A 52-WEEK PLACEBO-CONTROLLED TRIALOF EVOLOCUMAB IN HYPERLIPIDEMIA

By : Dr. NITESH PANSARI

GUIDE : Dr. HEMANT MAHUR SIR

UNIT HEAD & HOD : Dr. D.P. SINGH SIR

Durable Effect of PCSK9

Antibody CompARed wiTh

PlacEbo Study

INTRODUCTION Hyperlipidemia involves abnormally elevated levels

of any or all lipids and/or lipoproteins in the blood.

It is the most common form of Dyslipidemia (which

includes any abnormal lipid levels).

Elevated low-density lipoprotein cholesterol

(LDLC) levels in the plasma is the most

important causative factor of atherosclerosis

and associated ischemic cardiovascular

diseases.

The LDL receptor (LDLR) is the preferential

pathway through which LDLs are cleared from

the circulation.

Familial hypercholesterolemia (FH) is an autosomal

dominant disorder associated with elevated LDL

levels and premature coronary heart disease.

FH is caused primarily by mutations of the LDLR or

of apolipoprotein B100 (apoB100), the protein

component of LDL that interacts with the LDLR.

In 2003, “gain of function” mutations on a newly

identified gene, proprotein convertase

subtilisin/kexin type 9(PCSK9), were associated

with FH.

In 2005, a causative association was established

between “loss of function” mutations in PCSK9 and

low LDLC levels in 2% of the African-American

population.

BACKGROUND Evolocumab, a monoclonal antibody that inhibits

proprotein convertase subtilisin/ kexin type 9 (PCSK9),

significantly reduced low-density lipoprotein (LDL)

cholesterol levels in phase 2 studies.

In short-term (8-to-12-week), placebo-controlled, phase 2

trials, PCSK9 inhibitors have been shown to significantly

reduce LDL cholesterol levels.

Four of these trials involved the use of evolocumab (AMG

145), a fully human monoclonal PCSK9 antibody, and

assessed different doses and regimens in diverse patient

populations with varying lipid phenotypes, cardiovascular

disease risks, and baseline use of lipid-lowering therapy.

A longer-term, open-label extension study involving

1104 patients from the phase 2 trials compared

evolocumab administered monthly (at a dose of 420

mg) plus standard medical care with standard medical

care alone.

In DESCARTES, we compared evolocumab with

placebo in patients with hyperlipidemia who received

the study drug for 52 weeks after a run-in period of 4

to 12 weeks of background lipid lowering therapy.

INCLUSION CRITERIA1. Subject has provided informed consent.

2. Male or female ≥ 18 to ≤ 75 years of age at screening

3. Fasting LDL-C ≥ 75 mg/dL at the initial screening visit

4. Fasting LDL-C at the end of the lipid stabilization period ≥ 75

mg/dL (2.0 mmol/L) and meeting the following LDL-C values based

on risk factor status (NCEP ATPIII risk categories):

• < 100 mg/dL (2.6 mmol/L) for subjects with diagnosed CHD or

CHD risk equivalent

• < 130 mg/dL (3.4 mmol/L) for subjects without diagnosed CHD or

CHD risk equivalent

• OR for subjects on maximal background lipid-lowering therapy

(defined as atorvastatin 80 mg PO QD and ezetimibe 10 mg PO QD),

LDL-C at the end of the lipid stabilization period of ≥75 mg/dL (2.0

mmol/L)

5. Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) at screening and

at end of lipid stabilization period

EXCLUSION CRITERIA1. Diagnosed with CHD or CHD risk equivalent and not receiving statin

therapy, with LDL-C at screening ≤ 99 mg/dL

2. NYHA class II, III or IV heart failure, or last known left ventricular

ejection fraction < 30%

3. Uncontrolled cardiac arrhythmia that are not controlled by

medications, in the past 3 months prior to randomization

4. Myocardial infarction, unstable angina, percutaneous coronary

intervention (PCI), coronary artery bypass graft (CABG) or stroke

within 3 months prior to randomization

5. Planned cardiac surgery or revascularization

6. Type 1 diabetes or newly diagnosed type 2 diabetes (within 6 months

of randomization) or poorly controlled type 2 diabetes (HbA1c >

8.5%).

7. Uncontrolled hypertension defined as sitting systolic blood pressure

(SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg

8. Subject has taken lipid-regulating drugs other than statins or

ezetimibe, such as fibrates and derivatives, or bile-acid sequestering

resins in the last 6 weeks prior to LDL-C screening

9. Treatment in the last 3 months prior to LDL-C screening with any of

the following drugs: systemic cyclosporine, systemic steroids,

vitamin A derivatives and retinol derivatives

10. Hyperthyroidism or hypothyroidism

11. Moderate to severe renal dysfunction (eGFR) < 30 ml/min/1.73m2

12. Active liver disease or hepatic dysfunction

13. CK > 3 times the ULN at screening or at end of lipid stabilization

period, confirmed by a repeat measurement at least 1 week apart

STUDY DESIGN AND OVERSIGHT This study was conducted at 88 centers in nine countries.

This is a phase 2, multicenter, double-blind, randomized,

stratified, placebo- controlled study of AMG 145.

Subjects with screening central laboratory LDL-C values ≥

75 mg/dL (2.0 mmol/L) who met inclusion/exclusion criteria

were instructed to follow National Cholesterol Education

Program (NCEP) Adult Treatment Panel III (ATP)

Therapeutic Lifestyle Changes (TLC) diet and assigned to 1

of 4 background LDL-C treatment levels based upon their

screening LDL-C and its distance from the individual’s

required goal as stipulated by their NCEP ATP III risk

category.

1. No drug therapy required - diet alone

2. Low dose drug therapy required - diet plus atorvastatin

10mg PO QD

3. High dose drug therapy required - diet plus atorvastatin

80mg PO QD

4. Maximal drug therapy required - diet plus atorvastatin 80mg

PO QD plus ezetimibe 10mg PO QD

At the end of a 4 week stabilization period, eligibility were

assessed based upon central LDL-C values.

Subjects who exceed the eligible LDL-C value for their

NCEP risk category were allowed to undergo background

treatment up-titration to the next treatment level and entered

an additional 4 week stabilization period after which

eligibility based on LDL-C was reassessed.

A maximum of 2 treatment up-titrations were permitted

during this period.

Patients with an LDL cholesterol level of less than 75 mg

per deciliter were excluded, except for those who were

receiving 80 mg of atorvastatin plus 10 mg of ezetimibe

daily.

These patients were allowed to discontinue ezetimibe and to

participate in the study if the ATP-III goal was maintained

after 4 weeks on the regimen of 80 mg of atorvastatin daily.

Amgen sponsored and designed the Trial and was

responsible for data collection and analysis.

RANDOMIZATION Randomization to the blinded phase of the trial, which

was stratified according to background therapy, was

performed centrally with the use of an interactive voice-

response system.

Patients were assigned in a 2:1 ratio to receive either 6

ml (420 mg) of evolocumab or placebo, administered

subcutaneously every 4 weeks for 48 weeks.

Study visits were scheduled every 4 weeks, with

additional visits at weeks 13 and 37.

Final administration of a study drug occurred at week

48.

During the 12, 24, 36, and 52 week visits vital signs were

obtained, Adverse Events, Serious Adverse Events, and

concomitant medications were recorded and laboratory tests

and additional study procedures were performed.

Patients who discontinued a study drug for any reason were

asked to continue all other study activities through week 52.

Anti-evolocumab antibodies were assayed at baseline and at

weeks 12, 24, 36, and 52.

The end-of-study (EOS) visit and the last estimation of

lipids occurred at week 52 for all subjects.

PRIMARY ENDPOINT : • Percent change from baseline in LDL-C at week 52

SECONDARY ENDPOINT(S) :• Percent change from baseline in LDL-C at week 12

• Percent change from week 12 in LDL-C at week 52

• Absolute change from baseline in LDL-C at week 52

• Percent change from baseline in non-HDL-C at week 52

• Percent change from baseline in ApoB at week 52

• Percent change from baseline in the total cholesterol/HDL-

C ratio at week 52

• Percent change from baseline in ApoB/ApoA1 ratio at week

52

RESULTS Among the 901 patients included in the primary analysis, the overall

least-squares mean (±SE) reduction in LDL cholesterol from baseline

in the evolocumab group, taking into account the change in the

placebo group, was 57.0±2.1% (P<0.001).

The mean reduction was

55.7±4.2% among patients who underwent background therapy with

diet alone,

61.6±2.6% among those who received 10 mg of atorvastatin,

56.8±5.3% among those who received 80 mg of atorvastatin, and

48.5±5.2% among those who received a combination of 80 mg of

atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons).

Evolocumab treatment also significantly reduced levels of

apolipoprotein B, non–high-density lipoprotein cholesterol,

lipoprotein(a), and triglycerides.

All

Pa

tint

s

Diet

-

only

Atorva

statin

10 mg

Atorva

statin

80 mg

Atorvast

atin 80

mg plus

ezetimib

e 10 mg

The target of an LDL cholesterol level of less than 70

mg per deciliter as recommended by The American

College of Cardiology and the American Heart

Association (ACC–AHA) was achieved in more than

80% of patients with the use of 420 mg of evolocumab

every 4 weeks.

In addition, there were significant reductions in the

levels of other atherogenic, apolipoprotein B–containing

lipoproteins, including lipoprotein(a), and modest but

significant increases in levels of HDL cholesterol and

apolipoprotein A1.

In the evolocumab group, mean reductions from baseline

in unbound PCSK9 levels that were measured at weeks

13 and 37 at an interval of 1 week after administration

were 91.1±1.8% and 86.9±1.3%, respectively; in

measurements performed at weeks 12, 24, 36, and 52 at

an interval of 4 weeks after administration, there were

mean reductions of 41.2±1.2%, 38.3±2.2%, 38.3±2.2%,

and 42.4±1.8%, respectively.

Reductions after 1 week were consistently around 90%

regardless of background therapy, but those at 4 weeks

after drug administration were greater in the diet alone

group and the group receiving 10 mg of atorvastatin than

in the two groups receiving 80 mg of atorvastatin.

ADVERSE EVENTS AND

IMMUNOGENICITY The overall incidence of adverse events occurring during treatment

was similar in the evolocumab group and the placebo group, with 448

of 599 patients (74.8%) and 224 of 302 patients (74.2%), respectively,

having an adverse event.

The most common adverse events in the evolocumab group were

nasopharyngitis, upper respiratory tract infection, influenza, and back

pain.

Evolocumab treatment did not have an adverse effect on glycemic

measures.

Serious adverse events occurred in 33 patients (5.5%) in the

evolocumab group and 13 patients (4.3%) in the placebo group .

Adverse events leading to the discontinuation of a study drug occurred

in 13 patients (2.2%) in the evolocumab group and 3 patients (1.0%) in

the placebo group.

Two patients in the evolocumab group had detectable

binding antibodies before or at the time of randomization.

One patient in the evolocumab group had newly detected

transient anti-evolocumab binding antibodies during

treatment.

No anti-evolocumab neutralizing antibodies were detected

in any patients.

DISCUSSION

Treatment with 420 mg of evolocumab every 4 weeks for

52 weeks resulted in a relative reduction in LDL cholesterol

levels of 57%, taking into account the change in the

placebo group.

No decrement in the efficacy of evolocumab from week 12

to week 52.

Findings were also similar to the finding of a relative

reduction of 52% in LDL cholesterol levels reported in the

first year of the Open-Label Study of Long-Term

Evaluation against LDL-C (OSLER) study.

In our study, unbound PCSK9 was measured at 1 week and

at 4 weeks after the administration of evolocumab.

The differences in unbound PCSK9 among background

therapy groups at 1 week were minimal, despite substantial

differences in baseline levels, indicating that virtually all

PCSK9 is antibody-bound initially.

However, not only were baseline levels of PCSK9 higher

among patients receiving high dose atorvastatin than among

patients in the other groups, but there also was a more rapid

increase in PCSK9 levels 4 weeks after the administration of

each dose of evolocumab in these patients, suggesting that

the rate of PCSK9 production is increased in patients

receiving intensive statin therapy.

Patients who have already been treated with high-dose

statins or combination lipid-lowering therapy may have

slightly less capacity to further up-regulate LDL-receptor

activity with PCSK9 inhibition or may require higher doses

of antibody.

In our study, target of an LDL cholesterol level of less than

70 mg per deciliter was achieved in more than 80% of

patients with the use of 420 mg of evolocumab every 4

weeks.

In addition, there were significant reductions in the levels of

other atherogenic, apolipoprotein B–containing lipoproteins,

including lipoprotein(a), and modest but significant

increases in levels of HDL cholesterol and apolipoprotein

A1, similar to those reported with evolocumab previously.

More patients in the evolocumab group than in the placebo

group were reported to have serious adverse events during

treatment and to have adverse events leading to drug

discontinuation.

CONCLUSIONS At 52 weeks, evolocumab added to diet alone, to low-dose

atorvastatin, or to highdose atorvastatin with or without

ezetimibe significantly reduced LDL cholesterol levels in

patients with a range of cardiovascular risks.

Among patients at risk for a wide range of coronary diseases

who were receiving guideline-recommended background

lipidlowering therapy, the monoclonal PCSK9 antibody

evolocumab reduced LDL cholesterol levels by 57%, as

compared with placebo, at 52 weeks.