NICE Rejects Caplacizumab-yhdp for Acute Episodes of Acquired TTP

The United Kingdom’s National Institute for Health and Care Excellence (NICE) has chosen not to recommend caplacizumab-yhdp (Cablivi) for use with plasma exchange and immunosuppression in the treatment of acute episodes of acquired thrombotic thrombocytopenic purpura (TTP) in adults and those aged 12 years and over who weigh at least 40 kg.¹

The agency agreed that trial evidence demonstrates caplacizumab plus the standard care for an acute episode of acquired TTP, which is comprised of plasma exchange and immunosuppressant medications, decreases the time it takes to bring platelet levels back to normal, the number of required plasma exchange treatments, and the time in hospital and intensive care.

Additionally, the addition of caplacizumab could reduce long-term complications associated with acquired TTP as well as the risk of death around the time of an acute episode. However, the trial examined does not assess whether the agent extends or improves quality of life in the long term. This must be confirmed with further research.

These limitations in the clinical evidence make the cost-effectiveness estimates for the agent compared with standard care alone very unclear. However, the agency postulates that these estimates might potentially be higher than what is considered to be acceptable with regard to National Health Service (NHS) resources.

The decision is not intended to affect treatment with caplacizumab that was initiated in the NHS before this guidance was published. The agent will continue to be funded by Sanofi, the developer of the drug, until patients and their NHS physician choose to discontinue treatment.

Clinical evidence for the decision came from the double-blind, randomized phase 3 HERCULES trial, which included 145 patients with an acute episode of acquired TTP. In the trial, investigators compared caplacizumab plus plasma exchange and immunosuppressant drugs, which included rituximab (Rituxan), with placebo plus standard care. Notably, although the marketing authorization for the agent calls for the agent to be administered prior to plasma exchange, in the trial, caplacizumab was given afterward.

Results showed that the addition of caplacizumab decreased the time to platelet normalization. The difference in the median time to platelet normalization between treatments was very small, at just 0.2 days (2.7 days in the caplacizumab arm vs 2.9 days in the placebo arm; P <.01).

Caplacizumab also reduced the composite outcome, in that 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 the standard care arm (P <.001).

Additionally, less patients on the caplacizumab arm experienced disease recurrence while on treatment or in the 28 days after treatment was stopped, at 13% versus 38% (P <.001). The addition of the agent also resulted in less mean duration of plasma exchange versus standard care alone (6 days vs 9 days), 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 versus standard care alone. They also concluded that the data observed in the HERCULES trial were generalizable to clinical practice in the United Kingdom. However, although the outcomes in the trial were considered to be clinically relevant, the committee did not feel that the trial tested for short- or long-term morbidity or mortality.

With regard to safety, the most common adverse event reported was mucocutaneous bleeding, which was reported in 65% of those on the caplacizumab arm versus 48% of those on the standard care arm.² During the treatment period, 1 patient randomized to the caplacizumab arm died versus 3 patients on the standard care arm. The company and clinical experts both agreed that the number of deaths reported on the trial is likely lower than what would be expected in clinical practice.

No quality-of-life (QoL) data were collected on the trial. Instead, Sanofi used QoL data from those who were hospitalized with stroke to estimate QoL during an acute episode of acquired TTP. Doing so, resulted in a baseline utility value of 0.64. The committee noted that the value was high, suggestive of better QoL than would normally be expected for patients who are in the hospital for a potentially life-threatening condition.

After considering QoL on the company’s cost-effectiveness estimates, factoring in the fear of relapse, and the estimated QoL associated with cognitive impairment and mental health in patients, the committee concluded that the impact of acquired TTP on QoL is considerable but unclear and the effect of alternative QoL assumptions should undergo further exploration.

With regard to cost effectiveness, the company’s and the evidence review group’s base-case cost-effectiveness estimates were comparable, at £28,000 and £31,000 per quality-adjusted life year (QALY) gained, respectively.

“The committee considered that caplacizumab might reduce short-term deaths around an acute episode. However, it thought that the limitations of the data meant that the extent of the survival benefit was unclear,” the agency wrote in the appraisal consultation document. “Any evidence for a benefit of caplacizumab on long-term complications and acquired TTP-related death was even more limited.”

With the assumption of no survival benefit in the short term around an acute episode and no survival benefit in the long term led to an incremental cost-effectiveness ratio (ICER) of approximately £120,000 per QALY gained. The assumption of no benefit of caplacizumab on the rate of long-term complications such as cognitive impairment and mental health issues versus standard care further increased the ICER.

Furthermore, acceptance of the company’s estimate of short-term survival benefit without assuming survival benefit in the long term led to an ICER of approximately £47,000 per QALY gained. Assumption of no benefit with caplacizumab on decreasing the number of long-term complications further increased the ICER.

However, the committee deemed that neither the company’s nor the ERG’s cost-effectiveness estimates accounted for the uncertainty surrounding the assumptions in the economic model, particularly those pertaining to death rates.

Before the cost-effectiveness of caplacizumab can be considered, Sanofi will need to address the following uncertainties as outlined by the committee:

• Estimates of the probability of dying around an acute episode
• Estimates of the long-term treatment effect of caplacizumab
• Utility values, including alternative QoL scenarios
• Scenario analyses

“Caplacizumab is the first new treatment for acquired TTP in about 25 years. It has a different mechanism of action to the other drugs and treatments that form current standard care. Caplacizumab has additional benefits to standard care,” the agency wrote in the appraisal consultation document. “However, the committee thought the extent to which it is a step change in the treatment of acquired TTP was unclear because of the uncertainty about its effect on overall survival and long-term complications.”

References

1. Appraisal consultation document: caplacizumab for treating acute acquired thrombotic thrombocytopenic purpura. National Institute for Health and Care Excellence. June 2020. Accessed June 16, 2020. bit.ly/3fzIX39.
2. Scully M, Cataland SR, Payvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4)335-346. doi:10.1056/NEJMoa1806311

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