Continued improvement in disease manifestations of acid sphingomyelinase deficiency for adults with up to 2 years of olipudase alfa treatment: open-label extension of the ASCEND trial.

BACKGROUND: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DLCO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment. RESULTS: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DLCO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DLCO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event. CONCLUSION: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691.

A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results.

PURPOSE: This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults. METHODS: A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics. RESULTS: Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, P = .0004), spleen volume (39% decrease vs 0.5% increase, P < .0001), and liver volume (28% vs 1.5% decreases, P < .0001). Splenomegaly-related score decreased in both groups (P = .64). Other clinical outcomes improved in the olipudase alfa group compared with the placebo group. There were no treatment-related serious adverse events or adverse event-related discontinuations. Most adverse events were mild. CONCLUSION: Olipudase alfa was well tolerated and associated with significant and comprehensive improvements in disease pathology and clinically relevant endpoints compared with placebo in adults with ASMD.

Patologías genéticas de atesoramiento lisosomal: caracteristicas nosológica, descripción de variantes y estimación de la prevalencia relativa de las diferentes entidades de la casupística autoctona / Patologia geneticas of lisosomal hoarding: nosologia characteristic, description of variants and relative estimation of the prevalence of the different organizations from the casupistica autoctona

Las patologías de atesoramiento lisosomal (PALs) constituyen, dentro de los errores congénitos del metabolismo, un grupo de más de 40 enfermedades con grave compromiso neuro-somático y gran heterogeneidad de expresión. El defecto radica en la incapacidad del lisosoma para degradar macromoléculas complejas debido a deficiencias enzimáticas específicas, lo que conduce al atesormaineto de las mismas con alteración de la función de la función celular y aparición de sintomas que configuran un fenotipo particular. En la actualidad y tomando en cuenta su fisiopatogenia, las PALs se clasifican en 4 grupos: a)Grupo I, deficiencia enzimática específica debida a un defecto en el ADN nuclear codificante (mucopolisacaridosis, glucogenosis tipo II, esfinolipidosis, lipidosis, Glicoproteinosis y picnodisostois); b)Grupo II, deficiencias enzimáticas múltiples por defectos co-o post-translacional, debidos a la falta de marcación de las hidrolasas ácidas lisosomales en el aparato de Golgi (mucolipidosis tipo II y III, deficiencias de múltiples sulfatasas); c)Grupo III, por defectos en el transporte a través de la menmbrana lisosomal (Sistinosis, Enfermedad de Salla, Atesoramiento de Ácido Siálico Infantil, transporte de Cobalamina) y d)Grupo IV, debido a defectos en el endosoma tardío (Lipofuscinosis Neuronal Ceroidea, Niemann-Pick tipo C, Mucolipidosis IV, Enfermedad de Danon)