Transcript Effect of ALN-PCS treatment on serum LDL cholesterol

Journal Club
Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR,
Sutherland JE, Hutabarat RM, Clausen VA, Karsten V, Cehelsky J, Nochur SV, Kotelianski V,
Horton J, Mant T, Chiesa J, Ritter J, Munisamy M, Vaishnaw AK, Gollob JA, Simon A.
Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin
type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a
randomised, single-blind, placebo-controlled, phase 1 trial.
Lancet. 2013 Oct 1. pii: S0140-6736(13)61914-5. doi: 10.1016/S0140-6736(13)61914-5.
Ly TT, Nicholas JA, Retterath A, Lim EM, Davis EA, Jones TW.
Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs
standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a
randomized clinical trial.
JAMA. 2013 Sep 25;310(12):1240-7. doi: 10.1001/jama.2013.277818.
2013年10月17日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文 坂下 杏奈
Matsuda, Masafumi, Sakashita, Anna
Autosomal dominant hypercholesterolemia (ADH;
OMIM144400), a risk factor for coronary heart
disease, is characterized by an increase in lowdensity lipoprotein cholesterol levels that is
associated with mutations in the genes LDLR
(encoding low-density lipoprotein receptor) or APOB
(encoding apolipoprotein B). We mapped a third
locus associated with ADH, HCHOLA3 at 1p32, and
now report two mutations in the gene PCSK9
(encoding proprotein convertase subtilisin/kexin
type 9) that cause ADH. PCSK9 encodes NARC-1
(neural apoptosis regulated convertase), a newly
identified human subtilase that is highly expressed
in the liver and contributes to cholesterol
homeostasis.
Nature Genetics 34, 154 - 156 (2003)
PCSK9 (neural apoptosis-regulated convertase, NARC-1) is a 692-residue
extracellular protein representing the 9th member of the secretory subtilase
family expressed primarily in the kidneys, liver and intestines.
Genetic studies mapped PCSK9 along with LDLR and APOB to cause autosomal
dominant hypercholesterolemia (ADH). Gain-of-function mutations increased
plasma levels of low-density lipoprotein cholesterol (LDL-C), whereas nonsense or
missense (loss-of-function) mutations, which interfere with folding or secretion of
PCSK9, led to a reduction of plasma levels of LDL-C and an 88% decrease in the
risk of coronary heart disease (CHD).
http://caltagmedsystems.blogspot.jp/2012/04/pcsk9-attractive-drug-target-for.html
抗体治療！！
single ascending-dose studies of REGN727
N Engl J Med 2012;366:1108-18.
抗体治療+スタチン
N Engl J Med 2012;367:1891-900. DOI: 10.1056/NEJMoa1201832
Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa (Prof F J Raal MD); Lipid
Clinic, Heart Institute (InCor) University of Sao Paulo Medical School, Sao Paulo, Brazil (R D Santos MD); Division
of Lipidology, Department of Medicine, University of Cape Town, Cape Town, South Africa (D J Blom MD, Prof A D
Marais MD); Department of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University,
Taipei, Taiwan (M-J Charng MD); Division of Atherosclerosis and Lipoprotein Disorders, Presbyterian Center for
Preventative Cardiology, Charlotte, NC, USA (W C Cromwell MD); Charles Dent Metabolic Unit, University
College London Hospitals, London, UK (R H Lachmann MRCP); Universite de Montreal, ECOGENE-21 Clinical
Research Center and Lipid Clinic, Chicoutimi, Canada (D Gaudet MD); Department of Cardiology, National Heart
Centre, Singapore (J L Tan MB BS); Biomedical Data Sciences and Informatics, Genzyme Corporation, Cambridge,
MA, USA (S Chasan-Taber PhD); and Isis Pharmaceuticals, Carlsbad, CA, USA (D L Tribble PhD, J D Flaim PhD,
S T Crooke MD)
Lancet 2010; 375: 998–1006
KYNAMROTM (mipomersen sodium)
KYNAMROTM is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis
Alnylam Pharmaceuticals, Cambridge, MA, USA (K Fitzgerald PhD, M FrankKamenetsky PhD, S Shulga-Morskaya MSc, A Liebow BS, B R Bettencourt PhD, J E
Sutherland PhD, R M Hutabarat PhD, V A Clausen PhD, V Karsten PhD, J Cehelsky
MBA, S V Nochur PhD, V Kotelianski MD, A K Vaishnaw MD, J A Gollob MD, A Simon
MD); Internal Medicine and Molecular Genetics, University of Texas South Western,
Dallas, TX, USA (J Horton MD); Quintiles Drug Research Unit at Guy’s Hospital,
London, UK (T Mant MD, J Ritter MD); and Covance Clinical Research Unit, Leeds,
UK (J Chiesa MD, M Munisamy MD)
www.thelancet.com Published online October 3, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61914-5
Background Proprotein convertase
subtilisin/kexin type 9 (PCSK9) binds to LDL
receptors, leading to their degradation.
Genetics studies have shown that loss-offunction mutations in PCSK9 result in
reduced plasma LDL cholesterol and
decreased risk of coronary heart disease.
We aimed to investigate the safety and
efficacy of ALN-PCS, a small interfering
RNA that inhibits PCSK9 synthesis, in
healthy volunteers with raised cholesterol
who were not on lipid-lowering treatment.
Methods We did a randomised, single-blind, placebocontrolled, phase 1 dose-escalation study in healthy
adult volunteers with serum LDL cholesterol of 3·00
mmol/L or higher. Participants were randomly assigned
in a 3:1 ratio by computer algorithm to receive one dose
of intravenous ALN-PCS (with doses ranging from 0·015
to 0·400 mg/kg) or placebo. The primary endpoint was
safety and tolerability of ALN-PCS. Secondary endpoints
were the pharmacokinetic characteristics of ALN-PCS
and its pharmacodynamic effects on PCSK9 and LDL
cholesterol. Study participants were masked to
treatment assignment. Analysis was per protocol and we
used ANCOVA to analyse pharmacodynamic endpoint
data. This trial is registered with ClinicalTrials.gov,
number NCT01437059.
On the first day of dosing (day 1), all
monkeys were given a single 15 min
or 60 min i.v. infusion of ALN-PCS.
Blood samples were collected for
pharmacodynamic analysis at various
time points after dose administration.
Serum chemistry experiments were
carried out at Charles River
Laboratories via direct measurements
of LDLc, HDLc, TGs, or Tc on the
Olympus AU2700.
Figure 2: Trial profile
On the evening before and the morning of dosing, all participants
received oral corticosteroids, histamine receptor (H1 and H2) blockers,
and paracetamol (para-acetylaminophenol)to reduce the potential for
infusion-related reactions. Specifically, participants received
dexamethasone (8 mg the evening before dosing and 20 mg 60 min before
the start of infusion of ALN-PCS or placebo) and paracetamol (500 mg
orally the evening before dosing and again 30–60 min before the start of
infusion). They also received an oral H2 blocker (ranitidine 150 mg or
famotidine 20 mg) and an H1 blocker (10 mg cetirizine) the evening before
dosing and again 30–60 min before the start of infusion.
A single 1 h intravenous infusion of ALN-PCS or placebo (normal saline)
was given to all participants. Six different doses (0・015, 0・045, 0・090, 0・
150, 0・250, and 0・400 mg/ kg) of ALN-PCS were assessed. Each dose
cohort consisted of four participants randomly assigned in a 3:1 ratio of
ALN-PCS treatment to placebo. Two additional cohorts of four
participants (randomly assigned in the same ratio) were given the 0・250
and 0・400 mg/kg doses of ALN-PCS (or placebo). Dose was escalated
after satisfactory review of all safety information by the safety review
committee.
Figure 3
Figure 3:
Effect of ALN-PCS treatment on plasma PCSK9 concentration
(A) Mean plasma PCSK9 concentrations relative to baseline and placebo. Error bars are
SEs. PCSK9 concentrations were normalised per-individual to baseline and then perday to placebo group means. For 0・045 mg/kg group at day 10, data from only one of
three participants were available; for days 10 and 17, blood samples were only available
for the 0・250 mg/kg and 0・400 mg/kg dose groups and their affiliated placebo
participants, so values at these days are derived from or normalised to data from two of
eight placebo participants.
(B) Maximum plasma PCSK9 percentage reduction after treatment with ALN-PCS.
Maximum reductions were determined per individual, at lowest PCSK9 value from days
1–28. Data are least-square means and error bars are 95% CIs, determined from
analysis of covariance with baseline PCSK9 as covariate. *p<0・05; **p<0・001 (Tukey’s
post-hoc tests vs placebo). Least-square mean PCSK9 reductions per dose group were
estimated via a linear model with dose group as a factor and baseline PCSK9 as a
covariate. The overall model was significant (F=8・821; p=2・307x10–5).
(C) Mean plasma PCSK9 concentrations relative to baseline. Error bars are SEs.
(D) Mean maximum percentage reductions in PCSK9 and LDL cholesterol in participants
given 0・150, 0・250, and 0・400 mg/kg ALN-PCS, grouped by low, intermediate, and high
baseline PCSK9 concentrations (<0・5, within 0・5, and >0・5 SDs from the mean,
respectively). Error bars are SEs.
Figure 4
Figure 4:
Effect of ALN-PCS treatment on serum LDL cholesterol
(A) Mean serum LDL cholesterol concentrations relative to baseline and placebo. Error
bars are SEs. LDL cholesterol concentrations were normalised per-individual to baseline
and then per-day to placebo group means. For 0・045 mg/kg group at day 10, data from
only one of three participants were available; for days 10 and 17, blood samples were
only available for the 0・250 mg/kg and 0・400 mg/kg dose groups and their affiliated
placebo participants, so values at these days are derived from or normalised to data
from two of eight placebo participants.
(B) Maximum serum LDL cholesterol percentage reductions after treatment with ALNPCS. Maximum reductions were determined per individual, at nadir LDL cholesterol
value from days 1–28. Data are least-square means and error bars are 95% CIs,
determined from analysis of covariance with baseline LDL cholesterol as covariate.
*p<0・01 (Tukey’s post hoc test vs placebo). Least-square mean LDL cholesterol
reductions per dose group were estimated via a linear model with dose group as a factor
and baseline LDL cholesterol as a covariate. The overall model was significant (F=4・
888; p=0・0015).
(C) Mean serum LDL cholesterol concentrations relative to baseline and placebo. Error
bars are SEs. For days 10 and 17, blood samples were only available for the 0・250
mg/kg and 0・400 mg/kg dose groups and their affiliated placebo participants, so values
at these days are derived from or normalised to data from two of eight placebo
participants.
(D) Mean serum LDL cholesterol concentrations at per-individual nadir from days 1–28.
Error bars are SEs.
Findings Of 32 participants, 24 were randomly allocated
to receive a single dose of ALN-PCS (0・015 mg/kg [n=3],
0・045 mg/kg [n=3], 0・090 mg/kg [n=3], 0・150 mg/kg
[n=3], 0・250 mg/kg [n=6], or 0・400 mg/kg [n=6]) and
eight to placebo. The proportions of patients aff ected by
treatment-emergent adverse events were similar in the
ALN-PCS and placebo groups (19 [79%] vs seven
[88%]). ALN-PCS was rapidly distributed, with peak
concentration and area under the curve (0 to last
measurement) increasing in a roughly dose-proportional
way across the dose range tested. In the group given 0・
400 mg/kg of ALN-PCS, treatment resulted in a mean
70% reduction in circulating PCSK9 plasma protein
(p<0・0001) and a mean 40% reduction in LDL
cholesterol from baseline relative to placebo (p<0・0001).
Interpretation Our results suggest that inhibition
of PCSK9 synthesis by RNA interference (RNAi)
provides a potentially safe mechanism to reduce
LDL cholesterol concentration in healthy
individuals with raised cholesterol. These results
support the further assessment of ALN-PCS in
patients with hypercholesterolaemia, including
those being treated with statins. This study is the
first to show an RNAi drug being used to affect a
clinically validated endpoint (ie, LDL cholesterol)
in human beings.
Funding Alnylam Pharmaceuticals.
Message
健常者32人を対象に、前駆タンパク質転換酵素サブチリ
シン/ケキシン9型（PCSK9）合成を阻害するRNA干渉に基
づいた新薬ALN-PCSを第1相用量漸増試験で評価。有害事
象発生率はプラセボ群と同等。ALN-PCS群でのPCSK9合成
阻害が示唆され、0.400mg/kg投与群ではLDL-Cの平均
40％低下が見られた。
LDL-C低下に使ってゆくのだろうか？前駆たんぱく質転
換酵素サブチリシン/ケキシン9型（PCSK9）モノクロー
ナル抗体SAR236553の併用効果試験ではLDLコレステロー
ル値のベースラインからの低下は、アトルバスタチン単
独群17.3％、10mg＋抗体併用群66.2％、80 mg＋抗体併
用群73.2％もあったが。
Insulin pump therapy with automated insulin suspension
10. Choudhary P, Shin J,Wang Y, et al. Insulin pump therapy with
automated insulin suspension in response to hypoglycemia:
reduction in nocturnal hypoglycemia in those at greatest risk.
Diabetes Care. 2011;34(9):2023-2025.
11. Ly TT, Nicholas JA, Retterath A, et al. Effect of sensoraugmented insulin pump therapy and automated insulin
suspension vs standard insulin pump therapy on hypoglycemia in
patients with type 1 diabetes: a randomized clinical trial. JAMA.
2013;310(12):1240-1247.
15. Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based
insulin-pump interruption for reduction of hypoglycemia. N Engl J
Med. 2013;369(3):224-232.
16. Choudhary P, Ramasamy S, Gallen G, et al. Reduction in
severe hypoglycaemia with the use of continuous glucose
monitoring in clinical practice. Diabetic Med. 2013;30(suppl
1):398.
MiniMed® 530G with Enlite®
MINNEAPOLIS – September 27, 2013 –Medtronic, Inc. (NYSE:MDT) today announced the U.S. Food and Drug
Administration (FDA) approval of the MiniMed® 530G with Enlite®, a breakthrough, first-generation artificial
pancreas system with Threshold Suspend automation for people with diabetes. Medtronic’s system is the first in
the United States that can automatically stop insulin delivery when sensor glucose values reach a preset level and
when the patient doesn't respond to the Threshold Suspend alarm. The MiniMed 530G system incorporates the
new Enlite sensor, Medtronic’s most accurate and comfortable continuous glucose sensor with a 31 percent
improvement in overall accuracy from the previous generation.i
The MiniMed 530G system was approved for use by people with diabetes ages 16 and older. Medtronic will
conduct a post-approval study including children ages two and older. The Enlite sensor can be worn for six days.
As a condition of approval, in addition to the post-approval study, Medtronic will engage in direct patient follow up
and will make certain manufacturing accommodations.
These commitments are consistent with the product approval by the FDA and an accompanying warning letter
issued to Medtronic on Sept. 19, 2013. Medtronic has already addressed many of the observations noted in the
warning letter and is committed to resolving the remaining observations as quickly as possible and in accordance
with the product approval requirements. Medtronic is committed to providing safe and effective products for people
with diabetes. Medtronic will begin ramping up production immediately to prepare for a launch of the MiniMed
530G in the next several weeks.
Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children,
Perth,Western Australia, Australia (Ly, Nicholas, Davis, Jones); Telethon Institute for Child Health
Research, Centre for Child Health Research, The University ofWestern Australia, Perth,Western
Australia, Australia (Ly, Nicholas, Retterath, Davis, Jones); School of Paediatrics and Child Health,
The University ofWestern Australia, Perth,Western Australia, Australia (Ly, Davis, Jones); PathWest
Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands,Western Australia, Australia
(Lim); Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital,
Nedlands,Western Australia, Australia (Lim).
JAMA. 2013;310(12):1240-1247. doi:10.1001/jama.2013.277818
IMPORTANCE Hypoglycemia is a critical
obstacle to the care of patients with type 1
diabetes. Sensor-augmented insulin pump
with automated low-glucose insulin
suspension has the potential to reduce the
incidence of major hypoglycemic events.
OBJECTIVE To determine the incidence of
severe and moderate hypoglycemia with
sensor-augmented pump with low-glucose
suspension compared with standard insulin
pump therapy.
DESIGN, SETTING, AND PARTICIPANTS A
randomized clinical trial involving 95 patients with
type 1 diabetes, recruited from December 2009 to
January 2012 in Australia.
INTERVENTIONS Patients were randomized to
insulin pump only or automated insulin suspension
for 6 months.
MAIN OUTCOMES AND MEASURES The primary
outcome was the combined incidence of severe
(hypoglycemic seizure or coma) and moderate
hypoglycemia (an event requiring assistance for
treatment). In a subgroup, counterregulatory
hormone responses to hypoglycemia were assessed
using the hypoglycemic clamp technique.
Patients in the low-glucose suspension group began
using the sensor-augmented pump (Medtronic
Paradigm Veo System, Medtronic Minimed) with
automated insulin suspension when the sensor
glucose reached a preset low-glucose threshold of
60mg/dL (to convert glucose to mmol/L, multiply by
0.0555). As sensor glucose decreases to this level,
the pump emits an alarm. If the patient does not
respond to the alarm, insulin delivery is suspended
for up to 2 hours, after which standard basal insulin
delivery resumes. The patient may intervene at any
stage throughout this 2-hour period to either
continue suspension or resume insulin delivery.
RESULTS Of the 95 patients randomized, 49 were assigned to the
standard-pump (pump-only) therapy and 46 to the low-glucose
suspension group. The mean (SD) age was 18.6 (11.8) years;
duration of diabetes, 11.0 (8.9) years; and duration of pump therapy,
4.1 (3.4) years. The baseline rate of severe and moderate
hypoglycemic events in the pump-only group was 20.7 vs 129.6
events per 100 patient months in the low-glucose suspension group.
After 6 months of treatment, the event rates decreased from 28 to 16
in the pump-only group vs 175 to 35 in the low-glucose suspension
group. The adjusted incidence rate per 100 patient-months was 34.2
(95%CI, 22.0-53.3) for the pump-only group vs 9.5 (95%CI, 5.2-17.4)
for the low-glucose suspension group. The incidence rate ratio was
3.6 (95%CI, 1.7-7.5; P <.001). There was no change in glycated
hemoglobin in either group: mean, 7.4 (95% CI, 7.2-7.6) to 7.4
(95%CI, 7.2-7.7) in the pump-only group vs mean, 7.6 (95%, CI, 7.47.9) to 7.5 (95%CI, 7.3-7.7) in the low-glucose suspension group.
Counter regulatory hormone responses to hypoglycemia were not
changed. There were no episodes of diabetic ketoacidosis or
hyperglycemia with ketosis.
CONCLUSIONS AND RELEVANCE
Sensor-augmented pump therapy with
automated insulin suspension reduced
the combined rate of severe and
moderate hypoglycemia in patients with
type 1 diabetes.
TRIAL REGISTRATION
anzctr.org.au Identifier: ACTRN12610000024044
Taken together, the data from all these studies, demonstrate the ability of
sensor-augmented insulin pumps with threshold suspension function to
provide a significant reduction in severe hypoglycemia. These data can now
be used to evaluate the health economic benefits of this therapy and also
can be used by clinicians, payers, and regulatory authorities to help make
this therapy and technology more widely available to patients who struggle
daily with hypoglycemia.
JAMA September 25, 2013 Volume 310, Number 12 1235
Message
最近低血糖にならないようにポンプ治療で
はポンプを止める機構があるのがよいとい
うようである。ポンプ治療といってもイン
スリンは皮下注射なので2時間くらい止める
くらいがよいのであろう。
２年くらい前からヨーロッパで認可されて
いたが、エンライトセンサーになり今年９
月27日に米国FDAで認可された。来月くらい
からおそらく実臨床で用いられるのだろう
（米国で）。