A PIVOTAL, OPEN-LABEL, MULTICENTER STUDY TO ASSESS THE EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH PRIMARY COLD AGGLUTININ DISEASE WHO HAVE A RECENT HISTORY OF BLOOD TRANSFUSION

The CP has been implicated in many diseases that are driven by the presence of
a pathogenic antibody; CAgD is one such example. Complement inhibition has
proven to be a safe and effective treatment for another form of hemolytic
anemia, paroxysmal nocturnal hemoglobinuria. Currently, there are approved
complement inhibitors being used therapeutically for various indications,
including Soliris® (eculizumab), a mAb targeting C5; Berinert® and Cinryze®,
both C1 esterase inhibitors purified from human plasma; and Ruconest®, a
recombinant form of human C1 esterase inhibitor. Unlike Soliris and the C1
esterase inhibitors, by specifically targeting C1s, BIVV009 inhibits only the
CP, leaving the alternative complement pathway and the lectin complement
pathway available for immune surveillance. Furthermore, by blocking at the
level of the C1 complex, BIVV009 is expected to prevent generation of all
anaphylatoxins and opsonins (eg, C3 fragments) that produce pathologic lesions
in CP-mediated disorders.
CAgD is an autoimmune hemolytic anemia caused by IgM-induced CP activation,
which is typically triggered by exposure to cold environmental temperatures or
viral infections (Arthold et al. 2014; Berentsen 2011; Berentsen 2014;
Berentsen et al. 2007; Petz 2008; Swiecicki et al. 2013). CAgD is typically not
responsive to treatment with steroids or splenectomy and can only be managed by
supportive measures (avoidance of cold, blood transfusions as needed), and/or
immunosuppressive, cytotoxic therapies (eg, rituximab with or without
fludarabine or bendamustine). A Phase 1b clinical trial of BIVV009 in patients
with CAgD showed that it can rapidly induce complete remission of anemia (Jager
and Gilbert 2016).

Part A
Primary Objective:
• The primary objective of Part A is to determine whether BIVV009
administration results in a >= 2 g/dL increase in hemoglobin (Hgb) levels or
increases Hgb to >= 12 g/dL and obviates the need for blood transfusion during
treatment in patients with primary CAgD who have a recent history of transfusion
Secondary Objectives:
Efficacy:
• To assess the effect of BIVV009 on clinical events and laboratory parameters
related to hemolysis and anemia in patients with primary CAgD
• To assess the effect of BIVV009 on quality of life (QOL) in patients with
primary CAgD
Safety:
• To evaluate the overall safety and tolerability of BIVV009 in patients with
primary CAgD
Exploratory:
• To assess the effect of BIVV009 on specific complications of CAgD
(acrocyanosis, Raynaud*s syndrome, hemoglobinuria, and thromboembolism)
• To evaluate the effect of BIVV009 on certain disease-related biomarkers in
patients with primary CAgD
• To evaluate the pharmacokinetics of BIVV009
Part B
Primary Objective:
• The primary objective of Part B is to evaluate the long-term safety and
tolerability of BIVV009 in patients with primary CAgD.
Secondary Objective:
• The secondary objective of Part B is to investigate the durability of
response during long-term treatment with BIVV009 in patients with primary CAgD.

This open-label, single-arm study is designed to evaluate the efficacy, safety,
and tolerability of BIVV009 in patients with the complement-mediated disorder
primary CAgD who have a recent history of transfusion.
During the 6-week Screening/Observation Period, prospective patients will have
a detailed medical history documented (including transfusion history of >= 6
months), physical evaluations for screening, and blood samples collected for
characterization of CAgD biomarkers, including Hgb levels on 3 occasions
approximately every 2 weeks.
Patients may receive a transfusion(s) during the Screening/Observation Period
prior to the first study drug infusion if medically indicated per the
Investigator*s discretion. However, the baseline visit (and first infusion of
study drug) must occur at least 7 days following the transfusion.
Part A
The study will enroll 20 primary CAgD patients who have a recent history of
transfusion, defined as at least 1 transfusion during the last 6 months prior
to enrollment. Eligible patients will receive an intravenous (IV) infusion of
BIVV009 over approximately 60 minutes on Day 0, Day 7, and every 14 days
thereafter through Week 25 (ie, Days 21, 35, 49, 63, 77, 91, 105, 119, 133,
147, 161, and 175). Patients who miss a dose (ie, outside the dosing window or
> 17 days since last dose) should return to the site for an unscheduled visit 1
week prior to the next scheduled dose in order to receive an additional loading
dose. Patients will have an End of Treatment (EOT) visit in Part A on Day 182
(Week 26).
Patients who meet the transfusion criteria in Table 1 during the 6-month
treatment period will receive a transfusion.
Table 1: Transfusion Criteria
A patient will receive a transfusion during Part A if his or her Hgb level
meets either of the following criteria:
• Hgb is < 9 g/dL and the patient is symptomatic, or
• Hgb is < 7 g/dL and the patient is asymptomatic
A responder analysis will be conducted following completion of the EOT visit at
Week 26. The responder definition is provided in Table 2.
Table 2: Responder Definition
A patient will be considered a responder in Part A if he or she did not receive
a blood transfusion from Week 5 through Week 26 (EOT) and did not receive
treatment for CAgD beyond what is permitted per protocol. Additionally, the
patient*s Hgb level must meet either of the following criteria:
• Hgb level is >= 12 g/dL at treatment assessment endpoint (defined as mean
value from Weeks 23, 25, and 26), or
• Hgb increased >= 2 g/dL from baseline (defined as the last Hgb value before
administration of the first dose of study drug) at treatment assessment endpoint
Note: Any patient withdrawing from the study after Week 5 and prior to the Week
23 visit will be considered a non-responder.
A list of excluded concomitant medications, as well as allowed concomitant
medications with restrictions, is provided in the protocol. Beyond the
permitted concomitant medications, study drug, and transfusions, patients may
receive no other therapies for the treatment of CAgD while enrolled in this
study; patients requiring other treatment for their CAgD in Part A will be
withdrawn from the study and counted as non-responders.
Part B
Following completion of dosing in the 6-month treatment period, patients will
continue to receive BIVV009 dosing during Part B, the long-term safety and
durability of response extension phase. Part B will run for approximately one
year following LPO under Part A.
Patients will be dosed with BIVV009 every 2 weeks, as in Part A. Should
patients deviate from their scheduled dosing a repeat loading dose may be
required. Optional in home visits may be utilized in Part B to ease the
patient*s travel burden; however, on site visits will be completed ~every 3
months (at a minimum) for collection of pharmacodynamic (PD) and
pharmacokinetic (PK) samples, and additional safety and efficacy measures. PK,
PD and antidrug antibodies (ADA) samples will be collected 6 weeks after
administration of the last dose of study drug in patients who discontinue
early, as well as in patients who experience a hematological breakthrough
event.

All patients will receive the following interventions:
- ECG
- Blood draws for safety (chemistry and hematology)
- Blood draws for pharmacokinetic parameters
- Bone marrow biopsy if needed
- Study drug will be administered over approximately 60 minutes by IV infusion
in accordance with the Pharmacy Manual. Patients with underlying
cardiopulmonary disease may receive a 2-hour infusion with Sponsor approval.

2.2.4. Potential Risks and Benefits
As previously noted, clinical proof of concept for BIVV009 was achieved in a
Phase 1b study, which demonstrated immediate cessation of hemolysis and rapid
correction of anemia during short-term treatment of patients with CAgD.
The human safety risk from off-target effects of mAb therapeutics is generally
considered to be low, and in this regard BIVV009 is no exception. The human
safety risk from short-term inhibition of the complement system also appears to
be low, based upon the experience with five approved products in this
therapeutic class. Long-term, complement inhibition may increase the risk of
infection with encapsulated bacteria, as reflected in the product label for
eculizumab (Soliris), an inhibitor of the terminal portion of the complement
system. However, this risk can be mitigated with an appropriate program of
prophylactic vaccinations, which has been incorporated into the design of this
study.
The risks associated with long-term inhibition of the proximal portion of the
CP are presently unknown. Theoretically, it could increase the risk of SLE or
circulating immune complexes (CIC) disease due to the role of the C1 complex in
immune complex clearance, as observed in patients with congenital deficiencies
of C1 complex components (C1q, C1s, and C1r). However, pharmacologic inhibition
of C1s differs from congenital deficiency of the C1 complex because: 1)
congenital C1 complex component deficiency are commonly not single gene
mutations but typically are associated with second mutations in other immune
system genes; 2) pharmacologic inhibition of C1s enzymatic function in the C1
complex leaves intact the non-enzymatic function of C1q, which is important for
the opsonization and phagocytic removal of apoptotic cells which protects
against autoimmunity; and 3) the phenotype associated with life-long, often
total absence of C1 complex structure and function is unlikely to be reproduced
by pharmacologic antagonism of C1 enzymatic function in fully developed adults.
Nevertheless, standard clinical biomarkers related to SLE (eg, antibodies to
double-stranded DNA [dsDNA]) have been incorporated into the study design as
safety surveillance measures.
The overall risk/benefit balance for participants in Study BIVV009-03 is
favorable based on available data to date.