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Jerry R Mendell - One of the best experts on this subject based on the ideXlab platform.

  • p07 onasemnoGene abeparvovec Gene Replacement Therapy grt for spinal muscular atrophy sma from bench to bedside
    Archives of Disease in Childhood, 2020
    Co-Authors: P Kaufmann, Jerry R Mendell, K Foust, J Loukes
    Abstract:

    Aims Report onasemnoGene abeparvovec (formerly AVXS-101) GRT development for SMA. OnasemnoGene abeparvovec is a one-time, intravenous GRT that addresses the Genetic root cause of SMA, a progressive neurological disease. OnasemnoGene abeparvovec delivers the survival motor neuron Gene (SMN) via a self-complementary adeno-associated serotype 9 viral vector (scAAV9) that crosses the blood-brain barrier. OnasemnoGene abeparvovec is designed for immediate and sustained expression of SMN protein in non-dividing neurons, allowing for rapid onset and durable therapeutic effect. Methods SMA mice (SMN2+/+; SMNΔ7+/+; Smn-/-) received intravenous scAAV9-SMN or scAAV9-GFP at post-natal day 1; survival and motor function were assessed. Non-human primates (NHPs) received intravenous scAAV9-GFP; transduced cell types were assessed. A phase 1/2a study (START; NCT02122952) evaluated onasemnoGene abeparvovec infused at low (Cohort 1, n=3) or high (Cohort 2, n=12) doses in symptomatic SMA type 1 (SMA1) infants; patients were followed for 2 years for safety/tolerability and efficacy and could enroll in a long-term follow-up (LTFU) study to assess long-term safety. Results In SMA mice, scAAV9-SMN improved survival (>200 versus 15 days in controls), and increased motor function. In NHPs, scAAV9-GFP efficiently targeted motor neurons throughout the central nervous system. In the phase 1/2a START trial, all patients survived free of permanent ventilation at 24 months. In the high-dose cohort, 11/12 patients reached CHOP INTEND >40; 11 sat unassisted ≥5s, 10 for ≥10s, 9 for ≥30s. Two patients crawled, stood, and walked. No patient received nusinersen during the 24-month study period. In the LTFU study, 2 more patients in Cohort 2 have gained the motor milestone of standing with assistance (as of 31 Dec 2019); neither patient has ever received nusinersen. No new treatment-related serious adverse events or adverse events of special interest have occurred in LTFU (as of 31 Dec 2019). The oldest patient in Cohort 2 is aged 5.6 years, with 5.2 years of follow-up since onasemnoGene abeparvovec dosing. Conclusion OnasemnoGene abeparvovec has demonstrated unprecedented outcomes in patients with SMA compared with untreated natural history. Phase 3 trials of onasemnoGene abeparvovec in SMA1 are ongoing (US, EU, Asia-Pacific); additional trials are investigating presymptomatic SMA and intrathecal administration in older patients.

  • Gene Replacement Therapy in spinal muscular atrophy type 1 long term follow up from the onasemnoGene abeparvovec xioi phase 1 2a clinical trial 1808
    Neurology, 2020
    Co-Authors: Jerry R Mendell, Richard Shell, L Alfano, Kelly J Lehman, Markus Mccolly, L Lowes, N Miller, M Iammarino, Kathleen Church
    Abstract:

    Objective: To evaluate long-term safety and efficacy of onasemnoGene abeparvovec-xioi (formerly AVXS-101). Background: Spinal muscular atrophy type 1 (SMA1) is a rapidly progressing disease caused by biallelic survival motor neuron 1 Gene (SMN1) deletion/mutation, resulting in death/permanent ventilation by 2 years of age if untreated. OnasemnoGene abeparvovec, an SMN Gene-Replacement Therapy, addresses the Genetic root cause of SMA. In the phase 1/2a trial (START; NCT02122952), SMA1 patients who received a one-time intravenous (IV) infusion of onasemnoGene abeparvovec at high dose (Cohort 2, n=12) demonstrated significantly improved outcomes relative to untreated natural history. Design/Methods: Patients in START could rollover into a long-term follow-up (LTFU) study (Study LT-001; NCT03421977). Primary objective: long-term safety. Patients have annual visits (5 years) followed by annual phone contact (additional 10 years). Patient record transfers from local physicians and/or neurologists are requested. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include evaluation of developmental milestones maintenance. Results: As of 31 May 2019, 13 patients (Cohort 1, n=3; Cohort 2, n=10) enrolled in Study LT-001 and had a baseline visit. For patients in Cohort 2, the mean (range) age and time since dosing were 4.2 (3.7–5.0) years and 3.9 (3.5–4.6) years, respectively. All patients in Cohort 2 were alive and free of permanent ventilation. No developmental milestones achieved at the end of START were lost; 2 patients have gained the standing with assistance milestone during LTFU (video-confirmed; neither patient has received nusinersen), further supporting the durability of onasemnoGene abeparvovec. No new treatment-related serious adverse events or adverse events of special interest have occurred in LTFU (as of 8 March 2019). Conclusions: One-time IV administration of onasemnoGene abeparvovec at the high dose in START continues to provide prolonged and durable efficacy with milestone development in Study LT-001. Disclosure: 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.. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.. Dr. Lehman has nothing to disclose. Dr. McColly has nothing to disclose. Dr. Lowes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with ATOM International. Dr. Lowes has received royalty, license fees, or contractual rights payments from Nationwide Children’s Hospital. Dr. Alfano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Alfano has received research support from Sarepta Therapeutics. Dr. Miller has nothing to disclose. Dr. Iammarino has nothing to disclose. Dr. Church has nothing to disclose. 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. Ouyang 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. 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. Joshi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis Inc.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. 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. 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. Al-Zaidy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Al-Zaidy has received royalty, license fees, or contractual rights payments from Mile Biotech. Dr. Al-Zaidy has received research support from AveXis, Inc., and Catalyst.

  • p37 onasemnoGene abeparvovec Gene Replacement Therapy for spinal muscular atrophy from bench to bedside
    Thorax, 2019
    Co-Authors: P Kaufmann, I Kausar, K D Foust, A Kaspar, Brian K Kaspar, Jerry R Mendell
    Abstract:

    Introduction and objectives Spinal muscular atrophy (SMA) is a progressive neurologic disease that causes loss of motor and bulbar muscle function essential for normal breathing and swallowing. If untreated, SMA can lead to death/need for permanent ventilation by 2 years of age. The Genetic root cause of SMA is lack of a functional survival motor neuron 1 (SMN1) Gene. Here we describe the development of onasemnoGene abeparvovec (formerly AVXS-101), a one-time intravenous (IV) SMN Gene-Replacement Therapy (GRT) that treats the Genetic root cause of SMA by delivering the SMN Gene. OnasemnoGene abeparvovec crosses the blood-brain barrier to target non-dividing motor neurons and is designed for immediate, sustained SMN expression. Methods SMA mice (Smn-/-) received IV scAAV9-SMN or scAAV9-GFP. Non-human primates (NHPs) received IV scAAV9-GFP and transduced cell types were assessed. In the first-in-human, open-label phase 1/2a study (NCT02122952), onasemnoGene abeparvovec was administered as a one-time IV infusion at low (n=3) or therapeutic dose (n=12) in patients with SMA type 1 (SMA1); patients were followed for 2 years for safety/tolerability, survival (no death/permanent ventilation), motor milestones, and motor function. Patients could enroll in a long-term follow-up (LTFU) study that assesses safety. Results scAAV9-SMN improved survival and motor function in SMA mice. scAAV9-GFP targeted motor neurons in NHPs. In the phase 1/2a trial, all patients given the therapeutic dose survived event free to 24 months post-treatment; 11/12 patients reached CHOP INTEND ≥40 points (maximum: 60); 11 sat unassisted ≥5s, 9 for ≥30s; 2 crawled, stood, and walked. No previously attained milestone has been lost in LTFU; 2 patients have gained milestones. No patient received nusinersen during the 24-month study; 4 patients had asymptomatic transient rise in serum aminotransferase. As of 8 March 2019, the oldest patient was 4.8 years old (4.3 years post-treatment). Conclusions In the phase 1/2a study, onasemnoGene abeparvovec GRT demonstrated unprecedented outcomes in symptomatic SMA1 infants compared with the untreated natural history of the disease. Long-term safety is being monitored for 15 years (LTFU). Global phase 3 trials in SMA1 are ongoing/planned. Additional trials are investigating the GRT in pre-symptomatic SMA and in older patients using intrathecal administration.

  • from clinical trials to clinical practice practical considerations for Gene Replacement Therapy in sma type 1
    Pediatric Neurology, 2019
    Co-Authors: Jerry R Mendell, Samiah Alzaidy
    Abstract:

    Abstract Spinal muscular atrophy is a devastating neurodeGenerative autosomal recessive disease that results from survival of motor neuron 1 (SMN1) Gene mutation or deletion. Patients with spinal muscular atrophy type 1 utilizing supportive care, which focuses on symptom management, never sit unassisted, and 75% die or require permanent ventilation by age 13.6 months. OnasemnoGene abeparvovec (Zolgensma, formerly AVXS-101) is a Gene Replacement Therapy comprising an adeno-associated viral vector containing the human SMN Gene under control of the chicken beta-actin promoter. This Therapy addresses the Genetic root cause of the disease by increasing functional SMN protein in motor neurons and preventing neuronal cell death, resulting in improved neuronal and muscular function as previously demonstrated in transgenic animal models. In an open-label, one-arm, dose-escalation phase 1 trial, systemic administration of onasemnoGene abeparvovec via a one-time infusion over one hour demonstrated improved motor function and survival in all infants symptomatic for spinal muscular atrophy type 1. Of the 12 patients who received the proposed therapeutic dose, 11 achieved independent sitting, two achieved independent standing, and two are able to walk. Most of these 12 patients remained free of respiratory supportive care. The only treatment-related adverse event observed was transient asymptomatic transaminasemia that resolved with a short course of prednisolone treatment. This review discusses the biological rationale underlying Gene Replacement Therapy for spinal muscular atrophy, describes the onasemnoGene abeparvovec clinical trial experience, and provides expert recommendations as a reference for the real-world use of onasemnoGene abeparvovec in clinical practice. As of May 24, 2019, the Food and Drug Administration approved onasemnoGene abeparvovec, the first Gene Therapy approved to treat children younger than two years with spinal muscular atrophy.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 continued event free survival and achievement of developmental milestones s29 001
    Neurology, 2018
    Co-Authors: Thomas W. Prior, Jerry R Mendell, Samiah Alzaidy, Richard Shell, Louise R Rodinoklapac, Dave W Arnold, L Lowes
    Abstract:

    Objective: This trial explores safety and efficacy of a one-time administration of Gene Replacement Therapy. AVXS-101 delivers the SMN Gene in a one-time dose via the AAV9 viral vector, which crosses the blood-brain barrier. Background: Spinal muscular atrophy (SMA) is a devastating, monogenic neurodeGenerative disease. Children with SMA Type 1 (SMA1) will never sit unassisted or maintain head control. A natural history study of this patient population reported that none achieved a CHOP-INTEND score of ≥40 by 6 months of age (one transient exception) and 75% died or required permanent ventilation by 13.6 months. Design/Methods: In this Phase 1 trial, 15 patients with SMA1 confirmed by Genetic testing (with 2xSMN2 copies) were enrolled. Patients received an intravenous dose of low dose AVXS-101 (Cohort 1, n=3) or proposed therapeutic dose (Cohort 2, n=12). The primary objective was safety and secondary objectives included survival (avoidance of death/permanent ventilation) and ability to sit unassisted (video confirmed by external independent reviewer). CHOP-INTEND scores and other motor milestones were additional objectives. Results: AVXS-101 appeared to have a favorable safety profile and to improve survival at data cut-off (20 January 2017). All patients reached 13.6 months free of permanent ventilation and none have died (3 live >30 months). Cohort 2 patients demonstrated improvement in motor function: 11/12 achieved head control and sat with support, and 9/12 sat unassisted. Two patients stood and walked independently. Conclusions: In contrast with the natural history, a one-time intravenous administration of AVXS-101 appeared to demonstrate a positive impact on the survival of both cohorts and a dramatic, sustained impact on motor function of Cohort 2: 11/12 patients achieved CHOP-INTEND scores and motor milestones rarely or never seen in this population. A clinical update will be given at the time of presentation demonstrating continued improvements in patients. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc. Dr. Al-Zaidy has nothing to disclose. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.

Samiah Alzaidy - One of the best experts on this subject based on the ideXlab platform.

  • from clinical trials to clinical practice practical considerations for Gene Replacement Therapy in sma type 1
    Pediatric Neurology, 2019
    Co-Authors: Jerry R Mendell, Samiah Alzaidy
    Abstract:

    Abstract Spinal muscular atrophy is a devastating neurodeGenerative autosomal recessive disease that results from survival of motor neuron 1 (SMN1) Gene mutation or deletion. Patients with spinal muscular atrophy type 1 utilizing supportive care, which focuses on symptom management, never sit unassisted, and 75% die or require permanent ventilation by age 13.6 months. OnasemnoGene abeparvovec (Zolgensma, formerly AVXS-101) is a Gene Replacement Therapy comprising an adeno-associated viral vector containing the human SMN Gene under control of the chicken beta-actin promoter. This Therapy addresses the Genetic root cause of the disease by increasing functional SMN protein in motor neurons and preventing neuronal cell death, resulting in improved neuronal and muscular function as previously demonstrated in transgenic animal models. In an open-label, one-arm, dose-escalation phase 1 trial, systemic administration of onasemnoGene abeparvovec via a one-time infusion over one hour demonstrated improved motor function and survival in all infants symptomatic for spinal muscular atrophy type 1. Of the 12 patients who received the proposed therapeutic dose, 11 achieved independent sitting, two achieved independent standing, and two are able to walk. Most of these 12 patients remained free of respiratory supportive care. The only treatment-related adverse event observed was transient asymptomatic transaminasemia that resolved with a short course of prednisolone treatment. This review discusses the biological rationale underlying Gene Replacement Therapy for spinal muscular atrophy, describes the onasemnoGene abeparvovec clinical trial experience, and provides expert recommendations as a reference for the real-world use of onasemnoGene abeparvovec in clinical practice. As of May 24, 2019, the Food and Drug Administration approved onasemnoGene abeparvovec, the first Gene Therapy approved to treat children younger than two years with spinal muscular atrophy.

  • health outcomes in spinal muscular atrophy type 1 following avxs 101 Gene Replacement Therapy
    Pediatric Pulmonology, 2019
    Co-Authors: Samiah Alzaidy, Linda Lowes, L Alfano, Kathleen Church, Simon A Pickard, Kavitha Kotha, Grace R Paul, Kelly J Lehman, Douglas M Sproule, O Dabbous
    Abstract:

    Background Spinal Muscular Atrophy type 1 (SMA1) is a rare Genetic neuromuscular disease where 75% of SMA1 patients die/require permanent-ventilation by 13.6 months. This study assessed the health outcomes of SMA1 infants treated with AVXS-101 Gene Replacement Therapy. Methods Twelve Genetically confirmed SMA1 infants with homozygous deletions of the SMN1 Gene and two SMN2 Gene copies received a one-time intravenous proposed therapeutic dose of AVXS-101 in an open label study conducted between December 2014 and 2017. Patients were followed for 2-years post-treatment for outcomes including (1) pulmonary interventions; (2) nutritional interventions; (3) swallow function; (4) hospitalization rates; and (5) motor function. Results All 12 patients completed the study. Seven infants did not require noninvasive ventilation (NIV) by study completion. Eleven patients had stable or improved swallow function, demonstrated by the ability to feed orally; 11 patients were able to speak. The mean proportion of time hospitalized was 4.4%; the mean unadjusted annualized hospitalization rate was 2.1 (range = 0, 7.6), with a mean length of stay/hospitalization of 6.7 (range = 3, 12.1) days. Eleven patients achieved full head control and sitting unassisted and two patients were walking independently. Conclusions AVXS-101 treatment in SMA1 was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow-up period. This contrasts with the natural history of progressive respiratory failure and reduced survival. The reduced healthcare utilization could potentially alleviate patient and caregiver burden, suggesting an overall improved quality of life following Gene Replacement Therapy. Trial registration ClinicalTrials.gov number, NCT02122952.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 continued event free survival and achievement of developmental milestones s29 001
    Neurology, 2018
    Co-Authors: Thomas W. Prior, Jerry R Mendell, Samiah Alzaidy, Richard Shell, Louise R Rodinoklapac, Dave W Arnold, L Lowes
    Abstract:

    Objective: This trial explores safety and efficacy of a one-time administration of Gene Replacement Therapy. AVXS-101 delivers the SMN Gene in a one-time dose via the AAV9 viral vector, which crosses the blood-brain barrier. Background: Spinal muscular atrophy (SMA) is a devastating, monogenic neurodeGenerative disease. Children with SMA Type 1 (SMA1) will never sit unassisted or maintain head control. A natural history study of this patient population reported that none achieved a CHOP-INTEND score of ≥40 by 6 months of age (one transient exception) and 75% died or required permanent ventilation by 13.6 months. Design/Methods: In this Phase 1 trial, 15 patients with SMA1 confirmed by Genetic testing (with 2xSMN2 copies) were enrolled. Patients received an intravenous dose of low dose AVXS-101 (Cohort 1, n=3) or proposed therapeutic dose (Cohort 2, n=12). The primary objective was safety and secondary objectives included survival (avoidance of death/permanent ventilation) and ability to sit unassisted (video confirmed by external independent reviewer). CHOP-INTEND scores and other motor milestones were additional objectives. Results: AVXS-101 appeared to have a favorable safety profile and to improve survival at data cut-off (20 January 2017). All patients reached 13.6 months free of permanent ventilation and none have died (3 live >30 months). Cohort 2 patients demonstrated improvement in motor function: 11/12 achieved head control and sat with support, and 9/12 sat unassisted. Two patients stood and walked independently. Conclusions: In contrast with the natural history, a one-time intravenous administration of AVXS-101 appeared to demonstrate a positive impact on the survival of both cohorts and a dramatic, sustained impact on motor function of Cohort 2: 11/12 patients achieved CHOP-INTEND scores and motor milestones rarely or never seen in this population. A clinical update will be given at the time of presentation demonstrating continued improvements in patients. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc. Dr. Al-Zaidy has nothing to disclose. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 continued independence from nutritional and ventilatory support in patients dosed early in disease progression s29 003
    Neurology, 2018
    Co-Authors: Richard Shell, Thomas W. Prior, Samiah Alzaidy, Louise R Rodinoklapac, Dave W Arnold, L Lowes, L Alfano
    Abstract:

    Objective: Here we report clinical data of Spinal muscular atrophy Type 1 (SMA1) infants treated with a one-time intravenous dose of the proposed therapeutic dose of AVXS-101, a Gene Replacement Therapy that crosses the blood-brain-barrier. Background: Spinal muscular atrophy (SMA) is devastating monogenic neurodeGenerative disease characterized by lower motor neuron loss. Children with SMA1 experience severe swallowing and breathing dysfunction that, without nutritional/ventilatory support, leads to malnutrition, chronic aspiration, and ultimately death via respiratory failure. Natural history studies have shown that SMA1 patients will require nutritional and ventilatory support by 12 months of age. Design/Methods: In this study, 15 patients with SMA with 2xSMN2 copies confirmed by Genetic testing were enrolled; all patients had bi-allelic Exon 7 deletions of SMN1 and no SMN2 disease modifying mutation (mutation predicts a milder phenotype). Cohort 2 (n=12) received the proposed therapeutic dose of AVXS-101. Results: By Jan 20, 2017, all patients in Cohort2 were ≥13.6 months and free of permanent-ventilation. At study enrollment, 10 patients did not require ventilatory support; at end-of-study, 7/10 remained free of ventilatory support. At baseline, 7 patients did not require nutritional support at baseline; at end-of-study, 6/7 remained free of nutritional support. At baseline, 7 patients were able to feed orally; at end-of-study 11 were able to feed orally; no patient lost the ability to feed orally following dosing. Conclusions: In contrast to natural history, the majority of patients in this Phase 1 trial who did not require nutritional or ventilatory support at baseline did not require either at end-of-study. Moreover, 4 patients acquired the ability to feed orally, suggesting the potential of AVXS-101 to improve swallowing function. Patients treated early in age and early in disease course have continued to avoid the need for ventilatory and/or nutritional support. A clinical update will be given at the time of presentation demonstrating continued independence. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Al-Zaidy has nothing to disclose. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Kotha has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 patients treated early with the proposed therapeutic dose were able to sit unassisted at a younger age s29 002
    Neurology, 2018
    Co-Authors: Samiah Alzaidy, Richard Shell, Louise R Rodinoklapac, L Alfano, Dave W Arnold, L Lowes
    Abstract:

    Objective: This trial explored safety and efficacy one-time intravenous administration of Gene Replacement Therapy (AVXS-101) in Spinal Muscular Atrophy Type 1 (SMA1). Background: Spinal Muscular Atrophy (SMA) is a devastating monogenic neurodeGenerative disease. Children with SMA1 will never sit unassisted. By 6 months, almost no children with SMA1 achieve a score >40 points (maximum 64). Design/Methods: In this study, 15 patients with SMA1 confirmed by Genetic testing (with 2x SMN2 copies) were enrolled; all patients had bi-allelic Exon 7 deletions of SMN1 and no SMN2 disease modifying mutation. Patients received an intravenous dose of AVXS-101 at low dose (Cohort1, n=3) or proposed therapeutic dose (Cohort2, n=12). The primary objective was safety and secondary objectives included survival (avoidance of death/permanent-ventilation) and sitting unassisted (video confirmed by external reviewer). CHOP-INTEND scores and motor milestones were evaluated. Results: The vast majority of patients in Cohort 2 demonstrated improvements in motor function superior to the natural history (20 January 2017). 11 of 12 patients achieved CHOP-INTEND scores ≥40, and 10 of 12 achieved scores ≥50, both significantly superior to the published natural history (Exact Binomial test; both p 3 months of age (median 22.2 months of age) (Wilcoxon non-parametric two-sample test, p=0.0159). Conclusions: The vast majority of patients in Cohort 2 achieved levels of motor function never seen in SMA1 patients. The majority of Cohort 2 patients achieved sitting unassisted regardless of age at dosing; however, those dosed early achieved this milestone more quickly, emphasizing the need for newborn screening for SMA. Additional children have achieved sitting unassisted since January 20, 2017; an update to the data described here will be given at the time of presentation. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Alfano has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Al-Zaidy has nothing to disclose. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc.

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

  • Gene Replacement Therapy in spinal muscular atrophy type 1 long term follow up from the onasemnoGene abeparvovec xioi phase 1 2a clinical trial 1808
    Neurology, 2020
    Co-Authors: Jerry R Mendell, Richard Shell, L Alfano, Kelly J Lehman, Markus Mccolly, L Lowes, N Miller, M Iammarino, Kathleen Church
    Abstract:

    Objective: To evaluate long-term safety and efficacy of onasemnoGene abeparvovec-xioi (formerly AVXS-101). Background: Spinal muscular atrophy type 1 (SMA1) is a rapidly progressing disease caused by biallelic survival motor neuron 1 Gene (SMN1) deletion/mutation, resulting in death/permanent ventilation by 2 years of age if untreated. OnasemnoGene abeparvovec, an SMN Gene-Replacement Therapy, addresses the Genetic root cause of SMA. In the phase 1/2a trial (START; NCT02122952), SMA1 patients who received a one-time intravenous (IV) infusion of onasemnoGene abeparvovec at high dose (Cohort 2, n=12) demonstrated significantly improved outcomes relative to untreated natural history. Design/Methods: Patients in START could rollover into a long-term follow-up (LTFU) study (Study LT-001; NCT03421977). Primary objective: long-term safety. Patients have annual visits (5 years) followed by annual phone contact (additional 10 years). Patient record transfers from local physicians and/or neurologists are requested. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include evaluation of developmental milestones maintenance. Results: As of 31 May 2019, 13 patients (Cohort 1, n=3; Cohort 2, n=10) enrolled in Study LT-001 and had a baseline visit. For patients in Cohort 2, the mean (range) age and time since dosing were 4.2 (3.7–5.0) years and 3.9 (3.5–4.6) years, respectively. All patients in Cohort 2 were alive and free of permanent ventilation. No developmental milestones achieved at the end of START were lost; 2 patients have gained the standing with assistance milestone during LTFU (video-confirmed; neither patient has received nusinersen), further supporting the durability of onasemnoGene abeparvovec. No new treatment-related serious adverse events or adverse events of special interest have occurred in LTFU (as of 8 March 2019). Conclusions: One-time IV administration of onasemnoGene abeparvovec at the high dose in START continues to provide prolonged and durable efficacy with milestone development in Study LT-001. Disclosure: 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.. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.. Dr. Lehman has nothing to disclose. Dr. McColly has nothing to disclose. Dr. Lowes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with ATOM International. Dr. Lowes has received royalty, license fees, or contractual rights payments from Nationwide Children’s Hospital. Dr. Alfano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Alfano has received research support from Sarepta Therapeutics. Dr. Miller has nothing to disclose. Dr. Iammarino has nothing to disclose. Dr. Church has nothing to disclose. 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. Ouyang 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. 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. Joshi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis Inc.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. 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. 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. Al-Zaidy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Al-Zaidy has received royalty, license fees, or contractual rights payments from Mile Biotech. Dr. Al-Zaidy has received research support from AveXis, Inc., and Catalyst.

  • s61 onasemnoGene abeparvovec Gene Replacement Therapy grt for spinal muscular atrophy type 1 sma1 preliminary pulmonary and ventilatory findings from the phase 3 study str1ve
    Thorax, 2019
    Co-Authors: Richard Shell, Thomas O Crawford, Richard S. Finkel, Basil T Darras, John W. Day, Nancy L. Kuntz, Anne M. Connolly, Susan T. Iannaccone, Claudia A Chiriboga, Loren D M Pena
    Abstract:

    Introduction and objectives SMA1 is a rapidly progressing neurologic disease caused by biallelic loss/mutation of the survival motor neuron 1 Gene (SMN1). OnasemnoGene abeparvovec (formerly AVXS-101) is a one-time GRT designed to treat the Genetic root cause of SMA by providing immediate, sustained neuronal SMN protein expression. In the phase 1/2a study (NCT02122952), symptomatic SMA1 infants treated with onasemnoGene abeparvovec demonstrated exceptional permanent ventilation-free survival, motor milestone achievements, and increased independence from ventilatory and nutritional support. Here we report study design and preliminary pulmonary and bulbar function data from the STR1VE study (NCT03306277). Methods STR1VE is a phase 3, multicenter, open-label, single-arm study in SMA1 patients aged Results Enrollment is complete (N=22 dosed patients). Mean (range) age at symptom onset, Genetic diagnosis, and enrollment: 1.9 (0–4.0), 2.6 (0–5.4), and 3.7 (0.5–5.9) months. At baseline, no patient required ventilatory/nutritional support; all exclusively fed by mouth. As of 8 March 2019, 1 patient died due to causes unrelated to onasemnoGene abeparvovec (May 2018); 1 withdrew consent. Eighteen of 22 patients had not had any bilevel positive airway pressure (BiPAP) support during the study. All 20 (100%) continuing patients had functional/normal swallowing. Two patients had gastrostomy tubes; 1 who discontinued the study. Eleven of 22 patients achieved independent sitting (mean, 8.2 months post-treatment); 19/20 patients ≥10.5 months of age or who discontinued the study prior to 10.5 months were surviving without permanent ventilation. The discontinued patient met the ventilatory support endpoint by clinical report, but this was not verified by download of ventilator usage from the BiPAP machine. Conclusions Preliminary data from STR1VE parallel the phase 1/2a study findings and may be associated with future survival, as well as pulmonary and bulbar function improvements.

  • impact of age and motor function in a phase 1 2a study of infants with sma type 1 receiving single dose Gene Replacement Therapy
    Pediatric Neurology, 2019
    Co-Authors: Thomas W. Prior, Richard Shell, Dave W Arnold, Linda Lowes, L Alfano, Kathleen Church, Kelly J Lehman, Markus Mccolly, Douglas M Sproule
    Abstract:

    Abstract Background This study characterizes motor function responses after early dosing of AVXS-101 (onasemnoGene abeparvovec) in Gene Replacement Therapy in infants with severe spinal muscular atrophy type 1 (SMA1). Methods This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study ( NCT02122952 ). Infants were grouped according to age at dosing and baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores Results Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months). Conclusions The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 continued event free survival and achievement of developmental milestones s29 001
    Neurology, 2018
    Co-Authors: Thomas W. Prior, Jerry R Mendell, Samiah Alzaidy, Richard Shell, Louise R Rodinoklapac, Dave W Arnold, L Lowes
    Abstract:

    Objective: This trial explores safety and efficacy of a one-time administration of Gene Replacement Therapy. AVXS-101 delivers the SMN Gene in a one-time dose via the AAV9 viral vector, which crosses the blood-brain barrier. Background: Spinal muscular atrophy (SMA) is a devastating, monogenic neurodeGenerative disease. Children with SMA Type 1 (SMA1) will never sit unassisted or maintain head control. A natural history study of this patient population reported that none achieved a CHOP-INTEND score of ≥40 by 6 months of age (one transient exception) and 75% died or required permanent ventilation by 13.6 months. Design/Methods: In this Phase 1 trial, 15 patients with SMA1 confirmed by Genetic testing (with 2xSMN2 copies) were enrolled. Patients received an intravenous dose of low dose AVXS-101 (Cohort 1, n=3) or proposed therapeutic dose (Cohort 2, n=12). The primary objective was safety and secondary objectives included survival (avoidance of death/permanent ventilation) and ability to sit unassisted (video confirmed by external independent reviewer). CHOP-INTEND scores and other motor milestones were additional objectives. Results: AVXS-101 appeared to have a favorable safety profile and to improve survival at data cut-off (20 January 2017). All patients reached 13.6 months free of permanent ventilation and none have died (3 live >30 months). Cohort 2 patients demonstrated improvement in motor function: 11/12 achieved head control and sat with support, and 9/12 sat unassisted. Two patients stood and walked independently. Conclusions: In contrast with the natural history, a one-time intravenous administration of AVXS-101 appeared to demonstrate a positive impact on the survival of both cohorts and a dramatic, sustained impact on motor function of Cohort 2: 11/12 patients achieved CHOP-INTEND scores and motor milestones rarely or never seen in this population. A clinical update will be given at the time of presentation demonstrating continued improvements in patients. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc. Dr. Al-Zaidy has nothing to disclose. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 continued independence from nutritional and ventilatory support in patients dosed early in disease progression s29 003
    Neurology, 2018
    Co-Authors: Richard Shell, Thomas W. Prior, Samiah Alzaidy, Louise R Rodinoklapac, Dave W Arnold, L Lowes, L Alfano
    Abstract:

    Objective: Here we report clinical data of Spinal muscular atrophy Type 1 (SMA1) infants treated with a one-time intravenous dose of the proposed therapeutic dose of AVXS-101, a Gene Replacement Therapy that crosses the blood-brain-barrier. Background: Spinal muscular atrophy (SMA) is devastating monogenic neurodeGenerative disease characterized by lower motor neuron loss. Children with SMA1 experience severe swallowing and breathing dysfunction that, without nutritional/ventilatory support, leads to malnutrition, chronic aspiration, and ultimately death via respiratory failure. Natural history studies have shown that SMA1 patients will require nutritional and ventilatory support by 12 months of age. Design/Methods: In this study, 15 patients with SMA with 2xSMN2 copies confirmed by Genetic testing were enrolled; all patients had bi-allelic Exon 7 deletions of SMN1 and no SMN2 disease modifying mutation (mutation predicts a milder phenotype). Cohort 2 (n=12) received the proposed therapeutic dose of AVXS-101. Results: By Jan 20, 2017, all patients in Cohort2 were ≥13.6 months and free of permanent-ventilation. At study enrollment, 10 patients did not require ventilatory support; at end-of-study, 7/10 remained free of ventilatory support. At baseline, 7 patients did not require nutritional support at baseline; at end-of-study, 6/7 remained free of nutritional support. At baseline, 7 patients were able to feed orally; at end-of-study 11 were able to feed orally; no patient lost the ability to feed orally following dosing. Conclusions: In contrast to natural history, the majority of patients in this Phase 1 trial who did not require nutritional or ventilatory support at baseline did not require either at end-of-study. Moreover, 4 patients acquired the ability to feed orally, suggesting the potential of AVXS-101 to improve swallowing function. Patients treated early in age and early in disease course have continued to avoid the need for ventilatory and/or nutritional support. A clinical update will be given at the time of presentation demonstrating continued independence. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Al-Zaidy has nothing to disclose. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Kotha has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc.

L Alfano - One of the best experts on this subject based on the ideXlab platform.

  • Gene Replacement Therapy in spinal muscular atrophy type 1 long term follow up from the onasemnoGene abeparvovec xioi phase 1 2a clinical trial 1808
    Neurology, 2020
    Co-Authors: Jerry R Mendell, Richard Shell, L Alfano, Kelly J Lehman, Markus Mccolly, L Lowes, N Miller, M Iammarino, Kathleen Church
    Abstract:

    Objective: To evaluate long-term safety and efficacy of onasemnoGene abeparvovec-xioi (formerly AVXS-101). Background: Spinal muscular atrophy type 1 (SMA1) is a rapidly progressing disease caused by biallelic survival motor neuron 1 Gene (SMN1) deletion/mutation, resulting in death/permanent ventilation by 2 years of age if untreated. OnasemnoGene abeparvovec, an SMN Gene-Replacement Therapy, addresses the Genetic root cause of SMA. In the phase 1/2a trial (START; NCT02122952), SMA1 patients who received a one-time intravenous (IV) infusion of onasemnoGene abeparvovec at high dose (Cohort 2, n=12) demonstrated significantly improved outcomes relative to untreated natural history. Design/Methods: Patients in START could rollover into a long-term follow-up (LTFU) study (Study LT-001; NCT03421977). Primary objective: long-term safety. Patients have annual visits (5 years) followed by annual phone contact (additional 10 years). Patient record transfers from local physicians and/or neurologists are requested. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include evaluation of developmental milestones maintenance. Results: As of 31 May 2019, 13 patients (Cohort 1, n=3; Cohort 2, n=10) enrolled in Study LT-001 and had a baseline visit. For patients in Cohort 2, the mean (range) age and time since dosing were 4.2 (3.7–5.0) years and 3.9 (3.5–4.6) years, respectively. All patients in Cohort 2 were alive and free of permanent ventilation. No developmental milestones achieved at the end of START were lost; 2 patients have gained the standing with assistance milestone during LTFU (video-confirmed; neither patient has received nusinersen), further supporting the durability of onasemnoGene abeparvovec. No new treatment-related serious adverse events or adverse events of special interest have occurred in LTFU (as of 8 March 2019). Conclusions: One-time IV administration of onasemnoGene abeparvovec at the high dose in START continues to provide prolonged and durable efficacy with milestone development in Study LT-001. Disclosure: 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.. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.. Dr. Lehman has nothing to disclose. Dr. McColly has nothing to disclose. Dr. Lowes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with ATOM International. Dr. Lowes has received royalty, license fees, or contractual rights payments from Nationwide Children’s Hospital. Dr. Alfano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Alfano has received research support from Sarepta Therapeutics. Dr. Miller has nothing to disclose. Dr. Iammarino has nothing to disclose. Dr. Church has nothing to disclose. 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. Ouyang 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. 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. Joshi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis Inc.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. 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. 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. Al-Zaidy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Al-Zaidy has received royalty, license fees, or contractual rights payments from Mile Biotech. Dr. Al-Zaidy has received research support from AveXis, Inc., and Catalyst.

  • impact of age and motor function in a phase 1 2a study of infants with sma type 1 receiving single dose Gene Replacement Therapy
    Pediatric Neurology, 2019
    Co-Authors: Thomas W. Prior, Richard Shell, Dave W Arnold, Linda Lowes, L Alfano, Kathleen Church, Kelly J Lehman, Markus Mccolly, Douglas M Sproule
    Abstract:

    Abstract Background This study characterizes motor function responses after early dosing of AVXS-101 (onasemnoGene abeparvovec) in Gene Replacement Therapy in infants with severe spinal muscular atrophy type 1 (SMA1). Methods This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study ( NCT02122952 ). Infants were grouped according to age at dosing and baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores Results Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months). Conclusions The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function.

  • health outcomes in spinal muscular atrophy type 1 following avxs 101 Gene Replacement Therapy
    Pediatric Pulmonology, 2019
    Co-Authors: Samiah Alzaidy, Linda Lowes, L Alfano, Kathleen Church, Simon A Pickard, Kavitha Kotha, Grace R Paul, Kelly J Lehman, Douglas M Sproule, O Dabbous
    Abstract:

    Background Spinal Muscular Atrophy type 1 (SMA1) is a rare Genetic neuromuscular disease where 75% of SMA1 patients die/require permanent-ventilation by 13.6 months. This study assessed the health outcomes of SMA1 infants treated with AVXS-101 Gene Replacement Therapy. Methods Twelve Genetically confirmed SMA1 infants with homozygous deletions of the SMN1 Gene and two SMN2 Gene copies received a one-time intravenous proposed therapeutic dose of AVXS-101 in an open label study conducted between December 2014 and 2017. Patients were followed for 2-years post-treatment for outcomes including (1) pulmonary interventions; (2) nutritional interventions; (3) swallow function; (4) hospitalization rates; and (5) motor function. Results All 12 patients completed the study. Seven infants did not require noninvasive ventilation (NIV) by study completion. Eleven patients had stable or improved swallow function, demonstrated by the ability to feed orally; 11 patients were able to speak. The mean proportion of time hospitalized was 4.4%; the mean unadjusted annualized hospitalization rate was 2.1 (range = 0, 7.6), with a mean length of stay/hospitalization of 6.7 (range = 3, 12.1) days. Eleven patients achieved full head control and sitting unassisted and two patients were walking independently. Conclusions AVXS-101 treatment in SMA1 was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow-up period. This contrasts with the natural history of progressive respiratory failure and reduced survival. The reduced healthcare utilization could potentially alleviate patient and caregiver burden, suggesting an overall improved quality of life following Gene Replacement Therapy. Trial registration ClinicalTrials.gov number, NCT02122952.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 continued independence from nutritional and ventilatory support in patients dosed early in disease progression s29 003
    Neurology, 2018
    Co-Authors: Richard Shell, Thomas W. Prior, Samiah Alzaidy, Louise R Rodinoklapac, Dave W Arnold, L Lowes, L Alfano
    Abstract:

    Objective: Here we report clinical data of Spinal muscular atrophy Type 1 (SMA1) infants treated with a one-time intravenous dose of the proposed therapeutic dose of AVXS-101, a Gene Replacement Therapy that crosses the blood-brain-barrier. Background: Spinal muscular atrophy (SMA) is devastating monogenic neurodeGenerative disease characterized by lower motor neuron loss. Children with SMA1 experience severe swallowing and breathing dysfunction that, without nutritional/ventilatory support, leads to malnutrition, chronic aspiration, and ultimately death via respiratory failure. Natural history studies have shown that SMA1 patients will require nutritional and ventilatory support by 12 months of age. Design/Methods: In this study, 15 patients with SMA with 2xSMN2 copies confirmed by Genetic testing were enrolled; all patients had bi-allelic Exon 7 deletions of SMN1 and no SMN2 disease modifying mutation (mutation predicts a milder phenotype). Cohort 2 (n=12) received the proposed therapeutic dose of AVXS-101. Results: By Jan 20, 2017, all patients in Cohort2 were ≥13.6 months and free of permanent-ventilation. At study enrollment, 10 patients did not require ventilatory support; at end-of-study, 7/10 remained free of ventilatory support. At baseline, 7 patients did not require nutritional support at baseline; at end-of-study, 6/7 remained free of nutritional support. At baseline, 7 patients were able to feed orally; at end-of-study 11 were able to feed orally; no patient lost the ability to feed orally following dosing. Conclusions: In contrast to natural history, the majority of patients in this Phase 1 trial who did not require nutritional or ventilatory support at baseline did not require either at end-of-study. Moreover, 4 patients acquired the ability to feed orally, suggesting the potential of AVXS-101 to improve swallowing function. Patients treated early in age and early in disease course have continued to avoid the need for ventilatory and/or nutritional support. A clinical update will be given at the time of presentation demonstrating continued independence. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Al-Zaidy has nothing to disclose. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Kotha has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 patients treated early with the proposed therapeutic dose were able to sit unassisted at a younger age s29 002
    Neurology, 2018
    Co-Authors: Samiah Alzaidy, Richard Shell, Louise R Rodinoklapac, L Alfano, Dave W Arnold, L Lowes
    Abstract:

    Objective: This trial explored safety and efficacy one-time intravenous administration of Gene Replacement Therapy (AVXS-101) in Spinal Muscular Atrophy Type 1 (SMA1). Background: Spinal Muscular Atrophy (SMA) is a devastating monogenic neurodeGenerative disease. Children with SMA1 will never sit unassisted. By 6 months, almost no children with SMA1 achieve a score >40 points (maximum 64). Design/Methods: In this study, 15 patients with SMA1 confirmed by Genetic testing (with 2x SMN2 copies) were enrolled; all patients had bi-allelic Exon 7 deletions of SMN1 and no SMN2 disease modifying mutation. Patients received an intravenous dose of AVXS-101 at low dose (Cohort1, n=3) or proposed therapeutic dose (Cohort2, n=12). The primary objective was safety and secondary objectives included survival (avoidance of death/permanent-ventilation) and sitting unassisted (video confirmed by external reviewer). CHOP-INTEND scores and motor milestones were evaluated. Results: The vast majority of patients in Cohort 2 demonstrated improvements in motor function superior to the natural history (20 January 2017). 11 of 12 patients achieved CHOP-INTEND scores ≥40, and 10 of 12 achieved scores ≥50, both significantly superior to the published natural history (Exact Binomial test; both p 3 months of age (median 22.2 months of age) (Wilcoxon non-parametric two-sample test, p=0.0159). Conclusions: The vast majority of patients in Cohort 2 achieved levels of motor function never seen in SMA1 patients. The majority of Cohort 2 patients achieved sitting unassisted regardless of age at dosing; however, those dosed early achieved this milestone more quickly, emphasizing the need for newborn screening for SMA. Additional children have achieved sitting unassisted since January 20, 2017; an update to the data described here will be given at the time of presentation. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Alfano has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Al-Zaidy has nothing to disclose. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc.

Louise R Rodinoklapac - One of the best experts on this subject based on the ideXlab platform.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 continued independence from nutritional and ventilatory support in patients dosed early in disease progression s29 003
    Neurology, 2018
    Co-Authors: Richard Shell, Thomas W. Prior, Samiah Alzaidy, Louise R Rodinoklapac, Dave W Arnold, L Lowes, L Alfano
    Abstract:

    Objective: Here we report clinical data of Spinal muscular atrophy Type 1 (SMA1) infants treated with a one-time intravenous dose of the proposed therapeutic dose of AVXS-101, a Gene Replacement Therapy that crosses the blood-brain-barrier. Background: Spinal muscular atrophy (SMA) is devastating monogenic neurodeGenerative disease characterized by lower motor neuron loss. Children with SMA1 experience severe swallowing and breathing dysfunction that, without nutritional/ventilatory support, leads to malnutrition, chronic aspiration, and ultimately death via respiratory failure. Natural history studies have shown that SMA1 patients will require nutritional and ventilatory support by 12 months of age. Design/Methods: In this study, 15 patients with SMA with 2xSMN2 copies confirmed by Genetic testing were enrolled; all patients had bi-allelic Exon 7 deletions of SMN1 and no SMN2 disease modifying mutation (mutation predicts a milder phenotype). Cohort 2 (n=12) received the proposed therapeutic dose of AVXS-101. Results: By Jan 20, 2017, all patients in Cohort2 were ≥13.6 months and free of permanent-ventilation. At study enrollment, 10 patients did not require ventilatory support; at end-of-study, 7/10 remained free of ventilatory support. At baseline, 7 patients did not require nutritional support at baseline; at end-of-study, 6/7 remained free of nutritional support. At baseline, 7 patients were able to feed orally; at end-of-study 11 were able to feed orally; no patient lost the ability to feed orally following dosing. Conclusions: In contrast to natural history, the majority of patients in this Phase 1 trial who did not require nutritional or ventilatory support at baseline did not require either at end-of-study. Moreover, 4 patients acquired the ability to feed orally, suggesting the potential of AVXS-101 to improve swallowing function. Patients treated early in age and early in disease course have continued to avoid the need for ventilatory and/or nutritional support. A clinical update will be given at the time of presentation demonstrating continued independence. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Al-Zaidy has nothing to disclose. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Kotha has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 continued event free survival and achievement of developmental milestones s29 001
    Neurology, 2018
    Co-Authors: Thomas W. Prior, Jerry R Mendell, Samiah Alzaidy, Richard Shell, Louise R Rodinoklapac, Dave W Arnold, L Lowes
    Abstract:

    Objective: This trial explores safety and efficacy of a one-time administration of Gene Replacement Therapy. AVXS-101 delivers the SMN Gene in a one-time dose via the AAV9 viral vector, which crosses the blood-brain barrier. Background: Spinal muscular atrophy (SMA) is a devastating, monogenic neurodeGenerative disease. Children with SMA Type 1 (SMA1) will never sit unassisted or maintain head control. A natural history study of this patient population reported that none achieved a CHOP-INTEND score of ≥40 by 6 months of age (one transient exception) and 75% died or required permanent ventilation by 13.6 months. Design/Methods: In this Phase 1 trial, 15 patients with SMA1 confirmed by Genetic testing (with 2xSMN2 copies) were enrolled. Patients received an intravenous dose of low dose AVXS-101 (Cohort 1, n=3) or proposed therapeutic dose (Cohort 2, n=12). The primary objective was safety and secondary objectives included survival (avoidance of death/permanent ventilation) and ability to sit unassisted (video confirmed by external independent reviewer). CHOP-INTEND scores and other motor milestones were additional objectives. Results: AVXS-101 appeared to have a favorable safety profile and to improve survival at data cut-off (20 January 2017). All patients reached 13.6 months free of permanent ventilation and none have died (3 live >30 months). Cohort 2 patients demonstrated improvement in motor function: 11/12 achieved head control and sat with support, and 9/12 sat unassisted. Two patients stood and walked independently. Conclusions: In contrast with the natural history, a one-time intravenous administration of AVXS-101 appeared to demonstrate a positive impact on the survival of both cohorts and a dramatic, sustained impact on motor function of Cohort 2: 11/12 patients achieved CHOP-INTEND scores and motor milestones rarely or never seen in this population. A clinical update will be given at the time of presentation demonstrating continued improvements in patients. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc. Dr. Al-Zaidy has nothing to disclose. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Alfano has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.

  • avxs 101 phase 1 Gene Replacement Therapy clinical trial in sma type 1 patients treated early with the proposed therapeutic dose were able to sit unassisted at a younger age s29 002
    Neurology, 2018
    Co-Authors: Samiah Alzaidy, Richard Shell, Louise R Rodinoklapac, L Alfano, Dave W Arnold, L Lowes
    Abstract:

    Objective: This trial explored safety and efficacy one-time intravenous administration of Gene Replacement Therapy (AVXS-101) in Spinal Muscular Atrophy Type 1 (SMA1). Background: Spinal Muscular Atrophy (SMA) is a devastating monogenic neurodeGenerative disease. Children with SMA1 will never sit unassisted. By 6 months, almost no children with SMA1 achieve a score >40 points (maximum 64). Design/Methods: In this study, 15 patients with SMA1 confirmed by Genetic testing (with 2x SMN2 copies) were enrolled; all patients had bi-allelic Exon 7 deletions of SMN1 and no SMN2 disease modifying mutation. Patients received an intravenous dose of AVXS-101 at low dose (Cohort1, n=3) or proposed therapeutic dose (Cohort2, n=12). The primary objective was safety and secondary objectives included survival (avoidance of death/permanent-ventilation) and sitting unassisted (video confirmed by external reviewer). CHOP-INTEND scores and motor milestones were evaluated. Results: The vast majority of patients in Cohort 2 demonstrated improvements in motor function superior to the natural history (20 January 2017). 11 of 12 patients achieved CHOP-INTEND scores ≥40, and 10 of 12 achieved scores ≥50, both significantly superior to the published natural history (Exact Binomial test; both p 3 months of age (median 22.2 months of age) (Wilcoxon non-parametric two-sample test, p=0.0159). Conclusions: The vast majority of patients in Cohort 2 achieved levels of motor function never seen in SMA1 patients. The majority of Cohort 2 patients achieved sitting unassisted regardless of age at dosing; however, those dosed early achieved this milestone more quickly, emphasizing the need for newborn screening for SMA. Additional children have achieved sitting unassisted since January 20, 2017; an update to the data described here will be given at the time of presentation. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Alfano has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Al-Zaidy has nothing to disclose. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule 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, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc.

  • single dose Gene Replacement Therapy for spinal muscular atrophy
    The New England Journal of Medicine, 2017
    Co-Authors: Jerry R Mendell, Thomas W. Prior, Samiah Alzaidy, Richard Shell, Dave W Arnold, Louise R Rodinoklapac, Linda Lowes, L Alfano, Katherine Berry, Kathleen Church
    Abstract:

    BackgroundSpinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional Replacement of the mutated Gene encoding survival motor neuron 1 (SMN1) in this disease. MethodsFifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×1013 vg per kilogram of body weight), and 12 received a high dose (2.0×1014 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating be...