Cold Agglutinin Disease (CAD)

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Enjaymo™ (sutimlimab), formerly known as BIVV009 or TNT009, was approved by the US Food and Drug Administration in February 2022 as the first treatment designated for cold agglutinin disease (CAD). It is an investigational monoclonal antibody that causes selective blockade of complement C1, a protein with an integral role in the classical complement pathway. This pathway is overactivated in cold agglutinin disease (CAD). By blocking C1, sutimlimab treats the underlying cause of hemolysis, thus preventing hemolytic anemia and reducing the disease burden. Sutimlimab was developed by Bioverativ, a Sanofi company.

The US Food and Drug Administration (FDA) granted priority review to Sanofi’s Biologics License Application (BLA) for sutimlimab as a treatment for hemolysis in adult patients with CAD. The FDA has granted sutimlimab a breakthrough therapy designation in the United States, and an orphan drug designation was granted in both the United States and Europe, for the treatment of hemolysis in CAD.1,2 

Mechanism of Action

Sutimlimab prevents C1-activated hemolysis in CAD. The drug selectively binds and inhibits complement protein C1s, which is a C1 complex serine protease that activates the classical complement pathway, part of the innate immune system. Thus, by inhibiting the classical pathway at C1s, sunitinib prevents complement-mediated hemolysis in CAD. The immune surveillance functional properties of the alternative or lectin complement pathway are retained.2

Clinical Trials

In an in vitro study, TNT003, a murine monoclonal antibody that targets C1s, demonstrated the ability to inhibit complement-mediated phagocytosis and red blood cell (RBC) lysis in serum derived from a healthy individual as a source of complement and serum from a patient as a source of cold agglutinin.3

In a first-in-human phase 1B study of 10 patients with CAD (​​NCT02502903), weekly intravenous infusions of sutimlimab were found to be safe and well-tolerated. This trial tested the ability of the anti-C1s antibody sutimlimab to alleviate hemolytic anemia in CAD. 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, the 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 re-administration restored the inhibition of hemolysis.4 Thus, sutimlimab rapidly stopped hemolysis mediated by complement C1s in patients with CAD, achieving a significant improvement in hemoglobin levels and preventing the need for transfusions.4 

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Similar results were confirmed in an open-label, single-group, multicenter phase 3 study (NCT03347396),5 the CARDINAL trial, which evaluated the efficacy and safety of intravenous sutimlimab in 24 adult patients with transfusion-dependent CAD. Sutimlimab treatment was shown to be safe, rapid, and sustained; it quickly inhibited the classical complement pathway and hemolysis, significantly increased Hb levels, decreased bilirubin levels and fatigue, and improved quality of life. Of 24 enrolled patients, 54% had an Hb level of 12 g/dL or higher or an Hb level increase of at least 2 g/dL, and 71% of the patients did not require blood transfusion therapy after the fifth week of treatment. No serious adverse events related to sutimlimab were observed.6,7

Another randomized, double-blind, placebo-controlled phase 3 study (NCT03347422),8 CADENZA, was conducted to assess the efficacy and safety of sutimlimab in 42 transfusion-independent patients with CAD. The study was completed in December 2021, but the results have not been released.

In a recent open-label study, long-term maintenance treatment (2-20 months) with sutimlimab in 7 transfusion-dependent patients with CAD was safe, effectively inhibited hemolysis, and significantly increased and maintained Hb at normal levels, with all patients remaining transfusion-free while receiving sutimlimab. Patients who received overlapping treatments with erythropoietin, rituximab, and ibrutinib did not experience any adverse drug interactions.9

Warnings, Precautions, and Adverse Reactions

Only mild to moderate side effects were noted in clinical trials. These included gastrointestinal issues (10%), palpitations (6%), the common cold (6%), sore throat (6%), and night sweats (5%). Sutimlimab infusions were well tolerated overall, and only one adverse reaction was associated with treatment.10

Sutimlimab is also considered safe in combination with other drugs, such as rituximab. No increase in susceptibility to infections was noted. The biweekly infusion therapy was found to be safe and effective in treating complement-mediated hemolysis and to improve Hb levels and maintain normal Hb levels in all cases upon re-exposure.10

References 

  1. Figueiredo M. Manufacturing deficiencies delay FDA decision on sutimlimab for adults. News release. Cold Agglutinin Disease News. November 20, 2020.
  2. FDA grants priority review of sutimlimab, potential first approved treatment of hemolysis in adult patients with cold agglutinin disease. News release. Sanofi; May 14, 2020.
  3. 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
  4. 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
  5. ClinicalTrials.gov. 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). NCT03347396. https://clinicaltrials.gov/ct2/show/NCT03347396 Accessed September 14, 2021.
  6. 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(Suppl 2):LBA-2. doi:10.1182/blood-2019-132490
  7. 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
  8. ClinicalTrials.gov. 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). NCT03347422. https://clinicaltrials.gov/ct2/show/NCT03347422. Accessed September 14, 2021.
  9. 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
  10. Martins I. Sutimlimab safe, effective as long-term therapy for CAD, study finds. News release. Cold Agglutinin News. March 25, 2020.

Updated 02/08/2022.

Reviewed by Kyle Habet, MD, on 9/20/2021.