Clinical Feature: PCSK9 Monoclonal Antibody Therapy – The Latest Data and Who is Appropriate for Treatment

The most significant advance in clinical lipidology and preventive cardiology in 2015 is the availability of proprotein convertase subtilisin-like kexin type 9 (PCSK9) monoclonal antibody (mAb) therapy. This potent breakthrough therapy has garnered as much excitement as the release of statin therapies more than two decades ago, but important considerations remain regarding patient selection, regulatory limitations of use and unproven ASCVD risk reduction benefits in the absence of long-term outcome trials. Alirocumab and evolocumab were approved by the U.S. Food and Drug Administration (FDA) in July and August 2015, respectively, and by the European Medicines Association in September and July, respectively.  Additional PCSK9 monoclonal antibody therapies in active clinical development include bococizumab (RN316), MPSK3169A (RG7652), and LY3015014.

The primary pathway for the clearance of circulating low-density lipoprotein particles (LDL-P) is LDL receptor (LDLR)-mediated hepatic internalization or endocytosis of the LDL apolipoprotein B (apo B)-LDLR complex. While LDLRs potentially can recycle (up to 150 times) back to the cell surface after delivering cholesterol, PCSK9 — a 692 amino acid mature protein mainly expressed as a secreted protease in the liver, intestines, and kidneys — acts as a “chaperone” protein by combining with the LDLR extracellular domain. The domain then undergoes endocytosis creating a pathway of subsequent LDLR degradation, and with the presence of fewer LDLRs able to process LDL, there are increased circulating plasma LDL particles.1,2,3 PCSK9 mAbs act by binding to PCSK9, preventing the association between PCSK9 and the LDL receptor, thus blocking the effects of PCSK9. This allows the LDLRs to recycle to its higher potential, thus lowering LDL-C levels dramatically.

While statin therapy is first-line, lowering hepatic cholesterol content upregulates, not only LDLRs, but also the synthesis and secretion of PCSK9,4 which may account for the limited increase in efficacy, lowering LDL-C by only 6 percent with each consecutive doubling of statin doses.

Recent Larger Trials Evaluating Safety and Efficacy
A wealth of Phase II and III trials, involving a variety of populations, examined the efficacy and safety of alirocumab, evolocumab, and bococizumab. Many of these were reviewed in an earlier issue of LipidSpin.5 LDL-C reductions of 50 to 60 percent or greater have been consistently observed in statin-treated or statin-intolerant patients with or without known coronary heart disease (CHD) and in those with heterozygous familial hypercholesterolemia (HeFH). Reductions of 25 to 30 percent in LDL-C have been seen when treating patients with homozygous familial hypercholesterolemia (HoFH). In addition, approximately 50 percent reductions in non-HDL-C and apolipoprotein B, and 25 percent reductions in lipoprotein(a) typically are observed.

Pooled data from relatively short-term safety and efficacy open-label studies were published in spring 2015, providing significant additional insight into safety and preliminary outcomes prior to the launch of alirocumab and evolocumab.

The Long-Term Safety and Tolerability of Alirocumab in High Cardiovascular  Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying  Therapy  (ODYSSEY LONG- TERM) placebo-controlled trial evaluated 2,341 patients with hyperlipidemia on maximally tolerated statins who were at high risk for CHD (69 percent with prior CHD and 35 percent with diabetes) and was published in March 2015. It showed alirocumab (150 mg Q2W) reduced LDL-C 62 percent at 24 weeks, compared to placebo, with an achieved mean LDL-C of 48 mg/dL in the alirocumab group compared to 119 mg/dL in those on placebo (a 71 mg/dL between-group LDL-C difference), and a persistent LDL-C reduction of 52 percent out to 78 weeks.6 Among the alirocumab group, 79 percent achieved an LDL-C <70 mg/dL at week 24, compared to only 8 percent in the placebo group. Certain adverse events were higher in the alirocumab group compared to placebo: injection site reactions 5.9 percent vs. 4.2 percent, myalgia 5.4 percent vs. 2.9 percent, neurocognitive events 1.2 percent vs. 0.5 percent, and opthalmologic events 2.9 percent vs. 1.9 percent. Adverse events in the subgroup of 575 patients who achieved an LDL-C <25 percent were similar to the overall alirocumab group. Of particular interest, the post-hoc analysis of the composite of cardiovascular events over 78 weeks — including CHD death, myocardial infarction, ischemic stroke, and unstable angina requiring hospitalization — showed those in the alirocumab group compared to placebo had a 48 percent reduced risk of such events (1.7 percent vs. 3.3 percent, HR=0.52, 95 percent CI=0.31-0.90). (Figure) Since the total number of events was small (n=53) and follow-up periods are relatively short, verification is needed from the larger, longer-term outcome trials currently in progress. However, the between-group atherogenic cholesterol differences and the magnitude of risk reduction in just 1.5 years is striking and would suggest a very favorable number needed-to-treat (NNT) of close to 50 from only two years of treatment, assuming the divergence of benefit between the two groups persists.

A similar study of evolocumab, the Open- Label Study of Long-Term Evaluation Against LDL-cholesterol (OSLER) involving a pre-specified combined analysis of 4,465 patients who completed one of 12 Phase 2 or 3 studies of evolocumab was also published in March 2015.7 These subjects were randomized either to evolocumab 420 mg every four weeks plus standard of care versus standard of care alone in an open-label extension study averaging 11 months. The evolocumab group showed a 61 percent reduction in LDL-C, from 120 to 48 mg/dL (a 72 mg/ dL between-group LDL-C difference), at 12 weeks. There was no difference in the rate of serious adverse events (7.5 percent in each group). Neurocognitive events were more frequent (0.9 percent vs. 0.3 percent) in the evolocumab group, however, the incidence did not appear to be related to the achieved LDL-C levels ranging down to <25 mg/dL; there was no difference in the incidence of these or other adverse events (an ongoing study (EBBINGHAUS) is prospectively evaluating neurocognitive issues in patients with normal cognitive function enrolled in a Phase 3 outcomes study with evolocumab).8 OSLER noted a 53 percent reduction in the incidence of the pre- specified composite endpoint of death, myocardial infarction, hospitalization for unstable angina, coronary revascularization, stroke, transient ischemic attack, and hospitalization for heart failure (0.95 percent vs. 2.18 percent, HR=0.47, 95 percent CI=0.28-0.78), a promising outcome in a short time, despite a limited number of events (n=60).  (Figure) This strikingly similar cardiovascular event-risk reduction is noteworthy because of the lower-risk subject population enrolled (only 20 percent with prior CHD and 13 percent with diabetes), as compared to the ODESSEY LONG-TERM study.6 Should event-rate trends continue to diverge, a favorable NNT close to 50 in this trial also could be observed within about two years of treatment.

Following these reports, a systemic review and meta-analysis involving 24 phase 2 and 3 randomized controlled trials comprising 10,159 patients where there was a 47.5 percent LDL-C reduction in those on PCSK9 mAb treatment versus not, showed significant 55 percent reductions in cardiovascular mortality (p=0.015)  and borderline significant 50 percent reductions in all-cause mortality (p=0.08),  without any increase in overall serious adverse events.9 These preliminary findings also appear consistent with that of the Cholesterol Treatment Trialists Collaboration, which shows an absolute reduction in LDL-C levels  (1mmol/L, 39mg/dL) produces a 23 percent risk reduction in major coronary events that is consistent across baseline levels of LDL-C.10 Thus, the approximate 70 mg/dL treatment group differences in LDL-C seen from alirocumab and evolocumab would project an approximate 40 percent risk reduction, which is well within the confidence intervals for the 11- to 18- month CVD outcome risk reductions observed thus far.6,7 Large Phase 3 trials involving >70,000 patients (Table) will provide definitive data on reduction in cardiovascular outcomes, with the first of these due for completion by the fourth quarter of 2017.

Who is Appropriate for Treatment?
The current indications for both alirocumab and evolocumab, as approved by the FDA, call for their usage as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of LDL-C;11,12 additionally,  evolocumab  is indicated for such persons with HoFH who require additional  LDL-C lowering beyond what other lipid-lowering therapies provide.12 Of note, while the FDA has not given guidance as to what specific lipid levels on maximal tolerated statin or other therapy might be suitable for starting a PCSK9 mAb, the National Lipid Association’s recent recommendations note that until cardiovascular outcome trials are completed that these drugs should be considered primarily in those with 1) ASCVD who have an LDL-C of >=100 mg/dl (non-HDL-C of >=130 mg/dl) while on maximally-tolerated statin (+/- ezetimibe ) therapy and 2) HeFH patients without ASCVD who have LDL-C >=130 mg/dl (non-HDL-C >=160 mg/dl) while on maximally-tolerated statin therapy (strength B recommendation).13 In Europe, the European Medicines Association14 approved a broader indication for evolocumab in which usage can be considered for adults with primary hypercholesterolemia  (HeFH and nonfamilial) or mixed dyslipidemia. It can be an adjunct to diet in combination with a statin or with a statin with other lipid-lowering therapies in patients unable to reach LDL-C goals via the maximum tolerated dose of a statin or alone or in combination with other lipid-lowering therapies in patients who are statin- intolerant, or for whom a statin is contra- indicated. There also is an indication for use by adults and adolescents ages 12 years and older with HoFH in combination with other lipid-lowering therapies. However, both products clearly state in their labeling that the effects on cardiovascular outcomes have not been determined.

Roughly 1 in 300 to 500 adults have HeFH15 and, given their marked CHD risk, most experts would classify them as a CHD-risk equivalent, warranting a need for additional LDL-C lowering if the achieved LDL-C on a high-intensity (or maximum tolerated) statin is still 70 mg/ dL or greater. An approximate 50 percent further lowering of LDL-C would result in LDL-C levels well below 50 mg/dL in many such persons from the addition of a PCSK9 mAb. A much smaller proportion of persons (1 in 500,000 to 1 million) have HoFH; however, these persons have substantially higher LDL-C levels than do those with HeFH and they normally cannot achieve reasonable “goal” levels, despite being on a high-intensity statin. Thus, they often require additional therapy. Aside from LDL apheresis and certain high-intensity statin drugs such as atorvastatin and rosuvastatin, mipomersen (an antisense oligonucleotide therapy), and lomitapide (a microsomal triglyceride transfer protein inhibitor), evolocumab also has an indication (in Europe and the U.S.) for HoFH, although reductions of LDL-C in such patients are more modest, averaging approximately 25 to 30 percent. The LDL-C reduction response to PCSK9 mAb in HoFH does require at least some LDL receptor activity (which is present in many despite HoFH); the few without LDL receptor activity appear not to respond.

A report from statin-treated U.S. adults in the National Health and Nutrition Examination  Survey (NHANES) 2009-2010 showed that only 27 percent of those with CHD were at LDL-C<70 mg/dL, and those not at goal averaged 33.9 mg/dL above this point. While it is unclear how many such persons were on recommended moderate or high-intensity therapy,16 these data suggest a significant opportunity for the consideration of newer therapies, such as PCSK9 monoclonal antibodies, when reasonable targets cannot be reached. While the American College of Cardiology/ American Heart Association (ACC/AHA) guidelines17 focus on use of high-intensity statin therapy in such individuals, consideration for evidence-based non-statin therapy also is an option, especially when there is inadequate response or tolerability from statin therapy alone.

The recent results of the IMPROVE-IT trial18  in acute coronary syndrome patients with the addition of ezetimibe confirm the value of additional LDL-C lowering with non-statin therapy, however, the relatively modest 6 percent relative risk reduction and number needed to treat (NNT) of 50 took seven years to accrue. Of interest, if the trends from the 11-month and 18-month data from evolocumab and alirocumab, respectively, continue and are confirmed from the ongoing long-term outcome trials, such a beneficial NNT of 50 is likely to occur within approximately only two years.

Limitations of Use That May Contribute to Clinical Inertia in the U.S.
The broader indication for evolocumab and alirocumab in Europe to include those with non-familial primary hypercholesterolemia or mixed dyslipidemia who are on maximal statin therapy unable to reach goals or who are intolerant to a statin indicates that a much larger segment of the population could be considered for this therapy. While these patients are not within current FDA indications for PCSK9 monoclonal antibody therapy, there clearly are large numbers of individuals with multiple risk factors, especially older persons, and those with unfavorable discordance between LDL-C and other atherogenic markers (i.e. non- HDL-C, apo B, and LDL-P), including those with metabolic syndrome or diabetes of long duration, especially in the presence of multiple or single severe risk factors or substantial subclinical atherosclerosis. Such factors would bring many up to a “true CHD risk equivalent” (or higher) status that could be seen by some clinicians as reasonable for such therapy if response to statin therapy alone, or combination therapies with non-statins, is inadequate. For instance, Malik, et al.19 show those with metabolic syndrome or diabetes who have coronary calcium scores >=100 have annual CHD event rates of >2 percent placing them at such increased risk. Moreover, current ACC/ AHA guidelines indicate a 10-year  ASCVD risk >7.5 percent identifies a higher-risk person with diabetes, warranting high- intensity statin therapy.17 However, it also can be shown that those with diabetes who have additional risk factors have a >=50 percent lifetime risk of CHD,20 suggesting a short-sighted limitation of focusing on 10-year risk estimates.

In addition, those who are completely statin intolerant — estimates range from 10 to 15 percent of statin users21 — may be an important patient population for these agents, however, prescribers clearly will need to document the details concluding the patient is statin intolerant (e.g., using an objective comparison of pre- vs. post-statin complaints) and ideally has failed >2 statin drugs, as was the requirement for most patients in PCSK9 trials studying statin intolerance.22-23

Finally, not widely appreciated is the extent of statin non-responders, which can be substantial, even among those on high-intensity statins. A major problem contributing to residual risk is the considerable variability of LDL-C response with statins and that achieving a goal of LDL-C <70 mg/dL is more difficult than achieving a goal of >50 percent reduction in LDL-C. For instance, the VOYAGER high-risk  patient database [n = 20,539] of subjects with mean baseline LDL-C 168 mg/dL showed that, even on atorvastatin 80 mg/dL, while 60 percent achieved >50 percent reduction in LDL- C, only 30 percent achieved <70 mg/dL. On rosuvastatin 40 mg/day, 78 percent achieved >50 percent reduction in LDL-C, while only 42 percent achieved <70 mg/ dL.24 These patient groups suggest a need for the potency associated with PCSK9 inhibitors for addressing what can be substantial residual lipid risk but do not explicitly meet the current FDA indications of HeFH or clinical ASCVD.

The inclusion of these therapies in future clinical practice guidelines as well as optimal cost negotiations with payers (given current wholesale pricing of approximately $1,200 per month) will be important for accessibility of the PCSK9 mAb agents by those patients who need them and are indicated for their use. Certainly, much broader indications for PCSK9 mAb therapy may be more appropriate once further data become available in certain patient subgroups, cost-effectiveness is better documented, including and, most importantly, an improvement of outcomes has been demonstrated on the basis of the ongoing large CVD event trials.

Conclusions
The most significant development this year in clinical lipidology and preventive cardiology is the availability of PCSK9 monoclonal antibody therapies for the management of dyslipidemia. This new and potent atherogenic cholesterol lowering class of medicine now provides clinicians with the opportunity to address the significant residual atherogenic lipid risk present in many high-risk patients because of inadequate response or unacceptable drug intolerance. However, until the results of ongoing large trials provide important information on the long- term safety, efficacy, and cardiovascular outcomes of PCSK9 mAb therapy, clinical practice guidelines have adopted them, and their cost-effectiveness has been demonstrated, these products will likely be reserved for those at highest risk consistent with current labeling.

Disclosure statement: Dr. Wong has received research support through his institution from Amgen and Regeneron, and he is a consultant. He has also served on an advisory board for Amgen, served as a consultant for Pfizer, and has lectured for Sanofi. Dr. Rosenblit has received advisory board honoraria from Amarin, Astra-Zeneca, Lilly, Merck, and Sanofi-Regeneron; clinical research trials support, as site Principal Investigator, from Amgen, AstraZeneca (Bristol Myers Squibb), DexCom,  Eli Lilly, GSK, Merck, Novo Nordisk, Orexigen, Pfizer, and Sanofi-Regeneron; and speaker faculty honoraria from AbbVie, AstraZeneca (Bristol-Myers Squibb), Boehringer-Ingelheim, GlaxoSmithKline, Janssen, Kowa, Merck, and Takeda.

References are listed on page 35 of the PDF.