guselkumab, infliximab (branded), ixekizumab, secukinumab, and ustekinumab. BSC consisted of treatment with cyclosporine, methotrexate, acitretin, and/or phototherapy. The analysis was conducted from a Canadian publicly funded health care payer perspective using two-week cycles over a lifetime horizon. The model had two time periods: the initial period, from treatment initiation to the initial assessment of treatment response (i.e., 10 to 16 weeks); and the maintenance period. Treatment response was defined as achieving PASI 75 or greater. Following the initiation period, patients achieving PASI 75 would continue treatment and those who did not would switch to BSC. Patients who responded to treatment in the initiation phase continued treatment in the maintenance phase until discontinuation due to loss of response or death. Patients continuing treatment were assumed to maintain the same level of PASI response and remained in the same health state until discontinuation. Upon discontinuation, patients were assumed to receive BSC.
In the sponsor’s base case, CZP 200 mg was dominated by ixekizumab (i.e., ixekizumab was associated with lower total costs and more quality-adjusted life-years [QALYs] gained when compared with CZP 200 mg), and CZP 400 mg was extendedly dominated through brodalumab and BSC (i.e., compared with BSC, brodalumab was more cost-effective than CZP 400 mg). At a willingness-to-pay threshold of $50,000 per QALY gained, CZP had a 0% probability of being cost-effective.
CADTH identified the following key limitations of the sponsor’s submitted economic analysis:
The comparative treatment effects of CZP with other biologics are uncertain given the limitations of the clinical trial studies and the sponsor-submitted ITC as identified by CADTH clinical reviewers.
The sponsor assumed that the efficacy of treatment, measured in terms of PASI 75, observed during the clinical trial (48 weeks) will continue until the end of the model time horizon. No evidence has been provided to support this assumption.
The sponsor assumed that patients who discontinue their primary treatment during the maintenance period would be switched to BSC. However, in clinical practice, patients who discontinue initial treatment would likely receive a higher dose of the same drug or switch to another active treatment instead of BSC.
In clinical practice, BSC is only used prior to patients being eligible for treatment with a biologic, therefore BSC is not an appropriate comparator. Further, BSC costs were estimated using a UK study; however, Canadian values were available and would be more appropriate.
The use of a lifetime model horizon is likely too long given the uncertainty in the long-term maintenance of PASI response and the inappropriate assumption that patients who discontinue treatment receive BSC for the remainder of the time horizon.
The sponsor assumed differential time points for the initial assessment of treatment response for comparators as per the product monographs or clinical trials. This assumption is not reflective of clinical practice and favoured CZP, which has a longer time for initial assessment of treatment response and therefore a longer initial therapy duration.
The cost of infliximab was based on branded drug prices. Infliximab biosimilar was not included in the analysis.
In the CADTH reanalysis, the following assumptions were considered: BSC was excluded as a comparator; a 10-year time horizon and a consistent time point for the initial assessment of treatment response were applied; pharmacotherapy and phototherapy costs for BSC were excluded; a Canadian source for BSC costs was used; and, the cost of infliximab was based on the subsequent entry biologic price. Based on the revised assumptions, etanercept was associated with the lowest cost and lowest QALYs, followed by brodalumab, infliximab, and then guselkumab. CZP 200 mg and 400 mg were dominated by infliximab and ixekizumab, respectively. At a willingness-to-pay threshold of $50,000 per QALY gained, CZP 200 mg and 400 mg had a 0% probability of being cost-effective. Results should be interpreted with caution as effectiveness estimates based on the ITC may not be reliable given the limitations identified by CADTH clinical reviewers.
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