Summary of Patient Input

One patient group, the Answering TTP Foundation (with the support of the Canadian Organization for Rare Disorders), provided input for this submission. Patient perspectives were obtained from a survey and interviews with patients, caregivers or family members, and health care professionals in Canada, as well as in other countries. The following is a summary of key input from the perspective of the patient group:

• The Answering TTP Foundation indicated that challenges of aTTP are mostly the result of acute TTP episodes, which can be life-threatening and require intensive treatment. Patients’ quality of life was significantly impacted as a result of an aTTP episode. Canadian patients expressed a sense of frustration with challenges to obtaining an initial diagnosis and receiving timely care for the acute episodes. In addition, patients highlighted the financial burden associated with the disease and treatment.
• Almost all respondents reported experience with PEX and corticosteroids, and 70% of them had or were currently receiving rituximab. Timely access to PEX was a challenge for some patients. When PEX was unable to stabilize platelet counts, patients reported limited options for effective treatment. In addition, patients reported experiencing adverse events with PEX, which were sometimes serious in nature. Patients also noted adverse events associated with receiving corticosteroids and other treatments for aTTP.
• Approximately 5% to 6% of respondents had received caplacizumab. The feedback regarding treatment with caplacizumab was positive, particularly regarding time to response (platelet control recovery), time spent in hospital, and improved physical and mental well-being. Patients also reported experiencing minimal side effects associated with the use of caplacizumab (primarily minor, localized bleeding in soft tissues such as the gums).
• Patients expressed a desire for a new treatment to provide faster normalization of platelet counts, reduced frequency and length of PEX, shorter hospital stays, quicker return to normal life, improved survival, and reduced disease relapse.

Clinical Trials

The systematic review included one phase III, double-blind RCT (HERCULES, N = 145) that evaluated the efficacy and safety of caplacizumab in adult patients with aTTP. Eligible participants were randomized to receive caplacizumab 11 mg or placebo, in addition to standard of care, which consisted of PEX and corticosteroid treatment, as well as other immunosuppressive drugs, per study site treatment procedures for aTTP. The double-blind treatment phase consisted of a daily PEX period plus a 30-day post-daily PEX period. A treatment extension phase of seven to 28 days with the patient’s originally assigned treatment (caplacizumab or placebo) was allowed for those with risk factors of relapse of the presenting aTTP episode. During the double-blind treatment period of HERCULES, in cases of first exacerbation or relapse of the presenting aTTP episode, patients would receive open-label caplacizumab together with daily PEX irrespective of what the initial treatment allocation was. After treatment, all patients were followed for four weeks. The primary efficacy outcome of this study was time to platelet count response (defined as initial platelet count ≥ 150 × 10⁹/L with subsequent stop of daily PEX within five days of treatment). Other efficacy outcomes included prevention of recurrence of aTTP, prevention of refractory aTTP, prevention of major thromboembolic event, normalization of organ damage markers, and intensive care unit (ICU) or hospital stay related to aTTP episodes. A composite end point including aTTP-related death, recurrence of aTTP, or a thromboembolic event during the treatment period were assessed as well. Health-related quality of life was not assessed. The median duration of exposure to caplacizumab during the double-blind period was 35 days (maximum of 65 days).

Key limitations of HERCULES included potential biases on the study results due to imbalanced patient baseline characteristics, uncertainty around the validity of using platelet count for treatment effect evaluation, missing data for some efficacy outcomes, and a lack of statistical testing and/or adjustments for multiplicity for some of the clinically relevant secondary efficacy outcomes. Long-term clinical benefits and harms were not explored in HERCULES due to its duration.

Outcomes

Outcomes of interest were defined a priori in CADTH’s systematic review protocol. Of these, the committee discussed survival, reduction in use of PEX, aTTP recurrence, organ damage, prevention of major thromboembolic events, prevention of refractory aTTP to treatment, platelet count response, and hospitalization due to aTTP episodes. The absence of health-related quality of life data was noted.

Efficacy

Harms (Safety)

During the overall study period of HERCULES, almost all patients reported adverse events: 97.2% in the caplacizumab group and 97.3% in the placebo group. The most common adverse events reported in the caplacizumab group were epistaxis, headache, gingival bleeding, urticaria, pyrexia, fatigue, nausea, and aTTP episodes. There were fewer serious adverse events with caplacizumab (28 patients; 39.4%) compared with placebo (39 patients; 53.4%) during the overall study period. aTTP episodes were the most commonly reported serious adverse event, and the incidence of aTTP episodes was higher in the placebo group (39.7%) than in the caplacizumab group (12.7%). Five patients (7.0%) treated with caplacizumab and nine patients (12.3%) treated with placebo withdrew from the study or treatment due to adverse events.

Bleeding events, hypersensitivity, and anti-drug antibody development were adverse events prespecified to be of interest for the CADTH review. The frequency of bleeding events was similar between treatment groups, occurring in 49 patients (69%) in the caplacizumab group and 49 patients (67.1%) in the placebo group. Likewise, the frequency of hypersensitivity reactions ▬▬▬▬▬ and development of anti-drug antibodies (caplacizumab = 2.8%; placebo = 1.4%) were similar between groups during the overall study period.

Other Relevant Evidence

The TITAN study was considered a supportive study of the pivotal HERCULES RCT in the CADTH review of caplacizumab. TITAN was a phase II, multicenter, single-blinded, parallel design, placebo-controlled RCT conducted in adult patients who were symptomatic and experiencing acute episodes of aTTP that required treatment with PEX. Approximately 90% of patients in each group received concomitant corticosteroids. A total of 75 patients were included in the TITAN study; 36 received caplacizumab and 39 received placebo. The primary outcome in the TITAN study was confirmed platelet response. The mean duration of treatment with caplacizumab was approximately 38 days (with a maximum of 77 days).

Patients treated with caplacizumab reached a confirmed platelet response more rapidly than patients treated with placebo (hazard ratio of 2.20; 95% CI, 1.28 to 3.78; P = 0.005).

In terms of safety, almost every patient experienced at least one adverse event, and more than half of all patients experienced at least one serious adverse event. The most common adverse event was aTTP. Serious reports of aTTP and bleeding events were more common among patients treated with caplacizumab compared to placebo. ▬▬▬▬▬, respectively, and bleeding events were reported by 54.3% and 37.8% of treated patients, respectively.

Although TITAN suggested that caplacizumab is more efficacious than placebo in patients receiving PEX and corticosteroids, the interpretation of the results is limited by concerns with the internal validity. More specifically, in terms of the single-blinded study design, the primary efficacy outcome, and lack of adjustment for multiplicity of statistical testing. As well, the generalizability of the results to the Canadian context may be limited given the lack of study sites in Canada, that not all patients received corticosteroids, and that the demographics of the study may not reflect the diversity of the patient population with aTTP in Canada.

Cost and Cost-Effectiveness

The submitted price of caplacizumab is $6,200 per 11 mg dose. Assuming 37.2 days of therapy (i.e., the mean exposure to caplacizumab for patients in the active treatment group of the HERCULES trial; the reported maximum was 65 days), the cost of caplacizumab for an aTTP episode is $236,840 per patient (maximum = $409,200).

The sponsor submitted a cost-utility analysis comparing caplacizumab in addition to standard of care to standard of care alone in adult patients with aTTP from the perspective of a Canadian public health care payer. Standard of care consisted of PEX; a corticosteroid regimen of three days of IV prednisolone followed by oral prednisone for the duration of daily PEX and for a week afterward; and the option of other immunosuppressant therapies, such as rituximab. The analysis was conducted over a lifetime time horizon (60 years) with cycle length defined as three months. Patients entered the model in an acute aTTP state and, during the first cycle, patients could experience events with long-term consequences, such as a myocardial infarction (MI), stroke, or death. Patients could also experience other adverse events, such as a PEX complication, and be at risk of exacerbation within this first cycle, defined as a platelet count drop after initial normalization requiring the re-initiation of daily PEX within 30 days of stopping it. Relative risks of these events in the caplacizumab group were derived from the HERCULES trial, while the underlying probability of each event occurring in the standard of care group was derived from a variety of sources. Following the first cycle, patients who remained alive transitioned to the remission phase in either a chronic MI or chronic stroke health state if they had MI or stroke, respectively, or to a no neurologic or cardiac condition health state. As the analysis only modelled a single aTTP event, patients then stayed in their respective remission states until death. These health states were associated with different costs, utilities, and mortality risks with patients in the “no neurologic or cardiac condition” remission health state having mortality rates and utility scores consistent with the general population. Patients were assigned a disutility for an acute aTTP episode and an acute and chronic utility multiplier for MI or stroke events. Costs included hospitalization in the ICU and general ward, acquisition and administration of PEX, acquisition of caplacizumab and other pharmacotherapies (i.e., prednisolone, prednisone, and rituximab), laboratory testing, and specialist visits.

CADTH identified a number of limitations in the model submitted by the sponsor:

• The sponsor considered only a single episode of aTTP in its analysis, which is inconsistent with many patients’ lifetime experiences with aTTP recurrences.
• Not all deaths within the HERCULES trial for caplacizumab were accounted for in the economic model. The approach to model mortality during the acute aTTP episode further inflated the survival benefit of caplacizumab plus standard of care.
• aTTP relapses occurring after 30-days post-PEX in the HERCULES trial were not included in the submitted model, despite occurring within the follow-up time modelled in the first cycle.
• The sponsor assumed the mortality rate of patients in remission was identical to the general population despite long-term observational studies reporting higher mortality. Overall mortality was underestimated.
• The health utility score of patients in remission without stroke or MI was likely overestimated and may not be generalizable to the Canadian setting.
• Uncertainty associated with the relative risk of death, MI, and stroke during the aTTP episode was underestimated as an arbitrary coefficient of variation was assumed.

CADTH attempted to address most of these issues. The CADTH base-case analysis incorporated all deaths and recurrences in the caplacizumab group of the HERCULES trial to re-estimate relative risks; increased mortality rate for patients in remission based on the rates reported in an observational study; incorporated more recent Canadian utility scores and further incorporated a utility modifier to reflect the reduced quality of life of patients with chronic conditions; and captured the uncertainty inherent to the HERCULES trial for certain relative risk parameters. In CADTH’s base-case analysis, the incremental cost-effectiveness ratio associated with caplacizumab plus standard of care compared to standard of care alone was $237,053 per quality-adjusted life-year (QALY). At a willingness-to-pay of $50,000 per QALY, the price of caplacizumab would need to be reduced by approximately 75% to be considered cost-effective.

There is uncertainty associated with the cost-effectiveness of caplacizumab plus standard of care as CADTH was unable to consider future aTTP episodes, specifically the potential impact of caplacizumab on reducing or delaying them, or the costs associated with further treatment for acute episodes. In the HERCULES trial, the use of caplacizumab in addition to standard of care was associated with ▬▬▬▬▬, which is a key driver in the economic analysis. The vast majority of incremental QALYs gained within the model occurred during the extrapolated remission period rather than during the acute phase for which data exists. As such, assumptions around the quantity and quality of life experienced by patients who survive an aTTP episode are also key drivers of the cost-effectiveness results.