A Three-Part, Single-Arm, Open-Label Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Evinacumab in Pediatric Patients with Homozygous Familial Hypercholesterolemia

Familial hypercholesterolemia (FH), a primary hyperlipidemia driven by genetic
mutation(s) primarily in the low-density lipoprotein (LDL) receptor (LDLR), is
the most common monogenic hypercholesterolemia condition in children. The most
rare and severe form of FH is homozygous familial hypercholesterolemia (HoFH).
It is an inherited autosomal dominant disorder primarily resulting from
mutations in the LDLR or, less frequently, from mutations in 3 associated
genes: proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B
(APOB), and LDL receptor adaptor protein 1 (LDLRAP1). Depending on the genes
affected and the mutations that are present, patients are categorized as either
true homozygotes, compound heterozygotes, or double heterozygotes. True
homozygotes have the same mutation on both alleles. Compound heterozygotes have
different mutations on the 2 alleles. Double heterozygotes have mutations in 2
different genes. The resulting phenotype includes deficient or defective LDL
receptors on the surface of hepatocytes causing impaired clearance of
circulating low-density lipoprotein cholesterol (LDL-C). This leads to severe
hypercholesterolemia, often 3 to 6 times normal (>=500 mg/dL), starting in
infancy, which results in an exceedingly high risk of developing premature
atherosclerosis, as well as valvular and supravalvular stenosis.
The etiology of the hypercholesterolemia observed in patients with HoFH is the
same for both adult and pediatric patients. It is a consequence of the above
mentioned abnormal lipoprotein metabolism due to mutations in the key genes
listed above, and the markedly diminished hepatic LDL-C clearance from plasma
(Goldstein, 2001)(Kolansky, 2008)(Macchiaiolo, 2012) (Rader, 2003). These high
plasma levels lead to vascular damage starting from birth and morphological and
functional vascular changes by 8 years of age or earlier. Children as young as
7 years of age can present with coronary atherosclerosis even without any
clinically apparent coronary artery disease. This accelerated atherosclerosis
results in premature cardiovascular disease (CVD) and an increased risk of CV
events at a young age. Evidence of accelerated atherosclerosis include children
with increased carotid intima-media thickness (cIMT) and cIMT progression at a
rate approximately double that of unaffected siblings. An observational study
of HoFH patients showed that the mean age for first major CV event was 20 years
(Goldstein, 2001)(Kolansky, 2008)(Macchiaiolo, 2012)(Rader, 2003). Indeed, if
left untreated, children and adolescents with HoFH, have an extremely high risk
for premature CVD and reduced life expectancy. For example, in a longitudinal
study of 39 pediatric patients with HoFH followed for up to 8 years, 88% of
patients >16 years of age and 9% <16 years of age developed CVD. Further,
during follow-up, 7 patients developed progression of coronary and/or aortic
valvular disease and 4 required surgical intervention (Kolansky, 2008),
demonstrating the need for early aggressive lipid-lowering therapy in pediatric
subjects with HoFH.
The frequency of HoFH in the general population is historically reported as
1/1,000,000. This estimate is based on a heterozygous familial
hypercholesterolemia (HeFH) prevalence of 1/500 and the application of the
Hardy-Weinberg equilibrium (1/1,000,000 = 1/500 mother * 1/500 father * 1/4
risk for child). However, based on more recent data, HoFH has an estimated
prevalence of 1/300,000, which would be the same in children. Populations with
a founder effect have higher prevalence rates.
Diagnosis of HoFH can be made based on clinical criteria or genetic criteria
(Section 7.2.1 ). An LDL-C level >=13 mmol/L (>=500 mg/dL) is consistent with
phenotypic HoFH. However, the LDL-C criteria could be lower depending on the
presence of positive family history and age of screening. Additional phenotypic
characteristics include premature coronary heart disease, aortic valve disease,
and tendon xanthomas in the hands and Achilles tendons. Clinically identified
patients could undergo genetic testing to confirm diagnosis.
Patients with HoFH can be further classified based on the phenotype of the LDLR
mutation(s), ranging from defective mutations (where the LDLR retains some
LDL-binding functionality) to null or negative mutations where no functioning
LDLR is expressed. Patients who have LDLR activity <15% are considered null and
patients whose LDLR activity is impaired but >15% are LDLR defective (Banerjee,
2019). Another method that could be used to categorize these mutations is to
define a negative mutation status as having mutations in stop codons, frame
shifts, splice site changes, small and large insertions/deletions, and copy
number variations (CNVs) predicted to result in the loss of function of the
LDLR. The most extreme cases are those patients who are LDL-receptor negative
or null in both alleles. These patients tend to have LDL-C levels at the
highest end of the range and experience very little efficacy from existing
therapies such as statins and PCSK9 inhibitors. As such, significantly
accelerated atherosclerosis and worse clinical outcomes are observed in these
patients compared to those who are LDLR defective (Kolansky, 2008) (Moorjani,
1993). Patients who are LDLR null or negative develop xanthomas sooner than
patients who are LDLR receptor defective, and untreated patients who are LDLR
null or negative rarely live past the second decade of life (Kolansky, 2008)
(Moorjani, 1993).
Current approved therapies for patients with HoFH include statins, lomitapide,
ezetimibe, evolocumab, and lipoprotein apheresis. All but lomitapide are
approved for use in pediatric patients >=12 years of age. Some of the statins
are approved in younger patients (rosuvastatin approved in ages >=6 years;
atorvastatin and simvastatin approved for ages >=10 years). Because the etiology
of the disease is the same for both adult and pediatric patients, the
overarching goal of therapy is also the same, to lower LDL-C. The current
American College of Cardiology/American Heart Association (ACC/AHA) guidelines
and the European Atherosclerosis Society (EAS) recommend at least a 50%
reduction in LDL-C in all patients with FH to reduce the risk of CVD (Gidding,
2015)(Grundy, 2019)(Wiegman, 2015). The EAS further recommends a target LDL-C
<130 mg/dl (3.5 mmol/L) in patients >10 years (Wiegman, 2015). Lipid-lowering
therapy should be started as early as possible (Cuchel, 2014) (France, 2016)
(Wiegman, 2015).
Angiopoietin-like protein 3 (ANGPTL3) has recently emerged as a target for
treatment of elevated levels of LDL-C. Individuals who are homozygous for loss
of function (LOF) mutations in ANGPTL3 have lower levels of LDL-C (mean
difference of >50% versus control subjects (Minicocci, 2012)). The mechanism by
which ANGPTL3 LOF mutations result in lowering LDL-C is not fully understood
but appears to be independent of the LDLR. These data suggest that inhibiting
ANGPTL3 may be a meaningful and well-tolerated strategy for lowering serum
LDL-C in patients with HoFH, especially those considered to have LDLR negative
mutations in both alleles.
Evinacumab (REGN1500) is a fully human monoclonal antibody (mAb), created with
Regeneron*s VelocImmune® technology platform, which specifically binds to and
inhibits ANGPTL3. In an open-label, single-arm, proof-of-concept study in
patients with HoFH (R1500 CL-1331), evinacumab demonstrated a mean percent
reduction from baseline of 49.2% (n=9) at week 4, 2 weeks after a single dose
of 15 mg/kg IV, with a duration of effect of at least 10 weeks (n=7). A peak
mean reduction of 52.1% was observed at week 6. Three patients in the study had
null/null mutations in the LDLR. Treatment with evinacumab in these
difficult-to-treat patients reduced LDL-C by an average of 37.3% at week 4 with
peak reductions up to 59.5%.
The LDL-C lowering effect observed with evinacumab in the R1500-CL-1331 study
was confirmed in study R1500-CL-1629, a large randomized, double-blind,
placebo-controlled study consisting of adult and adolescent patients with HoFH.
On average, patients entered the trial with a mean baseline LDL-C of 255 mg/dL,
despite treatment with other lipid-lowering therapies, including
maximally-tolerated statins, PCSK9 inhibitors, ezetimibe, LDL apheresis and
lomitapide. The trial met its primary endpoint, showing that adding evinacumab
to other lipid lowering therapies decreased LDL-C by a mean of 49% from
baseline to week 24, compared to lipid-lowering therapies alone (47% reduction
for evinacumab compared to a 2% increase for placebo, p<0.0001). This reduction
translates to a mean absolute change in LDL-C of 132 mg/dL from baseline,
compared to placebo (135 mg/dL reduction for evinacumab compared to a 3 mg/dL
reduction for placebo, p<0.0001). The decreases in LDL-C were observed from the
first lipid assessment at week 2 and were maintained throughout the 24-week
double-blind treatment period. Importantly, similar levels of LDL-C lowering
were observed in the most difficult-to-treat null/null or negative/negative
patients. The dramatic reduction in LDL C led to the achievement of LDL-C
levels <100 mg/dL in 47% of the patients treated with evinacumab compared to
23% treated with placebo (nominal p=0.0203). Evinacumab also reduced
apolipoprotein B (Apo B), non-high-density lipoprotein (HDL) cholesterol (non
HDL C) and total cholesterol (TC) compared to placebo.
The positive efficacy data in the R1500-CL-1629 study were accompanied by an
acceptable safety profile. Evinacumab was generally well-tolerated. During the
double-blind treatment period, 66% of evinacumab patients and 81% of placebo
patients experienced an adverse event (AE). AEs that occurred in at least 5% of
patients and more commonly with evinacumab were influenza-like illness (11%
evinacumab, 0% placebo) and rhinorrhea (7% evinacumab, 0% placebo). During the
double-blind treatment period there was no difference in the incidence of
nausea, abdominal pain or diarrhea between treatment groups, and there were no
deaths, major adverse cardiovascular events or findings related to hepatic
disorders.
The primary purpose of this current study is to demonstrate the efficacy,
safety and tolerability of evinacumab in pediatric patients, aged 5 through 11
years, with HoFH. The study will consist of 3 parts: Part A (phase 1b), Part B
(phase 3), and Part C (phase 3). Part A is a single-dose, open label study to
determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of
evinacumab 15 mg/kg intravenous (IV) in approximately 6 patients ages 5 to 11
years with HoFH. Part B is a 24-week, single-arm, open-label study to assess
the efficacy and safety of evinacumab in approximately 14 pediatric patients
with HoFH. Part B will begin when PK data from all patients in Part A have been
sufficiently analyzed to determine the dose for Part B. Part C is an extension
of the study available to patients who complete Part A or Part B to continue to
receive evinacumab.
Additional background information on the study drug and development program can
be found in the Investigator*s Brochure.

Primary
The primary objective for Part A of the study is to assess the pharmacokinetics
(PK) of evinacumab in pediatric patients with homozygous familial
hypercholesterolemia (HoFH).
The primary objective for Part B of the study is to demonstrate a reduction of
low-density lipoprotein (LDL) cholesterol (LDL-C) by evinacumab in pediatric (5
to 11 years of age) patients with HoFH.

Secondary
The secondary objective for Part A of the study is to evaluate the safety and
tolerability of evinacumab administered IV in pediatric patients with HoFH
The secondary objectives for Part B of the study are:
• To evaluate the effect of evinacumab on other lipid parameters (ie, Apo B,
non-HDL-C, TC, lipoprotein a [Lp(a)]) in pediatric patients with HoFH
• To evaluate the safety and tolerability of evinacumab administered IV in
pediatric patients with HoFH
• To assess the PK of evinacumab in pediatric patients with HoFH
• To assess the immunogenicity of evinacumab in pediatric patients with HoFH
over time
• To evaluate patient efficacy by mutation status

Part A is a phase 1B single-dose, open-label study to determine the safety, PK
and pharmacodynamics (PD) of evinacumab 15 mg/kg intravenous (IV) in
approximately 6 patients ages 5 to 11 years with HoFH. To ensure a distribution
of body weight within Part A of the study, every effort will be made to enroll
3 patients <25 kg and 3 patients >=25 kg. Additionally, to ensure a distribution
of ages, every effort will be made to enroll 2 patients <10 years of age. All
patients who successfully complete Part A may continue receiving evinacumab in
an extension of the study, Part C. Initially, patients from Part A who enter
the Part C will receive evinacumab 15 mg/kg IV Q4W. When PK data from all
patients in Part A have been sufficiently analyzed, the dose for Part B will be
determined using the cumulative data to date with evinacumab and data from Part
A. If data from 6 patients is insufficient, up to 4 more patients may be
enrolled to confirm the dose in Part B. The dose for Part B will also be the
final dose in Part C. The dose for Part B (and final dose in Part C) will
likely remain at 15 mg/kg IV every 4 weeks (Q4W). However, there is a small
possibility that the exposure analysis or the observed PD effect indicate a
small increase in the dose is needed for the pediatric population to match the
exposure and PD effect observed in adult patients. As such, the dose in Part B
(and final dose in Part C) could be between 15-20 mg/kg IV Q4W. A maximum dose
of 20 mg/kg is selected as the top dose because it is the highest dose
evaluated in the prior evinacumab studies.
Part A consists of up to 4 periods: run-in, screening, single-dose, open-label
treatment, and 16-week observation. Upon completion of Part A, patients will
have the opportunity to continue into Part C.

Part B is a phase 3 single-arm, open-label study to assess the efficacy and
safety of evinacumab in pediatric patients (age 5 to 11 years) with HoFH. Part
B will begin once dose-selection for Part B has been completed. Part B will
enroll approximately 14 pediatric patients. Patients enrolled in Part B will
not include patients from Part A. Upon completion of Part B, patients will have
the opportunity to continue into the extension, Part C.
Part B consists of up to 4 periods: run-in, screening, 24-week open-label
treatment, and follow-up (for patients who do not enter the extension, Part C).

Part C is an extension of the study for patients from both Part A and Part B
and consists of 2 periods, a 48-week treatment period and a 24-week follow-up
period after the last dose of study drug. All patients from Part A who enter
Part C will initially receive open-label evinacumab 15 mg/kg IV Q4W. The final
dose in Part C will be the same as the dose in Part B; therefore, the dose in
Part C could be adjusted to align with the dose in Part B. Patients who are
receiving background LMT or who are undergoing apheresis should make every
effort to maintain a stable LMT and a stable apheresis schedule (as applicable)
throughout the duration of the study to the end of the study. The frequency of
apheresis may be reduced during this part of the study based on the
investigator*s judgement. The Sponsor of this study, consistent with our
corporate policy governing access to investigational drugs in confirmatory
clinical studies, is committed to provide evinacumab to patients after their
participation in this trial has concluded, if permitted per local laws.
Agreement to continue treatment beyond this study is a treatment decision that
must be made by the investigator, and the patient or their parent/guardian.
After completion of the study, investigators interested in continuing treatment
with evinacumab in patients considered to have a positive response can discuss
post-trial treatment options with the Sponsor, including participation in a CUP
or EAP.

For Part A, a single administration of evinacumab 15 mg/kg IV, given over a 65
minute infusion
For Part B, evinacumab with a dose determined by Part A, will be administered
IV over a 65 minute infusion Q4W starting at day 1. The last dose will be at
week 20.
All patients from Part A who enter Part C will initially receive evinacumab 15
mg/kg IV Q4W. The final dose for Part C will be based on data from Part A and
all available data from other evinacumab studies. Therefore, the dose for Part
C for patients from Part A may be adjusted once the dose selection for Part B
is completed.

Patients with HoFH have extremely high LDL-C levels are far from their target
level and will require significant reductions to get to their treatment goal.
Statins are the only pharmacological LMT approved for use in pediatric patients
below the age of 10. Unfortunately, they are unable to lower LDL-C
sufficiently, even when used in the highest doses and in combination with other
therapies. Moreover, the unmet need is greatest in patients with null/null
mutations of the LDLR who typically have the highest levels of LDL-C and in
whom statins have minimum to no effects. In addition to pharmacologic
treatment, lipoprotein apheresis is the standard of care for pediatric patients
with HoFH. However, the availability of lipoprotein apheresis is limited, and
the procedure is expensive, invasive and burdensome for young children and
their caregivers. Therefore, there is a high unmet need for additional
therapeutic options for pediatric patients with HoFH. Evinacumab could be a new
addition to the armamentarium of LMT that could contribute to lowering the
LDL-C of HoFH pediatric patients, including patients with null/null mutations.
In study R1500-CL-1331, evinacumab demonstrated a mean percent reduction from
baseline of 49.2% (n=9) at week 4, 2 weeks after a single dose of 15 mg/kg IV,
with a duration of effect of at least 10 weeks (n=7). A peak mean reduction of
52.1% was observed at week 6. Three patients in the study had null/null
mutations in the LDLR. Treatment with evinacumab in these difficult to-treat
patients reduced LDL-C by an average of 37.3% at week 4 with peak reductions up
to 59.5%. The LDL-C lowering effect observed with evinacumab in the
R1500-CL-1331 study was confirmed in study R1500-CL-1629, a large randomized,
double-blind, placebo-controlled study consisting of adult and adolescent
patients with HoFH. On average, patients entered the trial with a mean baseline
LDL-C of 255 mg/dL, despite treatment with other lipid lowering therapies,
including maximally-tolerated statins, PCSK9 inhibitors, ezetimibe, LDL
apheresis and lomitapide. The trial met its primary endpoint, showing that
adding evinacumab to other lipid-lowering therapies decreased LDL-C by a mean
of 49% from baseline to week 24, compared to lipid-lowering therapies alone
(47% reduction for evinacumab compared to a 2% increase for placebo, p<0.0001).
This reduction translated in this study to a mean absolute change in LDL-C of
132 mg/dL from baseline, compared to placebo (135 mg/dL reduction for
evinacumab compared to a 3 mg/dL reduction for placebo, p<0.0001). The
decreases in LDL-C were observed from the first lipid assessment at week 2 and
were maintained throughout the 24-week double-blind treatment period.
Importantly, similar levels of LDL-C lowering were observed in the most
difficult-to-treat null/null or negative/negative patients. The dramatic
reduction in LDL-C led to the achievement of LDL-C levels <100 mg/dL in 47% of
the patients treated with evinacumab compared to 23% treated with placebo
(nominal p=0.0203). Evinacumab also reduced Apo B, non-HDL-C and TC compared to
placebo. Based on these data in adults, it is expected that the addition of
evinacumab to existing treatments will lead to significant LDL-C reductions in
the pediatric HoFH population.
In non-FH populations, numerous epidemiological studies and CV outcomes studies
with lipid lowering therapies have continually demonstrated that lowering LDL-C
reduces the risk of CV events. In fact, the body of evidence from the statin
literature shows that the relationship between LDL-C reduction and CV event
reduction is approximately linear and for every 1 mmol/L (38.7 mg/dL) reduction
in LDL-C there is a corresponding 22% risk reduction in CV events (Baigent,
2010). Moreover, results from recent outcomes trials with ezetimibe (IMPROVE-IT
(Cannon, 2015)), alirocumab (ODYSSEY OUTCOMES (Schwartz, 2018)) and evolocumab
(FOURIER (Sabatine, 2017)) reinforce this concept, providing additional
evidence for the relationship between LDL-C lowering through diverse mechanisms
and reductions in CV events. Within the context of this study in the HoFH
pediatric patient population, additional reductions in LDL-C at an early age
may get patients closer to their LDL-C target and maintaining these levels
could translate into significant benefit in reducing CV risk.
It is also expected that treatment with evinacumab will be well tolerated and
have an acceptable safety profile. The accumulated safety information from the
most recent phase 2 and phase 3 studies where evinacumab was given IV in
patients with HoFH (R1500 CL 1629, R1500 CL 1719) or persistent
hypercholesterolemia (R1500-CL-1643) shows that the more common adverse events
across all the studies include Nasopharyngitis, Rhinorrhoea, Upper respiratory
tract infection, Influenza-like illness, Back pain, Pain in extremity,
Dizziness, Headache, Nausea, Abdominal pain, and Fatigue.
A review of all available safety data shows there is one identified risk of
Systemic hypersensitivity reactions, including Infusion reactions, and rarely
Anaphylaxis. In most cases, the allergic reactions were mild to moderate in
intensity, nonserious and, in the case of infusion reactions, did not lead to
interruption or discontinuation of the evinacumab infusion. One event of
Anaphylaxis was observed in the phase 2 dose ranging study in patients with
severe hypercholesterolemia (R1500-CL-1643). Briefly, the anaphylactic reaction
was reported in a single patient randomized to the evinacumab 15 mg/kg IV
treatment group. This patient with relevant medical history of syncope,
palpitations, asthma, obesity, and seasonal allergy experienced an anaphylactic
reaction during the second infusion of evinacumab on study day 28. Within 5
minutes of initiating the infusion, the patient felt dizzy with a racing heart,
followed by chest pressure, arms and legs tingling, shortness of breath,
itchiness, and feeling warm and lethargic. The patient was noticeably flushed
with face and chest redness. The infusion was stopped. The patient was treated
with diphenhydramine orally due to continued itching. The event was considered
resolved on the same day. The investigator assessed the event as moderate in
severity and related to study treatment. Study treatment was permanently
discontinued. Further details of this event are provided in the Investigator*s
Brochure.
The important potential risks include immunogenicity and embryofetal toxicity.
These risks will be managed through careful patient selection and monitoring.
Additionally, any potential effects of evinacumab on a child*s development
during childhood and early adolescence will be monitored via Tanner staging,
sex hormones, and overall growth by tracking weight and height.
A risk-benefit statement with respect to the overall development program is
provided in the Investigator*s Brochure.
Recognizing that the *Coronavirus Disease 2019* (COVID-19) pandemic will have
an impact on the conduct of clinical trials, the Sponsor does not intend to
screen any patients in this study until the impact of the COVID-19 pandemic is
deemed manageable and no longer interfering with the conduct of trials at
individual sites, and patients can safely participate in this study. Until
then, the Sponsor plans to obtain approvals from Health Authorities/Ethics
Committees to enable initiation of study sites for this study, as allowed by
local laws and regulations.