Efficacy and Safety of M281 in Adults with Warm Autoimmune Hemolytic Anemia: A Multicenter, Randomized, Double blind, Placebo controlled Study with a Long-term Open-label Extension

Inclusion Criteria, Double-blind Period
Patients who meet the following criteria will be eligible for enrollment into
the double-blind period of the study.
1. Male or female >=18 years of age.
2. Diagnosed with active primary or secondary wAIHA, defined as having all of
the following:
a) Hgb value<10 g / dl AND
b) Signs of hemolysis, defined as: lactate dehydrogenase (LDH) levels above the
upper limit of normal (ULN), or haptoglobin below the lower limit of normal, or
indirect bilirubin above the ULN AND
c) Serological evidence of anti erythrocyte antibodies associated with a DAT
that is either positive for IgG only or is positive for IgG and C3d (fragment
of the third component of complement) at screening at the central laboratory.
If the DAT is negative, it can be repeated once. If the repeat is negative,
participant not eligible.
3. Have been diagnosed with wAIHA for at least 3 months, and are currently
receiving treatment for wAIHA OR have previously received treatment for wAIHA
(treatment-naïve participants are not eligible)
4. If on corticosteroids, participants must have been on treatment for at least
4 weeks with a stable dose during the screening period or for at least 14 days
prior to randomization. whichever is longer. Note:
Investigators can optimize the above background medications prior to
randomization if they are following the above rules for stable dose duration.
5. If receiving immunosuppressants, following drugs allowed:
concomitant immunosuppressants are azathioprine, mycophenolate
mofetil/mycophenolic acid, methotrexate,
cyclosporine, tacrolimus, danazol, and cyclophosphamide. Participants must have
been on a stable dose of any of
these drugs for =12 weeks prior to screening and during the screening period.
If any of these drugs were stopped,
it must have been stopped for at least 8 weeks prior to screening. Note:
Investigators can optimize the above background medications prior to
randomization if they are following the above rules for stable dose duration.
6. Have a platelet count >=30 × 109/L.
Note: Patients with Evans syndrome who do not have primary immunodeficiency
will be eligible as long as they meet all other entry criteria, including
having a platelet count >=30 × 109/L.
7. Participants who have undergone splenectomy must be at least 3 months post
resection prior to screening and must be vaccinated as per the United States
Center for Disease Control and Prevention (CDC) annual Recommended Immunization
Schedule for Adults Aged 19 Years or Older, United States
(https://www.cdc.gov/vaccines/schedules/hcp/imz/adult-conditions.html) OR must
be vaccinated as per country-specific guidelines (Davies 2011).
8. Participants with other autoimmune disease (e.g., systemic lupus
erythematosus or rheumatoid arthritis) or lymphoproliferative disorders may be
eligible if they are stable (no changes in concomitant disease-related
medications and severity of disease) for at least 3 months prior to screening.
Participants with lymphoproliferative disease must also have a low grade, be
stable and be, in the opinion of the Investigator, unlikely to require
chemotherapy or monoclonal antibody therapy during the double-blind period of
the study. Participants requiring change of treatment or new treatment for
autoimmune or lymphoproliferative diseases ((but not rescue therapy for wAIHA)
during the double-blind period will be terminated from the study.
9. Have sufficient venous access to allow drug administration by IV infusion
and blood sampling as per the protocol.
10. Women of childbearing potential, defined as women physiologically capable
of becoming pregnant, must have a negative serum pregnancy test at screening
and a negative urine pregnancy test at baseline. Menopausal women must have an
elevated serum follicle-stimulating hormone (FSH) level at screening; if the
FSH is not elevated, they are considered to be of childbearing potential and
must have a negative serum pregnancy test at screening and a negative urine
pregnancy test at baseline to be eligible.
11. Women of childbearing potential (including menopausal women who do not have
elevated FSH) must agree to remain totally abstinent or to consistently use a
reliable and highly effective method of contraception during the study and for
30 days after the last dose of study drug.
12. Male participants must wear a condom when engaging in any activity that
allows for passage of ejaculate to another person during the study and for at
least 90 days after receiving the last dose of study drug. In addition, male
participants with partners who are a woman of childbearing potential are to be
highly encouraged to inform their partner to use highly effective contraception
methods that result in low failure rate (less than 1% per year)
13. Participants who use herbal, naturopathic, traditional Chinese remedies,
ayurvedic and nutritional supplements, or medical marijuana (with a doctor*s
prescription) are eligible if the use of these medications is acceptable to the
Investigator. These remedies must be at a stable dose and regimen using the
same preparation for >=2 months prior to Screening.
14. Are able to understand and voluntarily provide written informed consent to
participate in the study and comply with all study procedures. Patients who
initially provide consent and subsequently withdraw it prior to randomization,
will be deemed as having failed this inclusion criterion.
15. Vaccinations prior to screening as per routine local guidelines (including
COVID-19).

Inclusion Criteria, Open-label Extension
1. Participants have completed the double-blind period (through Week 24), or
have required rescue therapy at/or after Week 4 of the double-blind period, or
failed to demonstrate an increase from baseline in Hgb of at least 1 g/dL and
are symptomatic at or after Week 16 of the double-blind period.
2. Are able to understand and voluntarily provide written informed consent to
participate in the OLE period and comply with all study procedures.

Exclusion Criteria, Double-blind Period
Patients who meet any of the following criteria will not be eligible for
enrollment into the double-blind period of the study.
1. Are currently taking IgG Fc-related protein therapeutics.
2. Have received a transfusion within 30 days prior to randomization.
3. Have any other associated cause of hereditary or acquired hemolytic anemia.
4. Have received rituximab within 3 months prior to screening.
5. Have received IVIg within 6 weeks prior to screening.
6. Have been diagnosed with cold antibody AIHA, cold agglutinin syndrome, mixed
type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria.
7. Have a severe infection (e.g., pneumonia, biliary tract infection,
diverticulitis, Clostridium difficile infection) that requires parenteral
anti-infectives and/or hospitalization, and/or is assessed as
serious/clinically significant (CS) by the Investigator, within 8 weeks prior
to screening. Any participant with an infection requiring oral anti-infectives
(e.g., sinusitis, bronchitis, uncomplicated urinary tract infection) within 4
weeks prior to screening will be excluded.
8. Have a chronic infection (e.g., bronchiectasis, chronic osteomyelitis,
chronic pyelonephritis) or require chronic treatment with anti-infectives
(e.g., antibiotics, antivirals).
9. Have received a live viral or bacterial vaccine within 4 weeks prior to
first dose of study drug, or have a known need to receive a live viral or
bacterial vaccine during the study or within at least 3 months after the last
dose of study drug. For information regarding the Bacille Calmette-Guérin (BCG)
vaccine, please see Exclusion Criterion 25.
10. Have any confirmed or suspected clinical immunodeficiency syndrome not
related to treatment of their wAIHA, or has a family history of congenital or
hereditary immunodeficiency unless confirmed absent in the participant.
11. Have any of the following viral testing outcomes:
• A history of human immunodeficiency virus (HIV) infection or positive test
result for HIV-1 and HIV 2 antibodies.
• A positive test for hepatitis B virus surface antigen (HBsAg). For
participants with a negative test for HBsAg along with a positive test for
anti-hepatitis B core (HBc) antibodies and a positive or negative test for
anti-HBs antibodies, hepatitis B viral DNA detection will be performed.
Participants with a positive hepatitis B viral DNA detection will be excluded.
If HBV DNA testing cannot be performed, or there is evidence of chronic liver
disease, the participant is not eligible for the protocol; A positive test for
hepatitis C virus (HCV) unless 1 of the following conditions are met: (a) Has a
history of successful treatment, defined as being negative for HCV RNA at least
24 weeks after completing antiviral treatment, and has a negative HCV RNA test
result at least 24 weeks prior to screening and a negative HCV RNA test at the
screening.
12. Are currently breastfeeding, pregnant, intend to become pregnant during the
study, or are planning egg donation during the study or within 30 days after
the last dose of study drug.
13. Have current alcohol/substance abuse/dependence, a history of
alcohol/substance abuse/dependence within the 12 months prior to screening, or,
in the Investigator*s opinion, show evidence of ongoing alcohol/substance
abuse/dependence.
14. Are currently participating in another interventional clinical trial or
have received any investigational drug within the past 3 months prior to
screening.
15. Have had any major surgery within 3 months prior to screening or have plans
for or have been scheduled for any elective surgery or major dental procedure
during the study.
16. Have a history of a major organ transplant (e.g., heart, lung, kidney,
liver), or hematopoietic stem cell/marrow transplant.

Further exclusion criteria listed in the protocol not listed here due to
character restriction.

Exclusion Criteria, Open-label Extension
1. Met any of the stopping criteria (see Section 6.4.1) or discontinued study
drug during the double-blind period due to treatment-related AE.
2. Currently have a serious or clinically significant infection (e.g.,
pneumonia, biliary tract infection, diverticulitis, C. difficile infection)
requiring parenteral anti-infectives and/or hospitalization.

The following exclusion criterion from the double-blind period also applies to
enrollment in the OLE: Exclusion Criteria #8 and #21.
Exception: Participants who were previously enrolled in this study and was
unable to complete the DBP due to the Sponsor suspending dosing due to the
COVID-19 pandemic can be enrolled in the OLE after meeting all of the
double-blind eligibility criteria. Participants who completed the 28-week OLE
before Amendment 6 can be re-enrolled in the OLE per investigator's discretion
if the participants continue meet the eligibility criteria for the OLE.
Participants will resume study treatment calculated from the baseline visit
once they have reconsented to the study.