Vimizim (elosulfase alfa) / BioMarin - LARVOL DELTA

Role of Real-World Evidence (RWE) in Pricing and Reimbursement Decisions for Rare Disease in Health Technology Assessment (HTA) Submissions Across EU4 + UK (ISPOR-EU 2025) - "Onasemnogene abeparvovec and Elosulfase alfa were reimbursed in all five markets... HTA bodies have primarily accepted RWE to provide external comparators or to supplement clinical effectiveness data in rare disease therapies, though acceptance remains variable across agencies and may become more standardized under the EU Joint Clinical Assessment (EU-JCA)."

Clinical • HEOR • Pricing • Real-world • Real-world evidence • Reimbursement • US reimbursement • CNS Disorders • Gene Therapies • Rare Diseases

Association of Elosulfase Alpha for Quality of Life In Morquio IV-A Syndrome: A Case Series (SSIEM 2023) - No abstract available

Clinical • HEOR

Long-term outcomes of elosulfase alfa enzyme replacement therapy in adults with MPS IVA: a sub-analysis of the Morquio A Registry Study (MARS). (PubMed, Orphanet J Rare Dis) - "Real-world data collected from MARS suggest that patients with MPS IVA who initiated ERT in adulthood remained stable over 7 years of follow-up. No new safety signals were identified."

Journal • Rare Diseases

Recent advances in mucopolysaccharidosis IVA treatment. (PubMed, Orphanet J Rare Dis) - "Although enzyme replacement therapy (ERT) with elosulfase alfa is currently the only approved treatment, its clinical benefit on bone pathology is limited due to rapid clearance and poor penetration into avascular cartilage. Strategies to enhance enzyme stability and targeting, such as PEGylated hydrogels and extracellular vesicles, have shown promise in enhancing the biodistribution and stability of GALNS, while pharmacological chaperones, including ezetimibe, pranlukast, and bromocriptine, seem to stabilize GALNS in vitro...Importantly, recent evidence revealed that mitochondrial dysfunction in chondrocytes may contribute to the pathology of MPS IVA, uncovering new targets beyond GALNS enzyme activity recovery. This review highlights recent advances in the treatment of MPS IVA and discusses new directions to improve outcomes in MPS IVA treatment."

Journal • Review • Gene Therapies • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

Natural History of Atypical Morquio A Disease (clinicaltrials.gov) - P=N/A | N=7 | Completed | Sponsor: GOIZET | Recruiting ➔ Completed | N=10 ➔ 7 | Trial completion date: Jul 2027 ➔ Sep 2025

Enrollment change • Trial completion • Trial completion date

Real-world treatment with elosulfase alfa in patients with MPS IVA is associated with improved endurance over time. (PubMed, Genet Med Open) - "Standing height was also associated with longer 6MWT in the multivariate quantile analysis, except in participants aged 5 to <7 years. This analysis assessed associations between ERT exposure and endurance to confirm the real-world, long-term effectiveness of elosulfase alfa in participants with MPS IVA."

HEOR • Journal • Real-world evidence

Exploring Multivalent Architectures for Binding and Stabilization of N-Acetylgalactosamine 6-Sulfatase. (PubMed, Molecules) - "Currently, enzyme replacement therapy (ERT) is used to treat Morquio A through the infusion of the recombinant enzyme VIMIZIM® (elosulfase alfa, BioMarin)...We report in this work the synthesis of a library of multivalent glycomimetics exploiting the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between several dendrimeric scaffolds armed with terminal alkynes and azido ending iminosugars of different structures (pyrrolidines, piperidines, and pyrrolizidines) or simple azido ending carbohydrates as bioactive units. The biological evaluation identified pyrrolidine-based nonavalent dendrimers 1 and 36 as the most promising compounds, able both to bind the native enzyme with IC50 in the micromolar range and to act as enzyme stabilizers toward rhGALNS in a thermal denaturation study, thus identifying promising compounds for a combined PC/ERT therapy."

Journal

Efficacy of different treatment strategies in patients with mucopolysaccharidosis: a systematic review and network meta-analysis of randomized controlled trials. (PubMed, Orphanet J Rare Dis) - "In MPS IV, 6-min walking test (6MWT) (40.82, 95% CI[16.19, 64.92]) and 3-min stair climb test (3MSCT) (16.07, 95% CI[12.16, 21.62]) were significantly increased in patients who took elosulfase alfa at a dose of 4.0 mg/kg/week compared with the placebo group. In MPS VI, recombinant human arylsulfatase B (rhASB) and galsulfase (1.0 mg/kg/week) significantly reduced uGAG aggregation compared with the placebo group (-217, 95% CI[-258, -176]) and galsulfase (2.0 mg/kg/week) group (-286.5, 95% CI[-436.5, -136.5]), respectively...ERT alleviated symptoms to some extent, but current evidence was insufficient. Hence, further evidence from large-sample RCT is needed."

Journal • Retrospective data • Review

Long-term outcomes of enzyme replacement therapy from a large cohort of Korean patients with mucopolysaccharidosis IVA (Morquio A syndrome). (PubMed, Mol Genet Metab Rep) - "At follow-up, patients experienced improvements in functional independence measure score, ejection fraction, and the 6-min walk test compared with the pre-treatment baseline. This study provides real-world evidence for long-term stabilization of functional independence, endurance, and respiratory function among patients with MPS IVA treated with ERT, with no new safety concerns identified."

Journal • Dermatology • Hurler Syndrome • Immunology • Lysosomal Storage Diseases • Metabolic Disorders • Pain • Rare Diseases • Urticaria

The Impact of Weight-Based Dosing on Pricing and Reimbursement Outcomes for Ultra-Rare Disease Treatments in the EU4 (ISPOR-EU 2024) - "All 7 drugs were reimbursed in all EU4 markets, except for vestronidase alfa in France and elosulfase alfa, asfotase alfa, velmanase alfa and olipudase alfa in Spain where these treatments were not recommended for reimbursement. Although most treatments were reimbursed in all markets at a relatively high list price, it is likely that significant confidential discounts would have been required, as suggested by price reductions following negotiations in Germany. The high number of treatments not recommended for reimbursement in Spain suggests payer uncertainty due to high costs and weight-based dosing in this budget-focused market. It is important for payers and manufacturers to work together to manage the uncertainty of weight-based dosing to reach an agreement that satisfies all stakeholders and enables access for patients in need."

Pricing • Reimbursement • US reimbursement • Pediatrics • Rare Diseases

Cost of Treatment for Mucopolysaccharidosis IV-A in a Poor Population in Colombia (ISPOR-EU 2024) - "Elosulfase Alfa IV was the main and most expensive treatment consumed by these patients... This study provides strategic information for the planning of health care strategies. Extrapolating the costs to the prevalence of the disease in Colombia could estimate the economic burden and its impact on the Colombian health system. The use of enzyme replacement therapy (ERT) contributes to cost reduction by minimizing the risk of bone, respiratory, infectious, ear/hearing, cardiovascular, dental, and ophthalmological complications that deteriorate the quality of life of patients."

Clinical • HEOR • Treatment costs • Cardiovascular • Genetic Disorders • Ophthalmology

FOUR SIBLINGS WITH MUCOPOLYSACCHARIDOSIS TYPE IV A RECEIVING ENZYME REPLACEMENT THERAPY: IMPACT OF CONSANGUINITY (SSIEM 2024) - "Lysosomal storage disease was suspected clinically, and the diagnosis was confirmed by whole exome sequence showing homozygous pathogenic mutation in the GALNS gene and was accordingly started on ERT, Elosulfase Alfa...Given the disease's mode of inheritance, this family reflects the effects of increased consanguinity rate among Saudi population, therefore we recommend to add MPS IVA to premarital screening for families at risk. Palavras-chave : Mucopolysaccharidosis, Consanguinity, Enzyme Replacement Therapy (ERT)"

Hurler Syndrome • Lysosomal Storage Diseases • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Rare Diseases

MUCOPOLYSACCHARIDOSES IN ADULT PATIENTS – ONE CENTRE EXPERIENCE (SSIEM 2024) - "ERT depended on the MPS`s type and included laronidase, idursulfase, elosulfase alfa, and galsulfase. Our patients treated with ERT have good compliance and almost no significant progression of their diseases in ten-year follow-up."

Clinical • Alzheimer's Disease • Atrial Fibrillation • Cardiovascular • Cognitive Disorders • Hurler Syndrome • Infectious Disease • Lysosomal Storage Diseases • Metabolic Disorders • Musculoskeletal Diseases • Rare Diseases • Respiratory Diseases

LONG-TERM OUTCOME OF ENZYME REPLACEMENT THERAPY FROM A LARGE COHORT OF KOREAN PATIENTS WITH MUCOPOLYSACCHARIDOSIS IVA (MORQUIO A SYNDROME) (SSIEM 2024) - "We report the long-term outcome of elosulfase alfa enzyme replacement therapy (ERT) as well as clinical and genetic features in Korean patients with MPS IVA... This is a long-term observational study of Korean MPS IVA patients in one single center. We provide real-world evidence for long-term stabilization of functional independence, endurance, and respiratory function among ERT-treated patients, with no new safety concerns identified."

Clinical • Lysosomal Storage Diseases • Metabolic Disorders • Orthopedics • Rare Diseases

Potential Targeting Mechanisms for Bone-Directed Therapies. (PubMed, Int J Mol Sci) - "Although direct recombinant enzymes (e.g., Vimizim for Morquio, Cerezyme for Gaucher, Elaprase for Hunter, Mepsevii for Sly diseases) or hormone infusions (estrogen for osteoporosis and osteoarthritis), traditional gene delivery (e.g., direct infusion of viral or non-viral vectors with no modifications on capsid, envelope, or nanoparticles), and cell therapy strategies (healthy bone marrow or hematopoietic stem cell transplantation) partially improve bone lesions, novel delivery methods must be addressed regarding target specificity, less immunogenicity, and duration in circulation. Targeted drug delivery using organic and inorganic compounds is a promising approach in mostly preclinical settings and future clinical translation. This review comprehensively summarizes the current bone-targeting strategies based on bone structure and remodeling concepts while emphasizing potential approaches for future bone-targeting systems."

Journal • Review • Bone Marrow Transplantation • Immunology • Osteoarthritis • Osteoporosis • Pain • Rheumatology • Transplantation

A Multicenter, Multinational, Observational Morquio A Registry Study (MARS) (clinicaltrials.gov) - P=N/A | N=418 | Completed | Sponsor: BioMarin Pharmaceutical | Active, not recruiting ➔ Completed | Trial completion date: Sep 2024 ➔ Feb 2024 | Trial primary completion date: Sep 2024 ➔ Feb 2024

Trial completion • Trial completion date • Trial primary completion date

Integrated Management of an Adult Patient with Mucopolysaccharidosis type IVA: A Case Report with a Six-Year Follow-up. (PubMed, Eur J Case Rep Intern Med) - "Mucopolysaccharidosis type IVA (MPS-IVA) is a genetic, rare, and degenerative spondylo-epiphyso-metaphyseal dysplasia characterized by extra-skeletal and skeletal manifestations. The latter impacts on MPS-IVA patient daily activities, and enzyme replacement therapy has a poor efficacy in improving skeletal involvement.The proposed integrated management with enzyme replacement therapy, zoledronic acid, cholecalciferol and bone diet improve both bone mineral density and the prognosis quoad valetudinem of our MPS-IVA patient."

Journal • Lysosomal Storage Diseases • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoporosis • Pain • Rare Diseases • Rheumatology

A Multicenter, Multinational, Observational Morquio A Registry Study (MARS) (clinicaltrials.gov) - P=N/A | N=418 | Active, not recruiting | Sponsor: BioMarin Pharmaceutical

Trial completion date • Trial primary completion date

Natural History of Atypical Morquio A Disease (clinicaltrials.gov) - P=N/A | N=10 | Recruiting | Sponsor: GOIZET | Active, not recruiting ➔ Recruiting | Trial completion date: Jul 2023 ➔ Jul 2027 | Trial primary completion date: Feb 2020 ➔ Feb 2025

Enrollment open • Trial completion date • Trial primary completion date

Bone Growth Induction in Mucopolysaccharidosis IVA Mouse. (PubMed, Int J Mol Sci) - "Enzyme replacement therapy with elosulfase alpha provides a limited impact on bone growth and skeletal lesions in MPS IVA patients...CNP peptide also changed the pattern of GAG levels in bone and liver. These results suggest the potential for CNP peptide to be used as a treatment in MPS IVA patients."

Journal • Preclinical • Cardiovascular • Gene Therapies • Lysosomal Storage Diseases • Metabolic Disorders • Orthopedics • Rare Diseases

Economic Modeling Insights for Ultra Orphan Drugs Based on Review of NICE Highly Specialized Technology (HST) Assessment Reports (ISPOR 2023) - "Case studies highlight lessons related to change in comparators (e.g. Givosiran), allowing proxy collection of utility scores from clinical experts (e.g. Cerliponase alfa; which could potentially addresses the disability paradox issue for severe rare diseases), allowing caregiver and sibling disutility in nearly all submissions (e.g. Cerliponase alfa, Setmelanotide, Atidarsagene, Burosumab, Elosulfase alfa), stopping rules (e.g. Inotersen, Volanesorsen, Patisiran), use of transition probabilities from trial versus natural history study (e.g. for Cerliponase alfa NICE preferred trial based probabilities), capturing mortality from trial, real-world or general population (e.g for Voretigene neparvovec) and treatment effect waning assumptions (eg. Burosumab, Odevixibat). Previous HST submissions provide valuable insights and lessons for future ultra orphan economic modeling. In many instances NICE mentioned benefits that were not captured by the sponsor and also allowed or..."

NICE • Orphan drug • Review • Rare Diseases

The First Managed Entry Agreements Based on Health Technology Assessment Approved in Ukraine: Analysis and Future Perspectives (ISPOR 2023) - "So, henceforth patients in Ukraine will get an improved access to 10 medicines for rare diseases: risdiplam, plasma-derived C1-esterase inhibitor, factor VIII inhibitor bypassing activity, alglucosidase alfa, imiglucerase, velaglucerase alfa, elosulfase alfa, galsulfase, idursulfase, laronidase. Conclusion of the first MEAs based on HTA is an effective tool to improve patients' access to innovative medicines and make efficient resource allocation for public payer expenditures in Ukraine."

Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Modelling Long-Term Treatment Effects for Chronic Progressive Conditions (ISPOR-EU 2022) - " Three SMA appraisals and two appraisals in other relevant chronic disease areas were reviewed: TA588 (nusinersen in SMA), TA755 (risdiplam in SMA), HST15 (onasemnogene abeparvovec in SMA), TA585 (ocrelizumab in primary progressive multiple sclerosis) and HST19 (elosulfase alfa in mucopolysaccharidosis type 4a)... The modelling of long-term treatment effects, in the light of limited data to robustly inform this, remains challenging and has been addressed through different pragmatic approaches in recent NICE appraisals. The inclusion of treatment effect maintenance or waning should therefore generally be considered early on."

CNS Disorders • Genetic Disorders • Movement Disorders • Multiple Sclerosis • Muscular Atrophy • Rare Diseases

IUERT: In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases (clinicaltrials.gov) - P1 | N=10 | Recruiting | Sponsor: University of California, San Francisco | Trial completion date: Apr 2032 ➔ Jul 2032 | Trial primary completion date: Apr 2031 ➔ Jul 2031

Trial completion date • Trial primary completion date • Gaucher Disease • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Pompe Disease • Rare Diseases

Findings from the Morquio A Registry Study (MARS) after 6 years: Long-term outcomes of MPS IVA patients treated with elosulfase alfa. (PubMed, Mol Genet Metab) - "MARS is the longest and largest observational study of MPS IVA patients to date, with a heterogenous population that is representative of the MPS IVA population overall. Data collected over the first 6 years of MARS provide real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients, with no new safety concerns identified."

Journal • Dermatology • Immunology • Urticaria