In the burgeoning age of personalized medicine, the treatment of rare anaemias is being transformed from one relying on transfusions and general immunosuppressants to one targeting the underlying disease pathology. Rare anaemias currently experiencing this shift include the autoimmune haemolytic anaemia (AIHA) cold agglutinin disease (CAD), which results from the immune-mediated destruction of erythrocytes. A novel treatment currently under investigation for CAD is the complement inhibitor pegcetacoplan in the phase III CASCADE trial (ClinicalTrials.gov identifier: NCT05096403).
In this article, we provide an overview of CAD, its disease burden and current unmet needs, and discuss the CASCADE trial, which was presented by Dr Bernd Jilma from the Medical University of Vienna in Austria at the American Society of Hematology 2022 meeting in New Orleans, LA, USA in December 2022.
Cold agglutinin disease
Although CAD is a rare disease, which typically affects elderly or middle-aged people, it accounts for up to ~25% of AIHA cases.1,2 Patients with CAD produce cold agglutinin autoantibodies, which recognize erythrocyte antigens at temperatures below physiological body temperature.3 This results in the agglutination of erythrocytes and extravascular haemolysis, leading to anaemia but generally without haemoglobinuria.3 Primary CAD is a low-grade clonal bone marrow disorder,4 although the disease can also arise secondary to a lymphoid malignancy, autoimmune disorder or viral infection.3
Research into the underlying mechanisms of CAD has led to the understanding that cold agglutinin autoantibodies, the majority of which are of the immunoglobulin (Ig)-M class, binding to erythrocyte antigens leads to the recruitment of components from the classical complement pathway.2,5 This includes C3 convertase, which cleaves C3 to C3a and C3b, the latter of which coats erythrocytes leading to macrophage phagocytosis of the whole erythrocyte.3 Typically, intravascular haemolysis only occurs in patients during certain disease states, such as infection, or in patients with IgG cold agglutinin autoantibodies.3
Disease burden and unmet needs
CAD exerts a significant burden on patients due to disease manifestations and their negative impact on health-related quality of life (HRQoL), both of which are not sufficiently improved by most current treatment options. The typical clinical presentation of CAD includes anaemia in 90% of patients (with compensated haemolysis in the remaining 10% of patients), markers of haemolysis including low haptoglobin, and high lactate dehydrogenase (LDH) and bilirubin levels (90% of patients for each marker) and cold-induced symptoms, particularly acrocyanosis.2 Low haemoglobin (Hb) levels necessitate blood transfusions in more than half of patients, and fatal complications can occur due to exacerbations of haemolysis and treatment complications.6,7 Patients are also at an increased risk of thromboembolic events compared with the general population.8 Beyond physiological symptoms, complement-mediated haemolysis, in addition to pro-inflammatory pathway activation, contributes to both anaemia and fatigue,9 whereas cold-induced symptoms are agglutination mediated.10 The fatigue and general weakness in CAD adversely impact HRQoL, contributing to extra-haematologic manifestations such as depression and anxiety.11–13
The current management approach to primary CAD focuses on increasing Hb level and suppressing the underlying pathology.3,14 Severe anaemia resulting in an emergency situation is typically managed with blood transfusions, with plasmapheresis used as a temporizing measure, whereas cold-induced symptoms are typically managed with behavioural changes to reduce exposure to cold environments. Suppressing the underlying pathology focuses on targeting B-cells and the complement cascade.3,14 However, the use of the B-cell-directed therapy rituximab is off-label, frequently results in low response rates and, when used in combination with cytotoxic chemo-immunotherapies, is associated with significant toxicity, particularly severe neutropenia and infection.3,14–16
Complement cascade inhibitors used in CAD include the monoclonal antibodies eculizumab, which blocks the activation of C5, and sutimlimab, a C1a inhibitor.3 Patients treated with eculizumab have only marginal increases in Hb level, with no change in HRQoL.17 Sutimlimab is currently the only approved treatment for CAD and increases Hb levels and improves HRQoL.18,19 However, not all patients achieve clinical responses including sufficient increases in Hb levels (≥1.5 g/dL), no transfusions, avoidance of other CAD medication and clinically meaningful improvements in disease severity, highlighting a continued need for novel treatment options.18
Pegcetacoplan
Pegcetacoplan is a pegylated cyclic peptide that binds C3 and its activation fragment C3b, controlling the activation of the downstream complement cascade. As the C3 protein is the point of convergence for all three complement activation pathways, pegcetacoplan has the potential to reduce activity of the main complement drivers of CAD.20
Pegcetacoplan has previously demonstrated promise in an open-label, phase II pilot trial (ClinicalTrials.gov identifier: NCT03226678) of 13 patients with CAD and 11 patients with another AIHA, termed warm AIHA. Dr Bernd Jilma noted for this trial that “pegcetacoplan produced meaningful increases in Hb, even normalized Hb levels in some patients, and it provided relevant measures of efficacy. Pegcetacoplan was also well tolerated, and these data support the clinical development of the drug for its treatment of CAD, which is currently on-going.”
The CASCADE trial
To continue research into pegcetacoplan, the phase III CASCADE trial will enrol a larger group of patients with CAD than the phase II trial, targeting an enrolment of 57 patients in Europe, Japan and the USA.21 Using a double-blind placebo-controlled design, patients will be randomized (2:1) to receive twice-weekly pegcetacoplan 1,080 mg or placebo via a subcutaneous injection using an infusion pump for 24 weeks in Part A of the study. In Part B, all patients who complete Part A will be eligible to receive open-label pegcetacoplan for a further 24 weeks, followed by an open-label maintenance period (Part C). An end-of-treatment visit will be done when patients complete the study or discontinue treatment, followed by an end-of-study visit 8 weeks later.
To be eligible for the CASCADE trial, patients need to be at least 18 years of age with a diagnosis of primary CAD and have a Hb level ≤9 g/dL, in addition to a documented bone marrow biopsy result in the year before study screening. They are also required to have been previously vaccinated against Streptococcus pneumoniae, Neisseria meningitidis (types A, C, W, Y and B) and Haemophilus influenzae (type B) or agree to be vaccinated against these bacteria before study entry.
The study design also includes several disease- and treatment-based exclusion criteria. “We want to exclude patients with diagnosed lymphoma, patients with cold agglutinin syndrome due to infections and of course, other drugs which may have an influence on cold agglutinin indices. So, a patient should not have received rituximab for 3 months or chemotherapy for 6 months prior to randomization,” Dr Bernd Jilma explained. In addition, patients who have received an organ transplant or received treatment with an approved or under-investigation anti-complement therapy within five half-lives of randomization are also excluded.
To determine the efficacy of pegcetacoplan in CAD, the primary efficacy endpoint is response to treatment, defined as at least a 1.5 g/dL increase from baseline in Hb level, maintained for Weeks 16–24 without the need for any blood transfusions in Weeks 5–24. Secondary endpoints include change in Hb level, transfusion avoidance, change in fatigue score, change in biomarker levels including LDH, haptoglobin level, indirect bilirubin level and absolute reticulocyte counts, change in HRQoL and the number of erythrocyte transfusions.
The CASCADE trial is currently on-going and estimated to complete in 2023. Dr Bernd Jilma provided an update on its current status: “The trial has started recently, is currently recruiting and I am hopeful that the trial can finish recruitment later this year and perhaps we will see the 24-week results by the end of this year.” Overall, the CASCADE trial represents another step in the journey to providing more personalized treatment options for patients with the rare anaemia CAD.
The full meeting interview with Dr Bernd Jilma is available on touchONCOLOGY here
The ASH Annual Meeting abstract entitled ‘Trial in Progress: Randomized, Double-Blind, Placebo-Controlled Multicenter Phase 3 Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients with Cold Agglutinin Disease (CASCADE)’ (Abstract #2333) is available online.
Interested in seeing more content around cold agglutinin disease?
Read the short article ‘Sutimlimab potently inhibits the classical complement pathway, with efficacy against cold agglutinin disease’ here on touchHAEMATOLOGY
View the video ‘The pathophysiology and unmet treatment needs in cold agglutinin disease” with Dr Berns Jilma here on touchONCOLOGY
