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External Control Using RWE and Historical Data in Clinical Development
Published in Harry Yang, Binbing Yu, Real-World Evidence in Drug Development and Evaluation, 2021
Qing Li, Guang Chen, Jianchang Lin, Andy Chi, Simon Davies
Batten disease, which is also called neuronal ceroid lipofuscinoses (NCLs), is a family of rare, fatal, inherited disorders of the nervous system. It is estimated that 2–4 births per 100,000 in the United States are affected by Batten disease, which is considered as a rare disease. Batten disease was named after British pediatrician Frederick Batten, who first described the disease in 1903; however, there were no approved drugs until recently. In April 2017, the FDA approved Brineura® (cerliponase alfa), which was developed by BioMarin Pharmaceutical, Inc. as a treatment for a specific form of Batten disease (FDA 2017c). It is the first FDA-approved treatment to slow the loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency. The BLA of Brineura® received priority review and breakthrough therapy designation.
Considerations and Bayesian Applications in Pharmaceutical Development for Rare Diseases
Published in Mani Lakshminarayanan, Fanni Natanegara, Bayesian Applications in Pharmaceutical Development, 2019
Batten disease is a fatal rare disease of the nervous system that typically has onset of symptoms in childhood and causes worsening problems with vision, movement, and thinking ability.39,40 It is usually referring to a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), to which CLN2 disease belong. CLN2 disease is also known as tripeptidyl peptidase-1 (TPP1) deficiency. In the late infantile form of the CLN2 disease, signs and symptoms typically begin between ages 2 and 4. The initial symptoms usually include language delay, recurrent seizures (epilepsy), and difficulty coordinating movements (ataxia). Affected children also develop muscle twitches (myoclonus) and vision loss. CLN2 disease affects essential motor skills, such as sitting and walking. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. Batten disease collectively is relatively rare, occurring in an estimated two to four of every 100,000 live births in the United States.41
Paediatric Neurology
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
The neuronal ceroid lipofuscinoses (NCLs) are a family of autosomal recessive disorders, usually with onset in childhood, characterized by abnormal storage in neurones and other cells. Progressive myoclonic epilepsy, cognitive deterioration and visual failure are markers of these disorders with death in childhood or early adulthood. An expanding number of variants are being identified and diagnosis arises from the characteristic clinical and neurophysiological features, enzyme analysis and identification of vacuolated lymphocytes or inclusion bodies, and subsequent genetics. Of the more common forms, the juvenile type is heralded by visual failure, with emerging educational difficulties, later seizures, mental health difficulties, speech and gait disturbance. Diagnosis is often first suggested following ophthalmology review, with identification of retinal changes and early loss of ERG, leading to the finding of vacuolated lymphocytes and then genetic confirmation. Classical late infantile NCL usually presents with seizures in early childhood, often with background of some speech delay. There is steady deterioration with loss of developmental skills and onset of motor difficulties with ataxia and pyramidal signs. Visual failure is a later feature. Clues may come from the abnormal response on EEG to slow photic stimulation. Lysosomal enzyme studies show low activity of tripeptyl peptidase 1 (TPP1), vacuolated lymphocytes are not found, but there are curvilinear inclusion bodies in white cells seen on electron microscopy. Again mutation analysis provides confirmation and is crucial for genetic counselling.
The role of precision medicine in bronchiectasis: emerging data and clinical implications
Published in Expert Review of Respiratory Medicine, 2023
Grace Oscullo, David de la Rosa, Marta Garcia Clemente, Rosa Giron, Rafael Golpe, Luis Máiz, Miguel Angel Martinez-Garcia
The inhibition of neutrophilic elastase (NE) is the treatment that has been most fully evaluated. This involves either blocking NE’s peripheral action to prevent the activation of serine proteases in the bone marrow or reducing the number of neutrophils entering tissues by preventing chemotaxis. In the former case, preliminary studies have been published with the oral NE inhibitors AZD966843 [127] and BAY85–850144 [128], but their results were inconclusive, due to the studies’ short duration. A trial with the inhaled drug CHF 6333 is currently in progress [129]. The evidence from the second approach is more substantial, especially with respect to Brensocatib, an oral inhibitor of dipeptidyl peptidase 1 (or cathepsin C). One 24-week trial has already shown a reduction in exacerbations [93], but new and longer studies are already underway with this and other similar drugs. Finally, we must highlight a preliminary study with the oral CXCR2 antagonist AZD5069 [130], as its results have motivated the launch of new trials with this molecule in COPD [131].
Ocular Manifestations of Neuronal Ceroid Lipofuscinoses
Published in Seminars in Ophthalmology, 2021
Rohan Bir Singh, Prakash Gupta, Akash Kartik, Naba Farooqui, Sachi Singhal, Sukhman Shergill, Kanwar Partap Singh, Aniruddha Agarwal
CLN2 encodes for tripeptidyl-peptidase 1 (TPP1), a lysosomal serine protease.45–47CLN-2 is an autosomal recessive disease which occurs as a consequence of loss of function in the TPP1/CLN2 gene on chromosome 11p15 which leads to deficient activity of TPP1.48 Though the exact pathophysiology is yet to be elucidated, animal studies have shown that insufficient TPP1 activity leads to intralysosomal accumulation of autofluorescent storage material, which causes pronounced neurodegeneration within the thalamocortical system, cerebellum and retinal pathway along with progressive reactive astrocytosis in the motor cortex, hippocampus, striatum, and cerebellum.49,50 Retinal degeneration begins at the photoreceptor and outer retinal levels and advances from the macular area to the periphery, eventually leading to complete atrophy of retina and blindness. Curvilinear deposits in the lysosomes on electron microscopy is characteristic of CLN-2.14,40 Clinical manifestations of CLN-2 usually starts with language delay and epilepsy around 2–3 years of age with progression to ataxia and global developmental delay by 5 years of age.42,43,51,52
Batten disease: an expert update on agents in preclinical and clinical trials
Published in Expert Opinion on Investigational Drugs, 2020
Margaux C. Masten, Jonathan W. Mink, Erika F. Augustine
NCL forms differ by the causative gene, gene product, and affected the biologic process. Some of the affected proteins are soluble enzymes and others are membrane-bound proteins. There are no blood biomarkers that have been shown to correlate with disease progression in any form of NCL. Successful disease-modifying therapy (DMT) approaches may differ based on the location and function of the individual protein. For example, CLN2 disease is caused by a mutation in the gene that codes for tripeptidyl peptidase 1 (TPP1), a soluble lysosomal enzyme, which can be treated with enzyme replacement therapy (ERT). By contrast, CLN3 disease is caused by a mutation that affects a transmembrane protein and thus is not a candidate for ERT. Potential approaches to disease modification include, but are not limited to, small-molecule drugs, large-molecule drugs, genetic medicines, and combination therapies. There is currently one disease-modifying ERT (cerliponase alfa) that has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of CLN2 disease. Several other potential disease-modifying therapies have been tested in small clinical studies (Table 1), but none of these has led to FDA or EMA approval. The focus of this editorial is on the current therapeutic pipeline for DMTs in the NCLs, including promising pre-clinical studies and planned and ongoing clinical trials. For a more extensive review, see [2].