A Phase 2 Study Evaluating the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Narsoplimab in Paediatric Patients (28 Days to 18 Y.O.) with High Risk Haematopoietic Stem Cell Transplant Thrombotic Microangiopathy

5.1. Background
5.1.1. Description of Narsoplimab
Omeros Corporation (Omeros, Sponsor) is developing narsoplimab (company code
OMS721), a human IgG4 monoclonal antibody (mAb) that specifically binds to
mannan-binding lectin-associated serine protease 2 (MASP-2) and inhibits the
lectin
pathway of complement for the treatment of lectin complement pathway-mediated
diseases.
The primary function of the complement system, a part of the innate immune
system, is
to protect the host against infectious agents [Ricklin 2010]. This complex
system targets
immune and inflammatory responses to surfaces that display molecular patterns
not
usually present on healthy host cells. Activation of the complement system
initiates a
series of proteolytic steps that culminate in the formation of a membrane
attack complex,
which disrupts the membranes of targeted cells causing lysis and cell death. In
addition,
complement activation triggers the release of anaphylatoxins to recruit
leukocytes and
activate endothelium and many other cell types, as well as opsonization and
activation of
phagocytic cells, to further engage the infectious agents.
Three pathways activate complement in response to distinct initiating events:
the
classical, lectin, and alternative pathways. The classical pathway is triggered
by immune
complexes and mediates important immune effector functions. The lectin pathway
can be
activated by specific types of damage-associated molecular patterns (DAMPs)
that are
usually found on microbes but not on healthy host cell surfaces. These DAMPS
are also
found on injured host tissue. Lectin pathway activation is initiated by a group
of enzymes
known as MASPs. These proteases are synthesized as proenzymes that form a
complex in
blood with lectins, such as the mannan-binding lectin (MBL), ficolins, and a
lectin known
as Collectin 11. These lectins bind to carbohydrate patterns on foreign or
injured host cell
surfaces, targeting MASPs to their site(s) of action and leading to activation
of MASPs.
There are three known MASPs: MASP-1, MASP-2, and MASP-3 [Yongqing 2012].
MASP-2 is thought to be the key enzyme responsible for activation of the lectin
pathway;
upon activation, it cleaves its substrates, C2 and C4, resulting in the
formation of the
convertase C4b2a, which cleaves and activates C3, a central component of
complement
activation. Narsoplimab blocks the action of MASP-2, thereby inhibiting the
lectin
pathway of complement activation. The alternative pathway, by contrast, is
continuously
activated at a low level and is kept in check by a series of regulatory
proteins. The
alternative pathway also acts as an amplification loop, increasing the host
immune
response following activation of the classical and the lectin pathways. While
the
complement system supports innate host defense against pathogens, mutations in
the
genome or tissue damage can cause inappropriate activation and lead to serious
disease,
e.g., thrombotic microangiopathy (TMA), in which endothelial damage, as well as
deposition of fibrin and platelet-rich thrombi in the microvasculature, leads
to end organ
damage.

Narsoplimab is a fully human IgG4 mAb directed against MASP-2. Narsoplimab
avidly
binds to recombinant MASP-2 (apparent Kd in the range of 100 pM) and exhibits
greater
than 5000-fold selectivity over the homologous proteins C1s, C1r, and MASP-1. In
functional assays, Narsoplimab inhibits the human lectin pathway with nanomolar
potency (concentration leading to 50% inhibition [IC50] of approximately 3 nM),
but it
has no significant effect on the classical or alternative complement pathways.
An intact
classical and alternative complement pathway is important to prevent lethal
infections
during complement inhibitory therapy, which has been a major concern that
requires pretreatment
vaccination and/or prophylactic antibiotics. Narsoplimab administered either by
intravenous (IV) or subcutaneous (SC) injection to mice and non-human primates
resulted in high plasma concentrations that were associated with suppression of
lectin
pathway activation in an ex vivo assay. Narsoplimab blocks the crosstalk
between the
lectin pathway and the coagulation system (activation of Factor XII) and
contact system
(activation of Kallikrein) (Omeros unpublished data). Narsoplimab treatment
reduced
thrombus formation in a mouse model of TMA, thus demonstrating that narsoplimab
is a
potential candidate for the treatment of haematopoietic stem cell
transplant-associated
thrombotic microangiopathy (HSCT-TMA) that results from inappropriate lectin
pathway
activation. Narsoplimab has also been shown to reduce platelet aggregation and
endothelial cell death in models employing human sera from HSCT-TMA patients
[Elhadad 2020].

This study has been transitioned to CTIS with ID 2023-509710-11-00 check the CTIS register for the current data.

Study Objectives:
The purpose of this Phase 2 study is to evaluate the safety, efficacy,
pharmacokinetics (PK),
pharmacodynamics (PD), and immunogenicity of narsoplimab in paediatric-aged
patients with
thrombotic microangiopathies (TMA) following haematopoietic stem cell
transplant (HSCT).

Methodology
This is the first study of narsoplimab in paediatric patients. This study is an
open-label, multicenter
study evaluating the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic
(PD) of narsoplimab in male and/or female patients 28 days old to less than 18
years old who
received an allogeneic HSCT for the treatment of benign or malignant disease
and have
high risk HSCT-TMA. The study has three periods: Screening (Days -28 to Day 0);
Treatment
(Day 1 to Day 56); Follow-up (Days 57 to Day 365).
Screening Period
Patients will be evaluated for eligibility between Day -28 and Day 0 prior to
the first drug
administration. If the ADAMTS13 activity response results are not available to
confirm
eligibility before the Screening period ends, then Screening can be extended.
Treatment Period
Treatment with narsoplimab 4 mg/kg (not to exceed 370 mg) IV will be
administered by IV
infusion twice a week, with 2 to 4 days between doses, with no more than 2
doses per week,
over 8 consecutive weeks, starting at Visit 1 (Day 1). If patient achieves all
clinical response
criteria during the Treatment Period before 8 weeks, frequency will be reduced
to narsoplimab
4 mg/kg IV once a week until patient completes the 8 full weeks of treatment.
See the Schedule of Events (Section 0) for the procedures to be done during the
study. For
evaluation of laboratory assessments, local laboratory will be used for all of
the sites because
paediatric patients are critically ill and will need lab results as soon as
possible and because of
blood draw limitations based on regulatory guidelines. If study labs have
already been drawn
as standard of care ± 48 to 72 hours of the screening and Day 1 visit, labs do
not need to be
redrawn.
Narsoplimab is to be used in conjunction with standard of care treatments.
Standard of care
treatments are not to be delayed or withheld from patients entering this study.
These treatments
should be initiated according to local standard of care. For example, plasma
exchange should
not be delayed while waiting for initiation of narsoplimab treatment if local
standard of care is
to administer plasma exchange.
Depending on the patient*s clinical status at the completion of dosing for 8
weeks, the
Investigator may request compassionate use treatment with narsoplimab for the
patient after
discussion with the Omeros medical monitor.
Follow-Up
All patients will enter Follow-up Period at the end of 8 weeks of study drug
treatment. Followup
visits will begin at Day 60 and be completed 365 days after the first dose of
study drug.

Investigational Product, Dosage, and Mode of Administration:
* Narsoplimab for injection, formulated in 20 mM citrate, 200 mM arginine, and
0.01%
polysorbate 80, pH 5.8, 185 mg/mL
* IV infusion: appropriate volume of narsoplimab added to 0.9% sodium chloride
for
injection (normal saline or NS) or dextrose in water (D5W), infused over 30 to
90
minutes

5.3. Potential Risk and Benefits
5.3.1. Known and Potential Risks
5.3.1.1. Human MASP-2 Deficiency
A MASP-2 deficiency has been reported to occur in humans, and the clinical
phenotype
of MASP-2 deficiency may be relevant to risk assessment of MASP-2 inhibition
with
narsoplimab. The literature contains conflicting reports as to whether patients
with
MASP-2 deficiency are at risk for adverse effects.
Two case reports described individuals with MASP-2 deficiency due to a
homozygous
mutation (D120G) with clinical associations with autoimmunity or recurrent
bacterial
infections; 1 patient was healthy until 13 years of age, and the other patient
had cystic
fibrosis [Olesen 2006, Stengaard-Pedersen 2003]. A genetic screen of 335 Polish
children
with recurrent respiratory tract infections identified 1 child with MASP-2
deficiency
[Cedzynski 2004]. In contrast, in a genetic screen of 868 healthy Spaniards, 2
homozygous D120G individuals were identified; both patients were healthy
without
clinical evidence of recurrent infections or autoimmune disorders, and both had
normal levels of circulating complement [Garcia-Laorden 2006].
The gene frequency of the D120G mutation is 2% to 4% in European populations,
which would predict that approximately 1 in 625 to 2000 individuals in this
population would be homozygotes with MASP-2 deficiency [Garcia-Laorden 2006,
Thiel 2007]. Polymorphisms in the MASP-2 gene as well as the plasma
concentration of MASP-2 are influenced by race. For example, the D120G mutation
is the most common one in Caucasians, but it is not found in Chinese or
Africans [Thiel 2007, Urbano-Ispizua 2011]. Moreover, the circulating levels of
MASP-2 were lowest in Africans (median 196 ng/mL), followed by Chinese (262
ng/mL) and Native American (290 ng/mL), and highest in Caucasian Danes (416
ng/mL) [Thiel 2007]. The initial studies were in Danes, and a plasma
concentration below 100 ng/mL was suggested as indicating MASP-2 deficiency
because only individuals homozygous for the D120G mutation had this level.
Subsequent studies in broader populations showed that this cutoff was
inappropriate because 5% of Chinese and 19% of Africans tested had values below
100 ng/mL.
Several studies have examined the relationship between MASP-2 concentration and
susceptibility to infections. In a Swiss study of 94 paediatric cancer
patients, MASP-2 deficiency, defined as serum levels below 200 ng/mL, was
identified in 9 children [Schlapbach 2007].
Patients with low MASP-2 levels had significantly more episodes of febrile
neutropenia with no identified microbial etiology and had longer duration of IV
antibacterial therapy than those with normal MASP-2 levels. In a Polish study
of 1788 neonates, cord blood serum MASP-2 concentration correlated with
gestational age and birth weight and was significantly lower in premature
babies and other pre-term babies compared with term babies [St Swierzko 2009].
Neonates with low MASP-2 concentrations did not have a higher incidence of
perinatal infections when compared with those with normal MASP-2. Indeed, there
was a trend toward higher MASP-2 concentrations among babies with infections. A
study in Spain evaluated the frequency of D120G mutation in 868 healthy
individuals as well as 967 adult patients with community-acquired pneumonia, 43
children with recurrent respiratory infections, and 130 patients with systemic
lupus erythematosus and found that the allelic frequency of the D120G mutation
was similar in all of these clinical groups [Garcia-Laorden 2006]. These
investigators conducted a follow-up study in which they evaluated the
significance of MASP-2 deficiency in the susceptibility and outcome of
community-acquired pneumonia in adults and found similar MASP-2 alleles and
genotypes among patients and control individuals, leading to the conclusion
that MASP-2 deficiency was not associated with an increased risk of
community-acquired pneumonias [Garcia-Laorden 2008] .
In summary, the literature does not provide a clear indication as to the risk
for increased susceptibility to infections in individuals with MASP-2
deficiency. The researchers in Denmark who were the first to describe MASP-2
deficiency and have done the most work in this area stated in 1 article [Thiel
2007] that *One must conclude that (MASP-2) deficiency in itself does not
result in disease, rather, it is a modifier, which may penetrate when also
other elements are compromised.*

Clinical experience with narsoplimab has not demonstrated safety concerns.
Infections,
some severe and fatal, have been reported in clinical trials; however, these
infections
have been similar to infections occurring in the respective patient populations
who have
not received narsoplimab. The independent Data Monitoring Committee (DMC) of the
adult TMA study has not observed an increased signal of infection.

5.3.1.2. Animal Models of Infection
The role of MASP-2 in bacterial infection has been evaluated in animal models,
and the
results vary depending on the model, ranging from disease worsening to no
effect to
protection. In a murine model of pneumococcal infection, inhibition of MASP-2
with a
MASP-2 mAb prior to nasal inoculation of Streptococcus pneumonia resulted in
increased severity of disease compared to isotype control mAb [Ali 2012]. In
this model,
antibiotic treatment was effective in MASP-2 mAb-treated animals, resulting in
a similar
outcome to that in untreated controls. In contrast, in a murine model of
pneumococcal
meningitis, MASP-2-deficient mice had a better outcome compared to wild-type
littermates [van de Beek D, unpublished observations]. In a murine model of
Pseudomonas aeruginosa infection, MASP-2-deficient mice had no significant
survival
disadvantage compared to wild-type littermates [Kenawy 2012]. In a murine model
of
meningococcal infection, treatment with a MASP-2 mAb prior to bacterial
challenge
resulted in increased survival compared to treatment with isotype control mAb,
demonstrating a protective effect [Omeros unpublished observations].
5.3.1.3. Adult TMA Infections

Based on complement pathway inhibition, a potential risk is an increased
susceptibility to
systemic infection or worsening of an existing infection. Infections, some
severe and
fatal, have been reported in clinical trials, but these infections have been
similar to
infections occurring in the respective corresponding patient populations who
have not
received narsoplimab.

Patients should be monitored closely for the development of
infections, and appropriate antimicrobial treatment should be promptly
initiated in the
event of a suspected infection. However, because lectin pathway (MASP-2)
inhibition
does not impact innate/acquired immunity, vaccination for encapsulated bacteria
is not
required.

The most commonly reported AEs were infections. Twenty out of 28 treated
patients
reported an infection. All reported infections Grade 2 or greater have been
reviewed for
temporal relationship to narsoplimab treatment, severity, other potential risk
factors, and
outcome. Temporal relationship was defined as infection onset occurring between
the
first narsoplimab dose and 37 days following the last narsoplimab dose (AE
evaluation
period). Risk factors were considered only when they were present at the start
of the
infection and included corticosteroid treatment, other immunosuppressive
treatment,
neutropenia, and venous catheterization (only for catheter-related infections).

Three patients died of infection during the HSCT-TMA Core Study period. Three
died of sepsis. All were receiving corticosteroids and had neutropenia. One was
receiving cyclosporin and another was receiving sirolimus.
The infections were typical for this seriously ill population. All fatal
infections were associated with corticosteroid treatment. The fatal infections
in HSCT-TMA patients were also associated with neutropenia. Almost all severe
infect