SAT-248 A Case Series of Heterozygous Familial Hypercholesteremia With PCSK9 Inhibitor Failure

Abstract Disclosure: A. Varghese: None. R.A. Hegele: None. A. Berberich: None. Background: Monoclonal antibodies (MABs) to proprotein convertase subtilisin/kexin 9 (PCSK9) are commonly used to treat heterozygous familial hypercholesterolemia (HeFH). Both evolocumab and alirocumab have demonstrated efficacy in reducing low-density-lipoprotein cholesterol (LDL-C) in patients with HeFH. While a few reports describing patients with initial non-response to PCSK9 MAbs, with proposed mechanisms including the development of anti-drug antibodies, medication injection technique and LDLR variant classification, we describe here the rare scenario of initial robust response followed by subsequent loss of response to PCSK9 MAbs in two individuals with HeFH.CASE 1: A 60-year-old woman with a history of relapsing polychondritis was evaluated for dyslipidemia with an initial LDL-C of 6.49mmol/L (251mg/dL). She was diagnosed with HeFH via clinical criteria. Despite treatment with rosuvastatin 40mg daily, LDL-C remained high at 5.35mmol/L (207mg/dL). Evolocumab 140mg every 2 weeks was started and her LDL-C improved to 0.97mmol/L (36.4mg/dL). After one year of stable response, her LDL-C increased to 6.00mmol/L (232mg/dL) despite ongoing treatment. Evolocumab was switched to alirocumab which initially reduced her LDL-C to 2.65 mmol/L (102.5 mg/dL), but it later rose again. Ezetimibe 10mg daily was added and patient is awaiting approval for inclisiran.CASE 2: An 18-year-old woman with type 1 diabetes and celiac disease was seen in September 2012 for dyslipidemia. Prior statin and ezetimibe treatments were discontinued due to myalgias. Her initial LDL-C was 7.23mmol/L (279.6mg/dL). Genetic testing revealed a heterozygous pathogenic LDLR variant (p.Gly723Ter). Pravastatin 40 mg was started but discontinued due to myalgias. Evolocumab 140 mg every two weeks was initiated, and her LDL-C improved to 3.26 mmol/L (126.1 mg/dL). However, after a year, her LDL-C rose to 7.72 mmol/L (298.5 mg/dL). Switching to alirocumab reduced her LDL-C to 1.76 mmol/L (68.1 mg/dL), but within three years, it increased again to 7.65 mmol/L (295.8 mg/dL). Ezetimibe 10 mg daily was reintroduced, but the patient continues to experience refractory hyperlipidemia. Discussion: These two cases demonstrate an unusual loss of response to PCSK9 MAbs after initial successful reduction in LDL-C. We have identified only one other report describing this clinical phenomenon in a patient taking alirocumab. The mechanism underlying these observations is unclear but could include the development of neutralizing antibodies. Both patients described here have a history of autoimmunity, which may suggest a common causal link. Further research is needed to understand the underlying mechanisms and the likelihood of this occurring in other patients. These cases also highlight the need for ongoing vigilance in patients with high cholesterol and HeFH to ensure optimal cardiovascular protection. Presentation: Saturday, July 12, 2025