Expert Opinion on Biological Therapy

Will evinacumab become the standard treatment
for homozygous familial hypercholesterolemia?


Introduction: Homozygous Familial Hypercholesterolemia (HoFH) is a very severe genetic form of
hypercholesterolemia. Lacking LDL receptors in the liver, subjects with HoFH have raised plasma levels
of LDL cholesterol, and up to 100 times higher risk of premature atherosclerotic cardiovascular disease
than the general population.
Areas covered: This evaluation is of a phase 3 trial of evinacumab; Evinacumab Lipid Studies in Patients
with Homozygous Familial Hypercholesterolemia (ELIPSE HoFH). Evinacumab is a human monoclonal
antibody inhibitor of angiopoietin-like protein 3 (ANGPTL3). In ELIPSE HoFH, evinacumab reduced LDL
cholesterol by 47.1 ± 4.6%, HDL cholesterol by 30.4%, and triglycerides by 50.4 ± 7.7%.
Expert opinion: Evinacumab is not the ideal treatment for HoFH as it does not reduce LDL cholesterol
levels to treatment targets while increasing HDL cholesterol. Although the incidence of adverse effects
with evinacumab was low in ELIPSE HoFH, further studies are necessary to clarify its effects on liver
enzymes and clinical cardiovascular outcomes. Evinacumab is a candidate to become the standard
treatment for HoFH, as it may be better tolerated and/or more efficacious than the presently available
specific treatment (lomitapide). However, the widespread use of evinacumab to treat high triglycerides
or LDL cholesterol is unlikely due to evinacumab decreasing HDL cholesterol.
Received 22 October 2020
Accepted 7 December 2020
ANGPTL3; clinical trial;
elipse; evinacumab;
homozygous familial
hypercholesterolemia; LDL
cholesterol; triglycerides
1. Introduction
This key paper evaluation is of a phase 3 trial of evinacu￾mab; Evinacumab Lipid Studies in Patients with
Homozygous Familial Hypercholesterolemia (ELIPSE HoFH)
[1]. HoFH only occurs in 1 in 300,000 people. It is a very
severe genetic form of hypercholesterolemia, as these peo￾ple lack LDL receptors in the liver, which means they are
unable to clear LDL cholesterol from the plasma. This leads
to raised plasma levels of LDL cholesterol, the LDL choles￾terol containing lipoprotein(a), and up to 100 times higher
risk of premature atherosclerotic cardiovascular disease than
the general population [2].
The statins are the standard medicinal treatment for
high LDL cholesterol. Statins inhibit HMG CoA reductase,
an enzyme involved in cholesterol synthesis in the liver,
and this inhibition leads to increased synthesis of LDL
receptors, and removal of LDL cholesterol from the plasma.
When statins do not give the required reduction in LDL
cholesterol levels, monoclonal antibodies to proprotein
convertase subtilisin-kexin type 9 (PCSK9) may be added.
PCSK9 has a key role in degrading LDL receptors within the
liver, and inhibition leads to increased LDL receptors and
reduced plasma LDL cholesterol. Neither of these mechan￾isms is effective in reducing plasma LDL cholesterol in
HoFH, as these subjects lack the ability to make LDL
receptors [2].
To be effective in the treatment of HoFH, medicines must
bypass the LDL receptor, and this is the case for the two
medicines that have been licensed to treat HoFH in the US;
lomitapide and mipomersen. Lomitapide is an inhibitor of
microsomal triglyceride transfer protein, which transfers trigly￾cerides to triglyceride-rich proteins, such as chylomicrons in
the intestine, VLDL cholesterol in the liver, and consequently
lowers LDL cholesterol. Although lomitapide can lower LDL
cholesterol by 50% in subjects with HoFH, its use is associated
with gastrointestinal disturbances and liver toxicity.
Mipomersen is an antisense oligonucleotide to liver apoB100
mRNA, which like lomitapide, reduces VLDL in the liver.
Mipomersen lowered LDL cholesterol by 26% in HoFH. Its
use was associated with injection site reactions, flu-like symp￾toms, hepatic steatosis, and elevated liver enzymes [3], which
led to it being discontinued by its manufacturer. Thus, medi￾cines that are more effective and less toxic are required for the
treatment of HoFH.
A new medicine that bypasses the LDL receptor is evina￾cumab (REGN1500). Evinacumab is a human monoclonal
antibody inhibitor of angiopoietin-like protein 3 ANGPTL3.
ANGPTL3 is a liver protein that acts as an endogenous
inhibitor of lipoprotein lipase, an enzyme on the vascular
endothelium that degrades circulating triglycerides. Genetic
variants of ANGPTL3 that lead to a loss of function are
associated with decreases in the levels of triglyceride, LDL
cholesterol, and HDL cholesterol. Despite the unwanted
CONTACT Sheila A. Doggrell [email protected] Faculty of Health, Queensland University of Technology, Brisbane, QLD 4002, Australia
Evaluation of Raal FJ, Rosenson RS, Reeskamp LF et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med 2020;383:711-20.


© 2020 Informa UK Limited, trading as Taylor & Francis Group
effect of the variants lowering HDL cholesterol, loss of
function of ANGPTL3 does decrease atherosclerotic cardio￾vascular disease [4]. Evinacumab reduced triglycerides, LDL
cholesterol, and HDL cholesterol in human healthy volun￾teers [4] and in nine subjects with homozygous familial
hypercholesterolemia [5].
ELIPSE HoFH was a double-blind, placebo-controlled, phase
3 trial performed in 11 countries. To be eligible, subjects
had to have HoFH, defined by genetics or clinical criteria.
The genetics included variants in two genes for the low￾density lipoprotein receptor, heterozygous variants in apo￾lipoprotein B or PCSK9, heterozygous or homozygous var￾iants for the LDL receptor adaptor protein 1. The clinical
criteria were total cholesterol of 12.9 mmol/L with choles￾terol and fat lesions (xanthomas) before the age of
10 years or total cholesterol of 6.5 mmol/L in both parents.
Most of the subjects enrolled were by genotyping
(67%) [1].
Subjects were required to have an LDL cholesterol level of
≥1.8 mmol/L despite receiving lipid-lowering therapy, which
was statins in 94% of the subjects, ezetimibe in 75%, PCSK9
inhibitor in 77%, lomitapide (22%), or apheresis (34%). The
enrolled subjects (65) had a mean age of 42 years, 54% were
female, and 91% had a history of coronary artery disease.
Levels of LDL cholesterol were 6.60 mmol/L, lipoprotein(a)
57 nmol/L, and HDL cholesterol 1.5 mmol/L. Subjects were
randomized (2:1) to either iv evinacumab (15 mg/kg every
4 weeks) or placebo, for 24 weeks [1].
The primary outcome was a percent change in LDL
cholesterol from baseline at 24 weeks, and this was
a reduction of 47.1 ± 4.6% (SD), in the evinacumab group
compared to a 1.9% increase in the placebo group. The
reduction in LDL cholesterol with evinacumab was similar
regardless of other medicines or apheresis. Lipoprotein(a)
levels were unchanged by evinacumab. Secondary out￾comes included HDL cholesterol which was reduced by
30.4% and triglycerides reduced by 50.4 ± 7.7% [1].
There was no excess of adverse effects with evinacumab,
although more subjects reported influenza-like illness in the
evinacumab group (11%) than the placebo group (0%).
Alanine or aspartate aminotransferase levels were increased
in 5% of evinacumab group, compared to 10% in the placebo
group. No cardiovascular events were reported in either
group [1].
As discussed by the authors, apheresis is an expensive,
invasive, and time-consuming process, which might be able
to be avoided by some subjects by using evinacumab instead
of resorting to apheresis. The authors also point out that the
relatively short duration of the trial and small numbers of
subjects are limitations to the trial [1].
Based on ELIPSE HoFH, the company behind evinacumab
(Regeneron) has applied to the FDA for approval of evinacu￾mab for the treatment of HoFN, and a decision is expected in
February 2021 [6].
3. Expert opinion
3.1. Percent reduction vs absolute values
The data for cholesterol levels in ELIPSE HoFH are presented as
percentage changes from baseline. In contrast, the beneficial
effects of lowering LDL cholesterol are considered in absolute
values. The goal for LDL cholesterol levels in subjects with
severely elevated LDL cholesterol is 2.59 mmol/L and
1.81 mmol/L in subjects with atherosclerotic disease [7]. The
baseline level of LDL cholesterol in ELIPSE HoFH was
6.60 mmol/L, and the reduction with evinacumab was 49%,
which is 3.23 mmol/L. As 91% of the subjects in ELIPSE HoFH
had a history of coronary heart disease, a reduction in LDL
cholesterol to therapeutic targets would be ideal, but treat￾ment with evinacumab does not reach therapeutic targets in
3.2. HDL cholesterol and fibrates
Optimal levels of HDL cholesterol are 1.6 mmol/l or above, and
men and women with levels of 1.0 and 1.3 mmol/L, respec￾tively, are considered at cardiovascular risk. The levels of HDL
cholesterol at baseline in ELIPSE HoFH were 1.2 mol/L and was
reduced by 30% by evinacumab to 0.81 mmol/L, which
increases the risk due to low HDL cholesterol levels. Thus,
any cardiovascular benefit evinacumab has by lowering LDL
cholesterol may be partly offset by the detrimental effect of
lowering HDL cholesterol.
In subjects with low HDL cholesterol levels, the fibrates are
often used to increase HDL cholesterol. The fibrates stimulate
PPARα to increase HDL cholesterol, and this mechanism may
be independent of the LDL receptor. The effects of combining
evinacumab with the fibrates have not been tested to date
and should be.
3.3. Lipoprotein(a) levels
It has been suggested that elevated lipoprotein(a) levels may
contribute to the cardiovascular disease in familial hypercho￾lesterolemia [8]. In ELIPSE HoFH, the lipoprotein(a) levels were
in the normal range at baseline and not changed by evinacu￾mab. Thus, evinacumab will have no effects on cardiovascular
events via lipoprotein(a).
3.4. Liver enzymes, safety and clinical outcomes
In 83 human healthy volunteers, six different subcutaneous
(75, 150, or 250 mg) or intravenous doses (5, 10, or 20 mg/kg)
of evinacumab were compared to placebo over 4 weeks.
Evinacumab elevated alanine aminotransferase to more than
3 times the upper normal levels in two-treated subjects (3%).
The levels of alanine and aspartate aminotransferase were
elevated in one subject on evinacumab 250 mg sc, one subject
on evinacumab 5 mg/kg iv, and two subjects on evinacumab
10 mg/kg iv, and the levels of alanine aminotransferase only
were elevated in two further subjects on evinacumab 10 mg/
kg iv [4].
In the 2017 study of evinacumab in 9 subjects with HoFH,
effects on liver enzymes over 4 weeks are not reported [5]. In
a phase 1, 2019 study of single or multiple ascending doses of
evinacumab in 83 subjects with hypertriglyceridemia, eleva￾tions in alanine aminotransferase were observed in seven
subjects, aspartate aminotransferase in four subjects, and crea￾tinine phosphokinase in two subjects [9].
In ELIPSE HoFH, alanine or aspartate aminotransferase
levels were increased in 2 of 44 subjects (5%) in the evinacu￾mab group (15 mg/kg iv every 4 weeks), compared to 10% in
the placebo group, over 24 weeks [1]. Given the mixed results
on liver enzymes with evinacumab, and that the studies to
date have been relatively short term, liver enzymes should be
closely monitored for longer periods in future trials with
The long-term safety of evinacumab has not been estab￾lished [10]. At present, subjects (adults and adolescents) are
being enrolled by invitation to NCT03409744, which is a trial
to evaluate the long-term safety and efficacy of evinacumab in
subjects with HoFH. This trial is an open-label trial due to run
for up to 192 weeks with 120 participants and has as its
primary outcome measure the incidence and severity of treat￾ment-emergent adverse events [11]. This trial may clarify
whether evinacumab has detrimental effects on the liver and
will determine the long-term safety of evinacumab.
Ultimately, we will need to know whether evinacumab
reduces cardiovascular risk in subjects with HoFH without
adverse effects on the liver. However, no clinical trials are
presently registered that include cardiovascular outcomes as
an outcome. It is presumed that these will be forthcoming, if
the present clinical development of evinacumab does not hit
a major hitch.
3.5. Gene therapy for familial hypercholesterolemia
Most subjects, >90%, with HoFH have biallelic loss of function
mutations of the LDLR gene. Consequently, adeno-associated
virus (AAV) mediated gene therapy is another option being
developed for the treatment of HoFH [12], and a clinical trial of
a functional replacement of the defective LDLR via AAV-based
liver-directed gene therapy is underway in 12 participants [13].
3.6. Will the mechanism of evinacumab be suitable for
other forms of hypercholesterolemia?
The mechanism of evinacumab is not specific to HoFH, and
consequently, evinacumab would be expected to reduce LDL
cholesterol and triglyceride levels in other forms of hypercho￾lesterolemia. However, its ability to reduce HDL cholesterol is
a disadvantage.
Evinacumab has undergone phase 1 trialing in 83 sub￾jects with hypertriglyceridemia and has been shown to
reduce triglyceride, LDL cholesterol levels, and HDL choles￾terol [9]. At present, evinacumab is being tested in subjects
with persistent hypercholesterolemia despite being treated
with the maximum tolerated dose of lipid modify therapy
(statins, PCSK9 inhibitors) over 16 weeks [14]. Evinacumab is
also being tested in subjects with severe hypertriglyceride￾mia at risk of acute pancreatitis. To be enrolled in this trial,
subjects must have triglyceride levels ≥ 11.3 mmol/L on
more than one occasion, and fasting triglycerides ≥
5.6 mmol/L, and a history of hospitalization and diagnosis
of acute pancreatitis in the past 10 years [15]. As in this trial,
subjects taking the HDL cholesterol-increasing fibrates will
be required to continue taking these, it will be of interest to
know whether the ability of evinacumab to lower HDL cho￾lesterol is curtailed by the fibrates.
3.7. Cost
To date, there is no information about how much evinacumab
will cost, but as it is a monoclonal antibody inhibitor, it is likely to
be expensive. Given the high mortality with HoFH, any expense
may be warranted. However, cost maybe a factor preventing the
wider use of evinacumab in treating high LDL cholesterol.
3.8. Will evinacumab become the standard treatment for
At present, lomitapide is the only specific medicine licensed
and manufactured to treat HoFH in the US. Evinacumab has
not been directly compared to lomitapide, and probably
should be. Evidence to date suggests that evinacumab has
less adverse effects than lomitapide. Thus, evinacumab is
a candidate to become the standard treatment of HoFH.
This manuscript has not been funded.
Declaration of interest
The author has no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
One of the reviewers on this manuscript is on Scientific Advisory Boards for
Alexion, Amgen, Esperion and Novartis. Two additional reviewers on this
manuscript have no relevant financial relationships or otherwise to disclose.
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homo￾zygous familial hypercholesterolemia. N Engl J Med.
• Important clinical trial of evinacumab in HoFH
2. Santos RD, Gidding S, Hegele RA, et al. Defining severe familial
hypercholesterolaemia and the implications for clinical manage￾ment; a consensus statement from the international atherosclerosis
society severe familial hypercholesterolemia panel. Lancet Diabetes
Endocrinol. 2016;4:850–861.
3. Blom DJ, Raal FJ, Santos RD, et al. Lomitapide and
mipomersen-inhibiting microsomal triglyceride transfer protein
(MTP) and apoB100 synthesis. Curr Atheroscler Rep. 2019;21:48..
Discussion of present specific treatments for HoFH
4. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacolo￾gical inactivation of ANGPTL3 and cardiovascular disease. N Engl
J Med. 2017;377:211–221.
5. Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in homozygous
familial hypercholesterolemia. N Engl J Med. 2017;377:296–298..
Preliminary trial of evinacumab in HoFH
6. Regeneron. FDA accepts evinacumab biologics license application
for priority review as a treatment for patients with HoFH, an
ultra-rare inherited form of high cholesterol. [cited 2020 Oct 19].
Available from: https://investor.regeneron.com/news-releases
7. Michos ED, McEvoy JW, Blumenthal RS. Lipid management for the
prevention of atherosclerotic cardiovascular disease. N Engl J Med.
8. Anagnostis P, Vaitsi K, Mintziori G, et al. Non-coronary atherosclerotic
cardiovascular disease in patient with familial hypercholesterolaemia.
Curr Med Res Opin. 2020;36:731–740.
9. Ahmad Z, Banerjee P, Hamon S, et al. Inhibition of angiopoietin-like
protein 3 with a monoclonal antibody reduces triglycerides in
hypertriglyceridemia. Circulation. 2019;140:470–486..
Phase 1 trial of evinacumab in hypertriglyceridemia
10. Strilchuk L, Fogacci F, Cicero AF. Safety and tolerability of injectable
lipid-lowering drugs: an update of clinical data. Expert Opin Drug
Saf. 2019;18:611–621.
11. ClinicalTrials.gov Evaluate the long-term safety and efficacy of
evinacumab in patients with homozygous familial
hypercholesterolemia. cited 2020 Oct 12. Available from: https://
12. Bajaj A, Cuchel M. Homozygous familial hypercholesterolemia:
what treatments are on the horizon? Curr Opin Lipidol.
13. ClinicalTrials.gov A gene therapy study for homozygous familial
hypercholesterolemia (HoFH). [cited 2020 Oct 12]. Available from:


14. ClinicalTrials.gov Study of evinacumab (REGN 1500) in participants
with persistent hypercholesterolemia. [cited 2020 Oct 12]. Available
from: https://clinicaltrials.gov/ct2/show/NCT03175367?term=evina
15. ClinicalTrials.gov Safety and efficacy following repeat-dose of evi￾nacumab (anti-ANGPTL3) in patients with severe Lomitapide  hypertriglyceride￾mia (Shtg) at risk of acute pancreatitis. [cited 2020 Oct 12]. Availabe
from: https://clinicaltrials.gov/ct2/show/NCT03452228?term=evina