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Background: No meta-analysis has holistically analyzed and summarized the safety and therapeutic efficacy of the newer RNA interference (RNAi) therapies, olezarsen, plozasiran, and zodasiran, in managing conditions associated with hypertriglyceridemia (HTG)., Methods: Randomized controlled trials (RCTs) involving patients with HTG or mixed hyperlipidemia (MHL) receiving either olezarsen, plozasiran, or zodasiran in the intervention arm and a placebo in the control arm were searched through electronic databases. The primary outcome was the safety profile of the drugs studied; secondary outcomes included the percent change from baseline (CFB) in the lipid levels, including triglyceride (TG)., Results: Six RCTs with 334 participants were evaluated. Olezarsen, plozasiran, and zodasiran were well-tolerated with no higher risk of serious adverse events or injection-site reactions. After 24 weeks, plozasiran increased alanine aminotransferase and HbA1c more than placebo, although the difference was insignificant at 48 weeks. Plozasiran and zodasiran had little effect on hyperglycemia worsening. Olezarsen increased the likelihood of mild platelet count decreases without clinical harm. At their longest clinical trial follow-up, the highest doses of olezarsen, plozasiran, and zodasiran lowered TG by 55.2%, 50.57%, and 51.2% of baseline levels. All three drugs decreased non-HDL-C and remnant cholesterol. Olezarsen and plozasiran lowered ApoC-III and increased HDL-C, whereas zodasiran reduced HDL-C. Zodasiran decreased LDL-C, whereas olezarsen and plozasiran had no effects on LDL-C. Plozasiran and zodasiran lowered apolipoprotein B, but not olezarsen., Conclusion: The newer RNA interference (RNAi) therapies appear safe and have excellent TG-lowering efficacy in patients with HTG and MHL., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Introduction/aims: Following the approval of risdiplam, there are more possibilities for disease-modifying therapy (DMT) in children with spinal muscular atrophy (SMA). Non-treatment-naïve subjects with SMA involved in the JEWELFISH study, designed to evaluate the safety and tolerability of risdiplam, were required to undergo a washout period before receiving risdiplam. This study aims to investigate the safety of administering risdiplam in patients within 90 days of receiving treatment with nusinersen., Methods: Data were collected on SMA patients who had undergone treatment with nusinersen, and who then received risdiplam within 90 days of their last dose of nusinersen, including demographic characteristics, information on treatment with nusinersen and risdiplam, adverse events, and laboratory assessments in a follow-up period of 90 days, presented as median (range)., Results: A total of 15 children with SMA were reported, including 8 males and 7 females. The median number of doses of previous nusinersen treatment received was 8 (6-17) doses, and the median age at first risdiplam treatment was 4.3 (1.9-11.2) years. Specifically, 8 children received risdiplam 30 days or less after their most recent nusinersen treatment, 2 at 31-60 days after nusinersen, and 5 at 61-89 days post-nusinersen. Adverse events of pyrexia, pneumonia, vomiting and rash were reported in 4 patients., Discussion: Our study showed good safety data on patients who received risdiplam following nusinersen within the washout period of 90 days. This supplements the JEWELFISH study in the era of DMT, providing additional guidance for clinicians, but additional data from other centers is needed., (© 2024 Wiley Periodicals LLC.)

Background: Nusinersen is the first drug for precise targeted therapy of spinal muscular atrophy, a rare disease that occurs in one of 10,000 to 20,000 live births. Therefore, thorough and comprehensive reports on the safety of nusinersen in large, real-world populations are necessary. This study aimed to mine the adverse event (AE) signals related to nusinersen through the Food and Drug Administration Adverse Event Reporting System (FAERS) database., Methods: We extracted reports of AEs with nusinersen as the primary suspect from FAERS between December 2016 and March 2023. Reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) were used for AE signal detection., Results: We extracted a total of 4807 suspected AE cases with nusinersen as the primary suspect from the FAERS database. Among them, 106 positive signals were obtained using the ROR and BCPNN. The highest frequency reported systemic organ class was general disorders and administration site conditions. Common clinical AEs of nusinersen were detected in the FAERS database, such as pneumonia, vomiting, back pain, headache, pyrexia, and post-lumbar puncture syndrome. In addition, we identified potential unexpected serious AEs through disproportionality analysis, including sepsis, seizure, epilepsy, brain injury, cardiorespiratory arrest, and cardiac arrest., Conclusions: Analyzing large amounts of real-world data from the FAERS database, we identified potential new AEs of nusinersen by disproportionate analysis. It is advantageous for health care professionals and pharmacists to concentrate on effectively managing high-risk AEs of nusinersen, improve medication levels in clinical settings, and uphold patient medication safety., Competing Interests: Declaration of competing interest The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Imetelstat (RYTELO™), an oligonucleotide telomerase inhibitor, is being developed by Geron Corporation for the treatment of myeloid hematologic malignancies. In June 2024, imetelstat was approved in the USA for use in adult patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring 4 or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESA). This article summarizes the milestones in the development of imetelstat leading to this first approval for the treatment of adult patients with low- to intermediate-1 risk MDS with transfusion-dependent anemia., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To evaluate the effectiveness and safety of nusinersen for the treatment of 5q-spinal muscular atrophy (SMA) among Chinese pediatric patients., Methods: Using a longitudinal, multi-center registry, both prospective and retrospective data were collected from pediatric patients with 5q-SMA receiving nusinersen treatment across 18 centers in China. All patients fulfilling the eligibility criteria were included consecutively. Motor function outcomes were assessed post-treatment by SMA type. Safety profile was evaluated among patients starting nusinersen treatment post-enrollment. Descriptive analyses were used to report baseline characteristics, effectiveness, and safety results., Results: As of March 2nd, 2023, 385 patients were included. Most patients demonstrated improvements or stability in motor function across all SMA types. Type II patients demonstrated mean changes [95% confidence interval (CI)] of 4.4 (3.4-5.4) and 4.1 (2.8-5.4) in Hammersmith Functional Motor Scale-Expanded (HFMSE), and 2.4 (1.7-3.1) and 2.3 (1.2-3.4) in Revised Upper Limb Module (RULM) scores at months 6 and 10. Type III patients exhibited mean changes (95% CI) of 3.9 (2.5-5.3) and 4.3 (2.6-6.0) in HFMSE, and 2.1 (1.2-3.0) and 1.5 (0.0-3.0) in RULM scores at months 6 and 10. Of the 132 patients, 62.9% experienced adverse events (AEs). Two patients experienced mild AEs (aseptic meningitis and myalgia) considered to be related to nusinersen by the investigator, with no sequelae., Conclusions: These data underscore the significance of nusinersen in Chinese pediatric patients with SMA regarding motor function improvement or stability, and support recommendations on nusinersen treatment by Chinese SMA guidelines and continuous coverage of nusinersen by basic medical insurance., (© 2024. The Author(s).)

This study aims to collect and analyze adverse event (AE) reports related to Nusinersen from the FAERS database. The study employed a combination of signal quantification techniques, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), to enhance the accuracy of signal detection and reduce the risk of false positives or negatives. Between the first quarter of 2017 and the third quarter of 2023, the FAERS database collected a total of 11,485,105 drug AE reports, of which 5772 were related to Nusinersen. Through signal mining analysis, 218 preferred term (PT) signals involving 27 system organ classes (SOCs) were identified. The study discovered AEs related to metabolism and nutrition disorders, psychiatric disorders, and cardiac disorders SOCs, which were not mentioned in the product information. Additionally, complications directly related to the intrathecal administration of Nusinersen, such as increased CSF pressure, positive CSF red blood cell count, and AEs related to the method of drug use, such as neuromuscular scoliosis and cerebrospinal fluid reservoir placement, were highlighted. Notably, AEs related to renal function abnormalities, such as abnormal Urine protein/creatinine ratio and protein urine presence, showed higher frequency and signal strength. The findings of this study emphasize the importance of comprehensive safety monitoring in the clinical application of Nusinersen. These results are significant for guiding future clinical practices, improving disease management strategies, and developing safer treatment protocols., (© 2024. The Author(s).)

Objectives: To investigate the efficacy and safety of nusinersen sodium in the treatment of children with spinal muscular atrophy (SMA)., Methods: A retrospective analysis was conducted on the clinical data of 50 children with 5q SMA who received nusinersen sodium treatment and multidisciplinary treatment management in Shanxi Children's Hospital from February 2022 to February 2024., Results: Compared with the baseline data, 67% (8/12), 74% (35/47), and 74% (35/47) of the SMA children had a clinically significant improvement in the scores of Philadelphia Infant Test of Neuromuscular Disorders, Hammersmith Functional Motor Scale Expanded, and Revised Upper Limb Module, respectively, and the distance of 6-minute walking test increased from 207.00 (179.00, 281.50) meters to 233.00 (205.25, 287.50) meters ( P <0.05) after nusinersen sodium treatment. Of all 50 children with SMA, 24 (48%) showed good tolerability after administration, with no significant or persistent abnormalities observed in 2 034 laboratory test results, and furthermore, there were no serious or immunological adverse events related to the treatment. After treatment, there was a significant change in forced vital capacity as a percentage of the predicted value in 27 children with restrictive ventilatory dysfunction, as well as a significant change in the level of 25-(OH) vitamin D in 15 children with vitamin D deficiency ( P <0.05)., Conclusions: For children with SMA, treatment with nusinersen sodium can continuously improve the response rates of motor function scales, with good tolerability and safety.

Oligonucleotide therapeutics (ONTs) represent a new modality with unique pharmacological and chemical properties that modulate gene expression with a high degree of target specificity mediated by complementary Watson-Crick base pair hybridization. To date, the proarrhythmic assessment of ONTs has been influenced by International Conference on Harmonization (ICH) E14 and S7B guidance. To document current hERG/QTc evaluation practices, we reviewed US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Approval Packages (source: PharmaPendium.com) and collated preclinical and clinical studies for 17 marketed ONTs. In addition, clinical QTc data from 12 investigational ONTs were obtained from the literature. Of the marketed ONTs, eight were tested in the hERG assay with no inhibitory effect identified at the top concentration (range: 34-3,000 μM) tested. Fourteen of the ONTs were evaluated in nonhuman primate cardiovascular studies with 11 of them in dedicated telemetry studies. No effect on QTc intervals were observed (at high exposure multiples) in all studies. Clinically, four ONTs were evaluated in TQT studies; an additional six ONTs were assessed by concentration-QTc interval analysis, and six by routine safety electrocardiogram monitoring. None of the clinical studies identified a QTc prolongation risk; the same was true for the 12 investigational ONTs. A search of the FDA Adverse Event Database indicated no association between approved ONTs and proarrhythmias. Overall, the collective weight of evidence from 29 ONTs demonstrate no clinical proarrhythmic risk based on data obtained from ICH S7B/E14 studies. Thus, new ONTs may benefit from reduced testing strategies because they have no proarrhythmic risk, a similar cardiac safety profile as monoclonal antibodies, proteins, and peptides., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: This study was based on a retrospective clinical observational cohort study of a two-center application of nusinersen in China to evaluate the clinical efficacy and adverse effects of nusinersen in the treatment of SMA (spinal muscular atrophy) Types 1-3., Methods: Clinical data from children with clinically and genetically confirmed 5qSMA from a double center in western China (the Second Affiliated Hospital of Xi'an Jiaotong University and the Second Hospital of West China of Sichuan University). All children were younger than 18 years of age. Patients were assessed for motor function and underwent blood and fluid tests before each nusinersen injection., Results: At 14-month follow-up, 100% of children had improved their HFMSE (Hammersmith Functional Motor Scale Expanded) score, 83.6% had improved their CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) score, and 66.6% had improved their RULM (Revised Upper Limb Module) score by ≥3 points from baseline, and their 6MWT (6-min walk test) was 216.00 ± 52.08 m longer than at baseline. The age of the child at the start of treatment was negatively correlated with the clinical efficacy of nusinersen; the younger the child, the better the response to treatment. No significant adverse effects affecting the treatment and quality of life of the child were observed during the treatment of SMA with nusinersen., Conclusion: This study concluded that nusinersen is clinically beneficial for children with SMA in western China, with mild adverse effects., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Introduction: Spinal muscular atrophy (SMA) is a rare, autosomal recessive, neuromuscular disease that leads to progressive muscular weakness and atrophy. Nusinersen, an antisense oligonucleotide, was approved for SMA in China in February 2019. We report interim results from a post-marketing surveillance phase 4 study, PANDA (NCT04419233), that collects data on the safety, efficacy, and pharmacokinetics of nusinersen in children with SMA in routine clinical practice in China., Methods: Participants enrolled in PANDA will be observed for 2 years following nusinersen treatment initiation. The primary endpoint is the incidence of adverse events (AEs)/serious AEs (SAEs) during the treatment period. Efficacy assessments include World Health Organization (WHO) Motor Milestones assessment, the Hammersmith Infant Neurological Examination (HINE), and ventilation support. Plasma and cerebrospinal fluid (CSF) concentrations of nusinersen are measured at each dose visit., Results: Fifty participants were enrolled as of the January 4, 2023, data cutoff: 10 with infantile-onset (≤ 6 months) and 40 with later-onset (> 6 months) SMA. All 50 participants have received at least one dose of nusinersen; 6 have completed the study. AEs were experienced by 45 (90%) participants and were mostly mild/moderate; no AEs led to nusinersen discontinuation or study withdrawal. Eleven participants experienced SAEs, most commonly pneumonia (n = 9); none were considered related to study treatment. Stability or gain of WHO motor milestone was observed and mean HINE-2 scores improved in both subgroups throughout the study. No serious respiratory events occurred, and no permanent ventilation support was initiated during the study. Pre-dose nusinersen CSF concentrations increased steadily through the loading-dose period, with no accumulation in plasma after multiple doses., Conclusion: Nusinersen was generally well tolerated with an acceptable overall safety profile, consistent with the known safety of nusinersen. Efficacy, safety, and nusinersen exposure are consistent with prior observations. These results support continuing PANDA and evaluation of nusinersen in Chinese participants with SMA., Trial Registration: ClinicalTrials.gov identifier, NCT04419233., (© 2024. The Author(s).)

Objective: This systematic review provides an update on outcomes for patients with spinal muscular atrophy (SMA) type 1 to 4 treated with approved therapeutics, including the most recent, risdiplam, for an observation period of up to 48 months., Methods: A systematic literature search was conducted in July 2023 in four databases. Selected publications were assessed for internal validity and risk of bias by two authors and relevant data were extracted into standardised tables. Results were summarised narratively as substantial heterogeneity of studies prevents meaningful quantitative analysis., Results: Twenty observational studies and one RCT were included in the analysis, fifteen studies on nusinersen, one on onasemnogene abeparvovec and two on risdiplam. Evidence supports the effectiveness of the therapies in motor function improvement for up to 48 months of follow-up in the SMA types specified in their respective indications. Better results were observed with earlier treatment initiation and higher baseline function. Whilst motor improvement was consistently observed, regardless of SMA type or treatment used, we noted no significant improvements in respiratory and nutritional outcomes. Quality of life endpoints were rarely investigated. Adverse events were common but seldom classified as treatment-related except for post-lumbar puncture syndrome, which was frequently reported across nusinersen studies., Conclusion: The treatment of SMA with the new therapies changes the disease phenotype with changes in motor function far exceeding any improvement in respiratory and nutritional function. Questions persist on long-term efficacy, potential regressions, impact on quality of life and social functioning, therapy duration, and discontinuation indicators., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients with kidney failure on hemodialysis (KF-HD) are at high risk for both atherothrombotic events and bleeding. This Phase IIb study evaluated the dose-response of fesomersen, an inhibitor of hepatic Factor XI expression, versus placebo, for bleeding and atherothrombosis in patients with KF-HD. Patients were randomized to receive fesomersen 40, 80, or 120 mg once-monthly, or matching placebo, for up to 12 months. The primary safety endpoint was a composite of major bleeding and clinically relevant non-major bleeding (MB/CRNMB). Exploratory endpoints included post-dialysis arterio-venous (AV)-access bleeding, major atherothrombotic events (composite of fatal or non-fatal myocardial infarction, ischemic stroke, acute limb ischemia/major amputation, systemic embolism, symptomatic venous thromboembolism), AV-access thrombosis, and clotting of the hemodialysis circuit. Of 308 participants randomized, 307 received study treatment and were analyzed. Fesomersen led to a dose-dependent and sustained reduction of steady-state median FXI levels by 53.6% (40 mg group), 71.3% (80 mg group), 86.0% (120 mg group), versus 1.9% in the placebo group. MB/CRNMB events occurred in 6.5% (40 mg group), 5.1% (80 mg group), 3.9% (120 mg group), and in 4.0% of those receiving placebo (pooled fesomersen versus placebo P = 0.78). Major atherothrombotic events occurred in 1 patient (1.3%) in each treatment arm. MB/CRNMB bleeding and post-dialysis AV-access bleeding were not related to predicted FXI levels. Lower predicted FXI levels were associated with reductions in hemodialysis circuit clotting (P = 0.002) and AV-access thrombosis (P = 0.014). In patients with KF-HD, fesomersen produced a dose-dependent reduction in FXI levels associated with similar rates of major bleeding compared with placebo. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT04534114., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Vupanorsen is a GalNAc 3 -conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia., Objectives: The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG)., Methods: In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80 mg or 160 mg. PK parameters, PD markers (including ANGPTL3, TG, non-high-density lipoprotein cholesterol [non-HDL-C]), and safety were assessed., Results: Absorption of vupanorsen was rapid (median time to maximum concentration [T max ]: 2.0 h for both doses), followed by a multiphasic decline (mean terminal half-life 475.9 [80 mg] and 465.2 h [160 mg]). Exposure (area under curve [AUC] and maximum plasma concentration [C max ]) generally increased in a greater than dose-proportional manner from 80 mg to 160 mg. Time-dependent reductions in ANGPTL3 and lipid parameters were observed. Mean percentage change from baseline for the 80-mg and 160-mg doses, respectively, were - 59.7% and - 69.5% for ANGPTL3, - 41.9% and - 52.5% for TG, and - 23.2% and - 25.4% for non-HDL-C. No serious or severe adverse events (AEs), deaths, or discontinuations due to AEs were reported. Three participants experienced treatment-related AEs; all were mild and resolved by end of study., Conclusions: This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted., Trial Registration: ClinicalTrials.gov identifier: NCT04916795., (© 2024. The Author(s).)

Purpose: Nusinersen is an antisense oligonucleotide for the treatment of spinal muscular atrophy (SMA). A post-marketing surveillance (PMS) has been ongoing (August 2017-August 2025) in all patients in Japan who received intrathecal nusinersen in real-world clinical settings. We report the interim analysis results of safety and effectiveness. Methods: This interim analysis was conducted using data collected from 401 patients whose case report forms were obtained at least once by 30 May 2020. Collected data included patient demographics and adverse events (AEs) for safety, and motor function assessments and Clinical Global Impressions of Improvement (CGI-I) for effectiveness. Results: All 401 patients were diagnosed with SMA and were included in the safety and effectiveness analysis (infantile-onset SMA [ n  = 126, 31.4%], later-onset SMA [ n  = 275, 68.6%]). The median duration of treatment was 330 days (range 1-823 days). The incidence proportion of AEs was 31.7% (37.3% in infantile-onset SMA and 29.1% in later-onset SMA). The most common AEs were headache (4.5%), pyrexia (4.2%), and pneumonia (3.7%). The incidence proportion of serious AEs was 11.5%. Nusinersen improved motor function scores and was assessed as 'effective' based on CGI-I in 99.7-100% of patients. Conclusions: This interim analysis of the PMS in Japanese patients treated with nusinersen found no new safety concerns, with the type of AEs consistent with the expected safety profile. The benefit-risk balance of nusinersen treatment remains favorable.

Introduction: Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disease characterized by a loss of motor neurons and progressive muscle weakness. Children with untreated type 1 SMA never sit independently and require increasing levels of ventilatory support as the disease progresses. Without intervention, and lacking ventilatory support, death typically occurs before the age of 2 years. There are currently no head-to-head trials comparing available treatments in SMA. Indirect treatment comparisons are therefore needed to provide information on the relative efficacy and safety of SMA treatments for healthcare decision-making., Methods: The long-term efficacy and safety of risdiplam versus nusinersen in children with type 1 SMA was evaluated using indirect treatment comparison methodology to adjust for differences between population baseline characteristics, to reduce any potential bias in the comparative analysis. An unanchored matching-adjusted indirect comparison was conducted using risdiplam data from 58 children in FIREFISH (NCT02913482) and published aggregate nusinersen data from 81 children obtained from the ENDEAR (NCT02193074) and SHINE (NCT02594124) clinical trials with at least 36 months of follow-up., Results: Children with type 1 SMA treated with risdiplam had a 78% reduction in the rate of death, an 81% reduction in the rate of death or permanent ventilation, and a 57% reduction in the rate of serious adverse events compared with children treated with nusinersen. Children treated with risdiplam also had a 45% higher rate of achieving a Hammersmith Infant Neurological Examination, Module 2 motor milestone response and a 186% higher rate of achieving a ≥ 4-point improvement in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders compared with children treated with nusinersen., Conclusion: Long-term data supported risdiplam as a superior alternative to nusinersen in children with type 1 SMA. Video abstract available for this article. Video abstract (MP4 184542 KB)., (© 2024. The Author(s).)

Background: Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering., Methods: In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol., Results: A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups., Conclusions: In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III., Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis., Results: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group., Conclusions: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.)., (Copyright © 2024 Massachusetts Medical Society.)

Background and Aims: Carbohydrate sulfotransferase 15 [CHST15] biosynthesizes sulphated matrix glycosaminoglycans and is implicated in intestinal inflammation and fibrosis. Here, we evaluate the efficacy and safety of the double-stranded RNA oligonucleotide GUT-1, a specific blocker of CHST15, as induction therapy in patients with ulcerative colitis [UC]., Methods: In this randomized, double-blind, placebo-controlled, phase 2a study, we enrolled endoscopically active UC patients, refractory to conventional therapy, in five hospital centres across Germany. Patients were randomized 1:1:1 using a block randomized technique to receive a single dosing of 25 nM GUT-1, 250 nM GUT-1, or placebo by endoscopic submucosal injections. The primary outcome measure was improvement of endoscopic lesions at weeks 2 or 4. The secondary outcome measures included clinical and histological responses. Safety was assessed in all patients who received treatment., Results: Twenty-eight patients were screened, 24 were randomized, and 21 were evaluated. Endoscopic improvement at weeks 2 or 4 was achieved by 71.4% in the GUT-1 250 nM, 0% in the GUT-1 25 nM, and 28.6% in the placebo group. Clinical remission was shown by 57.1% in the GUT-1 250 nM, 0% in the GUT-1 25 nM, and 14.3% in the placebo groups. Histological improvement was shown by 42.9% in the GUT-1 250 nM, 0% in the GUT-1 25 nM, and 0% in the placebo groups. GUT-1 250 nM reduced CHST15 expression significantly and suppressed mucosal inflammation and fibrosis. GUT-1 application was well tolerated., Conclusion: Single dosing by submucosal injection of GUT-1 repressed CHST15 mucosal expression and may represent a novel induction therapy by modulating tissue remodelling in UC., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Nusinersen is the first disease-modifying therapy to treat spinal muscular atrophy (SMA). This report describes the safety and effectiveness of nusinersen in Japanese clinical use using two data sources: an ongoing Japanese post-marketing surveillance (PMS) and the safety database of the marketing authorisation holder, Biogen ., Materials and Methods: The PMS is evaluating the safety and effectiveness of nusinersen in all patients treated with nusinersen in Japan between August 2017 and August 2025; this interim analysis included data up to May 30, 2019. Biogen safety database data up to June 30, 2019 were also included to capture adverse events (AEs) from after the interim analysis cutoff date. Collected data included medical history, dosage and administration, and AEs. Safety assessment included AEs and serious AEs (SAEs). Effectiveness analyses included motor function assessments and clinical global impressions of improvement., Results: Of 271 patients in the PMS population, 94 had SMA type I (34.7%), and 177 had SMA types II-IV (65.3%). AEs occurred in 67 patients (24.7%) and SAEs in 23 patients (8.5%). The Biogen safety database contained reports of 345 AEs; the most common were pneumonia, headache, and pyrexia, consistent with symptoms of SMA and lumbar puncture. In the analysis set, 26.2% of patients receiving nusinersen showed motor function improvements and 99.6-100.0% showed overall improvement., Conclusion: In this interim analysis of the PMS and Biogen safety database, nusinersen had a favourable benefit-risk profile in Japanese patients with SMA.

Background: Spinal muscular atrophy (SMA) is a severe neuromuscular disorder, the phenotype of the disease is caused by the mutation of the SMN1 (survival motor neuron 1) gene which encodes for the SMN protein. Innovative treatments for SMA have become available and the first molecule approved is Nusinersen, an antisense oligonucleotide that increases the production of SMN protein. Nusinersen has been shown to be associated with a significant motor improvement and an increase of the event-free survival. For these reasons the aim of the present study is to assess if Nusinersen is able modify sleep architecture and microstructure and to improve sleep structure in these patients., Methods: Sixteen patients affected by SMA1 were enrolled in the study (4 boys, 12 girls; median age 72.5 months, intelligence quotient range 24-84). All patients underwent complete nocturnal PSG before the start of the treatment trough intrathecal injections with Nusinersen (T0) and after the fifth infusion (day 180, T180). PSG recordings were visually scored and interpreted according to the indications of the American Academy of Sleep Medicine (AASM) and and microstructure by means of the Cyclic Alternating Pattern (CAP)., Results: After 6 months therapy we found a significantly reduced sleep latency and a significantly increased sleep efficiency. Regarding sleep microstructure parameters (CAP), we did not find any significant change after therapy however, it is worth mentioning that a moderate effect size was observed for the increase in CAP A3 index., Conclusions: We observed short-term effects of Nusinersen on sleep with an improvement in sleep efficiency and reduction in sleep onset latency; regarding sleep microstructure, a moderate effect size was found for the number of CAP A3 subtypes that slightly increased, possibly indicating a slightly higher arousability. This finding points at a probably overall better sleep pattern organization associated with the treatment, but they need to be confirmed by larger studies with patients treated earlier in life and for a longer period., Competing Interests: Declaration of competing interest Authors declare none., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Familial chylomicronemia syndrome (FCS) is a rare, autosomal recessive genetic disorder characterized by a marked increase in plasma triglyceride (TG) levels and recurrent episodes of pancreatitis. The response to conventional TG-lowering therapies is suboptimal. Volanesorsen, an antisense oligonucleotide that targets hepatic apoC-III mRNA, has been shown to significantly reduce TGs in patients with FCS., Objective: To further evaluate the safety and efficacy of extended treatment with volanesorsen in patients with FCS., Methods: This phase 3 open-label extension study evaluated the efficacy and safety of extended treatment with volanesorsen in three groups of patients with FCS: Those who had previously received volanesorsen or placebo in the APPROACH and COMPASS studies, and treatment-naive patients not participating in either study. Key endpoints included change in fasting TG and other lipid measurements, and safety over 52 weeks., Results: Volanesorsen treatment resulted in sustained reductions in plasma TG levels in previously treated patients from the APPROACH and COMPASS studies. Volanesorsen-treated patients from the three populations studied had mean decreases in fasting plasma TGs from index study baseline to months 3, 6, 12 and 24 as follows: decreases of 48%, 55%, 50%, and 50%, respectively (APPROACH); decreases of 65%, 43%, 42%, and 66%, respectively (COMPASS); and decreases of 60%, 51%, 47%, and 46%, respectively (treatment-naive). Common adverse events were injection site reactions and platelet count decrease, consistent with previous studies., Conclusion: Extended open-label treatment with volanesorsen in patients with FCS resulted in sustained reductions of plasma TG levels and safety consistent with the index studies., Competing Interests: Declaration of Competing Interest JLW is a consultant to Ionis Pharmaceuticals and ST is an employee of Ionis Pharmaceuticals. JLW and ST are co-inventors and receive royalties from patents owned by the University of California, San Diego on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins. They are co-founders and have an equity interest in Oxitope, Inc and its affiliates (“Oxitope”) as well as in Kleanthi Diagnostics, LLC (“Kleanthi”). Although these relationships have been identified for conflict of interest management based on the overall scope of the project and its potential benefit to Oxitope and Kleanthi, the research findings included in this particular publication may not necessarily relate to the interests of Oxitope and Kleanthi. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. DG reports grants and personal fees from Ionis Pharmaceuticals during the conduct of the study; grants and personal fees from Allergan, Amgen, Amryt, Arrowhead, Eli Lilly, Novartis, NovoNordisk, Regeneron, and Sanofi outside the submitted work; grants from Acasti, Aegerion, Applied Therapeutics, AstraZeneca, Boehringer-Ingelheim, Ceapro, Dalcor, Esperion, Kowa, The Medicine Company, and Uniqure outside the submitted work; and personal fees from CRISPR Therapeutics, Saliogen, and Verve Therapeutics outside the submitted work. MA has received research grant support and lecturing fees from Alfasigma, Amgen, Amryt, Daiichi Sankyo, Ionis/Akcea, Novartis, Pfizer, Regeneron, and Sanofi. AJ has provided services to the following companies: Akcea, Amgen, Sanofi, and SOBI. HS received research and education grants and honoraria from Akcea Therapeutics, Alexion, Amryt, Synageva, Kowa, MSD, NAPP, Novartis, Pfizer, Sanofi, Synageva, and Takeda. IG-B has received personal honoraria from Aegerion, Akcea, Amarin, Amgen, Daiichi Sankyo, Novartis, Regeneron, and Sanofi; and nonfinancial support from Akcea, Amgen, and Sanofi. ESGS has received advisory board/lecturing fees, paid to institution, from: Amgen, Sanofi, NovoNordisk, AstraZeneca, Esperion, Daiichi-Sankyo, and Ionis/Akcea. No patents/stocks. VJA, LW, and SX are employees of Ionis Pharmaceuticals. RJ was an employee of Akcea Therapeutics at the time of the study and manuscript development and may own stock in Ionis Pharmaceuticals, parent company of Akcea Therapeutics., (Copyright © 2023 National Lipid Association. All rights reserved.)

Background: Inotersen is an antisense oligonucleotide used to treat hereditary transthyretin amyloidosis (ATTRv). The most common drug-related adverse effects (AEs) include thrombocytopenia and glomerulonephritis. Hepatic damage is rare, but liver enzyme monitoring is mandatory., Case Report: A 70-year-old man with ATTRv (Val30Met) treated with inotersen developed a severe increase of transaminases, with normal bilirubin and cholinesterase levels, that forced us to stop therapy. At the same time, other causes of acquired hepatitis were excluded, and the hypothesis of an inotersen-related hepatic toxicity was supported by the normalization of liver enzymes after 40 days from the drug interruption., Discussion: Our case showed that 1-year inotersen treatment can stabilize neurological impairment and even improve quality of life and suggests to carefully monitor liver enzymes in order to avoid an inotersen-related hepatic dysfunction., (© 2022. Fondazione Società Italiana di Neurologia.)

Objectives: This study aimed to evaluate the potential budget impact of nusinersen in the treatment of spinal muscular atrophy (SMA) from the perspective of the basic medical insurance payer in China., Methods: A budget impact analysis model was developed according to ISPOR budget impact analysis guidelines; we integrated health resource consumption, epidemiology, and market data for the treatment of patients with SMA in China, to estimate the impact of nusinersen on basic medical insurance. The microcosting method was conducted to evaluate the treatment cost. One-way sensitivity analysis was performed to explore the stability of the results., Results: If nusinersen could be reimbursed, the impact on the medical insurance funds in the next 1 to 3 years will be 253 million, 333 million, and 426 million, respectively. In addition, it can reduce 0.73 million, 2.17 million, and 2.22 million in complication costs, respectively., Conclusions: SMA is a rare disease with a very low prevalence; reimbursement of nusinersen will lead to a limited impact on the basic medical insurance and improve the accessibility of treatment., (Copyright © 2022 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Objectives: Thrombocytopenia is a condition that causes a low amount of blood platelets. Platelets are blood cells that play an essential role in blood coagulation. Therefore, thrombocytopenia can put the patient at risk for mild to severe bleeding. Thrombocytopenia is caused by a decrease in platelet production in the bone marrow or by a drug or immune system problem when production is normal. In particular, in some ASO-induced thrombocytopenia, the mechanism is not clear. Therefore, whole genome sequencing (WGS) was performed to discover genetic differences that affect thrombocytopenia and individual susceptibility to drugs between normal and reduced platelet monkeys despite administering the same ASO., Data Description: Three antisense oligonucleotide (ASO) substances were injected into the subcutaneous tissue of monkeys for 12 weeks in two experiments. The monkeys were classified into three groups: monkeys with thrombocytopenia, monkeys without thrombocytopenia, and control monkeys not treated with ASO substances. Whole genome sequencing data was generated using liver tissues of monkeys. These data will be useful for identifying genetic differences that affect thrombocytopenia and drug sensitivity., (© 2023. The Author(s).)

Introduction: Fibrotic lung diseases represent a large subset of diseases with an unmet clinical need. Oligonucleotide therapies (ONT) are a promising therapeutic approach for the treatment of pulmonary disease as they can inhibit pathways that are otherwise difficult to target. Additionally, targeting the lung specifically with ONT is advantageous because it reduces the possibilities of systemic side effects and tolerability concerns., Areas Covered: This review presents the chemical basis of designing various ONTs currently known to treat fibrotic lung diseases. Further, the authors have also discussed the delivery vehicle, routes of administration, physiological barriers of the lung, and toxicity concerns with ONTs., Expert Opinion: ONTs provide a promising therapeutic approach for the treatment of fibrotic diseases of the lung, particularly because ONTs directly delivered to the lung show little systemic side effects compared to current therapeutic strategies. Dry powder aerosolized inhalers may be a good strategy for getting ONTs into the lung in humans. However, as of now, no dry powder ONTs have been approved for use in the clinical setting, and this challenge must be overcome for future therapies. Various delivery methods that can aid in direct targeting may also improve the use of ONTs for lung fibrotic diseases.

Background: Pharmacokinetic/pharmacodynamic modeling indicates that the higher dose of nusinersen may be associated with a clinically meaningful increase in efficacy above that seen with the 12-mg approved dose., Objective: Here we describe both the design of DEVOTE (NCT04089566), a 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A., Methods: DEVOTE Part A evaluates safety and tolerability of a higher nusinersen dose; Part B assesses efficacy in a randomized, double-blind design; and Part C assesses safety and tolerability of participants transitioning from the 12-mg dose to higher doses., Results: In the completed Part A of DEVOTE, all 6 enrolled participants aged 6.1-12.6 years have completed the study. Four participants experienced treatment-emergent adverse events (TEAEs), the majority of which were mild. Common TEAEs of headache, pain, chills, vomiting, and paresthesia were considered related to the lumbar puncture procedure. There were no safety concerns regarding clinical or laboratory parameters. Nusinersen levels in the cerebrospinal fluid were within the range of modeled predictions for higher dose of nusinersen. While Part A was not designed for assessing efficacy, most participants showed stabilization or improvement in motor function. Parts B and C of DEVOTE are ongoing., Conclusions: The findings from Part A of the DEVOTE study support further development of higher dose of nusinersen.

Background: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of > 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS])., Objective: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD., Methods: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to < 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed., Results: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study., Conclusions: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping.

Background: Hereditary transthyretin amyloidosis (hATTR/ATTRv) results from the deposition of misfolded transthyretin (TTR) throughout the body, including peripheral nerves. Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3 years., Methods: Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score + 7 (mNIS + 7), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9 months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004., Results: In the Europe and North America cohort of the NEURO-TTR study, 113/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen-inotersen) and 39 switched from placebo to inotersen (placebo-inotersen). The placebo-inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS + 7, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen-inotersen group demonstrated sustained benefit, as measured by mNIS + 7, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo-inotersen group. With a maximum exposure of 6.2 years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study., Conclusion: Inotersen treatment for > 3 years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed., (© 2022. The Author(s).)

Aims: Transthyretin-mediated amyloidosis is a progressive and fatal disease caused by the build-up of misfolded transthyretin (TTR) protein. Eplontersen is a triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotide targeting TTR messenger ribonucleic acid (mRNA) to inhibit production of both variant and wild-type TTR. We aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for eplontersen and to evaluate the impact of covariates on exposure and response., Methods: Plasma eplontersen and serum TTR concentration data were obtained from two phase 1 studies in healthy volunteers (ClinicalTrials.gov: NCT03728634, NCT04302064). Model development was conducted using a nonlinear mixed-effects approach., Results: Eplontersen PK was well described by a two-compartment model. Evaluation of demographics identified significant covariates of lean body mass on clearance and body weight on intercompartmental clearance and volumes of distribution. Population PK modelling showed the absorption rate was 29.6% greater with injection into the abdomen versus the arm. The typical population terminal elimination half-life was 25.5 days. Serum TTR was well described by an indirect response model with inhibition of TTR production by eplontersen. Maximum fractional inhibition (I max ) was 0.970 (0.549%RSE) and the half maximal inhibitory concentration (IC 50 ) was 0.0283 ng/ml (13.3%RSE). Simulations showed subjects with lower weight had higher exposure (AUC, C max ), while higher C max was observed when comparing site of administration (ratio abdomen/arm = 1.18), but differences in exposure did not significantly impact response at evaluated doses., Conclusion: The exposure-response relationship of eplontersen was well characterised by the PKPD model. Weight and injection site were found to affect systemic exposure, but this effect does not seem to result in clinically relevant variation in response., (© 2022 British Pharmacological Society.)

Background and Purpose: The aim was to assess the safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients., Methods: Patients older than 15 years and followed for at least 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb Module, RULM) in five referral centers were included. The clinical and patients' global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percentage predicted forced vital capacity were collected when available., Results: Seventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points (±0.46) in RULM (p &lt; 0.001) after 6 months. After a mean follow-up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (odds ratio [OR] 1.15, p = 0.006), the 6-min walk test (OR = 1.07, p &lt; 0.001) and the EK2 (OR = 0.81, p = 0.001). Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p = 0.033), ALSFRS-R (p = 0.005) and EK2 (p &lt; 0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being a non-sitter was associated with less response to treatment, whilst a longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild., Conclusions: Nusinersen treatment is associated with some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: We evaluated the effect of nusinersen on clinical and laboratory parameters and presented its safety and effect on laboratory parameters., Methods: Two groups were formed from among patients with spinal muscular atrophy (SMA) followed up between September 2017 and June 2021: group 1, SMA type 1; group 2, SMA type 2 and 3. The laboratory parameters were evaluated in groups 1 and 2 between doses. Motor scale tests were performed on patients before each dose of nusinersen., Results: Twenty seven patients (group 1; n  = 13, group 2; n  = 14) were included. The mean age (±standard deviation) at the onset of symptoms was 3 ± 1.21 (range, 1.5-6) months in group 1 and 12 ± 4.27 (range, 8-24) months in group 2. No significant laboratory treatment-related abnormalities and adverse effects were observed. The cerebrospinal fluid protein levels and the frequency of conventional LP were higher in group 1. Serum creatinine (Cr) levels were higher in group 1 before the first dose and higher in group 2 before the fifth dose ( p  < 0.05). With treatment, the Cr levels of group 1 decreased and group 2 remained constant or increased. We observed that the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and Hammersmith Functional Motor Scale-Expand scores increased as our patients received treatment ( p  < 0.05)., Conclusion: Our results support the safety and efficacy of nusinersen. However, changes in Cr levels according to the clinical type and treatment suggested that serum Cr could be a candidate marker for treatment follow-up., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction/aims: Patients undergoing nusinersen treatment for spinal muscular atrophy are subject to measurements of platelet count and urine protein before each injection due to concern for platelet depletion and renal dysfunction according to the prescribing information. These tests may be uncomfortable or inconvenient and may cause delays in treatment. However, it is still unclear whether these values have been significantly affected by nusinersen treatment. Our aim in this study was to determine whether these measurements ever reached critical values that necessitated withholding treatment at our center., Methods: Records from 57 patients treated with nusinersen at our institution between 2017 and 2020 were retrospectively analyzed. Laboratory values for platelet count, random urine protein, and total urine protein:creatinine ratio were collected from all patients before each procedure., Results: Mean patient age was 28.9 years (range, 2-76 years). Mean platelet count was 307 × 10 9 /L (range, 96-755 × 10 9 /L; normal lab limits, 150-450 × 10 9 /L), mean random urine protein was 0.164 g/L (range, <0.05-0.73 g/L), and mean total urine protein:creatinine ratio was 0.885 g per gram creatinine (range, 0.12-9.71 g per gram creatinine). No laboratory values precluded continuing treatment for any patient., Discussion: Although further study on a larger cohort is warranted for more definitive conclusions, it may not be necessary to measure platelet count and urine protein before each nusinersen treatment, particularly in the maintenance phase., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder with limited treatment options. Nusinersen is the first disease-modifying therapy to treat children and adults with SMA. This study aimed to review the safety, tolerability, and efficacy data of a nusinersen treatment program in Polish children. A total of 298 patients aged from 0 to 18 years were included in the nusinersen treatment program in Poland between March 1 and September 20, 2019. All patients were prospectively followed for at least one year. The mean age at treatment onset was 6.9 years. SMA type 1 symptoms were reported in 127 patients (43.5%), SMA type 2 symptoms in 68 cases (23.3%), and SMA type 3 in 93 patients (31.8%). No patient met the inefficiency criteria defined in the program. One year after treatment initiation, all patients assessed by the CHOP-INTEND scale had improved or remained stable. The mean change in CHOP-INTEND score was an increase of 8.9 points between baseline and after one-year treatment (p < 0.001). Except for 2 fatal cases, not related to the treatment, no serious adverse events were reported. The results of our study indicate that treatment with nusinersen is beneficial for children with SMA regardless of their age, baseline functional status, or the number of SMN2 gene copies. Therapy with nusinersen was effective and well tolerated by patients., (© 2022 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Hereditary transthyretin amyloidosis (hATTR) is an ultra-rare illness. Inotersen is a 2'-O-methoxyethyl (2'MOE)-modified antisense oligonucleotides (ASO) approved in 2018 as a polyneuropathy treatment for adults with hereditary transthyretin amyloidosis stages 1 or 2. Inotersen can produce grade 4 thrombocytopenia as a severe adverse reaction that can lead to potentially fatal hemorrhage complications. We describe our experience in the management of severe thrombocytopenia with inotersen. The onset of the thrombocytopenia and the incidences described in the cases in our hospital are different from that described in the literature. Also, recovery of platelet levels was faster in our patient who was administered human immunoglobulin G, which suggests that there is an immunological component.

We appreciate Ahmed Sami Aljabali and his colleagues for their interest and comments [...].

We read with interest the article by Abbas et al. [...].

The effectiveness of nusinersen treatment in patients with spinal muscular atrophy (SMA) was established in clinical trials only for pediatric patients. Few cohort studies confirmed its benefit in adults up to 22 months of treatment. We report a longer-term observation of nusinersen treatment effects and safety in a large cohort of adult patients. Patients with SMA type 2 and 3 treated with nusinersen at Tel-Aviv Medical Center between March 2018 and September 2020 were prospectively recruited. Neurological impairment, motor, respiratory function, and side effects were recorded. We compared baseline measurements with those after 6, 14, and 26 months of treatment and calculated the annual rates of change. Overall, 37 patients were treated (21-64 years old). 16 completed 26 months, and 8 completed 30 months of treatment. The median score on the Medical Research Council strength scale increased from baseline to visits at 6 and 14 months (p ≤ 0.03), but not afterwards, with a median increase of 1.85 points per year. Revised Hammersmith Scale median score increased only from baseline to 6 months (p = 0.02), with a calculated annual rate of change of 0 points. No significant change was noticed in the respiratory function. The only side effect was post lumbar puncture headache. In conclusion, our study further supports the efficacy and safety of nusinersen treatment in adult patients with SMA2 and SMA3, with modest improvement in muscle strength, and stabilization of motor function over a relatively long period of observation., Competing Interests: Declaration of Competing Interest YF, VED, and SBS received speaker fees form Biogen and Roche. None of the other authors have any conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The market for large molecule biologic drugs has grown rapidly, including antisense oligonucleotide (ASO) drugs. ASO drugs work as single-stranded synthetic oligonucleotides that reduce production or alter functions of disease-causing proteins through various mechanisms, such as mRNA degradation, exon skipping, and ASO-protein interactions. Since the first ASO drug, fomivirsen, was approved in 1998, the U.S. Food and Drug Administration (FDA) has approved 10 ASO drugs to date. Although ASO drugs are efficacious in treating some diseases that are untargetable by small-molecule chemical drugs, concerns on adverse drug reactions (ADRs) and toxicity cannot be ignored. Illustrative of this, mipomersen was recently taken off the market due to its hepatotoxicity risk. This paper reviews ADRs and toxicity from FDA drug labeling, preclinical studies, clinical trials, and postmarketing real-world studies on the 10 FDA-approved ASO drugs, including fomivirsen and pegaptanib, mipomersen, nusinersen, inotersen, defibrotide, eteplirsen, golodirsen, viltolarsen, and casimersen. Unique and common ADRs and toxicity for each ASO drug are summarized here. The risk of developing hepatotoxicity, kidney toxicity, and hypersensitivity reactions co-exists for multiple ASO drugs. Special precautions need to be in place when certain ASO drugs are administrated. Further discussion is extended on studying the mechanisms of ADRs and toxicity of these drugs, evaluating the existing physiologic and pathologic states of patients, optimizing the dose and route of administration, and formulating personalized treatment plans to improve the clinical utility of FDA-approved ASO drugs and discovery and development of new ASO drugs with reduced ADRs. SIGNIFICANCE STATEMENT: The current review provides a comprehensive analysis of unique and common ADRs and the toxicity of FDA-approved ASO drugs. The information can help better manage the risk of severe hepatotoxicity, kidney toxicity, and hypersensitivity reactions in the usage of currently approved ASO drugs and the discovery and development of new and safer ASO drugs., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: Familial celiac disease syndrome (FCS) is a form of hypertriglyceridemia (HTG) caused by the accumulation of celiac particles. Currently, volanesorsen is considered to be used to treat patients with FCS and HTG to improve symptoms. To evaluate the effect of volanesorsen on lipid metabolism in patients with FCS, we performed a systematic evaluation and meta-analysis., Methods: A systematic search of PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library was conducted, and the bibliographies of original articles were checked manually. The quality of the studies was assessed using the Cochrane Risk of Bias tool., Results: Four randomized, controlled trials involving 246 patients were analyzed in this study. Patients treated with volanesorsen showed (MD = -78.85%; 95% CI = -96.04 to -61.65, P = 0.67, I 2  = 0%) decrease in TG and (MD = -80.08%; 95% CI = -90.02 to -71.54, P = 0.25, I 2  = 29%) decrease in ApoC-III levels compared to patients in the placebo group showing a significant decrease. In addition, HDL-C increased (MD = 46.01% 95% CI = 41.03 to 50.99, P = 0.41, I 2  = 0%), NHDL-C decreased (MD = -32.12%; 95% CI = -44.39 to -19.85, P = 0.11, I 2  = 55%), VLDL-C decreased (MD = -65.88%; 95% CI = -83.97 to -47.79, P = 0.71, I 2  = 0%), apo A1 increased (MD = 13.12%; 95% CI = 7.83 to 18.40, P = 0.72, I 2  = 0%), and apoB increased (MD = 7.94 %; 95% CI = -1.90 to 17.78, P = 0.54, I 2  = 0%) all suggest that volanesorsen has an overall FCS with a therapeutic effect. However, LDL-C increased (MD = 99.59%; 95% CI = 69.19 to 130.00, P = 0.61, I 2  = 0%) and apo B48 decreased (MD = 82.89%; 95% CI = -100.88 to -64.91, P = 0.42, I 2  = 0%), showing an inverse effect, suggesting that volanesorsen's did not target all proteins of lipid metabolism., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Emergence of new treatments for spinal muscular atrophy type 1 (SMA1) has led to dramatic improvements in respiratory failure and survival. However, these "treated" patients sustain major problems in other organ systems, which may directly or indirectly affect their respiratory function. We observed three main nonrespiratory manifestations in these patients comprised of facial deformities, feeding problems, and spinal deformities., Objective: To investigate these three main sequelae in nusinersen-treated SMA1 patients., Methods: Data on nusinersen-treated SMA1 patients were prospectively collected throughout a 3-year period, with special focus upon nonrespiratory features of the disease., Results: Twenty nusinersen-treated SMA1 patients were included (eight males, median age 13.5 months, interquartile range: 4-56.2 months), among whom 17 survived after 3 years of follow-up. At follow-up, 15 (88%) patients were diagnosed with facial weakness, hypoplasia, or deformity. All but one patient (94%) were fed invasively by percutaneous endoscopic gastrostomy or nasogastric tube feeding. Four patients (25%) had maintained oral feeding in parallel to gastrostomy feeding and had clinical and radiologic evidence of aspirations. Fifteen (88%) patients were diagnosed with scoliosis, of whom seven had undergone or were scheduled to undergo corrective surgery., Conclusions: Nusinersen-treated SMA1 patients may sustain facial deformities, feeding problems, and severe scoliosis, all of which affect their respiratory system. Strict surveillance of these complications is essential to avoid further respiratory morbidity., (© 2021 Wiley Periodicals LLC.)

Background and objectives : Spinal muscular atrophy (SMA) is a neurodegenerative disease that leads to progressive proximal muscle weakness and muscle atrophy. To assess the beneficial and adverse effects of nusinersen, a promising intervention for SMA, we conducted a systematic search and meta-analysis of the published randomized control trials (RCTs) of nusinersen for SMA. Materials and methods : Utilizing the Preferred Reporting for Systematic Review and Meta-Analysis (PRISMA), we searched PubMed, Scopus, Web of Science, Cochrane Central, and Clinicaltrials.gov from inception to 22 July 2021. Results : Three RCTs satisfying the inclusion and exclusion criteria covered 274 patients: 178 patients in the nusinersen group. Our results show a significant risk difference (RD) in the motor milestone response (RD: 0.51; 95% CI: 0.39, 0.62; p < 0.00001) and improvement in the HINE-2 score (RD: 0.26; 95% CI: 0.12, 0.40; p < 0.0003) in the nusinersen group compared to the control group. Moreover, a significant decrease in the risk ratio (RR) for severe adverse events (RR: 0.72; 95% CI: 0.57, 0.92; p = 0.007) and any adverse event leading to treatment discontinuation (RR: 0.40; 95% CI: 0.22, 0.74; p = 0.004) was observed. An insignificant result was found for any adverse effects (RR: 0.93; 95% CI: 0.97, 1.01; p = 0.14) and for serious adverse effects (RR: 0.81; 95% CI: 0.60, 1.07; p = 0.14). Conclusions : This review provides evidence that nusinersen treatment was effective in treatment for infants with SMA and was associated with fewer severe adverse events; however, more RCTs are needed to establish evidence.

Background: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups., Methods: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity., Findings: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8-59·0, IQR 9-23) and a mean weight of 9·1 kg (range 4·0-15·0, IQR 7·4-10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9-19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings., Interpretation: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored., Funding: None., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests No author received financial support for the present manuscript. CW declares consulting fees from Novartis and Biogen (paid personally) and Roche (paid to institution); honoraria from Novartis and Biogen; and travel support from Biogen. AZ declares grants and travel support from Biogen; consulting fees and honoraria from Novartis, Roche, and Biogen; and advisory board participation for Novartis and Roche. JJ declares honoraria for review writing from Biogen; and travel support and personal fees for advisory board participation from Biogen, Roche, Novartis/Avexis, Sarepta Therapeutics, and PTC. GS declares payment for consulting from Novartis. MF-B declares consulting fees from Novartis Gene Therapy, Biogen, and Roche. CS declares training support from Biogen. HH declares support from the SMArtCARE registry (paid to institution) and payment for participation on advisory board from Novartis; and is a board member of the International Child Neurology Association. SI declares support from SMArtCARE (paid to institution) and payments for advisory board participation from Novartis. AP declares financial support from Biogen for the SMArtCARE registry; compensation for training activities from Biogen; and advisory board participation for Novartis Gene Therapy. WM-F declares consulting fees and honoraria from Novartis and Roche; honoraria from Biogen; and advisory board participation for Novartis and Roche. KV declares speaker's honoraria from Biogen and travel fees from Biogen and Santhera. AB declares speaker's honoraria from Biogen and Genzyme; travel support from Merck group; and advisory board participation for Novartis. MS declares payments for lectures from Novartis, Biogen, and Genzyme. BW declares honoraria for lectures, interviews, and workshops from Novartis, Biogen, and Pfizer; travel support for meetings from Novartis and Biogen; and advisory board participation for Novartis and Biogen. BP declares support for advisory board participation from Novartis, Biogen, Roche, Zogenix, and PCT; payment for manuscript writing from Novartis; and payment for workshop from Biogen. GB declares consulting fee from PTC; honoraria for lectures and information events; payment for participation on advisory boards from PTC, Roche, Novartis, Pfizer, and Biogen; and being an unpaid consultant for Wiener Gesundheitsverbund (WiGeV), Austrian Social Insurance, and Austrian Department of Pharmaceutical Affairs. RAF declares consulting fees, payment for lecture, and travel support from Biogen; and payment for advisory board participation from AveXis/Novartis. CR declares consulting fees from Biogen, EISAI, Novartis, PTC, Roche, and UCB; and payment for participation on advisory boards from Biogen, Novartis, and Roche. MvdH declares payment for lecture from Avexis/Novartis, Biogen, and PTC; payment for manuscript writing from Biogen; and advisory board participation for Avexis/Novartis, Biogen, Roche, and Sarepta. AMK declares grants from the German Research Foundation; consulting fees from Covance; payment for lecture from Ethypharm; and advisory board participation from Novartis, GW Pharma, and Ethypharm. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused by mutations in the DMD gene resulting in an absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes in viltolarsen treated patients were compared to a matched historical control group., Objective: To evaluate long-term efficacy and safety of the anti-sense oligonucleotide viltolarsen in the treatment of patients with DMD amenable to exon 53 skipping therapy., Methods: This trial (NCT03167255) is the extension of a previously published 24-week trial in North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety., Results: Time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations., Conclusions: Based on these results at over 2 years, viltolarsen can be a new treatment option for patients with DMD amenable to exon 53 skipping.

During the last decade, therapeutic oligonucleotide drugs (OND) have witnessed a tremendous development in chemistry and mechanistic understanding that have translated into successful clinical applications. Depending on the specific OND mechanism, chemistry, and design, the DMPK and toxicity properties can vary significantly between different OND classes and delivery approaches, the latter including lipid formulations or conjugation approaches to enhance productive OND uptake. At the same time, with the only difference between compounds being the nucleobase sequence, ONDs with same mechanism of action, chemistry, and design show relatively consistent behavior, allowing certain extrapolations between compounds within an OND class. This chapter provides a summary of the most common toxicities, the improved mechanistic understanding and the safety assessment activities performed for therapeutic oligonucleotides during the drug discovery and development process. Several of the considerations described for therapeutic applications should also be of value for the scientists mainly using oligonucleotides as research tools to explore various biological processes., (© 2022. The Author(s).)

In the MYF2001 trial, treatment of Janus kinase (JAK) inhibitor-relapsed/refractory intermediate-2 or high-risk myelofibrosis (MF) with imetelstat 9.4 mg/kg every 3 weeks demonstrated encouraging median overall survival of 29.9 months. To provide historical context, external real-world data (RWD) were collected from a study of 96 patients who had discontinued ruxolitinib and were subsequently treated with best available therapy (BAT) at Moffitt Cancer Center. A closely matched cohort was identified using the MYF2001 eligibility criteria, including patients with MF who had discontinued ruxolitinib due to lack or loss of response. Overall survival was measured from time of JAK inhibitor discontinuation to death or censored at last follow-up. To improve comparability, propensity score weighting approaches using average treatment effect for overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) were used for 10 critical baseline covariates. Fifty-seven patients treated with imetelstat 9.4 mg/kg from MYF2001 and 38 patients treated with BAT from RWD were analyzed with improved balanced baseline covariates after propensity score adjustment, showing significantly lower risk of death with imetelstat compared with BAT (hazard ratio: 0.35; p = 0.0019). With sIPTW, results were similar. Results of sensitivity analyses were consistent with the primary analysis. In conclusion, treatment with imetelstat was associated with longer overall survival compared to BAT (30 vs 12 months, respectively) in closely matched patients with MF after JAK inhibitor failure, warranting further evaluation of imetelstat in this poor-prognosis patient population., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086)., Patients and Methods: Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenous once every 3 weeks. Spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score) rates at week 24 were coprimary end points. Secondary end points included OS and safety., Results: Study enrollment was closed early, and patients treated with 4.7 mg/kg were permitted to continue treatment with 9.4 mg/kg. At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg arm and 0% and 6.3% in the 4.7-mg/kg arm. Treatment with imetelstat 9.4 mg/kg led to a median OS of 29.9 months and bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. Fibrosis improvement and variant allele frequency reduction correlated with OS. Target inhibition was demonstrated by reduction of telomerase activity and human telomerase reverse transcriptase level and correlated with spleen response, symptom response, and OS. Most common adverse events on both arms were grade 3 or 4 reversible cytopenias., Conclusion: In this phase II study of two imetelstat doses, 9.4 mg/kg once every 3 weeks demonstrated clinical benefits in symptom response rate, with an acceptable safety profile for this poor-risk JAKi R/R population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway., Competing Interests: John MascarenhasConsulting or Advisory Role: Incyte, Geron, Celgene/Bristol Myers Squibb, Novartis, CTI BioPharma Corp, Kartos Therapeutics, Constellation Pharmaceuticals, Sierra Oncology, AbbVie, Roche/GenentechResearch Funding: Incyte, Pharmaessentia, Merck, Forbius, Geron, AbbVie, Kartos Therapeutics, Roche/Genentech, CTI BioPharma Corp Rami KomrokjiStock and Other Ownership Interests: AbbVieConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Jazz Pharmaceuticals, AbbVie, Geron, Acceleron PharmaSpeakers' Bureau: Jazz Pharmaceuticals, Bristol Myers Squibb, AgiosTravel, Accommodations, Expenses: Jazz Pharmaceuticals, Bristol Myers Squibb, Agios Dietger NiederwieserConsulting or Advisory Role: Cellectis, Amgen, NovartisSpeakers' Bureau: NovartisResearch Funding: Daiichi Sankyo Andreas ReiterHonoraria: Novartis, Blueprint Medicines, Incyte, Celgene/Bristol Myers Squibb, AOP Orphan PharmaceuticalsConsulting or Advisory Role: Novartis, Blueprint Medicines, Incyte, Celgene/Bristol Myers Squibb, AOP Orphan PharmaceuticalsResearch Funding: Blueprint Medicines, Deciphera, Novartis, Incyte, AOP Orphan PharmaceuticalsExpert Testimony: NovartisTravel, Accommodations, Expenses: Novartis, Deciphera, Blueprint Medicines, Incyte Bart ScottHonoraria: Bristol Myers SquibbConsulting or Advisory Role: Celgene, Acceleron Pharma, Astex Pharmaceuticals, NovartisSpeakers' Bureau: Alexion Pharmaceuticals, Celgene, Jazz Pharmaceuticals, NovartisResearch Funding: Celgene Maria BaerResearch Funding: AbbVie, AI Therapeutics, FORMA Therapeutics, Kite, a Gilead company, Oscotec, Takeda Ronald HoffmanConsulting or Advisory Role: Protagonist Therapeutics, NovartisResearch Funding: Novartis, Scholar Rock, Turning Point Therapeutics Olatoyosi OdenikeConsulting or Advisory Role: AbbVie, Impact Biomedicines, Celgene, Novartis, BMS, Taiho PharmaceuticalResearch Funding: Celgene, Incyte, Astex Pharmaceuticals, NS Pharma, AbbVie, Janssen Oncology, OncoTherapy Science, Agios, AstraZeneca, CTI BioPharma Corp, Kartos Therapeutics, Aprea AB Alessandro VannucchiConsulting or Advisory Role: Novartis, AbbVie, Roche, Incyte, CelgeneSpeakers' Bureau: Novartis, AOP Orphan Pharmaceuticals, Incyte, Roche, Celgene Jacqueline BussolariEmployment: Johnson & Johnson, Bristol Myers Squibb, HotSpot TherapeuticsLeadership: HotSpot TherapeuticsStock and Other Ownership Interests: Johnson & Johnson, Bristol Myers Squibb, HotSpot TherapeuticsTravel, Accommodations, Expenses: Johnson & Johnson Eugene ZhuEmployment: Johnson & JohnsonStock and Other Ownership Interests: Johnson & Johnson Esther RoseEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & JohnsonConsulting or Advisory Role: Geron CorpTravel, Accommodations, Expenses: Janssen Research & Development Laurie ShermanEmployment: Geron, JanssenStock and Other Ownership Interests: Janssen, Geron Souria DoughertyEmployment: GeronStock and Other Ownership Interests: Geron Libo SunEmployment: GeronStock and Other Ownership Interests: Geron, Johnson & Johnson, Moderna TherapeuticsTravel, Accommodations, Expenses: Geron Fei HuangStock and Other Ownership Interests: Bristol Myers Squibb, Geron, Johnson & Johnson Ying WanEmployment: GeronStock and Other Ownership Interests: Geron Faye FellerEmployment: Geron, JanssenStock and Other Ownership Interests: Geron, JanssenTravel, Accommodations, Expenses: Geron, Janssen Aleksandra RizoLeadership: GeronStock and Other Ownership Interests: Geron, Johnson & Johnson Jean-Jacques KiladjianConsulting or Advisory Role: Novartis, Incyte, BMS, AOP Orphan Pharmaceuticals, AbbVie, PharmaessentiaNo other potential conflicts of interest were reported.