HoFH is a rare genetic lipid disorder that is characterized by loss of function or impaired function of the LDL receptor (LDLR), which phenotypically presents as extremely elevated LDL-C levels and early onset of atherosclerotic cardiovascular disease (ASCVD) . The most common causal mutation is found within the LDLR gene. Mutations in three other genes within the LDLR pathway, APOB encoding apolipoprotein B, PCSK9 encoding pro-protein convertase subtilisin/kexin type 9 (PCSK9), and LDLRAP1 encoding LDL receptor adapter protein 1 (LDLRAP), can also lead to the disease [5, 6]. Genetically, patients with HoFH include those who are true homozygotes but also encompasses compound heterozygotes and double heterozygotes . Due to impairment of the LDLR, most conventional LDL cholesterol lowering medications, which ultimately work by upregulation the LDLR in the liver, are not effective in the treatment of HoFH .
Study Overview: Alirocumab Efficacy and Safety in Adults with Homozygous Familial Hypercholesterolemia (ODYSSEY HoFH)
Alirocumab is a human monoclonal antibody against PCKS9 that has been shown to significantly lower LDL-C and reduce risk for ASCVD in high-risk secondary prevention patients [9••]. ODYSSEY HoHF was a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of alirocumab in patients with HoFH . The study enrolled patients with a diagnosis of HoFH by at least 1 of the following genotypic or clinical criteria: documented homozygous or compound heterozygous mutations in both LDLR alleles; presence of homozygous or compound heterozygous mutations in APOB, PCSK9, or LDLRAP1; presence of double heterozygous mutations; untreated total cholesterol (TC) > 500 mg/dL and TG < 300 mg/dL and both parents with history of TC > 250 mg/dL or cutaneous or tendinous xanthomas before age 10 years. Of note, patients with null mutations in both LDLR alleles were excluded. Other inclusion criteria included age ≥ 18 years, LDL-C ≥ 70 mg/dL, and being on stable lipid lowering therapy and/or apheresis. Patients were randomized 2:1 to either alirocumab 150 mg IV every 2 weeks or placebo IV every 2 weeks for 12 weeks. The primary efficacy endpoint was percent change (standard error [SE]) from baseline in LDL-C versus placebo at week 12. Secondary endpoints included the proportion of participants with ≥ 30% and ≥ 50% reduction in LDL-C at week 12 as well as percent change in TC, apoB, non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein (a) (Lp[a]) from baseline to 12 weeks.
Overall, the trial included 69 patients, 45 in the alirocumab group and 24 in the placebo group. The mean baseline LDL-C for the alirocumab and placebo groups were 295.0 mg/dL and 259.6 mg/dL, respectively. At screening, 97.8% of participants in the alirocumab group were on a statin, 66.7% were on statin plus ezetimibe, 15.6% were on lomitapide, and 13.3% were on apheresis plus other lipid lowering agents. By comparison, 95.8% of participants in the placebo group were on a statin, 79.2% were on statin plus ezetimibe, 12.5% were on lomitapide, and 16.7% were on apheresis plus other lipid lowering therapy. At 12 weeks, there was a LDL-C change of − 26.9 (4.6)% from baseline (− 62.8 [14.0]mg/dL) in the alirocumab group and 8.6 (6.3)% from baseline (8.9 [19.0]mg/dL) in the placebo group. The least squares (LS) mean difference of LDL-C percent change versus placebo at week 12 was − 35.6 (7.8)%, p < 0.0001. There were 57.1% of participants in the alirocumab group that demonstrated ≥ 30% reduction in LDL-C at 12 weeks compared to 4.2% in the placebo group (p = 0.0010). Meanwhile, there were 26.7% of participants in the alirocumab group that demonstrated ≥ 50% reduction in LDL-C at 12 weeks compared with 0% in the placebo group (p = 0.0017). There was a further significant reduction (LS mean [SE]) in TC (− 26.5 [6.2]%, p < 0.0001), apoB (− 29.8 [6.3]%, p < 0.0001), non-HDL-C (− 32.9 [7.4]%, p < 0.0001), and Lp(a) (− 28.4 [6.7]%), p < 0.0001). There appeared to be a more consistent effect of alirocumab compared with placebo in patients with compound heterozygous mutations for LDLR and those who were double heterozygotes or heterozygotes (LDLR mutation + other benign variant). With regard to safety, the percentage of total treatment-emergent adverse events (TEAEs) were numerically similar (44.4% in the alirocumab group and 50.0% in the placebo group). Injection site reactions (2.2%), general allergic events (2.2%), and diarrhea (6.7%) were observed in the alirocumab group but not in the placebo group. There were no serious adverse events, deaths, or discontinuations due to TEAEs.
Study Overview: Evinacumab in Patients with Homozygous Familial Hypercholesterolemia
Angiopoeitin-like protein 3 (ANGPTL3) is a hepatic secretory protein that inhibits lipoprotein lipase and endothelial lipase, enzymes involved in triglyceride and HDL-C metabolism. Mendelian randomization studies have shown that ANGPTL3 is likely casually related to ASCVD . In animal models including LDLR knockouts as well as early human studies of hypercholesterolemia, lowering levels of ANGPTL3 is also associated with reduction in LDL-C, though the mechanism remains unclear . Evinacumab is a human monoclonal antibody directed against the ANGPTL3 protein. Targeting of ANGPTL3 is thought to reduce LDL-C independent of LDLR .
This phase 3, randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of evinacumab compared to placebo . Enrolled patients had a diagnosis of HoFH by at least 1 of the following criteria: homozygous mutations in both LDLR alleles; homozygous or compound heterozygous mutations in APOB or PCSK9; double heterozygous mutations or patients with homozygous LDLRAP1 mutations; untreated TC > 500 mg/dL and TG < 300 mg/dL and both parents with history of TC >250 mg/dL or cutaneous or tendinous xanthomas before age 10 years. Included patients also had to be ≥ 12 years of age, have LDL-C ≥ 70 mg/dL, and be on stable, maximally tolerated lipid-lowering therapy. Included patients were then randomized 2:1 to either evinacumab 15 mg/kg IV every 4 weeks or placebo IV every 4 weeks for 24 weeks. The primary efficacy endpoint was percent change (standard error [SE]) from baseline in LDL-C versus placebo at week 24. Key secondary endpoints included absolute change in LDL-C, the proportion of participants with ≥ 30% and ≥ 50% reduction in LDL-C at week 24 as well as the proportion of patients who met US apheresis eligibility criteria (LDL ≥ 300 mg/dL), and the proportion of patients with LDL-C < 100 mg/dL.
The study included a total of 65 participants, 43 in the evinacumab group and 22 in the placebo group. The mean baseline LDL-C for the evinacumab and placebo groups were 259.5 mg/dL and 246.5 mg/dL, respectively. At screening, 95.3% of participants in the evinacumab group were on a statin, 76.7% were on ezetimibe, 79.1% were on a PCSK9 inhibitor, 48.8% were on statin, ezetimibe plus PCSK9 inhibitor, 25.6% were on lomitapide, and 32.6% received apheresis. In the placebo group, 90.9% were on a statin, 72.7% were on ezetimibe, 72.7% were on a PCSK9 inhibitor, 36.4% were on statin, ezetimibe plus PCSK9 inhibitor, 13.6% were on lomitapide, and 36.4% received apheresis. At 24 weeks, the evinacumab group showed a LDL-C change of − 47.1 (4.6)% from baseline compared with 1.9 (6.5)% in the placebo group. The LS mean difference for LDL-C percent change versus placebo was − 49.0 (8.0)%, p < 0.0001. There did not appear to be a significant difference of effect in participants with null/null mutations compared with those with not null/null mutations. The absolute change in LDL-C was − 134.7 (12.4) mg/dL in the evinacumab group versus − 2.6 (17.6) mg/dL in the placebo group with a LS mean difference of − 132.1 (21.5) mg/dL, p < 0.0001). When evinacumab was compared with placebo, 83.7% vs. 18.2% demonstrated ≥ 30% reduction in LDL-C at 24 weeks (p < 0.0001); 55.8% vs. 4.5% demonstrated ≥ 50% reduction in LDL-C at 24 weeks (p = 0.003); 7.0% vs. 22.7% met US apheresis eligibility criteria at 24 weeks (p = 0.085); 46.5% vs. 22.7% had LDL-C < 100 mg/dL at 24 weeks (p = 0.020). There was a further significant reduction (LS mean) in TC (− 48.4%, p < 0.0001), apoB (− 36.9%, p < 0.0001), non-HDL-C (− 51.7%, p < 0.0001), and triglycerides (− 50.4%, p < 0.0001). There was not a significant change in Lp(a) between the evinacumab and placebo groups at 24 weeks (− 1.9%, p = 0.7906). With regard to safety, there were numerically less TEAEs in the evinacumab compared with the placebo group (65.9% vs. 81.0%). However, there were numerically more, though rare, SAEs in the evinacumab group compared with placebo (4.5% vs. 0%).
HoFH patients are at very high risk for the development of ASCVD due to cumulative exposure to severely elevated LDL-C levels starting in early age. Moreover, HoFH is a difficult lipid disorder to treat given modest response to traditional lipid lowering agents. The above studies suggest the PCSK9 inhibitor alirocumab has some effect on LDL-C, which is consistent with previous studies in HoFH with evolocumab [15•]. However, the response to treatment appeared more robust and consistent in patients who were compound or double heterozygotes compared with those who were homozygotes for pathogenic mutations. In addition, null/null homozygous patients were excluded from ODYSSEY-HoFH. Evinacumab, which likely acts independently of LDLR pathway, appears to be a more potent LDL-C agent in patients with HoFH, even in those with null/null LDLR mutations. The results from the evinacumab study, while promising, should be viewed with caution as more data is needed to ascertain its long-term efficacy, safety, and tolerability. Finally, these studies underscore the potential role of genetic testing in HoFH, which may ultimately guide therapy.