Open-Label Extension Study of EFC12492, R727-CL-1112, EFC12732 and LTS11717 Studies to Assess the Long-Term Safety and Efficacy of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia

This open-label extension study will include patients diagnosed with
heterozygous familial hypercholesterolemia (heFH) who have completed EFC12492,
R727-CL-1112, EFC12732 or LTS11717.

Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism
that predisposes a person to premature severe cardiovascular disease (CVD).
Familial hypercholesterolemia has a high prevalence in Caucasian populations,
where an estimated 1 in 500 individuals are affected. Defects in at least 3
different genes that code for proteins involved in hepatic clearance of low
density lipoprotein-cholesterol (LDL-C) can cause FH. These include mutations
in the gene coding for the LDL receptor (LDL-R) that removes LDL-C from the
circulation, and less commonly, in the gene for Apo B, which is the major
protein of the LDL particle. In rare cases, the gene coding for proprotein
convertase subtilisin/kexin type 9 (PCSK9), an enzyme involved in degrading the
LDL-R (gain of function mutation), is mutated. In all cases, this results in an
accumulation of LDL-C in the plasma from birth, and subsequent development of
tendon xanthomas, xanthelasmas, atheromata, and premature CVD.

In the heterozygous form of FH (heFH), the cumulative risk of experiencing a
coronary event by the age of 60 years without effective treatment is at least
50% in men and approximately 30% in women (coronary disease occurs
approximately 10 years later in women than in men, with a marked increase in
post-menopausal women). Before effective treatment with
3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (commonly referred to as
statins) became available, mortality from coronary disease was increased by
nearly 100 fold in young FH adults aged 20 to 39 years, and approximately 4
fold for FH patients aged 40 to 59 years.

In the real world, a large proportion of patients with FH do not reach
treatment goals and, by consequence, remain at increased risk of CVD. In a
recent large cross-sectional study conducted in the Netherlands, nearly all
heterozygous FH patients (96%) were on statin treatment. Only 21% of patients
achieved the LDL-C goal of less than 100 mg/dL (less than 2.59 mmol/L) and
about 5% of patients still had an LDL-C concentration greater than 200 mg/dL.
Among those not at goal, 27% were on combination therapy of maximum statin dose
and ezetimibe. These data emphasize the need for new LDL-lowering therapies.

Primary objective
* To assess the long-term safety of alirocumab when added to currently
available lipid-modifying drug therapy in patients with heterozygous familial
hypercholesterolemia (heFH) who have completed one of the following studies:
EFC12492, R727-CL-1112, EFC12732 & LTS11717.

Secondary objectives
* To evaluate the long-term efficacy of alirocumab on lipid parameters.
* To evaluate the long term immunogenicity of alirocumab.

This is a Phase 3, open-label extension (OLE), uncontrolled study.

Patients must have been diagnosed with heFH in the parent study and have
completed one of the four randomized, double-blind, 18-month parent studies.
Patietns who missed the last injection or who perfromed the end of treatment
visti outside the expected timelines can also be enrolled.

The end of treatment visit of the Double-Blind Treatment Period of the parent
study corresponds to the visit 1 (Day 1) of the OLE study, except for the
patients having participated in the LTS11717. These latter patients will have
the opportunity to enter the OLE study, after they have completed the parent
study, including the 8 week follow-up period. Patients who meet eligibility
criteria at the visit 1 (Day 1) will receive a first SC injection of alirocumab
on that day.

All patients will receive 75 mg Q2W at entry into the OLE, with the exception
of patients from EFC12732 (ODYSSEY High-FH). These latter patients, who had a
screening LDL-C *160 mg/dL in the parent study, will hence receive 150 mg Q2W
at entry into the OLE, as in the parent study.

At entry in the OLE (at visit 1 on Day 1):
* All eligible patients from EFC12732 will get the alirocumab dose 150 mg at
Day 1.
* All eligible patients from EFC12492, R727-CL-1112 and LTS11717 will get 75 mg
alirocumab.

The first SC injection of alirocumab will be administered in the clinic (Day 1,
Visit 1). Patients from the LTS11717 will have the possibility to perform a
placebo self-injection training before the first alirocumab administration
using an auto-injector on that same day (Day 1), as they used a different
device (a prefilled syringe) in the parent study.

From Visit 1, patients have the option to self-administer or have the study
drug injection administered by another designated person (such as spouse,
relative, etc.).

From Day 1 (Visit 1) until Week 8 (first unblinded LDL-C value), neither the
treatment received at the end of the double-blind treatment period in the
parent study, nor the lipid parameters level, will be known by the
Investigator, and by the patient, in order to prevent any potential blinding
breaking of the parent clinical study. However, from Week 8 (Visit 3) in the
OLE, the lipid values will be communicated to the investigator in real time.

From Week 12 (Visit 4), the Investigator will be responsible, based on his/her
own judgment and the patients* LDL levels, to manage alirocumab dose
(up-titration from 75 to 150 mg every 2 weeks, down-titration from 150 to
75 mg every 2 weeks or maintenance of the dose, will be possible).

Daily dose of statin or of other lipid-modifying therapy (LMT) (if applicable)
can be modified based on the Investigator*s judgment throughout the study.

After Week 24 (visit 5), visits will be scheduled every 24 weeks (approximately
6 months) and a dispensation visit will be scheduled in between the 24 weeks
visits interval. This dispensation visit will allow to supply IMP for the next
3 months, and will also allow to check the treatment compliance, the
concomitant medications, and occurrence of any adverse event.

Patients should be on a stable diet (NCEP-ATPIII TLC diet or equivalent)
throughout the entire study duration from visit 1 (V1) to the end of OLE
treatment period (OLETP) (V17).

Injection at site

Patient assessments in the OLE period
* Day 1 / Week 0 (End of treatment visit of the parent double-blind study = OLE
Visit 1, except for the patients having participated in the LTS11717).
* Complete study visits: Patients will be assessed in the clinic at Weeks 4
(Visit 2), 8 (Visit 3), 12 (Visit 4), 24 (Visit 5), and then every 24 weeks
until Visit 17, or early termination.
* IMP dispensing visits: Between Week 24 and Week 120, IMP dispensing visits
will be scheduled in-between the clinic visits in order to allow for dispensing
IMP; they will be done at Weeks 36 (Visit 6), week 60 (Visit 8), 84 (Visit 10)
and 108 (Visit 12), week 132 (visit 14), week 156 (visit 16)

The risks associated with administration of alirocumab to humans are not fully
known. Clinical and laboratory evaluations will be reviewed and monitored
closely on an on-going basis.

Side effects of alirocumab: Every drug has side effects, and alirocumab has
these as well. These effects may be mild, but can also be of a serious nature
and in a few cases life threatening. However, not every person will experience
these side effects.

The most common side effects reported with alirocumab (occurring in at least 1%
of patients) include: injection site reactions (such as, but not limited to
redness, pain, bruising, swelling) , itching and flu (upper respiratory
symptoms). None occurred in more than 6% of the patients

During the study, there is a chance that your LDL cholesterol may go to very
low levels; lower than what is usually seen with other medicines used to treat
high cholesterol. The potential consequences of developing low LDL cholesterol
are unknown. Theoretical concerns related to low LDL-C include: decrease of
hormones, peripheral nerve (part of the nervous system outside of the brain and
spinal cord) abnormalities, anemia (decreased of number of cells in the blood
that carry oxygen in the body), bleeding in the brain, impairment of thinking
or memory and vitamin deficiencies. It should be noted that these theoretical
risks have not been confirmed with alirocumab in human studies of up to 18
months where these specific risks were carefully monitored. Potential side
effects will be monitored very closely during the study.

In studies done in rats, findings were seen in the eyes of some animals. In a
six month study, the finding was in the nerve of the eye. In most cases, this
was thought to be caused by trauma to the eye that was the result of a study
procedure. The meaning of this finding is not clear. However, if a similar
finding occurs in people it could result in vision changes. In studies done in
people treated for up to 18 months with alirocumab, no increased risk was
confirmed in vision changes due to the nerve of the eye. The only observation
related to eyes was regarding
cataracts (clouding of the normally clear lens of the eye). It should be noted
that no difference
was observed in the frequency of cataract between patients treated with
alirocumab and patients
who received placebo or another treatment. However, in patients treated with
alirocumab who
achieved a very low LDLC level, cataracts were observed in 2.1% of these
patients versus 0.6 %
of patients with a higher LDL-C level.

Other potential risks that have been linked to blocking PCSK9: a decrease in
the immune defense, liver disease, colorectal cancer or increased
susceptibility to hepatitis C virus infection; however, it should be noted that
these potential risks have not been confirmed in human studies of up to 18
months with alirocumab.

Allergic reactions: Rare side effects (occurring in less than 1% of patients)
were noted in patients who received alirocumab including allergic reaction,
eczema (skin inflammation), urticaria (wheals), and vasculitis (inflammation of
the walls of blood vessels in the skin).

Sometimes, people have serious allergic reactions to drugs. A severe allergic
reaction could be life-threatening and may result in death. Symptoms of
allergic reactions include rash, difficulty breathing, and coughing, wheezing,
sudden drop of blood pressure, swelling of the mouth, throat or eyes, seizures,
flushing, a fast pulse, and sweating.

Since alirocumab is an investigational drug when taken alone or in combination
with other medications, there may be other risks that are unknown. All drugs
have potential risk of an allergic reaction, which, if not treated promptly,
could become life-threatening. Other rare or unknown side effects could
possibly occur, including life-threatening reactions or death.

During blood draws, the patient may have pain and/or bruising at the place on
the arm arm where blood is taken. Blood clots may form and infections may
occur, but these events are rare. If the patient feels faint, the patient
should lie down right away to avoid falling down.

During this study, the patient may benefit from closer medical observation,
dietetic follow-up, and study drug administration. In connection with these
activities, cholesterol may improve.