Cold Agglutinin Disease (CAD)

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Since complement proteins are central in mediating hemolysis and cold agglutinin disease (CAD) pathogenesis, several complement-directed therapies such as sutimlimab and eculizumab are being investigated for the treatment of CAD.1 

However, these therapies have limitations; they may not relieve ischemic symptoms that are unrelated to complement proteins, treatment may be costly, and the therapy may need to be continued throughout a patient’s life to maintain its effect.

Sutimlimab

Sutimlimab (BIVV009, TNT009) is an investigational first-in-class monoclonal antibody that selectively binds and inhibits the complement protein C1s, which is a C1 complex serine protease that activates the complement pathway. Thus, sutimlimab-mediated inhibition of C1s prevents complement pathway activation.1

In an in vitro study, TNT003, a murine monoclonal antibody that targets C1s, demonstrated the ability to efficiently inhibit complement-mediated phagocytosis and lysis of red blood cells (RBCs) in the presence of serum derived from a healthy individual as a source of complement and patient sera as a source of cold agglutinin.2

In a first-in-human phase 1B study of 10 patients with CAD, weekly intravenous infusions of sutimlimab were found to be safe and well tolerated. The treatment rapidly increased hemoglobin (Hb) levels by a median of 1.6 g/dL within 1 week and by 3.9 g/dL within 6 weeks. In addition, sutimlimab treatment rapidly inhibited hemolysis and normalized bilirubin levels within 24 hours in most patients, and all 6 previously transfusion-dependent patients became transfusion-free. Hemolysis recurred 3 to 4 weeks after sutimlimab was discontinued, but readministration restored the inhibition of hemolysis.3

Similar results were confirmed in an open-label, single-group, multicenter phase 3 study (NCT03347396),4 the Cardinal trial, that evaluated the efficacy and safety of intravenous sutimlimab in 24 adult transfusion-dependent CAD patients. The results showed that sutimlimab treatment was safe, rapid, and sustained with rapid inhibition of the classic complement pathway and hemolysis, significant increase in Hb levels, reduction of bilirubin levels, decrease in fatigue, and improvement in quality of life. Of the 24 enrolled patients, 54% achieved a Hb level of 12 g/dL or higher or an increase in the Hb level of at least 2 g/dL, with 71% of patients not requiring blood transfusion therapy after the fifth week of treatment. No serious adverse events related to sutimlimab were observed.5,6

Another randomized, double-blind, placebo-controlled phase 3 study (NCT03347422),7 Cadenza, is currently ongoing to assess the efficacy and safety of sutimlimab in 40 transfusion-independent CAD patients.

A recent open-label study showed that long-term maintenance treatment (2 to 20 months) with sutimlimab in 7 transfusion-dependent CAD patients was safe, effectively inhibited hemolysis, and significantly increased and maintained Hb at normal levels, with all patients remaining transfusion-free while receiving sutimlimab. Patients receiving overlapping treatment with erythropoietin, rituximab, or ibrutinib did not have any untoward drug interactions.8

Eculizumab

Eculizumab is an approved first-of-its-kind monoclonal antibody that binds and inhibits the complement protein C5, thereby inhibiting the formation of the terminal complement complex and consequently preventing inflammation and cell lysis. It is developed and marketed as Soliris® by Alexion Pharmaceuticals.9

Eculizumab is prescribed for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), some forms of generalized myasthenia gravis, and some forms of neuromyelitis optica spectrum disorder (NMOSD). It is also being investigated for the treatment of hemolytic anemia in patients with CAD.9

In CAD, the main mechanism of RBC breakdown seems to be C3b-mediated opsonization followed by extravascular hemolysis, and the involvement of the terminal complement complex-mediated lysis is believed to be limited. Thus, C5 is not an optimal target for the treatment of CAD. 

Since C5 is involved in all 3 complement pathways that converge at a common terminal pathway (classic, alternative, and lectin), eculizumab blocks the entire complement pathway. This increases the risk of infections and related complications. Thus, eculizumab is used as a therapy only when other options such as rituximab or other treatments are ineffective in patients with CAD.

In a prospective, controlled, non-randomized phase 2 trial (NCT01303952)10 that included 13 patients with CAD, eculizumab was well tolerated and significantly inhibited intravascular hemolysis (mediated by the C5-containing terminal complement complex), and most patients became transfusion-independent. However, anemia and quality of life did not improve significantly.11

Eculizumab has been found to be effective in severely affected patients.12 It has also been used as a prophylactic therapy to prevent exacerbation of hemolysis following heart surgery,13 where intravascular hemolysis mediated by the terminal complement pathway is believed to be more prominent.

References

  1. Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol. 2020;11:590. doi:10.3389/fimmu.2020.00590
  2. Shi J, Rose EL, Singh A, et al. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood. 2014;123(26):4015-4022. doi:10.1182/blood-2014-02-556027
  3. Jäger U, D’Sa S, Schörgenhofer C, et al. Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood. 2019;133(9):893-901. doi:10.1182/blood-2018-06-856930
  4. A study to assess the efficacy and safety of BIVV009 (sutimlimab) in participants with primary cold agglutinin disease who have a recent history of blood transfusion (Cardinal study). ClinicalTrials.gov. November 20, 2017. Updated March 16, 2021. Accessed September 7, 2021.
  5. Röth A, Barcellini W, D’Sa S, et al. Inhibition of complement C1s with sutimlimab in patients with cold agglutinin disease (CAD): results from the phase 3 Cardinal study. Blood. 2019;134(Supplement_2):LBA-2. doi:10.1182/blood-2019-132490
  6. Röth A, Barcellini W, D’Sa S, et al. Sutimlimab in cold agglutinin disease. N Engl J Med. 2021;384(14):1323-1334. doi:10.1056/NEJMOA2027760
  7. A study to assess the efficacy and safety of BIVV009 (sutimlimab) in participants with primary cold agglutinin disease without a recent history of blood transfusion (Cadenza). ClinicalTrials.gov. November 20, 2017. Updated September 3, 2020. Accessed September 7, 2021.
  8. Gelbenegger G, Schoergenhofer C, Derhaschnig U, et al. Inhibition of complement C1s in patients with cold agglutinin disease: lessons learned from a named patient program. Blood Adv. 2020;4(6):997-1005. doi:10.1182/bloodadvances.2019001321
  9. Soliris: patient indication. Alexion. Accessed September 7, 2021.
  10. Therapy of chronic cold agglutinin disease with eculizumab. ClinicalTrials.gov. February 25, 2011. Updated July 19, 2017. Accessed September 7, 2021.
  11. Röth A, Bommer M, Hüttmann A, et al. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv. 2018;2(19):2543-2549. doi:10.1182/bloodadvances.2018024190
  12. Makishima K, Obara N, Ishitsuka K, et al. High efficacy of eculizumab treatment for fulminant hemolytic anemia in primary cold agglutinin disease. Ann Hematol. 2019;98(4):1031-1032. doi:10.1007/s00277-018-3521-4
  13. Tjønnfjord E, Vengen ØA, Berentsen S, Tjønnfjord GE. Prophylactic use of eculizumab during surgery in chronic cold agglutinin disease. BMJ Case Rep. 2017;2017:bcr2016219066. doi:10.1136/bcr-2016-219066

Reviewed by Harshi Dhingra, MD, on 9/8/2021.

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