Cardiovascular Journal of Africa: Vol 30 No 5 (October 2019)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 5, September/October 2019

280

AFRICA

fully human monoclonal antibody directed against PCSK9,

which reduces LDL-C by up to 61%.

The safety and efficacy of alirocumab in various populations

have been assessed in the phase 3 ODYSSEY programme. Three

of these studies investigated the effect of alirocumab in patients

with HeFH and confirmed the significant reduction in LDL-C

levels of alirocumab-treated patients over a period of 78 weeks.

8-10

The ODYSSEY Open-Label Extension study (OLE;

LTS13463) was a 144-week open-label extension study of

alirocumab in HeFH patients who had previously participated in

theODYSSEYFHstudies [replicate studies FHI (NCT01623115)

and FH II (NCT01709500)], High FH (NCT01617655) or Long-

Term study (NCT01507831, the HeFH stratum of patients). The

objective of the ODYSSEYOLE study was to describe additional

long-term safety, efficacy and tolerability of alirocumab in

HeFH patients.

This report focuses specifically on the South African

patients who participated in this study. Because familial

hypercholesterolaemia is so common in South African founder

populations, it is important to confirm that the safety and

efficacy of alirocumab in South African patients are no different

from that observed in the rest of the world.

Methods

The ODYSSEY OLE study was a phase 3, single-arm, open-

label extension, multicentre, 144-week study evaluating the long-

term safety of alirocumab when added to currently available

lipid-modifying drug therapy in patients with HeFH. Detailed

inclusion and exclusion criteria for these studies have been

published,

8-10

and are included in Table 1. For entry into the

parent study, diagnosis of HeFH could be substantiated either by

genotyping or using one of the following diagnostic algorithms:

Simon Broome (Scientific Steering Committee on behalf of

the Simon Broome Register Group, 1991)

or the Dutch Lipid

Network criteria with a score

In FH I and FH II, patients were randomised to either

alirocumab 75 mg Q2W SC or placebo. Subsequently the dose of

75 mg Q2W could be up-titrated in a blinded fashion at week 12

to 150 mg Q2W in the active-treatment arm if the LDL-C level

at week 8 was

1.8 mmol/l. In the High FH and Long-Term

studies, patients were randomised to either alirocumab 150 mg

Q2W or placebo. In the High FH study, the LDL-C threshold

for entry was

≥

4.14 mmol/l, whereas for Long-Term, the

LDL-C threshold for entry was

≥

1.81 mmol/l. The study flow

is indicated in Fig. 1.

The start of the OLE study corresponded with the end of

the treatment visit of the double-blind treatment period for the

patients enrolled in the parent studies. Upon entry into the OLE

study, patients were receiving their original treatment allocation

of either alirocumab 75 mg Q2W or alirocumab 150 mg Q2W,

or placebo. Patients that participated in the Long-Term study

had an eight-week off-treatment period before commencing the

ODYSSEY OLE study.

In the ODYSSEY OLE study, patients were initiated on

alirocumab 75 mg Q2W as a starting dose, regardless of the

Table 1. Description of the parent studies

Variables

ODYSSEY

FH I

(EFC12492)

ODYSSEY

FH II (R727-

CL-1112)

ODYSSEY

High FH

(EFC12732)

ODYSSEY

Long-Term

(LTS11717)

Patient population

enrolled

Patients diagnosed with HeFH, not adequately controlled

with a maximally tolerated daily dose (MTD) of statin,

stable for at least 4 weeks prior to the screening visit, with

or without other lipid-modifying therapy (LMT)

Screening LDL-C level

at entry

≥

1.80 mmol/l with a history

of documented cardiovas-

cular disease

≥

2.59 mmol/l without a

history of documented

cardiovascular disease

4.14 mmol/l

2.59 mmol/l

with or

without

documented

cardiovascu-

lar disease

Sample size (HeFH

patients actually

randomised in the

parent study)

486

249

107

385

Placebo or alirocumab

dose at entry in the

parent study

75 mg Q2W

150 mg Q2W

Double-blind treatment

period duration (weeks)

Background LMT

MTD* statin (atorvastatin, rosuvastatin, simvastatin)

other LMT

% LDL-C reduction

from baseline to week

−57.9

−51.4

−39.1

−62.0

*Maximum tolerated dose defined as:

• Rosuvastatin 20 or 40 mg daily

• Atorvastatin 40 or 80 mg daily

• Simvastatin 80 mg daily (if already on this dose for

one year)

• Patients not able to be on any of the above statin doses should be treated with

the daily dose of atorvastatin, rosuvastatin or simvastatin that is considered

appropriate for the patient as per the investigator’s judgment or concerns. Some

examples of acceptable reasons for a patient taking a lower statin dose include,

but are not limited to, adverse effects on higher doses, advanced age, low body

mass index, regional practices, local prescribing information, concomitant medi-

cations, co-morbid conditions such as impaired glucose tolerance or impaired

fasting glucose.

FH I (NCT01623115)

Alirocumab 75 mg or placebo Q2W

FH II (NCT01709500)

Alirocumab 75 mg or placebo Q2W

LONG-TERM (NCT01507831)

Alirocumab 150 mg or placebo Q2W

HIGH FH (NCT01617655)

Alirocumab 150 mg or placebo Q2W

Alirocumab 75 mg or 150 mg Q2W

Alirocumab 150 mg Q2W

Double-blind treatment period in parent studies (78 weeks)

Open label extension treatment period (144 weeks)

At the start of the open-label extension study, patients were on treatment (75 or 150 mg) alirocumab Q2W or placebo

Up-titration of alirocumab dose at the investigators discretion permitted at week 12 if LDL-C was

≥

1.8 mmol/l

Fig. 1.

Study flow of the ODYSSEY Open label study.