There has been considerable and justifiable excitement within the cardiology community regarding proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as alirocumab and evolocumab. Results of early phase III trials evaluating this new class of medications in patients with heterozygous familial hypercholesterolemia (HeFH) and/or high cardiovascular risk who were either on statins or statin-intolerant have demonstrated dramatic reductions in low-density lipoprotein cholesterol (LDL-C) levels without excess adverse events.^1,2 These trials, coupled with cohort studies showing significant reductions in coronary events among persons with low LDL-C levels due to loss-of-function PCSK9 mutations,³ offer hope that PCSK9 inhibitors will reduce atherothrombotic events.

On the heels of the ODYSSEY LONG TERM 78-week follow-up results,¹ which were published in April 2015 and represented a substantial step forward for PCSK9 inhibitors, the results of ODYSSEY FH I and FH II should be viewed as an expected but necessary incremental gain.⁴ ODYSSEY FH I and FH II enrolled patients with HeFH on maximally tolerated statin therapy with LDL-C ≥70 mg/dl with a history of cardiovascular disease (CVD) or LDL-C ≥100 mg/dl without a history of CVD; these two trials of HeFH patients comprise part of the ODYSSEY LONG TERM trial, which also included non-FH patients at high cardiovascular risk.

The ODYSSEY LONG TERM trial demonstrated a consistent 62% decrease in LDL-C levels over 78 weeks among patients randomized to alirocumab versus placebo; a post hoc preliminary analysis found a decreased rate of major adverse cardiovascular events with alirocumab versus placebo. Notably, although low LDL-C levels have previously been postulated to be associated with excess adverse effects, the slight excess of adverse events in ODYSSEY LONG TERM for alirocumab versus placebo (primarily myalgias, injection-site reactions, and self-reported neurocognitive disorders) were similarly frequent among patients with achieved LDL-C levels below or above 25 mg/dl.

ODYSSEY FH I was performed at 89 sites in North America, Europe, and South Africa, whereas FH II was performed at 26 sites in Europe.⁴ Both were randomized, blinded, placebo-controlled, parallel group trials designed to test PCSK9 inhibition on top of current standard of care. The 735 enrollees across the two trials were randomized 2:1 to receive alirocumab 75 mg by subcutaneous injection every two weeks (with a further increase to 150 mg at week 12 for participants with LDL-C ≥70 mg/dl) or placebo. Participants were treated for 78 weeks, after which all were given the option to enter a (presently ongoing) three-year open-label extension study in which all receive alirocumab.

The primary endpoints for FH I and FH II, percent change in calculated LDL-C from baseline to week 24 for patients randomized to alirocumab versus placebo, were -57.9% and -51.4%, respectively; these LDL-C reductions from baseline remained after 78 weeks of treatment (-51.8% FH I, -52.1% in FH II). Alirocumab treatment also significantly reduced apolipoprotein B, lipoprotein(a), and triglycerides and modestly increased apolipoprotein A1 and HDL-C. Treatment-related adverse events were similar between the alirocumab and placebo groups; notably, there was no significant difference between alirocumab and placebo groups regarding neurological or neurocognitive events. Although anti-drug antibodies were observed in a small minority (<10%) of alirocumab-treated participants, these antibodies did not meaningfully inhibit alirocumab's LDL-C-lowering efficacy and were not associated with excess adverse events.

What new information do these data offer? While the results largely parallel those of the ODYSSEY LONG TERM 78-week follow-up, albeit in an HeFH-only population, there are a few essential points to consider from ODYSSEY FH I and FH II:

1. The absolute number of self-reported neurocognitive disorders observed was quite low and no higher for the alirocumab group versus placebo. There were a total of two neurocognitive disorders noted in the combined alirocumab arms (n = 489) and three in the placebo arms (n = 244). This is reassuring in light of concerns regarding neurocognitive side effects of LDL-lowering medications such as statins and PCSK9 inhibitors, which have often been driven by non-blinded treatment allocation and inconsistent ascertainment of adverse neurocognitive events. This concern will be best addressed by formal neurocognitive testing, which is being performed in ongoing large outcomes trials of PCSK9 inhibitors.
   
   
2. Anti-drug antibodies may occur with alirocumab use...but these do not yet appear to be clinically meaningful. The <10% of patients treated with alirocumab who developed anti-drug antibodies experienced LDL-C lowering similar to those without anti-drug antibodies and have not yet experienced excess adverse events through 78 weeks of study.
   
   
3. With regard to LDL-C, the jury is still out on the question, "How low is too low?" In ODYSSEY LONG TERM, the mean LDL-C for patients taking alirocumab was 48 mg/dl at 24 weeks and 58 mg/dl at 78 weeks, and patients with LDL-C levels <25 mg/dl did not experience excess adverse events. Meanwhile, ODYSSEY FH I and FH II were comprised exclusively of HeFH patients with higher baseline LDL-C levels; mean achieved LDL-C levels in the alirocumab arms were consistently higher [71 mg/dl (FH I) and 68 mg/dl (FH II) at 24 weeks and 84 (FH I) and 70 mg/dl (FH II) at 78 weeks] than in ODYSSEY LONG-TERM. Because baseline LDL-C levels among HeFH patients are so high, that their LDL-C levels on treatment with a statin plus alirocumab generally are not <40 mg/dl, questions regarding theoretical adverse events associated with very low LDL-C levels are probably best answered in trials of non-FH populations.

While the clear LDL-lowering efficacy and reasonably benign safety profile of alirocumab over 78 weeks^1,4 – and of evolocumab at one year² – are certainly promising, a few barriers to widespread use of PCSK9 inhibitors remain. Statins are such a central part of our medical armamentarium because of their truly long-term efficacy and safety data that has played out over decades; health care providers can hope and even anticipate that PCSK9 inhibitors will likewise prove efficacious and safe over years-to-decades, but only longer-term follow-up data in large outcomes trials can ultimately prove this.

Exploratory analyses have suggested significant decreases in major adverse cardiovascular events with alirocumab and evolocumab compared with placebo,^1,2 which are unsurprising but require confirmation in ongoing trials intended to evaluate cardiovascular outcomes (alirocumab: ODYSSEY OUTCOMES, NCT01663402; evolocumab: FOURIER, NCT01764633; bococizumab: SPIRE-1, NCT01975376, and SPIRE-2, NCT01975389). Cost-effectiveness of PCSK9 inhibitors will also require further study and will depend to a large extent on still-evolving payer reimbursement practices. Of course, we must also keep in mind that none of these trials evaluated PCSK9 inhibitors as first-line therapy, but rather as additive therapy on top of maximally tolerated statins for patients thought to benefit from further lipid lowering.

Despite these potential barriers, PCSK9 inhibitors represent a major breakthrough in the treatment of LDL-C for selected patients with HeFH and/or high cardiovascular risk thought to benefit from additional LDL-C lowering. Whether this breakthrough also extends to significant cardiovascular risk reductions without excess adverse events in these populations remains to be seen and will be determined in the coming years by large, longer-term outcome trials.

References

1. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
2. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.
3. Cohen J, Persemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005;37:161-5.
4. Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015 Sep 1. [Epub ahead of print]

Keywords: Antibodies, Monoclonal, Apolipoprotein A-I, Apolipoproteins B, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Cholesterol, VLDL, Cohort Studies, Follow-Up Studies, Health Personnel, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Injections, Subcutaneous, Lipoprotein(a), Lipoproteins, LDL, Mutation, Myalgia, Proprotein Convertases, Risk Factors, Self Report, Standard of Care, Subtilisins, Triglycerides

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