A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia

Hypothesis: Blockade of ANGPTL3 with evinacumab will reduce LDL-C in patients
with HoFH.

Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic
condition resulting in severely elevated low-density lipoprotein cholesterol
(LDL-C) and accelerated cardiovascular disease (CVD). Familial
hypercholesterolemia results from mutations in the low density lipoprotein
receptor (LDLR).
HoFH is frequently caused by mutations in both alleles of the LDLR gene and
results in the decreased clearance of LDL particles from plasma. Patients with
HoFH have severe hypercholesterolemia, often 3 to 6 times normal (500 to 1000
mg/dL), which can lead to an exceedingly high risk of developing premature
atherosclerosis, as well as valvular and supravalvular stenosis.
Many of the therapies for hypercholesterolemia are dependent on their
stimulating an increase in activity of the LDLR. Part of the basis for the
refractory nature of treatments is linked to the mutations in the LDLR that are
the driver of HoFH. The presence of mutations in both LDLR alleles can result
in far less efficacy for therapies that rely on the LDLR as part of their
mechanism of action. Examples of such therapies include statins and PCSK9
inhibitor antibodies.
Despite treatment with lipid modifying therapies (LMTs), such as
pharmacological agents, as well as mechanical removal by lipid apheresis, many
patients with HoFH remain far from their LDL-C treatment goal. Therefore, the
need for more intensive treatment in HoFH, especially those patients with
double null mutations remains.
Angiopoietin-like 3 (ANGPTL3) has recently emerged as a potential target for
the treatment of elevated levels of triglycerides (TGs) and for the treatment
of elevated levels of LDL-C, both risk factors for the development of CVD.
ANGPTL3 acts as a natural inhibitor of lipoprotein lipase, an endothelial-bound
enzyme involved in the hydrolysis of the TG content of very low density
lipoproteins and chylomicron lipoproteins. Inhibiting ANGPTL3 may be a
meaningful and well-tolerated strategy for lowering serum LDL-C and TGs.
Evinacumab (REGN1500) is a fully human mAb, created with Regeneron*s
VelocImmune technology platform, which specifically binds to ANGPTL3.
Experiments performed in animals demonstrate that the administration of
evinacumab results in a reduction of serum LDL-C and serum TGs.
In a phase 1, first-in-human, placebo-controlled, double-blind, ascending
single-dose study the maximal mean percent LDL-C decrease from baseline of
27.8% was observed on day 15 in the 20 mg/kg IV group (n=11) compared to a
decrease of 4.5% in the placebo IV group (n=12).
In a randomized, double-blind, placebo-controlled, multiple ascending dose
study achieved a mean percent reduction from baseline in LDL-C of 34.7% at day
57. Those patients who received evinacumab 300 mg SC every 2 weeks (Q2W)
achieved a mean percent reduction in LDL-C of 33.4% from baseline. Evinacumab
was well tolerated in doses up to 20 mg/kg IV Q4W.
In an open-label, single-arm, proof-of-concept study in patients with HoFH,
(Study R1500 CL 1331), evinacumab demonstrated a mean percent reduction from
baseline of 49.2% (n=9) at week 4, with a duration of effect of at least 10
weeks after a 15 mg/kg IV dose (n=7). A peak mean reduction of 52.1% was
observed at week 6. Three patients enrolled in Study R1500-CL-1331 are
homozygous for null mutations in the LDLR. Evinacumab provided meaningful
reductions in LDL-C in these 3 null/null HoFH patients (26-44% percent change
in LDL-C by week 4).
Evinacumab has been well tolerated at all dose levels in these studies.

The primary objective of the study is:
* To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C)
by evinacumab 15 mg/kg intravenously (IV) in comparison to placebo after 24
weeks in patients with homozygous familial hypercholesterolemia (HoFH).

The secondary objectives of the study are:
* To evaluate the effect of evinacumab 15 mg/kg IV on other lipid parameters
(ie, apolipoprotein B [Apo B], non-high-density lipoprotein cholesterol
[HDL-C], total-cholesterol [TC]) in patients with HoFH
* To evaluate the effect of evinacumab on LDL-C goal attainment
* To assess the effect of evinacumab on eligibility for apheresis (using German
and US apheresis criteria)
* To evaluate the safety and tolerability of evinacumab 15 mg/kg in patients
with HoFH
* To assess the pharmacokinetics (PK) of evinacumab in patients with HoFH
* To evaluate the potential development of anti-evinacumab antibodies

The study consists of 4 periods: up to 8-week run-in period (for patients who
may require HoFH genotyping, for patients whose background medical lipid
modifying therapy (LMT) has not been stable prior to screening or whose
apheresis settings and/or schedule have not been stable for at least 8 weeks
prior to screening), a 2-week screening period, a 24-week double-blind
treatment period (DBTP), and a 24-week open-label treatment period (OLTP), and
a 24-week follow-up period after the last dose of study drug for those patients
who choose not to enter the open-label study.
Patients who are not undergoing apheresis therapy, patients who have been on a
stable apheresis schedule for at least 8 weeks before the screening visit, and
patients on stable background medical LMT (as applicable) for at least 4 weeks
(6 weeks for fibrates, 8 weeks for proprotein convertase subtilisin/kexin type
9 [PCSK9] inhibitor antibodies, 12 weeks for lomitapide, 24 weeks for
mipomersen) before the screening visit, will enter a 2-week screening period.
Patients who meet all the inclusion criteria and none of the exclusion criteria
will be randomized 2:1 to receive evinacumab 15 mg/kg IV every 4 weeks (Q4W) or
matching placebo IV Q4W for the double-blind portion of the study (24 weeks).
Randomization will be stratified by apheresis treatment (Yes, No) and by region
(Japan, Rest of World).
After completion of the DBTP, all patients will enter a 24-week OLTP and
receive open-label evinacumab 15 mg/kg IV Q4W.
After completion of the 24-week OLTP, all patients who have successfully
completed this study might have the opportunity to participate in a separate
open-label (OL) study. All patients that enroll in the separate OL study will
continue to receive open-label evinacumab at a dose of 15 mg/kg IV Q4W. Those
patients who do not participate in the separate open-label study will undergo a
24 week follow-up after the last dose of study drug.

In the double-blind treatment period, eligible patients will be enrolled to
receive evinacumab 15 mg/kg IV Q4W
In the open-label portion of the study, all patients will receive evinacumab 15
mg/kg IV Q4W starting at week 24

Patients with HoFH have extremely high LDL-C levels, are far from their target
level and will require significant reductions to get to their goal. Despite the
approval of newer treatments including evolocumab, lomitapide and mipomersen,
the need for more intensive therapies remains. Evinacumab could be a new
addition to the armamentarium of LMT that could contribute to lowering the
LDL-C of patients with HoFH. As mentioned above, in study R1500 CL-1331,
evinacumab demonstrated a mean percent reduction from baseline of 49.2% (n=9)
at week 4, with a duration of effect of at least 10 weeks after a 15 mg/kg IV
dose (n=7). A peak mean reduction of 52.1% was observed at week 6. Three
patients in the study are homozygous for 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%. Based on these
data, it is expected that the addition of evinacumab to existing treatments
will lead to significant LDL-C reductions in the HoFH population. 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 (Cholesterol Treatment Trialists* Collaboration 2010). Moreover, the
results from the recent outcomes trials with ezetimibe (IMPROVE-IT [Cannon
2015], alirocumab (ODYSSEY OUTCOMES [Steg 2018]) and evolocumab (FOURIER
[Sabatine 2017]) reinforce this concept, providing additional evidence for the
relationship between LDL-C lowering and reductions in CV events and the
importance for patients to achieve their target LDL-C. Within the context of
this study in the HoFH patient population, additional reduction in LDL-C may
get patients closer their LDL-C target, which could translate into significant
benefits.
It is also expected that treatment with evinacumab will be well tolerated and
have an acceptable safety profile. The accumulated safety information from the
completed and ongoing clinical studies is marked by the absence of any
important identified risks. There are potential risks that include systemic
hypersensitivity reactions, immunogenicity, and embryofetal toxicity. These
risks will be managed through careful patient selection and monitoring. For the
potential embryofetal toxicity risk, there is a strict risk mitigation plan,
including requirements for consistent use of contraception.
See protocol page 25-26 for more information.