Employee Of Novartis Research Articles

Remibrutinib Inhibits Neuroinflammation Driven by B Cells and Myeloid Cells in Preclinical Models of Multiple Sclerosis (P2-3.013)

<h3>Objective:</h3> To assess the mechanism of action and efficacy of remibrutinib in experimental autoimmune encephalomyelitis (EAE) mouse models of multiple sclerosis (MS). <h3>Background:</h3> Bruton’s tyrosine kinase (BTK) is a key node in B-cell receptor and fragment crystallizable receptor signaling. BTK inhibitors (BTKis) are an emerging oral option for patients with MS. Remibrutinib (LOU064) is a potent and highly selective covalent BTKi with promising preclinical and clinical profiles for the treatment of MS. <h3>Design/Methods:</h3> Two C57BL/6 mouse EAE models (induced by immunization with human or rat myelin oligodendrocyte glycoprotein [HuMOG and RatMOG EAE, respectively]) were used. Target engagement was assessed in tissue and clinical disease activity was determined. Serum antibody levels, biomarkers, and central nervous system tissue transcriptome were analyzed. <h3>Results:</h3> Remibrutinib inhibited B-cell–dependent HuMOG EAE at daily oral doses of 3 and 30 mg/kg and strongly reduced neurological symptoms. The ex vivo MOG-specific T-cell recall response was inhibited, but the polyclonal T-cell response was not, indicating selective B-cell inhibition. Remibrutinib did not decrease total immunoglobulin G antibody levels. Remibrutinib demonstrated strong BTK occupancy in the peripheral immune organs and brain at the efficacious dose of 30 mg/kg. Remibrutinib also inhibited RatMOG EAE, indicating that myeloid cell and microglia inhibition contributes to its efficacy in MS; this is supported by anti-inflammatory effects detected via single-cell RNA sequencing of the mouse brain and spinal cord. Remibrutinib also significantly reduced neurofilament light chain levels in serum. <h3>Conclusions:</h3> Remibrutinib exhibited dose-dependent efficacy in B-cell–driven EAE models. Potential for efficacy and anti-inflammatory effects on myeloid cells and microglia was observed. Remibrutinib may represent a novel treatment option for patients with MS. <b>Disclosure:</b> Bernd C. Kieseier, MD has nothing to disclose. Mr. Cenni has received personal compensation for serving as an employee of Novartis. Dr. Nuesslein-Hildesheim has received personal compensation for serving as an employee of Novartis Pharma AG. Dr. Nuesslein-Hildesheim has stock in Novartis Pharma AG. Dr. Ferrero has received personal compensation for serving as an employee of Novartis. Catherine Huck has received personal compensation for serving as an employee of Novartis. Mr. Eichlisberger has nothing to disclose. Dr. Ziehn has received personal compensation for serving as an employee of Novartis AG.

Compliance and Persistence With Ofatumumab Treatment in Patients With Relapsing Multiple Sclerosis in Clinical Trials for Up to 4 Years (P8-3.002)

Compliance and Persistence With Ofatumumab Treatment in Patients With Relapsing Multiple Sclerosis in Clinical Trials for Up to 4 Years (P8-3.002)

Long-term Effect of Ofatumumab Treatment on Serum Neurofilament Light Chain Levels and NEDA-3 Status in Patients With RMS: Results From ASCLEPIOS I/II and ALITHIOS (P6-3.013)

Long-term Effect of Ofatumumab Treatment on Serum Neurofilament Light Chain Levels and NEDA-3 Status in Patients With RMS: Results From ASCLEPIOS I/II and ALITHIOS (P6-3.013)

Siponimod Stabilizes Physical Disability Scores in People Living With Secondary Progressive Multiple Sclerosis After 2 Years of Treatment: Analysis From the Novartis Global Managed Access Program (P8-3.010)

<h3>Objective:</h3> To describe demographic and clinical characteristics and characterize change in Expanded Disability Status Scale (EDSS) score in people living with secondary progressive multiple sclerosis (plwSPMS) receiving siponimod under the managed access program (MAP; Global Siponimod MAP cohort [BAF2001M cohort]). <h3>Background:</h3> Siponimod significantly reduced the risk of confirmed disability progression and worsening of cognitive processing speed vs placebo in the phase 3 EXPAND trial (NCT01665144). However, real-world effectiveness data for siponimod remain scarce. <h3>Design/Methods:</h3> The BAF2001M cohort is an umbrella program to facilitate access to siponimod when marketing authorization is pending (under physician request) in the absence of acceptable alternative treatments. The program started in March 2019 and is ongoing. The target population included adult patients with SPMS and an EDSS score &lt;7 from March 2019 to January 2021. After January 2021, access to the MAP required SPMS with active disease. Treatment selection and patient monitoring were based on physician assessment. Baseline characteristics included country, age, sex, relapse, MRI activity in the last 2 years, EDSS, and cognition evaluation. <h3>Results:</h3> A total of 632 cases were analyzed (153 excluded from analysis due to local country restrictions). Mean (SD) age was 52.3 (8.7) years, 60% of patients were female, and median (IQR) EDSS was 5.5 (4.5–6.5). Prior to siponimod start, ~51% experienced a relapse in the last 2 years, 54% had previous cognitive evaluation, and 52% had an MRI scan in the last 2 years (48% showed activity). Mean change in EDSS from baseline was approximately −0.02/−0.03 at Months 6, 12, 18, and 24 (not significantly different vs baseline). Approximately 94% (140/149) of patients improved or were stable at Month 24. <h3>Conclusions:</h3> Most plwSPMS demonstrated improved or stabilized EDSS scores over 2 years. This population was older than the EXPAND study population and around half demonstrated relapse/MRI activity. Results support the effectiveness of siponimod in SPMS. <b>Disclosure:</b> Dr. Mavrikis Cox has received personal compensation for serving as an employee of Novartis Pharmaceuticals. Dr. Mavrikis Cox has stock in Novartis Pharmaceuticals. Virginia DeLasHeras has nothing to disclose. Dr. Ryan has received personal compensation for serving as an employee of Novartis. Mrs. Istrate has nothing to disclose. Soudeh Ansari has received personal compensation for serving as an employee of Novartis. Sophie Arnould has nothing to disclose. Dr. Piani Meier has received personal compensation for serving as an employee of Novartis. Dr. Piani Meier has received personal compensation for serving as an employee of Merck Group.

Remibrutinib, a Novel Bruton’s Tyrosine Kinase Inhibitor, Exhibits Improved Target Selectivity and Potency In Vitro (P8-3.003)

<h3>Objective:</h3> To assess the potency and selectivity of Bruton’s tyrosine kinase inhibitors (BTKis) under comparable experimental conditions. <h3>Background:</h3> BTK is a key node in B-cell receptor and Fc receptor signaling. BTKis are an emerging oral option for patients with multiple sclerosis (MS). Several covalent and reversible BTKis are in clinical development for the treatment of MS. For covalent enzyme inhibitors, in vitro assays are influenced by experimental conditions and are time dependent. <h3>Design/Methods:</h3> In vitro binding of covalent BTKis was assessed over time and concentration in human blood. Inhibition of B cells and basophils, including the impact of drug washout on B-cell inhibition, was assessed for covalent and reversible BTKis. Kinase selectivity was studied (first screened kinome wide, then using the dissociation constant for select kinases) via a binding assay to allow for the direct comparison of covalent and reversible BTKis. <h3>Results:</h3> Covalent inhibitors demonstrated time- and concentration-dependent BTK binding in human blood; the IC50 at 1 hour was 21 nM for remibrutinib, 508 nM for evobrutinib, 165 nM for tolebrutinib, and 427 nM for orelabrutinib. These values correlated with B-cell inhibition; the IC₅₀ was 18 nM for remibrutinib, 320 nM for evobrutinib, 74 nM for tolebrutinib, 185 nM for orelabrutinib, and 15 nM for fenebrutinib (reversible). Basophil inhibition potency was comparable. B-cell inhibition by remibrutinib (covalent) was not sensitive to washout, but B-cell inhibition by fenebrutinib was. Kinome selectivity screening at 1 μM showed the following ranking (from least to most off-target kinase binding): remibrutinib, fenebrutinib, evobrutinib, orelabrutinib, and tolebrutinib. A quantitative assessment of binding constants to a subset of kinases confirmed this ranking. <h3>Conclusions:</h3> BTKis undergoing development for MS exhibit varying selectivity across the human kinome, with the highest level of selectivity observed for remibrutinib. This distinction may translate into differences in clinical efficacy and safety. <b>Disclosure:</b> Bernd C. Kieseier, MD has nothing to disclose. Mr. Cenni has received personal compensation for serving as an employee of Novartis. Dr. Pulz has received personal compensation for serving as an employee of Novartis Pharma AG. Dr. Pulz has stock in Novartis Pharma AG. Dr. Angst has received personal compensation for serving as an employee of Novartis. Dr. Angst has stock in Novartis. Mr. Eichlisberger has nothing to disclose. Dr. Ziehn has received personal compensation for serving as an employee of Novartis AG.

Effect of Longer-term Ofatumumab Treatment on Disability Progression and Brain Volume Change (S16.009)

Effect of Longer-term Ofatumumab Treatment on Disability Progression and Brain Volume Change (S16.009)

Five-Year Safety of Ofatumumab in People Living With Relapsing Multiple Sclerosis (P8-3.004)

Five-Year Safety of Ofatumumab in People Living With Relapsing Multiple Sclerosis (P8-3.004)

JEWELFISH: 24-month Safety, Pharmacodynamic and Exploratory Efficacy Data in Non-Treatment-Naïve Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam (P7-9.004)

JEWELFISH: 24-month Safety, Pharmacodynamic and Exploratory Efficacy Data in Non-Treatment-Naïve Patients with Spinal Muscular Atrophy (SMA) Receiving Treatment with Risdiplam (P7-9.004)

Intravenous and Intrathecal Onasemnogene Abeparvovec Gene Therapy in Symptomatic and Presymptomatic Spinal Muscular Atrophy: Long-Term Follow-Up Study (S34.002)

Intravenous and Intrathecal Onasemnogene Abeparvovec Gene Therapy in Symptomatic and Presymptomatic Spinal Muscular Atrophy: Long-Term Follow-Up Study (S34.002)

Patterns and Predictors of Multiple Sclerosis Phenotype Transitions: A Longitudinal Analysis Using the CLIMB Study (P5-3.018)

Patterns and Predictors of Multiple Sclerosis Phenotype Transitions: A Longitudinal Analysis Using the CLIMB Study (P5-3.018)

Patient-identified most bothersome symptom as a driver of health-related quality of life experienced by patients with migraine (P8-12.010)

Patient-identified most bothersome symptom as a driver of health-related quality of life experienced by patients with migraine (P8-12.010)

Long-term Safety of Satralizumab in Adults with Aquaporin-4-IgG-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD): Results from SAkuraMoon (P13-5.002)

Long-term Safety of Satralizumab in Adults with Aquaporin-4-IgG-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD): Results from SAkuraMoon (P13-5.002)

Effect of Eptinezumab on Utility Scores in Patients with Migraine: Results from the DELIVER Study (P13-12.011)

Effect of Eptinezumab on Utility Scores in Patients with Migraine: Results from the DELIVER Study (P13-12.011)

Real-World Effectiveness of Fremanezumab in Patients with Migraine who Switched From Another mAb Targeting the CGRP Pathway (Subgroup Analysis From FINESSE) (P13-12.007)

Real-World Effectiveness of Fremanezumab in Patients with Migraine who Switched From Another mAb Targeting the CGRP Pathway (Subgroup Analysis From FINESSE) (P13-12.007)

Feasibility of a Home-Based Exergame Therapy for Youth with Spinal Muscular Atrophy (P7-9.005)

Feasibility of a Home-Based Exergame Therapy for Youth with Spinal Muscular Atrophy (P7-9.005)

Outcomes in Patients with Spinal Muscular Atrophy and Four or More SMN2 Copies Treated with Onasemnogene Abeparvovec: Findings from RESTORE (P7-9.007)

Outcomes in Patients with Spinal Muscular Atrophy and Four or More SMN2 Copies Treated with Onasemnogene Abeparvovec: Findings from RESTORE (P7-9.007)

Toward a Biomarker Panel measured in CNS-originating Extracellular Vesicles for Differential Diagnosis of Parkinson’s Disease and Multiple System Atrophy (S37.005)

Toward a Biomarker Panel measured in CNS-originating Extracellular Vesicles for Differential Diagnosis of Parkinson’s Disease and Multiple System Atrophy (S37.005)

Persistence to OnabotulinumtoxinA or Calcitonin Gene-Related Peptide Monoclonal Antibody Therapy Among Patients With Migraine: A Retrospective Cohort Study (P10-12.001)

<h3>Objective:</h3> To compare treatment persistency among patients with migraine on calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs; erenumab, fremanezumab, galcanezumab, or eptinezumab) or onabotulinumtoxinA. <h3>Background:</h3> To date, real-world evidence on persistence to CGRP mAbs or onabotulinumtoxinA have excluded eptinezumab. <h3>Design/Methods:</h3> This retrospective study used IQVIA PharmMetrics data. Adult patients with migraine treated with a CGRP mAb or onabotulinumtoxinA who had 12 months of continuous insurance enrollment before starting treatment were included. A “most recent treatment episode” analysis was used in which the most recent episode was defined as the latest treatment period with the same drug (CGRP mAb or onabotulinumtoxinA) without a 15-day gap in medication supply on/after 25June2020–31December2021. Patients were indexed at the start of their most recent episode. Patients were non-persistent and discontinued the therapy associated with their most recent episode if there was ≥15-day gap in medication supply. A Cox proportional-hazards model estimated the discontinuation hazard between treatments. The gap periods and cohort definition were varied in sensitivity analyses. <h3>Results:</h3> The study included 66,576 patients (median age 46 years, 88.6% female). More eptinezumab-treated patients had chronic migraine (727/1074), ≥3 previous uses of acute (323/1074) or preventive (333/1074) therapies, and more prior treatment episodes than other treatment groups (3 [Q1–Q3, 2–5]). Based on a 15-day treatment gap, patients on subcutaneous CGRP mAbs had 32% (95%CI: 1.185, 1.494; erenumab) to 58% (95%CI: 1.418, 1.796; fremanezumab) higher discontinuation hazard than those receiving eptinezumab, with this relationship attenuated but significant with 30-day and 60-day treatment gaps. There was no significant difference in the discontinuation hazard between eptinezumab and onabotulinumtoxinA. Based on a 15-day treatment gap among patients who newly initiated therapy, the discontinuation hazard of subcutaneous CGRP mAbs remained significantly higher compared to eptinezumab and onabotulinumtoxinA. <h3>Conclusions:</h3> Eptinezumab had similar persistency with treatment to onabotulinumtoxinA, which was higher than subcutaneous CGRP mAbs. <b>Disclosure:</b> Dr. Talon has nothing to disclose. Christine Sullivan has received personal compensation for serving as an employee of Lundbeck. Meghana Karnik-Henry has received personal compensation for serving as an employee of Lundbeck. Seema Soni-Brahmbhatt has nothing to disclose. Mr. Anderson has nothing to disclose. Steven Kymes has received personal compensation for serving as an employee of Lundbeck. Steven Kymes has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Journal of Ophthalmology. Steven Kymes has received research support from Emmes Corporation. Mr. Regnier has received personal compensation for serving as an employee of Lundbeck. Mr. Regnier has received personal compensation for serving as an employee of Novartis. Mr. Regnier has stock in Novartis.

Fremanezumab for Migraine Prevention: Interim Analysis of the Non-Interventional FINESSE Study (P13-12.010)

Fremanezumab for Migraine Prevention: Interim Analysis of the Non-Interventional FINESSE Study (P13-12.010)

Characterization of the Monoamine Oxidase-B (MAO-B) Expression in Postmortem Normal and Alzheimer’s Disease Brains (S39.006)

<h3>Objective:</h3> To characterize MAO-B expression in postmortem human control (CTRL) and Alzheimer’s disease (AD) brains. Specifically, we sought to: (1) Identify the cell type(s) expressing MAO-B; (2) Compare MAO-B immunoreactivity in CTRL vs. AD brains; (3) Correlate MAO-B levels with local measures of AD neuropathological changes, cortical thickness, and reactive glia; (4) Evaluate the impact of the <i>MAOB</i> rs1799836 SNP genotype on MAO-B immunoreactivity and all these other measures. <h3>Background:</h3> MAO-B has been proposed as a novel PET imaging biomarker of AD-associated reactive astrogliosis. However, a thorough characterization in postmortem CTRL and AD brains—including the impact of the <i>MAOB</i> rs1799836 SNP genotype, which may affect MAO-B enzymatic activity—is lacking. <h3>Design/Methods:</h3> We performed automated MAO-B immunohistochemistry on FFPE sections from multiple brain regions of CTRL and AD brain donors followed by whole-slide scan and quantification of cortical and white matter immunoreactivity using QuPath pixel classifier. <i>MAOB</i> rs1799836 SNP was genotyped in cerebellar DNA via Taqman assay. <h3>Results:</h3> We found that: (1) MAO-B is primarily expressed by cortical and white matter astrocytes; (2) MAO-B is elevated in AD vs. CTRL astrocytes uniformly across the temporal, frontal, and occipital cortex and white matter; (3) cortical MAO-B immunoreactivity correlates positively with the number of GFAP+ reactive astrocytes and CD68+ activated microglia, and negatively with cortical thickness, but not with Aβ plaque load or number of neurofibrillary tangles; (4) the <i>MAOB</i> rs1799836 SNP genotype does not affect MAO-B immunoreactivity, AD neuropathological changes, or reactive glia. <h3>Conclusions:</h3> Astrocytes are the main cellular source of MAO-B in the cerebral cortex. MAO-B levels are significantly increased in the AD cortex and parallel the number of GFAP+ reactive astrocytes. The <i>MAOB</i> rs1799836 SNP genotype does not impact any of these measures. MAO-B is a promising target for the development of PET imaging radiotracers of reactive astrogliosis. <b>Disclosure:</b> Dr. Jaisa-aad has nothing to disclose. Ms. Connors has nothing to disclose. An immediate family member of Dr. Hyman has received personal compensation for serving as an employee of novartis. Dr. Hyman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for dewpoint. Dr. Hyman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for abbvie. Dr. Hyman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Arvinas. Dr. Hyman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for avrobio. Dr. Hyman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Hyman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Dept of Justice. Dr. Hyman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cell Signalling. Dr. Hyman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sangamo. Dr. Hyman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for sanofi. Dr. Hyman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for vigil. Dr. Hyman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for voyager. Dr. Hyman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for biogen. Dr. Hyman has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for dept of justice. Dr. Hyman has stock in dewpoint. The institution of Dr. Hyman has received research support from nih. The institution of Dr. Hyman has received research support from JPB. The institution of Dr. Hyman has received research support from Cure Alz Fund. The institution of Dr. Hyman has received research support from Tau consortium. The institution of Dr. Hyman has received research support from abbvie. The institution of Dr. Hyman has received research support from BMS. Dr. Serrano-Pozo has received research support from NIH/NIA. Dr. Serrano-Pozo has received research support from Alzheimer’s Association. Dr. Serrano-Pozo has received research support from The Jack Satter Foundation. Dr. Serrano-Pozo has received research support from The Karen Toffler Charitable Trust. Dr. Serrano-Pozo has received research support from Ionis Pharmaceuticals, Inc. Dr. Serrano-Pozo has received research support from AbbVie, Inc..