Cost Effectiveness of Caplacizumab in Acquired Thrombotic Thrombocytopenic Purpura

Introduction: Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by thrombotic microangiopathy leading to end-organ damage. The standard of care (SOC) treatment is therapeutic plasma exchange (TPE) alongside immunomodulation with steroids, with increasing use of rituximab +/- other immunomodulatory agents. The addition of caplacizumab, a nanobody targeting von Willebrand factor, was shown to accelerate platelet count recovery, reduce TPE treatments and hospital length of stay, decrease exacerbations and increase relapses in TTP patients treated in the TITAN and HERCULES trials. Given the efficacy of caplacizumab in the TITAN and HERCULES trials, we conducted a cost effectiveness analysis (CEA) of caplacizumab in acquired TTP, representing the first-ever CEA in TTP. Methods: We built decision tree models to evaluate the cost effectiveness of SOC plus caplacizumab versus SOC in acquired TTP based on the results of each of the phase II TITAN trial at 12-month follow-up and the phase III HERCULES trial at 1-month follow-up. Costs were assessed from the health system perspective. For each trial, the SOC cost was calculated as the sum of TPE sessions, hospital length-of-stay (LOS), intensive care unit (ICU) stay, and rituximab use, while the cost of the SOC plus caplacizumab arm included the SOC cost plus the list price of caplacizumab (USD $270,000 per TTP episode). Effectiveness was calculated in quality-adjusted life years (QALY). Cost effectiveness of each treatment arm was calculated as the ratio of cost divided by QALYs. The incremental cost effectiveness ratio (ICER) of adding caplacizumab to SOC was calculated as the difference between the costs of the two treatment arms divided by the difference in QALYs; the ICER was then compared against the 2019 US willingness-to-pay (WTP) threshold of $195,300 USD as a measure of overall cost effectiveness. To avoid potential confounding factors that might inadvertently bias our analysis against the addition of caplacizumab, all values used in our models were selected to maximize cost in the SOC arm and minimize cost in the SOC plus caplacizumab arm in the two clinical trials. We also created a Markov model comparing cost effectiveness of SOC plus caplacizumab versus SOC in acquired TTP with a 5-year time horizon. We performed one-way sensitivity analyses for all models varying parameters including LOS, ICU stay, number of TPE sessions, rituximab use, utilities of the well and diseases states, and caplacizumab cost. Results: In the decision tree models, caplacizumab use yielded a higher cost of treatment compared to SOC alone in both trials (TITAN: $325,647 for caplacizumab plus SOC, versus $89,750 for SOC; HERCULES: $323,547 for caplacizumab plus SOC, versus $83,634 for SOC). An improvement in QALYs with the addition of caplacizumab was noted as compared to SOC in both trials (0.07 in TITAN and 0.26 in HERCULES). The ICER for adding caplacizumab to SOC versus SOC alone was $3.7 million in the TITAN trial and $0.9 million in the HERCULES trial, well above the US WTP threshold. The 5-year horizon Markov model yielded higher cost of caplacizumab treatment compared to SOC alone ($551,878 versus $151,947) and an improvement in QALYs (3.19 versus 2.92). The ICER for adding caplacizumab to SOC was $1.5 million (95% confidence interval $1.25-$1.72 million) with SOC favored in 100% of 10,000 Monte Carlo simulations in a probabilistic sensitivity analysis. Among all parameters, decreasing the cost of caplacizumab had the greatest impact on decreasing the ICERs in all models. The price of caplacizumab treatment for one TTP episode to meet the 2019 US WTP would have to be $46,424 and $80,848 in the TITAN and HERCULES decision tree models, respectively, and $65,106 in a Markov model with a 5-year horizon. Conclusion: The addition of caplacizumab to SOC treatment is not cost effective at its current drug pricing. As our models are designed to maximize the cost effectiveness of caplacizumab, it is very likely that the actual costs incurred by this medication will be much higher than what we report here. Compared to CEA studies of other orphan drugs that, unlike caplacizumab, alter long-term disease course, the costs incurred by caplacizumab treatment in acquired TTP are at the higher end of the spectrum. Additional studies utilizing longer-term follow-up data are warranted to assess the full impact of caplacizumab on the cost of treating TTP. Figure Disclosures No relevant conflicts of interest to declare.

A cost-utility analysis of apalutamide for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC).

e19369 Background: The therapeutic landscape for patients with mCSPC has evolved over the last decade given the growing body of evidence demonstrating efficacy for the earlier application of oral androgen receptor signaling inhibitors, such as with abiraterone and enzalutamide. Recently the success of the TITAN trial established the superior efficacy of apalutamide combined with androgen deprivation therapy (ADT), with a 33% reduction in mortality versus ADT alone, and a tolerable toxicity profile. However, with substantially higher costs than ADT alone, the cost-effectiveness of this combination is critical to evaluate. Methods: A cost-utility analysis of apalutamide+ADT versus ADT alone was conducted from the Canadian healthcare perspective. A state-transition model with probabilistic analysis was used to compare the two strategies over a lifetime horizon. Model inputs were informed by the TITAN trial (transition probabilities, adverse events [AE], subsequent therapy), published literature (utilities) and Canadian costing resources (systemic therapy [initial and subsequent], routine care [physician visits, imaging], AE, end-of-life care costs). Primary outcomes included expected life-year gains (LYG), quality-adjusted life-years (QALY), lifetime cost (in 2018 Canadian dollars), and the incremental cost-effectiveness ratio (ICER). Multiple scenario analyses were conducted to assess parameter and model uncertainty. Cost and effectiveness were discounted at 1.5% as per Canadian guidelines. Results: From the base-case analysis expected LYG and QALY for ADT and apalutamide+ADT were 4.11, 5.57 and 3.50, 4.85, respectively. Expected cost over a lifetime horizon was $37,553 and $254,205, respectively. The ICER for apalutamide+ADT as compared to ADT alone was $160,483/QALY. Through scenario analysis, cost-effectiveness of apaluatmide+ADT was achieved with apalutamide price reductions of >50%, relative to a cost-effectiveness threshold (CET) of $100,000/QALY. Scenario analysis of alternative long-term survival expectations with apalutamide+ADT demonstrated cost-effectiveness (relative to CET $100,000/QALY) with expected improvements in the 5-year survival rate of 29% as compared to ADT (versus base-case expected improvement in 5-year survival of 15%). Conclusions: Apalutamide+ADT is unlikely to be cost-effective from the Canadian healthcare perspective at current list prices. Improvement in cost-effectiveness is most likely to be achieved through price reductions in apalutamide drug costs.

Caplacizumab, Anti-Vwf Nanobody Potentially Changing the Treatment Paradigm in Thrombotic Thrombocytopenic Purpura: Results of the TITAN Trial

INTRODUCTION: The TITAN trial achieved its primary endpoint in the ITT analysis of 75 subjects treated either with caplacizumab or placebo added to daily plasma exchange (PE). METHODS: Caplacizumab is a Nanobody which binds the A1 domain of vWF and thereby blocks the interaction of multimeric vWF with the GPIb-IX-V platelet receptor, preventing platelet aggregation typical of TTP. TITAN was a randomized, placebo controlled, single-blind, parallel design study. The primary endpoint was time to confirmed platelet response defined as platelet count normalization confirmed 48 hours later. Analysis was prospectively stratified according to whether or not subjects received a single PE prior to randomization. Treatment consisted of one IV bolus injection of caplacizumab 10mg (CAP) or placebo (PLC) prior to first on-study PE, followed by daily SC administration after PE. Once PE was stopped, CAP or PLC SC administration continued, daily for 30 days. RESULTS: The ITT population consisted of 36 and 39 subjects randomized 1:1 to CAP or PLC, respectively. Treatment arms were well balanced for age, race, body mass index. Presentation of TTP as an initial TTP episode or recurrent TTP was similar for both groups with 2/3 first episode and 1/3 recurrent. Platelet count and LDH were similar as summarized in table 1. Table 1 at baseline CAP N=36 PLC N=39 Platelets (10³/mm³) mean ± SD 21.1 ± 18.2 28.0 ± 20.0 LDH (U/L) mean ± SD 1277 ± 853 1270 ± 939 % subjects with ADAMTS-13 activity < 5% (FRET) 58.3 % 56.4 % Time to reach platelet response was almost 2 days shorter for CAP versus PLC, with a 39% reduction in time to response in the stratum with no prior PE, and 43% reduction in time to response in the stratum with a single prior PE. The overall hazard ratio was 2.197 for obtaining the confirmed platelet response with CAP over PLC, with a significance of p=0.013. The distribution of time to response was narrower for CAP in comparison to the distribution of subjects receiving PLC which was skewed towards longer confirmed platelet response time in table 2. Table 2 CAP PLC Median days to confirmed platelet response – subjects with no prior PE (95% CI) 3.00 (2.74, 3.88)N = 34 4.92 (3.21, 6.59)N = 35 25th & 75th percentile 2.72 & 4.31 3.01 & 11.37 Median days to confirmed platelet response – subjects with one single prior PE (95% CI) 2.44 (1.92, 2.97)N = 2 4.31 (2.91, 5.68)N = 4 25th & 75th percentile 1.92 & 2.97 3.37 & 5.23 N = 36 N = 39 Overall Hazard Rate Ratio for CAP vs. PLC (95% CI) 2.197 (1.278, 3.778) Stratified Log-rank Test p-value 0.013 Exacerbation of TTP occurred in 3 (8%) subjects receiving CAP versus 11 (28%) in the PLC arm. Complete remission defined as confirmed platelet response and absence of exacerbation up to 30 days after end of daily PE was achieved in 29 (81%) subjects of the CAP arm versus 18 (46%) subjects receiving PLC. The greater proportion of complete remission, coupled with the faster and narrower distribution of time to confirmed platelet response supports a greater predictability of patient response to PE in the CAP arm, and is reflected in number of days of PE. The number of consecutive days of PE was (mean ± st dev) 6.6 ± 3.4 days for CAP versus 8.1 ± 6.5 days for PLC with a total plasma volume administered including tapering of 22.5 ± 15.9 liters for CAP versus 28.4 ± 21.3 liters for PLC. The proportion of subjects with exacerbation and/or relapse up to the 1 month follow-up was even for both groups: 13 (36.1%) and 13 (33.3%) for both arms. Higher number of early relapses in the CAP arm substantiates a protective effect and warrants longer CAP treatment in some patients. Treatment emergent adverse events (TEAE) and deaths are summarized in table 3. Table 3 Safety population CAP N=35 PLC N=37 Subjects with any TEAE N (%) 34 (97%) 37 (100%) Subjects with bleeding related TEAEs N (%) 19 (54%) 14 (38%) Subjects with any TE Serious AEs N (%) 20 (57%) 19 (51%) Deaths N (%) 0 2 (5%) CONCLUSIONS: Caplacizumab, as a novel treatment, improved standard of care of patients affected with acquired TTP by a more rapid achievement of platelet normalization and lower number of exacerbations with manageable side effects and bleeding episodes. The TEAEs were consistent with the serious and potentially life-threatening condition of TTP. Further reducing PE and optimizing duration of caplacizumab should be investigated in future clinical trials. Disclosures Peyvandi: Ablynx: Investigator fees Other. Duby:Ablynx: Employment.