Brineura (cerliponase alfa) / BioMarin - LARVOL DELTA

LTS-101: An Intracerebroventricular Delivered AAV Gene Therapy Using a Novel Capsid Variant for the Treatment of CLN2 Batten Disease (ASGCT 2025) - "While bi-monthly infusions of recombinant human TPP1 (cerliponase alfa) to the brain have provided benefit to patients, significant disease burden remains and the therapy requires families relocate to infusion centers for the frequent, hours long, infusions...LTS-101 is a promising gene therapy candidate with the potential to treat CLN2 Batten disease patients with a one-time ICV administration providing stable, long-term expression of TPP1 while eliminating the caregiver and patient burden of repeated ERT treatments. Disease Focus of Abstract:Storage/Lysosomal Disorders"

Gene therapy • CNS Disorders • Gene Therapies • Genetic Disorders • Pediatrics • TPP1

ORPHAN DRUGS IN ALZHEIMER'S DISEASE: CROSSROAD OF AMYLOID PATHOLOGY AND LYSOSOMAL STORAGE DISEASES (ADPD 2025) - "To test this hypothesis the effects of cerliponase alfa and taliglucerase alfa on A β accumulation in mouse hippocampal neurons (HT -22 neuronal cells) exposed to fAβ1-42 (a toxic fragment of full -length A β) and markers of autophagy -lysosome pathway related to AD were investigated. Therefore, we suggest that these orphan drugs could be considered promising novel therapeutics for neurodegenerative diseases in which autophagy pathways are impaired."

Alzheimer's Disease • CNS Disorders • Gaucher Disease • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • ATG5 • GBA1 • mTOR

Real-world clinical outcomes of patients with CLN2 disease treated with cerliponase alfa. (PubMed, Front Neurol) - "No ERT-treated patients died. Cerliponase alfa for real-world CLN2 disease treatment slowed decline in motor and language function and demonstrated an acceptable safety profile."

Clinical data • Journal • Real-world evidence • CNS Disorders

Progress in gene therapy for CLN2 Batten disease related retinopathy (ARVO 2025) - "The gene encodes TPP1, a lysosomal enzyme, that permits clearance of toxic lipofuschin particularly in neurons.The disease typically presents with loss of perifoveal ellipsoid at the age of 3-4 years progressing to loss of sub-foveal ellipsoid, and subsequent centripetal spread throughout the fundus; complete vision loss typically occurs by the age of 7-8 years.Intracerebroventricular infusions of the recombinent pro-enzyme rhTPP1 - cerliponase alfa - now mean that children are surviving the disease, but continue to go blind. Our previous work (ARVO poster 2023) has demonstrated intravitreal enzyme replacement slows the progress of decline which maybe dose dependent but studies of the frequency of injection and dose escalation are still required.At ARVO 2024 we presented interim data from the RGX-381 study of ocular CLN2 gene replacement therapy based on the initial 4 patients recruited up to day 180 follow-up...This programme has now transferred ownership to Tern..."

Gene therapy • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders • TPP1

Enzyme Replacement Therapy in CLN2-Associated Retinopathy. (PubMed, Klin Monbl Augenheilkd) - P1/2 | "In 2017, an intracerebroventricular enzyme replacement therapy (ERT) using recombinant human TPP1 (rhTPP1), cerliponase alfa, was approved as a disease-modifying treatment for CLN2 disease...This could be particularly relevant for those patients who were started on intracerebroventricular ERT early and still have good motor and language function. For this patient population, intravitreal ERT could be a valuable bridging therapy until other therapies such as gene therapy become available."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Epilepsy • Gene Therapies • Macular Degeneration • Ophthalmology • Retinal Disorders • TPP1

Speech, Language and Non-verbal Communication in CLN2 and CLN3 Batten Disease. (PubMed, J Inherit Metab Dis) - "Challenging behaviours were common in CLN3 (11/17, 65%), but less frequent in CLN2 (4/16, 25%) disease. Individuals with Batten disease require tailored speech therapy incorporating communication partner training utilising environment adaptations and informal communication behaviours."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Five-year Seizure Outcomes of Pediatric NCL2 Patients Treated with Cerliponase Alfa (AES 2024) - "Patients with NCL2 present with seizures of varying semiology which progresses to refractory epilepsy. Based on this case series, cerliponase alfa infusions improve the seizure burden of patients with NCL2 initially; however, patients show evidence of disease progression after several years on the therapy."

Clinical • CNS Disorders • Developmental Disorders • Epilepsy • Movement Disorders • Pediatrics • TPP1

Adverse Reactions to the Orphan Drug Cerliponase Alfa in the Treatment of Neurolipofuscinosis Type 2 (CLN2). (PubMed, Pharmaceuticals (Basel)) - "The most common adverse reactions were, in decreasing order, fever/pyrexia, device-related infection, vomiting, seizures/convulsions, pleocytosis, irritability, ventriculitis, and respiratory disorders. The results confirm the safety profile of cerliponase alfa established with pre-registration clinical studies but suggest the need for further studies to investigate the occurrence of adverse reactions, as possible predictive prognostic markers, in more depth."

Journal • Orphan drug • CNS Disorders • Epilepsy • Infectious Disease • Respiratory Diseases • TPP1

Psychometric Validation of the CLN2 Quality of Life Questionnaire in Participants with CLN2 Disease Treated with Cerliponase Alfa. (PubMed, Healthcare (Basel)) - "This study is the first to validate the CLN2 QoL and to estimate the CID of this instrument in CLN2 patients. Our results show good validity and reliability of this tool."

HEOR • Journal • CNS Disorders • Epilepsy • Pediatrics

Peripapillary Retinal Nerve Fiber Layer (pRNFL) Thickness - A Novel Biomarker of Neurodegeneration in Late-Infantile CLN2 Disease. (PubMed, Eye Brain) - "All patients received 300 mg of intracerebroventricular enzyme replacement treatment (cerliponase alfa) once every two weeks...Repeated measurements indicated decreases in pRNFL thickness over time in most patients. Patients with late-infantile CLN2 disease exhibit early onset progressive pRNFL loss regardless of outer retinal degeneration, highlighting the potential of pRNFL as an independent ocular biomarker for retinal pathology in late-infantile CLN2 disease."

Biomarker • Journal • Anesthesia • CNS Disorders • Ophthalmology • Pediatrics

Cerliponase alfa decreases Aβ load and alters autophagy- related pathways in mouse hippocampal neurons exposed to fAβ1-42. (PubMed, Life Sci) - "Furthermore, exposure to CER and fAβ1-42 induced the autophagy-regulatory/related pathways in HT-22 cells and exposure to CER alone increased sirtuin-1 activity. Based on the present findings, we suggest that augmentation of TPP1 with enzyme replacement therapy may be a potential therapeutic option for the treatment of AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • ATG5 • BECN1 • SQSTM1 • TPP1

LATE INFANTILE NEURONAL CEROID LIPOFUSCINOSIS TYPE 2 (CLN2): A MOSCOW CASE SERIES. (SSIEM 2024) - "All patients received Cerliponase alfa ERT, beginning at a mean age of 49 months (range 27–61 months)... In conclusion, our cohort highlights CLN2 disease's key features and provides additional EEG phenotypic data and insights into ERT efficacy for both symptomatic and asymptomatic patients."

Clinical • CNS Disorders • Developmental Disorders • Epilepsy • Lysosomal Storage Diseases • Metabolic Disorders • Ophthalmology • Rare Diseases • TPP1

SEIZURES AND MOVEMENT DISORDERS IN PATIENTS WITH CLN2 DISEASE TREATED WITH CERLIPONASE ALFA IN THE REAL-WORLD SETTING (SSIEM 2024) - "This analysis provides the first comprehensive description of the time course of seizures and movement disorders in a cohort of CLN2 disease patients receiving treatment with cerliponase alfa in the real-world setting."

Clinical • Real-world • Real-world evidence • Ataxia • CNS Disorders • Dystonia • Epilepsy • Movement Disorders • TPP1

IMPACT OF CERLIPONASE ALFA ON LIPIDOMIC CSF PROFILES IN CLN2 PATIENTS. (SSIEM 2024) - "In conclusion, the lipid profile of ventricular CSF in CLN2 patients differs from that of controls. Cerliponase alfa treatment can reverse some of these effects. Future studies aim to confirm results obtained so far with ventricular CSF of control patients."

Clinical • Ataxia • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Movement Disorders • Pediatrics • TPP1

Early Symptoms and Treatment Outcomes in Neuronal Ceroid Lipofuscinosis Type 2: Croatian Experience. (PubMed, J Pers Med) - "The early onset of seizures between ages 2 and 4, alongside delayed language development, is a defining characteristic of CLN2 disease. Enzyme replacement therapy using cerliponase alfa represents the initial treatment for neuronal ceroid lipofuscinosis type 2, targeting the underlying cause of the disease. It effectively delays the progression of language and motor decline in patients diagnosed with this condition."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Ophthalmology

OCT Biomarkers in Ocular CLN2 Disease in Patients Treated With Intraventricular Enzyme Replacement Therapy. (PubMed, Invest Ophthalmol Vis Sci) - "This study details the pattern of morphological changes underlying CRT loss and disease progression in patients receiving intracerebroventricular (ICV) enzyme replacement therapy (ERT) with cerliponase alfa...CRT, ONL thickness, and PR layer thickness are useful anatomical biomarkers for understanding disease progression and treatment efficacy in CLN2. Studies using en face images will further clarify CLN2-related retinal degeneration."

Biomarker • Journal • CNS Disorders • Ophthalmology

Evolution of Movement Disorders in Patients With CLN2-Batten Disease Treated With Enzyme Replacement Therapy. (PubMed, Neurology) - "Movement disorders are a core feature of CLN2-disease and follow a typical pattern of progression which is slowed by ERT. Identifying and treating movement disorders should become standard, especially given increased patient survival."

Journal • Ataxia • CNS Disorders • Dystonia • Epilepsy • Movement Disorders

Exploring concurrent validity of the CLN2 Clinical Rating Scale: Comparison to PedsQL using cerliponase alfa clinical trial data. (PubMed, PLoS One) - P1/2 | "Each domain of the Clinical Rating Scale provides unique information on disease state. Validity of the scale is supported by its relationship with the PedsQL. Among the four domains of the Clinical Rating Scale, motor has the highest correlation to PedsQL, suggesting motor function as a driver of patients' quality of life. The lack of association between the remaining domains of the Clinical Rating Scale and PedsQL suggests that additional disease-specific measures may be needed to fully capture the quality of life impact of CLN2 disease."

Clinical • Journal • P1 data • P2 data • CNS Disorders • Pediatrics

Interim results for RGX-381: a first in human phase 1/2 clinical trial of AAV.CB7.hCLN2 gene therapy for CLN2 Batten disease-associated retinopathy (ARVO 2024) - "Cerliponase alfa (BioMarin), a recombinant proenzyme given via intracerebroventricular (ICV) infusion every 2 weeks, significantly ameliorates the neurological decline and children now survive; it does not affect the retinal dystrophy.RGX-381 (AAV9.CB7.hCLN2) is an investigational gene therapy comprised of a recombinant AAV9 vector that delivers a human CLN2 transgene with the aim of sustained secretion of TPP1 enzyme to prevent progressive photoreceptor degeneration. This first-in-human administration of RGX-381 has been well tolerated, with one resolved drug- and/or procedure-related AE as of Day 90. Efficacy data suggest a rapid restoration of TPP1 levels in the treated eye, and concomitant preservation of photoreceptors. Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand."

Clinical • Gene therapy • P1/2 data • Inherited Retinal Dystrophy • Macular Degeneration • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • TPP1

Classic and Atypical Late Infantile Neuronal Ceroid Lipofuscinosis in Latin America: Clinical and Genetic Aspects, and Treatment Outcome with Cerliponase Alfa. (PubMed, Mol Genet Metab Rep) - "Follow-up after the initiation of cerliponase alfa showed slower progression or stabilization of the disease, associated with adequate clinical outcomes and stable functional scores. These improvements were consistent in both clinical phenotypes."

Journal • Ataxia • CNS Disorders • Developmental Disorders • Epilepsy • Movement Disorders • Pediatrics • TPP1

Cerliponase Alfa Observational Study in the US (clinicaltrials.gov) - P=N/A | N=35 | Active, not recruiting | Sponsor: BioMarin Pharmaceutical | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders

Intravitreal enzyme replacement for inherited retinal diseases. (PubMed, Curr Opin Ophthalmol) - "The evidence suggests that IVT ERT with rhTPP1 may be a safe and effective treatment for CLN2 retinopathy. However, the optimal dosage and frequency to achieve the best possible outcomes requires further investigation as does patient selection."

Journal • CNS Disorders • Ophthalmology • Retinal Disorders • TPP1

Cerliponase alfa and neuronal ceroid lipofuscinosis type 2: long-term outcomes and lessons for future research. (PubMed, Lancet Neurol) - No abstract available

Journal • CNS Disorders

Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study. (PubMed, Lancet Neurol) - P1/2 | "Cerliponase alfa over a mean treatment period of more than 5 years was seen to confer a clinically meaningful slowing of decline of motor and language function in children with CLN2 disease. Although our study does not have a contemporaneous control group, the results provide crucial insights into the effects of long-term treatment."

Journal • CNS Disorders • Infectious Disease • TPP1

Case Report: Intraventricular Cerliponase Alfa Treatment in a Patient with Advanced Neuronal Ceroid Lipofuscinosis Type 2. (PubMed, Intern Med) - "We herein report a case of intraventricular cerliponase alfa treatment for over a year in a patient with advanced-stage CLN2. The results suggest the safety and potential efficacy of treatment at an advanced stage of CLN2."

Journal • Metastases • CNS Disorders • Epilepsy • Rare Diseases • TPP1