Enzyme Replacement Therapy:

Approvals and Management

Growth of the ERT landscape is trending, and the market is anticipated to grow significantly over the next decade.

Enzyme replacement therapy (ERT) is a treatment of congenital enzyme deficiencies using purified human, animal, or recombinant enzyme preparations in patients who suffer from chronic conditions due to enzyme deficiencies or malfunction.1, 2 The replacement enzymes used for ERT are derived from genetically modified and processed human, animal, and plant cells.1, 2 ERT is most commonly administered via intravenous (IV) infusion.

Lysosomal storage diseases (LSDs) are rare, chronic, inherited diseases that are the most common conditions treated with ERT.1, 2 These diseases occur when enzymes are absent or malfunctioning inside the lysosomes, which break down proteins and other macromolecules in the body. Some LSDs treated with ERT include Fabry, Gaucher, and Pompe diseases.1, 2

Recent Approvals

Velmanase alfa-tycv (Lamzede®)

In February 2023, velmanase alfa-tycv (Lamzede®) was approved by the U.S. Food & Drug Administration (FDA) for the treatment of adults and children with non-central nervous system manifestations of α-mannosidosis, a rare genetic condition in which the body is unable to properly break down certain complex sugars in cells.3 This condition is an ultra-rare, progressive LSD caused by deficiency in the enzyme α-mannosidase.3 Velmanase alfa is a recombinant form of human α-mannosidase used to provide or supplement natural α-mannosidase and is the first ERT approved for the treatment of rare α-mannosidasis in the U.S.3

The effectiveness of velmanase alfa was evaluated in adults and pediatric patients with α-mannosidosis in a phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel group study.4 Efficacy was evaluated over 52 weeks at a dose of 1 mg/kg given weekly as an IV infusion.4 Of a total of 25 enrolled patients, including 13 adults and 12 pediatric patients, 15 patients (eight adult, seven pediatric) received velmanase alfa and 10 patients (five adult, five pediatric) received placebo.4 Clinical endpoints assessed at 12 months included a 3-minute stair climbing test, 6-minute walking test, and forced vital capacity, all of which favored the velmanase alfa group and were supported by a reduction in serum oligosaccharide concentration.4

Adverse reactions associated with velmanase alfa include hypersensitivity reactions, including anaphylaxis; thus, appropriate medical support measures, including resuscitation equipment, should be readily available during administration.3 Additional warnings include infusion-associated reactions and risk of embryo-fetal toxicity.

Pegunigalsidase alfa-iwxi (ELFABRIO)

The FDA approved pegunigalsidase alfa-iwxi (ELFABRIO) in May 2023 for the treatment of adults with Fabry disease.5 This is an alternate treatment with a unique mechanism of action for this rare disease patient population.5 Pegunigalsidase alfa is a PEGylated ERT comprised of recombinant human α-Galactosidase-A enzyme, expressed in plant-cell culture designed for elongated half-life.5

Approval was based on findings from three phase 3 trials: BALANCE, BRIDGE, and BRIGHT, along with a phase 1/2 trial.5 The combined trials involved more than 140 individuals with Fabry disease with up to 7.5 years of follow-up treatment. Results showed efficacy in both ERT-naïve and ERT-experienced patients.5

The open-label, single-arm, phase 3 BRIDGE trial assessed the safety and efficacy of treatment in adults with Fabry, aged 24 to 60 years, who previously received a stable dose of agalsidase alfa for at least two years.6 Patients showed substantial improvement in renal function as measured by mean annualized estimated Glomerular Filtration Rate (eGFR slope) in patients who were switched from agalsidase alfa to pegunigalsidase alfa.6 BRIDGE results showed mean annualized eGFR slope of the study participants improved from -5.90 ml/min/1.73m2/year to -1.19 mL/min/1.73m2/year on agalsidase alfa to pegunigalsidase alfa, respectively.

A 12-month, open-label, switch-over BRIGHT study of 30 patients with Fabry disease treated previously with an ERT such as agalsidase alfa or agalsidase beta assessed patients after receiving treatment with pegunigalsidase alfa 2 mg/kg every four weeks; no patients developed treatment-induced anti-drug antibodies and no Fabry clinical events were reported.6 During the study, plasma lso-Gb3 concentrations remained stable during the study with a mean change of 3.01 nM from baseline to week 52.6 Mean absolute change of eGFR values remained stable during the treatment period.6

Pegunigalsidase alfa comes with a safety label stating clinicians should consider pretreating Fabry with antihistamines, antipyretics, and/or corticosteroids before administration and that patients should immediately discontinue treatment if a severe hypersensitivity reaction or severe infusion-associated reaction occurs.5

Avalglucosidase alfa-ngpt (NEXVIAZYME®)

The FDA previously approved avalglucosidase alfa-ngpt (NEXVIAZYME®) for the treatment of late-onset Pompe disease in patients 1 and older in August 2021. Avalglucosidase alfa is an IV ERT that helps reduce glycogen accumulation.7 A study of 100 patients demonstrated effectiveness; patients were randomized to receive avalglucosidase alfa or another FDA-approved ERT for Pompe disease.8 Avalglucosidase alfa treatment was associated