An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Indication: Ultomiris (ravulizumab for injection) is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH)
CADTH recommends that Ultomiris should be reimbursed by public drug plans for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) if certain conditions are met.
Ultomiris should only be covered to treat patients who meet existing reimbursement criteria for a similar drug, eculizumab, for the treatment of PNH. Patients already receiving eculizumab for treatment of PNH are eligible to switch to Ultomiris as long as they still have a good response to treatment with eculizumab.
Ultomiris should be reimbursed in a similar way to eculizumab for PNH. Also, the cost of treatment with Ultomiris should not be more than the cost of treatment with eculizumab.
PNH is an extremely rare disease in which the bone marrow produces abnormal red blood cells 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 of per year per 100,000 persons.
Some patients treated with eculizumab do not have a good treatment response or their treatment causes hemolysis outside of blood vessels. Intravenous infusions of eculizumab every 2 weeks are burdensome to patients.
Treatment with Ultomiris is expected to cost the public drug plans between $569,140 and $685,887 in year 1 and between $474,284 and $569,140 in subsequent years, depending on patient weight.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that ravulizumab be reimbursed for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) only if the conditions listed in Table 1 are met.
Two randomized controlled trials (RCTs) demonstrated that treatment with ravulizumab resulted in similar clinical benefit for adult patients with PNH compared with eculizumab. Results from Study 301 (N = 246) in treatment-naive patients and Study 302 (N = 197) in patients with adequately controlled intravascular hemolysis while on the labelled dosage of eculizumab showed that ravulizumab was noninferior to eculizumab in percentage of patients achieving transfusion avoidance (noninferiority margin of 20% for the mean difference), proportion of patients with lactate dehydrogenase (LDH) normalization (noninferiority margin of 0.39 for the odds ratio in Study 301 and not part of the statistical testing hierarchy in Study 302), and mean percent change in LDH level (noninferiority margins of 20% in Study 301 and 15% in Study 302 for the mean difference) over 26 weeks of treatment, with maintenance of efficacy up to 52 weeks of treatment in the extension periods of the studies. Evidence regarding symptom control, such as improvement of fatigue, was supportive of noninferiority of ravulizumab versus eculizumab. There is a need for treatments that are effective in patients who have insufficient control of intravascular hemolysis despite treatment with eculizumab, treatments that address the issue of extravascular hemolysis (an iatrogenic effect of eculizumab in some patients), and treatments that are less burdensome to patients (e.g., less frequent administration or improved ease of administration). The latter unmet need was emphasized in the patient input to CADTH. Given the evidence and the same mechanism of action for ravulizumab as for eculizumab, there is insufficient evidence to suggest that ravulizumab meets the first 2 unmet needs. Although ravulizumab may meet the third unmet need based on its less frequent administration, it was not possible to conclude whether ravulizumab treatment was associated with better health-related quality of life versus eculizumab treatment due to the lack of statistical testing for health-related quality of life outcomes, the open-label study design of both studies, and the lack of evidence in patients with PNH for the validity of the health-related quality of life scale used in the studies.
Using the sponsor-submitted price for ravulizumab and publicly listed price for eculizumab, ravulizumab was equally as effective and less costly compared with eculizumab for adult patients with PNH in the CADTH base case reanalysis. However, these results are extremely sensitive to the assumptions around the price of eculizumab. If the reimbursed price of eculizumab is 1% less than the list price, ravulizumab is more costly. The available clinical evidence suggests that ravulizumab is noninferior to eculizumab; as such, there is no evidence to support a price premium for ravulizumab.
Reimbursement Conditions and Reasons.
Issues that may impact the drug plan’s ability to implement a recommendation as identified by CDEC and the drug plans are summarized in Table 2.
Implementation Guidance From CDEC.
Ravulizumab has a Health Canada indication for the treatment of adult patients with PNH. Ravulizumab is a terminal complement inhibitor that specifically binds to the complement protein C5 and inhibits terminal complement–mediated intravascular hemolysis. It is available as a 10 mg/mL concentrate for solution for infusion; the Health Canada–recommended dosing regimen consists of a single loading dose followed 2 weeks later by the first maintenance dose, with maintenance doses administered every 8 weeks. The loading and maintenance doses are weight-based according to 3 different body weight ranges.
To make their recommendation, the committee considered the following information:
One patient group submission was received from the Canadian Association of PNH Patients. Information was gathered through one-on-one interviews with 6 individuals living with PNH in Canada and from the scientific literature. The following negative impacts of PNH were described: dependence on frequent transfusions and difficulty in maintaining school attendance or employment for patients and caregivers due to frequent clinic visits, blood transfusions, and hospitalizations. According to the patient input, patients want treatment options and the less-burdensome treatment regimen of ravulizumab (every 8 weeks) compared with eculizumab (every 2 weeks) represents an improvement in quality of life and the opportunity to travel for longer periods of time. It was also noted that patients with PNH, who are immunocompromised, would prefer to visit the clinic for infusions less frequently in the context of the current pandemic.
The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of PNH.
One unmet need of patients with PNH is that the quality of life of patients being treated with eculizumab could be improved by modifying the treatment schedule or ease of treatment administration. Additionally, at the Health Canada–approved product monograph–recommended dosage for eculizumab in PNH, approximately 20% of patients do not have complete control of signs and symptoms associated with incomplete pharmacologic C5 inhibition though this can be addressed by administering higher doses of eculizumab. Finally, patients who have clinically significant anemia secondary to eculizumab treatment have an unmet need for extravascular hemolysis control; however, extravascular hemolysis would not be expected to improve with ravulizumab treatment.
Ravulizumab has the same mechanism of action as eculizumab and, if funded, would be considered first-line therapy in place of eculizumab for most patients. Patients in need of anti-complement therapy include those with evidence of a PNH clone (usually white blood cell clone size > 10%), hemolysis (i.e., LDH > 1.5 × the upper limit of normal [ULN]), and symptoms. Almost all, if not all, patients with hemolytic PNH who would qualify for eculizumab would similarly be expected to respond to ravulizumab. Neither treatment would be effective in the small proportion of patients of Japanese (approximately 3%) and Han Chinese (approximately 1%) descent who have a polymorphism which negates the effect of eculizumab as there is no effective target on C5. Currently, eculizumab may be preferred over ravulizumab during pregnancy given the available efficacy and safety data for eculizumab though this may change as more clinical experience with ravulizumab accumulates.
A clinically meaningful response to treatment would include improved symptoms and signs (e.g., fatigue, dyspnea, kidney function, abdominal pain, erectile dysfunction) and/or reduced transfusion demands. Response is assessed by review of the signs or symptoms and mapping onto biochemical evidence of reduced intravascular hemolysis (LDH < 1.5 × ULN) and improved counts (e.g., hemoglobin), and other parameters (e.g., creatinine, echocardiogram). Discontinuation of anti-complement therapy would rarely be considered, and relevant situations would include nonresponse (almost always associated with the polymorphism that negates the effect of C5 inhibition); persistent, severe adverse reactions (very rare); progression to severe bone marrow failure requiring bone marrow transplant; and regression of PNH clone to less than 10%, if associated with resolution of clinically significant hemolysis.
Responses to Questions From the Drug Programs.
Two relevant studies, the ALXN1210-PNH-301 and ALXN1210-PNH-302 studies (referred to here as Study 301 and Study 302, respectively), were selected for inclusion in the CADTH systematic review. Both studies were open-label, active-controlled, parallel-group, noninferiority RCTs. Both studies were sponsored by Alexion Pharmaceuticals, Inc., and the primary evaluation periods of both studies took place from 2016 to 2018. Study 301 (N = 246) enrolled adult patients with PNH who were treatment naive, whereas Study 302 (N = 197) enrolled adult patients with PNH who had been receiving eculizumab. Patients were randomized 1:1 to ravulizumab or eculizumab. Noninferiority of ravulizumab compared with eculizumab was assessed for transfusion avoidance, fatigue, breakthrough hemolysis, LDH normalization, and hemoglobin stabilization during a 26-week primary evaluation period.
Patients in both studies had to have a PNH diagnosis confirmed by flow cytometry (granulocyte or monocyte clone size of at least 5%); patients in Study 301 had to have an LDH level of at least 1.5 × ULN and at least 1 PNH-related sign or symptom in the past 3 months. Patients in Study 302 had to have received eculizumab and have controlled LDH for at least the 6 months before the study. Across both studies, approximately half of patients were male, most were either Asian or White, and the mean age was 45 years to 49 years. In Study 301, most patients had an LDH level of 3 × ULN or greater and had received at least 1 transfusion in the past year. Patients in Study 302 had a mean LDH of 228 U/L to 235 U/L (with ULN for LDH considered to be 246 U/L), with 12.2% to 13.4% of patients having received at least 1 transfusion in the past year. Patients in Study 301 had a shorter mean disease duration (6.4 years to 6.7 years) than patients in Study 302 (11.9 years to 12.4 years), who had been receiving eculizumab for a mean of 5.6 years to 6.0 years. There were lower percentages of patients in Study 301 who had experienced a major adverse vascular event (13.6% to 20.7%) than in Study 302 (22.4% to 28.9%).
The results for transfusion avoidance, LDH normalization, and percent change in LDH level, which were the primary and co-primary end points in the studies, are presented in this summary. Results for other clinically important outcomes — health-related quality of life and fatigue — are also presented. The results for the per-protocol analyses for all primary and key secondary end points were consistent with the primary analyses.
Transfusion avoidance was a co-primary end point in Study 301 and a key secondary end point in Study 302 that was tested for noninferiority in both studies according to the closed testing procedure. In Study 301, 73.6% of the ravulizumab group and 66.1% of the eculizumab group achieved transfusion avoidance throughout the 26-week primary evaluation period; the mean difference for ravulizumab versus eculizumab was 6.8% (95% confidence interval [CI], –4.66% to 18.14%). In Study 302, 87.6% of the ravulizumab group and 82.7% of the eculizumab group achieved transfusion avoidance throughout the 26-week primary evaluation period; the mean difference for ravulizumab versus eculizumab was 5.5% (95% CI, –4.27% to 15.68%). Noninferiority was met in both studies as the lower bounds of the 95% CIs were higher than –20%.
LDH normalization was a co-primary end point in Study 301 and a secondary end point in Study 302. In Study 301, the proportion of patients achieving LDH normalization from day 29 to day 183 was 0.536 (95% CI, 0.459 to 0.612) in the ravulizumab group and 0.494 (95% CI, 0.417 to 0.570) in the eculizumab group, with an odds ratio of 1.187 (95% CI, 0.796 to 1.769) for ravulizumab versus eculizumab. Noninferiority was met as the lower bound of the 95% CI was greater than 0.39. In Study 302, the proportion of patients achieving LDH normalization from baseline to day 183 was 0.660 (95% CI, 0.561 to 0.747) in the ravulizumab group and 0.708 (95% CI, 0.613 to 0.788) in the eculizumab group, with an odds ratio of 0.801 (95% CI, 0.500 to 1.282) for ravulizumab versus eculizumab (the outcome was not part of the statistical testing hierarchy).
Mean percent change in LDH level from baseline to day 183 was the primary end point in Study 302 and a key secondary end point in Study 301. It was tested for noninferiority in both studies and for superiority in Study 302 in accordance with the closed testing procedure. In Study 302, the least mean squares difference in percent change in LDH level was –9.21% (95% CI, –18.84% to 0.42%) for ravulizumab versus eculizumab. Noninferiority was met as the upper bound of the 95% CI was lower than 15%. Percent change in LDH was the first outcome in the Study 302 testing hierarchy for superiority. The significance level was not met for superiority and no further testing was performed. In Study 301, the least mean squares difference in percent change in LDH level was –0.83% (95% CI, –5.21% to 3.56%) for ravulizumab versus eculizumab. Noninferiority was met as the upper bound of the 95% CI was lower than 20%.
Change in the European Organisation for Research and Treatment of Cancer Questionnaire (EORTC QLQ-C30) global health status score from baseline to week 26 was a secondary end point and not part of the closed testing procedure in either study. Increase in global health status score corresponds to improvement. In Study 301, patients in the ravulizumab and eculizumab groups had a change in global health status score of 13.17 (standard deviation [SD] = 21.44) and 12.85 (SD = 21.83), respectively. In Study 302, baseline and week 26 scores were similar to each other within each group, with a change in global health status score of 1.15 (SD = 16.51) in the ravulizumab group and –1.93 (SD = 15.34) in the eculizumab group
The change in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) total score was a key secondary end point and was tested for noninferiority in accordance with the closed testing procedure in both studies. Lower FACIT-Fatigue scores correspond to greater fatigue. In Study 301, least squares mean (LSM) change from baseline to week 26 in total score was 7.07 (standard error of the mean [SEM] = 0.77) in the ravulizumab group and 6.40 (SEM = 0.79) in the eculizumab group, with a mean difference for ravulizumab versus eculizumab of 0.67 (95% CI, –1.21 to 2.55). In Study 302, LSM change from baseline to week 26 in total score was 2.01 (SEM = 0.697) in the ravulizumab group and 0.54 (SEM = 0.704) in the eculizumab group, with a mean difference for ravulizumab versus eculizumab of 1.47 (95% CI, –0.21 to 3.15). Noninferiority was met in both studies as the lower bounds of the 95% CIs were higher than –5 and –3 in Study 301 and Study 302, respectively.
Most patients (86.8% to 88.0%) in both treatment groups in both studies reported at least 1 adverse event (AE). The most common AE was headache; there were no notable imbalances in AEs. Serious AEs were reported in 4.1% to 8.8% of each treatment group in both studies. The most common serious AEs were hemolysis and pyrexia, which occurred in 3.1% of patients or less in each treatment group. There were no withdrawals due to AE in either study. One patient in the eculizumab group in Study 301 died due to lung adenocarcinoma during the extension phase of the study.
In terms of notable harms, serious infections were reported in 1.0% to 3.3% of each treatment group in both studies. Infusion reactions were reported in 3.1% to 8.8% of patients across each treatment group in both studies. As for treatment-emergent anti-drug antibody–positive samples, there was 1 in each treatment group in Study 301 and 1 in the eculizumab group in Study 302 and titres were considered to be low.
The prespecified noninferiority margins for the primary and key secondary end points (aside from percent change in LDH, potentially) were based on a magnitude of loss of benefit that may not be clinically acceptable. However, there are several factors that mitigate the risk of unacceptable loss of benefit with ravulizumab versus eculizumab. All the primary and key secondary end points met their respective noninferiority margins, there was minimal missing data, the per-protocol analyses were consistent with the primary analyses for all end points, and a more conservative margin would have been met for all end points.
The open-label nature of the studies means that outcomes relying on subjective reporting, such as the EORTC QLQ-C30 and the FACIT-Fatigue, could have been biased with potential for bias in favour of ravulizumab. Additionally, the reliability, validity, and responsiveness of the EORTC QLQ-C30 and the FACIT-Fatigue have yet to be characterized in patients with PNH. Statistical testing was only performed for the FACIT-Fatigue score and not for other symptom assessments or for the EORTC QLQ-C30 scales.
The criteria for Study 302 were chosen in such a way that patients requiring a higher dose or more frequent dosing of eculizumab beyond the product monograph–recommended dosage would have been excluded. Although these patients were included in Study 301, the studies did not allow for deviation from the labelled dosage of eculizumab (900 mg maintenance dose) and this may have biased the efficacy results in favour of ravulizumab relative to how eculizumab is dosed in clinical practice.
Safety and efficacy results from the respective extension periods for Study 301 (N = 243) and Study 302 (N = 191), when all patients received ravulizumab, were also submitted by the sponsor and are presented in this report for the 26-week period following the randomized treatment period. Also included in the sponsor’s submission was a patient preference substudy (N = 95) in which patients from Study 302 who enrolled in the extension period and had received at least 2 doses of ravulizumab during the extension period were eligible to enrol. A novel patient preference questionnaire was developed for the study and the objective of the study was to assess patient preferences for ravulizumab or eculizumab and to identify the key factors influencing preference.
The results from the extension periods of Study 301 and Study 302 were reported as summary statistics and indicated that efficacy, as assessed through transfusion avoidance, FACIT-Fatigue score, breakthrough hemolysis, LDH normalization, and hemoglobin stabilization, was generally maintained with ravulizumab treatment for another 26 weeks following the randomized treatment period.
According to the results from the questionnaire administered in the patient preference substudy, 93% of patients preferred ravulizumab overall with 43% of patients choosing frequency of infusions and 23% of patients choosing overall quality of life as the most important treatment factor when decided preference.
The AE profiles in the extension periods of Study 301 and Study 302 were similar to those in the randomized treatment periods, with no new safety signals identified. The frequency of headaches numerically decreased between the 2 periods in both treatment groups in both studies.
The extension periods of Study 301 and Study 302 do not provide evidence for the comparative efficacy of ravulizumab versus eculizumab because all patients who continued in the extension periods received ravulizumab. As well, reductions in sample size in periods beyond the first 52 weeks of study treatment precluded the ability to assess results beyond 1 year of treatment, which is a concern given the chronic nature of the disease.
There were several limitations identified in the patient preference substudy that introduce substantial uncertainty in the results. These include the lack of evidence for the reliability and responsiveness of the questionnaire, the potential for recall bias given that ravulizumab was the most recent treatment for all patients, the small sample size relative to the population of Study 302, and uncertainty surrounding reasons for the reduction in sample size.
Cost and Cost-Effectiveness.
CADTH identified the following key limitations with the sponsor’s analysis.
CADTH reanalyses included increasing the uptake of ravulizumab, changing the number of new patients eligible for complement inhibitor therapy from 0 to 14 each year, increasing the proportion of new patients who initiate ravulizumab, using the discontinuation rate for ravulizumab observed in Study 302, assuming no up-dosing with eculizumab, and assuming that ravulizumab patients receive 7 maintenance dose administrations in the first year of treatment. Based on the CADTH reanalyses, the estimated budget impact from reimbursing ravulizumab is expected to be $6,956,164 in year 1, $3,259,336 in year 2, and $2,965,349 in year 3 for a 3-year total of $13,180,849. Note that the there is uncertainty in the budget impact estimate as CADTH’s 3-year budget impact is greater than double that estimated by the sponsor ($1,055,670 over 3 years). If a proportion of patients receiving eculizumab are continuously receiving a higher than 900 mg dose, the expected budget impact associated with reimbursing ravulizumab will be less. This scenario also assumes no up-dosing is required for patients receiving ravulizumab.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, 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: December 15, 2021
Regrets: One expert committee member did not attend
Conflicts of interest: None
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third-party supplier of information.
This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.
This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
Redactions: Confidential information in this document may be redacted at the request of the sponsor in accordance with the CADTH Drug Reimbursement Review Confidentiality Guidelines.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Indication: Ultomiris (ravulizumab for injection) is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH)
Sponsor: Alexion Pharma Canada Corp.
Final recommendation: Reimburse with conditions
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
Your browsing activity is empty.
Activity recording is turned off.
See more...
