Study to Assess the Safety, Tolerability, Efficacy and PK of APL-2 in Patients With Warm Type Autoimmune Hemolytic Anemia (wAIHA) or Cold Agglutinin Disease (CAD)

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)

This study is to assess the safety, tolerability, preliminary efficacy, and pharmacokinetics of APL-2 in subjects with warm Autoimmune Hemolytic Anemia (wAIHA) or Cold Agglutinin Disease (CAD).

Inclusion Criteria:

1. At least 18 years of age.

2. Weight < 125 Kg.

3. Subjects must have a primary diagnosis of wAIHA or CAD defined by the presence of hemolytic anemia and positive DAT for wAIHA (IgG) or CAD (C3).

4. Hemoglobin <11 g/dL.

5. Signs of hemolysis with abnormal values by any of the hemolytic markers:

   1. Increased absolute reticulocyte count (above ULN)
   2. Reduced haptoglobin (below LLN)
   3. Increased lactase dehydrogenase (LDH) (above ULN)
   4. Increased indirect bilirubin (above ULN)

6. Women of child-bearing potential (WOCBP) (defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause) 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 60 days after their last dose of study drug.

7. Males must agree to use protocol defined methods of contraception and agree to refrain from donating sperm for the duration of the study and 60 days after their last dose of study drug.

8. Able to provide documentary evidence of the following vaccinations within 2 years prior to screening:

   1. Neisseria meningitides types A, C, W, Y and type B (administered as two separate vaccinations)
   2. Streptococcus pneumoniae (Pneumococcal conjugate vaccine and Pneumococcal polysaccharide vaccine 23 [PCV13 and/or PPSV23, respectively])
   3. Haemophilus influenzae Type B (Hib) vaccine

   Subjects that do not have documentary evidence must be willing to receive any missing vaccinations as outlined below:

   1. Neisseria meningitides types A, C, W, Y and type B must be administered prior to dosing on Day 1. A booster is administered after at least 8 weeks (Day 56; for both vaccinations).
   2. Streptococcus pneumoniae PCV13 must be administered prior to dosing on Day 1 (see Section 12.2 for details). A PPSV23 booster is administered after at least 8 weeks (Day 56)
   3. Haemophilus influenze Type B (Hib) must be administered prior to dosing on Day 1.

9. Willing and able to give informed consent.

10. Specific for wAIHA: Relapsed from, did not respond or relapsed, or did not tolerate, at least one prior wAIHA treatment regimen (such as prednisone, rituximab).

Exclusion Criteria:

1. Prior treatment with rituximab within 90 days.
2. Deficiency of iron, folic acid and vitamin B12 prior to treatment phase
3. Abnormal liver function as indicated by a direct bilirubin above normal level, and/or an AST or ALT level > 2x upper limit of normal. Please note elevated indirect bilirubin due to hemolysis is not an exclusion criteria.
4. Elevated bilirubin not due to active hemolysis. Any elevation of bilirubin >ULN will require Sponsor review and approval for subject enrollment into the trial.
5. Active aggressive lymphoma requiring therapy or an active non-lymphatic malignant disease other than basal cell carcinoma or carcinoma in situ (CIS) of the cervix.
6. Presence or suspicion of active bacterial or viral infection, in the opinion of the Investigator, at screening or severe recurrent bacterial infections.
7. Participation in any other investigational drug trial or exposure to other investigational agent, device, or procedure within 30 days prior to screening period.
8. Pregnant, breast-feeding, or intending to conceive during the course of the study, including the Post-Treatment Phase.
9. Inability to cooperate or any condition that, in the opinion of the investigator, could increase the subject's risk by participating in the study or confound the outcome of the study.
10. Myocardial infarction, CABG, coronary or cerebral artery stenting and /or angioplasty, stroke, cardiac surgery, or hospitalization for congestive heart failure within 3 months or > Class 2 Angina Pectoris or NYHA Heart Failure Class >2
11. QTcF > 470 ms
12. PR > 280 ms
13. Mobitz II 2nd degree AV Block, 2:1 AV Block, High Grade AV Block, or Complete Heart Block unless the patient has an implanted pacemaker or implantable cardiac defibrillator (ICD) with backup pacing capabilities