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Indication: For the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease after failure of at least 2 prior lines of systemic therapy
CADTH recommends that Rezurock be reimbursed by public drug plans for the treatment of chronic graft-versus-host disease (cGVHD) if certain conditions are met.
Rezurock should only be covered to treat patients aged 12 years and older who have clinically diagnosed moderate to severe cGVHD and whose disease has not shown an adequate response to at least 2 prior lines of systemic therapy (1 of which is corticosteroids with or without calcineurin inhibitors).
Rezurock should only be reimbursed if prescribed by clinicians who have experience in the diagnosis and management of patients with cGVHD, and the cost of Rezurock is reduced.
Approximately 35% to 50% of patients who receive a stem cell transplant from a donor will experience cGVHD. cGVHD occurs when the donor’s cells attack the transplant recipient’s cells and body parts. cGVHD can last for months to a lifetime and is the leading cause of illness and death after stem cell transplant.
Patients with cGVHD need effective therapies with tolerable side effects that can improve HRQoL, reduce disease symptoms, reduce corticosteroid dosages, and extend survival.
Treatment with Rezurock is expected to cost approximately $137,313 per year (and $274,626 per year if the patient is receiving concomitant proton pump inhibitors and requires Rezurock twice daily).
The CADTH Canadian Drug Expert Committee (CDEC) recommends that belumosudil be reimbursed for the treatment of adult and pediatric patients 12 years and older with cGVHD after failure of at least 2 prior lines of systemic therapy only if the conditions listed in Table 1 are met.
Two phase II, open-label trials (studies KD025-213 and KD025-208) demonstrated that treatment with belumosudil 200 mg daily produced clinically beneficial results for patients with active cGVHD. In total, || patients in study KD025-213 and 17 patients in study KD025-208 received the Health Canada–approved dose. Study KD025-213 showed that belumosudil in combination with standard systemic cGVHD therapies was associated with a statistically significant improvement in overall response rate (ORR) that was greater than 30% (which was considered clinically meaningful in the trial) at 6 months compared to baseline (ORR = |||||; 95% confidence interval [CI], ||||| || |||||). Study KD025-208 was a dose-finding trial and its results supported the findings from study KD025-213. CDEC acknowledged the rarity of cGVHD and the unmet need for additional treatment options in this setting given the severe nature of this disease with substantial morbidity.
Patients expressed a need for treatments that improve survival and quality of life, reduce disease symptoms, reduce corticosteroid dosages, and produce fewer adverse effects. CDEC concluded that belumosudil met some important patient needs by reducing the disease symptoms of cGvHD and corticosteroid dosages, as well as providing an oral drug option that can be administered as an outpatient treatment. The clinical experts indicated that the results for duration of response (DOR), time to response (TTR), failure-free survival (FFS), and overall survival (OS) in the studies were clinically important. Due to the lack of a valid comparator in the pivotal studies and open-label design of the studies, no definitive conclusions could be reached regarding the effects of belumosudil on HRQoL.
Using the sponsor-submitted price for belumosudil and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio for belumosudil was $313,874 per quality-adjusted life-year (QALY) gained compared with best available therapy (BAT). At this incremental cost-effectiveness ratio, belumosudil is not cost-effective at a $50,000 per QALY willingness-to-pay threshold for the indicated population. A price reduction is required for belumosudil to be considered cost-effective at a $50,000 per QALY gained threshold.
Reimbursement Conditions and Reasons.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) involves the transplant of a donor’s stem cells to a recipient (i.e., patient). With allo-HSCT there is a risk that the transplanted stem cells will die or be destroyed by the recipient’s cells, or that the donor’s transplanted immune cells will attack the recipient’s healthy cells; the latter is called graft-versus-host disease (GVHD). cGVHD can last for months to a lifetime and is the leading cause of late morbidity and death after allo-HSCT. Patients with cGVHD face physical, functional, and psychosocial deficits that have a profound negative impact on HRQoL. It is estimated that 35% to 50% of patients who undergo allo-HSCT will develop cGVHD. The treatment goals for cGVHD are to prolong survival, alleviate symptoms, control disease activity, prevent damage and disability, and maintain or improve HRQoL, without causing extensive toxicity or harms. First-line treatment is generally considered standard across clinical practice and consists of topical or systemic corticosteroids (CSs), with or without calcineurin inhibitors (CNIs). In Canada, second-line options include extracorporeal photopheresis (ECP), mycophenolate mofetil, etanercept, low-dose methotrexate, infliximab, mammalian target of rapamycin inhibitors, imatinib, rituximab, ruxolitinib, ibrutinib, low-dose interleukin-2, pulsed cyclophosphamide, and pentostatin. There is a lack of consensus for standard cGVHD treatment after first-line therapy due to the evidence being insufficient to recommend any treatment over another and the variability in accessing treatments across Canada. Only ruxolitinib and ibrutinib have Health Canada indications for the treatment of cGVHD, while ruxolitinib has Health Canada indications for the treatment of cGVHD in adults and pediatric patients aged 12 years and older who have inadequate response to CSs or other systemic therapies, and ibrutinib has Health Canada indications for the treatment of adults with steroid dependent or refractory cGVHD, and for the treatment of pediatric patients age 1 year and older with cGVHD after failure of 1 or more lines of systemic therapy.
Belumosudil is a selective oral inhibitor of Rho-associated, coiled-coil-containing protein kinase-2 (ROCK2) and ROCK1 and has been approved by Health Canada for the treatment of adult and pediatric patients 12 years and older with cGVHD after failure of at least 2 prior lines of systemic therapy. The recommended dose of belumosudil is 200 mg given orally once daily and treatment should continue until progression of cGVHD that requires a new systemic therapy or occurrence of unacceptable toxicity. No dose adjustments are required in adolescents 12 to 18 years or in patients 65 years or older. Although no patients under the age of 18 were enrolled in the clinical development program, Health Canada indicated that the use of belumosudil in pediatric patients 12 years and older is supported by evidence from studies in adults with additional population pharmacokinetic data, the expectation that drug exposure is similar between adults and pediatric patients age 12 years and older, and that the disease course is sufficiently similar in adult and pediatric patients to allow for data extrapolation.
To make its recommendation, the committee considered the following information:
One joint input was submitted by 2 patient groups, the Leukemia & Lymphoma Society of Canada and Myeloma Canada, based on information gathered from a survey of 62 respondents conducted in July 2023 for the CADTH review of belumosudil.
The patient groups emphasized that the experience of going through cancer treatment, stem cell transplant, and receiving a GVHD diagnosis is disheartening and terrifying for both patients and caregivers. The respondents indicated that the full range of GVHD symptoms significantly affects their physical and mental health and their daily activities, and has detrimental effects on their HRQoL. Many patients lose their independence and require caregiver support to manage the disease.
Despite being necessary to treat cGVHD, the respondents described the negative impact of CS treatment, including the many physical, neurologic, and circulatory side effects that greatly impact HRQoL. According to the input, patients and caregivers seek a treatment that enables them to continue with their daily lives, is more accessible, improves OS, and preserves their HRQoL, with minimal impact on work or school; finances; and social, physical, and mental health.
Of the 5 respondents who indicated having experience with belumosudil, 3 stated that the drug had a positive impact on their lives, allowed them to reduce steroid dosage, and was tolerable with minimal side effects.
According to the clinical experts consulted by CADTH, there is a lack of good treatment options beyond second-line therapy for patients with cGVHD. As a result, patients with refractory or progressive disease have impacted HRQoL and ability to work and study, and have increased risk of mortality due to cGVHD, associated organ impairment, and risk of infections.
The clinical experts indicated that belumosudil would be used per the Health Canada indication in the third-line setting and would likely be used in combination with CSs, and earlier use in the first- or second-line setting would require good randomized controlled trial evidence. Per the clinical experts, patients with moderate to severe cGVHD who are refractory or intolerant to 2 prior lines of therapy would most likely receive belumosudil.
The experts stated that partial response and complete response, as well as maintenance of stable disease with clinically meaningful reduction in CS dose, are indicators that a patient is responding to treatment in clinical practice. Improvement in functional status, symptoms, and ability to return to school or work were also noted as being important outcomes.
Reasons for discontinuing treatment identified by the clinical experts included disease progression (based on signs, symptoms, examination, laboratory tests) or having stable disease but still requiring significant amounts of CSs that cannot be tapered. The experts also noted meaningful adverse effects, such as derangement of liver function tests or significant gastrointestinal upset due to belumosudil, as being reason to stop. Lastly, disease resolution in which a patient has stopped other immunosuppressants (or may be on low-dose CSs [e.g., 10 mg]) with symptom resolution is a third reason. The experts highlighted that stopping treatment in the last instance is done cautiously as patients can experience disease flares when going off treatment.
The clinical experts noted that stem cell transplant specialists should initiate belumosudil in either a community or hospital setting, and treatment decisions may involve other specialists (e.g., respirologists).
Two clinician groups, the OH-CCO Hematology Cancer Drug Advisory Committee and CTTC provided input for the CADTH review of belumosudil. Clinician perspectives from OH-CCO were obtained through videoconferencing. CTTC gathered information through literature review and discussion with the CTTC board of directors and the standing committee of program directors.
Input from the clinician groups was largely aligned with that of the clinical experts consulted by CADTH. The clinician groups reiterated the variation in standard practice for treatment beyond second-line therapy based on local funding of available options. OH-CCO indicated that responsiveness and tolerability vary among patients and that oral therapies are often preferred, while CTTC noted that current treatments are suboptimal and require high doses and prolonged use of CSs, which have many adverse effects. According to the clinician groups, the outcomes used to assess response to treatment include standard GVHD response criteria and significant functional and HRQoL improvements, as well as patients showing stable disease but with a significant reduction of immunosuppressive treatments. The 2 clinician groups agreed that treatment discontinuation should be considered in patients with significant intolerance or cGVHD progression. According to OH-CCO, patients receiving belumosudil should be managed by cGVHD specialists practising in inpatient or outpatient settings, while CTTC added that the drug should only be prescribed by specialists working in a clinical setting associated with allo-HSCT programs for patients who are refractory to steroids or ruxolitinib.
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 impact the implementation of a CADTH recommendation for belumosudil:
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.
Study KD025-213 (N = |||) is a phase II, open-label study with a latest data cut-off date of ||||||||| ||| ||||. Eligible patients must have been 12 years of age or older with active cGVHD, undergone allo-HSCT, and received 2 to 5 prior lines of therapy for cGVHD. Study KD025-208 (N = 54) is a phase IIa, dose-escalation, ongoing, open-label study with a latest data cut-off date of |||| ||| ||||. Eligible patients must have been 18 years of age or older with active cGVHD, undergone allogeneic bone marrow transplant or allo-HSCT, and received 1 to 3 prior lines of therapy for cGVHD (not including ECP). In studies KD025-213 and KD025-208, || patients and 17 patients, respectively, received belumosudil 200 mg once daily and there were no relevant comparator or control groups in either study (belumosudil 200 mg twice daily and belumosudil 400 mg once daily are outside of the Health Canada indication for the indication under review and are not further discussed in this CADTH report). Patients were permitted to have concomitant treatment with standard of care systemic cGVHD therapies, such as CNIs, sirolimus, mycophenolate mofetil, methotrexate, rituximab, ECP, or topical or organ-specific therapies if they had been on a stable regimen; however, initiation of new systemic therapy was not permitted. The primary outcome of both studies was ORR by investigator assessment, measured on day 1 of each 28-day cycle for cycles 2 to 5 and every other cycle thereafter until clinically meaningful disease progression or end of treatment, and was the only end point controlled for multiple testing. Secondary outcomes of interest to the CADTH review included DOR, TTR, FFS, OS, Lee Symptom Scale (LSS) score, and safety outcomes. Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health summary scores for physical and mental functioning were exploratory outcomes in study KD025-213. Although the studies had 4 definitions for DOR, according to the clinical experts consulted by CADTH, the tertiary and secondary DOR definitions were considered to be the most clinically relevant. The tertiary definition of DOR was the time from first documented response to the time of initiation of a new systemic cGVHD therapy or death (reviewed by a clinical team). The secondary definition of DOR was the time from first documented response to the time of first documented lack of response.
The median age of patients was 53 years (range, 21 years to 77 years) in study KD025-213 and 50 years (range, 20 years to 63 years) in study KD025-208. There were no patients younger than 20 years old in the relevant datasets to support the pediatric portion of the indication. In both studies, more than 76% of patients had a Karnofsky Performance Scale score of 80 or higher, the median time from cGVHD diagnosis to study enrolment was approximately 25 months, and more than 70% of patients had severe cGVHD according to the 2014 National Institutes of Health (NIH) Consensus Criteria. In total, 100% of patients in study KD025-213 and 88% of patients in study KD025-208 had 2 or more prior lines of therapy. CSs were the most common prior cGVHD treatment (more than 99%) followed by tacrolimus in study KD025-213 (64%) and sirolimus in study KD025-208 (59%).
In study KD025-213, the ORR was 72.7% (95% CI, 60.4% to 83.0%; P < 0.0001) as of the primary analysis cut-off date (February 19, 2020; 6 months after enrolment of 126 patients into the modified intention-to-treat population). In study KD025-208, the ORR was 64.7% (95% CI, 38.3% to 85.8%) as of the primary reporting data cut-off date (February 19, 2020, corresponding to the primary analysis data cut-off date for study KD025-213).
At the latest cut-off date for study KD025-213 (||||||||| ||| ||||), after a median of |||| (range, ||| || ||||) months of follow-up, the ORR was ||||| (95% CI, ||||| || |||||||). At the latest cut-off date for study KD025-208 (|||| ||| ||||), after a median of |||| (range, ||| || ||||) months of follow-up, the ORR was ||||| (95% CI, ||||| || |||||||).The findings for ORR appeared to be generally similar across the subgroups.
Of patients who responded to treatment (n = ||), the median Kaplan-Meier (KM) estimate for tertiary DOR (time to first response to initiation of a new cGVHD therapy or death) was ||||| weeks (95% CI lower bound = |||| weeks; upper bound not reached) in study KD025-213; in study KD025-208 the median KM estimate for tertiary DOR was not reached (95% CI lower bound = ||| weeks; upper bound not reached) in. At 24 weeks, the KM estimate of the event-free probability for tertiary DOR was ||% (95% CI, ||% to ||%) in study KD025-213 and ||% (95% CI, ||% to ||%) in study KD025-208.
The median KM estimate for secondary DOR (time to first response to time of first lack of response) was |||| weeks (95% CI, |||| weeks to |||| weeks) in study KD025-213; in study KD025-208, the median KM estimate for secondary DOR was |||| weeks (95% CI lower bound = ||| weeks; upper bound not reached). At 24 weeks, the KM estimate of the event-free probability for secondary DOR was ||% (95% CI, ||% to ||%) in study KD025-213 and ||% (95% CI, ||% to ||%) in study KD025-208.
Based on the responder population, the median TTR was ||| weeks (range, 3.7 weeks to |||| weeks) in study KD025-213 and 8.1 weeks (range, 7.9 weeks to 26.1 weeks) in study KD025-208. At weeks 8 and 12, the cumulative response rate was ||||% and ||||%, respectively, in study KD025-213 and ||||% and ||||%, respectively, in study KD025-208.
The median KM estimate for FFS was |||| weeks (95% CI, |||| weeks to |||| weeks) in study KD025-213 and 10.6 weeks (95% CI lower bound = 3.8 weeks; upper bound not reached) in study KD025-208. According to the KM estimate, the FFS probability was ||% (95% CI, ||% to ||%) at 12 months in study KD025-213 and 47% (95% CI, 23% to 68%) at 12 months in study KD025-208.
The median KM estimate for OS was not reached in either study KD025-213 or study KD025-208. According to the KM estimate, the OS probability was ||% (95% CI, ||% to ||%) at 12 months in study KD025-213 and ||% (95% CI, ||% to ||%) at 12 months in study KD025-208.
The LSS score measures changes in symptom burden using 30 items over 7 domains, where a higher score indicates more bothersome symptoms. A 7-point or greater reduction in score was considered clinically meaningful. In study KD025-213, ||||||||| patients had a 7-point or greater reduction in LSS score from baseline. In study KD025-208, 9 (52.9%) patients had a 7-point or greater reduction in LSS score from baseline.
The PROMIS Global Health score assesses general health, ability to carry out physical activities, emotional problems, fatigue, and pain. Two summary scores are determined for physical and mental functioning, with higher scores indicating better functioning. In study KD025-213, | | (||||%) patients had a 4.7-point or greater change from baseline for physical health and || (||||%) patients had a 4.7-point or greater change from baseline for mental health. This outcome was not assessed in study KD025-208.
In study KD025-213, || ||||||| patients had their CS dose reduced and || ||||||| discontinued CS use while receiving belumosudil. In study KD025-208, || ||||||| patients had their CS dose reduced and | | (||||%) discontinued CS use while receiving belumosudil.
Most patients experienced at least 1 treatment-emergent adverse event (AE) in study KD025-213 (||||%) and study KD025-208 (100%). The most common were diarrhea (||||%) and fatigue (||||%) in study KD025-213 and upper respiratory tract infection (53%), diarrhea (35%), fatigue (35%), nausea (35%), and increased alanine aminotransferase (||||%) in study KD025-208.
In study KD025-213, ||||% of patients experienced a serious adverse event (SAE) while 29.4% of patients in study KD025-208 experienced an SAE. Pneumonia (|||%) was the most frequently reported SAE in study KD025-213. No other SAEs occurred in more than 3 patients in either study.
In study KD025-213, ||||% of patients stopped belumosudil due to an AE, while ||||% of patients in study KD025-208 stopped the drug due to an AE.
Overall, | | patients died in study KD025-213 (reasons included hemothorax, aspiration and respiratory failure, septic shock and multiple organ dysfunction, and acute myeloid leukemia recurrent) and 0 patients died in study KD025-208.
Based on the Health Canada product monograph warnings and precautions, hematologic (blood and lymphatic system disorders) and immune (infections and infestations) AEs were identified as being important to the CADTH review. Overall, ||||% of patients in study KD025-213 and ||||% of patients in study KD025-208 experienced a blood or lymphatic system disorder AE and anemia was the most common AE, reported by |||% and ||||% of patients in study KD025-213 and study KD025-208, respectively. For infections and infestations, ||||% or patients in study KD025-213 and ||||% of patients in study KD025-208 experienced an AE. Upper respiratory tract infection was the most common AE reported by ||||% and ||||% of patients in studies KD025-213 and KD025-208, respectively.
The main limitations with both studies are the lack of control (or comparator) group and lack of randomization to a valid comparator, which results in a high risk of bias due to confounding and uncertainty in causal conclusions between the study drug and possible benefits or harms. Another limitation was the knowledge of treatment assignment, which results in an increased risk of performance bias (particularly for subjective measures) and of potentially overestimating the treatment effect of belumosudil. All patients had discontinued from the study and treatment by the latest data cut-off date and there is an increased risk of attrition bias due to missing outcomes data for longer-term results. The findings of time-to-event analyses and later time points had few patients at risk and therefore may be unstable.
Between the studies, 94 patients received the approved 200 mg every day dose for a median treatment duration of about 9 months, which is a relatively small number of patients compared to the total number who could potentially receive belumosudil (active cGVHD after at least 2 prior lines of systemic therapy) for a somewhat short duration, considering that treatment can be for years. This may be especially true for OS, for which few events were captured and longer follow-up would be needed to understand the full effect of belumosudil on mortality. Also, there were no data available for patients younger than 20 years of age to support the Health Canada indication for patients in the 12 years to younger than 20 years of age range, though the clinical experts were of the opinion that the results for adults could be generalizable to a younger patient population and belumosudil gained regulatory approval for a 12 and older population based on pharmacokinetic analyses, indicating that age and body mass did not have a clinically meaningful effect on drug pharmacokinetics. Racial diversity was limited in the study (compared to what is expected in Canadian practice) and the prior and concomitant cGVHD therapies differed from the experts’ experience in treating patients with cGVHD (which may be due to varying availability of treatments across jurisdictions and the studies taking place in the US).
For pivotal studies identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for the 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. Although GRADE guidance is not available for noncomparative studies, the CADTH review team assessed pivotal trials for study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for trials with only a single relevant treatment group (i.e., no valid comparator) started at very low certainty with no opportunity for rating up.
The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with the 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: response to treatment (ORR by investigator assessment and tertiary and secondary DOR, TTR, and FFS), survival (OS), disease-specific measure of symptoms (LSS score), HRQoL (PROMIS Global Health summary scores), and harms (SAEs).
When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of a clinically important effect for ORR, tertiary and secondary DOR, TTR, FFS, and OS based on a threshold informed by the clinical experts consulted by CADTH for this review. The target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for the number of patients who achieved an LSS score or PROMIS Global Health summary scores greater than or equal to the minimal important differences identified from the literature and who experienced SAEs.
For the GRADE assessments, the findings from studies KD025-213 and KD025-208 were considered together (except for PROMIS, which was only assessed in study KD025-213) and summarized narratively by outcome because the studies were similar in population, intervention, design, and outcome measures.
Data from the latest cut-off dates for the ongoing studies (studies KD025-213 and KD025-208) were included in the main report. No additional long-term extension studies were submitted in the systematic review evidence.
No direct comparative data for the use of belumosudil for the treatment of patients 12 years and older with cGVHD were submitted by the sponsor. As a result, a systematic literature review was conducted to identify efficacy and safety evidence for belumosudil versus other treatments for patients with cGVHD after allo-HSCT for whom prior therapies have failed. It was known that no randomized controlled trials were available for belumosudil versus other active therapies for cGVHD; therefore, the feasibility of conducting a valid population-adjusted indirect comparison was assessed and determined to be infeasible.
Compared to the data available for belumosudil, potential comparator studies were heterogeneous with respect to patient characteristics, study designs (e.g., eligibility criteria, length of follow-up, timing of assessments, and outcome measures), and data availability. Specifically, the CADTH review team scrutinized the potential to perform an indirect treatment comparison (ITC) versus the 2 main comparators of relevance, ruxolitinib and ibrutinib. As compared to studies of the comparators, study KD205-213 of belumosudil enrolled patients with more prior lines of therapy and more severe disease. Given the small number of patients enrolled in the studies and the fact that the eligible population in the belumosudil trial was narrower, the CADTH review team agreed that it would not have been feasible to perform a valid population-adjusted indirect comparison that fully adjusted for the differences in populations across the trials. However, as noted by Health Canada, this is an important limitation of the belumosudil KD205-213 trial that may have been foreseen. Given that the trial was initiated in 2018 (after Health Canada’s approval of ibrutinib), it may have been possible at the outset to align enrolment criteria to facilitate a valid ITC with both ibrutinib and ruxolitinib.
Due to the lack of head-to-head data and the inability to conduct an ITC, 1 observational study using inverse probability of treatment weighting (IPTW) was summarized to provide indirect comparative evidence in the treatment of belumosudil versus BAT for patients with cGVHD. The observational study was conducted using real-world data from the US Optum Clinformatics Data Mart database and pooled results from the main studies (studies KD025-213 and KD025-208).
From the database, patients were eligible if they had at least 1 inpatient or outpatient claim with a diagnosis code for cGVHD from January 1, 2000, to the most recent available data; had at least 3 systemic lines of therapy following cGVHD diagnosis (first-line therapy must have been CSs); were 12 years of age or older; and had at least 6 months of continuous enrolment with medical and pharmacy benefits before the third line of therapy. BAT included ECP, mycophenolate mofetil, imatinib, rituximab, mammalian target of rapamycin inhibitors, ruxolitinib, CNIs, methotrexate, ibrutinib, pentostatin, etanercept, abatacept, alemtuzumab, hydroxychloroquine, and interleukin-2. IPTW methods were used in an attempt to reduce the risk of bias due to confounding that would result from differences in populations across the 2 study arms. The primary outcome was FFS and the secondary outcomes included rate of OS and safety events.
Median FFS was |||| months (95% CI, |||| months to |||| months) in the belumosudil group and ||| months (95% CI, ||| months to |||| months) in the BAT group (hazard ratio = ||||; 95% CI, |||| to ||||). Median OS was not estimable for the belumosudil group and was |||| months (95% CI, ||||| months to ||||| months) for the BAT group (hazard ratio = ||||; 95% CI, |||| to ||||).
The most common AEs in the belumosudil group were infections (||||%), fatigue or asthenia (||||%), and nausea or vomiting (||||%). The most common AEs in the BAT group were infections (||||%), dyspnea (||||%), hypertension (||||%), and anemia (||||%).
There were numerous internal validity concerns with the studies, including lack of a valid comparator, missing data for variables of interest, heterogeneity in baseline characteristics (even after IPTW procedures were applied), differences in study designs that cannot be adjusted for, and increased risk of inaccuracies in the claims database due to patients changing insurance plans and possible miscoding of claims. Therefore, it was not possible to make firm conclusions on how belumosudil compares to BAT from the data, as the studies are considered to be at high risk of bias. Moreover, data for both belumosudil 200 mg every day and belumosudil 200 mg twice daily appeared to be pooled in the analyses, though only the former dose has a Health Canada indication for the treatment of cGVHD. Despite the use of real-world data, which could improve generalizability, the internal validity issues minimize the utility and applicability of the findings to clinical practice in Canada.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis: the market uptake of belumosudil is underestimated in years 1 and 2; the BAT components and distribution do not align with Canadian clinical practice; the exclusion of concomitant medication costs does not align with Canadian clinical practice; and the assumption that no patients will receive belumosudil twice daily does not align with the cost-utility analysis. The CADTH reanalysis included adjusting the belumosudil market uptake in years 1 and 2, revising BAT components, including costs of concomitant medications, and revising dosing assumptions for belumosudil.
Based on the CADTH reanalysis, the 3-year budget impact to the public drug plans of introducing belumosudil for the treatment of patients with cGVHD for whom 2 or more prior lines of systemic therapy have failed is expected to be $13,457,590 (year 1 = $4,331,056; year 2 = $4,484,061; year 3 = $4,642,472). This was approximately 25% higher than the estimated impact by the sponsor and it was driven by the assumptions of a faster uptake of the new drug and the use of a twice daily dose in a small proportion of patients.
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: December 20, 2023
Regrets: None
Conflicts of interest: None
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Indication: For the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease after failure of at least 2 prior lines of systemic therapy
Sponsor: Sanofi-Aventis Canada Inc.
Final recommendation: Reimburse with conditions
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