Plaudit: A Phase 2 Clinical Study of APL-2 for the Treatment of AIHA

A prospective, open-label study to assess the safety, tolerability, preliminary efficacy, pharmacokinetics, and pharmacodynamics of multiple doses of APL-2 in patients with autoimmune hemolytic anemia (AIHA)

Designed for patients

Age 18 or older

With a primary diagnosis of wAIHA and who had a recurrence, did not respond to, or did not tolerate ≥1 prior wAIHA treatment such as prednisone or rituximab, or with cold agglutinin disease (CAD) in the presence of red blood cells (RBCs) being destroyed prematurely

With a positive Coombs test, which measures the presence of antibodies and/or complement proteins bound to the surface of RBCs

With abnormal laboratory values of any markers that indicate RBC destruction

Any patient who meets these 4 criteria may be eligible for the Plaudit AIHA clinical trial.

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Disease Overview

Autoimmune Hemolytic Anemia (AIHA)

Autoimmune hemolytic anemia (AIHA) is a group of rare autoimmune disorders characterized by the premature destruction (hemolysis) of red blood cells (RBCs) by autoantibodies, at a rate faster than they can be replaced.1

The incidence of autoimmune hemolytic anemia (AIHA) is about 1-3 per 100,000 per year in adults, and the overall mortality rate is about 11%.2 Most cases of AIHA are classified as either warm antibody (60% to 70% of cases), or cold agglutinin disease (CAD, 20% to 25% of cases), depending upon the temperature at which the autoantibodies show maximum binding.3

Warm Autoimmune Hemolytic Anemia (wAIHA)

Warm autoimmune hemolytic anemia (wAIHA) accounts for 70% to 75% of all adult AIHA and is defined by the presence of autoantibodies (usually IgG) that attach to and destroy RBCs at temperatures equal to or greater than the normal body temperature of 37°C (98.6°F).4 The disease is characterized by the symptoms of hemolytic anemia, including fatigue, shortness of breath, jaundice, and dark urine.3,5,6 The warm forms may be primary or idiopathic (35% to 40% of cases). However, 60% to 65% of cases appear to be secondary to malignancy or to other lymphoproliferative disease or to other autoimmune diseases (eg, lupus, rheumatoid arthritis).7,8 wAIHA is associated with life-threatening outcomes such as venous thrombosis and pulmonary embolism; mortality is often related to infectious complications.8,9

Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD), also called cold autoimmune hemolytic anemia, is a rare type of autoimmune hemolytic anemia (AIHA) that accounts for 15% to 20% of all adult AIHA cases.10 In CAD, the autoantibodies (usually IgM) cause RBCs to clump together (agglutinate) when the person's blood is exposed to cold temperatures (4° to 10°C, 32° to 50°F) such as in cold-exposed extremities (nose, ears, fingers, toes).11 This eventually causes premature destruction of RBCs (hemolysis), which leads to anemia and other associated signs and symptoms.12,13 Acute cold forms are mainly secondary to infections, whereas chronic CADs are frequently associated with lymphoproliferative or neoplastic diseases.3 The associated symptoms and signs are fatigue and weakness due to hemoglobinuria and anemia, acrocyanosis of the body extremities (nose, ears, fingers, toes), and dyspnea.14

Role of Complement in Warm Autoimmune Hemolytic Anemia (wAIHA)

Illustration of the role of C3 complement protien in wAIHA hemolysis. Learn how the C3 protein is at the center of RBC lysis.The complement system plays a major role in the destruction (lysis) of red blood cells (RBCs) in wAIHA and cold agglutinin disease.

In wAIHA, extravascular hemolysis is the unique route of RBC destruction. This occurs when IgG antibodies inappropriately bind to self-proteins on the surface of RBCs, and activate the classical complement pathway.6 This coating of C3b on the RBCs facilitates their destruction in the liver (extravascular hemolysis).6

The direct antiglobulin test (DAT) is positive for C3 fragments in up to 50% of cases of wAIHA, serving as a marker of complement involvement.3,6

Learn More About the Complement System?

Role of Complement in Cold Agglutinin Disease (CAD)

The complement system plays a major role in the destruction (lysis) of red blood cells (RBCs) in wAIHA and cold agglutinin disease.

Illustration of the role of C3 complement protien in cold agglutinin disease hemolysis. Learn how the C3 protien is at the center of RBC lysis.Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease [CAD], secondary cold agglutinin syndrome, and paroxysmal cold hemoglobinuria [PCH]) are entirely complement-mediated disorders. In CAD, extravascular hemolysis is the predominant route of hemolysis (red blood cell [RBC] destruction). IgM, called cold agglutinin, binds and agglutinates RBCs, which strongly activate the classical complement pathway and deposit complement factor C3b on the RBC surface. This coating of C3b facilitates the destruction of RBCs in the liver (extravascular hemolysis). Less frequently, in severe cases of CAD, C3b activates the complete complement cascade, resulting in intravascular hemolysis (the abnormal breakdown of RBCs within the blood vessels).6 As a result, heme is released from the destroyed RBCs and, in a second hit, can lead to activation of the alternative pathway of complement.15,16

Although the classical complement pathway is the main pathway involved in the disease, the alternative pathway may also be activated, which would amplify complement activation and may exacerbate the breakdown of RBCs. Therefore, both the classical and the alternative pathways should be inhibited.15,16

More About Complement

The Complement System

Diagram of the complement system pathways and its role in AIHA. Learn how the C3 protien is at the center of intravascular and extravascular hemolysis.The complement system is an integral part of our immune defense system. In healthy people, complement orchestrates the destruction and clearance of pathogens or of host cells that need to be replaced. It also has proinflammatory capabilities.17

Complement may be activated by different pathways, in particular, the classical and alternative pathways for AIHA.17 The classical complement pathway is activated when an antibody recognizes a non-self target that invaded the body and needs to be destroyed.17 The alternative complement pathway can be initiated by spontaneously activated complement.17

The complement system consists of a cascade of more than 40 proteins, each of which activates the next protein in the cascade by cleavage.17 Complement C3 is the central protein of the cascade, positioned at the point of convergence of all complement activation pathways and upstream of all effectors (Figure 1).17

Complement activation is regulated to avoid its overactivation and to protect the host against immune attack.17

In autoimmune hemolytic anemia (AIHA), autoantibodies inaccurately recognize an individual's own proteins at the surface of red blood cells (RBCs) as non-self and activate the complement system to destroy these RBCs.3,6

Disease Overview

Autoimmune Hemolytic Anemia (AIHA)

Autoimmune hemolytic anemia (AIHA) is a group of rare autoimmune disorders characterized by the premature destruction (hemolysis) of red blood cells (RBCs) by autoantibodies, at a rate faster than they can be replaced.1

The incidence of autoimmune hemolytic anemia (AIHA) is about 1-3 per 100,000 per year in adults, and the overall mortality rate is about 11%.2 Most cases of AIHA are classified as either warm antibody (60% to 70% of cases), or cold agglutinin disease (CAD, 20% to 25% of cases), depending upon the temperature at which the autoantibodies show maximum binding.3

Warm Autoimmune Hemolytic Anemia (wAIHA)

Warm autoimmune hemolytic anemia (wAIHA) accounts for 70% to 75% of all adult AIHA and is defined by the presence of autoantibodies (usually IgG) that attach to and destroy RBCs at temperatures equal to or greater than the normal body temperature of 37°C (98.6°F).4 The disease is characterized by the symptoms of hemolytic anemia symptoms, including fatigue, shortness of breath, jaundice, and dark urine.3,5,6 The warm forms may be primary or idiopathic (35% to 40% of cases). However, 60% to 65% of cases appear to be secondary to malignancy or to other lymphoproliferative disease or to other autoimmune diseases (eg, lupus, rheumatoid arthritis).7,8 wAIHA is associated with life-threatening outcomes such as venous thrombosis and pulmonary embolism; mortality is often related to infectious complications.8,9

Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD), also called cold autoimmune hemolytic anemia, is a rare type of autoimmune hemolytic anemia (AIHA) that accounts for 15% to 20% of all adult AIHA cases.10 In CAD, the autoantibodies (usually IgM) cause RBCs to clump together (agglutinate) when the person's blood is exposed to cold temperatures (4° to 10°C, 32° to 50°F) such as in cold-exposed extremities (nose, ears, fingers, toes).11 This eventually causes premature destruction of RBCs (hemolysis), which leads to anemia and other associated signs and symptoms.12,13 Acute cold forms are mainly secondary to infections, whereas chronic CADs are frequently associated with lymphoproliferative or neoplastic diseases.3 The associated symptoms and signs are fatigue and weakness due to hemoglobinuria and anemia, acrocyanosis of the body extremities (nose, ears, fingers, toes), and dyspnea.14

Role of Complement in Warm Autoimmune Hemolytic Anemia (wAIHA)

The complement system plays a major role in the destruction (lysis) of red blood cells (RBCs) in wAIHA and cold agglutinin disease.

In wAIHA, extravascular hemolysis is the unique route of RBC destruction. This occurs when IgG antibodies inappropriately bind to self-proteins on the surface of RBCs, and activate the classical complement pathway.6 This coating of C3b on the RBCs facilitates their destruction in the liver (extravascular hemolysis). 6

The direct antiglobulin test (DAT) is positive for C3 fragments in up to 50% of cases of wAIHA, serving as a marker of complement involvement.3,6

Learn More About the Complement System?

Illustration of the role of C3 complement protien in wAIHA hemolysis. Learn how the C3 protein is at the center of RBC lysis.

Role of Complement in Cold Agglutinin Disease (CAD)

The complement system plays a major role in the destruction (lysis) of red blood cells (RBCs) in wAIHA and cold agglutinin disease.

Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease [CAD], secondary cold agglutinin syndrome, and paroxysmal cold hemoglobinuria [PCH]) are entirely complement-mediated disorders. In CAD, extravascular hemolysis is the predominant route of hemolysis (red blood cell [RBC] destruction). IgM, called cold agglutinin, binds and agglutinates RBCs, which strongly activate the classical complement pathway and deposit complement factor C3b on the RBC surface. This coating of C3b facilitates the destruction of RBCs in the liver (extravascular hemolysis). Less frequently, in severe cases of CAD, C3b activates the complete complement cascade, resulting in intravascular hemolysis (the abnormal breakdown of RBCs within the blood vessels).6 As a result, heme is released from the destroyed RBCs and, in a second hit, can lead to activation of the alternative pathway of complement.15,16

Although the classical complement pathway is the main pathway involved in the disease, the alternative pathway may also be activated, which would amplify complement activation and may exacerbate the breakdown of RBCs. Therefore, both the classical and the alternative pathways should be inhibited.15,16

More About Complement

Illustration of the role of C3 complement protien in cold agglutinin disease hemolysis. Learn how the C3 protien is at the center of RBC lysis.

The Complement System

The complement system is an integral part of our immune defense system. In healthy people, complement orchestrates the destruction and clearance of pathogens or of host cells that need to be replaced. It also has proinflammatory capabilities.17

Complement may be activated by different pathways, in particular, the classical and alternative pathways for AIHA.17 The classical complement pathway is activated when an antibody recognizes a non-self target that invaded the body and needs to be destroyed.17 The alternative complement pathway can be initiated by spontaneously activated complement.17

The complement system consists of a cascade of more than 40 proteins, each of which activates the next protein in the cascade by cleavage.17 Complement C3 is the central protein of the cascade, positioned at the point of convergence of all complement activation pathways and upstream of all effectors (Figure 1).17

Complement activation is regulated to avoid its overactivation and to protect the host against immune attack.17

In autoimmune hemolytic anemia (AIHA), autoantibodies inaccurately recognize an individual's own proteins at the surface of red blood cells (RBCs) as non-self and activate the complement system to destroy these RBCs.3,6

Diagram of the complement system pathways and its role in AIHA. Learn how the C3 protien is at the center of intravascular and extravascular hemolysis.

About APL-2

What is APL-2?

APL-2 is a small (13-amino-acid) cyclic peptide coupled via a linker to each end of a linear 40 kDa polyethylene glycol (PEG) chain. APL-2 binds to complement C3 and exerts broad inhibition of the complement cascade, a biological process that is part of innate immunity and is involved in multiple inflammatory processes. PEGylation imparts longer residence time in the body after administration of the drug.18

Why Evaluate APL-2 in wAIHA and cold agglutinin disease?

By targeting C3 at the point of convergence of all complement activation pathways and upstream of C5, APL-2 has the potential to block both the classical and the alternative pathways AND to prevent both intravascular and extravascular hemolysis in AIHA patients and thus reduce the risk of anemia and the associated signs and symptoms of anemia.18

In What Other Hemolytic Diseases is APL-2 Being Studied?

APL-2 is currently being developed for the management of paroxysmal nocturnal hemoglobinuria (PNH), another rare, chronic, debilitating blood disorder. PNH is caused by the presence of mutant stem cells, produced in the bone marrow, that lack important surface proteins that protect against activation of the complement system.19

Image of APL-2 molecule. Discover the potential of broad complement cascade inhibition by targeting the C3 protein.

About APL-2

What is APL-2?

APL-2 is a small (13-amino-acid) cyclic peptide coupled via a linker to each end of a linear 40 kDa polyethylene glycol (PEG) chain. APL-2 binds to complement C3 and exerts broad inhibition of the complement cascade, a biological process that is part of innate immunity and is involved in multiple inflammatory processes. PEGylation imparts longer residence time in the body after administration of the drug.18

Why Evaluate APL-2 in wAIHA and cold agglutinin disease?

By targeting C3 at the point of convergence of all complement activation pathways and upstream of C5, APL-2 has the potential to block both the classical and the alternative pathways AND to prevent both intravascular and extravascular hemolysis in AIHA patients and thus reduce the risk of anemia and the associated signs and symptoms of anemia.18

In What Other Hemolytic Diseases is APL-2 Being Studied?

APL-2 is currently being developed for the management of paroxysmal nocturnal hemoglobinuria (PNH), another rare, chronic, debilitating blood disorder. PNH is caused by the presence of mutant stem cells, produced in the bone marrow, that lack important surface proteins that protect against activation of the complement system.19

Image of APL-2 molecule. Discover the potential of broad complement cascade inhibition by targeting the C3 protein.

About APL-2

What is APL-2?

APL-2 is a small (13-amino-acid) cyclic peptide coupled via a linker to each end of a linear 40 kDa polyethylene glycol (PEG) chain. APL-2 binds to complement C3 and exerts broad inhibition of the complement cascade, a biological process that is part of innate immunity and is involved in multiple inflammatory processes. PEGylation imparts longer residence time in the body after administration of the drug.18

Why Evaluate APL-2 in wAIHA and cold agglutinin disease?

By targeting C3 at the point of convergence of all complement activation pathways and upstream of C5, APL-2 has the potential to block both the classical and the alternative pathways AND to prevent both intravascular and extravascular hemolysis in AIHA patients and thus reduce the risk of anemia and the associated signs and symptoms of anemia.18

In What Other Hemolytic Diseases is APL-2 Being Studied?

APL-2 is currently being developed for the management of paroxysmal nocturnal hemoglobinuria (PNH), another rare, chronic, debilitating blood disorder. PNH is caused by the presence of mutant stem cells, produced in the bone marrow, that lack important surface proteins that protect against activation of the complement system.19

Image of APL-2 molecule. Discover the potential of broad complement cascade inhibition by targeting the C3 protein.

Plaudit AIHA (warm autoimmune hemolytic anemia and cold agglutinin disease) Phase 2 Study Design

A prospective, open-label study to assess the safety, tolerability, preliminary efficacy, pharmacokinetics, and pharmacodynamics of multiple doses of APL-2 in patients with autoimmune hemolytic anemia (AIHA)

Purpose of This AIHA Clinical Trial

This open-label study will assess the safety, tolerability, preliminary efficacy, pharmacokinetics and pharmacodynamics of multiple doses of APL-2 in patients with autoimmune hemolytic anemia (AIHA).18

There are 2 arms to this study:

  1. Subjects to enroll in the warm autoimmune hemolytic anemia (wAIHA) clinical trial arm (N=6)
  2. Subjects to enroll in the cold agglutinin disease (CAD) clinical trial arm (N=6)

Key Inclusion Criteria18

  1. At least 18 years of age
  2. Weight <125 kg
  3. Primary diagnosis of wAIHA or CAD as defined by the presence of hemolytic anemia and positive direct antiglobulin test (DAT) for wAIHA (IgG) or CAD (C3)
    1. wAIHA: Did not respond to, relapsed after, or did not tolerate at least one prior wAIHA treatment regimen (eg, prednisone, rituximab)
  4. Hemoglobin <11 g/dL
  5. Clinical symptoms of hemolysis with abnormal values by any of the hemolytic markers:
    1. Increased absolute reticulocyte count above upper limit of normal (ULN)
    2. Reduced haptoglobin below lower limit of normal (LLN)
    3. Increased lactase dehydrogenase (LDH; above ULN)
    4. Increased indirect bilirubin (above ULN)

Key Exclusion Criteria18

  1. Prior treatment with rituximab within 90 days
  2. Deficiency of iron, folic acid, or vitamin B12 prior to treatment phase
  3. Abnormal liver function as indicated by a direct bilirubin above the normal level, and/or an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level > 2x ULN
  4. Active aggressive lymphoma requiring therapy or an active nonlymphatic malignant disease other than basal cell carcinoma or carcinoma in situ of the cervix
  5. Presence or suspicion of active bacterial or viral infection at screening or severe recurrent bacterial infections

Dosing

Subjects from the wAIHA and cold agglutinin disease (CAD) cohorts will be randomly (1:1) assigned to receive either 270 mg/day or 360 mg/day of APL-2 treatment for up to 12 months to identify an optimal dose for this new disease indication as a C3 complement inhibition monotherapy. The dose will be delivered subcutaneously (SC) with a programmed pump designed for self-administration.

The first 3 daily SC doses of APL-2 (Day 1 to 3) as well as doses on Day 7 and 14 will be administered at the clinical site. From Day 4 to Day 336, daily doses of APL-2 will be administered off-site by a study nurse or self-administered by the subject and/or caregiver (at the subject's home, workplace, or other location convenient to the subject), with the exception of those days where dosing is at the clinical site.18

Plaudit Key Endpoints18

Study endpoints will be assessed at months 2, 3, 6, and 12.

Primary Safety Endpoints:

Incidence and severity of treatment-emergent adverse events (TEAEs) following administration of multiple doses of SC APL-2.

Efficacy Endpoints:
  • Change from baseline in hemoglobin (Hb)
  • Number of red blood cell transfusions during study
  • Change from baseline in absolute reticulocyte count
  • Change from baseline in LDH
  • Change from baseline in haptoglobin
  • Change from baseline in indirect bilirubin
  • APL-2 serum concentrations and pharmacokinetic (PK) parameters as appropriate
  • Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) scale and the Linear Analog Scale Assessment scale (LASA), including energy level, ability to perform daily activity, and overall quality of life (QoL)
Exploratory PD markers:
  • Complement (eg, CH50, AP50, C3 and Bb) activity and levels
  • C3 deposition on RBC cells

Study Locations

For qualified patients who do not live near a study location and are interested in participating, Apellis may reimburse you for costs associated with travel. Please submit your contact information in the online form and someone will contact you to provide additional details.

Miami Lakes, FL

Rochester, MN

Whittier, CA

Greenville, NC

Grand Rapids, MI

Tacoma, WA

Orange City, FL

Iowa City, IA

Baltimore, MD

Memphis, TN

Brick, NJ

Trial sites in the following cities are anticipated in the near future:

  • Atlanta, GA
  • Knoxville, TN
  • New York, NY

Study Locations

For qualified patients who do not live near a study location and are interested in participating, Apellis may reimburse you for costs associated with travel. Please submit your contact information in the online form and someone will contact you to provide additional details.

Miami Lakes, FL

Rochester, MN

Whittier, CA

Greenville, NC

Grand Rapids, MI

Tacoma, WA

Orange City, FL

Iowa City, IA

Baltimore, MD

Memphis, TN

Brick, NJ

Trial sites in the following cities are anticipated in the near future:

  • Atlanta, GA
  • Knoxville, TN
  • New York, NY

Common Questions About Warm Autoimmune Hemolytic Anemia

AIHA is a rare autoimmune disorder characterized by the premature destruction (hemolysis) of red blood cells (RBCs) by autoantibodies, at a rate faster than they can be replaced.1

Warm autoimmune hemolytic anemia (wAIHA) accounts for 70% to 75% of all adult AIHA and is defined by the presence of autoantibodies (usually IgG) that attach to and destroy RBCs at temperatures equal to or greater than normal body temperature of 37°C (98.6°F).4 The disease is characterized by hemolytic anemia symptoms, including fatigue, difficulty in breathing, jaundice, dark urine.3,5,6

The age range for adult AIHA is 18 to >70 years and the median age of wAIHA patients at diagnosis is ~53 years.

Symptoms for wAIHA can happen suddenly (in the case of idiopathic wAIHA) or develop over time if the condition is chronic. Symptoms of wAIHA may include1,2,4:

  • Fatigue (tiredness)
  • Shortness of breath
  • Jaundice (yellowing of the skin or whites of the eye)
  • Backache
  • Pale color
  • Abdominal discomfort
  • Bloating
  • Fever
  • Rapid heartbeat
  • Dark urine

In many cases, the cause of autoimmune hemolytic anemia remains unknown. Some researchers believe that there are multiple factors involved, including genetic and environmental influences. In a very small number of cases, autoimmune hemolytic anemia appears to run in families. In these cases, it appears to follow an autosomal recessive pattern of inheritance.21

The diagnosis of wAIHA is based on the presence of hemolytic anemia, signs of hemolysis with reticulocytosis, low haptoglobin, increased lactate dehydrogenase, elevated indirect bilirubin, and a positive direct antiglobulin test (DAT) for IgG and/or complement C3.22 The degree of anemia at presentation correlates with the severity of AIHA and with the probability of relapse.23

There are no FDA-approved drugs available for the treatment of autoimmune hemolytic anemia (AIHA), and current medications used to treat AIHA are far from satisfactory. Available treatment options include the off-label use of steroids, immunosuppressants, and rituximab; RBC transfusions; and splenectomy (surgical removal of the spleen).

  • First-line therapy is corticosteroids, which are effective in 70% to 85% of wAIHA cases but only 14% of CAD cases. Long-term use of corticosteroids is associated with many complications.8,24,25
  • Most patients with AIHA (55% to 65%) have a need for RBC transfusions. These transfusions may worsen hemolysis, potentially increasing the risk of hyperhemolysis, which can be life-threatening, and of RBC alloantibodies (ie, antibodies against a blood group antigen that is not present on the person's red blood cells) resulting in an inadequate recovery because of autoantibodies that will react with donor cells in AIHA patients.23,26

For relapse/refractory cases where patients do not respond to the initial treatment(s), second-line therapy includes splenectomy and immunosuppressive drugs.

  • Splenectomy is associated with a 33% relapse rate in patients with wAIHA and a low response rate (~40%) and a short response duration in CAD.14,27 Although the perioperative risk and mortality rate are less than 1%,13 overwhelming sepsis and post-operative cytotoxic immunosuppressants are often associated with serious adverse events.27,28
  • The biologic agent rituximab can induce remission in approximately half of the patients with CAD, although complete remissions are unusual, and the relapse-free survival at 1 year and 2 years is 59% and 40%, respectively.6,29

These therapeutic approaches need time to become effective. In patients presenting with acute symptomatic AIHA or experiencing an exacerbation of AIHA, the primary goal of treatment is to halt the acute hemolysis. Moreover, restoration of oxygen carrier in symptomatic anemia is mandatory.

The complement system is an integral part of our immune defense system. In healthy subjects, complement orchestrates the destruction and clearance of pathogens or of host cells that need to be replaced. It also has proinflammatory capabilities.

In autoimmune hemolytic anemia (AIHA), autoantibodies inaccurately recognize the subject's own proteins at the surface of red blood cells (RBCs) as non-self and activate the complement system to destroy these RBCs.

Learn MoreLearn More

Complement plays an important role in warm antibody AIHA. In wAIHA, red blood cells are heavily coated with antibodies that inappropriately recognize surface self-proteins. The complexes formed on the RBC surface activate the classical complement pathway. RBCs are coated with C3b, thus marking them for destruction by extravascular hemolysis, the unique route of RBC destruction for wAIHA.29

Treatment with complement inhibitors may halt or improve complement-mediated hemolysis of red blood cells in patients with AIHA and thus reduce the risk of anemia and the associated symptoms and complications of anemia.18

There is a potential health benefit for trial participants receiving study drug. At the proposed dose levels of APL-2, a significant decrease in complement-mediated hemolytic activity was observed in all APL-2-treated subjects (both in treatment-naïve patients and in patients treated previously with eculizumab) in phase 1 studies of patients with PNH and in studies of healthy volunteers. APL-2 may therefore reduce complement-mediated hemolytic activity in AIHA patients.19

If efficacious and safe, APL-2 is expected to continue to improve hemoglobin levels and reduce transfusion dependency in these patients throughout the treatment period.19

APL-2 is an experimental drug, not yet marketed. Ongoing treatment (in previous clinical trials) with APL-2 has been well-tolerated for at least 2 months.19

The following safety monitoring practices are in place to protect the safety of participating subjects in the wAIHA trial/ cold agglutinin disease trial:

  • Recording of adverse events, and prompt reporting of predefined adverse events of special interest
  • Volume of blood collected from each subject will be minimized to limit the impact on the overall health of these anemic subjects
  • Vaccinations against encapsulated organisms that can cause infection when systemic complement is inhibited will be given along with prophylactic antibiotic therapy
  • Body temperature, vital signs, and relevant blood parameters will be monitored to assess for signs of infection18

The ICD-10-CM diagnosis code of D59.1, D59.0 covers reimbursement for:

  • Warm autoimmune hemolytic anemia (wAIHA)
  • Autoimmune hemolytic disease (warm type)
  • Warm type (secondary) (symptomatic) hemolytic anemia
  • Drug-induced autoimmune hemolytic anemia

Other terms that are searched in relation to this condition include:

  • Anemia, autoimmune hemolytic
  • Autoimmune hemolytic anemia
  • Hapten type high affinity hemolytic anemia
  • Hapten type low affinity hemolytic anemia
  • Hemolytic anemia associated with rheumatic disorder
  • Hemolytic anemia associated with systemic lupus erythematosus
  • Hemolytic anemia with systemic lupus erythematosus
  • Hemolytic anemia, drug induced autoimmune
  • Hemolytic anemia, due to warm antibody
  • Hemolytic anemia, high affinity hapten
  • Hemolytic anemia, low affinity hapten
  • Hemolytic anemia, rheumatic disease

Common Questions About Cold Agglutinin Disease

AIHA is a rare autoimmune disorder characterized by the premature destruction (hemolysis) of red blood cells (RBCs) by autoantibodies, at a rate faster than they can be replaced.1

Cold agglutinin disease(CAD), also referred to as cold autoimmune hemolytic anemia, is a rare type of autoimmune hemolytic anemia (AIHA) that accounts for 15% to 20% of all adult AIHA cases.10 In CAD, the autoantibodies (usually IgM) cause RBCs to clump together (agglutinate) when the person’s blood is exposed to cold temperatures (4º to 10°C, 32º to 50ºF) such as in cold-exposed extremities (nose, ears, fingers, toes).11

Symptoms of cold agglutinin disease (CAD) are often triggered or made worse by cold temperatures or a viral infection, which is why symptoms generally are worse during the winter. Symptoms may occur suddenly or gradually. These symptoms include12:

  • Fatigue (tiredness)
  • Dizziness
  • Headaches
  • Cold hands and feet
  • Pale skin
  • Dark urine
  • Jaundice (yellowing of the skin or whites of the eye)
  • Chest pain
  • Pain in the back or legs
  • Vomiting
  • Diarrhea
  • Heart problems like arrhythmia, heart murmur, or an enlarged heart
  • Many people also experience Raynaud’s disease (pain and bluish coloring of the hands and feet)

The age range for adult AIHA is 18 to >70 years and the median age of cold agglutinin disease (CAD) patients at diagnosis is ~67 years14

CAD is designated as either primary (unknown cause) or secondary (associated with or caused by another condition). Secondary cold agglutinin disease may be associated with:

  • Bacterial Infections such as mycoplasma, Legionnaires' disease, syphilis, listeriosis, or Escherichia coli
  • Viral infections such Epstein-Barr virus, cytomegalovirus, mumps, varicella, rubella, adenovirus, HIV, influenza, or hepatitis C
  • Parasitic infections such as malaria or trypanosomiasis
  • Other autoimmune diseases such as systemic lupus erythematosus
  • Certain types of cancers such as lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, multiple myeloma, and Kaposi sarcoma12

Cold agglutinin disease is not an inherited condition. In many cases, the cause of autoimmune hemolytic anemias remains unknown. Some researchers believe that there are multiple factors involved, including genetic and environmental influences.12

The diagnosis of cold agglutinin disease (CAD) is based on the presence of hemolytic anemia, signs of hemolysis with reticulocytosis, low haptoglobin, increased lactate dehydrogenase, elevated indirect bilirubin, and a positive direct antiglobulin test (DAT) for IgG and/or complement C3.22 The degree of anemia at presentation correlates with the severity of AIHA and with the probability of relapse.23

There are no FDA-approved drugs available for the treatment of cold agglutinin disease (CAD), and current medications used to treat CAD are limited. For people with secondary CAD, the underlying condition should be diagnosed and treated. For patients with idiopathic (primary) CAD, available treatment options include the off-label use of steroids, immunosuppressants, and rituximab; RBC transfusions.12,14

  • The biologic agent rituximab can induce remission in approximately half of the patients with CAD, although complete remissions are unusual, and the relapse-free survival at 1 year and 2 years is 59% and 40%, respectively.6,30
  • Combined treatment with rituximab and fludarabine has resulted in higher response rates (76% of cases) and longer periods of remissions (on average, 6.5 years). However the combined treatment may include serious side effects and is presently considered when rituximab monotherapy has failed.12
  • Corticosteroids used alone have been shown to be only effective in 14% of CAD, cases. Long-term use of corticosteroids is associated with many complications.8,24,25
  • Most patients with AIHA (55% to 65%) have a need for RBC transfusions. These transfusions may worsen hemolysis, potentially increasing the risk of hyperhemolysis, which can be life-threatening, and of RBC alloantibodies (ie, antibodies against a blood group antigen that is not present on the person's red blood cells) resulting in an inadequate recovery because of autoantibodies that will react with donor cells in AIHA patients.23,26

In severe cases of hemolysis, medical interventions may be necessary

  • Plasmapheresis, which involves filtering blood to remove antibodies, may be performed in acute hemolytic crisis or before surgery that would require hypothermia; however, the effect of plasmapheresis is only short term.12
  • Research has shown that performing a splenectomy is not recommended.14,27 Although the perioperative risk and mortality rate are less than 1%,13 overwhelming sepsis and postoperative cytotoxic immunosuppressants are often associated with serious adverse events.27,28
  • New therapeutic approaches are being studied and have reported positive results. However, more studies need to be performed before the safety and effectiveness of these therapies can be determined.12

The complement system is an integral part of our immune defense system. In healthy subjects, complement orchestrates the destruction and clearance of pathogens or of host cells that need to be replaced. It also has proinflammatory capabilities.

In autoimmune hemolytic anemia (AIHA), autoantibodies inaccurately recognize the subject's own proteins at the surface of red blood cells (RBCs) as non-self and activate the complement system to destroy these RBCs.

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Complement plays an important role in cold agglutinin disease (CAD). In CAD, red blood cells are heavily coated with antibodies that inappropriately recognize surface self-proteins. The complexes formed on the RBC surface activate the classical complement pathway. RBCs are coated with C3b, thus marking them for destruction by extravascular hemolysis, and the primary route of RBC destruction in CAD.29 Less frequently, in severe cases of CAD, C3b activates the complete complement cascade, which causes intravascular hemolysis (the abnormal breakdown of RBCs in the blood vessels).6,29

Free heme from RBC hemolysis can cause a second hit by mediating activation of the alternative pathway.15

There is a potential health benefit for trial participants receiving study drug. At the proposed dose levels of APL-2, a significant decrease in complement-mediated hemolytic activity was observed in all APL-2-treated subjects (both in treatment-naïve patients and in patients treated previously with eculizumab) in phase 1 studies of patients with PNH and in studies of healthy volunteers. APL-2 may therefore reduce complement-mediated hemolytic activity in AIHA patients.19

If efficacious and safe, APL-2 is expected to continue to improve hemoglobin levels and reduce transfusion dependency in these patients throughout the treatment period.19

APL-2 is an experimental drug, not yet marketed. Ongoing treatment (in previous clinical trials) with APL-2 has been well-tolerated for at least 2 months.19

The following safety monitoring practices are in place to protect the safety of participating subjects in the wAIHA trial/ cold agglutinin disease trial:

  • Recording of adverse events, and prompt reporting of predefined adverse events of special interest
  • Volume of blood collected from each subject will be minimized to limit the impact on the overall health of these anemic subjects
  • Vaccinations against encapsulated organisms that can cause infection when systemic complement is inhibited will be given along with prophylactic antibiotic therapy
  • Body temperature, vital signs, and relevant blood parameters will be monitored to assess for signs of infection18

The ICD-10-CM diagnosis code of D59.1 covers reimbursement for:

  • Autoimmune hemolytic disease (cold type)
  • Chronic cold hemagglutinin disease
  • Cold agglutinin disease
  • Cold agglutinin hemoglobinuria
  • Cold type (secondary) (symptomatic) hemolytic anemia

Other terms that are searched in relation to this condition include:

  • Chronic cold agglutinin disease
  • Cold agglutinin disease, chronic
  • Cold autoimmune hemolytic anemia
  • Hemolytic anemia, cold antibody

Common Questions About APL-2

APL-2 is a small (13–amino-acid) cyclic peptide coupled via a linker to each end of a linear 40 kDa PEG chain.19APL-2 binds to primate complement C3 and exerts broad inhibition of the complement cascade, a biological process that is part of innate immunity and is involved in multiple inflammatory processes. PEGylation imparts longer residence time in the body after administration of the drug.19

By targeting C3 at the point of convergence of all complement activation pathways and upstream of C5, APL-2 has the potential to block both the classical and the alternative pathway AND to prevent both intravascular and extravascular hemolysis in AIHA patients and thus reduce the risk of anemia and the associated signs and symptoms of anemia.19

Complement plays an important role in both warm antibody AIHA and CAD. In wAIHA and CAD, red blood cells are heavily coated with antibodies that inappropriately recognize surface self-proteins. The complexes formed on the RBC surface activate the classical complement pathway. RBCs are coated with C3b, thus marking them for destruction by extravascular hemolysis, the unique route of RBC destruction for wAIHA and the primary route of RBC destruction in CAD.29Less frequently, in severe cases of CAD, C3b activates the complete complement cascade, which causes intravascular hemolysis (the abnormal breakdown of RBCs in the blood vessels).6,29

Free heme from RBC hemolysis can cause a second hit by mediating activation of the alternative pathway.15

Treatment with complement inhibitors may halt or improve complement-mediated hemolysis of red blood cells in patients with AIHA and thus reduce the risk of anemia and the associated symptoms and complications of anemia.18

APL-2 is currently being developed for the management of paroxysmal nocturnal hemoglobinuria (PNH), which is another a rare, chronic, debilitating blood disorder. PNH is caused by the presence of mutant stem cells, produced in the bone marrow, that lack important surface proteins that protect against activation of the complement system.19

To recommend a patient or request information about this AIHA (warm autoimmune hemolytic anemia and cold agglutinin disease) trial

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References

  1. Anemia, hemolytic, acquired autoimmune. National Organization for Rare Disorders Web site. https://rarediseases.org/rare-diseases/anemia-hemolytic-acquired-autoimmune/. Accessed March 1, 2018.
  2. Park SH. Diagnosis and treatment of autoimmune hemolytic anemia: classic approach and recent advances. Blood Res. 2016;51(2):69-71.
  3. Barcellini W. New insights in the pathogenesis of autoimmune hemolytic anemia. Transfus Med Hemother. 2015;42(5):287-293.
  4. Warm antibody hemolytic anemia. Genetic and Rare Diseases Information Center Web site. http://www.orpha.net/consor/cgi-bin/Disease_Search_Simple.php?lng=EN&diseaseGroup=warm+autoimmune+hemolytic+anemia. Accessed March 1, 2018.
  5. Wheeler CA, Calhoun L, Blackall DP. Warm reactive autoantibodies: clinical and serologic correlations. Am J Clin Pathol. 2004;122(5):680-685.
  6. Berentsen S. Role of complement in autoimmune hemolytic anemia. Transfus Med Hemother. 2015;42(5):303-310.
  7. Packman CH. Hemolytic anemia due to warm autoantibodies. Blood Rev. 2008;22(1):17-31.
  8. Roumier M, Loustau V, Guillaud C, et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: New insights based on a single-center experience with 60 patients. Am J Hematol. 2014;89(9):E150-155.
  9. Michel M, Terriou L, Roudot-Thoraval F, et al. A randomized and double-blind controlled trial evaluating the safety and efficacy of rituximab for warm auto-immune hemolytic anemia in adults (the RAIHA study). Am J Hematol. 2017;92(1):23-27.
  10. Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre. Br Med J (Clin Res Ed). 1981;282(6281):2023-2027.
  11. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006;91(4):460-466.
  12. Cold agglutinin disease. Genetic and Rare Diseases Information Center Web site. https://rarediseases.info.nih.gov/diseases/6130/cold-agglutinin-disease. Accessed March 1, 2018.
  13. Reynaud Q, Durieu I, Dutertre M, et al. Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies. Autoimmun Rev. 2015;14(4):304-313.
  14. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121.
  15. Frimat M, Tabarin F, Dimitrov JD, et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood. 2013;122(2):282-292.
  16. Pawluczkowycz AW, Lindorfer MA, Waitumbi JN, Taylor RP. Hematin promotes complement alternative pathway-mediated deposition of C3 activation fragments on human erythrocytes: potential implications for the pathogenesis of anemia in malaria. J Immunol. 2007;179(8):5543-5552.
  17. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. The complement system and innate immunity. In: Immunobiology. 5th edition ed. New York, NY: Garland Science; 2001.
  18. Data on file, Appellis Pharmaceuticals.
  19. Paroxysmal noctural hemoglobinuria. www.apellis.com/focus-pnh.html. Accessed March 1, 2018.
  20. Autoimmune hemolytic anemia. Genetic and Rare Diseases Information Center Web site. https://rarediseases.info.nih.gov/diseases/5870/autoimmune-hemolytic-anemia. Accessed March 1, 2018.
  21. Anemia, autoimmune hemolytic. OMIM® - Online Mendelian Inheritance in Man® Web site. 1995; www.omim.org/entry/205700. Accessed March 19, 2018.
  22. Bass GF, Tuscano ET, Tuscano JM. Diagnosis and classification of autoimmune hemolytic anemia. Autoimmun Rev. 2014;13(4-5):560-564.
  23. Wouters D, Zeerleder S. Complement inhibitors to treat IgM-mediated autoimmune hemolysis. Haematologica. 2015;100(11):1388-1395.
  24. Genty I, Michel M, Hermine O, Schaeffer A, Godeau B, Rochant H. [Characteristics of autoimmune hemolytic anemia in adults: retrospective analysis of 83 cases]. Rev Med Interne. 2002;23(11):901-909.
  25. Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood. 2014;124(19):2930-2936.
  26. Michel M. Autoimmune hemolytic anemia, warm type. Orphanet Web site. www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=11931. Accessed March 1, 2018.
  27. Petz LD. Treatment of autoimmune hemolytic anemias. Curr Opin Hematol. 2001;8(6):411-416.
  28. Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias. Haematologica. 2014;99(10):1547-1554.
  29. Barcellini W, Zaja F, Zaninoni A, et al. Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies. Blood. 2012;119(16):3691-3697.
  30. Dhaliwal G, Cornett PA, Tierney LM, Jr. Hemolytic anemia. Am Fam Physician. 2004;69(11):2599-2606.

References

  1. Anemia, hemolytic, acquired autoimmune. National Organization for Rare Disorders Web site. https://rarediseases.org/rare-diseases/anemia-hemolytic-acquired-autoimmune/. Accessed March 1, 2018.
  2. Park SH. Diagnosis and treatment of autoimmune hemolytic anemia: classic approach and recent advances. Blood Res. 2016;51(2):69-71.
  3. Barcellini W. New insights in the pathogenesis of autoimmune hemolytic anemia. Transfus Med Hemother. 2015;42(5):287-293.
  4. Warm antibody hemolytic anemia. Genetic and Rare Diseases Information Center Web site. http://www.orpha.net/consor/cgi-bin/Disease_Search_Simple.php?lng=EN&diseaseGroup=warm+autoimmune+
    hemolytic+anemia
    . Accessed March 1, 2018.
  5. Wheeler CA, Calhoun L, Blackall DP. Warm reactive autoantibodies: clinical and serologic correlations. Am J Clin Pathol. 2004;122(5):680-685.
  6. Berentsen S. Role of complement in autoimmune hemolytic anemia. Transfus Med Hemother. 2015;42(5):303-310.
  7. Packman CH. Hemolytic anemia due to warm autoantibodies. Blood Rev. 2008;22(1):17-31.
  8. Roumier M, Loustau V, Guillaud C, et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: New insights based on a single-center experience with 60 patients. Am J Hematol. 2014;89(9):E150-155.
  9. Michel M, Terriou L, Roudot-Thoraval F, et al. A randomized and double-blind controlled trial evaluating the safety and efficacy of rituximab for warm auto-immune hemolytic anemia in adults (the RAIHA study). Am J Hematol. 2017;92(1):23-27.
  10. Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre. Br Med J (Clin Res Ed). 1981;282(6281):2023-2027.
  11. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006;91(4):460-466.
  12. Cold agglutinin disease. Genetic and Rare Diseases Information Center Web site. https://rarediseases.info.nih.gov/diseases/
    6130/cold-agglutinin-disease
    . Accessed March 1, 2018.
  13. Reynaud Q, Durieu I, Dutertre M, et al. Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies. Autoimmun Rev. 2015;14(4):304-313.
  14. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-1121.
  15. Frimat M, Tabarin F, Dimitrov JD, et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood. 2013;122(2):282-292.
  16. Pawluczkowycz AW, Lindorfer MA, Waitumbi JN, Taylor RP. Hematin promotes complement alternative pathway-mediated deposition of C3 activation fragments on human erythrocytes: potential implications for the pathogenesis of anemia in malaria. J Immunol. 2007;179(8):5543-5552.
  17. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. The complement system and innate immunity. In: Immunobiology. 5th edition ed. New York, NY: Garland Science; 2001.
  18. Data on file, Appellis Pharmaceuticals.
  19. Paroxysmal noctural hemoglobinuria. www.apellis.com/focus-pnh.html. Accessed March 1, 2018.
  20. Autoimmune hemolytic anemia. Genetic and Rare Diseases Information Center Web site. https://rarediseases.info.nih.gov/diseases/
    5870/autoimmune-hemolytic-anemia
    . Accessed March 1, 2018.
  21. Anemia, autoimmune hemolytic. OMIM® - Online Mendelian Inheritance in Man® Web site. 1995; www.omim.org/entry/205700. Accessed March 19, 2018.
  22. Bass GF, Tuscano ET, Tuscano JM. Diagnosis and classification of autoimmune hemolytic anemia. Autoimmun Rev. 2014;13(4-5):560-564.
  23. Wouters D, Zeerleder S. Complement inhibitors to treat IgM-mediated autoimmune hemolysis. Haematologica. 2015;100(11):1388-1395.
  24. Genty I, Michel M, Hermine O, Schaeffer A, Godeau B, Rochant H. [Characteristics of autoimmune hemolytic anemia in adults: retrospective analysis of 83 cases]. Rev Med Interne. 2002;23(11):901-909.
  25. Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood. 2014;124(19):2930-2936.
  26. Michel M. Autoimmune hemolytic anemia, warm type. Orphanet Web site. www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=11931. Accessed March 1, 2018.
  27. Petz LD. Treatment of autoimmune hemolytic anemias. Curr Opin Hematol. 2001;8(6):411-416.
  28. Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias. Haematologica. 2014;99(10):1547-1554.
  29. Barcellini W, Zaja F, Zaninoni A, et al. Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies. Blood. 2012;119(16):3691-3697.
  30. Dhaliwal G, Cornett PA, Tierney LM, Jr. Hemolytic anemia. Am Fam Physician. 2004;69(11):2599-2606.