A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Varying Doses and Dose Regimens of Evinacumab in Patients with Persistent Hypercholesterolemia Despite Maximally Tolerated Lipid Modifying Therapy

No randomized placebo-controlled clinical CV outcome trials of statin treatment
have been conducted in patients with HeFH due to ethical concerns of
withholding recommended therapy in this population. Clinical management of
HeFH is largely based on extrapolation from the results of clinical outcomes
trials conducted in patients with polygenic hypercholesterolemia, from studies
in FH patients that used carotid intima-media thickness as a surrogate outcome,
and from a small number of prospective observational studies in patients with
FH. In 4 observational studies, statin therapy was shown to reduce the risk of
CHD by 50% to 80% in patients with FH (Harada-Shiba 2010, Huijgen 2010,
Vermissen 2008). Unfortunately, even after treatment, the risk in HeFH can
still be almost 2-fold higher than the general population (Neil 2008).

The primary objective of the study is to evaluate the reduction of low density
lipoprotein cholesterol (LDL-C) by evinacumab in comparison to placebo after 16
weeks in patients with primary hypercholesterolemia (heterozygous familial
hypercholesterolemia [HeFH], or non-HeFH with a history of clinical
atherosclerotic cardiovascular disease [clinical ASCVD]) persistent
hypercholesterolemia despite receiving maximally-tolerated lipid-modifying
treatment (LMT). Persistent hypercholesterolemia is defined as LDL C * 70 mg/dL
(1.81 mmol/L) for those patients with clinical ASCVD and LDL C * 100 mg/dL
(2.59 mmol/L) for those patients without clinical ASCVD.

The study consists of 4 periods: run-in period of up to 8 weeks (for patients
whose background lipid modifying therapy [LMT] has not been stable prior to
screening, who are not already receiving a PCSK9 inhibitor, or whose background
LMT has not been optimized), 2-week screening, 16 week double-blind treatment
period for SC group and 24 week double blind treatment for IV group, and
follow-up period that lasts 24 weeks after the last dose of study drug.

Patients will be randomized 1:1:1:1:1:1:1 to one of 7 treatment groups as
follows:
* 300 mg SC of evinacumab (REGN1500) once every week (QW), or
* 300 mg SC of evinacumab once every 2 weeks (Q2W) (alternating with placebo on
opposite weeks), or
* 450 mg SC of evinacumab once every week (QW), OR
* 5 mg/kg IV of evinacumab once every 4 weeks (Q4W), or
* 15 mg/kg IV of evinacumab once every 4 weeks (Q4W), or
* Placebo SC once every week (QW)
* Placebo IV once every 4 weeks (Q4W)

A risk benefit assessment is provided in the protocol:

Section 3.2.3.
Of the current medications for lowering LDL-C, statins are the most commonly
prescribed because they are inexpensive and have demonstrated the ability to
reduce CHD events. PCSK9 inhibitor antibodies are a newer class of agents that
significantly lower LDL-C and recently demonstrated a reduction in the risk of
CV events (Sabatine 2017). Despite all of the available treatment options,
particularly statins and PCSK9 inhibitor antibodies, some patients still do not
reach their LDL-C goal and continue to have residual CV risk. In the Odyssey FH
1 and FH 2 studies, up to 19% and 28% in FH1 and FH2, respectively, did not
meet their LDL-C target despite 24 weeks of treatment with alirocumab.
Patient populations that continue to need additional LDL-C lowering include
those with severe HeFH as well as severe non-FH patients with polygenic
etiologies of their disease. It is important for all patients to achieve their
LDL-C target because the body of evidence from the statin literature shows that
the relationship between LDL-C reduction and CHD 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 CHD events (CTT study).
Moreover, the results from recent outcomes trials with ezetimibe (IMPROVE-IT)
and evolocumab (FOURIER) reinforce this concept, providing additional evidence
for the relationship between LDL-C lowering and reduction in risks for CV
events, thereby emphasizing the importance for patients to achieve their target
LDL-C.
Evinacumab is a new treatment option that could get patients to their target
LDL-C when added to a stable lipid-lowering regimen, including statins and a
PCSK9 inhibitor antibody. In the early clinical studies in healthy subjects,
monotherapy treatment with evinacumab resulted in up to 40% reduction in LDL-C
and up to 80% reduction in TG. In the R1500-CL-1331 study in patients with
HoFH, treatment with evinacumab on top of a stable lipid lowering regimen
resulted in peak mean LDL-C reductions of approximately 58%.
It is 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.
Taken together, these data show the positive benefit/risk assessment of
treatment with evinacumab in patients with HeFH, or non-HeFH with clinical
ASCVD, that have an LDL-C * 100 mg/dL (2.59 mmol/L), despite receiving a stable
maximally tolerated statin and PCSK9 inhibitor antibody therapy.