Soliris Therapy Eases Hemolysis and Blood Transfusion Needs in CAD Patients, Phase 2 Trial Shows

Off-label treatment with Soliris (eculizumab) was well-tolerated and lessened hemolysis — red blood cell destruction — and transfusion requirements in patients with cold agglutinin disease (CAD), a Phase 2 trial showed.

The study, “Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial,” appeared in Blood Advances.

CAD is caused by an autoimmune attack against the body’s red blood cells. At low temperatures, the autoantibodies bind to the cell surface, inducing cell clumping, activation of the complement system — a set of more than 20 blood proteins that are part of the body’s immune defenses — and hemolysis, leading to anemia.

Previous studies showed that pharmacological treatment of chronic CAD, the most common form, with the immune B-cell targeting medicine Rituxan (rituximab) — enables remission in 50% or 75% of patients when used alone or combined with chemotherapy, respectively. However, such an intense treatment approach may not be feasible for many elderly CAD patients.

Alexion’s Soliris is a monoclonal antibody against complement factor C5, which blocks the terminal complement cascade. Besides myasthenia gravis, the therapy is also approved for patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome. Although terminal complement activation is not as important in CAD, individual patient exams have shown long-lasting responses with Soliris.

In collaboration with Alexion, with the aim of further evaluating Soliris’ efficacy and safety in CAD, the team conducted DECADE, a prospective Phase 2 trial (NCT01303952), in Germany.

A total of 13 adult patients (10 women, median age 74 years) requiring treatment of anemia, or with blood transfusion dependency, were included. There were 12 chronic CAD (median disease duration of 42 months) cases, and one with acute cold agglutinin syndrome (CAS) — the other CAD type. CAS results from the production of a hemagglutinin — a type of protein that causes red blood cells to clump — as a byproduct of infection, cancer, or other disease.

Among the patients with chronic CAD, six had never undergone treatment, and six had been treated with a median of three prior lines of immunosuppressive therapy. The patient with acute CAS had received prednisone. Nine of the patients were transfusion-dependent.

After a screening period, the participants were treated with 600 mg of Soliris weekly over a four-week period.  This was followed one week later by 900 mg every other week through week 26. Two patients continued treatment with Soliris beyond this period. The two did not complete the 26 weeks because one patient did not respond to Soliris due to Raynaud’s syndrome, and because of hemorrhoidal hemorrhage and suspicion of peritonitis in the other.

The trial’s primary goal was to assess the difference in lactate dehydrogenase (LDH) levels between the first and last day of therapy. This enzyme is found at higher amounts in CAD patients, mirroring the intensity of hemolysis.

All included participants had a serum LDH level greater than or equal to twice the higher level of normal before treatment began. Response was defined as a reduction in LDH level not lower than 250 U/L.

Secondary endpoints included changes in indicators of hemolysis, transfusion requirement, venous thromboembolic events (blood clots in veins), exercise tolerance — as assessed with the six-minute walk test — quality of life (measured with Short Form 36v2) fatigue, and pharmacokinetics, which refers to Soliris’ absorption, distribution, metabolism, and excretion.

The results revealed a median LDH level decrease from 572 U/L to 334 U/L, with seven participants showing a reduction not inferior to 250 U/L (six had chronic CAD). This was associated with an increase in hemoglobin — the protein that carries oxygen in the blood — from 9.35 g/dL to 10.15 g/dL. Most patients experienced an increase in LDH levels after treatment.

Transfusion independence was achieved in eight patients. Exercise tolerance, quality of life and issues of fatigue did not change significantly. No venous thromboembolism events occurred during treatment.

In the 12 patients with chronic CAD, those with a thermal amplitude — the highest temperature at which the antibody reacts with the antigen and a measure of CAD severity — of 37°C tended to have less marked LDH reactions, and responded to higher serum levels of Soliris than participants showing cold agglutinins with narrower thermal amplitudes.

The patient with acute CAS improved within 24 hours of the first dose of Soliris. Hemolysis  resolved after four weeks, and cold agglutinin became undetectable after 12 weeks.

Unlike hemolysis, cold-induced circulatory symptoms remained unaffected. A total of 37 adverse events were recorded in 13 patients. Another 13 events occurring in four patients were classified as possibly related, and one other case (pneumonia) as probably related to treatment.

“In conclusion, [Soliris] significantly reduced hemolysis and transfusion requirement in patients with CAD,” the researchers said.