A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH PRIMARY COLD AGGLUTININ DISEASE WITHOUT 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 toprevent 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).

Primary Objective:
The purpose of Part A is to determine whether sutimlimab administration results
in a greater than or equal to (>=)1.5 gram per deciliter (g/dL) increase in
hemoglobin (Hgb) level and avoidance of transfusion in participants with
primary cold agglutinin disease (CAD) without a recent history of blood
transfusion.
The purpose of Part B is to evaluate the long-term safety and tolerability of
sutimlimab in participants with primary CAD.

Secondary Objective:
Part A:
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 specific complications of CAgD
(acrocyanosis, Raynaud's syndrome, hemoglobinuria, and thromboembolism)
To assess the effect of BIVV009 on quality of life (QOL) in patients with
primary CAgD
Part B:
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 randomized, double-blind, placebo-controlled study is designed to evaluate
the
efficacy, safety, and tolerability of BIVV009 in symptomatic patients with the
complement-mediated disorder primary CAgD who do not have a recent history of
blood
transfusion.
During the 6-week Screening/Observation Period, prospective patients will have a
detailed medical history documented (including all available transfusion
history),
physical evaluations, and blood samples collected for characterization of CAgD
biomarkers, including Hgb levels on 3 occasions approximately every 2 weeks.
Patients under screening for Cadenza who require a transfusion(s) during the
Screening/
Observation Period prior to the first study drug infusion (if medically
indicated per the
Investigator*s discretion and within the parameters of the protocol specified
transfusion
criteria, see Table 1) will be screen failed for Cadenza and enrolled into the
Cardinal trial
if they meet all the other study-specific entry criteria.
Part A
The study will enroll 40 primary CAgD patients who do not have a recent history
of
blood transfusion (ie, no transfusion during the last 6 months prior to
enrollment), or who
are newly diagnosed with an indeterminate transfusion history (ie, less than a
6-month
history with no transfusions), or no transfusion history.
Eligible patients will be randomized 1:1 to receive an intravenous (IV)
infusion of
BIVV009 or placebo 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 to receive another
loading dose
prior to their next scheduled visit. 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
double-blind
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 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 the following criterion:
* Hgb increase * 1.5 g/dL from baseline (defined as the last Hgb value before
administration of the first dose of study drug) at treatment assessment endpoint
(defined as mean value from Weeks 23, 25, and 26)
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 Part A of 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 initial 6-month treatment period,
patients will roll
into the long-term safety and durability of response extension phase and receive
BIVV009 in an open-label manner. Part B will run for approximately 1 year
following
LPO under Part A.
Blinding will be maintained when rolling patients into the extension period by
providing
a crossover dose at Week 26 to allow placebo patients to receive the BIVV009
loading
dose at start of BIVV009 dosing. Patients who were randomized to BIVV009 during
the
6-month treatment period will receive a placebo dose at Week 26 to maintain
blinding.
All patients will then continue to receive BIVV009 dosing every 2 weeks
starting at
Week 27. 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, ADA samples
and additional safety and efficacy measures. PK, PD and anti-drug antibodies
(ADAs)
samples will be collected 9 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.
Home infusions with the study drug will be proposed to a number of patients in
countries pre-selected to participate in home infusion (including The
Netherlands). Home infusions will be assisted by a trained healthcare
professional, and will concern patients who express such wish, after having
been qualified by the Investigator and no sooner than after Week 41 (Day 287)
and without evidence of intolerance of the study drug as determined by the
Investigator based on the criteria outlined in Appendix K (Appendix K of the
protocol).
The overall risk/benefit balance for participants in Study BIVV009-04 is
favorable based on
available data to date.