Publications

Professor of Neurology, of Pediatrics (Genetics) and, by Courtesy, of Pathology at the Stanford University Medical Center

Publications

  • Advances and limitations for the treatment of spinal muscular atrophy. BMC pediatrics Day, J. W., Howell, K., Place, A., Long, K., Rossello, J., Kertesz, N., Nomikos, G. 2022; 22 (1): 632

    Abstract

    Spinal muscular atrophy (5q-SMA; SMA), a genetic neuromuscular condition affecting spinal motor neurons, is caused by defects in both copies of the SMN1 gene that produces survival motor neuron (SMN) protein. The highly homologous SMN2 gene primarily expresses a rapidly degraded isoform of SMN protein that causes anterior horn cell degeneration, progressive motor neuron loss, skeletal muscle atrophy and weakness. Severe cases result in limited mobility and ventilatory insufficiency. Untreated SMA is the leading genetic cause of death in young children. Recently, three therapeutics that increase SMN protein levels in patients with SMA have provided incremental improvements in motor function and developmental milestones and prevented the worsening of SMA symptoms. While the therapeutic approaches with Spinraza®, Zolgensma®, and Evrysdi® have a clinically significant impact, they are not curative. For many patients, there remains a significant disease burden. A potential combination therapy under development for SMA targets myostatin, a negative regulator of muscle mass and strength. Myostatin inhibition in animal models increases muscle mass and function. Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds to proforms of myostatin, promyostatin and latent myostatin, thereby inhibiting myostatin activation. A recently completed phase 2 trial demonstrated the potential clinical benefit of apitegromab by improving or stabilizing motor function in patients with Type 2 and Type 3 SMA and providing positive proof-of-concept for myostatin inhibition as a target for managing SMA. The primary goal of this manuscript is to orient physicians to the evolving landscape of SMA treatment.

    View details for DOI 10.1186/s12887-022-03671-x

    View details for PubMedID 36329412

  • Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. The Lancet. Neurology Masson, R., Mazurkiewicz-Beldzinska, M., Rose, K., Servais, L., Xiong, H., Zanoteli, E., Baranello, G., Bruno, C., Day, J. W., Deconinck, N., Klein, A., Mercuri, E., Vlodavets, D., Wang, Y., Dodman, A., El-Khairi, M., Gorni, K., Jaber, B., Kletzl, H., Gaki, E., Fontoura, P., Darras, B. T., FIREFISH Study Group, Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Gerber, M., Khwaja, O., Scalco, R. S., Seabrook, T., Koch, A., Balikova, I., Joniau, I., Accou, G., Tahon, V., Wittevrongel, S., De Vos, E., de Holanda Mendonca, R., Matsui, C. J., Fornazieri Darcie, A. L., Machado, C., Kiyoko Oyamada, M., Martini, J., Polido, G., Rodrigues Iannicelli, J., Caires de Oliveira Achili Ferreira, J., Hu, C., Zhu, X., Qian, C., Shen, L., Li, H., Shi, Y., Zhou, S., Xiao, Y., Zhou, Z., Wang, S., Sang, T., Wei, C., Dong, H., Cao, Y., Wen, J., Li, W., Qin, L., Barisic, N., Celovec, I., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Tomas, J., Boespflug-Tanguy, O., De Lucia, S., Seferian, A., Barreau, E., Mnafek, N., Peche, H., Grange, A., Trang Nguyen, D., Milascevic, D., Tachibana, S., Pagliano, E., Bianchi Marzoli, S., Santarsiero, D., Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Dosi, C., Zanin, R., Schembri, V., Brolatti, N., Rao, G., Tassara, E., Morando, S., Tacchetti, P., Pedemonte, M., Priolo, E., Sposetti, L., Comi, G. P., Govoni, A., Osnaghi, S. G., Minorini, V., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Pane, M., Palermo, C., Pera, M. C., Amorelli, G. M., Barresi, C., D'Amico, G., Orazi, L., Coratti, G., Leone, D., Laura, A., De Sanctis, R., Berti, B., Kimura, N., Takeshima, Y., Shimomura, H., Lee, T., Gomi, F., Morimatsu, T., Furukawa, T., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Modrzejewska, S., Lemska, A., Melnik, E., Artemyeva, S., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Litvinova, E., Enzmann, C., Galiart, E., Gugleta, K., Wondrusch Haschke, C., Topaloglu, H., Oncel, I., Ertugrul, N. E., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Sari, S., Bilgin, N., Karaduman, A. A., Sarikaya, F. G., Graham, R. J., Ghosh, P., Casavant, D., Levine, A., Titus, R., Engelbrekt, A., Ambrosio, L., Fulton, A., Baglieri, A. M., Dias, C., Maczek, E., Pasternak, A., Beres, S., Duong, T., Gee, R., Young, S. 2022

    Abstract

    BACKGROUND: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment.METHODS: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing.FINDINGS: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p<0·0001 compared with the performance criterion derived from the natural history of untreated infants with type 1 spinal muscular atrophy). No infants could stand alone (0 [90% CI 0-7]) or walk alone (0 [0-7]) after 24 months of treatment. The most frequently reported adverse event was upper respiratory tract infection, in 22 infants (54%); the most common serious adverse events were pneumonia in 16 infants (39%) and respiratory distress in three infants (7%).INTERPRETATION: Treatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam.FUNDING: F Hoffmann-La Roche.

    View details for DOI 10.1016/S1474-4422(22)00339-8

    View details for PubMedID 36244364

  • Disease Progression in CMT related to MPZ Mutations: A Longitudinal Study. Annals of neurology Fridman, V., Sillau, S., Bockhorst, J., Smith, K., Moroni, I., Pagliano, E., Pisciotta, C., Piscosquito, G., Laura, M., Muntoni, F., Bacon, C., Feely, S., Grider, T., Gutmann, L., Shy, R., Wilcox, J., Herrmann, D. N., Li, J., Ramchandren, S., Sumner, C. J., Lloyd, T. E., Day, J., Siskind, C. E., Yum, S. W., Sadjadi, R., Finkel, R. S., Scherer, S. S., Pareyson, D., Reilly, M. M., Shy, M. E., Inherited Neuropathies Consortium-Rare Diseases Clinical Research Network (INC-RDCRN), Fridman, V., Sillau, S., Acsadi, G., Bacon, C., Dooley, K., Burns, J., Day, J., Feely, S., Finkel, R. S., Grider, T., Gutmann, L., Herrmann, D. N., Volpenhein, C., Bockhorst, J., Laura, M., Lewis, R. A., Li, J., Lloyd, T. E., Moroni, I., Muntoni, F., Pagliano, E., Pareyson, D., Pisciotta, C., Piscosquito, G., Ramchandren, S., Saporta, M., Sadjadi, R., Shy, R. R., Siskind, C. E., Sumner, C. J., Walk, D., Yum, S. W., Zuchner, S., Scherer, S. S., Reilly, M. M., Shy, M. E. 2022

    Abstract

    OBJECTIVE: The paucity of longitudinal natural history studies in MPZ-neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ-neuropathies across 13 sites of the Inherited Neuropathy Consortium.METHODS: Change in Charcot Marie Tooth Examination scores (CMTES) and Rasch modified CMTES (CMTES-R) scores were evaluated using longitudinal regression over a 5-year period in subjects with MPZ-neuropathy. Data from 139 patients with MPZ-neuropathy were examined.RESULTS: The average baseline CMTES and CMTES-R scores were 10.84 (SD 6.0, range 0 - 28) and 14.60 (SD=7.56, range 0 - 32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 [mean change from baseline of 0.87 points at 2years (p=0.008)]. Subgroup analysis revealed greater change in CMTES at 2years in subjects with axonal as compared to demyelinating neuropathy [mean change of 1.30 points, (p=0.016) versus 0.06 points, (p=0.889)]. Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy [mean 2 year change of 1.14 for baseline CMTES 8-14 (p=0.025), versus -0.03 for baseline CMTES 0-7 (p=0.958) and 0.25 for baseline CMTES ≥15 (p=0.6897)]. The progression in patients harboring specific MPZ mutations was highly variable.INTERPRETATION: CMTES scores are sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ-neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ-neuropathies. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.26518

    View details for PubMedID 36203352

  • Motor Responses in Pediatric Pompe Disease in the ADVANCE Participant Cohort. Journal of neuromuscular diseases Duong, T., Kishnani, P. S., An Haack, K., Foster, M. C., Gibson, J. B., Wilson, C., Hahn, S. H., Hillman, R., Kronn, D., Leslie, N. D., Peña, L. D., Sparks, S. E., Stockton, D. W., Tanpaiboon, P., Day, J. W. 2022

    Abstract

    ADVANCE (NCT01526785) presented an opportunity to obtain a more nuanced understanding of motor function changes in treatment-experienced children with Pompe disease receiving 4000L-production-scale alglucosidase alfa for 52 weeks.To estimate minimal detectable change (MDC) and effect size on Gross Motor Function Measure-88 (GMFM-88) after 52 weeks of 4000L alglucosidase alfa (complete data N =  90).The GMFM-88 mean total % score changes, MDC, and effect size were analyzed post hoc by Pompe Motor Function Level at enrollment, age groups at enrollment, and fraction of life on pre-study 160L-production-scale alglucosidase alfa.Overall, participants aged <  2 years surpassed MDC at Week 52 (change [mean±standard deviation] 21.1±14.1, MDC range 5.7-13.3, effect size 1.1), whereas participants aged≥2 years did not attain this (change -0.9±15.3, MDC range 10.8-25.2, effect size -0.03). In participants aged <  2 years, improvements surpassed the MDC for walkers (change 17.1±13.3, MDC range 3.0-6.9, effect size 1.7), supported standers (change 35.2±18.0, MDC range 5.9-13.7, effect size 1.8) and sitters (change 24.1±12.1, MDC range 2.6-6.2, effect size 2.7). Age-independent MDC ranges were only attained by walkers (change 7.7±12.3, MDC range 6.4-15.0, effect size 0.4) and sitters (change 9.9±17.2, MDC range 3.3-7.7, effect size 0.9).These first GMFM-88 minimal-detectable-change estimates for alglucosidase alfa-treated Pompe disease offer utility for monitoring motor skills.ClinicalTrials.gov; NCT01526785; Registered 6 February 2012; https://clinicaltrials.gov/ct2/show/NCT01526785.

    View details for DOI 10.3233/JND-210784

    View details for PubMedID 36214004

  • Adaptive test for neuromuscular disorders: Design of a wheelchair-based assessment Duong, T., Tang, W., Nelson, L., Parker, D., Pasternak, A., Young, S., Muni-Lofra, R., Maczek, E., Michell-Sodhi, J., Moat, D., Chatfield, S., Appleton, P., Day, J., Glanzman, A., Mayhew, A. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S61
  • Results from the end of Part A of the ongoing 3-part DEVOTE study to explore higher doses of nusinersen in SMA Day, J., Finkel, R., Pascual, S., Ryan, M., Mercuri, E., De Vivo, D., Montes, J., Gurgel-Giannetti, J., Gambino, G., Makepeace, C., Foster, R., Irzhevsky, V., Berger, Z. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S85
  • Evaluating 2-3 year responses to disease modifying treatment in adults with spinal muscular atrophy Duong, T., Tang, W., Young, S., Parker, D., Wolford, C., Sampson, J., Day, J. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S90
  • A phase 1/2 clinical trial evaluating the safety and pharmacokinetics of AOC 1001 in adults with myotonic dystrophy type 1: MARINA study design Johnson, N., Day, J., Hamel, J., Statland, J., Subramony, S., Arnold, W., Thornton, C., Wicklund, M., Soltanzadeh, P., Knisely, B., Goel, V., DiTrapani, K., Chen, C., Clark, K., Peters, A., Heusner, C., Younis, H., Tai, L., Ackermann, E. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S131
  • Myostatin concentration is unreliable as a biomarker of disease progression in dysferlinopathy Moore, U., Simon, E., Day, J., Jones, K., Bharucha-Goebel, D., Pestronk, A., Walter, M., Paradas, C., Stojkovic, T., Bravver, E., Pegoraro, E., Mendell, J., Guglieri, M., Straub, V., Diaz-Manera, J. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S113
  • Safety update: Risdiplam clinical trial development program Chiriboga, C., Servais, L., Baranello, G., Darras, B., Day, J., Deconinck, N., Farrar, M., Finkel, R., Bertini, E., Kirschner, J., Masson, R., Mazurkiewicz-Beldzinska, M., Vlodavets, D., Bader-Weder, S., Gorni, K., Jaber, B., McIver, T., Papp, G., Scalco, R., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S89
  • Multimodal fusion of neuroimaging and neuropsych data: A machine learning approach to study brain alterations linked with cognitive domains in DM1 Kamali, T., Parker, D., Deutsch, G., Sampson, J., Day, J., Wozniak, J. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S132
  • Efficacy and safety of Avalglucosidase Alfa in participants with late-onset Pompe Disease after 145 weeks' treatment during the COMET trial Schoser, B., Kishnani, P., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, Toscano, A., van der Ploeg, A., Clemens, P., Day, J., Illarioshkin, S., Roberts, M., Attarian, S., Carvalho, G., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Diaz-Manera, J., Dimachkie, M., COMET Investigator Grp PERGAMON-ELSEVIER SCIENCE LTD. 2022
  • Real-world outcomes of exon skipping therapy use in patients with Duchenne muscular dystrophy: Experience at a single, large tertiary care center Yaworski, A., Duong, T., Low, J., Gee, R., Watson, K., Buu, M., Kaufman, B., Klotz, J., Day, J., Guzman, J., Rocha, C. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S102
  • Clinical outcome study of dysferlinopathy 2: Characterising involvement of the intrinsic muscles of the hand in LGMDR2 James, M., Mayhew, A., Gordish-Dressman, H., Rufibach, L., Wong, K., Roper, W., Holsten, S., Lowes, L., Duong, T., Yochai, C., Zabala Pardo, A., Ogasawara, Y., Rudolph, K., Alarcon, S., Weber, J., Montiel Morillo, E., Pedrosa-Hernandez, I., Birnbaum, S., Rojas Rojas, J., Day, J., Straub, V. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S115
  • FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy (SMA) Servais, L., Baranello, G., Boespflug-Tanguy, O., Day, J., Deconinck, N., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Vlodavets, D., Xiong, H., Zanoteli, E., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Palfreeman, L., Dodman, A., Gaki, E., Darras, B. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S88
  • Prevalence of healthcare conditions and services used by patients with myotonic dystrophy (DM) pre- and post-diagnosis: A real-world data analysis Day, J., Munoz, K., Brook, R., McEvoy, B., Tai, L., DiTrapani, K., Kleinman, N., Chen, C., Stahl, M. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S131
  • Impact of nusinersen on respiratory progression in paediatric patients with spinal muscular atrophy type 2 and non-ambulant type 3 Trucco, F., Weststrate, H., Ridout, D., Scoto, M., Rohwer, A., Coratti, G., Main, M., Pane, M., Messina, S., D'Amico, A., Bruno, C., De Vivo, D., Darras, B., Day, J., Baranello, G., Sansona, V., Bertini, E., Finkel, R., Mercuri, E., Muntoni, F. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S89
  • SUNFISH parts 1 and 2: 3-year efficacy and safety of risdiplam in types 2 and 3 spinal muscular atrophy (SMA) Day, J., Deconinck, N., Mazzone, E., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Braid, J., Gerber, M., Gorni, K., Martin, C., Scalco, R., Yeung, W., Mercuri, E. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S89-S90
  • Apitegromab in SMA: An analysis of multiple efficacy endpoints in the TOPAZ extension study Crawford, T., Darras, B., Day, J., Barrett, D., Song, G., O'Neil, J., Kertesz, N., Bilic, S., Patel, J., Nomikos, G., Chyung, Y. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S86-S87
  • Integrated analyses of data from clinical trials of delandistrogene moxeparvovec in DMD Zaidman, C., Shieh, P., Proud, C., McDonald, C., Day, J., Mason, S., Guridi, M., Hu, L., Yu, L., Reid, C., Darton, E., Wandel, C., Richardson, J., Malhotra, J., Singh, T., Rodino-Klapac, L., Mendell, J. PERGAMON-ELSEVIER SCIENCE LTD. 2022: S101
  • Water T2 could predict functional decline in patients with dysferlinopathy. Journal of cachexia, sarcopenia and muscle Moore, U., Caldas de Almeida Araújo, E., Reyngoudt, H., Gordish-Dressman, H., Smith, F. E., Wilson, I., James, M., Mayhew, A., Rufibach, L., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Pegoraro, E., Mendell, J. R., Bushby, K., Blamire, A. M., Straub, V., Carlier, P. G., Diaz-Manera, J. 2022

    Abstract

    Water T2 (T2H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies.Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function.A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems.In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.

    View details for DOI 10.1002/jcsm.13063

    View details for PubMedID 36058852

  • Large Fenestrations Versus Scallops for the SMA During Fenestrated EVAR: Does it Matter? Annals of vascular surgery Sorondo, S. M., Ss, D., K, T., Vt, H., Jr, S., J, L. 2022

    Abstract

    FEVAR is an established customized treatment for aortic aneurysms with three current commercially available configurations for the superior mesenteric artery (SMA) - a single-wide scallop, large fenestration, or small fenestration, with the scallop or large fenestration most utilized. Outcomes comparing SMA single-wide scallops to large fenestrations with the ZFEN device are scarce. As large fenestrations have the benefit of extending the proximal seal zone compared to scalloped configurations, we sought to determine the differences in seal zone and sac regression outcomes between the two SMA configurations.We retrospectively reviewed our prospectively maintained complex EVAR database and included all patients treated with the Cook ZFEN device with an SMA scallop or large fenestration configuration at its most proximal build. All first post-operative CT scans (1-30 days) were analyzed on TeraRecon to determine precise proximal seal zone lengths, and standard follow-up anatomic and clinical metrics were tabulated.A total of 234 consecutive ZFEN patients from 2012-2021 were reviewed, and 137 had either a scallop or large fenestration for the SMA as the proximal-most configuration (72 scallops and 65 large fenestrations) with imaging available for analysis. Mean follow-up was 35 months. Mean proximal seal zone length was 19.5±7.9 mm for scallop vs 41.7±14.4 mm for large fenestration groups (P<.001). There was no difference in sac regression between scallop and large fenestration at one year (10.1±10.9 mm vs 11.0±12.1, P = 0.63). Overall, 30-day mortality (1.3% vs 2.5%, P=.51) and all-cause three-year mortality (72.5% vs 81.7%, P=.77) were not significantly different. Reinterventions within 30 days were primarily secondary to renal artery branch occlusions, with only one patient in the scallop group requiring reintervention for an SMA branch occlusion.Despite attaining longer proximal seal lengths, large SMA fenestrations were not associated with a difference in sac regression compared to scalloped SMA configurations at one-year follow up. There were no significant differences in reinterventions or overall long-term survival between the two SMA strategies.

    View details for DOI 10.1016/j.avsg.2022.07.013

    View details for PubMedID 36058451

  • SUNFISH 3-YEAR EFFICACY AND SAFETY OF RISDIPLAM IN TYPES 2 AND 3 SMA Servais, L., Day, J. W., Mazzone, E. S., Oskoui, M., Baranello, G., Gerber, M., Martin, C., McIver, T., Yeung, W., Mercuri, E. BMJ PUBLISHING GROUP. 2022
  • SUNFISH PART 2: 24-MONTH EFFICACY OF RISDIPLAM COMPARED WITH EXTERNAL CONTROL COMPARATORS Servais, L., Day, J. W., Mazzone, E. S., Oskoui, M., Baranello, G., Gerber, M., Martin, C., McIver, T., Yeung, W., Mercuri, E. BMJ PUBLISHING GROUP. 2022
  • PREVALENCE OF HEALTHCARE CONDITIONS AND SERVICES USED BY PATIENTS WITH MYOTONIC DYSTROPHY PRE-AND POST-DIAGNOSIS, A REAL-WORLD DATA ANALYSIS Day, J. W., Munoz, K., Brook, R. A., McEvoy, B., Tai, L. J., DiTrapani, K., Kleinman, N. L., Chen, C. Y., Stahl, M. ELSEVIER SCIENCE INC. 2022: S596
  • Cognitive Impairment Analysis of Myotonic Dystrophy via Weakly Supervised Classification of Neuropsychological Features. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference Kamali, T., Deutsch, G. K., Hagerman, K. A., Parker, D., Day, J. W., Sampson, J. B., Wozniak, J. R. 2022; 2022: 4377-4382

    Abstract

    The myotonic dystrophies (DM1 and DM2) are dominantly inherited disorders that cause pathological changes throughout the body. Many individuals with DM experience cognitive, behavioral and other functional central nervous system effects that impact their quality of life. The extent of psychological impairment that will develop in each patient is variable and unpredictable. Hence, it is difficult to get strong supervision information like fully ground truth labels for all cognitive involvement patterns. This study is to assess cognitive involvement among healthy controls and patients with DM. The DM cognitive impairment pattern observation is modeled in a weakly supervised setting and supervision information is used to transform the input feature space to a more discriminative representation suitable for pattern observation. This study incorporated results from 59 adults with DM and 92 control subjects. The developed system categorized the neuropsychological testing data into five cognitive clusters. The quality of the obtained clustering solution was assessed using an internal validity metric. The experimental results show that the proposed algorithm can discover interesting patterns and useful information from neuropsychological data, which will be be crucial in planning clinical trials and monitoring clinical performance. The proposed system resulted in an average classification accuracy of 88%, which is very promising considering the unique challenges present in this population.

    View details for DOI 10.1109/EMBC48229.2022.9871626

    View details for PubMedID 36086274

  • SUNFISH: 3-year efficacy and safety of risdiplam in Types 2 and 3 spinal muscular atrophy Goemans, N., Day, J., Deconinck, N., Mazzone, E., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Braid, J., Gerber, M., Gorni, K., Martin, C., Scalco, R., Yeung, W., Mercuri, E., SUNFISH Working Grp WILEY. 2022: 278
  • FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy Deconinck, N., Baranello, G., Boespflug-Tanguy, O., Day, J., Klein, A., Masson, R., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., El-Khairi, M., Gerber, M., Gorni, K., Kletzl, H., Dodman, A., Gaki, E., Darras, B., FIREFISH Working Grp WILEY. 2022: 279
  • Spinal Muscular Atrophy Type 1: Fetal Diagnosis, Prenatal Coordination, and Postnatal Management in the Era of Novel Therapies. NeoReviews Chitkara, R., Chock, V., Davis, A., Rocha, C. T., Day, J. W., Fluharty, B., Hintz, S. 2022; 23 (7): e520-e526

    View details for DOI 10.1542/neo.23-7-e520

    View details for PubMedID 35773512

  • COMET: Efficacy and safety of avalglucosidase alfa in late-onset Pompe disease participants after 97 weeks of treatment Schoser, B., Kishnani, P., Diaz-Manera, J., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., Van der Ploeg, A., Berger, K., Clemens, P., Chien, Y., Day, J., Ilarioshkin, S., Roberts, M., Attarian, S., Carvalho, G., Choi, Y., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Thibault, N., Zhou, T., Dimachkie, M., COMET Investigator Grp WILEY. 2022: 59-60
  • MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy. Science translational medicine Morelli, K. H., Jin, W., Shathe, S., Madrigal, A. A., Jones, K. L., Schwartz, J. L., Bridges, T., Mueller, J. R., Shankar, A., Chaim, I. A., Day, J. W., Yeo, G. W. 2022; 14 (651): eabn2375

    Abstract

    Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci found early in the maturation of three-dimensional (3D) cortical organoids from DM1 patient-derived induced pluripotent stem cells (iPSCs) cause hyperphosphorylation of CUGBP Elav-like family member 2 (CELF2) protein. Integrative single-cell RNA sequencing and enhanced cross-linking and immunoprecipitation (eCLIP) analysis revealed that reduced CELF2 protein-RNA substrate interactions results in misregulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2(y/-) cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify N-methyl-d-aspartic acid (NMDA) antagonists as potential treatment avenues for neuronal defects in DM1.

    View details for DOI 10.1126/scitranslmed.abn2375

    View details for PubMedID 35767654

  • Scientific rationale for a higher dose of nusinersen. Annals of clinical and translational neurology Finkel, R. S., Ryan, M. M., Pascual Pascual, S. I., Day, J. W., Mercuri, E., De Vivo, D. C., Foster, R., Montes, J., Gurgel-Giannetti, J., MacCannell, D., Berger, Z. 2022

    Abstract

    OBJECTIVE: The long-term favorable safety profile of nusinersen provides an opportunity to consider a higher dose. We report on the relationships between nusinersen cerebrospinal fluid (CSF) exposure, biomarker levels, and clinical efficacy.METHODS: The analyses used data from the CS3A and ENDEAR studies of nusinersen in participants with infantile-onset spinal muscular atrophy (SMA). Steady-state CSF trough (Ctrough ) levels, plasma phosphorylated neurofilament heavy chain (pNF-H) levels, body weight, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores were selected as parameters of interest. A validated population pharmacokinetic (PK) model was applied to predict the nusinersen CSF Ctrough . PK/pharmacodynamic (PK/PD) models used nusinersen CSF Ctrough measurements, which were time-matched with CHOP INTEND scores.RESULTS: Higher nusinersen CSF exposure was associated with a greater decrease in pNF-H levels and greater efficacy, as measured by change in the CHOP INTEND score from baseline. These findings indicate a dose-response relationship between CSF nusinersen levels and treatment response. The higher dose is predicted to lead to approximately a 2.4-fold increase in nusinersen CSF levels with fewer loading doses. PK/PD modeling indicates that a higher concentration of nusinersen may predict an additional 5-point increase in CHOP INTEND score beyond that observed with 12mg.INTERPRETATION: Our data indicate that a higher dose of nusinersen may lead to additional clinically meaningful improvement in efficacy when compared with the currently approved 12-mg dose. The efficacy, safety, and PK of a higher nusinersen dose are currently under investigation in the ongoing phase 2/3 DEVOTE study (NCT04089566).

    View details for DOI 10.1002/acn3.51562

    View details for PubMedID 35567345

  • Major Adverse Dystrophinopathy Event Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy Kaufman, B. D., Garcia, A., He, Z., Buu, M., Tesi-Rocha, C., Day, J. W., Rosenthal, D. N., Gordish-Dressman, H., Almond, C., Duong, T. ELSEVIER SCIENCE INC. 2022: S95
  • Cardiac and pulmonary findings in dysferlinopathy: a 3-year, longitudinal study. Muscle & nerve Moore, U., Fernandez-Torron, R., Jacobs, M., Gordish, H., Diaz-Manera, J., James, M. K., Mayhew, A. G., Harris, E., Guglieri, M., Rufibach, L. E., Feng, J., Blamire, A. M., Carlier, P. G., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Pegoraro, E., Lowes, L. P., Mendell, J. R., Bushby, K., Jain COS Consortium, Bourke, J., Straub, V. 2022

    Abstract

    INTRODUCTION/AIMS: There is debate about whether and to what extent either respiratory or cardiac dysfunction occur in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype.METHODS: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a three-year interval between tests, in 188 genetically confirmed patients aged 11-86years (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG) and echocardiogram (echo).RESULTS: Mean FVC was 90% predicted at baseline, decreasing to 88% at year three. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year three, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population.DISCUSSION: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.

    View details for DOI 10.1002/mus.27524

    View details for PubMedID 35179231

  • Intron Mutations and Early Transcription Termination in Duchenne and Becker muscular dystrophy. Human mutation Waldrop, M. A., Moore, S. A., Mathews, K. D., Darbro, B. W., Medne, L., Finkel, R., Connolly, A. M., Crawford, T. O., Drachman, D., Wein, N., Habib, A. A., Krzesniak-Swinarska, M. A., Zaidman, C. M., Collins, J. J., Jokela, M., Udd, B., Day, J. W., Ortiz-Guerrero, G., Statland, J., Butterfield, R. J., Dunn, D. M., Weiss, R. B., Flanigan, K. M. 2022

    Abstract

    DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription PCR (RT-PCR) or high-throughput RNA sequencing (RNA-Seq) methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/humu.24343

    View details for PubMedID 35165973

  • AT845 gene replacement therapy for late onset Pompe disease: Overview of clinical data from FORTIS, a phase 1/2 open-label clinical study Mozaffar, T., Day, J. W., Longo, N., Manera, J., Straub, V., Maruoka, M., Han, C., Foo, C., Smith, A. R., Bachtell, N. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: S85-S86
  • The avalglucosidase alfa phase 3 COMET trial in late-onset Pompe disease patients: Efficacy and safety results after 97 weeks Kishnani, P., Diaz-Manera, J., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., van der Ploeg, A. T., Berger, K. I., Clemens, P. R., Chien, Y., Day, J. W., Illarioshkin, S., Roberts, M., Attarian, S., Carvalho, G., Choi, Y., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Thibault, N., Zhou, T., Dimachkie, M. M., Schoser, B. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: S66-S67
  • Brief assessment of cognitive function in myotonic dystrophy: multicenter longitudinal study using computer-assisted evaluation. Muscle & nerve Deutsch, G. K., Hagerman, K. A., Sampson, J., Dent, G., Dekdebrun, J., Parker, D. M., Thornton, C. A., Heatwole, C. R., Subramony, S. H., Mankodi, A. K., Ashizawa, T., Statland, J. M., Arnold, W. D., Moxley, R. T., Day, J. W. 2022

    Abstract

    Myotonic dystrophy type 1 (DM1) is known to affect cognitive function, but the best methods to assess CNS involvement in multicenter studies have not been determined. This study's primary aim was to evaluate the potential of computerized cognitive tests to assess cognition in DM1.We conducted a prospective, longitudinal, observational study of 113 adults with DM1 at 6 sites. Psychomotor speed, attention, working memory, and executive functioning were assessed at baseline, 3-months and 12-months using computerized cognitive tests. Results were compared with assessments of muscle function and patient reported outcomes (PROs), including the Myotonic Dystrophy Health Index (MDHI) and EQ-5D-5L.Based on intra-class correlation coefficients (ICCs), computerized cognitive tests had moderate to good reliability for psychomotor speed (0.76), attention (0.82), working memory speed (0.79), working memory accuracy (0.65), and executive functioning (0.87). Performance at baseline was lowest for working memory accuracy (p < 0.0001). Executive function performance improved from baseline to 3-months (p < 0.0001), without further changes over one year. There was a moderate correlation between poorer executive function and larger CTG repeat size (r = -0.433). There were some weak associations between PROs and cognitive performance.Computerized tests of cognition are feasible in multicenter studies of DM1. Poor performance was exhibited in working memory, which may be a useful variable in clinical trials. Learning effects may have contributed to the improvement in executive functioning. The relationship between PROs and cognitive impairment in DM1 requires further study. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/mus.27520

    View details for PubMedID 35179228

  • Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. The Lancet. Neurology Mercuri, E., Deconinck, N., Mazzone, E. S., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W. Y., Martin, C., Fontoura, P., Day, J. W., SUNFISH Study Group, Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Fuerst-Recktenwald, S., Marquet, A., Mulhardt, N., Trundell, D., Daron, A., Delstanche, S., Romain, B., Dal Farra, F., Schneider, O., Deconinck, N., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Goemans, N., Casteels, I., De Waele, L., Balikova, I., Cassiman, C., Prove, L., Kinoo, D., Vancampenhout, L., Van Den Hauwe, M., Van Impe, A., Prufer de Queiroz Campos Araujo, A., Chacon Pereira, A., Nardes, F., Haefeli, L., Rossetto, J., Almeida Pereira, J., Ferreira Rebel, M., Campbell, C., Sharan, S., McDonald, W., Scholtes, C., Mah, J., Sframeli, M., Chiu, A., Hagel, J., Oskoui, M., Beneish, R., Pham, C., Toffoli, D., Arpin, S., Turgeon Desilets, S., Wang, Y., Hu, C., Huang, J., Qian, C., Shen, L., Xiao, Y., Zhou, Z., Li, H., Wang, S., Xiong, H., Chang, X., Dong, H., Liu, Y., Sang, T., Wei, C., Wen, J., Cao, Y., Lv, X., Wen, J., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Servais, L., Boespflug-Tanguy, O., Gidaro, T., Seferian, A., De Lucia, S., Barreau, E., Mnafek, N., Momtchilova, M. M., Peche, H., Valherie, C., Grange, A., Lilien, C., Milascevic, D., Tachibana, S., Ravelli, C., Cardas, R., Vanden Brande, L., Davion, J., Coopman, S., Bouacha, I., Debruyne, P., Defoort, S., Derlyn, G., Leroy, F., Danjoux, L., Guilbaud, J., Desguerre, I., Barnerias, C., Semeraro, M., Bremond-Gignac, D., Bruere, L., Rateaux, M., Deladriere, E., Germa, V., Pereon, Y., Magot, A., Mercie, S., Billaud, F., Le Goff, L., Letellier, G., Vuillerot, C., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Saidi, M., Kirschner, J., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, E., D'Amico, A., Petroni, S., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Priolo, E., Rao, G., Morando, S., Tacchetti, P., Zuffi, A., Comi, G. P., Brusa, R., Corti, S., Daniele, V., Govoni, A., Magri, F., Minorini, V., Osnaghi, S. G., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Meneri, M., Zoppas, F., Parente, V., Baranello, G., Masson, R., Bianchi Marzoli, S., Santarsiero, D., Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, R., Mercuri, E., Amorelli, G. M., Barresi, C., D'Amico, G., Orazi, L., Coratti, G., Haginoya, K., Kato, A., Morishita, Y., Kira, R., Akiyama, K., Goto, M., Mori, Y., Okamoto, M., Tsutsui, S., Takatsuji, Y., Tanaka, A., Komaki, H., Suzuki, I., Takeuchi, M., Todoroki, D., Watanabe, S., Omori, M., Matsubayashi, T., Inakazu, E., Nagura, H., Suzuki, A., Osaka, H., Ohashi, M., Ishikawa, N., Harada, Y., Fudeyasu, K., Hirata, K., Michiue, K., Ueda, K., Saito, K., Yashiro, S., Seki, M., Sano, N., Uemura, A., Fukuyama, K., Matsumoto, Y., Miyazaki, H., Shibata, M., Kobayashi, K., Nakamura, Y., Takeshima, Y., Kuma, M., Kostera-Pruszczyk, A., Fraczek, A., Jedrzejowska, M., Lusakowska, A., Czeszyk-Piotrowicz, A., Hautz, W., Rakusiewicz, K., Burlewicz, M., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Mazurkiewicz-Beldzinska, M., Lemska, A., Modrzejewska, S., Koberda, M., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Steinborn, B., Dalz, M., Grabowska, J., Hajduk, W., Janasiewicz-Karachitos, J., Klimas, M., Stopa, M., Gajewska, E., Pusz, B., Vlodavets, D., Melnik, E., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Milic Rasic, V., Brankovic, V., Kosac, A., Djokic, O., Jaksic, V., Pepic, A., Martinovic, J., Munell Casadesus, F., Tizzano, E., Martin Begue, N., Wolley Dod, C., Subira, O., Planas Pascual, B., Toro Tamargo, E., Madruga Garrido, M., Medina Romero, J. D., Salinas, M. P., Nascimento Osorio, A., Diaz Cortes, A., Jimenez Ganan, E., Suh, S. D., Medina Cantillo, J., Moya, O., Padros, N., Roca Urraca, S., Gonzalez Valdivia, H., Pascual Pascual, S., de Manuel, S., Noval Martin, S., Burnham, P., Espinosa Garcia, S., Martinez Moreno, M., Topaloglu, H., Oncel, I., Eroglu Ertugrul, N., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Ayse Karaduman, A., Tunca Yilmaz, O., Bilgin, N., Sari, S., Chiriboga, C., Kane, S., Lee, J., Rome-Martin, D., Day, J. W., Beres, S., Duong, T., Gee, R., Dunaway Young, S. 1800; 21 (1): 42-52

    Abstract

    BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy.METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing.FINDINGS: Between Oct 9, 2017, and Sept 4, 2018, 180 patients were randomly assigned to receive risdiplam (n=120) or placebo (n=60). For analysis of the primary endpoint, 115 patients from the risdiplam group and 59 patients from the placebo group were included. At month 12, the least squares mean change from baseline in 32-item Motor Function Measure was 1·36 (95% CI 0·61 to 2·11) in the risdiplam group and -0·19 (-1·22 to 0·84) in the placebo group, with a treatment difference of 1·55 (0·30 to 2·81, p=0·016) in favour of risdiplam. 120 patients who received risdiplam and 60 who received placebo were included in safety analyses. Adverse events that were reported in at least 5% more patients who received risdiplam than those who received placebo were pyrexia (25 [21%] of 120 patients who received risdiplam vs ten [17%] of 60 patients who received placebo), diarrhoea (20 [17%] vs five [8%]), rash (20 [17%] vs one [2%]), mouth and aphthous ulcers (eight [7%] vs 0), urinary tract infection (eight [7%] vs 0), and arthralgias (six [5%] vs 0). The incidence of serious adverse events was similar between treatment groups (24 [20%] of 120 patients in the risdiplam group; 11 [18%] of 60 patients in the placebo group), with the exception of pneumonia (nine [8%] in the risdiplam group; one [2%] in the placebo group).INTERPRETATION: Risdiplam resulted in a significant improvement in motor function compared with placebo in patients aged 2-25 years with type 2 or non-ambulant type 3 spinal muscular atrophy. Our exploratory subgroup analyses showed that motor function was generally improved in younger individuals and stabilised in older individuals, which requires confirmation in further studies. SUNFISH part 2 is ongoing and will provide additional evidence regarding the long-term safety and efficacy of risdiplam.FUNDING: F Hoffmann-La Roche.

    View details for DOI 10.1016/S1474-4422(21)00367-7

    View details for PubMedID 34942136

  • Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2) : a phase 3, double-blind, randomised, placebo-controlled trial LANCET NEUROLOGY Mercuri, E., Deconinck, N., Mazzone, E. S., Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, G., Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W., Martin, C., Fontoura, P., Day, J. W., SUNFISH Study Grp 2022; 21 (1): 42-52
  • Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach. Frontiers in neurology Mayhew, A. G., James, M. K., Moore, U., Sutherland, H., Jacobs, M., Feng, J., Lowes, L. P., Alfano, L. N., Muni Lofra, R., Rufibach, L. E., Rose, K., Duong, T., Bello, L., Pedrosa-Hernandez, I., Holsten, S., Sakamoto, C., Canal, A., Sanchez-Aguilera Praxedes, N., Thiele, S., Siener, C., Vandevelde, B., DeWolf, B., Maron, E., Gordish-Dressman, H., Hilsden, H., Guglieri, M., Hogrel, J., Blamire, A. M., Carlier, P. G., Spuler, S., Day, J. W., Jones, K. J., Bharucha-Goebel, D. X., Salort-Campana, E., Pestronk, A., Walter, M. C., Paradas, C., Stojkovic, T., Mori-Yoshimura, M., Bravver, E., Diaz-Manera, J., Pegoraro, E., Mendell, J. R., Straub, V. 2022; 13: 828525

    Abstract

    Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R 2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R 2 0.18). EK scores were strongly associated with PUL (Pseudo R 2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R 2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy.

    View details for DOI 10.3389/fneur.2022.828525

    View details for PubMedID 35359643

  • Correction to: Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug safety Day, J. W., Mendell, J. R., Mercuri, E., Finkel, R. S., Strauss, K. A., Kleyn, A., Tauscher-Wisniewski, S., Tukov, F. F., Reyna, S. P., Chand, D. H. 1800

    View details for DOI 10.1007/s40264-021-01130-7

    View details for PubMedID 34940960

  • Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial LANCET NEUROLOGY Diaz-Manera, J., Kishnani, P. S., Kushlaf, H., Ladha, S., Mozaffar, T., Straub, V., Toscano, A., Van der Ploeg, A. T., Berger, K. I., Clemens, P. R., Chien, Y., Day, J. W., Illarioshkin, S., Roberts, M., Attarian, S., Borges, J., Bouhour, F., Choi, Y., Erdem-Ozdamar, S., Goker-Alpan, O., Kostera-Pruszczyk, A., Haack, K., Hug, C., Huynh-Ba, O., Johnson, J., Thibault, N., Zhou, T., Dimachkie, M. M., Schoser, B., The Comet 2021; 20 (12): 1012-1026
  • Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes. Neuromuscular disorders : NMD Coratti, G., Carmela Pera, M., Montes, J., Scoto, M., Pasternak, A., Bovis, F., Sframeli, M., D'Amico, A., Pane, M., Albamonte, E., Antonaci, L., Lia Frongia, A., Mizzoni, I., Sansone, V. A., Russo, M., Bruno, C., Baranello, G., Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., de Sanctis, R., Stacy Mazzone, E., Milev, E., Rohwer, A., Civitello, M., Darras, B. T., Bertini, E., Day, J., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, E. 1800

    Abstract

    The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches.

    View details for DOI 10.1016/j.nmd.2021.10.009

    View details for PubMedID 34980538

  • Correction to: Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Rudnicki, S. A., Andrews, J. A., Duong, T., Cockroft, B. M., Malik, F. I., Meng, L., Wei, J., Wolff, A. A., Genge, A., Johnson, N. E., Tesi-Rocha, C., Connolly, A. M., Darras, B. T., Felice, K., Finkel, R. S., Shieh, P. B., Mah, J. K., Statland, J., Campbell, C., Habib, A. A., Kuntz, N. L., Oskoui, M., Day, J. W. 2021

    View details for DOI 10.1007/s13311-021-01120-8

    View details for PubMedID 34731415

  • Routine practices in use of onasemnogene abeparvovec (OA) in older patients with spinal muscular atrophy (SMA): Early findings from RESTORE Servais, L., De Vivo, D., Kirschner, J., Mercuri, E., Muntoni, F., Tizzano, E., Roy, S., Saito, K., Menier, M., LaMarca, N., Anderson, F., Dabbous, O., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S138
  • Real-world treatment patterns and outcomes in patients with spinal muscular atrophy (SMA): Updated findings from the RESTORE Registry Servais, L., Day, J., De Vivo, D., Mercuri, E., Muntoni, F., Shieh, P., Tizzano, E., Desguerre, I., Saito, K., Menier, M., LaMarca, N., Anderson, F., Dabbous, O., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S138-S139
  • Long-term follow-up (LTFU) of onasemnogene abeparvovec gene therapy in spinal muscular atrophy (SMA) Mendell, J., Finkel, R., Mercuri, E., Strauss, K., Day, J., Kleyn, A., Chand, D., Tauscher-Wisniewski, S., Meriggioli, M. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S132-S133
  • Newborn screening (NBS) for spinal muscular atrophy (SMA) in the United States (US): Early findings from the RESTORE registry Servais, L., De Vivo, D., Kirschner, J., Mercuri, E., Muntoni, F., Tizzano, E., Roy, S., Saito, K., Menier, M., LaMarca, N., Anderson, F., Dabbous, O., Finkel, R. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S138
  • IREFISH Parts 1 and 2: 24-month safety and efficacy of risdiplam in type 1 spinal muscular atrophy (SMA) Masson, R., Boespflug-Tanguy, O., Darras, B., Day, J., Deconinck, N., Klein, A., Mazurkiewicz-Beldzinska, M., Mercuri, E., Rose, K., Servais, L., Vlodavets, D., Xiong, H., Zanoteli, E., Dodman, A., El-Khairi, M., Gaki, E., Gerber, M., Gorni, K., Kletzl, H., Baranello, G. PERGAMON-ELSEVIER SCIENCE LTD. 2021: S134