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Indication: For the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who have an inadequate response to, or are intolerant of, a C5 inhibitor
CADTH recommends that Empaveli should be reimbursed by public drug plans for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who have an inadequate response to, or are intolerant of, a C5 inhibitor if certain conditions are met.
Empaveli should only be covered to treat patients with PNH who have met existing reimbursement criteria used by public drug plans for initiating C5 inhibitor treatment (e.g., eculizumab or ravulizumab). While receiving C5 inhibitor treatment, patients should have had persistently low hemoglobin levels, likely due to red blood cell (RBC) destruction occurring outside of blood vessels (known as extravascular hemolysis [EVH]), or intolerable side effects.
Empaveli should only be reimbursed if prescribed by or in consultation with a hematologist with experience managing PNH. It should not be used with other C5 inhibitors beyond the first 4 weeks of treatment. Also, the cost of Empaveli should be reduced.
PNH is an extremely rare disease in which the bone marrow produces abnormal RBCs that are prematurely destroyed by the immune system, leading to a wide range of symptoms and complications, including life-threatening blood clots. It is estimated that there are approximately 0.13 new cases per year per 100,000 persons based on a study in the UK.
Some patients treated with eculizumab or ravulizumab do not have a good response to treatment or their treatment causes EVH.
Treatment with Empaveli is expected to cost between $516,880 to $566,932 in the first year (depending on the C5 inhibitor prescribed during the first 4 weeks) and $516,880 thereafter per patient.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that pegcetacoplan be reimbursed for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who have an inadequate response to, or are intolerant of, a C5 inhibitor only if the conditions listed in Table 1 are met.
One phase III, open-label, randomized controlled trial (RCT) demonstrated that treatment with pegcetacoplan resulted in added clinical benefit for patients with PNH with clinically significant anemia and signs of extravascular hemolysis (EVH) despite eculizumab treatment. The PEGASUS trial (N = 80) demonstrated that treatment with pegcetacoplan was associated with a statistically significant and clinically meaningful improvement in change in hemoglobin level from baseline at week 16 compared with eculizumab (mean difference = 3.84 g/dL; 95% confidence interval [CI], 2.33 g/dL to 5.34 g/dL; P < 0.001). Transfusion avoidance, an important outcome according to patients and the clinical experts, was more commonly observed in the pegcetacoplan arm (85.4% versus 15.4% of patients; adjusted risk difference = 62.5%; 95% CI, 48.3% to 76.8%). Patients expressed a need for treatments that can effectively control intravascular hemolysis (IVH), reduce EVH, improve anemia, reduce or eliminate transfusion requirements, and improve fatigue and quality of life. CDEC concluded that pegcetacoplan treatment met some of the needs identified by patients in terms of improving anemia and reducing transfusion needs.
Without a head-to-head trial between pegcetacoplan and ravulizumab, the pharmacoeconomic model assumed equivalent clinical efficacy between eculizumab and ravulizumab. Using the sponsor-submitted price for pegcetacoplan and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for pegcetacoplan was $62,144 per quality-adjusted life-year (QALY) gained compared with ravulizumab. At this ICER, pegcetacoplan is not cost-effective at a willingness-to-pay (WTP) threshold of $50,000 per QALY for adult patients with PNH who have an inadequate response to C5 inhibitors. A price reduction is required for pegcetacoplan to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
PNH is an extremely rare, chronic disease characterized by IVH and heterogenous signs and symptoms, such as hemoglobinuria, anemia, abdominal pain, dyspnea, and fatigue, and could lead to complications including thrombosis, chronic kidney disease, and pulmonary hypertension. PNH is a consequence of an acquired genetic mutation leading to clonal expansion of hematopoietic stem cells that produce abnormal blood cells that are susceptible to complement-mediated IVH. The annual incidence of clinical PNH was estimated to be approximately 0.13 per 100,000 persons based on a study in the UK.
Approximately 20% to 30% of patients with PNH have ongoing clinically significant anemia despite first-line standard of care (SOC) with terminal complement component C5 inhibitor treatments (e.g., eculizumab, ravulizumab). Causes of inadequate treatment response include breakthrough IVH, C3-mediated EVH, development of human-anti-human or eculizumab-neutralizing antibodies, and C5 genetic polymorphism. The SOC for patients with C3-mediated EVH is to provide best supportive care (e.g., red blood cell [RBC] transfusion, steroids, splenectomy, danazol, epoetin alfa) while continuing C5 inhibitor treatment, or referral to clinical trials; however, many best supportive care therapies are associated with toxicities.
Pegcetacoplan has been approved by Health Canada for the treatment of adult patients with PNH who have an inadequate response to, or are intolerant of, a C5 inhibitor. Pegcetacoplan is a proximal complement C3 inhibitor. It is available as a 54 mg/mL solution for subcutaneous infusion use; the dosage recommended in the product monograph is 1,080 mg subcutaneous infusion twice weekly via a syringe system infusion pump. Dosage increase to 1,080 mg every third day may be considered if the LDH level is greater than 2 times the upper limit of normal on twice weekly dosing.
To make its recommendation, the committee considered the following information:
The Canadian Association of PNH Patients and the Aplastic Anemia & Myelodysplasia Association of Canada submitted 1 joint input for this review. Information was gathered from the scientific literature and one-on-one interviews with 6 individuals diagnosed with PNH living in Canada. The patient group expressed the following negative impacts of PNH: persistent anemia (manifested as fatigue or extreme fatigue), hemolysis leading to thrombosis, employment absenteeism for patients and caregivers, dependence on frequent blood transfusions, and reduced quality of life. According to the input, patients with PNH, particularly those experiencing EVH, need alternative treatment options because of the inability of available therapies with eculizumab or ravulizumab to thoroughly control IVH and prevent EVH. They also expressed the need for therapies to improve anemia, reduce or eliminate transfusion requirements, and improve fatigue and quality of life. Among 3 patients who had used pegcetacoplan, all noted an immediate normalization of hematological parameters, easier administration (self-administered subcutaneous injection twice weekly at home) compared with eculizumab or ravulizumab (visits for IV transfusions), reduced blood transfusions, and improved physical functioning and quality of life. Some patients stated the importance of proper injection training.
The clinical experts noted there is a need for treatments that are effective in patients who have insufficient control of IVH despite treatment with eculizumab, address the issue of C3-mediated EVH, and can be used in patients with intolerance to C5 inhibitors or poor venous access. The clinical experts noted that pegcetacoplan is a C3 inhibitor with a mechanism of action in addition to C5 inhibitors because it inhibits a more upstream effector in the complement activation pathway. They anticipated that the drug would serve as a second-line treatment for PNH.
The clinical experts noted that suitable candidates for pegcetacoplan treatment include patients with PNH who have persistent anemia (with or without history of ongoing blood transfusion needs) and evidence of EVH despite an adequate trial of C5 inhibitor treatment, patients with intolerance to a C5 inhibitor, or patients with a rare C5 genetic polymorphism (which prevents eculizumab from binding to its target molecule; mainly present in patients of Japanese descent). The clinical experts noted that pegcetacoplan could potentially be considered in patients who are geographically isolated or have poor venous access. Patients with a PNH clone size (i.e., proportion of blood cells deficient in complement system regulatory protein) of less than 10% should not receive pegcetacoplan.
The clinical experts noted that a clinically meaningful treatment response would include improvement in hemolytic parameters (LDH, bilirubin) and hemoglobin level, reduced transfusion need, and improved quality of life. In general, follow-up assessments are conducted every 3 months and treatment response is determined per clinical judgment by the treating physician based on a global assessment of all patient parameters, chronology of symptoms, and laboratory results. The clinical experts noted that treatment discontinuation is not considered unless any of the following occurs: treatment failure (persistent anemia and ongoing transfusion needs) necessitating a switch to a more effective treatment, intolerance to pegcetacoplan, or resolution of disease following bone marrow transplant. The clinical experts noted that patients with PNH should be managed by hematologists in consultation with PNH specialists.
One clinician group, the Canadian PNH Network, submitted input for this review based on contributions from 11 clinicians. The group noted that the current SOC for PNH is C5 inhibitors (i.e., eculizumab and ravulizumab), which act via terminal complement blockade. They noted that although C5 inhibitors are not curative treatment, these treatments have been shown to be effective in controlling IVH, leading to significant improvement in fatigue, quality of life, transfusion dependence, thrombosis, and overall survival. The only curative treatment for PNH is allogeneic hematopoietic stem cell transplant, which is available for patients with predominant or progressive bone marrow failure or for eligible patients with evidence of clonal evolution. However, the group highlighted 3 unmet needs: some patients do not have access to SOC due to highly restrictive reimbursement criteria, there is high treatment burden with eculizumab due to administration every 2 weeks requiring venous access and nurse visits, and despite treatment, approximately one-third of patients remain anemic due to EVH and possibly transfusion-dependent. The group expressed that drugs that exploit proximal complement blockade, such as C3 inhibitors, address the EVH risk, significantly increase hemoglobin, and improve quality of life. Regarding place in therapy, the group stated pegcetacoplan is the first C3 inhibitor that protects against EVH, and it would fit into the current treatment landscape as an alternative (i.e., switch) option in patients with no or inadequate response or who are intolerant to eculizumab or ravulizumab. These would include patients with persistent anemia (hemoglobin < 10.5 g/dL or could be higher if symptomatic) despite stable doses of eculizumab or ravulizumab and have other causes of ongoing anemia (e.g., breakthrough hemolysis or bone marrow failure) ruled out. The group indicated that a clinically meaningful response to treatment would be sustained control of LDH level (i.e., less than 1.5 times the upper limit of normal), increase in hemoglobin (or possibly hemoglobin stabilization without further needs of transfusion), and improvement in anemia-related symptoms. Treatment discontinuation should be considered in patients who have adverse events that preclude ongoing therapy (e.g., recurrent breakthrough hemolysis, issues with effective self-administration, intolerable pain from injection). The group indicated that treatment and monitoring of patients should ideally be done by clinicians who specialize in the area, although patients can self-administer pegcetacoplan at home or anywhere they prefer.
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 pegcetacoplan:
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.
The CADTH systematic review identified 1 relevant study, PEGASUS, which was a pivotal phase III, open-label RCT comparing pegcetacoplan (1,080 mg twice weekly via subcutaneous infusion) versus eculizumab (at patients’ established dosage regimen via IV infusion) in adult patients with PNH who continued to have hemoglobin levels of less than 10.5 g/dL despite treatment with eculizumab at a stable dosage for at least 3 months (N = 80). After receiving both interventions concurrently in a 4-week run-in period, patients were randomized to either pegcetacoplan or eculizumab monotherapy on a 1:1 ratio in a 16-week randomized controlled period. The primary outcome was change from baseline (before the run-in period) at week 16 in hemoglobin (primary end point), and the key secondary end points were transfusion avoidance, change in baseline at week 16 in ARC, LDH, and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score.
At baseline, the mean age of patients was 48.8 years (standard deviation [SD] = 16.0 years), with the majority of patients being female and white (both 61.3%). Mean time since diagnosis was 10.2 years (SD = 8.6 years); patients received eculizumab for a mean duration of 1,808.7 days (SD = 1,447.6 days) before the study and 30% of patients received eculizumab at a dose higher than the maintenance dose approved for PNH by Health Canada. The study population had a mean hemoglobin level of 8.7 g/dL (SD = 1.0 g/dL), reasonable control of IVH (mean LDH = 282.4 U/L; SD = 211.0 U/L), elevated mean ARC (216.9 × 109 cells/mL; SD = 71.7 × 109 cells/mL) and indirect bilirubin (mean = 33.8 µmol/L; SD = 25.8 µmol/L) levels, and low haptoglobin (mean = 0.135 g/L; SD = 0.121 g/L), consistent with the signs of EVH.
Survival was not assessed in the efficacy analysis.
Change from baseline at week 16 in hemoglobin level was the primary end point. The mean hemoglobin level at baseline was 8.69 g/dL (SD = 1.08 g/dL) in the pegcetacoplan arm and 8.68 g/dL (SD = 0.89 g/dL) in the eculizumab arm. The least square (LS) mean change from baseline at week 16 in hemoglobin level (censored for transfusion) was 2.37 g/dL (standard error [SE] = 0.36 g/dL) in the pegcetacoplan arm and −1.47 g/dL (SE = 0.67 g/dL) in the eculizumab arm, with a between-group difference of 3.84 g/dL (95% confidence interval [CI], 2.33 g/dL to 5.34 g/dL) in favour of pegcetacoplan (P < 0.0001). Results of the sensitivity analyses (controlled-based pattern imputation and tipping point analyses) and supportive analysis using all patient data (uncensored for transfusion) were consistent with the primary analysis.
Hemoglobin response (i.e., at least 1 g/dL increase) in the absence of transfusion (secondary end point) was achieved in 75.6% of patients in the pegcetacoplan arm and 0 patients in the eculizumab arm, with an adjusted risk difference of 67.5% (95% CI, 54.5% to 80.4%). Hemoglobin normalization in the absence of transfusion at week 16 (secondary end point) was achieved in 34.1% of patients in the pegcetacoplan arm, and 0 patients in the eculizumab arm, with an adjusted risk difference of 30.4% (95% CI, 14.9% to 45.9%). The differences between treatments for both outcomes were not tested for statistical significance.
Transfusion avoidance was a key secondary end point and was tested for noninferiority according to the hierarchal testing procedure. Transfusion avoidance was achieved in 85.4% of patients in the pegcetacoplan arm, and 15.4% in the eculizumab arm, with an adjusted risk difference of 62.5% (95% CI, 48.3% to 76.8%) in the intention-to-treat (ITT) analysis. The lower bound of the 95% CI for risk difference was greater than the noninferiority margin (NIM) of −20% in both the ITT and per-protocol (PP) analysis sets, supporting noninferiority of pegcetacoplan versus eculizumab.
The mean number of packed RBC units transfused (secondary end point) was 0.6 units (SD = 2.03 units) in the pegcetacoplan arm and 5.1 units (SD = 5.6 units) in the eculizumab arm. The difference between treatments was not tested for statistical significance.
Thrombotic events were not assessed in the efficacy analysis.
Change from baseline at week 16 in the FACIT-Fatigue score was a key secondary end point but was not tested for inferiority nor superiority due to prior failure in the testing hierarchy. The LS mean change from baseline at week 16 in the FACIT-Fatigue score in the ITT set (censored for transfusion) was 9.22 points (SE = 1.61 points) in the pegcetacoplan arm and −2.65 points (SE = 2.82 points) in the eculizumab arm, with a between-group difference in LS means of 11.87 points (95% CI, 5.49 to 18.25 points).
A responder analysis assessing the proportion of patients with at least a 3-point increase in the FACIT-Fatigue score from baseline at week 16 (censored for transfusion) was conducted; the proportion was 73.2% in the pegcetacoplan arm and 0% in the eculizumab arm. The differences between treatment arms were not tested for statistical significance.
Change from baseline at week 16 in Linear Analogue Scale Assessment (LASA) and European Organisation for Research and Treatment of Cancer Quality of life Questionnaire Core 30 (EORTC QLQ-C30) scores were secondary end points. The LS mean between-group difference in change from baseline at week 16 in LASA score (censored for transfusion) was 59.1 points (95% CI, 16.9 to 101.3 points). The LS mean between-group difference in LS mean change from baseline at week 16 in EORTC QLQ-C30 global health status, fatigue, pain, and dyspnea scale scores (censored for transfusion) was 18.62 points (95% CI, 0.12 to 37.13 points), −20.74 points (95% CI, −35.29 to −6.19 points), −2.76 points (95% CI, −20.36 to 14.85 points), and −14.57 points (95% CI, −29.90 to 0.76 points), respectively. The differences between treatment arms for all health-related quality of life outcomes were not adjusted for multiplicity.
Breakthrough hemolysis was not assessed in the efficacy analysis.
Complications of PNH were not assessed in the efficacy analysis.
Change from baseline at week 16 in LDH and ARC were key secondary end points and were tested for noninferiority according to the hierarchal testing procedure.
The mean LDH level at baseline was 257.5 U/L (SD = 97.6 U/L) in the pegcetacoplan arm and 308.6 U/L (SD = 284.8 U/L) in the eculizumab arm. The LS mean change from baseline at week 16 in LDH level (censored for transfusion) was –14.8 U/L (SE = 42.7 U/L) in the pegcetacoplan arm and –10.1 U/L (SE = 71.0 U/L) in the eculizumab arm, with a between-group difference in LS means of –4.6 U/L (95% CI, –181.3 to 172.0 U/L). Noninferiority was not met since the upper bound of the 95% CI of the between-group difference was not less than the NIM of 20 U/L in both the ITT and PP sets. Results of a supportive analysis based on data uncensored for transfusion were consistent with the primary analysis (between-group difference in LS means for ravulizumab versus eculizumab = –85.2 U/L; 95% CI, –192.9 U/L to 22.6 U/L).
The mean ARC at baseline was 217.5 × 109 cells/L (SD = 75.0 × 109 cells/L) in the pegcetacoplan arm and 216.2 × 109 cells/L (SD = 69.1 × 109 cells/L) in the eculizumab arm. The LS mean change from baseline in ARC at week 16 in the ITT set (censored for transfusion) was –135.8 × 109 cells/L (SE = 6.5 × 109 cells/L) in the pegcetacoplan arm and 27.9 × 109 cells/L (SE = 11.9 × 109 cells/L) in the eculizumab arm, with a between-group adjusted mean difference of –163.6 × 109 cells/L (95% CI, –189.9 × 109 cells/L to –137.3 × 109 cells/L). Noninferiority was met because the upper bound of the 95% CI of the adjusted mean difference was less than the prespecified NIM of 10 × 109 cells/L in the ITT set and the results were consistent in the PP set. Results of a supportive analysis based on data uncensored for transfusion were also consistent with the primary analysis.
LDH normalization in the absence of transfusion (secondary end point) was achieved in 70.7% of patients in the pegcetacoplan arm and 15.4% of patients in the eculizumab arm, with an adjusted risk difference of 48.8% (95% CI, 32.3% to 65.3%). LDH normalization (uncensored for transfusion) was achieved in 73.2% of patients in the pegcetacoplan arm and 59.0% in the eculizumab arm, with a risk difference of 12.3% (95% CI, 7.0% to 31.5%). The difference between treatment arms was not tested for statistical significance.
Reticulocyte normalization in the absence of transfusion (secondary end point) was achieved in 78.0% of patients in the pegcetacoplan arm and 2.6% of patients in the eculizumab arm, with a risk difference of 66.4% (95% CI, 53.1% to 79.7%). Reticulocyte normalization (uncensored for transfusion) was 80.5% in the pegcetacoplan arm and 17.9% in the eculizumab arm, with a risk difference of 54.8% (95% CI, 38.8% to 70.7%). The difference between treatment arms was not tested for statistical significance.
Health care resource utilization was not assessed in the study.
In the run-in period, treatment-emergent adverse events (TEAEs) were reported in 69 patients (86.3%), but none led to death or discontinuation of study treatment or study. A serious TEAE was reported in 1 patient due to sepsis, which resolved during the run-in period despite continued treatment with pegcetacoplan and eculizumab.
TEAEs were reported in 87.8% of patients in the pegcetacoplan arm and 87.2% of patients in the eculizumab arm. The most common TEAE of pegcetacoplan (in at least 10% of patients) were diarrhea, injection site erythema, injection site reaction, and abdominal pain. There was a similar incidence of serious TEAEs in both arms (pegcetacoplan: 17.1%; eculizumab 15.4%). Withdrawal from study treatment due to TEAE occurred in 3 (7.3%) patients in the pegcetacoplan arm, all due to breakthrough hemolysis. No patients in the eculizumab withdrew from study treatment due to a TEAE. No deaths were reported in either arm.
The incidence of injection site–related TEAEs (36.6%) was notably higher in the pegcetacoplan arm than the eculizumab arm (2.6%). Breakthrough hemolysis was less frequently reported in the pegcetacoplan arm (9.8%) relative to the eculizumab arm (23.1%). In the pegcetacoplan arm, there was no report of thrombosis or anti-pegcetacoplan peptide antibody response; 1 patient reported a serious treatment-emergent bacterial infection, but it was unrelated to encapsulated organism. There was no report of pulmonary hypertension or chronic kidney disease.
Appropriate methods of randomization were used. Imbalances in some baseline characteristics between treatment groups were noted; however, none were expected to cause confounding. The open-label design could introduce reporting bias for subjective efficacy end points (i.e., FACIT-Fatigue, LASA, EORTC QLQ-C30) in favour of pegcetacoplan. The high number of major protocol deviations related to study assessment or schedule noncompliance could compromise the completeness and reliability of study data and introduce uncertainties to the results, although the direction or extent of bias is unclear. The statistical analyses were generally well-designed, with adequate sample size and appropriate multiplicity adjustments for all key secondary outcomes. Other secondary outcomes were either not tested for statistical significance or not adjusted for multiplicity. No justification was provided for the chosen NIMs, although NIMs were considered reasonable by the clinical experts. Supportive PP analysis were conducted for end points tested for noninferiority and results were consistent with the primary ITT analysis. There was a high amount of missing data due to censoring for transfusion. Nonetheless, with respect to the primary end point (change in hemoglobin), results from the sensitivity analyses and supportive analysis using different imputation methods and censoring rules were consistent the primary analysis, increasing certainty of the findings. It is unclear if improvement in hemoglobin level is a predictor of long-term clinical outcomes given that long-term studies are scarce for this rare disease. The reliability, validity, and responsiveness of the FACIT-Fatigue, LASA, EORTC QLQ-C30 scales have not been previously characterized in patients with PNH, which limits conclusions that can be made on these outcomes.
There was no major concern with the generalizability of the study population because the inclusion and exclusion criteria and patient baseline characteristics were consistent with clinical practice. Patients with intolerance to eculizumab were not included; however, this represents a very small population of patients in clinical practice per clinical expert input. Eculizumab was considered a representative comparator, and the distribution of eculizumab dosing aligns with clinical practice. The follow-up duration was adequate for assessing the efficacy outcomes included in the study but inadequate for other clinically important outcomes, such as breakthrough hemolysis, survival, thrombosis, and other complications of PNH. The clinical relevance of the FACIT-Fatigue, EORTC QLQ-C30, and LASA instruments is uncertain because they are not used in clinical practice, although they did capture some common symptoms of PNH (e.g., fatigue, dyspnea, pain) reported by patients.
The sponsor submitted an anchored MAIC to evaluate the relative efficacy of pegcetacoplan to ravulizumab in adult patients with PNH previously treated with eculizumab. The MAIC did not report a systematic literature review to identify relevant studies for inclusion. Two studies were included in the analysis: patient level data from the PEGASUS study, comparing pegcetacoplan and eculizumab, and aggregate patient data from the ALXN study, comparing ravulizumab and eculizumab. Outcomes analyzed were transfusion avoidance, number of packed RBCs transfused, hemoglobin level stabilization, change from baseline in LDH level and LDH level normalization, fatigue and fatigue symptoms, global health status, and physical functioning. A propensity score model using logistic regression was used to account for between study differences in patient baseline characteristics. Effect modifiers were matched in the weighting process separately for clinical and hematological outcomes and fatigue and quality-of-life outcomes. Compared with patients who received ravulizumab, a greater proportion of patients who received pegcetacoplan had a history of transfusions during the year before the study (72.2% versus 13.4%) and mean hemoglobin was lower for patients who received pegcetacoplan (8.7 g/dL versus 11.1 g/dL). Transfusion history and mean hemoglobin were not adjusted for in the analysis.
After matching and anchoring on eculizumab, treatment with pegcetacoplan compared with ravulizumab was associated with more transfusion avoidance (adjusted difference = 71.4%; 95% CI, 53.5% to 89.3%), greater stabilization of hemoglobin levels (adjusted difference = 75.5%; 95% CI, 56.4% to 94.6%), greater normalization of LDH level in the absence of transfusions (adjusted difference = 64.0%; 95% CI, 41.8% to 86.1%), and fewer mean number of units of packed RBCs transfused (adjusted difference = –5.7 units; 95% CI, –7.2 to –4.2 units). In addition, treatment with pegcetacoplan compared with ravulizumab was associated with improvements in adjusted difference in mean change from baseline in fatigue (adjusted mean difference = 8.2 points; 95% CI, 3.8 to 12.6 points), global health status (adjusted mean difference = 9.6 points; 95% CI, 0.1 to 19.0 points), physical functioning (adjusted mean difference = 11.5 points; 95% CI, 3.6 to 19.5 points), and fatigue symptoms (adjusted mean difference = –13.3 points; 95% CI, –23.7 to –3.0 points). There was no difference in the mean change from baseline in LDH levels (adjusted mean difference = 0.3 U/L; 95% CI, –154.5 U/L to 155.1 U/L).
The anchored MAIC has several limitations, including the inability to adjust for 2 clinically important effect modifiers (hemoglobin level and history of transfusions), which differed substantially between the 2 studies at baseline, and heterogeneity between studies regarding duration of follow-up (i.e.,16 weeks for PEGASUS versus 26 weeks for ALXN), treatment administration schedule, and dosing regimen. These limitations may introduce unmeasurable confounding in the relative treatment effect estimates, although the direction or extent of bias is unclear. Overall, there is uncertainty in the relative treatment effect estimates favouring pegcetacoplan versus ravulizumab.
Safety and efficacy results from the 32-week single-arm extension period (following the randomized controlled period) for the PEGASUS trial (N = 77), during which all patients received pegcetacoplan, were also submitted by the sponsor and are presented in this report.
The results were reported as summary statistics, which indicated that efficacy as assessed through hemoglobin level, transfusion avoidance, ARC, LDH level, FACIT-Fatigue scale score, LASA scores, EORTC QLQ-C30 scores, as well as the number of packed RBC units transfused was generally maintained in the pegcetacoplan to pegcetacoplan group for another 32 weeks following the randomized controlled period. In the eculizumab to pegcetacoplan group, improvement was consistently observed across all outcomes after initiation of pegcetacoplan, and the group achieved similar benefits from pegcetacoplan as the pegcetacoplan to pegcetacoplan group.
The TEAE profile of pegcetacoplan was generally consistent with the randomized controlled period. Hemolysis was reported in 15 (19.5%) patients, which led to treatment discontinuation in 2 patients. Thrombosis was reported in 2 (2.6%) patients, but neither was deemed related to pegcetacoplan by the sponsor. There was no report of serious bacterial infection or renal failure. The incidence of pulmonary hypertension was not reported.
The noncomparative design of the extension period precludes conclusions about the comparative efficacy of pegcetacoplan and eculizumab beyond 16 weeks. It is difficult to ascertain if the observed effects can be attributed to pegcetacoplan alone due to lack of control for confounding in a nonrandomized study. No formal statistical testing was conducted, and results were presented using descriptive statistics. The open-label design can influence reporting of subjective outcomes (FACIT-Fatigue, LASA, EORTC QLQ-C30, harms), introducing uncertainties to the results. Although the study results seem to suggest that the efficacy and safety of pegcetacoplan can be maintained long term, outcomes such as survival, thrombosis, and other complications of PNH require a much longer duration of follow-up to gain certainty in the results.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s budget impact analysis: the size of the target population may have been overestimated, uncertainties in the uptake of pegcetacoplan, and inappropriate assumptions of continuous up-dosing of eculizumab that misalign with its product monograph. Furthermore, the prices of eculizumab and ravulizumab were based on publicly accessible list prices and do not reflect any confidential pricing that may have been negotiated by public plans. CADTH reanalyses reduced the proportion of patients who had inadequate response to, or intolerance for, C5 inhibitor treatment and revised the market share of pegcetacoplan. Based on the CADTH reanalyses, the estimated budget impact from reimbursing pegcetacoplan is expected to result in increased costs of $39,833 in year 1 but lead to budget savings of $461,559 in year 2 and $441,843 in year 3 for a 3-year total incremental savings of $863,569. Scenario analyses to explore the sensitivity of the budget impact model to the limitations noted found that pegcetacoplan may increase the drug budget depending on whether drug up-dosing is publicly reimbursed.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Mr. Morris Joseph, 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: January 25, 2023
Regrets: One expert committee member did not attend
Conflicts of interest: None
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Indication: For the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who have an inadequate response to, or are intolerant of, a C5 inhibitor
Sponsor: Sobi Canada Inc.
Final recommendation: Reimburse with conditions
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