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2017

Volume 3-The Informed Prescriber

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Anti PD-1 antibody: pembrolizumab
Effective only for non-small cell lung cancer of specific type

New Cholesterol Lowering Agents (PCSK9 Inhibitors)
Infection and neurological diseases increase

CONTENTS （April 2017, Vol. 3, No. 7）

Editorial
Time to wake up from a nightmare－ "cholesterol=devil" hypothesis
New Products
Anti PD-1 antibody: pembrolizumab

2

3

Effective only for non-small cell lung cancer of specific type

New Cholesterol Lowering Agents (PCSK9 Inhibitors)

6

Infection and neurological diseases increase

TopicsTop 1 most read for 5 month: paper on cholesterol
RCTs of cholesterol lowering agents of different classes were cancelled in succession

Page xvi ・ MED CHECK - TIP April 2017/ Vol.3 No.7

10

M
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-The Informed Prescriber

HECK

Editorial

Time to wake up from a nightmare－ "cholesterol=devil" hypothesis
Translated from the Editorial in Med Check-TIP (in Japanese) Jan 2017 ; 17 (69)
Keywords:
overall survival, cholesterol hypothesis, PCSK9inhibitor, CETP inhibitor,familial hypercholesterolemiaInterventions, including those with medicines, are

The guideline recommend that in people at very

not useful even if a medical complication is related

high cardiovascular risk, LDL-cholesterol should bewith some risk factors (e.g. remarkable hypertension

lowered to <1.8 mmol/L (70 mg/dL), or in people

and hyperglycemia), and those factors are mitigatedwhose baseline cholesterol level is between 1.8 andby the intervention. It must be demonstrated by

3.5 mmol/L (70-135 mg/dL), it should be lowered atlong-term randomized controlled studies that theleast by 50% .

intervention can reduce complications and improvesurvival.

Cholesterol lowering agents with new mechanismsof action, including PCSK9 inhibitors (p10) and CETP

However, it seems that the mainstream of theinhibitors (p 10 ), have been developed and many

medical world is going in a totally different direction.

are still underway to be developed. The idea ofPrevention of cardiovascular diseases by medical"Cholesterol= devil" is growing more aggressive as

treatment based on the "cholesterol hypothesis" is one

to support the development of the new agents. Inof the typical cases. We dare to say "cholesterol=devil

clinical trials, such as those on evolocumab, LDL -hypothesis" instead of "cholesterol hypothesis"cholesterol levels decreased by 30-40% , and in many

because the mainstream medical researchers andcases they decreased to 25 mg/dL or lower. These

practitioners are trying to remove cholesterol totally

data may mislead clinicians to believe that the lower,

as if it is a devil.

the better.

Contrarily, cholesterol is never a devil but an

The main reason why people w ith familial

essential substance for the body. It has become

hypercholesterolemia ( FH ) are prone to havewell known that people with higher total cholesterol

myocardial infarction is not because of their highmay live longer. Many epidemiologic surveys alsocholesterol level. The real reason is that they also

reported recently that people with higher LDL

have a genetic disposition to induce high level ofcholesterol level may live longer. A systematic

inflammatory cytokine, including TNF-alfa, which

review which was published in June 2016 revealed

easily causes inflammation. This predisposition isthat people aged 60 years and older with higher LDL

also the factor that prevents people with FH fromcholesterol lived longer almost without exception

being infected with various pathogens, and that is(abstract on p10). It was the article which was read

why they lived longer than non-FH people whenmost frequently for five months following the monthinfectious diseases were the main cause of death.

of the publication on the BMJ Open Journal. It showsthat the public has high interest in this issue.
On the other hand, scholars insisting on the"cholesterol=devil" hypothesis counterattack fiercely

Is it worth to spend approximately 23,000-70,000
yen (200-600US $)/2 weeks or 0.3-1.8 million yen(5,000-16,000 US $) per year for the agents whose
harm outweighs the benefit?

against this article. The prime example is the joint

Now is the time to wake up from the nightmare ofguideline by the European Society of Cardiology

the "cholesterol=devil" hypothesis, otherwise terrible

and European Atherosclerosis Society ( ESC/EAS ).

unwanted events may occur.

Page  ・ MED CHECK - TIP April 2017/ Vol.3 No.7

New Products

Anti PD-1 antibody:
pembrolizumab (brand name: Keytruda)
Effective only for non-small cell lung cancer of specific typeTranslated from Med Check-TIP (in Japanese) Mar. 2017 ; 17 (70):32-34

Abstract
Pembrolizumab, a class drug of nivolumab, prolongs progression free survival (PFS) and overall survival (OS) in patients
who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells. In patients whose
PD-L1 expression level was below 50%, the agent also disrupts function of PD-L1 on normal immune cells and may suppress
immunity, causing cancer progression, increased infection and autoimmune diseases.
The use of pembrolizumab should be restricted to patients with PD-L1 expression level of 50% or higher, in bothpreviously treated and untreated patients. For previously treated patients whose PD-L1 expression level is below 50%,
more detailed study is needed. Because the effectiveness of nivolumab has not been proven in patients with PD-L1
expression level of 50% or higher, it should be not used as a first-line treatment.
Keywords:
anti PD-1 antibody, pembrolizumab, PD-L1 expression level, immune disorders, overall survival,
progression free survival

Introduction

expression level of 5% or higher, the median progression

Anti PD-1 antibodies such as nivolumab ( brand name:free survival ( PFS) was 4.2 months in a nivolumab group

Opdivo) bind to Programmed cell Death-1 (PD-1) and preserveand 5.9 months in a chemotherapy group. Compared

the function of this protein. PD-1 is essential for normal

to the chemotherapy, nivolumab did not demonstrate

functioning of T-lymphocytes, which attack cancer cells andsuperiority, but it was even inferior. The hazard ratio (HR)viral-infected cells. Although their effect as an immunity

for progression/death was 1.15 (95%CI: 0.91-1.45, p=0.25).

booster has been highlighted, they disrupt the function of

The HR for death was reported to be 1.02 (0.80-1.30) [2, 3].

PD-L1 on normal immune cells and suppress immunity. As a

Nivolumab should not be used as a first-line treatment.

result, they may allow cancer progression, increase infection
and induce autoimmune diseases. This was emphasized in the
Med Check-TIP No. 66[1].

The phase I trial on pembrolizumab
In prior to the phase III trial [4], a large-scale phase I trial

Opdivo did not succeed as a first-line treatment of non-was conducted on pembrolizumab [5] which was different

small cell lung cancer with a PD-L1 expression level of 5%

from ordinary phase I trial. The study enrolled 495 non-small

or higher. However, pembrolizumab ( brand name: Keytruda)cell lung cancer patients who were classified into 3 groups

yielded a positive result as a first-line treatment of non-according to their PD-L1 expression levels. It compared thesmall cell lung cancer with a PD-L1 expression level of 50%

effect of pembrolizumab on patients who received it as a first-of higher[4]. This means that theory that had been asserted

line treatment and those who had been treated previously. No

in the Med Check-TIP No. 66 was confirmed. This article

difference was observed in patients with PD-L1 expression

examines the differences between these 2 drugs.

level of below 1% and 1%-49%, and positive result was
yielded in patients with PD-L1 expression level of 50%

Trial for a first-line treatment with nivolumab

or higher even as a first-line treatment (Figure 1a, 1b). For

In a trial in which nivolumab was used as a first-line

instance, as a first-line treatment, PFS (Figure 1a) was 12.5

treatment for non-small cell lung cancer with a PD-L1

months in patients with high PD-L1 expression level, which

MED CHECK - TIP April 2017/ Vol.3 No.7 ・ Page Figure 1: Result of the pembrolizumab phase I triala)Median progression free survival (PFS)b)Overall survival at 15 weeks (%)

Apart from PD-L1 expression level (%) and the number of initially/previously treated patients, these values were taken mainly from thegraphs. In both PFS and OS, patients with PD-L1 expression level of 50% or higher demonstrated extremely more positive outcome,compared with those whose PD-L1 expression level was below 50%. Pembrolizumab was administered at 2 mg/kg every 3 weeks, 10
mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, but no difference was found among these dosage groups.

c)PD-L1 expression

Whether the patients had been previously treated or untreated did not affect much the proportion of non-small cell lung cancer patients
whose PD-L1 expression level was 50% or higher. At least, a single use of chemotherapeutic agents does not seem to raise PD-L1
expression level. However, it remains unknown for patients at the terminal stage.

was more than 2-fold of that in patients with low PD-L1

50% or higher was approximately 30% in both previously

expression level. Overall survival (OS) (%) at 15 months wasuntreated and treated groups (Figure 1c). This indicates

95% in patients who was treated initially (40%-60% in patientsthat chemotherapy does not affect PD-L1 expression sowith a low PD-L1 expression level ) and 55% in previously

much.

treated patients ( 30%-35% in patients with a low PD-L1
expression level), showing marked improvement (Figure 1b).

The dosages of pembrolizumab were 2 mg/kg every 3
weeks, 10 mg/kg every 3 weeks, and 10 mg/kg every 2
weeks. No difference was reported by dosage [5].
The proportion of patients with PD-L1 expression level ofPage  ・ MED CHECK - TIP April 2017/ Vol.3 No.7

The phase II/III trial for previously treated non-small celllung cancer
The phase II/III trial for non-small cell lung cancer was
an open label trial that enrolled 1034 previously treatedpatients. In the trial, 2 dosages of pembrolizumab (2 mg/

Figure 2: KEYNOTE-024 (initial treatment for non-small cell lung cancer)

kg, 10 mg/kg) every 3 weeks and docetaxel 75 mg/m2 every 3

level below 50% at which both OS and PFS improve inweeks were administered and compared [6].

previously treated patients.

Almost no difference was found between the 2 dosagesof pembrolizumab in any outcomes. However, in patientswith PD-L1 expression level of 50% or higher, they showedmarked difference, compared with the docetaxel group.

KEYNOTE-024: a trial with untreated patients
A phase III trial was conducted to determine theeffectiveness of pembrolizumab as a first-line treatment,

Then, the results from the 2 dosage groups were combined

assigning 305 patients who had previously untreatedand compared with that from the docetaxel group. The HR for

advanced NSCLC with PD-L1 expression on at least 50% of

death was 0.53 (95%CI: 0.40-0.70), and HR for progression/

tumor cells and no sensitizing mutation of the epidermal

death was 0.59 (95%CI: 0.46-0.74), and they both improved

growth factor receptor (EGFR) gene or translocation of themarkedly. In patients with PD-L1 expression level of 1%-49%,

ALK (anaplastic lymphoma kinase) gene.

OS extended significantly ( 0.76, 95%CI: 0.60-0.96 ), but noIn a pembrolizumab group, a fixed dose of 200 mg wasdifference was found in PFS (1.04, 95%CI: 0.85-1.27). Moreadministered every 3 weeks, and in a control group, platinum-

detailed analysis is needed to determine the PD-L1 expression

containing chemotherapeutic agents were administered (thetype of the agents used was decided by investigators).

Table: summary of adverse events in KEYNOTE-024

It was an open label comparative study.
When disease progression was observed, it wasallowed to replace the chemotherapeutic agentswith pembrolizumab.
The primary endpoint was progression freesurvival ( PFS ), and the secondary endpoints
were overall survival ( OS ), response rate ( RR ),and safety (adverse events). Among the patientswith advanced lung cancer, in those with PD-L1
expression level of 50% or higher, hazard ratio( HR ) for aggravation/death was 0.50 ( 95%CI:

Immune-mediated disorders of Grade 3 or higher occurred only in 1 patient(pneumonitis) in the chemotherapy group while in the pembrolizumab group, drug

0.37-0.68, p<0.001), and HR for all deaths was 0.60

(95%CI: 0.41-0.89, p<0.005) (Figure 2).

eruption (6 patients), pneumonitis (4), colitis (2), hypophysitis (1), nephritis (1),pancreatitis (1), and type 1 diabetes (1) were reported.

MED CHECK - TIP April 2017/ Vol.3 No.7 ・ Page More serious adverse events with pembrolizumab?

The effect of pembrolizumab for previously treated NSCLC

Overall, a fewer number of adverse events was reported

should be reanalyzed in patients whose PD-L1 expression

with pembrolizumab, but there was no difference in serious

level is lower than 50% to establish more restricted

adverse events. Although neutropenia is serious, it is justindication. The same applies to nivolumab.

transient. In the pembrolizumab group, immunologicalby the Med Check -TIP Editorial Teamadverse events occurred significantly more frequently,

References

and those of grade 3 or higher occurred in 15 patients

1) Med Check-TIP Editorial team. New anticancer drug Nivolumab (brand(9.7%), 16 cases while they occurred in 1 patient (0.7%) in

name: Opdivo), MedCheckTIP (English); 2016: 2(6): 29-35.

a chemotherapy group (Table). They included severe drug
eruptions, pneumonitis, and colitis. These might persist until
death, and the frequency of the events alone is not sufficientfor evaluation of this issue.

2) ESMO 2016 Press Release: Greater Patient Selection May be Needed
for First Line Nivolumab to Improve Progression-free Survival in Advanced
Lung Cancer
http://www.esmo.org/Conferences/ESMO-2016-Congress/Press-Media/
Greater-Patient-Selection-May-be-Needed-for-First-Line-Nivolumab-toImprove-Progression-free-Survival-in-Advanced-Lung-Cancer
3) Bristol-Myers Squibb Presents Results From CheckMate -026, a Phase

In practice
When pembrolizumab is used in patients whose PD-L1
expression level is below 50%, the elderly patients, or
patients with EGFR gene mutation or ALK translocation, most3 Study of Opdivo (nivolumab) Monotherapy Versus Chemotherapy asFirst-Line Therapy in a Broad PD-L1 Positive Population With Advanced
Lung Cancer: https://www.ono.co.jp/eng/news/pdf/sm_cn161011_3.pdf
4) Reck M et al (KEYNOTE-024 Investigators). Pembrolizumab versusof whom have a low PD-L1 expression level, it inhibits PD-L1

Chemotherapy for PD-L1-Positive Non-Small Cell Lung Cancer. N Engl J

on normal immune cells, antigen presenting cells ( APCs ),Med. 2016;375(19):1823-33.

suppresses immunity, allows cancer progression, and increase5) Garon EB et al (KEYNOTE-001 Investigators) Pembrolizumab

infection. In addition, by disrupting the function of PD-L1 on

for the treatment of non-small cell lung cancer. N Engl J Med.

regulatory T cells, it induces autoimmune diseases.
Anti PD-1 antibodies do not demonstrate its benefit inpatients with a low PD-L1 expression level with 10% or lower.

2015;372(21):2018-28.
6) Herbst RS et al. Pembrolizumab versus docetaxel for previously treated,
PD-L1-positive, advanced non-small cell lung cancer (KEYNOTE-010): a
randomised controlled trial. Lancet. 2016:387(10027):1540-50.

New Products
Products
New

New Cholesterol Lowering Agents (PCSK9 Inhibitors)
Infection and neurological diseases increase

Translated from Med Check-TIP (in Japanese) Jan. 2017 ; 17 (1):8-9

Abstract
Cholesterol lowering agents, evolocumab and alirocumab were launched in April and August, 2016, respectively.
Evolocumab and alirocumab are monoclonal antibodies targeting at PCSK9, an enzyme that decomposes LDL receptors inhepatocytes. They are believed to increase LDL receptors and lower LDL-cholesterol level. They are injected subcutaneously
once every 2 or 4 weeks.
Only short-term clinical trials are available on these agents with the longest trial that lasted only about 1.5 years. No
evidence suggests that the agents reduce the incidence of cardiovascular diseases and overall mortality. However, they
increase the incidence of infection, and cause serious neurologic diseases and impairment of cognition. These agents are
not recommended.
Keywords:
overall survival, PCSK9 inhibitor, evolocumab, alirocumab, neurocognitive disorders, infection, familial hypercholesterolemia

Page  ・ MED CHECK - TIP April 2017/ Vol.3 No.7

People with higher cholesterol level live longer

Increased infection

Cholesterol, LDL-cholesterol in particular, is an essential

Trials that enrolled patients with familial

substance for the organism. Epidemiological studies [1-4]hypercholesterolemia ( FH ) showed marked increase of

in Japan and overseas have shown that people with higher

infection [7, 8]. In a trial with patients with homozygous

cholesterol level tend to live longer. Especially, people aged

FH ( HoFH ) [7], infection occurred in 6.3% ( 1/16 cases )60 or over with higher cholesterol level live longer almost

with placebo while it occurred in 30.3% (10/33 cases) withwithout exception [4]. Therefore, having a high cholesterol

evolocumab. The duration of the trial was 12 weeks.

level alone does not warrant medical intervention.

Although the difference was not statistically significant,infection occurred 5 times more frequently in the

PCSK9 inhibitors
PCSK9 is an enzyme which stands for proprotein convertase

evolocumab group. (Risk ratio, not odds ratio, is used here as
there might be overlap in the number of cases.)

subtilisin/kexin type 9. PCSK9 inhibitors are recombinant

In a trial with patients with heterozygous FH (HeFH) [8],human (IgG2) monoclonal antibodies that bind specifically

only nasopharyngitis was reported. No other infection wasto this enzyme and inhibit its interaction with low density

reported in a published paper [8] including in its appendix,

lipoprotein receptors (LDLRs). The mechanism of action is

and SBA. Nasopharyngitis occurred in 5.1% (5/99) in theillustrated in the Figure below [5].

placebo group and 8.6% (19/220) in the evolocumab group.
The odds ratio was 1.78. Although it was not significant, it

Results from clinical trials for PCSK9 inhibitors

was nearly 2-fold higher. Besides infection, high odds ratios

The results from clinical trials for evolocumab ( brandwere observed in bruising ( 4.2-fold ), back pain ( 3.7-fold ),name: Repatha ) and alirocumab ( brand name: Praluent ) thatand nausea (3.7-fold). In a placebo controlled trial enrollingwere conducted prior to approval are extracted frompatients with high cholesterol (HC ) level [9], many types

their respective summary basis of approval (SBA) [5a, 6a],of infection was reported more frequently in evolocumab

regulatory review reports [5b, 6b], and major papers [7-11],group, including upper respiratory tract infection (6.3% vsand shown in the Table. Pfizer discontinued all ongoing

9.3%, OR:1.54). In total, they occurred in 41% (125/302) ofclinical trials for PCSK9 inhibitors (bococizumab), concluding

the patients on placebo and 52.6% (315/599) of the patientsthat it was not likely to provide value to patients, physicians,or shareholders [12].
Randomized placebo-controlled trials (RCTs) wereconducted for evolocumab and alirocumab for the maximum

Figure 1: The mechanisms of LDL-cholesterol loweringby PCSK9 inhibitors

duration of 1 year and 1.5 years, respectively. In both trials,
the primary outcome was not the prevention of cardiovasculardiseases, but merely a lowered LDL cholesterol level at 12
to 52 weeks. The primary outcome of a RCT for alirocumabwith a follow-up duration of 1.5 years was also a lowered
LDL cholesterol level at 24 weeks.
Only a 1-year RCT for evolocumab suggested decreased
cardiovascular events, but it was not a double-blind but
open label trial which compared the agent with a standard
therapy. Hence the result in favor of evolocumab is notreliable. Furthermore, in this trial, patients were randomly
reassigned after completion of 12 RCTs. Patients who had

When LDL-cholesterol binds to its receptors (LDL receptors), it isusually endocytosed into the liver cells. When LDL receptors bindto PCSK9, they are decomposed in lysosomes and are not recycled.

been on evolocumab in the previous trials accounted forAnti PCSK9 monoclonal antibodies ( evolocumab, alirocumab )approximately two-thirds of the patients in the control group.

prevent PCSK9 from binding to LDL receptors, suppressing the

Therefore, difference in the incidence of adverse events isless likely to be detected.

decomposition of LDL receptors. Undecomposed LDL receptors arerecycled, increasing LDL receptors on cell surface. Consequently,
increased LDL-cholesterol is endocytosed into the liver cells, andLDL-cholesterol level is lowered [5].

MED CHECK - TIP April 2017/ Vol.3 No.7 ・ Page Table: Summary of the phase 2/3 Clinical trial of anti-PCSK9 antibody (As of Dec 2016)

FH: Familial hypercholesterolemia、Ho: Homozygote、He: Heterozygote、HC: Hypercholesterolemia、PL: placebo
AE: adverse events、 py: person-year、NS: not significant, S: significant*a：open study. The subjects were randomly reassigned to standard treatment (ST) group or ST + evolocumab group, after the completionof total 12 phase 2/3 trials. Consequently, those who were allocated to the placebo group among those who had been in the evolocumab
group in the parent trial may be influenced by the adverse effect of evolocumab. No difference was reported for infection. However, among
the adverse events, significant difference was found in impairment of cognition (OR:3.4), fatigue (OR:2.8), extremity pain (OR:1.6), joint
pain (OR:1.45), headache (OR:1.7), and nausea (OR:1.8).
*b: As this was an open trial, the favorable result for evolocumab is not reliable.

on evolocumab. The risk ratio was 1.16 ( 95%CI: 1.06-1.28,

be taken into consideration. It is questionable whether

p=0.0019 ), and the difference was significant. In an open

hypoesthesia alone can be considered as a serious event. A

trial on evolocumab [10], the risk ratio was 1.06 (95%CI:

typical example of central demyelinating diseases is multiple

1.01-1.11, p=0.016). When the 3 placebo controlled trials onsclerosis. Optic neuritis is also a serious symptom that may

evolocumab are combined, the risk ratio for infection is 1.31

be an initial sign that might develop to multiple sclerosis.

(95%CI: 1.13-1.53, p=0.0005).

According to the summary of overseas placebo RCTs on

In a Japanese clinical trial on alirocumab [6], the incidence

alirocumab [6] (pivotal RCT is reported as reference 11), optic

of infection was 25% ( 18/72 patients ) with placebo whilenerve damage occurred in 0.2% ( 3 patients) with placebo

it was 36.4% (52/143 patients) with alirocumab. The odds

and 0.7% (17 patients) with alirocumab, and the odds ratio

ratio was 1.71 ( p=0.093 ) and was nearly significant. As

was 2.9, which was almost statistically significant (p=0.072).

for alirocumab, increased infection was not reported in a

Guillain-Barre syndrome (GBS) occurred in 3.1% (39 patients)

published RCT [11], but the data suggested the tendencywith placebo and 3.2% (78 patients) with alirocumab.

toward increase when all overseas trials included in the SBA
were combined.
The combined results of these 5 RCTs and one combined
data for alirocumab showed significant risk ratio ( RR=1.15,
95%CI: 1.03-1.29, p=0.017).

Although the difference is not significant, the incidence isextremely high in both groups. It is not clear what unserious
GBS is like, but this shows that the substantial number ofcases were reported.
An open trial on evolocumab [10] reported a significantly
higher incidence of neurocognitive adverse events in the

Serious concern over harm to the central nervous systemstudy group (0.3% vs 0.9%, OR3.4, p=0.015).

Neurological adverse events reported in a placebo
controlled RCT [11] on alirocumab are important. In
alirocumab group, ataxia, demyelination, dysarthria, Miller
Fisher syndrome (note), and optic neuritis occurred in 1
patient each ( no overlap). In other words, total 5 patients(0.32%) reportedly experienced neurological serious adverse
events (SAEs). On the other hand, in a placebo group, 2 casesof a neurological SAE were reported, and it was hypoesthesia.
Although no significant difference was observed infrequency (0.32% vs 0.25%), seriousness of the events should

Page  ・ MED CHECK - TIP April 2017/ Vol.3 No.7

Note: Miller Fisher syndrome is a subtype of Guillain-Barre
syndrome (GBS). In most cases, following upper respiratory
tract infection, extraocular muscle palsies, ataxia and lossof tendon reflexes acutely progress over 1 to 2 weeks andparalysis in the legs, a typical form which GBS begins with,is absent, and then they naturally improve [13].

Injury adverse events such as bruising occurred frequently.
In the Japanese clinical trial on alirocumab, injury adverse
events such as falls and fracture occurred in 1 patient (1.4%)
with placebo while they occurred in 17 patients (12%) withalirocumab. The odds ratio was 9.6 (p=0.009). In the placebogroup, the patient had only wound, but in the treatmentgroup, they experienced falls (6 patients), fracture (5 patients),
bruising (6 patients) and traffic accidents (2 patients). Lackof attention may be a cause of all these events. Increased

References
1) Japan Society for Lipid Nutrition、Guideline: Cholesterol for long life 20102) Japan Society for Lipid Nutrition、Guideline 2nd: Cholesterol for long life 2014
3) Hamazaki T, Okuyama H, Ogushi Y, Hama R. Towards a Paradigm
Shift in Cholesterol Treatment. A Re-examination of the Cholesterol
Issue in Japan. Ann Nutr Metab. 2015;66 Suppl 4:1-116. Free
https://www.karger.com/Article/Abstract/381654
4) Ravnskov U, Diamond DM, Hama R, Hamazaki T, Ogushi Y,
Okuyama H et al. Lack of an association or an inverse association
between low-density-lipoprotein cholesterol and mortality in theelderly: a systematic review. BMJ Open. 2016 Jun 12;6(6):e010401 Free
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908872/pdf/

injuries and increased neurological adverse events share thebmjopen-2015-010401.pdf

same root cause.

5) Evolocumab a)Summary Basis of approval,b)Review report by PMDA

In a trial on evolocumab enrolling patients with HeFH, only
1 case (1%) of bruising was reported with placebo while 9cases were reported with the evolocumab (p=0.18).

6) Alirocumab a)Summary Basis of approval,b)Review report by PMDA
7) Raal FJ, Honarpour N, Blom DJ et al(TESLA Investigators).
Inhibition of PCSK9 with evolocumab in homozygous familial
hypercholesterolaemia (TESLA Part B): a randomised, double-blind,placebo-controlled trial. Lancet. 2015;385(9965):341-50.
https://www.ncbi.nlm.nih.gov/pubmed/25282520

In practicePCSK9 inhibitors markedly lower LDL-cholesterol level,8) Raal FJ, Stein EA, Dufour R, et al (RUTHERFORD-2 Investigators)
PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial

but their harm outweighs their benefit. They especially cause

hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind,increased infection as well as impairment in cognition andplacebo-controlled trial. Lancet. 2015; 385(9965):331-40.

neurological function, which is probably associated withincreased injuries due to accidents. Having a high cholesterollevel is not a sickness, and does not warrant medical
intervention at first place. Even in patients with FH, harm ofcholesterol lowering agents outweighs their benefit.
For more information, refer to the Med Check-TIP No. 67

https://www.ncbi.nlm.nih.gov/pubmed/25282519
9) Blom DJ, Hala T, Bolognese M et al(DESCARTES Investigators) A
52-week placebo-controlled trial of evolocumab in hyperlipidemia. N
Engl J Med. 2014;370(19): 1809-19
https://www.ncbi.nlm.nih.gov/pubmed/24678979
10) Sabatine MS, Giugliano RP, Wiviott SD, et al (OSLER Investigators)
Efficacy and safety of evolocumab in reducing lipids andcardiovascular events. N Engl J Med. 2015;372(16):1500-9.
https://www.ncbi.nlm.nih.gov/pubmed/25773607[14].

11) Robinson JG, Farnier M, Krempf M et al (ODYSSEY LONG TERM

by the Med Check -TIP Editorial Team

Investigators) Efficacy and safety of alirocumab in reducing lipids
and cardiovascular events. N Engl J Med. 2015;372(16):1489-99.
https://www.ncbi.nlm.nih.gov/pubmed/25773378
12) Pfizer: Pfizer Discontinues Global Development of Bococizumab,
Its Investigational PCSK9 Inhibitor http://www.pfizer.com/news/
press-release/press-release-detail/pfizer_discontinues_global_devel
opment_of_bococizumab_its_investigational_pcsk9_inhibitor
13) Japanese Society of Neurology,Practice Guidelines for GuillainBarré Syndrome and Fisher Syndrome 2013 https://www.neurologyjp.org/guidelinem/gbs.html
14) Hama R. On the treatment for Familial Hypercholesterolemia.
MedCheckTIP 2016: 16(6): 122-3.

MED CHECK - TIP April 2017/ Vol.3 No.7 ・ Page TopicTop 1 most read for 5 month:paper on cholesterol
Lack of an association or an inverse association between

RCTs of cholesterol lowering
agents of different classes
were cancelled in succession

low-density-lipoprotein cholesterol and mortality in the

Lilly announced in October 2015 that they had

elderly: a systematic review: Ravnskov U, Diamond DM,

discontinued development of evacetrapib, a cholesterol

Hama R, Hamazaki T, Ogushi Y, Okuyama H et al. BMJ Openlowering agent [1].It is an inhibitor of cholesteryl ester

2016;6:e010401

transfer protein (CETP). The phase 3 trial had been conducted

http://bmjopen.bmj.com/content/6/6/e010401

worldwide including in Japan. However, Lilly accepted
the recommendation of the independent data monitoring

This was the top 1 most read paper for 5 months fromcommittee to terminate the Phase 3 trial due to insufficient

June to October 2016 and has been the top 2 most read for 4

efficacy of the agent (a low probability the study would achievemonths thereafter in the BMJ Open.

its primary endpoint) [1].

http://blogs.bmj.com/bmjopen/

CETP transfers cholesterol ester of HDL-cholesterol to
LDL. When CETP is inhibited, LDL-cholesterol decreases andAbstract

HDL-cholesterol increases. Because of this clear theoretical

Objective It is well known that total cholesterol becomes lessbasis, these agents were expected to achieve a large market

of a risk factor or not at all for all-cause and cardiovascularshare, following statin. The major pharmaceutical companies(CV) mortality with increasing age, but as little is known ascompeted for development of this class agent. However,to whether low-density lipoprotein cholesterol (LDL-C), one

evacetrapib has become the third CETP inhibitor whose

component of total cholesterol, is associated with mortality indevelopment was cancelled after reaching phase 3, the final

the elderly, we decided to investigate this issue.

stage of the development.

Setting, participants and outcome measures We sought

Torcetrapib ( Pfizer) was the first CETP inhibitor halted.

PubMed for cohort studies, where LDL-C had been

All 6 phase 3 RCTs were stopped and development wasinvestigated as a risk factor for all-cause and/or CV mortality

discontinued in 2006 when it was revealed that all-cause

in individuals ≥60 years from the general population.

mortality increased by 60

Results We identified 19 cohort studies including 30 cohorts

combination of torcetrapib and atorvastatin compared with

with a total of 68 094 elderly people, where all-cause

atorvastatin alone [2].Development of dalcetrapib was alsomortality was recorded in 28 cohorts and CV mortality in 9

canceled because it significantly increased CRP and bloodcohorts. Inverse association between all-cause mortality andpressure compared with placebo, and was not expected

LDL-C was seen in 16 cohorts (in 14 with statistical significance)

to improve cardiovascular events [3]. The third case isrepresenting 92 % of the number of participants, where thisevacetrapib. Lilly commented the study was cancelled notassociation was recorded. In the rest, no association was

because of safety reason [1]. It seems there was no difference

found. In two cohorts, CV mortality was highest in the lowest

in cardiovascular events [4]. However, no detailed adverse

LDL-C quartile and with statistical significance; in seven

event data are available yet.

cohorts, no association was found.

% in the group receiving a

Development of PCSK9 inhibitor was stopped recently.

Conclusions High LDL-C is inversely associated with mortality

Pfizer discontinued development of bococizumab because

in most people over 60 years. This finding is inconsistent

it was not likely to provide value to patients, physicians, orwith the cholesterol hypothesis (ie, that cholesterol, particularly

shareholders. On November 1, 2016 they announced the

LDL-C, is inherently atherogenic ). Since elderly people withdiscontinuation of two ongoing long-term cardiovascularhigh LDL-C live as long or longer than those with low LDL-C,

outcome studies. Pfizer has observed an attenuation of LDL-

our analysis provides reason to question the validity of thecholesterol lowering over time, as well as a higher level ofcholesterol hypothesis. Moreover, our study provides theimmunogenicity ( antibody production ) and higher rate ofrationale for a re-evaluation of guidelines recommending

injection-site reactions [5]. However, it is unknown whether

pharmacological reduction of LDL-C in the elderly as aincidence of infection and neuropathy were frequent like twocomponent of cardiovascular disease prevention strategies

other PCSK9 inhibitors (cf. p 6~ and Editorial: p2)(see also Editorial:

p2.)

Page 10 ・ MED CHECK - TIP April 2017/ Vol.3 No.7

References
1) Eli Lilly and Company：
http://lilly.mediaroom.com/index.php?s=9042&item=137476
2) https://en.wikipedia.org/wiki/Torcetrapib3) Schwartz GG et al. N Engl J Med. 2012:;367(22):2089-99
4) https://en.wikipedia.org/wiki/Evacetrapib5) Pfizer 2016.11.1
http://www.pfizer.com/news/press-release/press-release-detail/pfizer_discontinues_global_development_of_bococizumab_its_in
vestigational_pcsk9_inhibitor

M
C

ED

HECK

The Informed Prescriber
2017

Vol.3

No.7

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD); TANIDA, Noritoshi (MD)Managing Editor: SAKAGUCHI, Keiko
Editorial Staff: NAKANISHI,Takeaki(Pharmacist); OHTSU,
Fumiko.(Pharmacist) ; TAKANO, Yoshihiko(MD[ pediatrician ]/Pharmacist) ; YANAGI, Motokazu (MD); YASUDA, Yoshinobu(Pharmacist)
Translators: NAKAMURA, Akari ; TAKAMACHI, Koji

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