Results on Evolocumab and Alirocumab for Lipid-Lowering Therapy Revealed at ESC

New results for Sanofi-Regeneron’s alirocumab, sold as Praluent, and Amgen’s evolocumab, sold as Repatha, were presented on the drugs’ effectiveness as lipid-lowering therapy, as well their role in secondary prevention for high-risk patients at the European Society of Cardiology 2019 Congress this weekend.

Results for both proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were presented at the meeting in Paris, France, which opened August 31 and runs through September 4.

The PCSK9 inhibitor class has come down significantly in price over the past year. Both injected therapies entered the market priced above $14,000 when first approved in 2015. But in May 2018, Sanofi-Regeneron announced a pricing deal with Express Scripts less than 6 weeks after releasing a value-based pricing analysis developed by the Institute for Clinical and Economic Review, which created a pricing range of $4500 to $8000 for alirocumab. The analysis was timed for the release of the ODYSSEY Outcomes trial, which showed that alirocumab significantly cut deaths by 29% in high-risk patients with low-density lipoprotein (LDL) cholesterol.

Amgen’s evolocumab had a shorter follow-up period in its FOURIER trial in 2017; it showed a reduction in cardiovascular events but the findings did not match those seen in ODYSSEY Outcomes. Amgen later announced a price break for evolocumab in the fall of 2018.

Both PCSK9 inhibitors tested the efficacy of their drug’s intervention in patients with varying metabolic disorders. The studies below on alirocumab were by Sanofi and Regeneron Pharmaceuticals, and those on evolocumab were funded by Amgen.

Results for Evolocumab Effectiveness in FH patients

In the study analyzing the effectiveness of evolocumab for patients with familial hypercholesterolemia (FH), researchers conducted an observational study across 10 European countries on 502 FH subjects, of which 477 had heterozygous FH (HeFH) and 25 had homozygous FH (HoFH).¹

After initiation of evolocumab, median LDL cholesterol fell by 56% in patients with HeFH (baseline LDL cholesterol=4.30 [3.41, 5.50] mmol/L, after evolocumab initiation LDL cholesterol=1.73 [1.03, 2.97] mmol/L) and by approximately 1/3 in HoFH patients (baseline LDL cholesterol=4.07 [2.68, 6.17] mmol/L, after evolocumab initiation LDL cholesterol=2.59 [1.63, 3.40] mmol/L) within 3 months.

The authors noted that in the real-world study of evolocumab use in clinical practice, a large proportion of FH patients were not on statins, and the drug was well tolerated.

Results for Lower Use of Statins in PAD Patients Compared With CHD Patients

In the study among patients with a history of peripheral artery disease (PAD) and those with coronary heart disease (CHD), researchers conducted a retrospective cohort study on 1,006,451 U.S. adults, of which 69.1% had CHD only, 21.4% had both CHD and PAD, and 9.5% had PAD only. Researchers compared the use of any statin and high-intensity statins in these subgroups.²

Statin use was shown in 66% of CHD only patients, 68.2% of CHD and PAD patients, and 47.5% of PAD only patients. Compared to patients with CHD only, the multivariable adjusted prevalence ratio (PR) for statin use in patients with CHD and PAD was 1.02 (95% CI; 1.01, 1.02), while PR for those with PAD only was 0.82 (95%; 0.82, 0.83).

Representation among patients who take high-intensity statin doses as their form of statin use was 29.4% for CHD only, 28.6% for PAD and CHD, and 17.3% for PAD only. Compared to patients with CHD only, the multivariable adjusted PR for high-intensity dosage intake in CHD and PAD patients was 1.05 (95% CI; 1.04, 1.06), and 0.71 (95%; 0.70, 0.73)

The authors noted that adults with PAD receive less intensive statin therapy compared with CHD patients. As adults with atherosclerotic cardiovascular disease are recommended to take a statin to reduce risk of future cardiovascular events, interventions are warranted to increase statin use in PAD patients.

Results for Evolocumab Effect on Lipoprotein(a) Levels

In a study examining the effect of evolocumab on lipoprotein(a) (Lp[a]), researchers conducted 15 phase 2 and phase 3 double-blind and open label extension studies on patients with hypercholesterolemia/mixed dyslipidemia, statin-intolerance, diabetes, and HeFH.³

Over a minimum of 12 weeks duration, patients received approved evolocumab doses of 140 mg every 2 weeks [Q2W] or 420 mg once monthly [QM]. Evolocumab was revealed to cause a median percent change in Lp(a) from baseline to week 12 of -21.0% to -33.33% overall. Results for median percent change were similar in evolocumab doses Q2W (-22% to -38.2%) and QM (-20% to -33.3%), while long term studies revealed sustained lowering of Lp(a) over 5 years (-23.8% to -33.3). The study showed the significant effect of evolocumab on reducing Lp(a) over time on a variety of patient populations.

Results for Efficacy of Alirocumab After ACS

The study analyzed the frequency of major adverse cardiovascular events (MACE) and efficacy of alirocumab to reduce MACE in patients with recent acute coronary syndrome (ACS).⁴ This follows the 2018 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol management guidelines of recommended additional lipid-lowering therapies for secondary prevention in very high-risk (LDL cholesterol=1.8 mmol/L) patients who are already administered maximally tolerated statin therapy.

Of the 18,924 randomized patients in ODYSSEY Outcomes with recent ACS and residual dyslipidemia despite optimal statin therapy, 63.1% were categorized as very high-risk and 36.9% were not very high-risk based on ACC/AHA guidelines. Alirocumab reduced risk of MACE vs placebo (9.5% vs 11.1%; hazard ratio [HR]=0.85, 95% CI, 0.78-0.93), with comparable reductions in both risk categories. A 2.1% absolute risk reduction (ARR) of MACE showed the importance of alirocumab in very high-risk patients compared to 0.8% in not very high risk.

The authors noted that ACC/AHA guidelines identify patients who are at very high risk for recurrent MACE, and the study distinguishes this group as the largest beneficiary of alirocumab treatment.

Results for Efficacy of Alirocumab on MACE after ACS Based on Statin Intensity

The study analyzed the relation of category of statin use to the effect of alirocumab on MACE, compared with placebo, in 18,924 patients with ACS and dyslipidemia.⁵ Statin use in the study patients was distinguished as 88.8% for high intensity, 8.7% for low moderate intensity, and 2.4% for no statin use.

Alirocumab reduced MACE overall (HR 0.85, 95% CI, 0.78-0.93; P < .001), with a mean reduction in LDL-C from baseline to month 4 increasing across the 3 statin categories. ARRs for MACE in high intensity statins was 1.3%, 3.2% in low moderate intensity, and 8.0% for no statin use.

The study’s data showcased the significant effect of alirocumab across statin categories. Patients unable to receive high-intensity statin treatment showed higher ARRs of alirocumab impact on LDL-C reduction, which highlights its importance among this group.

Results for Very Low LDL Cholesterol Patients With Alirocumab After ACS

The study analyzed the efficacy and safety of alirocumab in patients who reached very low LDL cholesterol (consecutively <0.39 mmol/L) with included data on the risk of new-onset diabetes.⁶ Researchers compared 7.7% of the 9462 patients randomized to receive alirocumab who had reached very low LDL cholesterol to 2152 patients initially assigned to the placebo. Placebo was substituted for the PCSK9 inhibitor at a median of 8.3 months after randomization.

Alirocumab showed an overall reduced incidence of MACE (9.5% vs 11.1%; HR 0.85; P < .001). Despite the switch to placebo, alirocumab administered patients who had very low LDL cholesterol showed fewer MACE than that of the initial placebo group (6.4% vs 8.5%; HR 0.71; P = .039). Additionally, there was no association with risk of new-onset diabetes when compared with matched patients from the placebo group (15.1% vs 13%; HR 1.10; P = .46).

Alirocumab efficacy was not hindered by blinded substitution of placebo within the group of very low LDL cholesterol patients, and this further reduced MACE risk. However, the authors noted that long-term safety of alirocumab in very low LDL cholesterol patients requires further study due to the switch to placebo.

References

1. Ray KK, Schoonen M, Annemans L, et al. Effectiveness of evolocumab for patients with familial hypercholesteraemia (FH) in European clinical practice. Presented at the European Society of Cardiology 2019 Congress, Paris, France; August 31-September 4, 2019; Abstract P654.
2. Colantonio LD, Dai Y, Hubbard D, et al. Lower use of statins among patients with peripheral artery disease compared with those with coronary heart disease. European Society of Cardiology 2019 Congress, Paris, France; August 31-September 4, 2019; Abstract P652.
3. Toth PP, Jones SR, Monsalvo ML, et al. Effect of evolocumab on lipoprotein(a) levels: results across 15 studies. European Society of Cardiology 2019 Congress, Paris, France; August 31-September 4, 2019; Abstract P5326.
4. Roe MT, Szarek M, Li QH, et al. Efficacy of alirocumab treatment after acute coronary syndrome according to new ACC/AHA guidelines for lipid-lowering therapy. Presented at the European Society of Cardiology 2019 Congress, Paris, France; August 31-September 4, 2019; Abstract 4114.
5. Diaz R, Li QH, Bhatt DL, et al. Effect of alirocumab on recurrent cardiovascular events after acute coronary syndrome, according to the intensity of background statin treatment. Presented at the European Society of Cardiology 2019 Congress, Paris, France; August 31-September 4, 2019; Abstract 4115.
6. Schwartz G, Szarek M, Li QH, et al. Very low achieved low-density lipoprotein cholesterol level with alirocumab treatment after acute coronary syndrome: ODYSSEY OUTCOMES. Presented at the European Society of Cardiology 2019 Congress, Paris, France; August 31-September 4, 2019; Abstract P1226.