CONTACTS
SUBJECTS
Research Clinical Trials Lower Cholesterol Without Statin Drugs Amge
4003 -
4003 - ..
4004 - Summary/Objective
4005 -
400501 - Follow up ref SDS 4 545O, ref SDS 3 PS4M.
400502 -
400503 - Evolocumab may be candidate to replace Atorvastatin and Ezetimibe when
400504 - efficacy of current regimine begins to wain, based on history of PCSK9
400505 - alternative drugs to statins for lowering cholesterol toward reducing
400506 - risk of CVD. ref SDS 0 FW9J New article published by New England
400507 - Journal of Medicine 2 days ago on 140329, reports clinical trials show
400508 - new Amgen drug "evolocumab" applies PCSK9 technology to lower LDL-C in
400509 - the range of 60%. ref SDS 0 925I More importantly, these results
400510 - persisted over 52-week period of study. ref SDS 0 W46H Study claims
400511 - significant decrease in triglycerides, but does not state the amount,
400512 - and reports evolocumab increases HDL only 5%. ref SDS 0 6N8J There is
400513 - no discussion of LDL-P.
400514 -
400515 -
400516 -
400517 -
400518 -
400520 - ..
4006 -
4007 -
4008 - Background
4009 -
400901 - On 101117 1018 Anacetrapib cholesterol non-statin drug lower LDL
400902 - cholesterol article reports. ref SDS 1 U75H
400904 - ..
400905 - On 120325 1312 Amgen and Regeneron developing PCSK9 drugs that cut
400906 - cholesterol through a new strategy, by blocking a protein called
400907 - PCSK9, article reported. ref SDS 2 GG5I
400909 - ..
400910 - On 131017 1000 Regeneron and Sanofi (evidently joint venture
400911 - project)... developing PCSK9 drug Alirocumab cuts LDL-C by 47.2%
400912 - article published by Reuters. ref SDS 3 6T5H
400914 - ..
400915 - On 140331 2137 Amgen developing PCSK9 drug evolocumab lowers LDL-C
400916 - 66%, article by Tech Times, ref SDS 0 LO6G; however, this figure is
400917 - not supported in the cited article published by New England Journal of
400918 - Medicine. ref SDS 0 MT5M
400920 - ..
400921 - On 140331 2137 original article published New England Journal of
400922 - Medicine reporting Amgen developing PCSK9 drug evolocumab lowers LDL-C
400923 - 60%. ref SDS 0 1V4F Study claims significant decrease in
400924 - triglycerides, but does not state the amount, and reports evolocumab
400925 - increases HDL only 5%. ref SDS 0 6N8J There is no discussion of
400926 - LDL-P, which research has previously indicated has the strongest
400927 - association with CVD risk, reported on 131125 0005. ref SDS 5 FI3G
400928 -
400929 -
400930 -
400931 -
400933 - ..
4010 -
4011 -
4012 - Progress
4013 -
401301 - Another article published...
401302 -
401303 - 1. Tech Times
401304 -
401305 - http://www.techtimes.com/articles/4984/20140401/new-experimental-cholesterol-drug-by-amgen-may-be-better-than-lipitor.htm
401307 - ..
401308 - New experimental cholesterol drug by Amgen may be better than Lipitor
401310 - ..
401311 - By Rhodi Lee, Tech Times April 1, 12:20 AM
401312 -
401313 - 1. Lipitor, which belongs to a group of drugs known as
401314 - statins, reduces the amount of bad cholesterol in the body
401315 - which in turn helps reduce a person's risks of heart
401316 - attack, stroke and other heart problems. It is especially
401317 - helpful to people with type 2 diabetes and coronary heart
401318 - disease but while the drug is widely recommended and used,
401319 - there are people who do not get much from taking Lipitor or
401320 - cannot simply tolerate the drug.
401322 - ..
401323 - 2. An experimental drug developed by biopharmaceutical company
401324 - Amgen Inc., however, may soon provide an alternative and
401325 - possibly even a better option to Lipitor for this group of
401326 - patients. The drug called evolocumab mimics the
401327 - cholesterol-reducing effects of a genetic mutation to lower
401328 - low-density lipoprotein (LDL), the bad cholesterol in the
401329 - blood. [...see report in New England Journal of Medicine,
401330 - published March 30, 2014, below. ref SDS 0 1V4F...]
401332 - ..
401333 - 3. Clinical trials show that evolocumab is effective in
401334 - reducing levels of blood fat. Data from three large
401335 - studies of the drug presented at the 63rd Annual Scientific
401336 - Session of the American College of Cardiology (ACC)
401337 - Saturday have shown that patients who received evolocumab
401338 - reduced their bad cholesterol by as much as 66 percent.
401340 - ..
401341 - Source for 66% not clear in the record.
401343 - ..
401344 - Tech Times article continues...
401345 -
401346 - 4. In the Descartes study involving subjects with high
401347 - cholesterol levels, subjects who received monthly
401348 - evolocumab injections for one year saw a 57 percent
401349 - reduction in bad cholesterol compared to subjects who
401350 - received placebo. The drug was also found beneficial to
401351 - patients already on Merck's cholesterol drug, Zetia and
401352 - Pfizer's Lipitor reducing their LDL level by an additional
401353 - 49 percent.
401355 - ..
401356 - 5. In the Mendel study published in the New England Journal
401357 - of Medicine March 29, high cholesterol patients who did
401358 - not receive other treatments slashed their bad cholesterol
401359 - level by up to 57 percent after getting evolocumab for
401360 - three months. The reduction is up to 40 percent more when
401361 - compared to those who take Zetia.
401363 - ..
401364 - 6. Meanwhile, in the Rutherford study involving patients with
401365 - an inherited condition that causes them to have high
401366 - levels of cholesterol , three months of evolocumab
401367 - combined with statins and other cholesterol reducing drugs
401368 - resulted in up to 66 percent bad cholesterol reduction.
401370 - ..
401371 - 7. "At 52 weeks, evolocumab added to diet alone, to low-dose
401372 - atorvastatin, or to high-dose atorvastatin with or without
401373 - ezetimibe significantly reduced LDL cholesterol levels in
401374 - patients with a range of cardiovascular risks,"
401375 - investigators of the evolocumab studies wrote. ref SDS 0
401376 - R57I
401377 -
401378 -
401380 - ..
401381 - Referenced article...
401382 -
401383 - 2. The New England Journal of Medicine
401384 -
401385 - A 52-Week Placebo-Controlled Trial of Evolocumab in
401386 - Hyperlipidemia
401387 -
401388 - http://www.nejm.org/doi/full/10.1056/NEJMoa1316222?query=featured_home&#t=abstract
401390 - ..
401391 - Dirk J. Blom, M.D., Ph.D., Tomas Hala, M.D., Michael
401392 - Bolognese, M.D., Michael J. Lillestol, M.D., Phillip D. Toth,
401393 - M.D., Lesley Burgess, M.B., B.Ch., M.Med., Ph.D., Richard
401394 - Ceska, M.D., Ph.D., Eli Roth, M.D., Michael J. Koren, M.D.,
401395 - Christie M. Ballantyne, M.D., Maria Laura Monsalvo, M.D., Kate
401396 - Tsirtsonis, M.Sc., Jae B. Kim, M.D., Rob Scott, M.D., Scott M.
401397 - Wasserman, M.D., and Evan A. Stein, M.D., Ph.D. for the
401398 - DESCARTES Investigators
401400 - ..
401401 - March 29, 2014DOI: 10.1056/NEJMoa1316222
401403 - ..
401404 - Abstract...
401405 -
401406 - 1. Background
401407 -
401408 - Evolocumab, a monoclonal antibody that inhibits proprotein
401409 - convertase subtilisin/kexin type 9 (PCSK9), significantly
401410 - reduced low-density lipoprotein (LDL) cholesterol levels
401411 - in phase 2 studies. We conducted a phase 3 trial to
401412 - evaluate the safety and efficacy of 52 weeks of treatment
401413 - with evolocumab.
401415 - ..
401416 - 2. Methods
401417 -
401418 - We stratified patients with hyperlipidemia according to the
401419 - risk categories outlined by the Adult Treatment Panel III
401420 - of the National Cholesterol Education Program. On the
401421 - basis of this classification, patients were started on
401422 - background lipid-lowering therapy with diet alone or diet
401423 - plus atorvastatin at a dose of 10 mg daily, atorvastatin at
401424 - a dose of 80 mg daily, or atorvastatin at a dose of 80 mg
401425 - daily plus ezetimibe at a dose of 10 mg daily, for a run-in
401426 - period of 4 to 12 weeks. Patients with an LDL cholesterol
401427 - level of 75 mg per deciliter (1.9 mmol per liter) or higher
401428 - were then randomly assigned in a 2:1 ratio to receive
401429 - either evolocumab (420 mg) or placebo every 4 weeks. The
401430 - primary end point was the percent change from baseline in
401431 - LDL cholesterol, as measured by means of
401432 - ultracentrifugation, at week 52.
401434 - ..
401435 - 3. RESULTS
401436 -
401437 - Among the 901 patients included in the primary analysis,
401438 - the overall least-squares mean (+/- SE) reduction in LDL
401439 - cholesterol from baseline in the evolocumab group, taking
401440 - into account the change in the placebo group, was 57.0 +/-
401441 - 2.1% (P<0.001). The mean reduction was 55.7 +/- 4.2% among
401442 - patients who underwent background therapy with diet alone,
401443 - 61.6 +/- 2.6% among those who received 10 mg of
401444 - atorvastatin, 56.8 +/- 5.3% among those who received 80 mg
401445 - of atorvastatin, and 48.5 +/- 5.2% among those who received
401446 - a combination of 80 mg of atorvastatin and 10 mg of
401447 - ezetimibe (P<0.001 for all comparisons). Evolocumab
401448 - treatment also significantly reduced levels of
401449 - apolipoprotein B, non?high-density lipoprotein cholesterol,
401450 - lipoprotein(a), and triglycerides. The most common adverse
401451 - events were nasopharyngitis, upper respiratory tract
401452 - infection, influenza, and back pain.
401454 - ..
401455 - 4. CONCLUSIONS
401456 -
401457 - At 52 weeks, evolocumab added to diet alone, to low-dose
401458 - atorvastatin, or to high-dose atorvastatin with or without
401459 - ezetimibe significantly reduced LDL cholesterol levels in
401460 - patients with a range of cardiovascular risks.
401462 - ..
401463 - Evolocumab may be candidate to replace Atorvastatin and Ezetimibe
401464 - when efficacy of current regimine begins to wain.
401466 - ..
401467 - Evolocumab study continues...
401468 -
401469 - (Funded by Amgen; DESCARTES ClinicalTrials.gov number,
401470 - NCT01516879.)
401472 - ..
401473 - Article
401474 -
401475 - 1. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a
401476 - serine protease that is produced predominantly in the
401477 - liver, is secreted into the plasma and plays a major role
401478 - in regulating levels of low-density lipoprotein (LDL)
401479 - cholesterol by binding to hepatic LDL receptors and
401480 - promoting their degradation.1,2 In short-term
401481 - (8-to-12-week), placebo-controlled, phase 2 trials, PCSK9
401482 - inhibitors have been shown to significantly reduce LDL
401483 - cholesterol levels.3-9 Four of these trials involved the
401484 - use of evolocumab (AMG 145), a fully human monoclonal PCSK9
401485 - antibody, and assessed different doses and regimens in
401486 - diverse patient populations with varying lipid phenotypes,
401487 - cardiovascular disease risks, and baseline use of
401488 - lipid-lowering therapy.3-6 A longer-term, open-label
401489 - extension study involving 1104 patients from the phase 2
401490 - trials compared evolocumab administered monthly (at a dose
401491 - of 420 mg) plus standard medical care with standard medical
401492 - care alone.10 In the Durable Effect of PCSK9 Antibody
401493 - Compared with Placebo Study (DESCARTES), a randomized,
401494 - double-blind, placebo-controlled, phase 3 trial, we
401495 - compared evolocumab with placebo in patients with
401496 - hyperlipidemia who received the study drug for 52 weeks
401497 - after a run-in period of 4 to 12 weeks of background
401498 - lipid-lowering therapy.
401499 -
401501 - ..
401502 - 2. Methods
401503 -
401504 - 1. Study Design and Oversight
401505 -
401506 - This study was conducted at 88 centers in nine
401507 - countries (for details, see the Supplementary Appendix,
401508 - available with the full text of this article at
401509 - NEJM.org). Amgen sponsored and designed the trial (the
401510 - latter in collaboration with the last author) and was
401511 - responsible for data collection and analysis. Local
401512 - institutional review boards approved the study
401513 - protocol, which is available at NEJM.org. The first
401514 - draft of the manuscript was written by the first and
401515 - last authors, and Amgen provided editorial assistance.
401516 - All the coauthors participated in subsequent revisions
401517 - of the manuscript. The academic authors had full
401518 - access to the data and vouch for their accuracy and
401519 - completeness, for the analyses as presented, and for
401520 - the fidelity of the study to the trial protocol.
401522 - ..
401523 - 2. Patients
401524 -
401525 - Patients were eligible for enrollment in the trial if
401526 - they were adults 18 to 75 years of age with an LDL
401527 - cholesterol level of 75 mg per deciliter (1.94 mmol
401528 - per liter) or higher and a fasting triglyceride level
401529 - of 400 mg per deciliter (4.52 mmol per liter) or
401530 - lower. Exclusion criteria were heart failure, recent
401531 - myocardial infarction, recent or planned
401532 - revascularization procedure, uncontrolled
401533 - hypertension, hyperthyroidism or hypothyroidism,
401534 - moderate-to-severe renal dysfunction, and active liver
401535 - disease or hepatic dysfunction. Full details of the
401536 - trial inclusion and exclusion criteria are provided in
401537 - the Supplementary Appendix. All patients provided
401538 - written informed consent before entering the trial.
401540 - ..
401541 - 3. Study Procedures
401542 -
401543 - 1. Patients who met eligibility criteria and, after
401544 - receiving a 6-ml test placebo injection, agreed to
401545 - undergo a regimen of monthly subcutaneous
401546 - injections for a year entered a run-in period of 4
401547 - to 12 weeks, during which open-label background
401548 - lipid-lowering therapy was administered (Figure S1
401549 - and S2 in the Supplementary Appendix). All patients
401550 - were counseled on the components of the Therapeutic
401551 - Lifestyle Changes diet, as outlined by the Adult
401552 - Treatment Panel III (ATP III) of the National
401553 - Cholesterol Education Program.11 On the basis of
401554 - the screening LDL cholesterol level, previous use
401555 - of statin therapy, and cardiovascular risk (as
401556 - determined by the ATP-III guidelines), we assigned
401557 - all patients to one of four lipid-lowering
401558 - regimens: diet alone, diet with 10 mg of
401559 - atorvastatin daily, diet with 80 mg of atorvastatin
401560 - daily, or diet with 80 mg of atorvastatin plus 10
401561 - mg of ezetimibe daily.
401563 - ..
401564 - 2. At the conclusion of the first 4 weeks of the
401565 - run-in period, eligibility for randomization was
401566 - based on a fasting LDL cholesterol level of 75 mg
401567 - per deciliter or higher, as determined by the
401568 - central laboratory (for details, see the
401569 - Supplementary Appendix). Among patients who met
401570 - that criterion, those with coronary heart disease
401571 - (or a coronary heart disease risk equivalent) who
401572 - had an LDL cholesterol level of less than 100 mg
401573 - per deciliter (2.59 mmol per liter) and those
401574 - without coronary heart disease (or a coronary heart
401575 - disease risk equivalent) who had an LDL cholesterol
401576 - level of less than 130 mg per deciliter (3.36 mmol
401577 - per liter) were eligible for randomization. Among
401578 - patients in whom the lipid-lowering goal had not
401579 - been reached, therapy was increased to the next
401580 - level for an additional 4 weeks; the process was
401581 - repeated a month later if the goal had still not
401582 - been reached. Patients who were receiving 80 mg of
401583 - atorvastatin plus 10 mg of ezetimibe daily but
401584 - whose LDL cholesterol level was still above the
401585 - target value were eligible for randomization.
401586 - Patients with an LDL cholesterol level of less than
401587 - 75 mg per deciliter were excluded, except for those
401588 - who were receiving 80 mg of atorvastatin plus 10 mg
401589 - of ezetimibe daily. These patients were allowed to
401590 - discontinue ezetimibe and to participate in the
401591 - study if the ATP-III goal was maintained after 4
401592 - weeks on the regimen of 80 mg of atorvastatin
401593 - daily.
401595 - ..
401596 - 3. After randomization, no changes to the assigned
401597 - background lipid-lowering therapy were permitted.
401598 - Randomization to the blinded phase of the trial,
401599 - which was stratified according to background
401600 - therapy, was performed centrally with the use of an
401601 - interactive voice-response system. Patients were
401602 - assigned in a 2:1 ratio to receive either 6 ml (420
401603 - mg) of evolocumab or placebo, administered
401604 - subcutaneously every 4 weeks for 48 weeks. The
401605 - monthly injections could be split (e.g., two 3-ml
401606 - doses or three 2-ml doses).
401608 - ..
401609 - 4. Study visits were scheduled every 4 weeks, with
401610 - additional visits at weeks 13 and 37. Final
401611 - administration of a study drug occurred at week 48.
401612 - Patients who discontinued a study drug for any
401613 - reason were asked to continue all other study
401614 - activities through week 52.
401616 - ..
401617 - 3. Efficacy and Safety End Points
401618 -
401619 - 1. The primary efficacy end point was the percent change
401620 - from baseline in the LDL cholesterol level at week 52
401621 - in patients receiving evolocumab, as compared with the
401622 - change in those receiving placebo. The primary
401623 - efficacy end point was also assessed separately for
401624 - each of the background-therapy groups. Secondary
401625 - efficacy end points included the absolute change from
401626 - baseline in the LDL cholesterol level at week 52, the
401627 - percent change from baseline in the LDL cholesterol at
401628 - week 12, and the percentage of patients with an LDL
401629 - cholesterol level of less than 70 mg per deciliter
401630 - (1.81 mmol per liter) at week 52. Additional secondary
401631 - end points included the percent change from baseline at
401632 - week 52 in levels of total cholesterol, high-density
401633 - lipoprotein (HDL) cholesterol, non-HDL cholesterol,
401634 - very-low-density lipoprotein (VLDL) cholesterol, and
401635 - apolipoprotein B, the ratio of total cholesterol to HDL
401636 - cholesterol, the ratio of apolipoprotein B to
401637 - apolipoprotein A1, and the levels of lipoprotein(a) and
401638 - triglycerides.
401640 - ..
401641 - 2. We assessed the long-term consistency of the effect of
401642 - evolocumab, as compared with placebo, by comparing the
401643 - percent change in the LDL cholesterol level at week 12
401644 - with that at week 52. All lipid analyses were performed
401645 - as described previously.5 All LDL cholesterol levels
401646 - that were used as primary or secondary trial end points
401647 - were measured by means of ultracentrifugation unless
401648 - otherwise specified.12,13
401650 - ..
401651 - 3. Tertiary and exploratory end points are listed in the
401652 - Supplementary Appendix. Long-term safety and
401653 - side-effect profiles were assessed by means of
401654 - adverse-event reporting, clinical examination, and
401655 - laboratory testing. Anti-evolocumab antibodies were
401656 - assayed at baseline and at weeks 12, 24, 36, and 52, as
401657 - described previously.14
401659 - ..
401660 - 4. Statistical Analysis
401661 -
401662 - 1. We determined that with enrollment of 900 patients
401663 - (600 in the evolocumab group and 300 in the placebo
401664 - group) the study would have sufficient power (>99%) to
401665 - detect at least a 20% reduction in the LDL cholesterol
401666 - level in the evolocumab group, as compared with the
401667 - placebo group, with a common standard deviation of
401668 - 20%, after accounting for treatment attenuation and
401669 - assuming that 2% of the patients would not receive a
401670 - study drug. All analyses included data from patients
401671 - who received at least one dose of a study drug. We
401672 - analyzed all primary and secondary efficacy end points
401673 - on the basis of the randomized study-group
401674 - assignments.
401676 - ..
401677 - 2. We used a repeated-measures linear-effects model to
401678 - assess the primary end point. Included in this model
401679 - were terms for the study group, background-therapy
401680 - group, scheduled visit, and the interaction between
401681 - the treatment and the scheduled visit (with the use of
401682 - an unstructured covariance matrix). Missing values
401683 - were not imputed. We used residual maximum likelihood
401684 - as the method of estimation and the Kenward?Roger
401685 - method to estimate denominator degrees of freedom for
401686 - the tests of fixed effects. Sensitivity and
401687 - nonparametric analyses as well as the analysis of
401688 - covariance are described in the Supplementary
401689 - Appendix.
401691 - ..
401692 - 3. All other hypothesis testing was two-sided with a
401693 - significance level of 0.05, with Hochberg adjustment
401694 - used to control for multiple testing. All P values
401695 - have been adjusted for multiple testing unless
401696 - otherwise specified. Key safety end points included
401697 - adverse events occurring during treatment, laboratory
401698 - values, and the presence of anti-evolocumab antibodies.
401699 - Safety analyses were conducted with the use of
401700 - descriptive statistics that were based on observed data
401701 - with no imputation. Adverse events were coded with the
401702 - use of the Medical Dictionary for Regulatory
401703 - Activities, version 16.1.
401705 - ..
401706 - 5. RESULTS
401707 -
401708 - 1. Patients
401709 -
401710 - 1. The study was conducted from January 2012 through
401711 - November 2013. Of the 2120 patients who were
401712 - screened, 905 underwent randomization, 901 received
401713 - at least one dose of a study drug, and 800 (88.4%)
401714 - completed 52 weeks of treatment (Figure 1). Of the
401715 - 901 patients who received a study drug, 111
401716 - received background lipid-lowering therapy with
401717 - diet alone, 383 received 10 mg of atorvastatin
401718 - daily, 218 received 80 mg of atorvastatin daily,
401719 - and 189 received 80 mg of atorvastatin plus 10 mg
401720 - of ezetimibe daily.
401722 - ..
401723 - 2. Baseline demographic and clinical variables are
401724 - shown in Table 1, and baseline lipid values in
401725 - Table 2; baseline apolipoprotein and PCSK9 measures
401726 - are shown in Tables S1 and S2 in the Supplementary
401727 - Appendix. As would be anticipated, the prevalence
401728 - of cardiovascular disease and of cardiovascular
401729 - risk factors was higher in the groups receiving
401730 - more intensive background lipid-lowering therapy
401731 - (Table 1). The mean baseline levels of unbound
401732 - (free) PCSK9 were lowest in the diet-alone group
401733 - and increased progressively with the intensity of
401734 - lipid-lowering therapy, as would be expected with
401735 - statin treatment (Table S2 in the Supplementary
401736 - Appendix).
401738 - ..
401739 - 2. Efficacy End Points
401740 -
401741 - 1. At 52 weeks, the least-squares mean (+/- SE)
401742 - reduction in LDL cholesterol from baseline in the
401743 - evolocumab group, taking into account the change in
401744 - the placebo group, was 57.0 +/- 2.1% at week 52
401745 - (Table 2) and 57.5 +/- 1.6% at week 12 (Figure 2
401746 - and Figure S3A in the Supplementary Appendix). In
401747 - the analysis according to background-therapy group,
401748 - the least-squares mean reduction in LDL cholesterol
401749 - in the evolocumab group, taking into account the
401750 - change in the placebo group, was 55.7+/- 4.2% in
401751 - the diet-alone group, 61.6 +/- 2.6% in the group
401752 - receiving 10 mg of atorvastatin, 56.8 +/- 5.3% in
401753 - the group receiving 80 mg of atorvastatin, and 48.5
401754 - +/- 5.2% in the group receiving 80 mg of
401755 - atorvastatin plus 10 mg of ezetimibe (P<0.001 for
401756 - all comparisons). The LDL cholesterol level at
401757 - baseline and the percent reductions from baseline
401758 - that were calculated with the use of the Friedewald
401759 - formula (Table S1 in the Supplementary Appendix)
401760 - were similar to those that were measured by means
401761 - of ultracentrifugation. The level of LDL
401762 - cholesterol was reduced below 70 mg per deciliter
401763 - in 82.3% of patients in the evolocumab group, as
401764 - compared with 6.4% of those in the placebo group
401765 - (Table 2).
401767 - ..
401768 - 2. Evolocumab treatment, as compared with placebo,
401769 - also resulted in significant least-squares mean
401770 - percent reductions from baseline in levels of
401771 - apolipoprotein B, non-HDL cholesterol,
401772 - lipoprotein(a), and triglycerides (Table S1 in the
401773 - Supplementary Appendix). After taking into account
401774 - the change in the placebo group, evolocumab
401775 - treatment resulted in a least-squares mean increase
401776 - of 5.4 +/- 1.1% in the HDL cholesterol level
401777 - (P<0.001) and of 3.0 +/- 0.8% in the apolipoprotein
401778 - A1 level (unadjusted P<0.001). No meaningful
401779 - changes were seen in levels of high-sensitivity
401780 - C-reactive protein (Table S1 in the Supplementary
401781 - Appendix).
401783 - ..
401784 - Study claim of "significant decrease" in triglycerides, is not
401785 - supported by measured amount. Findings evolocumab increases HDL only
401786 - 5%, does not suggest taken together LDL-P can be lowered to cause
401787 - regression of atherosclerosis through discordance with elevated LDL-C,
401788 - which previous research found provides the lowest risk for CVD,
401789 - reported on 131125 0005. ref SDS 5 FI3G
401791 - ..
401792 - While findings are encouraging for lowering and maintaining low LDL-C
401793 - over 52 weeks, since LDL-P has a stronger association with CVD risk,
401794 - noted by VA on 140213 0830, ref SDS 8 S35H, and previously by the VA
401795 - during meeting on 131219 0930, ref SDS 6 GO35, then no evident
401796 - conclusions can be drawn of efficacy of evolocumab to prevent advance
401797 - of atherosclerosis, nor achieving meaningful regression.
401799 - ..
401800 - Evolocumab study continues...
401801 -
401802 - 3. In the evolocumab group, mean reductions from
401803 - baseline in unbound PCSK9 levels that were measured
401804 - at weeks 13 and 37 at an interval of 1 week after
401805 - administration were 91.1 +/- 1.8% and 86.9 +/-
401806 - 1.3%, respectively; in measurements performed at
401807 - weeks 12, 24, 36, and 52 at an interval of 4 weeks
401808 - after administration, there were mean reductions of
401809 - 41.2 +/- 1.2%, 38.3 +/- 2.2%, 38.3 +/- 2.2%, and
401810 - 42.4 +/- 1.8%, respectively (Table S2 in the
401811 - Supplementary Appendix). Reductions after 1 week
401812 - were consistently around 90% regardless of
401813 - background therapy, but those at 4 weeks after drug
401814 - administration were greater in the diet-alone group
401815 - and the group receiving 10 mg of atorvastatin than
401816 - in the two groups receiving 80 mg of atorvastatin
401817 - (Table S2 and Figure S4 and S5 in the Supplementary
401818 - Appendix).
401820 - ..
401821 - 3. Adverse Events and Immunogenicity
401822 -
401823 - 1. The overall incidence of adverse events occurring
401824 - during treatment was similar in the evolocumab
401825 - group and the placebo group, with 448 of 599
401826 - patients (74.8%) and 224 of 302 patients (74.2%),
401827 - respectively, having an adverse event. The most
401828 - common adverse events in the evolocumab group were
401829 - nasopharyngitis, upper respiratory tract infection,
401830 - influenza, and back pain (Table 3 and Table S3 in
401831 - the Supplementary Appendix). Serious adverse
401832 - events occurred in 33 patients (5.5%) in the
401833 - evolocumab group and 13 patients (4.3%) in the
401834 - placebo group (Table S4 in the Supplementary
401835 - Appendix). Adverse events leading to the
401836 - discontinuation of a study drug occurred in 13
401837 - patients (2.2%) in the evolocumab group and 3
401838 - patients (1.0%) in the placebo group (Table S5 in
401839 - the Supplementary Appendix). Injection-site
401840 - reactions were reported in 34 patients (5.7%) in
401841 - the evolocumab group and 15 patients (5.0%) in the
401842 - placebo group, resulting in discontinuation of
401843 - evolocumab in 1 patient (Table S6 in the
401844 - Supplementary Appendix).
401846 - ..
401847 - 2. Elevations of creatine kinase levels to more than
401848 - five times the upper limit of the normal range
401849 - occurred in 7 patients (1.2%) in the evolocumab
401850 - group and 1 patient (0.3%) in the placebo group,
401851 - with myalgia reported by 24 patients (4.0%) and 9
401852 - patients (3.0%), respectively; elevations of
401853 - aminotransferase levels to more than three times
401854 - the upper limit of the normal range occurred in 5
401855 - patients (0.8%) and 3 patients (1.0%), respectively
401856 - (Table 3). Evolocumab treatment did not have an
401857 - adverse effect on glycemic measures (Table 3). Two
401858 - patients in the evolocumab group had detectable
401859 - binding antibodies before or at the time of
401860 - randomization. One patient in the evolocumab group
401861 - had newly detected transient anti-evolocumab
401862 - binding antibodies during treatment. No
401863 - anti-evolocumab neutralizing antibodies were
401864 - detected in any patient (Table S7 in the
401865 - Supplementary Appendix).
401867 - ..
401868 - 6. Discussion
401869 -
401870 - 1. We found that treatment with 420 mg of evolocumab every 4
401871 - weeks for 52 weeks resulted in a relative reduction in LDL
401872 - cholesterol levels of 57%, taking into account the change
401873 - in the placebo group. This result was consistent with the
401874 - effects that were observed with the same evolocumab
401875 - regimen in the 12-week phase 2 trials.3-6 In addition, we
401876 - found no decrement in the efficacy of evolocumab from week
401877 - 12 to week 52. Our findings were also similar to the
401878 - finding of a relative reduction of 52% in LDL cholesterol
401879 - levels reported in the first year of the Open-Label Study
401880 - of Long-Term Evaluation against LDL-C (OSLER) study.10
401882 - ..
401883 - This seems to indicate LDL-C does not increase with continuing cycles
401884 - of evolocumab, after initially dropping significantly following the
401885 - first 3 month cycle, as occurred in Welch lipid history taking statin
401886 - drugs, reported on 140203 1147. ref SDS 7 W25L
401888 - ..
401889 - There is no report lowering LDL-P, which research has previously
401890 - indicated has the strongest association with CVD risk, reported on
401891 - 131125 0005. ref SDS 5 FI3G Recent VA Progress Notes also cite LDL-P
401892 - most critical factor managing CVD risk, reported during meeting on
401893 - 140213 0830, ref SDS 8 S35H, and previously by the VA during meeting
401894 - on 131219 0930. ref SDS 6 GO35
401896 - ..
401897 - Evolocumab study continues...
401898 -
401899 - 2. Our study design called for a run-in period in which
401900 - background lipid-lowering therapy was adjusted on the
401901 - basis of LDL cholesterol goals, according to the
401902 - patient's ATP-III?defined cardiovascular risk. These
401903 - risk-based lipid-lowering therapies ranged from diet
401904 - alone to a combination of 80 mg of atorvastatin plus 10
401905 - mg of the cholesterol-absorption inhibitor ezetimibe
401906 - daily. Percent reductions in LDL cholesterol in the
401907 - evolocumab group, taking into account the change in the
401908 - placebo group, differed slightly according to
401909 - background therapy, ranging from 48.5% in the group
401910 - receiving atorvastatin plus ezetimibe to 61.6% in the
401911 - group receiving 10 mg of atorvastatin.
401913 - ..
401914 - 3. Our findings provide some insights into the magnitude
401915 - and duration of PCSK9 inhibition with antibodies as a
401916 - function of background lipid-lowering therapy. In our
401917 - study, unbound PCSK9 was measured at 1 week and at 4
401918 - weeks after the administration of evolocumab. The
401919 - differences in unbound PCSK9 among background-therapy
401920 - groups at 1 week were minimal, despite substantial
401921 - differences in baseline levels, indicating that
401922 - virtually all PCSK9 is antibody-bound initially.
401923 - However, not only were baseline levels of PCSK9 higher
401924 - among patients receiving high-dose atorvastatin than
401925 - among patients in the other groups, but there also was
401926 - a more rapid increase in PCSK9 levels 4 weeks after the
401927 - administration of each dose of evolocumab in these
401928 - patients, suggesting that the rate of PCSK9 production
401929 - is increased in patients receiving intensive statin
401930 - therapy.
401932 - ..
401933 - 4. The effect on PCSK9 levels that we observed and the
401934 - consequent reductions in LDL cholesterol levels at 4
401935 - weeks after the administration of evolocumab were
401936 - similar to those reported in patients receiving either
401937 - 10 mg or 80 mg of atorvastatin plus another PCSK9
401938 - monoclonal antibody, alirocumab (at a dose of 150 mg),
401939 - even though patients received alirocumab every 2 weeks
401940 - rather than every 4 weeks.7 Thus, it may be that
401941 - patients who have already been treated with high-dose
401942 - statins or combination lipid-lowering therapy may have
401943 - slightly less capacity to further up-regulate
401944 - LDL-receptor activity with PCSK9 inhibition or may
401945 - require higher doses of antibody. Our findings are
401946 - also in keeping with those of a number of other trials
401947 - in which no synergism between statins and PCSK9
401948 - inhibition was observed. Although statins up-regulate
401949 - PCSK9, this does not explain why the reduction in LDL
401950 - cholesterol levels that is associated with an initial
401951 - dose of a statin is relatively large in comparison to
401952 - the additional 6% reduction observed when the statin
401953 - dose is doubled.
401955 - ..
401956 - 5. The recently published cholesterol guidelines of the
401957 - American College of Cardiology and the American Heart
401958 - Association (ACC?AHA)15 include several changes from
401959 - the ATP-III guidelines published in 2002. Among these
401960 - changes is the recommendation that the intensity of
401961 - therapy be guided by cardiovascular risk rather than by
401962 - LDL cholesterol goals. However, despite this
401963 - recommendation, an LDL cholesterol level of less than
401964 - 70 mg per deciliter remains a treatment target for
401965 - patients at very high risk for cardiovascular disease
401966 - in many countries. In our study, this target was
401967 - achieved in more than 80% of patients with the use of
401968 - 420 mg of evolocumab every 4 weeks. In addition, there
401969 - were significant reductions in the levels of other
401970 - atherogenic, apolipoprotein B?containing lipoproteins,
401971 - including lipoprotein(a), and modest but significant
401972 - increases in levels of HDL cholesterol and
401973 - apolipoprotein A1, similar to those reported with
401974 - evolocumab previously.3-6,16
401976 - ..
401977 - 6. More patients in the evolocumab group than in the
401978 - placebo group were reported to have serious adverse
401979 - events during treatment and to have adverse events
401980 - leading to drug discontinuation. However, a review of
401981 - the individual adverse events in these categories does
401982 - not offer any clear indication of specific risks
401983 - associated with evolocumab. The most common adverse
401984 - events were nasopharyngitis, upper respiratory tract
401985 - infection, influenza, and back pain, all of which
401986 - occurred more frequently in the evolocumab group.
401987 - There were more reports of myalgia and elevated
401988 - creatine kinase levels among patients receiving
401989 - evolocumab.
401991 - ..
401992 - 7. In conclusion, among patients at risk for a wide range
401993 - of coronary diseases who were receiving
401994 - guideline-recommended background lipid-lowering
401995 - therapy, the monoclonal PCSK9 antibody evolocumab
401996 - reduced LDL cholesterol levels by 57%, as compared with
401997 - placebo, at 52 weeks.
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