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Indication: In addition to standard therapy for treatment of active lupus nephritis in adult patients
CADTH recommends that Benlysta be reimbursed by public drug plans in addition to standard therapy for treatment of active lupus nephritis (LN) in adult patients.
Benlysta should only be covered to treat adult patients with class III or IV, with or without class V, or pure class V active LN and who have started standard induction therapy within the previous 60 days. Benlysta should not be covered to treat patients who previously failed induction therapies or patients with an estimated glomerular filtration rate less than 30 mL/min/1.73 m2.
Benlysta should only be reimbursed if prescribed by either a rheumatologist or nephrologist with experience managing LN and if the cost of Benlysta is reduced.
Systemic lupus erythematosus (SLE) is a disorder in which the body’s immune system attacks its own cells and organs that occurs in about 1 in 2,000 individuals in Canada. LN is a complication of SLE that leads to kidney inflammation and may lead to protein and/or blood in the urine and impaired kidney function. This can worsen over time and lead to end-stage renal disease requiring dialysis or a kidney transplant. It is estimated that LN occurs in about 50% of patients with SLE.
Standard-of-care therapy is the only treatment available to patients with class III or IV, with or without class V, or pure class V active LN. Effective therapies with tolerable side effects that can reduce disease symptoms and disease progression are needed.
Treatment with Benlysta is expected to cost approximately $20,631 to $25,938 per patient per year.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that belimumab be reimbursed in addition to standard therapy for treatment of active lupus nephritis (LN) in adult patients only if the conditions listed in Table 1 are met.
One randomized, double-blind, placebo-controlled, phase III trial (BLISS-LN; N = 448) demonstrated that treatment with IV belimumab at a dose of 10 mg/kg resulted in added clinical benefit for patients with active LN. In the BLISS-LN trial, 104 weeks of treatment with belimumab was associated with statistically significant improvement in renal response compared with placebo as measured by the primary efficacy renal response (PERR). Statistically significant improvement was achieved by 96 (43.0%) patients in the belimumab treatment group and 72 (32.3%) patients in the placebo group, with an adjusted between–treatment group difference of 10.66% (95% confidence interval [CI],1.89 to 19.42; P = 0.0311). In addition, statistically significant differences in favour of the belimumab group were reported for all key secondary end points, including complete renal response (CRR) at week 104 (adjusted between-group difference = 10.27%; 95% CI, 2.40 to 18.14; P = 0.0167), PERR at week 52 (adjusted between–treatment group difference = 11.12%; 95% CI, 2.25 to 19.99; P = 0.0245), ordinal renal response (ORR) at week 104 (adjusted between-group difference = 10.27%; 95% CI, 2.40 to 18.14; P = 0.0167), and time to renal-related event or death (hazard ratio [HR] = 0.51; 95% CI, 0.34 to 0.77; P = 0.0014). The clinical expert stated that the benefits of belimumab reported in the BLISS-LN trial were clinically meaningful. Although other end points favoured belimumab, such as reduction in oral prednisone use, reduction in severe flares, and decreased disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-S2K) with modified scoring for proteinuria, these outcomes were considered supportive and were not adjusted for multiple statistical testing.
Patients and the clinical expert identified a need for treatment options that are effective in optimizing kidney function (i.e., preservation or improvement in estimated glomerular filtration rate [eGFR]) accompanied by reduction in proteinuria, reduction in fatigue and flares, reduction of oral prednisone use, and improved health-related quality of life (HRQoL). CDEC concluded that, based on the evidence, belimumab appears to address the most important unmet need identified by the patients by achieving improvement in renal response; however, no conclusions could be made regarding the effects of belimumab on the improvement of HRQoL.
Using the sponsor-submitted price for belimumab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for belimumab plus mycophenolate mofetil (MMF) was $352,880 per quality-adjusted life-year (QALY) compared with MMF alone. At this ICER, belimumab plus MMF is not cost-effective at a willingness-to-pay threshold of $50,000 per QALY for adult patients with active LN. A price reduction is required for belimumab to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
Lupus is an autoimmune disease characterized by inflammatory processes that can occur in various tissues and organs of the body. A common form of lupus is systemic lupus erythematosus (SLE), which has an estimated prevalence of about 1 in 2,000 individuals in Canada. The age of onset is primarily between 16 and 55 years, and it occurs more often in females than in males (9:1). According to UpToDate Epidemiology and pathogenesis of SLE, published in June 2022, the median ages at diagnosis for white females range from 37 to 50 years, in white males from 50 to 59 years, in Black females from 15 to 44 years, and in Black males from 45 to 64 years. Kidney injury is common in SLE; LN occurs in approximately 50% of patients with SLE, usually within 5 years of an SLE diagnosis. Kidney involvement can remain silent or asymptomatic for a significant period of time; however, patients may experience fatigue, joint and muscle pain, edema, rash, and a variety of other symptoms. The disease is associated with substantial morbidity; serious complications include progression to ESRD, which requires dialysis or kidney transplant.
Treatment options for class III, IV, and/or V active LN include a high-dose corticosteroid that is tapered down over time and immunosuppressive agents such as MMF or mycophenolic acid, cyclophosphamide, or azathioprine. The clinical expert for this review noted that other treatments in addition to standard of care for patients with an inadequate response to first-line induction therapy may include rituximab, cyclosporin, or tacrolimus. The clinical expert for this review stated that in all cases of class III, IV, and/or V active LN, off-label use of antimalarials (i.e., hydroxychloroquine), bone protection (vitamin D, calcium, possibly antiresorptive agents), immunizations with non-live vaccines, and adjunct treatment with renin-angiotensin blockade and statins should be considered.
Belimumab has been approved by Health Canada in addition to standard therapy for treatment of active LN in adult patients. Belimumab is a monoclonal antibody. It is available as an IV infusion; the dosage recommended in the product monograph is 10 mg/kg, administered over an hour, at 2-week intervals for the first 3 doses and at 4-week intervals thereafter. Belimumab is also available as a solution for SC injection; the dosage recommended in the product monograph is 400 mg (two 200 mg injections) once weekly for 4 doses, then 200 mg once weekly thereafter. The product monograph indicates that the infusion rate may be slowed or interrupted if the patient develops an infusion reaction. In the event of a serious infusion-related or hypersensitivity reaction (e.g., anaphylaxis), treatment should be discontinued immediately and appropriate therapy should be administered. The Health Canada–recommended dose for SC injection is 400 mg (two 200 mg injections) once weekly for 4 doses, then 200 mg once weekly thereafter. For adult patients with LN transitioning from belimumab IV therapy to SC therapy, the first SC dose is to be administered 1 to 2 weeks after the last IV dose. This transition can occur any time after the patient completes the first 2 IV doses. The product monograph further states that belimumab should be used in combination with corticosteroids and mycophenolate or cyclophosphamide for induction, or mycophenolate or azathioprine for maintenance, and the patient’s condition should be evaluated continuously.
To make their recommendation, the committee considered the following information:
Four responses to CADTH’s call for patient input for the belimumab submission were received. These consisted of submissions from Arthritis Consumer Experts, Lupus Ontario, a joint submission from the Kidney Foundation of Canada and Lupus Canada, and a cooperative submission from the Canadian Arthritis Patient Alliance, the Arthritis Society, the Canadian Skin Patient Alliance, and CreakyJoints. Patient input was gathered from surveys, video interviews, and focus group discussions among patients with lupus across Canada: 34 respondents (88% female) from Arthritis Consumer Experts, 10 respondents (90% female) with SLE from Lupus Ontario, 38 respondents (73% with LN and approximately 15% caregivers) from the Kidney Foundation of Canada and Lupus Canada. The cooperative submission conducted a focus group of 3 patients with LN as well as a video interview with 1 patient. The submission from Arthritis Consumer Experts also conducted an in-depth interview with 1 patient. A total of 17 patients (6 from a previous survey) in the included submissions had experience with the treatment under review.
Patients reported managing SLE was difficult given the severity of the physical symptoms, such as debilitating fatigue, joint pain, flares, skin rashes, nausea, loss of appetite, bruising, back pain, brain fog, mobility issues, and mental health issues. Respondents reported that currently available treatments are difficult to tolerate because of the many side effects. In their descriptions of their experiences with the current drug under review, patients reported both positive and negative outcomes. Some patients described experiencing side effects, such as severe allergic reaction, extreme nausea, sleep deprivation, frequent urinary tract infections, depression, and psychosis. Other patients reported an overall decrease in their disease symptoms and improvement in physical ability, leading to improvement in their HRQoL.
The key outcomes patients would like to see addressed by a new therapy are reduction of side effects and number of medications used; reduction in fatigue, flares, pain, and rash and skin irritations; increased mobility and participation in physical activities; overall improvement in HRQoL; improved engagement in social activities; and affordability of medication.
According to the clinical expert consulted by CADTH for this review, response to current standard-of-care induction therapy is suboptimal (only 20% to 35% of patients achieve a CRR within 6 to 12 months after initiation of induction therapy; of those who do respond, 20% to 35% relapse within 3 to 5 years), indicating a major unmet need because up to 40% of patients with LN can develop chronic kidney disease and progress to ESRD that requires dialysis or a transplant. Other unmet needs include lack of adherence, side effects (e.g., prednisone), and recurrent flares that cause progressive organ damage; in addition, only a few treatments are safe during pregnancy for a disease that largely affects those who can become pregnant. Currently, no treatments provide a long-term cure or long-term medication-free survival. According to the clinical expert, the current place in therapy for belimumab would be as add-on therapy to existing standard-of-care therapy (i.e., glucocorticoids and MMF or mycophenolic acid or cyclophosphamide) in patients with class III or IV (with or without class V) or pure class V active LN who have not attained an adequate renal response after 2 to 3 months of induction therapy. However, the clinical expert noted that the time to initiate belimumab may vary from start of induction therapy to 3 to 6 months after initiation of induction therapy depending on disease severity, patient response, and expert physician judgment. Other factors that may identify patients with active disease who may be most likely to respond to belimumab include:
The clinical expert identified those patients who are least likely to benefit from belimumab are those with active LN who are not currently receiving standard-of-care induction therapy, those who have previously failed induction therapy with both MMF or mycophenolic acid and cyclophosphamide agents, and those with an eGFR of 30 mL/min/1.73 m2 or less (it is unknown if belimumab would be efficacious in these patients because they were excluded from the BLISS-LN trial). In addition, patients who have attained a CRR after 6 to12 months of induction therapy will probably derive little incremental benefit from belimumab as an add-on to standard of care and should not be considered as candidates for belimumab.
In the opinion of the clinical expert, a clinically meaningful response to belimumab would include, in order of occurrence, at least a 25% reduction in proteinuria (as defined by the urine protein/creatine ratio [uPCR]) after 3 months of induction therapy, at least a 50% reduction in proteinuria after 6 months of therapy, a reduction in corticosteroids to 7.5 mg/day or less after 6 to 12 months of therapy, proteinuria no greater than 0.5 g/24 hours to 0.7 g/24 hours after 12 months of therapy (the response time can be delayed to 18 to 24 months if baseline proteinuria is in the nephrotic range; i.e., > 3.5 g/24 hours), and an estimated eGFR no more than 10% to 20% of preflare value and 60 mL/min/1.73 m2 or higher after 12 months of therapy.
The Canadian Network for Improved Outcomes for Systemic Lupus Erythematosus and 31 associated physicians provided input for this review.
The clinician group and physicians agreed that there have been some treatment gaps and unmet needs in the current LN therapeutics. These unmet needs include inability to achieve complete remission from currently existing treatment options (e.g., MMF and cyclophosphamide), increased risk for multiple complications from moderate or high doses of glucocorticoids, subsequent ESRD and renal replacement therapy associated with disease flares, and difficulty in maintaining adherence.
The clinician group and physicians indicated that a clinically meaningful response to treatment would include any of the following: complete remission (proteinuria < 0.5 g/24 hours) within 12 months of starting treatment, reduction in daily prednisone dose to levels less than 7.5 mg per day, or the reduction of the frequency and intensity of flares. According to the clinician group, sufficient time (at least 12 months) should be allowed for these outcomes to be observed and treatment should be discontinued after 12 months in cases in which no response can be demonstrated. The input stated that belimumab is expected to cause a shift in the current treatment paradigm for LN by addressing the disease mechanism. Its ability to modulate the maturation and functional differentiation of B cells, which produce autoantibodies that are central in SLE pathogenesis and tissue damage, renders it most suitable for patients who have not achieved at least partial remission, patients experiencing early and frequent flares, patients with steroid-dependent disease, and patients with adherence issues.
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 affect the implementation of a CADTH recommendation for belimumab:
The clinical expert consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
One double-blind placebo-controlled, phase III trial RCT (BLISS-LN) was included in this review (166 sites in 21 countries; N = 448) that evaluated the efficacy, safety, and tolerability of an IV treatment regimen of belimumab 10 mg/kg in adult patients with class III or IV (with or without the presence of class V) or pure class V active LN while receiving standard of care. The primary objective was to evaluate the effect of belimumab 10 mg/kg compared with placebo in renal response as measured by the difference in the proportion of patients who achieved a PERR at week 104. PERR was a dichotomous composite outcome (responder vs. nonresponder) that was considered achieved when all 3 of the following components were met: uPCR of 0.7 or less, eGFR no greater than 20% below preflare value or 60 mL/min/1.73 m2 or more and not a treatment failure (i.e., patients who did not take a protocol-prohibited or -restricted medication or a protocol-prohibited dose). A responder was defined by a response at the week 48 or week 100 visit that was confirmed by a repeat measure at the week 52 or week 104 visit, respectively. The key secondary objectives were to evaluate the effect of belimumab 10 mg/kg compared with placebo on CRR at week 104, PERR at week 52, time to renal-related event or death, and ORR at week 104. CRR was a composite outcome that was considered achieved when all 3 of the following components were met: uPCR was 0.5 or less, eGFR was no more than 10% below preflare value or within the normal range at 90 mL/min/1.73 m2 or higher, and not a treatment failure (i.e., patients did not take a protocol-prohibited or -restricted medication or a protocol-prohibited dose). A response was defined as a response at the week 100 visit confirmed by a repeat measurement at the week 104 visit. ORR was an outcome in which patients achieved a CRR, partial renal response, or no response. Treatment failure was defined as violating the corticosteroid rules (i.e., failed to taper corticosteroids to ≤ 10 mg/day by week 24 and not exceed this dose of 10 mg/day through week 104); receiving additional immunosuppressive agents (except topical agents) beyond the induction and maintenance regimens; initiating the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or antimalarial drugs after week 24; or the standard therapy (cyclophosphamide or azathioprine or MMF) exceeded permitted doses.
Baseline patient characteristics, including age, sex, and race were balanced between groups. Patients were predominantly female (88.3% in the belimumab group and 87.9% in the placebo group), a majority were Asian (51.1% in the belimumab group and 48.9% in the placebo group), followed by white (32.7% and 33.6%) and Black (13.5% and 13.9%), and 84% of patients in both the belimumab and placebo groups were categorized as renal biopsy class III or IV (with or without class V) according to the local reader. Disease characteristics, such as SLE and LN disease duration, mean score for the SLEDAI-S2K with modified scoring for proteinuria, mean eGFR, and mean uPCR were balanced between treatment groups at baseline. There were some baseline differences in use of concomitant medications between groups, including antimalarials (74.4% and 69.1%) as well as prednisone (steroids were converted to prednisone equivalent) with a mean dose of 66.5 mg/day (SD 99.6 mg/day) and 72.5 mg/day (SD 133.2 mg/day) for the belimumab and placebo groups, respectively. Patients also used immunosuppressants (88.8% in the belimumab group and 86.1% in the placebo group) and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (65.9% in the belimumab group and 67.3% in the placebo group) at baseline.
In the BLISS-LN study, the primary end point, PERR at week 104, was statistically significant in favour of belimumab 10 mg/kg group (43.0% vs. 32.3%) with an adjusted between–treatment group difference of 10.66% (95% confidence interval [CI], 1.89 to 19.42; P = 0.0311). In addition, statistically significant differences in favour of the belimumab 10 mg/kg group were reported for all key secondary end points of CRR at week 104 (30.0% vs. 19.7%) with an adjusted between-group difference of 10.27% (95% CI, 2.40 to 18.14; P = 0.0167); PERR at week 52 (46.6% vs. 35.4%) with an adjusted between–treatment group difference of 11.12% (95% CI, 2.25 to 19.99; P = 0.0245); ORR at week 104 (30.0% belimumab vs. 19.7% placebo achieving a complete response) with an adjusted between-group difference of 10.27% (95% CI, 2.40 to 18.14; P = 0.0167); and time to renal-related event or death (15.7% belimumab vs. 28.3% placebo experiencing an event), with an HR of 0.51 (95% CI, 0.34 to 0.77; P = 0.0014).
Subgroup analyses based on baseline renal biopsy class (class III or class IV vs. class III plus class V or class IV plus class V vs. class V) and the induction regimen (cyclophosphamide vs. MMF) for the primary and the key secondary end points were generally consistent with the overall results for all subgroups except for the baseline renal biopsy class V subgroup and the cyclophosphamide and azathioprine subgroup, the results of which were not statistically significantly different between treatment groups. However, the study was not designed nor powered to evaluate efficacy in subgroups, and the small number of patients in the class V and the cyclophosphamide and azathioprine subgroups might have led to the lack of statistical significance between treatment groups.
In terms of secondary outcomes, a higher proportion of patients in the belimumab 10 mg/kg group compared with the placebo group received an average daily prednisone dose of 7.5 mg or less at week 104 since the previous 4 week visit (40.8% vs. 29.6%) with an odds ratio (OR) of 1.65 (95% CI, 1.11 to 2.45). In terms of disease activity, the least squares mean change from baseline in SLEDAI-S2K at week 104 was −7.7 (standard error [SE] = 0.46) in the belimumab group and −6.1 (SE = 0.47) in the placebo group with a least squares mean difference of −1.5 (95% CI, −2.4 to −0.6). The proportion of patients with a SLEDAI-S2K score less than 4 at week 104 was higher in the belimumab group compared with the placebo group (27.8% vs. 18.4%) with an OR of 1.76 (95% CI, 1.11 to 2.78). A higher proportion of patients experienced a severe flare postbaseline to week 104 in the placebo group (31.4%) than in the belimumab 10 mg/kg group (18.8%), and the risk of experiencing a severe flare at any time, based on the SFI, was lower in patients in the belimumab 10 mg/kg group compared with patients in the placebo group (HR = 0.57; 95% CI, 0.39 to 0.84).
There was no HRQoL data assessed in the BLISS-LN trial.
Rates of adverse events (AEs) were similar in both treatment groups (95.5% belimumab vs. 94.25% placebo). Frequent AEs that occurred more commonly in the belimumab 10 mg/kg group than in the placebo group were urinary tract infection (19.2% vs. 15.6%), cough (12.5% vs. 8.5%), and upper abdominal pain (6.3% vs. 2.7%). The number of patients experiencing at least 1 serious AE (SAE) was similar in both treatment groups (25.9% belimumab vs. 29.9% placebo). The most common SAEs were pneumonia (4.0% vs. 3.1%), herpes zoster (1.8% vs. 0.9%), gastroenteritis (0% vs. 2.2%), lung infection 0.9% vs. 1.3%), LN (0.4% vs. 1.8%), and urinary tract infection (1.3% vs. 0.9%). An equal percentage of withdrawals due to AEs occurred in the belimumab 10 mg/kg group and placebo group (12.9% vs. 12.9%); the most common reason for withdrawal in both groups was pneumonia (4.0% vs. 3.1%).
A total of 11 deaths occurred during the double-blind phase of the BLISS-LN trial, mainly due to infections. There were 6 (2.7%) deaths in the belimumab 10 mg/kg group and 5 (2.2%) deaths the placebo group.
Common notable harms in the BLISS-LN trial included postinfusion-related systemic reactions (11.6% belimumab vs. 12.9% placebo); serious infections of herpes zoster (2.2% vs. 0.9%), active tuberculosis (0.9% vs. 0.4%), and sepsis (0% vs. 0.4%); malignancies (including nonmelanoma skin cancer) (1.3% vs. 0%), and serious suicidal behaviour (0.4% vs. 0%).
In terms of limitations, a greater proportion of patients discontinued from the placebo group than the belimumab group, which may have led to bias the results in favour of belimumab. However, the sensitivity analyses that assessed the impact of missing data showed results that were generally supportive of the primary analysis. Regarding calculations of patients’ average daily prednisone dose in the BLISS-LN trial, days when a patient did not have a prednisone dose recorded were considered as 0 mg for the day in the calculation, which would likely have underestimated the average dose of prednisone used in the study and may also have led to bias, although the direction of bias is unknown. Improvements in HRQoL were identified as important outcomes by the patient groups who provided input for this review. However, there were no HRQoL data collected in the BLISS-LN trial, hence it is unknown what impact belimumab would have on HRQoL.
The product monograph for belimumab authorized both IV and SC formulations for LN. However, the approval of SC formulations was based on extrapolated data, and there is no clinical evidence regarding the SC formulation for patients with active LN.
Overall, the clinical expert consulted felt the characteristics of the patient population enrolled in the trials was a good representation of the target population. The clinical expert did not identify any issues with the use of concurrent treatments or conduct of the trial that could substantially affect the generalizability of the findings.
No indirect evidence was available.
Data from 1 open-label extension (OLE) study was summarized in this report.
The OLE study provided supplemental safety and efficacy data for patients who received IV belimumab 10 mg/kg plus standard-of-care therapy for up to 28 weeks (N = 254) among eligible patients who completed all assessments at week 104 in the BLISS-LN trial. Patients received their first dose at week 104 of the double-blind phase of the BLISS-LN trial (marked as day 0 for the open-label phase). There were 2 groups in the extension phase: a placebo-to-belimumab group (patients switched from placebo to belimumab) and a belimumab-to-belimumab group (patients remained on belimumab). Criteria for the open-label phase allowed for the use of concomitant medications, including immunosuppressants and corticosteroids, which were prohibited in the BLISS-LN trial. Also, PERR and CRR were evaluated based on observed data at weeks 12, 24, and 28 of the open-label study and criteria were required to be met at a single time point only, meaning criteria did not have to be met on consecutive visits as was required for the double-blind phase of the BLISS-LN trial.
Results from the OLE study showed that the proportion of patients who achieved a PERR increased from baseline to week 28 in both the belimumab-to-belimumab group (from 71% to 75%) and the placebo-to-belimumab group (from 60% to 67%) using the open-label phase criteria. Post hoc analyses found that when using the pivotal trial–defined criteria for a PERR, the proportion of patients who achieved a PERR from baseline to week 28 decreased in the belimumab-to-belimumab group (from 66% to 52%) and remained stable in the placebo-to-belimumab group (from 54% to 53%). Similar results were found for the proportion of patients who achieved a CRR. Reductions in PERR and CRR rates at week 28 in the open-label study for the belimumab-to-belimumab group were mainly due to discontinuations (n = 8) or intake of concomitant medications (n = 9) allowed during the OLE phase but counted as treatment failures for the post hoc statistical analysis. Median uPCR and eGFR remained similar at baseline and at week 28 in both groups. There were no marked changes in the proportions of patients with SLEDAI-S2K scores less than 4 or in the proportion of patients who received an average daily prednisone equivalent dose of 7.5 mg/day or less in either group from baseline to week 28.
The number of patients who experienced at least 1 AE in the open-label phase was higher in the belimumab-to-belimumab group (70%) than in the placebo-to-belimumab (62%) group. The most common AEs that occurred in at least 5% of patients in either group included infections and infestations (49% vs. 42%), musculoskeletal and connective tissue disorders (12% vs. 13%), skin and subcutaneous tissue disorders (13% vs. 8%), gastrointestinal disorders (10% vs. 9%), and respiratory, thoracic, and mediastinal disorders (11% vs. 4%) in the belimumab-to-belimumab and placebo-to-belimumab groups, respectively. The percentage of patients who experienced at least 1 SAE during the open-label phase was low (8% in the belimumab-to-belimumab group and 4% in the placebo-to-belimumab group). The percentage of withdrawals due to AEs was also very low in both groups (3% vs. 0.8%). Common notable harms included post–infusion systemic reactions (4% vs. 3%) and infections of special interest (opportunistic infections, herpes zoster, tuberculosis, sepsis) (5% vs. 2%) in the belimumab-to-belimumab and placebo-to-belimumab groups, respectively. Two cases of serious infections of special interest were reported in the belimumab-to-belimumab group: serious tuberculosis and serious disseminated herpes zoster. One case of suicidal behaviour occurred in a patient diagnosed with an adjustment disorder. This patient recovered and completed the treatment throughout the open-label phase. One death, deemed SLE-related, occurred during the open-label phase in the placebo-to-belimumab group.
The extension study allowed for the investigation of long-term efficacy and harms of belimumab for an additional 28 weeks for eligible patients who completed the BLISS-LN trial. Because there was no active comparator and all outcomes were descriptive in nature, it is difficult to make any inferences regarding the results. Furthermore, extension studies are often limited by selection bias because only those patients who are tolerant to treatment and complete the parent studies are eligible to enrol into the OLE study. An additional limitation is the open-label nature of treatment, which can bias the reporting of subjective end points (i.e., harms). Finally, the relatively short duration of the OLE study is insufficient to observe whether an appreciable benefit was derived among those who had transitioned from placebo-to-belimumab group.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations within the sponsor’s BIA: proportion of patients eligible for belimumab treatment is uncertain, uncertainty in SC versus IV use of belimumab in Canadian clinical practice, proportion of patients requiring belimumab induction in year 1 was underestimated, and uncertainty in the proportion of patients requiring induction to re-establish remission. The CADTH reanalysis updated the proportion of patients expected to receive induction belimumab in year 1. In the CADTH base case, when considering belimumab as add-on treatment, the budget impact of reimbursement belimumab plus standard therapy is expected to be $2,796,447 in year 1, $4,884,617 in year 2, and $6,394,557 in year 3, for a 3-year expected budget impact of $14,075,621.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Mr. Morris Joseph, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed
Meeting date: November 24, 2022
Regrets: One expert committee member did not attend
Conflicts of interest: None
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Indication: In addition to standard therapy for treatment of active lupus nephritis in adult patients
Sponsor: GlaxoSmithKline Inc.
Final recommendation: Reimburse with conditions
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