Complement overactivation is a key underlying factor in many pathologic states. Eculizumab was the first complement-specific drug developed and has led to breakthroughs in the treatment of complement-mediated conditions such as paroxysmal nocturnal hemoglobinuria. Currently, complement therapeutics is a rich field for investigation, and many candidate drugs are being tested in clinical trials or are in preclinical development. Novel drugs that target the complement cascade are being investigated as potential therapeutic agents for cold agglutinin disease (CAD).1 The clinical trials of these novel agents currently underway are discussed below.
A multicenter, phase 1b, open-label, nonrandomized, single-dose study evaluating the safety, tolerability, and activity of BIVV020 (Bioverativ) in adults with CAD is currently in the recruitment stage.2 BIVV020 is a humanized monoclonal antibody (mAb) that targets complement C1s.1
Inclusion criteria are as follows:
- Patients 18 years of age or older with confirmed CAD
- Hemoglobin level at or below 11 mg/dL
- Elevation of total bilirubin level above the normal reference range that is thought to be due to hemolysis
- Documented vaccinations against encapsulated bacteria (Neisseria meningitidis, including serogroup B meningococcus and Streptococcus pneumoniae) within 5 years of screening or willingness to complete protocol-specified vaccinations
- Provision of written informed consent before start of any study-related procedure
Participants will receive a single administration of the experimental drug, BIVV020, plus 2 optional doses administered intravenously.2
The primary outcome is to assess adverse events from screening to day 106. Secondary outcome measures are as follows: evaluate the effect of BIVV020 on complement-mediated hemolysis, determine the pharmacodynamics of BIVV020 related to complement inhibition, study the pharmacokinetics of BIVV020, and determine the immunogenicity of BIVV020. The estimated date of completion is October 2022.2
Clinical Study Identifier: NCT04269551
A second trial, also in the recruitment phase, is being conducted to assess the long-term safety and tolerability of multiple doses of BIVV020 in patients with CAD. Estimated completion date is May 2023.3
Clinical Study Identifier: NCT04802057
A 2-part, phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of BIVV009 (sutimlimab) in patients with CAD without a recent history of blood transfusion is in the recruitment stage. The first part (part A) of the study is to determine whether the administration of sutimlimab results in a hemoglobin level increase of 1.5 g/dL or more and to avoid transfusion in participants with primary CAD without a recent history of blood transfusion. The purpose of the second part (part B) is to evaluate the long-term safety and tolerability of sutimlimab in participants with primary CAD.
Inclusion criteria are as follows:
- Body weight 39 kg or more at screening
- Confirmed diagnosis of primary CAD
- Absence of overt malignant disease
- Hemoglobin level of 10.0 g/dL or lower
- Bilirubin level above the normal reference range, including in patients with Gilbert syndrome
In part A, participants will be randomized in a 1:1 ratio to receive an intravenous infusion of sutimlimab or placebo. In part B, all participants will undergo blinded crossover loading doses to allow all participants to receive sutimlimab while part A blinding is maintained. The primary outcome for part A is the percentage of participants with a response. In part B, the primary outcome is the number of participants with treatment-emergent adverse events and serious adverse events. Estimated completion date is December 2021.4
Clinical Study Identifier: NCT03347422
APL-2 (Complement [C3] Inhibitor)
APL-2 is an investigational drug that inhibits C3 activation by blocking the cleavage of C3 into C3a and C3b. It is being researched as a potential therapy for conditions associated with overactivation of complement pathways.5 An open-label, prospective study to assess the safety, tolerability, efficacy, and pharmacokinetics of APL-2 in patients with warm autoimmune hemolytic anemia (wAIHA) or CAD is currently in phase 2.
Inclusion criteria are as follows:
- At least 18 years of age
- Weight below 125 kg
- Primary diagnosis of wAIHA or CAD
- Hemoglobin level below 11 g/dL
- Signs of hemolysis with abnormal hemolytic markers
- Women of child-bearing potential must have a negative pregnancy test at screening and must agree to use protocol-defined methods of contraception for the duration of the study and for 60 days after their last dose of the study drug.
- Male participants must agree to use protocol-defined methods of contraception and agree to refrain from donating sperm for the duration of the study and for 60 days after their last dose of the study drug.
- Documentary evidence of required vaccinations
- Willingness and ability to give informed consent
- Specifically for participants with wAIHA: relapse after, lack of response to, or inability to tolerate at least one prior wAIHA treatment regimen (eg, prednisone, rituximab)
Patients with CAD in the experimental arm will receive 270 or 360 mg of APL-2 administered subcutaneously daily. The primary goals of the study are to identify the total number of AEs associated with treatment and any change in the baseline hemoglobin concentration, and to study the serum concentrations and pharmacokinetic parameters of APL-2.6
Clinical Trials Identifier: NCT03226678
1. Ricklin D, Mastellos DC, Reis ES, Lambris JD. The renaissance of complement therapeutics. Nat Rev Nephrol. 2018;14(1):26-47. doi:10.1038/nrneph.2017.156
2. Clinical Trials.gov. A Multicenter, Phase 1b, Open Label, Nonrandomized, Single Dose Study Evaluating the Safety, Tolerability and Activity of BIVV020 in Adults With Cold Agglutinin Disease. NCT 04269551. https://clinicaltrials.gov/ct2/show/NCT04269551 Accessed September 15, 2021
3. Clinical Trials.gov. An Open Label, Long Term, Safety and Tolerability Study of Patients With Cold Agglutinin Disease Previously Treated With BIVV020. NCT 04802057. https://clinicaltrials.gov/ct2/show/NCT04802057 Accessed September 15, 2021.
4. Clinical Trials.gov. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Sutimlimab in Patients With Primary Cold Agglutinin Disease Without a Recent History of Blood Transfusion. NCT 03347422. https://clinicaltrials.gov/ct2/show/NCT03347422 Accessed September 15, 2021.
5. Definition of C3-targeted complement inhibitor APL-2 – NCI Drug Dictionary. National Cancer Institute. Accessed September 15, 2021.
6. Clinical Trials.gov. An Open Label, Prospective, Study to Assess the Safety, Tolerability, Efficacy and Pharmacokinetics of APL-2 in Patients With Warm Type Autoimmune Hemolytic Anemia (WAIHA) or Cold Agglutinin Disease (CAD). NCT 0322668. https://clinicaltrials.gov/ct2/show/study/NCT03226678 Accessed September 15, 2021.
Reviewed by Debjyoti Talukdar, MD, on 9/16/2021.