Novartis Gene Therapies Switzerland GmbH

Three new therapies for spinal muscular atrophy (SMA) have been approved by the United States Food and Drug Administration and the European Medicines Agency since 2016. Although these new therapies improve the quality of life of patients who are symptomatic at first treatment, administration before the onset of symptoms is significantly more effective. As a consequence, newborn screening programs have been initiated in several countries. In 2018, we launched a 3-year pilot program to screen newborns for SMA in the Belgian region of Liège. This program was rapidly expanding to all of Southern Belgium, a region of approximately 55,000 births annually. During the pilot program, 136,339 neonates were tested for deletion of exon 7 of SMN1, the most common cause of SMA. Nine SMA cases with homozygous deletion were identified through this screen. Another patient was identified after presenting with symptoms and was shown to be heterozygous for the SMN1 exon 7 deletion and a point mutation on the opposite allele. These ten patients were treated. The pilot program has now successfully transitioned into the official neonatal screening program in Southern Belgium. The lessons learned during implementation of this pilot program are reported.

Background: Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials. Objective: We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting. Methods: RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources. Results: Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. Median (IQR) age at initial SMA diagnosis was 1 (0-6) month and at onasemnogene abeparvovec infusion was 3 (1-10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2, and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0] points). All patients maintained/achieved motor milestones. 48.5% (n = 81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related. Conclusion: These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec.

We sought to devise a rational, systematic approach for defining/grouping survival motor neuron-targeted disease-modifying treatment (DMT) scenarios. The proposed classification is primarily based on a two-part differentiation: initial DMT, and persistence/discontinuation of subsequent DMT(s). Treatment categories were identified: monotherapy add-on, transient add-on, combination with onasemnogene abeparvovec, bridging to onasemnogene abeparvovec, and switching to onasemnogene abeparvovec. We validated this approach by applying the classification to the 443 patients currently in the RESTORE registry and explored the demographics of these different groups of patients. This work forms the basis to explore the safety and efficacy profile of the different combinations of DMT in SMA.

Since 72% of rare diseases are genetic in origin and mostly paediatrics, genetic newborn screening represents a diagnostic "window of opportunity". Therefore, many gNBS initiatives started in different European countries. Screen4Care is a research project, which resulted of a joint effort between the European Union Commission and the European Federation of Pharmaceutical Industries and Associations. It focuses on genetic newborn screening and artificial intelligence-based tools which will be applied to a large European population of about 25.000 infants. The neonatal screening strategy will be based on targeted sequencing, while whole genome sequencing will be offered to all enrolled infants who may show early symptoms but have resulted negative at the targeted sequencing-based newborn screening. We will leverage artificial intelligence-based algorithms to identify patients using Electronic Health Records (EHR) and to build a repository "symptom checkers" for patients and healthcare providers. S4C will design an equitable, ethical, and sustainable framework for genetic newborn screening and new digital tools, corroborated by a large workout where legal, ethical, and social complexities will be addressed with the intent of making the framework highly and flexibly translatable into the diverse European health systems.

Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9 (AAV9) vector-based gene therapy for spinal muscular atrophy (SMA). Patients with elevated titers of anti-AAV9 antibodies (AAV9-Ab) should not receive onasemnogene abeparvovec because of potential safety and efficacy implications. We conducted a retrospective study to describe the seroprevalence of anti-AAV9 binding antibodies for pediatric patients with SMA in the United States. At initial testing, 13.0% (115 of 882) of patients (mean [SD] age, 26.29 [33.66] weeks) had elevated AAV9-Ab titers. The prevalence of elevated titers decreased as age increased, with 18.2% (92 of 507) of patients ≤3 months old but only 1.1% (1 of 92) of patients ≥21 months old having elevated titers. This suggests transplacental maternal transfer of antibodies. No patterns of geographic variations in AAV9-Ab prevalence were confirmed. Elevated AAV9-Ab titers in children <6 weeks old decreased in all circumstances. Lower magnitudes of elevated titers declined more rapidly than greater magnitudes. Retesting was completed at the discretion of the treating clinician, so age at testing and time between tests varied. AAV9-Ab retesting should be considered when patients have elevated titers, and elevations at a young age are not a deterrent to eventual onasemnogene abeparvovec administration. Early disease-modifying treatment for SMA leads to optimal outcomes.

AIMS: Spinal muscular atrophy (SMA) is a rare genetic disorder characterized by progressive muscle weakness, atrophy, respiratory failure, and in severe cases, infantile death. Early detection and treatment before symptom onset may substantially improve outcomes, allowing patients to achieve age-appropriate motor milestones and longer survival. We assessed the cost-utility of newborn screening (NBS) for SMA in Japan. MATERIALS AND METHODS: A cost-utility model (decision tree and Markov model) compared lifetime health effects and costs between "NBS" for SMA (presymptomatic treatment) or "no NBS" (treatment initiated at symptom onset). Model inputs were sourced from literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess model robustness and data validity. RESULTS: Based on the 1:10,000 SMA incidence, it was estimated that 43 newborns/year would have SMA, and a total of 39 patients with SMA would initiate presymptomatic treatment after NBS. An estimated 736 quality-adjusted life-years were gained per annual birth cohort with NBS. NBS for SMA was dominant compared with no NBS (i.e. less costly and more effective), with ¥8,856,960,096 reduced total costs with NBS versus no NBS (base-case). Sensitivity and scenario analyses supported cost effectiveness of NBS for SMA versus no NBS. A greater percentage of patients was estimated to enjoy longer survival and be without permanent assisted ventilation with NBS versus no NBS. LIMITATIONS: Real-world observations may differ from single-arm clinical trial outcomes. It was assumed that patients with SMA identified via NBS were asymptomatic and would receive treatment prior to symptoms. Best supportive care was not considered, and Japan-specific variations in gene replacement therapy protocol were not fully reflected. CONCLUSION: NBS for SMA allows for early identification of patients with SMA and treatment initiation before symptom onset, improving health outcomes and reducing total costs than without NBS.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic disease resulting in loss of motor function and, in severe cases (e.g., SMA type 1), infantile death. While treatments like nusinersen and onasemnogene abeparvovec improve prognosis for patients with SMA, costs for these medications can contribute to economic burden. OBJECTIVE: Direct costs were compared for onasemnogene abeparvovec, a one-time gene replacement therapy, versus nusinersen, a lifelong therapy, for patients with SMA type 1 and/or three or more survival motor neuron 2 (SMN2) gene copies in the Netherlands. METHODS: A cost comparison analysis model of 1-year incident patient population from the Netherlands was used to compare costs of onasemnogene abeparvovec versus nusinersen for patients eligible for onasemnogene abeparvovec immediately after diagnosis. Multiple analyses were conducted for economic outcomes (e.g., base-case, break-even, deterministic sensitivity, probabilistic sensitivity, scenario analyses). RESULTS: Cost differences of -€2.9 million (undiscounted) and -€1.5 million (discounted) per patient with SMA type 1 treated with onasemnogene abeparvovec versus nusinersen over a 20-year time horizon were identified (base-case). Reduced costs with onasemnogene abeparvovec versus nusinersen were evident after 8.25 years. CONCLUSION: Onasemnogene abeparvovec was less costly than nusinersen after 8.25 years of treatment of patients with SMA type 1 in the Netherlands.

<h3>Objective:</h3> We sought to describe clinical outcomes after onasemnogene abeparvovec (OA) monotherapy for patients with ≥4 <i>SMN2</i> copies in RESTORE, a comprehensive, noninterventional spinal muscular atrophy (SMA) registry. <h3>Background:</h3> OA is a one-time gene replacement therapy for SMA. While clinical trials of OA included patients with two or three <i>SMN2</i> gene copies, patients with ≥4 copies may be treated in clinical practice. Natural history and outcomes following SMA treatment have not been well-characterized for these patients. <h3>Design/Methods:</h3> We evaluated baseline characteristics, and post-treatment motor function, motor milestone achievement, use of ventilatory/nutritional support, and adverse events (AEs) (as of May 23, 2022, data cut). Patients evaluable for motor function or milestone achievement had ≥2 assessments, with ≥1 after OA. <h3>Results:</h3> Nine children with four <i>SMN2</i> copies and five with ≥4 copies were included. All 14 cases were identified by newborn screening in the United States and treated presymptomatically. Median age at OA administration was 3.5 (range, 1–11) months. All six children with evaluable motor milestone assessments achieved new milestones. All four children evaluable for CHOP INTEND maintained/achieved the maximum score of 64 points. One child was evaluable for HINE-2 and achieved a ≥2-point increase. One child was evaluable for HFMSE and achieved a ≥3-point increase. Six children with recorded AE data had ≥1 treatment-emergent AE. Two children reported AEs ≥Grade 3 (one had otitis media and one with history of fetal stroke had seizure ~3.5 months post-OA). No deaths or use of ventilatory/nutritional support were reported. <h3>Conclusions:</h3> Patients with ≥4 <i>SMN2</i> gene copies attained improvements in motor function and achieved new milestones after treatment with OA. SMA presentation with ≥4 <i>SMN2</i> copies is heterogeneous, and laboratory determination of <i>SMN2</i> copy number may be unreliable, highlighting the importance of early identification and intervention to optimize outcomes for all SMA patients. <b>Disclosure:</b> Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AveXis. Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Catabasis. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Capricor. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ReveraGen. Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Finkel has received research support from AveXis. The institution of Dr. Finkel has received research support from Biogen. The institution of Dr. Finkel has received research support from Capricor. The institution of Dr. Finkel has received research support from Catabasis. The institution of Dr. Finkel has received research support from ReveraGen. The institution of Dr. Finkel has received research support from Roche. The institution of Dr. Finkel has received research support from Scholar Rock. Dr. Finkel has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Finkel has received intellectual property interests from a discovery or technology relating to health care. Dr. Finkel has received personal compensation in the range of $0-$499 for serving as a Speaker in workshop with National Academy of Sciences. Dr. Finkel has a non-compensated relationship as a advisor with n-Lorem Foundation that is relevant to AAN interests or activities. Dr. Finkel has a non-compensated relationship as a Board Member with EveryLife Foundation that is relevant to AAN interests or activities. Kamal Benguerba has received personal compensation for serving as an employee of Novartis Gene Therapies. Kamal Benguerba has stock in Novartis Gene Therapies. Dr. Gehani has received personal compensation for serving as an employee of Novartis. Dr. Raju has nothing to disclose. Mr. Faulkner has received personal compensation for serving as an employee of Novartis Gene Therapies. Ms. LaMarca has received personal compensation for serving as an employee of Novartis Gene Therapies. The institution of Laurent Servais has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Laurent Servais has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. The institution of Laurent Servais has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Avexis. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dynacure. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Audentes. The institution of Laurent Servais has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Pfizer. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Santhera. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for RegenexBio. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Affinia. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Anagenesis. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Catabasis. The institution of Laurent Servais has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Evox. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lupin. Laurent Servais has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fibrogen.

We sought to describe real-world treatment patterns and outcomes for patients with SMA type 2 (SMA2) receiving onasemnogene abeparvovec (OA) monotherapy or who switched to OA from nusinersen.