Homozygous Familial Hypercholesterolemia (HoFH)

Key Challenges and Opportunities in Accessing Evinacumab Therapy for Patients with HoFH

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Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease in which a low-density lipoprotein-C receptor (LDLR) malfunction hinders its ability to clear LDL-C from the bloodstream sufficiently, resulting in severely elevated low-density lipoprotein LDL-C levels.1,2 In fact, LDL-C levels in patients with HoFH are often twice that in patients with heterozygous FH.2 The HoFH is often noted by childhood onset, owing to markedly abnormal elevations in LDL-C that begin in utero.1

As a result, elevated LDL-C levels in the pediatric HoFH population increase the childhood risk of developing premature atherosclerotic-related complications and cardiovascular diseases such as coronary arterial atherosclerosis and valvular and supravalvular aortic stenosis.1 Patients with HoFH are as much as 3.8 times as likely to suffer a myocardial infarction before reaching 55 years of age.2 HoFH pathogenesis increases younger populations’ susceptibility to other cardiovascular diseases as well, even predisposing them to disability or death during their early childhood and adolescent years. These factors highlight an urgent need for early detection followed by prompt, aggressive intervention with LDL-C-lowering therapy.

Underdiagnosis and undertreatment fall among pediatric HoFH challenges
HoFH has a global prevalence of approximately 1 in 200 – 250 people, encompassing all races and ethnicities.3 Other data suggests a rare occurrence, affecting 1 in 300,000 subjects on average.2 Regardless, the condition remains largely under-diagnosed and addressed. Only 10% of the HoFH population received a diagnosis or sufficient treatment, due to the overall lack of awareness in both the general public as well as among healthcare professionals.3

In 1998, the World Health Organization declared a priority for public health and issued a report highlighting 11 recommendations to improve family screening and education as well as diagnosis and treatment. Yet, nearly 3 decades later, the medical community has made marginal improvements in enacting the recommendations to curtail premature atherosclerotic cardiovascular disease secondary to HoFH. Therefore, patients and healthcare professionals alike must receive education to increase awareness and advocacy.

An autosomal recessive disorder, HoFH requires genetic testing to confirm diagnosis.4 Pediatric patients with the condition carry 2 mutated copies of alleles for LDL, Apo[b], PCSK9, or LDLR adaptor protein gene locus 1. In the clinical setting, diagnosis of pediatric HoFH comprises an LDL-C of 400 mg/dL or greater and at least one parent with one of the following: a clinical diagnosis of FH, autosomal-recessive FH, or a positive result for a defective gene known to raise LDL-C (i.e., LDLR, PCSK9, Apo[b]). Other criteria that could grant a HoFH diagnosis are an LDL-C exceeding 560 mg/ml or 400 in the presence of either xanthomas or aortic valve disease in patients ages two years old and less.

Historically, HoFH treatment options were few and with limited reach
The in-utero onset of HoFH and heightened childhood predisposition to various cardiovascular pathologies expose some gaps in diagnosis and treatment. Because most antilipidemic therapies’ mechanisms of action do not involve the LDL-C pathway or act on the LDLR, they have limited effect on LDL-C.5 Historically, the only treatment options for HoFH were lomitapide, lipoprotein apheresis, and liver transplantation—none of which has mechanisms of action that involve LDLR.5 However, all have their limitations in HoFH. Because lomitapide can cause hepatic fat accumulation, patients on lomitapide therapy must adopt a low-fat diet. Moreover, the dose must be adjusted and titrated to help manage gastrointestinal symptoms. These 3 features make lomitapide therapy unsuitable for the pediatric population, therefore limiting the opportunity for earlier intervention.

Pediatric patients can receive lipoprotein apheresis therapy as early as 3 years of age. However, administration is time-consuming and has limited availability. Moreover, the invasive nature of the procedure can affect the patient’s quality of life.

Lastly, liver transplantation presents a curative option for HoFH; however, transplantation is limited by the scarcity of organ donors. In addition, donor recipients face challenges such as post-transplantation surgical complications and mortality. In addition, transplant recipients require life-long immunosuppressive treatment. The limitations of all 3 treatment options leave a huge void to be filled in the pediatric HoFH treatment space.

Despite the increased risk of morbidity and mortality, HoFH has had limited treatment options as a whole. That changed when the Food and Drug Administration approved evinacumab, an angiopoietin-like 3 inhibitor. A fully human monoclonal antibody, the agency first approved the treatment in February of 2021 for patients 12 years of age and older with HoFH. In March of 2023, the FDA extended the indication for concomitant administration with other lipid-lowering therapies for HoFH in pediatric patients ranging from 5 to 11 years of age.1,6

“Evinacumab is a breakthrough in treating pediatric HoFH because it is feasible in small patients, instead of being potentially dangerous in patients with very small plasma volume—true of apheresis and it does not require adherence to a low-fat diet, which is difficult in rapidly growing children,” explained Eliot Brinton, MD, President and Director of the Utah Lipid Center. “Evinacumab is in many ways the easiest of the 3 treatments useful in severe HoFH, even in adults.”

Prompt, accurate diagnosis and optimal treatment require interdisciplinary collaboration
Clinically, ensuring optimal outcomes in pediatric HoFH requires a concerted group effort among healthcare providers, ordinarily involving cardiologists and endocrinologists who routinely monitor patients’ lipid panels and other important laboratory markers.iv The interdisciplinary team may include pharmacists and nurses initiating intravenous lines and transfusion therapy. Various members of the allied healthcare team may contribute to treatment regimen preparation and administration.

Another critical aspect of the care plan entails granting informed consent regarding treatment risks and benefits before initiating evinacumab therapy.3 The potential risks require engaging emergency department professionals to act swiftly and stabilize the patient. Ultimately, robust and open communication between all medical professional stakeholders forms the foundation of the interdisciplinary team’s success.

Evinacumab therapy’s cost-prohibitive pricing hinders access
The wholesale cost of evinacumab is estimated at $450,000 annually.iv The cost follows the growing trend of many other dyslipidemia therapies and orphan drugs, exceeding many families’ financial reach and creating payer hurdles.

Evinacumab requires prior authorization, and the approval guidelines for evinacumab therapy may vary depending on the payer.v To curtail costs, the National Lipid Association encourages clinicians to implement cost-effective strategies. Among these are weight bands instead of mg/kg criteria and disease individualization based on how the patient’s LDL-C responds.7 Incorporating such strategies can reduce costs by more than one-third (34%) while still delivering the same clinical efficacy.

However, adopting weight band strategies may only ameliorate cost barriers partially. For example, the cost of another class of dyslipidemia therapy, PCSK9 inhibitors, ultimately caused the drugs to fail to achieve blockbuster status. In 2018, insurance companies responded to its $14,000-a-year price tag by instituting complex approval processes. Unfortunately, lowering costs to roughly $8,000 annually produced a minimal increase in prescribing uptake from 0.8% in 2018 to 3% in 2019. Patients whose PCSK9 inhibitor prescriptions were denied faced a 16% increased risk of a cardiovascular event compared to those with approved drugs. As a result, the PCKS9 aftermath has sparked discussion around whether evinacumab access barriers may trigger similar challenges with restrictions or unaffordable copays.

Finally, approval for drugs with orphan designation can vary significantly within the rare disease space.8 One study found that while health plans generally seemed more likely to approve orphan drugs than drugs with non-orphan status, payers rejected as many as one-third of the prior authorizations for orphan drugs. However, evinacumab manufacturer Regeneron has established a patient assistance program covering up to 100% of the first year of therapy for qualifying patients with commercial insurance.9

It takes a village to improve HoFH outcomes
Generally, the unique challenges in the rare disease space have created a unique, hyper-collaborative climate among numerous stakeholders rarely seen in common chronic illnesses. HoFH is no exception. In particular, specific features such as small population size, often-limited treatment options, and accessibility to treatment give rise to interprofessional collaborations among healthcare providers, biotech and pharmaceutical companies, regulatory agencies, academic researchers, centers of excellence, associations, patient advocacy groups, patients, and the like.10

Intimate collaboration optimizes the output of rare disease research efforts and can expedite results.7 For example, an enhanced understanding of causative genes can lead to faster diagnosis, while improving the creation of databases and common registries can improve the understanding of the condition’s natural history and plausible approaches to care. Moreover, the scattered population distribution across the globe warrants a level of international collaboration in rare diseases to improve patients’ outcomes and quality of life not seen with more common conditions.

“Education, by definition, is the most effective in increasing the large under-awareness of providers and patients,” said Dr Brinton. How to best educate them, however, is still being determined.

In some rare diseases, especially those affecting much smaller populations, patients and caregivers often must assume leadership roles to educate various individuals while advocating for increased awareness, treatment, payer coverage, and sometimes, legislation that supports coverage and other needs. Dr Brinton suggests utilizing social media for patient-focused education.

In the meantime, it is imperative that clinicians also receive education to identify the patient population most likely to benefit from evinacumab therapy. However, that knowledge offers little value without understanding how to assist patients in navigating payer barriers and other hurdles that may occur.


  1. Wiegman A, Greber-Platzer S, Ali S, Reijman MD, Brinton EA, Charng MJ, Srinivasan S, Baker-Smith C, Baum S, Brothers JA, Hartz J, Moriarty PM, Mendell J, Bihorel S, Banerjee P, George RT, Hirshberg B, Pordy R. Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia. Circulation. 2024 Jan 30;149(5):343-353. doi: 10.1161/CIRCULATIONAHA.123.065529.
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  6. FDA Update: Agency Expands Use of Evkeeva to Treat Young Children with HoFH. Available at: https://www.acc.org/Latest-in-Cardiology/Articles/2023/03/23/14/44/FDA-Update-Agency-Expands-Use-of-Evkeeva. Published March 23, 2023. Accessed on March 26, 2024.
  7. Ter Heine R, Rongen GA, Roeters van Lennep J, Rutten JHW. Individualized dosing of evinacumab is predicted to yield reductions in drug expenses. J Clin Lipidol. 2023 May-Jun;17(3):401-405. doi: 10.1016/j.jacl.2023.03.004.
  8. Chambers JD, Panzer AD, Kim DD, Margaretos NM, Neumann PJ. Variation in US private health plans’ coverage of orphan drugs. Am J Manag Care. 2019 Oct;25(10):508-512. PMID: 31622066.
  9. Evkeeza: Support your patients at every step. The Regeneron website. Available at: https://www.evkeezahcp.com/s/support-resources. Accessed March 27, 2024.
  10. Julkowska D, Austin CP, Cutillo CM, Gancberg D, Hager C, Halftermeyer J, Jonker AH, Lau LPL, Norstedt I, Rath A, Schuster R, Simelyte E, van Weely S. The importance of international collaboration for rare diseases research: a European perspective. Gene Ther. 2017 Sep;24(9):562-571. doi: 10.1038/gt.2017.29. Epub 2017 Jul 27. PMID: 28440796; PMCID: PMC5628265.