November 16, 2020 — The United Kingdom’s National Institute for Health and Care Excellence has recommended caplacizumab-yhdp with plasma exchange and immunosuppression for the treatment of an acute episode of acquired thrombotic thrombocytopenic purpura in adults and those aged 12 years and over who weigh at least 40 kg.
The United Kingdom’s National Institute for Health and Care Excellence (NICE) has recommended caplacizumab-yhdp (Cablivi) with plasma exchange and immunosuppression for the treatment of an acute episode of acquired thrombotic thrombocytopenic purpura (TTP) in adults and those aged 12 years and over who weigh at least 40 kg.1
Previously, in June 2020, NICE issued an appraisal consultation document in which they chose not to recommend caplacizumab for this indication.2 The committee cited limitations in clinical evidence that made the cost-effectiveness estimates for the agent versus standard care very unclear. At the time, they felt the estimates to be higher than what is considered to be acceptable.
Standard-of-care treatment for these patients is comprised of plasma exchange and immunosuppressant agents. The addition of caplacizumab to standard care has been found to reduce the time it takes to bring platelet levels back to normal, the number of plasma exchange treatments required, and the time in the hospital and intensive care unit, compared with standard care alone, according to NICE.
Although the addition of the bivalent single-domain antibody is thought to reduce the long-term complications associated with acquired TTP and diminish the risk of death around the time of an episode, the extent of this is unclear. Available data do not answer whether the addition of the drug improves length or quality of life (QoL) after the drug is discontinued. Moreover, limited information is available on what the longer-term complications of acquired TTP are following an acute episode.
“The assumptions in the economic modelling are plausible,” NICE stated in the final appraisal document. “Also, there are potential benefits with caplacizumab that are not included in the cost-effectiveness estimates. Overall, the estimates are within the range normally considered a cost-effective use of National Health Service resources. So, caplacizumab is recommended for treating acute acquired TTP.”
Two placebo-controlled trials of caplacizumab were considered by the committee when they were making this decision: HERCULES (NCT02553317) and TITAN (NCT01151423). Both were double-blind, randomized, controlled trials. TITAN enrolled 75 patients who were experiencing an acute episode of acquired TTP, while HERCULES enrolled 145 patients. In both trials, the addition of caplacizumab to standard care was compared with placebo/standard care. Although the marketing authorization for the drug calls for its administration before plasma exchange, caplacizumab was given afterward in the trial.
Results demonstrated that the addition of caplacizumab reduced the time to platelet normalization. The difference in the median time to platelet normalization between treatments
was very small, at just 0.2 days. Specifically, the median time was 2.7 days in the caplacizumab arm versus 2.9 days in the placebo arm (P <.01).
Caplacizumab was also found to decrease the composite outcome; 12% of those in the caplacizumab arm had an acquired TTP-associated death, disease recurrence while on treatment, or a major thromboembolic event compared with 49% of those who were in the standard-care arm (P <.001).
Moreover, fewer patients on the caplacizumab arm had disease recurrence while on treatment or in the 28 days following treatment discontinuation at 13% versus 38%, respectively (P <.001). The addition of caplacizumab also resulted in less mean duration of plasma exchange versus standard care alone (6 days vs 9 days, respectively), as well as reduced mean volume (21 liters vs 36 liters) and mean days in the hospital (10 days vs 14 days) and in intensive care (3 days vs 10 days).
Based on these data, the committee concluded that caplacizumab is clinically effective in the acute period compared with standard care alone. However, based on the data available, they still did not feel that there was sufficient evidence to reliably estimate how much caplacizumab might reduce deaths in the acute period.
Ablynx, the drug developer, responded to the appraisal consultation document by providing alternative estimates of benefit with caplacizumab in reducing deaths during an acute episode. However, despite these efforts, the committee found that the company’s estimates of the benefit of the agent on mortality based on trial data are not robust and are overestimated.
To identify the absolute risk of death following an acute episode over the long term in patients who had received standard care alone, the company calculated a standardized mortality ratio; this was then applied to the risk of dying in the United Kingdom with regard to the general population. The ratio reflects observed deaths following standard care during an acute episode divided by the expected number of deaths for the general population who are similar age and sex. Based on their calculations, the company reported that the standardized mortality ratio was 8.3. The committee concluded that in the long-term submodel, the company’s revised calculation of a standardized mortality ratio to estimate death rates is appropriate.
Moreover, the committed noted that QoL data from HERCULES are not available. Acquired TTP is known to lower QoL and the committee agrees that caplacizumab improves QoL, but by how much continues to be uncertain.
Caplacizumab is the first new treatment for the condition in approximately 25 years, according to the committee, and it has a different mechanism of action compared with other drugs and approaches that are used in standard care. The agent has additional benefits to standard-of-care treatment, and it’s possible that not all of these benefits were captured in the calculation of quality-adjusted life year (QALY). Some additional benefits of the drug include reducing the
use of scarce resources like plasma or beds in the intensive care unit. Based on this, the committee concluded that the agent is innovative.
Regarding cost, the list price of caplacizumab is £4,143 per 10 mg vial. Because of the limited clinical data, considerable uncertainty pertaining to estimates of cost effectiveness remains, according to the committee; this is particularly true when considering survival in the acute period and the long-term benefits of this approach.
“Using the committee’s preferred modelling assumptions resulted in an ICER of £29,537 per QALY gained. In line with the NICE methods guide for technology appraisal, when a most plausible [incremental cost effectiveness ratio] ICER is above £20,000 per QALY gained, the committee can take account certain factors, including innovation,” the committee concluded. “At its fourth meeting, the committee concluded that the ICER for caplacizumab fell within a range considered to be a cost-effective use of NHS resources and recommended caplacizumab as an option for treating acquired TTP.”