Amgen's PCSK9 Inhibitor Repatha Achieves Primary Endpoint in Phase 3b Pediatric Study for HeFH

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From August 27 to 29, 2020, the European Association for the Study of the Liver (EASL) Annual Meeting and the Digital International Liver Congress™ (DILC) were grandly convened as an online event. This marked the first time EASL held its annual flagship conference in a “digital congress” format, attracting scientific and medical experts from around the world to learn about the latest advances in liver research and to exchange clinical experience.

On August 29, Amgen announced positive data from the Phase IIIb HAUSER-RCT study evaluating Repatha (Chinese brand name: Ruibai’an; generic name: evolocumab) for the treatment of pediatric patients aged 10 to 17 years with heterozygous familial hypercholesterolemia (HeFH). The study demonstrated that, when used in combination with statins and other lipid-lowering therapies, Repatha significantly reduced low-density lipoprotein cholesterol (LDL-C) levels compared with placebo. These findings were presented at the European Society of Cardiology (ESC) 2020 Congress, held online from August 29 to September 1, and simultaneously published in The New England Journal of Medicine.

HeFH is a hereditary disorder characterized by elevated LDL-C levels at birth, which accelerates the progression of ASCVD and increases the overall risk of cardiovascular events. Patients with familial hypercholesterolemia (FH) have approximately a 20-fold higher risk of developing heart disease compared to the general population. Children with FH maintain high LDL-C levels despite having normal body weight, a healthy diet, and adequate physical activity, thereby facing the risk of cardiovascular events from an early age.

The HAUSER-RCT is a Phase 3b, multicenter, randomized (2:1), double-blind, placebo-controlled study conducted in patients aged 10–17 years with heterozygous familial hypercholesterolemia (HeFH) to evaluate the efficacy, safety, and tolerability of once-monthly subcutaneous injections of Repatha 420 mg (n=104) versus placebo (n=53) over 24 weeks. Randomization was stratified by LDL-C levels (<4.1 vs. ≥4.1 mmol/L) and age (<14 vs. ≥14 years). Key eligibility criteria included being on a low-fat diet and maximally tolerated lipid-lowering therapy (LLT) for at least 4 weeks prior to screening, with fasting LDL-C levels ≥3.4 mmol/L. The primary endpoint was the percentage change in LDL-C levels from baseline to Week 24 of treatment. Secondary endpoints included the mean percentage change in LDL-C from baseline to Weeks 22 and 24, the absolute change in LDL-C from baseline to Week 24, and the percentage changes from baseline to Week 24 in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), the total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio, and the ApoB/apolipoprotein A1 (ApoA1) ratio. Further safety assessments included Tanner staging, hormone levels, carotid intima-media thickness, and computerized cognitive assessments.

The results showed that the study met its primary endpoint: at Week 24 of treatment, the Repatha group demonstrated a mean relative reduction from baseline in LDL-C levels of 38.3% and an absolute reduction in LDL levels of 68.6 mg/dL, compared with the placebo group.

Furthermore, compared with the placebo group, the Repatha group also demonstrated improvements from baseline in secondary lipid parameters, including: a 42.1% reduction in mean LDL-C at weeks 22–24, a 35.0% reduction in non-HDL-C levels at week 24, a 32.5% reduction in ApoB levels at week 24, and a 36.4% reduction in the ApoB/ApoA1 ratio at week 24.

No new safety risks were identified in the study. The most common treatment-emergent adverse events (TEAEs, >2%) occurring at a higher incidence in the Repatha group than in the placebo group (>1%) included headache, oropharyngeal pain, influenza, influenza-like illness, upper respiratory tract infection, and constipation.

Effective management of LDL-C levels in children with HeFH is crucial, as it helps delay the progression of cardiovascular disease. Data from the HAUSER-RCT study confirm that Repatha is a safe and effective treatment option for children with HeFH who are already receiving lipid-lowering therapy but require further reduction in LDL-C levels.

Competitive Landscape of New Cholesterol-Lowering Drugs

Repatha is a human monoclonal antibody that targets proprotein convertase subtilisin/kexin type 9 (PCSK9). By binding to PCSK9, Repatha inhibits the interaction between circulating PCSK9 and low-density lipoprotein (LDL) receptors (LDLR), thereby preventing PCSK9-mediated LDLR degradation and allowing LDLRs to recycle back to the surface of hepatocytes. Through this inhibition of PCSK9-LDLR binding, Repatha increases the number of LDLRs available to clear LDL from the bloodstream, thus reducing LDL-C levels.

PCSK9 inhibition represents a major breakthrough in cholesterol-lowering therapy following statins. To date, two monoclonal antibody PCSK9 inhibitors have been approved, one of which is Sanofi/Regeneron’s Praluent. Both drugs are biologics with high prices, leading to an intense and prolonged price war since their market launch as they compete for dominance. The success of pediatric studies is crucial for Amgen, as it will help expand the patient pool for Repatha from adults to adolescents.

Amid intense competition, Novartis, as a latecomer, also aims to enter the PCSK9 market with its siRNA therapy inclisiran, the core asset acquired through the $9.7 billion purchase of The Medicines Company (TMC). This therapy requires only two subcutaneous injections per year and is currently under regulatory review in the United States and the European Union. Meanwhile, three existing drugs are facing new challengers: Esperion’s first-in-class ACL inhibitor Nexletol (bempedoic acid) and its combination product Nexlizet (bempedoic acid/ezetimibe). These two drugs feature a novel cholesterol-lowering mechanism and were approved for marketing in the United States and the European Union in the first half of this year, with prices representing only a fraction of those of PCSK9 monoclonal antibodies. It is foreseeable that competition in the cholesterol-lowering drug market will further intensify in the coming period.

Reference Source:

1.Amgen Announces Positive Data From Phase 3B Study Of Repatha? (Evolocumab) In Pediatric Patients With Heterozygous Familial Hypercholesterolemia At ESC Congress 2020

2.ESC: Amgen chases pediatric use for cholesterol-busting PCSK9 med Repatha

Original Title: Amgen’s PCSK9 Inhibitor Repatha Meets Primary Endpoint in Pediatric Phase 3b Study, Intensifying Competition in the Cholesterol-Lowering Market