The Experts below are selected from a list of 876 Experts worldwide ranked by ideXlab platform

Richard S. Finkel - One of the best experts on this subject based on the ideXlab platform.

  • One-Time Intrathecal (IT) Administration of AVXS-101 IT Gene-Replacement Therapy for Spinal Muscular Atrophy: Phase 1 Study (STRONG) (2493)
    Neurology, 2020
    Co-Authors: Richard S. Finkel, Thomas O Crawford, Basil T Darras, Perry B Shieh, John W. Day, Nancy L. Kuntz, Anne M. Connolly, Russell J. Butterfield, Gihan Tennekoon, Susan T. Iannaccone
    Abstract:

    Objective: To assess the safety/tolerability, optimal dose, and efficacy of AVXS-101 IT in sitting but non-ambulatory patients with spinal muscular atrophy (SMA). Background: SMA is a rapidly progressing disease causing loss of motor/respiratory functions due to survival motor neuron 1 gene (SMN1) deletion/mutation. Disease severity is modified by SMN2 copy number. AVXS-101 IT is a gene-replacement therapy that addresses the genetic root cause of SMA. Design/Methods: In STRONG (phase 1 study; NCT03381729), SMA patients (biallelic SMN1 loss, 3xSMN2) aged ≥6– Results: As of 31 May 2019, 31 patients were enrolled (dose A, complete: n=3, ≥6– Conclusions: Interim data from STRONG demonstrates early signs of efficacy in sitting but non-ambulatory patients with SMA. Disclosure: Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor fees from Biogen and Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; advisor to AveXis, Novartis, and Roche; data safety monitoring board for the AveXis AVX-101 Phase 1 gene transfer study and Roche Moonfish Phase 1b study; advisory capacit. Dr. Finkel has received compensation for serving on the Board of Directors of Royalty payments from Children’s Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale. Dr. Finkel has received royalty, license fees, or contractual rights payments from Royalty payments from Children’s Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale. Dr. Finkel has received research support from grants from Biogen and Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; grants from AveXis, Cytokinetics, and Roche. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant for AMO Pharma, AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc., Pfizer, Roche, Santhera, Sarepta.. Dr. Day has received royalty, license fees, or contractual rights payments from Patents licensed to Athena Diagnostics for genetic testing of myotonic dystrophy type 2 (US patent 7442782) and spinocerebellar ataxia type 5 (US patent 7527931). Dr. Day has received research support from Grants from AMO Pharma, aTyr, AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Ionis Pharmaceuticals, Inc., Roche, Sanofi-Genzyme, Sarepta.. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation; CureSMA, Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Cytokinetics, Fibrogen, PTC Th. Dr. Kuntz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for Argenyx, Audentes, AveXis, Biogen, Cytokinetics, PTC, Roche, and Sarepta.. Dr. Kuntz has received research support from Clinical trial research contracts with Audentes, AveXis, Biogen, Pfizer, Roche, and Sarepta.. Dr. Connolly has nothing to disclose. Dr. Crawford has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Muscular Dystrophy Association, Novartis, Roche, Sarepta, Scholar Rock, and the Spinal Muscular Atrophy Foundation. Dr. Butterfield has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Avexis, Pfizer. Dr. Butterfield has received research support from Pfizer, Avexis, Biogen, PTC Therapeutics, Acceleron, Catavasis Pharmaceuticals, and Sarepta Therapeutics. Dr. Shieh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes, Sarepta, Pfizer, Genentech, Avexis, Biogen, Catalyst, Argenyx, Alexion, CSL Behring, Grifols. Dr. Shieh has received research support from Sarepta, Pfizer, Audentes, Avexis, Biogen, PTC, Roche, Sanofi, Reveragen, Acceleron.Dr. Tennekoon has nothing to disclose. Dr. Iannaccone has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta, Avexis. Catabasis, Genentech, Texas Neurological Society, American Academy of Pediatrics, and Methodist Hospitals of Memphis. Dr. Iannaccone has received research support from Avexis, Biogen, Mallinckrodt, PTC Therapeutics, Sarepta, Regeneron, FibroGen, Scholar Rock, and Pfizer. Dr. Meriggioli has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Tauscher-Wisniewski has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Shoffner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Ogrinc has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Kavanagh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Has received consulting fees from UCB Pharma, Colorado Prevention Center, Zosano Pharma, Pure Tech Health, DiaMedica, Karuna Therapeutics. Dr. Kernbauer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Whittle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Sproule has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Sproule has received compensation for serving on the Board of Directors of AveXis, a Novartis company. Dr. Feltner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acadia Pharmaceuticals, AveXis, Inc., Embera NeuroTherapeutics. Dr. Feltner has received compensation for serving on the Board of Directors of Embera NeuroTherapeutics. Dr. Feltner holds stock and/or stock options in AveXis, Inc. which sponsored research in which Dr. Feltner was involved as an investigator. Dr. Feltner holds stock and/or stock options in AveXis, Inc.. Dr. Mendell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with For clinical trial consulting and serving on scientific advisory boards from AveXis, Inc.. Dr. Mendell has received research support from AveXis, Inc..

  • Phase 1 Study of Intrathecal Administration of AVXS-101 Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 2 (SMA2) (STRONG) (P1.6-059)
    Neurology, 2019
    Co-Authors: Richard S. Finkel, Thomas O Crawford, Basil T Darras, Perry B Shieh, John W. Day, Nancy L. Kuntz, Anne M. Connolly, Russell J. Butterfield, Gihan Tennekoon, Susan T. Iannaccone
    Abstract:

    Objective: To describe STRONG, a multicenter, open-label, phase 1 study (NCT03381729) of the safety, tolerability, optimal dose, and efficacy of onasemnogene abeparvovec (AVXS-101) in patients with SMA2. Background: SMA is a rapidly progressing neurodegenerative disease causing loss of motor and respiratory function. The genetic root cause is bi-allelic deletion/mutation of the survival motor neuron 1 gene (SMN1). Disease severity is modified by SMN2 copy number. AVXS-101 comprises an adeno-associated virus serotype 9-encapsulated transcript of human SMN that crosses the blood-brain barrier. In a phase 1 study (NCT02122952) in patients with SMA1, intravenous AVXS-101 demonstrated unprecedented improvements in survival, motor function, and motor milestone achievement Design/Methods: In STRONG, SMA2 patients (bi-allelic SMN1 mutations/deletions, 3 copies of SMN2) who could sit but not stand or walk independently were enrolled in 2 cohorts by age (cohort 1: ≥6 to Results: As of October 12, 2018, 28 patients have been enrolled at 11 sites. Enrollment is complete. To date, no safety or tolerability concerns have been identified. A study update will be provided. Conclusions: Results from STRONG show intrathecal delivery of AVXS-101 in infants is feasible and well tolerated, with no safety concerns to date, and may support AVXS-101 as a promising treatment option for patients with SMA2. Disclosure: Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Novartis, and Roche. Dr. Finkel has received royalty, license fees, or contractual rights payments from Licensing fees from Children’s Hospital of Philadelphia for development of the CHOP-INTEND motor scale. Dr. Finkel has received research support from Ionis Pharmaceuticals, Inc. and Biogen, grants from AveXis and Cytokinetics. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, and Sarepta. Dr. Day has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, and Sarepta. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation, CureSMA, Ionis Pharmaceuticals, Inc., Biogen, AveXis, Cytokinetics, Fibrogen, PTC Therapeutics, Roche, Santhera, Sarepta, and Summit. Dr. Kuntz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Audentes, AveXis, Catalyst, Cytokinetics, Marathon, PTC Therapeutics, and Sarepta Therapeutics. Dr. Kuntz has received research support from AveXis, Audentes, Biogen, Pfizer, Roche and Sarepta Therapeutics. Dr. Connolly has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Sarepta, Astelles, Marathon, Accelleron, Roche, (advisory boards) and Catabasis (DMSB). Dr. Connolly has received research support from Clinical trial site PI for Avexis, Sarepta, Biogen, Cytokinetics, NS Pharma, Pfizer, Roche, Italfarmaco, Fibrogen, and Capricor. Dr. Crawford has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Muscular Dystrophy Association, Novartis, Roche, Sarepta, Scholar Rock, and the Spinal Muscular Atrophy Foundation. Dr. Butterfield has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta Therapeutics and Biogen. Dr. Butterfield has received research support from PTC Therapeutics, Sarepta Therapeutics, Pfizer, and, Biogen. Dr. Shieh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, AveXis, Inc., Biogen, Grifols, PTC Therapeutics and Sarepta. Dr. Shieh has received research support from AveXis, Inc., Audentes, Biogen, Bristol-Myers Squibb, Cytokinetics, Catalyst, Fibrogen, Ionis Pharmaceuticals, Inc., Marathon, Pfizer, PTC Therapeutics, Sarepta, Santhera, Summit, Sanofi/Genzyme and Ultragenyx. Dr. Tennekoon has received research support from Catabasis Pharmaceuticals. Dr. Iannaccone has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Biogen, Sarepta, Capricor. Dr. Iannaccone has received research support from AveXis, Biogen, Sarepta, Capricor, Mallinckrodt, Fibrogen, Regeneron, PTC Therapeutics. Dr. Meriggioli has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Spector has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Ogrinc has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.. Dr. Wells has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Sproule has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as an employee of AveXis, a Novartis company. Dr. Sproule has received compensation for serving on the Board of Directors of AveXis, a Novartis company. Dr. Feltner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acadia, Embera NeurTherapeutics, AveXis, Inc. Dr. Feltner has received compensation for serving on the Board of Directors of Embera NeuroTherapeutics. Dr. Feltner holds stock and/or stock options in AveXis, Inc. Dr. Mendell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.

  • Nusinersen Efficacy in Adults with Spinal Muscular Atrophy (S58.007)
    Neurology, 2019
    Co-Authors: John W. Day, Richard S. Finkel, Basil T Darras, Connie Wolford, Chelsea Macpherson, William B. Martens, Michael P. Mcdermott, Darryl C. De Vivo, Zarazuela Zolkipli Cunningham, Michael Zeineh
    Abstract:

    Objective: To determine the clinical effects of nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability, in comparison to the natural history of untreated adults. Background: SMA is an autosomal recessive disorder affecting 1:10,000 live births, in which survival motor neuron (SMN) protein deficiency leads to motor neuron degeneration and progressive muscle atrophy, weakness, and early mortality. In December, 2016, nusinersen was approved by the FDA for SMA patients of all ages despite the lack of documented efficacy in adults Design/Methods: Outcome measures were collected prospectively on treatment-naive adult SMA patients followed in the Pediatric Neuromuscular Clinical Research (PNCR) Network and compared with a separate group of adults with SMA who were assessed before and after starting nusinersen. A minimal data set based on insurance requirements and validated SMA outcomes included: RULM, HFMSE, TUG, 6MWT, jaw ROM, and the CHOP-Intend neuromuscular scale that was revised for severely affected adults (CHOP-ATEND). Pulmonary function, strength and HHD, patient reported experiences, safety labs and adverse events also were monitored. Results: Results: Natural history was determined in 99 untreated adults and response to nusinersen in 34 adults. More than 90% of patients reported qualitative improvement in: strength, stamina, breathing strength, chewing/swallowing, jaw range of motion, voice strength, or muscle strength. Patients were assigned to one of three functional groups: ambulatory, non-ambulatory strong (RULM > 4), and non-ambulatory weak (RULM ≤ 4); primary functional measures in the groups were 6MWT, RULM, and CHOP-ATEND respectively. Additionally, MIP, MEP and FVC and HHD were monitored in all groups. All measures showed improvement in the treated groups compared to the progressive decline seen in untreated adults. Conclusions: Nusinersen has been well tolerated. Improvement trends are emerging at all disability levels by multiple outcome measures, demonstrating nusinersen efficacy for adults with SMA. Disclosure: Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, and Sarepta. Dr. Day has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, and Sarepta. Dr. Wolford has nothing to disclose. Dr. MacPherson has nothing to disclose. Dr. Martens has nothing to disclose. Dr. McDermott has nothing to disclose. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation, CureSMA, Ionis Pharmaceuticals, Inc., Biogen, AveXis, Cytokinetics, Fibrogen, PTC Therapeutics, Roche, Santhera, Sarepta, and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor, AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc., Metafora, Roche, Sanofi, Sarepta, and the SMA Foundation. Dr. De Vivo has received research support from grants from the Department of Defense, Hope for Children Research Foundation, the National Institutes of Health, and the SMA Foundation, and has received funding for clinical trials from Biogen, Mallinkrodt Pharmaceuticals, PTC Therapeutics, Sarepta Therapeutics, and Ultragenyx. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Novartis, and Roche. Dr. Finkel has received royalty, license fees, or contractual rights payments from Licensing fees from Children’s Hospital of Philadelphia for development of the CHOP-INTEND motor scale. Dr. Finkel has received research support from Ionis Pharmaceuticals, Inc. and Biogen, grants from AveXis and Cytokinetics. Dr. Zeineh has nothing to disclose. Dr. Sampson has nothing to disclose. Dr. Hagerman has nothing to disclose. Dr. Duong has nothing to disclose.

  • Nusinersen Efficacy in Adults with Spinal Muscular Atrophy (S46.001)
    Neurology, 2018
    Co-Authors: John W. Day, Richard S. Finkel, Basil T Darras, Connie Wolford, Chelsea Macpherson, William B. Martens, Michael P. Mcdermott, Darryl C. De Vivo, Zarazuela Zolkipli Cunningham, Jacinda B. Sampson
    Abstract:

    Objective: 1. Evaluate effectiveness of our clinical protocol for nusinersen treatment in adults with Spinal Muscular Atrophy (SMA). 2. Assess post-treatment functional changes of adults with SMA compared to their baseline and the natural history of SMA. Background: SMA is an autosomal recessive disorder affecting 1:10,000 live births, in which deficient survival motor neuron (SMN) protein leads to progressive muscle atrophy, weakness, and early mortality. Nusinersen is the first FDA approved treatment for SMA. Clinical trials have shown benefit in children, but the efficacy in adults has not been documented. Design/Methods: Functional and clinical measures prospectively collected on adult SMA patients in an international SMA network, PNCRN, were compared with nusinersen treated adults. Pre-approval visits included: medical & genetic history, standard of care, anatomic and radiologic findings, and insurance assessment. A minimal data set based on insurance requirements and validated outcomes in SMA included at least one of the following: CHOP-INTEND, RULM, HFMSE, TUG, 6MWT. We also monitored pulmonary function, strength, patient reported experiences, safety labs and adverse events. Results: Natural history was determined in 170 evaluations of 57 untreated adults. Assessments were obtained in 27 individuals desiring nusinersen, 20 of whom were treated. Individuals were not treated due to insurance denial (1), lack of access via routine fluoroscopy (5), and patient choice (1). Individuals were: 18–65 years old, non-ambulatory (75%), male (57%), requiring day/night ventilatory support (7), and with spinal fusion (8). Qualitative improvement was frequent (85%). Baseline measures (median and ranges) included for ambulatory (n=7): 6MWT (367.9m, 69.2–466.0m), TUG (9.9sec, 8.4–44.2sec) and for non-Ambulatory (n=20) RULM (12.5, 0–38), PFT (3.05L, 0.28–5.62L). Conclusions: Nusinersen has been well tolerated and improvement trends are emerging in multiple measures; data continue to be collected. Analyses of clinical outcomes, to be presented, will define nusinersen efficacy for adults with SMA. Disclosure: Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta. Dr. Wolford has nothing to disclose. Dr. MacPherson has nothing to disclose. Dr. Martens has nothing to disclose. Dr. McDermott has nothing to disclose. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Darras has served as an ad hoc scientific advisory board member for AveXis, Biogen, Cytokinetics, Marathon Pharmaceuticals, PTC Therapeutics, Roche, and Sarepta; and has been an advisor for Bristol-Myers Squibb and Ionis Pharmaceuticals, Inc.; he has. Dr. Darras has received research support from Dr. Darras has received research support from from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, CS2/CS12 studies, from Biogen for CS11 , as well as from Cytokinetics, PTC Therapeutics, Fibrogen and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting/Advisory Board membership with AveXis, Biogen, Sarepta, PTC, Cytokinetics, Ultragenyx, and Sanofi. Dr. De Vivo has received research support from Clinical trials support from Sarepta, PTC, Ultragenyx, and Biogen, animal model licensing to Sanofi. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting fees and travel costs from AveXis, Biogen, Catabasis, Ionis, Mitobridge, and Summit. Dr. Finkel has received research support from My institution received research support to perform clinical trials from Biogen, BMS, Catabasis, Cytokinetics, Ionis, Lilly, ReveraGen, Sarepta, and Summit. Dr. Sampson has nothing to disclose. Dr. Duong has nothing to disclose.

  • Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Feasibility for Individuals with Severe Spinal Muscular Atrophy II (S46.004)
    Neurology, 2018
    Co-Authors: Elizabeth A. Kichula, Richard S. Finkel, Basil T Darras, Darryl C. De Vivo, Tina Duong, Allan M. Glanzman, Amy Pasternak, Zarazuela Zolkipli-cunningham, John W. Day
    Abstract:

    Objective: NA Background: Outcome measure development for Spinal Muscular Atrophy (SMA) has focused on clinical trial readiness, and now exist across all SMA types. However, gross motor evaluation of older severely weak patients with SMA remains a challenge. The CHOP INTEND is a validated motor outcome measure developed for weak infants with type 1 SMA. Here we demonstrate its potential utility of a sub set of CHOP INTEND items for a series of individuals with type 2 SMA with scores on the Expanded Hammersmith Functional Motor Scale (HFMSE) of 2 or less. Design/Methods: We reviewed CHOP INTEND and HFMSE scores for 13 individuals (age 7–40) with type 2 SMA whose HFMSE scores were ≤2. The objective was to determine if the distribution of scores on subset of the CHOP INTEND was broader than the HFMSE scores, indicating enhanced sensitivity when administered in severe type 2 SMA. Qualitative review of difficulties experienced and clinical reasoning associated with testing non-infants was discussed among the physical therapists to determine themes. Results: Eight individuals scored 0 on the HFMSE and 5 scored 1 or 2 primarily reflecting minimal leg movement. The median CHOP INTEND score was 16.1 (IQR 10–22). Two patients were retested after their Spinraza loading doses and improved from 23 to 31 and from 27 to 29 while their HFMSE remained at 0. Items 11, 15, and 16 (requiring suspension) could not be tested in older individuals resulting in a score of 0. Conclusions: The CHOP INTEND may be more sensitive to changes in gross motor function and muscle strength in individuals with type 2 SMA due to a floor effect on HFMSE, and may be a reliable measure for long-term follow up. Longitudinal assessment to evaluate the sensitivity of a subset of the CHOP INTEND to detect change over time in weak SMA individuals is required. Disclosure: Dr. Kichula has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis. Dr. Duong has nothing to disclose. Dr. Glanzman has nothing to disclose. Dr. Pasternak has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Scientific advisory board for Avexis Pharmaceuticals. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Darras has served as an ad hoc scientific advisory board member for AveXis, Biogen, Cytokinetics, Marathon Pharmaceuticals, PTC Therapeutics, Roche, and Sarepta; and has been an advisor for Bristol-Myers Squibb and Ionis Pharmaceuticals, Inc.; he has. Dr. Darras has received research support from Dr. Darras has received research support from from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, CS2/CS12 studies, from Biogen for CS11 , as well as from Cytokinetics, PTC Therapeutics, Fibrogen and Summit. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting fees and travel costs from AveXis, Biogen, Catabasis, Ionis, Mitobridge, and Summit. Dr. Finkel has received research support from My institution received research support to perform clinical trials from Biogen, BMS, Catabasis, Cytokinetics, Ionis, Lilly, ReveraGen, Sarepta, and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting/Advisory Board membership with AveXis, Biogen, Sarepta, PTC, Cytokinetics, Ultragenyx, and Sanofi. Dr. De Vivo has received research support from Clinical trials support from Sarepta, PTC, Ultragenyx, and Biogen, animal model licensing to Sanofi. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta.

John W. Day - One of the best experts on this subject based on the ideXlab platform.

  • One-Time Intrathecal (IT) Administration of AVXS-101 IT Gene-Replacement Therapy for Spinal Muscular Atrophy: Phase 1 Study (STRONG) (2493)
    Neurology, 2020
    Co-Authors: Richard S. Finkel, Thomas O Crawford, Basil T Darras, Perry B Shieh, John W. Day, Nancy L. Kuntz, Anne M. Connolly, Russell J. Butterfield, Gihan Tennekoon, Susan T. Iannaccone
    Abstract:

    Objective: To assess the safety/tolerability, optimal dose, and efficacy of AVXS-101 IT in sitting but non-ambulatory patients with spinal muscular atrophy (SMA). Background: SMA is a rapidly progressing disease causing loss of motor/respiratory functions due to survival motor neuron 1 gene (SMN1) deletion/mutation. Disease severity is modified by SMN2 copy number. AVXS-101 IT is a gene-replacement therapy that addresses the genetic root cause of SMA. Design/Methods: In STRONG (phase 1 study; NCT03381729), SMA patients (biallelic SMN1 loss, 3xSMN2) aged ≥6– Results: As of 31 May 2019, 31 patients were enrolled (dose A, complete: n=3, ≥6– Conclusions: Interim data from STRONG demonstrates early signs of efficacy in sitting but non-ambulatory patients with SMA. Disclosure: Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor fees from Biogen and Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; advisor to AveXis, Novartis, and Roche; data safety monitoring board for the AveXis AVX-101 Phase 1 gene transfer study and Roche Moonfish Phase 1b study; advisory capacit. Dr. Finkel has received compensation for serving on the Board of Directors of Royalty payments from Children’s Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale. Dr. Finkel has received royalty, license fees, or contractual rights payments from Royalty payments from Children’s Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale. Dr. Finkel has received research support from grants from Biogen and Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; grants from AveXis, Cytokinetics, and Roche. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant for AMO Pharma, AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc., Pfizer, Roche, Santhera, Sarepta.. Dr. Day has received royalty, license fees, or contractual rights payments from Patents licensed to Athena Diagnostics for genetic testing of myotonic dystrophy type 2 (US patent 7442782) and spinocerebellar ataxia type 5 (US patent 7527931). Dr. Day has received research support from Grants from AMO Pharma, aTyr, AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Ionis Pharmaceuticals, Inc., Roche, Sanofi-Genzyme, Sarepta.. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation; CureSMA, Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Cytokinetics, Fibrogen, PTC Th. Dr. Kuntz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for Argenyx, Audentes, AveXis, Biogen, Cytokinetics, PTC, Roche, and Sarepta.. Dr. Kuntz has received research support from Clinical trial research contracts with Audentes, AveXis, Biogen, Pfizer, Roche, and Sarepta.. Dr. Connolly has nothing to disclose. Dr. Crawford has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Muscular Dystrophy Association, Novartis, Roche, Sarepta, Scholar Rock, and the Spinal Muscular Atrophy Foundation. Dr. Butterfield has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Avexis, Pfizer. Dr. Butterfield has received research support from Pfizer, Avexis, Biogen, PTC Therapeutics, Acceleron, Catavasis Pharmaceuticals, and Sarepta Therapeutics. Dr. Shieh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes, Sarepta, Pfizer, Genentech, Avexis, Biogen, Catalyst, Argenyx, Alexion, CSL Behring, Grifols. Dr. Shieh has received research support from Sarepta, Pfizer, Audentes, Avexis, Biogen, PTC, Roche, Sanofi, Reveragen, Acceleron.Dr. Tennekoon has nothing to disclose. Dr. Iannaccone has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta, Avexis. Catabasis, Genentech, Texas Neurological Society, American Academy of Pediatrics, and Methodist Hospitals of Memphis. Dr. Iannaccone has received research support from Avexis, Biogen, Mallinckrodt, PTC Therapeutics, Sarepta, Regeneron, FibroGen, Scholar Rock, and Pfizer. Dr. Meriggioli has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Tauscher-Wisniewski has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Shoffner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Ogrinc has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Kavanagh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Has received consulting fees from UCB Pharma, Colorado Prevention Center, Zosano Pharma, Pure Tech Health, DiaMedica, Karuna Therapeutics. Dr. Kernbauer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Whittle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Sproule has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Sproule has received compensation for serving on the Board of Directors of AveXis, a Novartis company. Dr. Feltner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acadia Pharmaceuticals, AveXis, Inc., Embera NeuroTherapeutics. Dr. Feltner has received compensation for serving on the Board of Directors of Embera NeuroTherapeutics. Dr. Feltner holds stock and/or stock options in AveXis, Inc. which sponsored research in which Dr. Feltner was involved as an investigator. Dr. Feltner holds stock and/or stock options in AveXis, Inc.. Dr. Mendell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with For clinical trial consulting and serving on scientific advisory boards from AveXis, Inc.. Dr. Mendell has received research support from AveXis, Inc..

  • Phase 1 Study of Intrathecal Administration of AVXS-101 Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 2 (SMA2) (STRONG) (P1.6-059)
    Neurology, 2019
    Co-Authors: Richard S. Finkel, Thomas O Crawford, Basil T Darras, Perry B Shieh, John W. Day, Nancy L. Kuntz, Anne M. Connolly, Russell J. Butterfield, Gihan Tennekoon, Susan T. Iannaccone
    Abstract:

    Objective: To describe STRONG, a multicenter, open-label, phase 1 study (NCT03381729) of the safety, tolerability, optimal dose, and efficacy of onasemnogene abeparvovec (AVXS-101) in patients with SMA2. Background: SMA is a rapidly progressing neurodegenerative disease causing loss of motor and respiratory function. The genetic root cause is bi-allelic deletion/mutation of the survival motor neuron 1 gene (SMN1). Disease severity is modified by SMN2 copy number. AVXS-101 comprises an adeno-associated virus serotype 9-encapsulated transcript of human SMN that crosses the blood-brain barrier. In a phase 1 study (NCT02122952) in patients with SMA1, intravenous AVXS-101 demonstrated unprecedented improvements in survival, motor function, and motor milestone achievement Design/Methods: In STRONG, SMA2 patients (bi-allelic SMN1 mutations/deletions, 3 copies of SMN2) who could sit but not stand or walk independently were enrolled in 2 cohorts by age (cohort 1: ≥6 to Results: As of October 12, 2018, 28 patients have been enrolled at 11 sites. Enrollment is complete. To date, no safety or tolerability concerns have been identified. A study update will be provided. Conclusions: Results from STRONG show intrathecal delivery of AVXS-101 in infants is feasible and well tolerated, with no safety concerns to date, and may support AVXS-101 as a promising treatment option for patients with SMA2. Disclosure: Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Novartis, and Roche. Dr. Finkel has received royalty, license fees, or contractual rights payments from Licensing fees from Children’s Hospital of Philadelphia for development of the CHOP-INTEND motor scale. Dr. Finkel has received research support from Ionis Pharmaceuticals, Inc. and Biogen, grants from AveXis and Cytokinetics. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, and Sarepta. Dr. Day has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, and Sarepta. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation, CureSMA, Ionis Pharmaceuticals, Inc., Biogen, AveXis, Cytokinetics, Fibrogen, PTC Therapeutics, Roche, Santhera, Sarepta, and Summit. Dr. Kuntz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Audentes, AveXis, Catalyst, Cytokinetics, Marathon, PTC Therapeutics, and Sarepta Therapeutics. Dr. Kuntz has received research support from AveXis, Audentes, Biogen, Pfizer, Roche and Sarepta Therapeutics. Dr. Connolly has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Sarepta, Astelles, Marathon, Accelleron, Roche, (advisory boards) and Catabasis (DMSB). Dr. Connolly has received research support from Clinical trial site PI for Avexis, Sarepta, Biogen, Cytokinetics, NS Pharma, Pfizer, Roche, Italfarmaco, Fibrogen, and Capricor. Dr. Crawford has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Muscular Dystrophy Association, Novartis, Roche, Sarepta, Scholar Rock, and the Spinal Muscular Atrophy Foundation. Dr. Butterfield has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta Therapeutics and Biogen. Dr. Butterfield has received research support from PTC Therapeutics, Sarepta Therapeutics, Pfizer, and, Biogen. Dr. Shieh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, AveXis, Inc., Biogen, Grifols, PTC Therapeutics and Sarepta. Dr. Shieh has received research support from AveXis, Inc., Audentes, Biogen, Bristol-Myers Squibb, Cytokinetics, Catalyst, Fibrogen, Ionis Pharmaceuticals, Inc., Marathon, Pfizer, PTC Therapeutics, Sarepta, Santhera, Summit, Sanofi/Genzyme and Ultragenyx. Dr. Tennekoon has received research support from Catabasis Pharmaceuticals. Dr. Iannaccone has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Biogen, Sarepta, Capricor. Dr. Iannaccone has received research support from AveXis, Biogen, Sarepta, Capricor, Mallinckrodt, Fibrogen, Regeneron, PTC Therapeutics. Dr. Meriggioli has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Spector has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Ogrinc has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.. Dr. Wells has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Sproule has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as an employee of AveXis, a Novartis company. Dr. Sproule has received compensation for serving on the Board of Directors of AveXis, a Novartis company. Dr. Feltner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acadia, Embera NeurTherapeutics, AveXis, Inc. Dr. Feltner has received compensation for serving on the Board of Directors of Embera NeuroTherapeutics. Dr. Feltner holds stock and/or stock options in AveXis, Inc. Dr. Mendell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.

  • Nusinersen Efficacy in Adults with Spinal Muscular Atrophy (S58.007)
    Neurology, 2019
    Co-Authors: John W. Day, Richard S. Finkel, Basil T Darras, Connie Wolford, Chelsea Macpherson, William B. Martens, Michael P. Mcdermott, Darryl C. De Vivo, Zarazuela Zolkipli Cunningham, Michael Zeineh
    Abstract:

    Objective: To determine the clinical effects of nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability, in comparison to the natural history of untreated adults. Background: SMA is an autosomal recessive disorder affecting 1:10,000 live births, in which survival motor neuron (SMN) protein deficiency leads to motor neuron degeneration and progressive muscle atrophy, weakness, and early mortality. In December, 2016, nusinersen was approved by the FDA for SMA patients of all ages despite the lack of documented efficacy in adults Design/Methods: Outcome measures were collected prospectively on treatment-naive adult SMA patients followed in the Pediatric Neuromuscular Clinical Research (PNCR) Network and compared with a separate group of adults with SMA who were assessed before and after starting nusinersen. A minimal data set based on insurance requirements and validated SMA outcomes included: RULM, HFMSE, TUG, 6MWT, jaw ROM, and the CHOP-Intend neuromuscular scale that was revised for severely affected adults (CHOP-ATEND). Pulmonary function, strength and HHD, patient reported experiences, safety labs and adverse events also were monitored. Results: Results: Natural history was determined in 99 untreated adults and response to nusinersen in 34 adults. More than 90% of patients reported qualitative improvement in: strength, stamina, breathing strength, chewing/swallowing, jaw range of motion, voice strength, or muscle strength. Patients were assigned to one of three functional groups: ambulatory, non-ambulatory strong (RULM > 4), and non-ambulatory weak (RULM ≤ 4); primary functional measures in the groups were 6MWT, RULM, and CHOP-ATEND respectively. Additionally, MIP, MEP and FVC and HHD were monitored in all groups. All measures showed improvement in the treated groups compared to the progressive decline seen in untreated adults. Conclusions: Nusinersen has been well tolerated. Improvement trends are emerging at all disability levels by multiple outcome measures, demonstrating nusinersen efficacy for adults with SMA. Disclosure: Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, and Sarepta. Dr. Day has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, and Sarepta. Dr. Wolford has nothing to disclose. Dr. MacPherson has nothing to disclose. Dr. Martens has nothing to disclose. Dr. McDermott has nothing to disclose. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation, CureSMA, Ionis Pharmaceuticals, Inc., Biogen, AveXis, Cytokinetics, Fibrogen, PTC Therapeutics, Roche, Santhera, Sarepta, and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor, AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc., Metafora, Roche, Sanofi, Sarepta, and the SMA Foundation. Dr. De Vivo has received research support from grants from the Department of Defense, Hope for Children Research Foundation, the National Institutes of Health, and the SMA Foundation, and has received funding for clinical trials from Biogen, Mallinkrodt Pharmaceuticals, PTC Therapeutics, Sarepta Therapeutics, and Ultragenyx. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Novartis, and Roche. Dr. Finkel has received royalty, license fees, or contractual rights payments from Licensing fees from Children’s Hospital of Philadelphia for development of the CHOP-INTEND motor scale. Dr. Finkel has received research support from Ionis Pharmaceuticals, Inc. and Biogen, grants from AveXis and Cytokinetics. Dr. Zeineh has nothing to disclose. Dr. Sampson has nothing to disclose. Dr. Hagerman has nothing to disclose. Dr. Duong has nothing to disclose.

  • Nusinersen Efficacy in Adults with Spinal Muscular Atrophy (S46.001)
    Neurology, 2018
    Co-Authors: John W. Day, Richard S. Finkel, Basil T Darras, Connie Wolford, Chelsea Macpherson, William B. Martens, Michael P. Mcdermott, Darryl C. De Vivo, Zarazuela Zolkipli Cunningham, Jacinda B. Sampson
    Abstract:

    Objective: 1. Evaluate effectiveness of our clinical protocol for nusinersen treatment in adults with Spinal Muscular Atrophy (SMA). 2. Assess post-treatment functional changes of adults with SMA compared to their baseline and the natural history of SMA. Background: SMA is an autosomal recessive disorder affecting 1:10,000 live births, in which deficient survival motor neuron (SMN) protein leads to progressive muscle atrophy, weakness, and early mortality. Nusinersen is the first FDA approved treatment for SMA. Clinical trials have shown benefit in children, but the efficacy in adults has not been documented. Design/Methods: Functional and clinical measures prospectively collected on adult SMA patients in an international SMA network, PNCRN, were compared with nusinersen treated adults. Pre-approval visits included: medical & genetic history, standard of care, anatomic and radiologic findings, and insurance assessment. A minimal data set based on insurance requirements and validated outcomes in SMA included at least one of the following: CHOP-INTEND, RULM, HFMSE, TUG, 6MWT. We also monitored pulmonary function, strength, patient reported experiences, safety labs and adverse events. Results: Natural history was determined in 170 evaluations of 57 untreated adults. Assessments were obtained in 27 individuals desiring nusinersen, 20 of whom were treated. Individuals were not treated due to insurance denial (1), lack of access via routine fluoroscopy (5), and patient choice (1). Individuals were: 18–65 years old, non-ambulatory (75%), male (57%), requiring day/night ventilatory support (7), and with spinal fusion (8). Qualitative improvement was frequent (85%). Baseline measures (median and ranges) included for ambulatory (n=7): 6MWT (367.9m, 69.2–466.0m), TUG (9.9sec, 8.4–44.2sec) and for non-Ambulatory (n=20) RULM (12.5, 0–38), PFT (3.05L, 0.28–5.62L). Conclusions: Nusinersen has been well tolerated and improvement trends are emerging in multiple measures; data continue to be collected. Analyses of clinical outcomes, to be presented, will define nusinersen efficacy for adults with SMA. Disclosure: Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta. Dr. Wolford has nothing to disclose. Dr. MacPherson has nothing to disclose. Dr. Martens has nothing to disclose. Dr. McDermott has nothing to disclose. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Darras has served as an ad hoc scientific advisory board member for AveXis, Biogen, Cytokinetics, Marathon Pharmaceuticals, PTC Therapeutics, Roche, and Sarepta; and has been an advisor for Bristol-Myers Squibb and Ionis Pharmaceuticals, Inc.; he has. Dr. Darras has received research support from Dr. Darras has received research support from from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, CS2/CS12 studies, from Biogen for CS11 , as well as from Cytokinetics, PTC Therapeutics, Fibrogen and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting/Advisory Board membership with AveXis, Biogen, Sarepta, PTC, Cytokinetics, Ultragenyx, and Sanofi. Dr. De Vivo has received research support from Clinical trials support from Sarepta, PTC, Ultragenyx, and Biogen, animal model licensing to Sanofi. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting fees and travel costs from AveXis, Biogen, Catabasis, Ionis, Mitobridge, and Summit. Dr. Finkel has received research support from My institution received research support to perform clinical trials from Biogen, BMS, Catabasis, Cytokinetics, Ionis, Lilly, ReveraGen, Sarepta, and Summit. Dr. Sampson has nothing to disclose. Dr. Duong has nothing to disclose.

  • Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Feasibility for Individuals with Severe Spinal Muscular Atrophy II (S46.004)
    Neurology, 2018
    Co-Authors: Elizabeth A. Kichula, Richard S. Finkel, Basil T Darras, Darryl C. De Vivo, Tina Duong, Allan M. Glanzman, Amy Pasternak, Zarazuela Zolkipli-cunningham, John W. Day
    Abstract:

    Objective: NA Background: Outcome measure development for Spinal Muscular Atrophy (SMA) has focused on clinical trial readiness, and now exist across all SMA types. However, gross motor evaluation of older severely weak patients with SMA remains a challenge. The CHOP INTEND is a validated motor outcome measure developed for weak infants with type 1 SMA. Here we demonstrate its potential utility of a sub set of CHOP INTEND items for a series of individuals with type 2 SMA with scores on the Expanded Hammersmith Functional Motor Scale (HFMSE) of 2 or less. Design/Methods: We reviewed CHOP INTEND and HFMSE scores for 13 individuals (age 7–40) with type 2 SMA whose HFMSE scores were ≤2. The objective was to determine if the distribution of scores on subset of the CHOP INTEND was broader than the HFMSE scores, indicating enhanced sensitivity when administered in severe type 2 SMA. Qualitative review of difficulties experienced and clinical reasoning associated with testing non-infants was discussed among the physical therapists to determine themes. Results: Eight individuals scored 0 on the HFMSE and 5 scored 1 or 2 primarily reflecting minimal leg movement. The median CHOP INTEND score was 16.1 (IQR 10–22). Two patients were retested after their Spinraza loading doses and improved from 23 to 31 and from 27 to 29 while their HFMSE remained at 0. Items 11, 15, and 16 (requiring suspension) could not be tested in older individuals resulting in a score of 0. Conclusions: The CHOP INTEND may be more sensitive to changes in gross motor function and muscle strength in individuals with type 2 SMA due to a floor effect on HFMSE, and may be a reliable measure for long-term follow up. Longitudinal assessment to evaluate the sensitivity of a subset of the CHOP INTEND to detect change over time in weak SMA individuals is required. Disclosure: Dr. Kichula has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis. Dr. Duong has nothing to disclose. Dr. Glanzman has nothing to disclose. Dr. Pasternak has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Scientific advisory board for Avexis Pharmaceuticals. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Darras has served as an ad hoc scientific advisory board member for AveXis, Biogen, Cytokinetics, Marathon Pharmaceuticals, PTC Therapeutics, Roche, and Sarepta; and has been an advisor for Bristol-Myers Squibb and Ionis Pharmaceuticals, Inc.; he has. Dr. Darras has received research support from Dr. Darras has received research support from from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, CS2/CS12 studies, from Biogen for CS11 , as well as from Cytokinetics, PTC Therapeutics, Fibrogen and Summit. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting fees and travel costs from AveXis, Biogen, Catabasis, Ionis, Mitobridge, and Summit. Dr. Finkel has received research support from My institution received research support to perform clinical trials from Biogen, BMS, Catabasis, Cytokinetics, Ionis, Lilly, ReveraGen, Sarepta, and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting/Advisory Board membership with AveXis, Biogen, Sarepta, PTC, Cytokinetics, Ultragenyx, and Sanofi. Dr. De Vivo has received research support from Clinical trials support from Sarepta, PTC, Ultragenyx, and Biogen, animal model licensing to Sanofi. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta.

Basil T Darras - One of the best experts on this subject based on the ideXlab platform.

  • One-Time Intrathecal (IT) Administration of AVXS-101 IT Gene-Replacement Therapy for Spinal Muscular Atrophy: Phase 1 Study (STRONG) (2493)
    Neurology, 2020
    Co-Authors: Richard S. Finkel, Thomas O Crawford, Basil T Darras, Perry B Shieh, John W. Day, Nancy L. Kuntz, Anne M. Connolly, Russell J. Butterfield, Gihan Tennekoon, Susan T. Iannaccone
    Abstract:

    Objective: To assess the safety/tolerability, optimal dose, and efficacy of AVXS-101 IT in sitting but non-ambulatory patients with spinal muscular atrophy (SMA). Background: SMA is a rapidly progressing disease causing loss of motor/respiratory functions due to survival motor neuron 1 gene (SMN1) deletion/mutation. Disease severity is modified by SMN2 copy number. AVXS-101 IT is a gene-replacement therapy that addresses the genetic root cause of SMA. Design/Methods: In STRONG (phase 1 study; NCT03381729), SMA patients (biallelic SMN1 loss, 3xSMN2) aged ≥6– Results: As of 31 May 2019, 31 patients were enrolled (dose A, complete: n=3, ≥6– Conclusions: Interim data from STRONG demonstrates early signs of efficacy in sitting but non-ambulatory patients with SMA. Disclosure: Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor fees from Biogen and Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; advisor to AveXis, Novartis, and Roche; data safety monitoring board for the AveXis AVX-101 Phase 1 gene transfer study and Roche Moonfish Phase 1b study; advisory capacit. Dr. Finkel has received compensation for serving on the Board of Directors of Royalty payments from Children’s Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale. Dr. Finkel has received royalty, license fees, or contractual rights payments from Royalty payments from Children’s Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale. Dr. Finkel has received research support from grants from Biogen and Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; grants from AveXis, Cytokinetics, and Roche. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant for AMO Pharma, AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc., Pfizer, Roche, Santhera, Sarepta.. Dr. Day has received royalty, license fees, or contractual rights payments from Patents licensed to Athena Diagnostics for genetic testing of myotonic dystrophy type 2 (US patent 7442782) and spinocerebellar ataxia type 5 (US patent 7527931). Dr. Day has received research support from Grants from AMO Pharma, aTyr, AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Ionis Pharmaceuticals, Inc., Roche, Sanofi-Genzyme, Sarepta.. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation; CureSMA, Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Cytokinetics, Fibrogen, PTC Th. Dr. Kuntz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory boards for Argenyx, Audentes, AveXis, Biogen, Cytokinetics, PTC, Roche, and Sarepta.. Dr. Kuntz has received research support from Clinical trial research contracts with Audentes, AveXis, Biogen, Pfizer, Roche, and Sarepta.. Dr. Connolly has nothing to disclose. Dr. Crawford has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Muscular Dystrophy Association, Novartis, Roche, Sarepta, Scholar Rock, and the Spinal Muscular Atrophy Foundation. Dr. Butterfield has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Avexis, Pfizer. Dr. Butterfield has received research support from Pfizer, Avexis, Biogen, PTC Therapeutics, Acceleron, Catavasis Pharmaceuticals, and Sarepta Therapeutics. Dr. Shieh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Audentes, Sarepta, Pfizer, Genentech, Avexis, Biogen, Catalyst, Argenyx, Alexion, CSL Behring, Grifols. Dr. Shieh has received research support from Sarepta, Pfizer, Audentes, Avexis, Biogen, PTC, Roche, Sanofi, Reveragen, Acceleron.Dr. Tennekoon has nothing to disclose. Dr. Iannaccone has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta, Avexis. Catabasis, Genentech, Texas Neurological Society, American Academy of Pediatrics, and Methodist Hospitals of Memphis. Dr. Iannaccone has received research support from Avexis, Biogen, Mallinckrodt, PTC Therapeutics, Sarepta, Regeneron, FibroGen, Scholar Rock, and Pfizer. Dr. Meriggioli has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Tauscher-Wisniewski has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Shoffner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Ogrinc has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Kavanagh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Has received consulting fees from UCB Pharma, Colorado Prevention Center, Zosano Pharma, Pure Tech Health, DiaMedica, Karuna Therapeutics. Dr. Kernbauer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Whittle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Sproule has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Sproule has received compensation for serving on the Board of Directors of AveXis, a Novartis company. Dr. Feltner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acadia Pharmaceuticals, AveXis, Inc., Embera NeuroTherapeutics. Dr. Feltner has received compensation for serving on the Board of Directors of Embera NeuroTherapeutics. Dr. Feltner holds stock and/or stock options in AveXis, Inc. which sponsored research in which Dr. Feltner was involved as an investigator. Dr. Feltner holds stock and/or stock options in AveXis, Inc.. Dr. Mendell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with For clinical trial consulting and serving on scientific advisory boards from AveXis, Inc.. Dr. Mendell has received research support from AveXis, Inc..

  • Phase 1 Study of Intrathecal Administration of AVXS-101 Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 2 (SMA2) (STRONG) (P1.6-059)
    Neurology, 2019
    Co-Authors: Richard S. Finkel, Thomas O Crawford, Basil T Darras, Perry B Shieh, John W. Day, Nancy L. Kuntz, Anne M. Connolly, Russell J. Butterfield, Gihan Tennekoon, Susan T. Iannaccone
    Abstract:

    Objective: To describe STRONG, a multicenter, open-label, phase 1 study (NCT03381729) of the safety, tolerability, optimal dose, and efficacy of onasemnogene abeparvovec (AVXS-101) in patients with SMA2. Background: SMA is a rapidly progressing neurodegenerative disease causing loss of motor and respiratory function. The genetic root cause is bi-allelic deletion/mutation of the survival motor neuron 1 gene (SMN1). Disease severity is modified by SMN2 copy number. AVXS-101 comprises an adeno-associated virus serotype 9-encapsulated transcript of human SMN that crosses the blood-brain barrier. In a phase 1 study (NCT02122952) in patients with SMA1, intravenous AVXS-101 demonstrated unprecedented improvements in survival, motor function, and motor milestone achievement Design/Methods: In STRONG, SMA2 patients (bi-allelic SMN1 mutations/deletions, 3 copies of SMN2) who could sit but not stand or walk independently were enrolled in 2 cohorts by age (cohort 1: ≥6 to Results: As of October 12, 2018, 28 patients have been enrolled at 11 sites. Enrollment is complete. To date, no safety or tolerability concerns have been identified. A study update will be provided. Conclusions: Results from STRONG show intrathecal delivery of AVXS-101 in infants is feasible and well tolerated, with no safety concerns to date, and may support AVXS-101 as a promising treatment option for patients with SMA2. Disclosure: Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Novartis, and Roche. Dr. Finkel has received royalty, license fees, or contractual rights payments from Licensing fees from Children’s Hospital of Philadelphia for development of the CHOP-INTEND motor scale. Dr. Finkel has received research support from Ionis Pharmaceuticals, Inc. and Biogen, grants from AveXis and Cytokinetics. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, and Sarepta. Dr. Day has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, and Sarepta. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation, CureSMA, Ionis Pharmaceuticals, Inc., Biogen, AveXis, Cytokinetics, Fibrogen, PTC Therapeutics, Roche, Santhera, Sarepta, and Summit. Dr. Kuntz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Audentes, AveXis, Catalyst, Cytokinetics, Marathon, PTC Therapeutics, and Sarepta Therapeutics. Dr. Kuntz has received research support from AveXis, Audentes, Biogen, Pfizer, Roche and Sarepta Therapeutics. Dr. Connolly has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Sarepta, Astelles, Marathon, Accelleron, Roche, (advisory boards) and Catabasis (DMSB). Dr. Connolly has received research support from Clinical trial site PI for Avexis, Sarepta, Biogen, Cytokinetics, NS Pharma, Pfizer, Roche, Italfarmaco, Fibrogen, and Capricor. Dr. Crawford has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Muscular Dystrophy Association, Novartis, Roche, Sarepta, Scholar Rock, and the Spinal Muscular Atrophy Foundation. Dr. Butterfield has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta Therapeutics and Biogen. Dr. Butterfield has received research support from PTC Therapeutics, Sarepta Therapeutics, Pfizer, and, Biogen. Dr. Shieh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, AveXis, Inc., Biogen, Grifols, PTC Therapeutics and Sarepta. Dr. Shieh has received research support from AveXis, Inc., Audentes, Biogen, Bristol-Myers Squibb, Cytokinetics, Catalyst, Fibrogen, Ionis Pharmaceuticals, Inc., Marathon, Pfizer, PTC Therapeutics, Sarepta, Santhera, Summit, Sanofi/Genzyme and Ultragenyx. Dr. Tennekoon has received research support from Catabasis Pharmaceuticals. Dr. Iannaccone has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Biogen, Sarepta, Capricor. Dr. Iannaccone has received research support from AveXis, Biogen, Sarepta, Capricor, Mallinckrodt, Fibrogen, Regeneron, PTC Therapeutics. Dr. Meriggioli has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Spector has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Ogrinc has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.. Dr. Wells has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Sproule has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as an employee of AveXis, a Novartis company. Dr. Sproule has received compensation for serving on the Board of Directors of AveXis, a Novartis company. Dr. Feltner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acadia, Embera NeurTherapeutics, AveXis, Inc. Dr. Feltner has received compensation for serving on the Board of Directors of Embera NeuroTherapeutics. Dr. Feltner holds stock and/or stock options in AveXis, Inc. Dr. Mendell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.

  • Nusinersen Efficacy in Adults with Spinal Muscular Atrophy (S58.007)
    Neurology, 2019
    Co-Authors: John W. Day, Richard S. Finkel, Basil T Darras, Connie Wolford, Chelsea Macpherson, William B. Martens, Michael P. Mcdermott, Darryl C. De Vivo, Zarazuela Zolkipli Cunningham, Michael Zeineh
    Abstract:

    Objective: To determine the clinical effects of nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability, in comparison to the natural history of untreated adults. Background: SMA is an autosomal recessive disorder affecting 1:10,000 live births, in which survival motor neuron (SMN) protein deficiency leads to motor neuron degeneration and progressive muscle atrophy, weakness, and early mortality. In December, 2016, nusinersen was approved by the FDA for SMA patients of all ages despite the lack of documented efficacy in adults Design/Methods: Outcome measures were collected prospectively on treatment-naive adult SMA patients followed in the Pediatric Neuromuscular Clinical Research (PNCR) Network and compared with a separate group of adults with SMA who were assessed before and after starting nusinersen. A minimal data set based on insurance requirements and validated SMA outcomes included: RULM, HFMSE, TUG, 6MWT, jaw ROM, and the CHOP-Intend neuromuscular scale that was revised for severely affected adults (CHOP-ATEND). Pulmonary function, strength and HHD, patient reported experiences, safety labs and adverse events also were monitored. Results: Results: Natural history was determined in 99 untreated adults and response to nusinersen in 34 adults. More than 90% of patients reported qualitative improvement in: strength, stamina, breathing strength, chewing/swallowing, jaw range of motion, voice strength, or muscle strength. Patients were assigned to one of three functional groups: ambulatory, non-ambulatory strong (RULM > 4), and non-ambulatory weak (RULM ≤ 4); primary functional measures in the groups were 6MWT, RULM, and CHOP-ATEND respectively. Additionally, MIP, MEP and FVC and HHD were monitored in all groups. All measures showed improvement in the treated groups compared to the progressive decline seen in untreated adults. Conclusions: Nusinersen has been well tolerated. Improvement trends are emerging at all disability levels by multiple outcome measures, demonstrating nusinersen efficacy for adults with SMA. Disclosure: Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, and Sarepta. Dr. Day has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, and Sarepta. Dr. Wolford has nothing to disclose. Dr. MacPherson has nothing to disclose. Dr. Martens has nothing to disclose. Dr. McDermott has nothing to disclose. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation, CureSMA, Ionis Pharmaceuticals, Inc., Biogen, AveXis, Cytokinetics, Fibrogen, PTC Therapeutics, Roche, Santhera, Sarepta, and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor, AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc., Metafora, Roche, Sanofi, Sarepta, and the SMA Foundation. Dr. De Vivo has received research support from grants from the Department of Defense, Hope for Children Research Foundation, the National Institutes of Health, and the SMA Foundation, and has received funding for clinical trials from Biogen, Mallinkrodt Pharmaceuticals, PTC Therapeutics, Sarepta Therapeutics, and Ultragenyx. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Novartis, and Roche. Dr. Finkel has received royalty, license fees, or contractual rights payments from Licensing fees from Children’s Hospital of Philadelphia for development of the CHOP-INTEND motor scale. Dr. Finkel has received research support from Ionis Pharmaceuticals, Inc. and Biogen, grants from AveXis and Cytokinetics. Dr. Zeineh has nothing to disclose. Dr. Sampson has nothing to disclose. Dr. Hagerman has nothing to disclose. Dr. Duong has nothing to disclose.

  • meta analysis of deflazacort vs prednisone prednisolone in patients with duchenne muscular dystrophy p2 325
    Neurology, 2018
    Co-Authors: Basil T Darras, G L Elfring, Panayiota Trifillis, Peter Riebling, Joseph Mcintosh, Edward Omara, Claudio Santos, Julie Parsons, Perry B Shieh, Susan D Apkon
    Abstract:

    Objective: To compare the efficacy of deflazacort vs prednisone/prednisolone in a posthoc meta-analysis of a phase 2b and phase 3 study. Background: Corticosteroids can slow the loss of motor function in patients with Duchenne muscular dystrophy (DMD) and are considered part of the standard of care. The phase 2b (Study 007) and phase 3 (ACT DMD) clinical trials of ataluren are the largest, randomized, double-blind, placebo-controlled studies in nonsense mutation DMD to date. Design/Methods: In a meta-analysis of the placebo arm of a phase 2b and phase 3 study, evidence comparing the efficacy of deflazacort vs prednisone/prednisolone was assessed post-hoc using the 6 minute walk test (6MWT) in patients with phenotypic and genotypic evidence of DMD aged ≥ 7 y, a baseline 6-minute walk distance (6MWD) ≥ 150 m, and ≤80% of predicted for their age and height. Patients in the placebo arms of each study received deflazacort (n=64) or prednisone/prednisolone (n=82) for 48 weeks after being on that same treatment for ≥12 months prior to the study start. The primary endpoint was change from baseline to week 48 in 6MWD. Safety parameters were also assessed. Results: The weighted estimate of the treatment differences in 6 MWD (m, ±SEM) is 34.1m ± 13.5m and 95% CI of 7.6 to 60.7, showing a significant difference (p=0.006) favoring deflazacort. Respective adverse events ≥10% for deflazacort or prednisone/prednisolone were: vomiting (21.9%, 19.5%) headache (18.8%, 20.7%), nasopharyngitis (12.5%, 24.4%), fall (14.1%, 18,3%) diarrhea (12.5%, 14.6%), upper abdominal pain (7.8%, 17.1%), cough (9.4%, 15.9%), pain in extremity (12.5%, 11.0%), pyrexia (9.4%, 12.2%). Conclusions: Deflazacort appeared to be more effective than prednisone/prednisolone in delaying progression of DMD. Study Supported by: PTC Therapeutics, Inc Disclosure: Dr. Riebling has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics. Dr. O9Mara has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Elfring has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Luo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Trifillis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. McIntosh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics. Dr. McIntosh holds stock and/or stock options in PTC Therapeutics. Dr. Santos has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Parsons has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, AveXis, Sarepta. Dr. Parsons has received research support from Biogen, AveXis, PTC, Sarepta. Dr. Shieh has nothing to disclose. Dr. Apkon has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Apkon has received research support from PTC, Sarepta, and Eli Lilly and Marathon Pharm. Dr. Campbell has nothing to disclose. Dr. McDonald has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC, Santhera, Sarepta, Catabasis, Mitobridge, Cardero, Capricor. Dr. McDonald has received research support from PTC, Sarepta, Santhera, Pfizer, Marathon.

  • Meta-Analysis of Deflazacort vs Prednisone/Prednisolone in Patients with Duchenne Muscular Dystrophy (P2.325)
    Neurology, 2018
    Co-Authors: Basil T Darras, Panayiota Trifillis, Peter Riebling, Edward O’mara, Xiaohui Luo, Joseph Mcintosh, Julie Parsons, Gary L. Elfring, Claudio L Santos, Perry B Shieh
    Abstract:

    Objective: To compare the efficacy of deflazacort vs prednisone/prednisolone in a posthoc meta-analysis of a phase 2b and phase 3 study. Background: Corticosteroids can slow the loss of motor function in patients with Duchenne muscular dystrophy (DMD) and are considered part of the standard of care. The phase 2b (Study 007) and phase 3 (ACT DMD) clinical trials of ataluren are the largest, randomized, double-blind, placebo-controlled studies in nonsense mutation DMD to date. Design/Methods: In a meta-analysis of the placebo arm of a phase 2b and phase 3 study, evidence comparing the efficacy of deflazacort vs prednisone/prednisolone was assessed post-hoc using the 6 minute walk test (6MWT) in patients with phenotypic and genotypic evidence of DMD aged ≥ 7 y, a baseline 6-minute walk distance (6MWD) ≥ 150 m, and ≤80% of predicted for their age and height. Patients in the placebo arms of each study received deflazacort (n=64) or prednisone/prednisolone (n=82) for 48 weeks after being on that same treatment for ≥12 months prior to the study start. The primary endpoint was change from baseline to week 48 in 6MWD. Safety parameters were also assessed. Results: The weighted estimate of the treatment differences in 6 MWD (m, ±SEM) is 34.1m ± 13.5m and 95% CI of 7.6 to 60.7, showing a significant difference (p=0.006) favoring deflazacort. Respective adverse events ≥10% for deflazacort or prednisone/prednisolone were: vomiting (21.9%, 19.5%) headache (18.8%, 20.7%), nasopharyngitis (12.5%, 24.4%), fall (14.1%, 18,3%) diarrhea (12.5%, 14.6%), upper abdominal pain (7.8%, 17.1%), cough (9.4%, 15.9%), pain in extremity (12.5%, 11.0%), pyrexia (9.4%, 12.2%). Conclusions: Deflazacort appeared to be more effective than prednisone/prednisolone in delaying progression of DMD. Study Supported by: PTC Therapeutics, Inc Disclosure: Dr. Riebling has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics. Dr. O9Mara has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Elfring has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Luo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Trifillis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. McIntosh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics. Dr. McIntosh holds stock and/or stock options in PTC Therapeutics. Dr. Santos has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC Therapeutics, Inc. Dr. Parsons has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, AveXis, Sarepta. Dr. Parsons has received research support from Biogen, AveXis, PTC, Sarepta. Dr. Shieh has nothing to disclose. Dr. Apkon has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Apkon has received research support from PTC, Sarepta, and Eli Lilly and Marathon Pharm. Dr. Campbell has nothing to disclose. Dr. McDonald has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with PTC, Santhera, Sarepta, Catabasis, Mitobridge, Cardero, Capricor. Dr. McDonald has received research support from PTC, Sarepta, Santhera, Pfizer, Marathon.

Darryl C. De Vivo - One of the best experts on this subject based on the ideXlab platform.

  • Nusinersen Efficacy in Adults with Spinal Muscular Atrophy (S58.007)
    Neurology, 2019
    Co-Authors: John W. Day, Richard S. Finkel, Basil T Darras, Connie Wolford, Chelsea Macpherson, William B. Martens, Michael P. Mcdermott, Darryl C. De Vivo, Zarazuela Zolkipli Cunningham, Michael Zeineh
    Abstract:

    Objective: To determine the clinical effects of nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability, in comparison to the natural history of untreated adults. Background: SMA is an autosomal recessive disorder affecting 1:10,000 live births, in which survival motor neuron (SMN) protein deficiency leads to motor neuron degeneration and progressive muscle atrophy, weakness, and early mortality. In December, 2016, nusinersen was approved by the FDA for SMA patients of all ages despite the lack of documented efficacy in adults Design/Methods: Outcome measures were collected prospectively on treatment-naive adult SMA patients followed in the Pediatric Neuromuscular Clinical Research (PNCR) Network and compared with a separate group of adults with SMA who were assessed before and after starting nusinersen. A minimal data set based on insurance requirements and validated SMA outcomes included: RULM, HFMSE, TUG, 6MWT, jaw ROM, and the CHOP-Intend neuromuscular scale that was revised for severely affected adults (CHOP-ATEND). Pulmonary function, strength and HHD, patient reported experiences, safety labs and adverse events also were monitored. Results: Results: Natural history was determined in 99 untreated adults and response to nusinersen in 34 adults. More than 90% of patients reported qualitative improvement in: strength, stamina, breathing strength, chewing/swallowing, jaw range of motion, voice strength, or muscle strength. Patients were assigned to one of three functional groups: ambulatory, non-ambulatory strong (RULM > 4), and non-ambulatory weak (RULM ≤ 4); primary functional measures in the groups were 6MWT, RULM, and CHOP-ATEND respectively. Additionally, MIP, MEP and FVC and HHD were monitored in all groups. All measures showed improvement in the treated groups compared to the progressive decline seen in untreated adults. Conclusions: Nusinersen has been well tolerated. Improvement trends are emerging at all disability levels by multiple outcome measures, demonstrating nusinersen efficacy for adults with SMA. Disclosure: Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, and Sarepta. Dr. Day has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, and Sarepta. Dr. Wolford has nothing to disclose. Dr. MacPherson has nothing to disclose. Dr. Martens has nothing to disclose. Dr. McDermott has nothing to disclose. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation, CureSMA, Ionis Pharmaceuticals, Inc., Biogen, AveXis, Cytokinetics, Fibrogen, PTC Therapeutics, Roche, Santhera, Sarepta, and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisor, AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc., Metafora, Roche, Sanofi, Sarepta, and the SMA Foundation. Dr. De Vivo has received research support from grants from the Department of Defense, Hope for Children Research Foundation, the National Institutes of Health, and the SMA Foundation, and has received funding for clinical trials from Biogen, Mallinkrodt Pharmaceuticals, PTC Therapeutics, Sarepta Therapeutics, and Ultragenyx. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Novartis, and Roche. Dr. Finkel has received royalty, license fees, or contractual rights payments from Licensing fees from Children’s Hospital of Philadelphia for development of the CHOP-INTEND motor scale. Dr. Finkel has received research support from Ionis Pharmaceuticals, Inc. and Biogen, grants from AveXis and Cytokinetics. Dr. Zeineh has nothing to disclose. Dr. Sampson has nothing to disclose. Dr. Hagerman has nothing to disclose. Dr. Duong has nothing to disclose.

  • Nusinersen Efficacy in Adults with Spinal Muscular Atrophy (S46.001)
    Neurology, 2018
    Co-Authors: John W. Day, Richard S. Finkel, Basil T Darras, Connie Wolford, Chelsea Macpherson, William B. Martens, Michael P. Mcdermott, Darryl C. De Vivo, Zarazuela Zolkipli Cunningham, Jacinda B. Sampson
    Abstract:

    Objective: 1. Evaluate effectiveness of our clinical protocol for nusinersen treatment in adults with Spinal Muscular Atrophy (SMA). 2. Assess post-treatment functional changes of adults with SMA compared to their baseline and the natural history of SMA. Background: SMA is an autosomal recessive disorder affecting 1:10,000 live births, in which deficient survival motor neuron (SMN) protein leads to progressive muscle atrophy, weakness, and early mortality. Nusinersen is the first FDA approved treatment for SMA. Clinical trials have shown benefit in children, but the efficacy in adults has not been documented. Design/Methods: Functional and clinical measures prospectively collected on adult SMA patients in an international SMA network, PNCRN, were compared with nusinersen treated adults. Pre-approval visits included: medical & genetic history, standard of care, anatomic and radiologic findings, and insurance assessment. A minimal data set based on insurance requirements and validated outcomes in SMA included at least one of the following: CHOP-INTEND, RULM, HFMSE, TUG, 6MWT. We also monitored pulmonary function, strength, patient reported experiences, safety labs and adverse events. Results: Natural history was determined in 170 evaluations of 57 untreated adults. Assessments were obtained in 27 individuals desiring nusinersen, 20 of whom were treated. Individuals were not treated due to insurance denial (1), lack of access via routine fluoroscopy (5), and patient choice (1). Individuals were: 18–65 years old, non-ambulatory (75%), male (57%), requiring day/night ventilatory support (7), and with spinal fusion (8). Qualitative improvement was frequent (85%). Baseline measures (median and ranges) included for ambulatory (n=7): 6MWT (367.9m, 69.2–466.0m), TUG (9.9sec, 8.4–44.2sec) and for non-Ambulatory (n=20) RULM (12.5, 0–38), PFT (3.05L, 0.28–5.62L). Conclusions: Nusinersen has been well tolerated and improvement trends are emerging in multiple measures; data continue to be collected. Analyses of clinical outcomes, to be presented, will define nusinersen efficacy for adults with SMA. Disclosure: Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta. Dr. Wolford has nothing to disclose. Dr. MacPherson has nothing to disclose. Dr. Martens has nothing to disclose. Dr. McDermott has nothing to disclose. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Darras has served as an ad hoc scientific advisory board member for AveXis, Biogen, Cytokinetics, Marathon Pharmaceuticals, PTC Therapeutics, Roche, and Sarepta; and has been an advisor for Bristol-Myers Squibb and Ionis Pharmaceuticals, Inc.; he has. Dr. Darras has received research support from Dr. Darras has received research support from from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, CS2/CS12 studies, from Biogen for CS11 , as well as from Cytokinetics, PTC Therapeutics, Fibrogen and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting/Advisory Board membership with AveXis, Biogen, Sarepta, PTC, Cytokinetics, Ultragenyx, and Sanofi. Dr. De Vivo has received research support from Clinical trials support from Sarepta, PTC, Ultragenyx, and Biogen, animal model licensing to Sanofi. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting fees and travel costs from AveXis, Biogen, Catabasis, Ionis, Mitobridge, and Summit. Dr. Finkel has received research support from My institution received research support to perform clinical trials from Biogen, BMS, Catabasis, Cytokinetics, Ionis, Lilly, ReveraGen, Sarepta, and Summit. Dr. Sampson has nothing to disclose. Dr. Duong has nothing to disclose.

  • Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Feasibility for Individuals with Severe Spinal Muscular Atrophy II (S46.004)
    Neurology, 2018
    Co-Authors: Elizabeth A. Kichula, Richard S. Finkel, Basil T Darras, Darryl C. De Vivo, Tina Duong, Allan M. Glanzman, Amy Pasternak, Zarazuela Zolkipli-cunningham, John W. Day
    Abstract:

    Objective: NA Background: Outcome measure development for Spinal Muscular Atrophy (SMA) has focused on clinical trial readiness, and now exist across all SMA types. However, gross motor evaluation of older severely weak patients with SMA remains a challenge. The CHOP INTEND is a validated motor outcome measure developed for weak infants with type 1 SMA. Here we demonstrate its potential utility of a sub set of CHOP INTEND items for a series of individuals with type 2 SMA with scores on the Expanded Hammersmith Functional Motor Scale (HFMSE) of 2 or less. Design/Methods: We reviewed CHOP INTEND and HFMSE scores for 13 individuals (age 7–40) with type 2 SMA whose HFMSE scores were ≤2. The objective was to determine if the distribution of scores on subset of the CHOP INTEND was broader than the HFMSE scores, indicating enhanced sensitivity when administered in severe type 2 SMA. Qualitative review of difficulties experienced and clinical reasoning associated with testing non-infants was discussed among the physical therapists to determine themes. Results: Eight individuals scored 0 on the HFMSE and 5 scored 1 or 2 primarily reflecting minimal leg movement. The median CHOP INTEND score was 16.1 (IQR 10–22). Two patients were retested after their Spinraza loading doses and improved from 23 to 31 and from 27 to 29 while their HFMSE remained at 0. Items 11, 15, and 16 (requiring suspension) could not be tested in older individuals resulting in a score of 0. Conclusions: The CHOP INTEND may be more sensitive to changes in gross motor function and muscle strength in individuals with type 2 SMA due to a floor effect on HFMSE, and may be a reliable measure for long-term follow up. Longitudinal assessment to evaluate the sensitivity of a subset of the CHOP INTEND to detect change over time in weak SMA individuals is required. Disclosure: Dr. Kichula has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis. Dr. Duong has nothing to disclose. Dr. Glanzman has nothing to disclose. Dr. Pasternak has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Scientific advisory board for Avexis Pharmaceuticals. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Darras has served as an ad hoc scientific advisory board member for AveXis, Biogen, Cytokinetics, Marathon Pharmaceuticals, PTC Therapeutics, Roche, and Sarepta; and has been an advisor for Bristol-Myers Squibb and Ionis Pharmaceuticals, Inc.; he has. Dr. Darras has received research support from Dr. Darras has received research support from from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, CS2/CS12 studies, from Biogen for CS11 , as well as from Cytokinetics, PTC Therapeutics, Fibrogen and Summit. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting fees and travel costs from AveXis, Biogen, Catabasis, Ionis, Mitobridge, and Summit. Dr. Finkel has received research support from My institution received research support to perform clinical trials from Biogen, BMS, Catabasis, Cytokinetics, Ionis, Lilly, ReveraGen, Sarepta, and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting/Advisory Board membership with AveXis, Biogen, Sarepta, PTC, Cytokinetics, Ultragenyx, and Sanofi. Dr. De Vivo has received research support from Clinical trials support from Sarepta, PTC, Ultragenyx, and Biogen, animal model licensing to Sanofi. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta.

  • Ambulatory function and fatigue in nusinersen-treated children with spinal muscular atrophy. (P2.322)
    Neurology, 2018
    Co-Authors: Jacqueline Montes, Richard S. Finkel, Basil T Darras, Francesco Muntoni, Allan M. Glanzman, Amy Pasternak, Sally Dunaway Young, Elena S. Mazzone, Eugenio Mercuri, Darryl C. De Vivo
    Abstract:

    Objective: To examine distance walked and fatigue during the six minute walk test (6MWT) in nusinersen-treated children with spinal muscular atrophy (SMA). Background: Individuals with milder SMA phenotypes are able to walk but weakness causes gait impairments and reduced endurance. Assessments of walking ability are clinically relevant in this population. The 6MWT is a valid and reliable functional outcome measure that captures weakness and fatigue in SMA patients. Design/Methods: Two multicenter, open-label clinical trials with nusinersen enrolled patients with SMA types 2 and 3, ages 2–15 years. CS2 (NCT01703988) was an 85-day (+168-day follow up [FU]) phase 1b/2a, multiple ascending dose (3, 6, 9 or 12 mg) study, where participants had an option to continue. After a varying treatment break, CS2 patients were enrolled later in the ongoing 533-day (+182-day FU) CS12 (NCT02052791, 12 mg dose) extension study. We evaluated change in 6MWT distance and fatigue over 253 and 1050 days. Fatigue was defined as the change in the 6MWT distance in the sixth minute as compared to the first minute, expressed as a percent. Results: Fourteen subjects were ambulatory during CS2 or CS12 and performed the 6MWT. Baseline characteristics were mean age of symptom onset 23.9 months; mean age at screening 8.6 years; 3 SMN2 copies, n=9; 4 SMN2 copies, n=5. Median (min, max) distance measured (meters) at baseline was 250.5 (0, 563). Median (min, max) distance walked (meters) increased over time by 17 (−47, 99) at Day 253 and 99.0 (31, 150) at Day 1050. Median (min, max) fatigue at baseline was 14.8 (−16, 100) %. Median (min, max) fatigue (%) decreased by 0.1 (−63, 33) at Day 253, and by 3.8 (−86, 20) at Day 1050. Conclusions: Nusinersen-treated ambulatory children demonstrated improvements in ambulatory function, as determined by 6MWT, with increases in walking distance and decreases in fatigue. Study Supported by: Biogen MA, Inc Disclosure: Dr. Montes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Biogen MA, inc, F. Hoffmann-La Roche. Dr. Dunaway has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals. Dr. Mazzone has nothing to disclose. Dr. Pasternak has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Scientific advisory board for Avexis Pharmaceuticals. Dr. Glanzman has nothing to disclose. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting fees and travel costs from AveXis, Biogen, Catabasis, Ionis, Mitobridge, and Summit. Dr. Finkel has received research support from My institution received research support to perform clinical trials from Biogen, BMS, Catabasis, Cytokinetics, Ionis, Lilly, ReveraGen, Sarepta, and Summit. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Darras has served as an ad hoc scientific advisory board member for AveXis, Biogen, Cytokinetics, Marathon Pharmaceuticals, PTC Therapeutics, Roche, and Sarepta; and has been an advisor for Bristol-Myers Squibb and Ionis Pharmaceuticals, Inc.; he has. Dr. Darras has received research support from Dr. Darras has received research support from from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, CS2/CS12 studies, from Biogen for CS11 , as well as from Cytokinetics, PTC Therapeutics, Fibrogen and Summit. Dr. Muntoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Participation to SAB meetings (Roche; Avexis and Biogen) and educational activities (Biogen). Dr. Muntoni has received research support from My institute receives support for Biogen and Roche sponsored clinical trials. Dr. Mercuri has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen MA, Inc, Ionis Pharmaceuticals, Inc. & F. Hoffman La-Roche Ltd. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting/Advisory Board membership with AveXis, Biogen, Sarepta, PTC, Cytokinetics, Ultragenyx, and Sanofi. Dr. De Vivo has received research support from Clinical trials support from Sarepta, PTC, Ultragenyx, and Biogen, animal model licensing to Sanofi. Dr. Bishop has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Full-time employee of Otonomy Inc. Dr. Schneider has nothing to disclose. Dr. Bennett has nothing to disclose. Dr. Foster has nothing to disclose. Dr. Farwell has nothing to disclose.

  • Interim Results of a Phase 2 Clinical Study of Nusinersen (ISIS-SMNRx) in Patients with Infantile-Onset Spinal Muscular Atrophy (P5.004)
    Neurology, 2016
    Co-Authors: Richard S. Finkel, John W. Day, Darryl C. De Vivo, Jacqueline Montes, Claudia A. Chiriboga, Jiri Vajsar, Mason Yamashita, Frank Rigo, Gene Hung, Eugene Schneider
    Abstract:

    Objective:To assess the safety, tolerability, pharmacokinetics and clinical effects of nusinersen (ISIS-SMNRx) in patients with infantile-onset Spinal Muscular Atrophy (SMA). Background:Infantile-onset SMA is a devastating and relentlessly progressive neurodegenerative disease caused by the deficiency of Survival of Motor Neuron (SMN) protein in motor neurons, accounts for over half of all patients with SMA, and is the most common genetic cause of death in infancy. Nusinersen is a novel antisense oligonucleotide drug designed to alter splicing of SMN2 mRNA thereby increasing the amount of functional SMN protein. Methods:This is an interim analysis of an ongoing multicenter, open-label, Phase 2 clinical study designed to evaluate the safety/tolerability, pharmacokinetics, and clinical effects of multiple intrathecal doses of nusinersen in patients with infantile-onset SMA. Twenty participants (4 in a lower-dose cohort, 16 in a higher-dose cohort) were enrolled. Autopsy tissue in 3 participants enabled pharmacodynamic analyses. Results:As of an interim analysis performed in August 2015, the study has been ongoing for 27 months. Nusinersen has been well tolerated with no safety concerns identified. Sixteen of 19 participants in the evaluable population remain alive (median age 20.1 months) and demonstrate significant (p=0.01) improvements in motor function scores, incremental achievement of motor milestones such as head control (10 participants), rolling (9 participants), sitting (6 participants), and improvements in neuromuscular electrophysiology compared to baseline and published natural history data. Pharmacodynamic data support drug delivery, enhancement of full-length SMN2 transcript, and an increase in SMN protein in target neurons. Conclusions:In this open-label Phase 2 study, nusinersen exhibits good safety and tolerability, pharmacology that is consistent with its intended mechanism of action, and encouraging evidence supporting meaningful clinical response. Importantly, a pivotal, sham-controlled Phase 3 clinical study of nusinersen in infantile-onset SMA is currently ongoing. Disclosure: Dr. Finkel has received personal compensation for activities with Isis Pharmaceuticals and Voyager Therapeutics as a consultant and/or speaker. Dr. Chiriboga has received personal compensation for activities with Up To Date, ISIS pharmaceuticals/Biogen, and Roche pharmaceuticals. Dr. Vajsar has nothing to disclose. Dr. Day has received personal compensation for activities with Sarepta Therapeutics and PTC Therapeutics as a consultant. Dr. Montes has received personal compensation for activities with Isis Pharmeceuticals as a consultant. Dr. De Vivo has received personal compensation for activities with Isis Pharmaceuticals as a consultant. Dr. Yamashita has received personal compensation for activities with Isis Pharmaceuticals as an employee. Dr. Rigo has nothing to disclose. Dr. Hung has nothing to disclose. Dr. Schneider has nothing to disclose. Dr. Norris has received personal compensation for activities with Isis Pharmaceuticals. Dr. Xia has received personal compensation for activities with Isis Pharmaceuticals as an employee. Dr. Bennett has received personal compensation for activities with Isis Pharmaceuticals, Inc. as an employee. Dr. Bishop has received personal compensation for activities with Isis Pharmaceuticals as an employee.

Jacinda B. Sampson - One of the best experts on this subject based on the ideXlab platform.

  • Nusinersen Efficacy in Adults with Spinal Muscular Atrophy (S46.001)
    Neurology, 2018
    Co-Authors: John W. Day, Richard S. Finkel, Basil T Darras, Connie Wolford, Chelsea Macpherson, William B. Martens, Michael P. Mcdermott, Darryl C. De Vivo, Zarazuela Zolkipli Cunningham, Jacinda B. Sampson
    Abstract:

    Objective: 1. Evaluate effectiveness of our clinical protocol for nusinersen treatment in adults with Spinal Muscular Atrophy (SMA). 2. Assess post-treatment functional changes of adults with SMA compared to their baseline and the natural history of SMA. Background: SMA is an autosomal recessive disorder affecting 1:10,000 live births, in which deficient survival motor neuron (SMN) protein leads to progressive muscle atrophy, weakness, and early mortality. Nusinersen is the first FDA approved treatment for SMA. Clinical trials have shown benefit in children, but the efficacy in adults has not been documented. Design/Methods: Functional and clinical measures prospectively collected on adult SMA patients in an international SMA network, PNCRN, were compared with nusinersen treated adults. Pre-approval visits included: medical & genetic history, standard of care, anatomic and radiologic findings, and insurance assessment. A minimal data set based on insurance requirements and validated outcomes in SMA included at least one of the following: CHOP-INTEND, RULM, HFMSE, TUG, 6MWT. We also monitored pulmonary function, strength, patient reported experiences, safety labs and adverse events. Results: Natural history was determined in 170 evaluations of 57 untreated adults. Assessments were obtained in 27 individuals desiring nusinersen, 20 of whom were treated. Individuals were not treated due to insurance denial (1), lack of access via routine fluoroscopy (5), and patient choice (1). Individuals were: 18–65 years old, non-ambulatory (75%), male (57%), requiring day/night ventilatory support (7), and with spinal fusion (8). Qualitative improvement was frequent (85%). Baseline measures (median and ranges) included for ambulatory (n=7): 6MWT (367.9m, 69.2–466.0m), TUG (9.9sec, 8.4–44.2sec) and for non-Ambulatory (n=20) RULM (12.5, 0–38), PFT (3.05L, 0.28–5.62L). Conclusions: Nusinersen has been well tolerated and improvement trends are emerging in multiple measures; data continue to be collected. Analyses of clinical outcomes, to be presented, will define nusinersen efficacy for adults with SMA. Disclosure: Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Pfizer, Santhera, Sarepta. Dr. Wolford has nothing to disclose. Dr. MacPherson has nothing to disclose. Dr. Martens has nothing to disclose. Dr. McDermott has nothing to disclose. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr. Darras has served as an ad hoc scientific advisory board member for AveXis, Biogen, Cytokinetics, Marathon Pharmaceuticals, PTC Therapeutics, Roche, and Sarepta; and has been an advisor for Bristol-Myers Squibb and Ionis Pharmaceuticals, Inc.; he has. Dr. Darras has received research support from Dr. Darras has received research support from from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, CS2/CS12 studies, from Biogen for CS11 , as well as from Cytokinetics, PTC Therapeutics, Fibrogen and Summit. Dr. De Vivo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting/Advisory Board membership with AveXis, Biogen, Sarepta, PTC, Cytokinetics, Ultragenyx, and Sanofi. Dr. De Vivo has received research support from Clinical trials support from Sarepta, PTC, Ultragenyx, and Biogen, animal model licensing to Sanofi. Dr. Zolkipli-Cunningham has nothing to disclose. Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting fees and travel costs from AveXis, Biogen, Catabasis, Ionis, Mitobridge, and Summit. Dr. Finkel has received research support from My institution received research support to perform clinical trials from Biogen, BMS, Catabasis, Cytokinetics, Ionis, Lilly, ReveraGen, Sarepta, and Summit. Dr. Sampson has nothing to disclose. Dr. Duong has nothing to disclose.

  • Increased EEG theta spectral power in polysomnography of myotonic dystrophy type 1 compared to matched controls. (P5.107)
    Neurology, 2017
    Co-Authors: Chad Ruoff, John W. Day, Joe Cheung, Jennifer Perez, Sarada Sakamuri, Emmanuel Mignot, Jacinda B. Sampson
    Abstract:

    Objective: To characterize EEG spectra from nocturnal polysomnography (PSG) in myotonic dystrophy type 1 (DM1) compared to matched controls. Background: Myotonic dystrophy type 1 (DM1) is a multisystemic polynucleotide repeat disorder. Excessive daytime sleepiness (EDS) and fatigue are common in DM1 (70–80%). EDS and fatigue are considered to be central nervous system manifestations of DM1; therefore, we hypothesized that EEG spectral power would be different in DM1 compared to controls. Design/Methods: A retrospective, case- control (1:2) chart review of DM1 (n=18) and matched controls (n=36) referred for clinical PSG at the Stanford Sleep Center was performed. Controls were matched based on age, gender, apnea-hypopnea index (AHI), body mass index (BMI), and Epworth Sleepiness Scale (ESS). Sleep stage and respiratory metrics were also compared. Power spectral analysis of the C3-M2 signal was performed using fast Fourier transform using a 6.0 second Hanning window and averaged according to sleep stage in 1/6 Hz increments, and artifacts removed. For each spectral frequency range, the wavelength maximum difference between DM1 and control populations was identified and tested for normal distribution, and Welch’s t test was performed. Results: A significant increase in wake after sleep onset (WASO) in DM1 subjects vs. controls (p Myotonic dystrophy patients had significantly increased theta power (p Conclusions: Compared to matched controls, DM1 patients had increased EEG theta spectral power. We plan to explore EEG spectral power as a DM1 disease biomarker. Study Supported by: NIH grant P01 NS05891 Disclosure: Dr. Ruoff has received personal compensation for activities with Jazz Pharmaceuticals as a scientific advisory board member. Dr. Cheung has nothing to disclose. Dr. Perez has nothing to disclose. Dr. Sakamuri has nothing to disclose. Dr. Mignot has nothing to disclose. Dr. Day has received personal compensation for activities with Sarepta Therapeutics and PTC Therapeutics as a consultant. Dr. Sampson has nothing to disclose.

  • Application of Digital Accelerometry for Swallow Imaging (DASI) for Dysphagia Evaluation and Treatment in a Series of Myotonic Dystrophy Type 1 (DM1) Patients (P05.189)
    Neurology, 2012
    Co-Authors: Lia-ana Farkas, Lane Entrekin, Norma Milstead, Kristin Mosman, Kiera Berggren, Jacinda B. Sampson
    Abstract:

    Objective: To use digital accelerometry for swallow imaging (DASI) for evaluation and treatment of dysphagia in DM1 patients. Background Dysphagia is a potentially life threatening complication of DM1 patients. Design/Methods: Patients with DM1 and history of aspiration or dysphagia underwent a formal swallow evaluation +/- modified barium swallow (MBS). We used noninvasive DASI technology with software designed for swallow imaging and calculation of key parameters of swallow biomechanics. Trials included spontaneous and instructed dry and wet swallows with different consistencies. We analyzed shape, amplitude, timing, frequency and jitter looking for swallow movement dysfunction. DASI biofeedback: Patients observed swallow traces on the computer screen and were coached in improving strength, duration and timing of swallow. Results: Case 1: A 24-year old man with congenital DM1, dysphagia, and repeated hospitalizations for aspiration pneumonia had a MBS showing aspiration of pyriform sinus residue. DASI evaluation showed excessive pre/post-swallow laryngeal movement, decreased pharyngeal phase control with multiple small amplitude peaks. DASI Treatment: Patient improved swallow strenght and control of pharyngeal movement. Case 2: A 46 year-old man with adult-onset DM1 and choking episodes was hospitalized with pneumonia and placed on a ventilator. MBS showed aspiration during/after the swallow with delayed cough. DASI evaluation showed low amplitude and frequency of swallow with increased jitter and frequent coughing. DASI Treatment: Patient improved swallow strength. Case 3: A 33 year-old female with adult-onset DM1 reported dysphagia. Clinical swallow evaluation showed oral residue, reduced hyolaryngeal excursion, and throat clearing. DASI evaluation showed reduced amplitude and increased jitter, with extraneous, inefficient lingual/hyolaryngeal movements. DASI Treatment: Reduced extraneous laryngeal movements and improved control of swallow. Conclusions: DASI is an adjunct in dysphagia evaluation in DM1. DASI biofeedback is helpful in gaining increased swallow function through Active Repetitive Motion Therapy which is instructive for reducing extraneous, inefficient laryngeal movements and can be personalized according to the patient physical and mental status. Supported by: DASI equipment on loan from Elixir Therapeutics. Disclosure: Dr. Farkas has nothing to disclose. Dr. Entrekin has nothing to disclose. Dr. Milstead has nothing to disclose. Dr. Mosman has nothing to disclose. Dr. Berggren has nothing to disclose. Dr. Sampson has received personal compensation for activities with PTC Therapeutics and Myotonic Dystrophy Foundation.