Summary Background Nusinersen is a 2′- O -methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing ...of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. Methods This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy. Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous gene deletion or mutation. Safety assessments included adverse events, physical and neurological examinations, vital signs, clinical laboratory tests, cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy assessments included event free survival, and change from baseline of two assessments of motor function: the motor milestones portion of the Hammersmith Infant Neurological Exam—Part 2 (HINE-2) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function test, and compound motor action potentials. Autopsy tissue was analysed for target engagement, drug concentrations, and pharmacological activity. HINE-2, CHOP-INTEND, and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test. Age at death or permanent ventilation was compared with natural history using the log-rank test. The study is registered at ClinicalTrials.gov , number NCT01839656. Findings 20 participants were enrolled between May 3, 2013, and July 9, 2014, and assessed through to an interim analysis done on Jan 26, 2016. All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor function scores (p=0·0013), and increased compound muscle action potential amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series (p=0·0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord. Interpretation Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability, pharmacology consistent with its intended mechanism of action, and encouraging clinical efficacy. Results informed the design of an ongoing, sham-controlled, phase 3 clinical study of nusinersen in infantile-onset spinal muscular atrophy. Funding Ionis Pharmaceuticals, Inc and Biogen.
Antisense oligonucleotide (ASO) drugs are an emerging class of therapeutics that have recently demonstrated progress and promise to treat diseases of the central nervous system (CNS). ASOs for a ...variety of targets and mechanisms are currently being investigated in clinical trials and pre-clinically for a number of CNS diseases. This review examines the available data regarding central ASO delivery, distribution, pharmacokinetics, pharmacodynamics and therapeutic opportunities.
This article is part of the Special Issue entitled “Beyond small molecules for neurological disorders”.
•Antisense oligonucleotides (ASOs) are an emerging class of therapeutics to treat diseases of the central nervous system.•ASOs for a variety of targets and mechanisms are currently being investigated for a number of CNS diseases.•To date, five ASO therapeutics have entered clinical development.•These include nusinersen for Spinal Muscular Atrophy, which recently reported positive results in two Phase 3 studies.•This review examines central ASO delivery, distribution, pharmacokinetics, pharmacodynamics and therapeutic opportunities.
Neurotology disorders such as vertigo, tinnitus, and hearing loss affect a significant proportion of the population (estimated 39 million in the United States with moderate to severe symptoms). Yet ...no pharmacological treatments have been developed, in part due to limitations in effective drug delivery to the anatomically protected inner ear compartment. Intratympanic delivery, a minimally invasive injection performed in the office setting, offers a potential direct route of administration. Currently, off-label use of therapeutics approved to treat disorders via systemic administration are being injected intratympanically, mostly in the form of aqueous solutions, but provide variable levels of drug exposure for a limited time requiring repeated injections. Hence, current drug delivery approaches for neurotology disorders are sub-optimal. This review, following a description of pharmacokinetic considerations of the inner ear, explores the merits of novel delivery approaches toward the treatment of neurotology disorders. Methodologies employing local delivery to the inner ear are described, including direct intracochlear delivery as well as intratympanic methods of infusion and injection. Intratympanic injection delivery formulation strategies including hydrogels, polymers and nanoparticulate systems are explored. These approaches represent progress toward more effective delivery options for the clinical treatment of a variety of neurotology disorders.
Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, ...and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study ( https://clinicaltrials.gov identifier NCT04181723 ), females with Rett syndrome received twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was -4.9 versus -1.7 (P = 0.0175; Cohen's d effect size, 0.37), and LSM Clinical Global Impression-Improvement at week 12 was 3.5 versus 3.8 (P = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist Social Composite score was -0.1 versus -1.1 (P = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome.
To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 ...mRNA, in patients with childhood spinal muscular atrophy (SMA).
Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory.
A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study.
Results from this study support continued development of nusinersen for treatment of SMA.
This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.
Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with ...spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post–lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture–related adverse event frequency was similar to that previously reported in children.
ABSTRACT
Introduction: In this study we examined the feasibility of assessing motor milestone performance of infants with spinal muscular atrophy (SMA) using the Hammersmith Infant Neurological ...Exam—Part 2 (HINE‐2) in a phase 2 study of nusinersen. Methods: Nineteen SMA infants were assessed using the HINE‐2 at baseline (≤7 months of age), and periodically up to 39 months of age. We evaluated whether the HINE‐2 was feasible, reliable, and sensitive to change. Results: Motor milestone assessments in SMA infants were feasible using the HINE‐2. Baseline test–retest reliability was excellent (R = 0.987; P < 0.0001). SMA infants were extremely low functioning at baseline and the HINE‐2 was able to detect changes over time in 16 of 19 infants within all 8 domains. HINE‐2 improvements were correlated with changes in other neuromuscular outcome measures. Conclusion: Results support the use of the HINE‐2 motor milestone assessment in clinical trials of SMA infants. Muscle Nerve 57: 143–146, 2017
Summary Background Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 ...delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1 -related familial amyotrophic lateral sclerosis. Methods In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11·5 h at increasing doses (0·15 mg, 0·50 mg, 1·50 mg, 3·00 mg) to four cohorts of eight patients with SOD1 -positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov , number NCT01041222. Findings Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 38% vs 8/24 33%), back pain (4/8 50% vs 4/24 17%), and nausea (0/8 0% vs 3/24 13%). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated. Interpretation This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders. Funding The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.
To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).
Analyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first ...received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2-15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196-413 days). Assessments included the Hammersmith Functional Motor Scale-Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed.
Twenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events.
Nusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III.
NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).
This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.
Introduction
Trofinetide was recently approved for the treatment of Rett syndrome (RTT) on the basis of the efficacy and safety findings of the phase 3 LAVENDER study, which used a body weight-based ...dosing regimen. Exposure–response (E–R) efficacy modeling was used to characterize relationships between trofinetide exposure measures (maximum drug concentration and area under the concentration–time curve for the dosing interval of 0–12 h AUC
0–12
) and efficacy endpoints in RTT clinical studies to support the trofinetide dosing regimen.
Methods
Efficacy endpoints were modeled using trofinetide exposure measures predicted from the population pharmacokinetic model and Bayesian estimates. The analysis population for each E–R model comprised individuals receiving placebo or trofinetide who had available trofinetide exposure measures. Efficacy endpoints were scores from the Rett Syndrome Behaviour Questionnaire (RSBQ), the Clinical Global Impression–Improvement, the Communication and Symbolic Behavior Scales Developmental Profile™ Infant–Toddler Checklist (CSBS-DP-IT) Social Composite, and the Rett Syndrome Clinician Rating of Ability to Communicate Choices (RTT-COMC).
Results
Higher trofinetide exposure was associated with improvements in RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Assuming target trofinetide AUC
0–12
values of 800–1200 μg·h/mL, the reductions in RSBQ total scores at week 12 were approximately five- to seven-fold greater with trofinetide (range 3.55–4.94) versus placebo (0.76). Significant E–R relationships were also found for the CSBS-DP-IT Social Composite and RTT-COMC scores.
Conclusion
E–R efficacy modeling demonstrated significant relationships between trofinetide exposure and RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Trofinetide is efficacious within the target exposure range, supporting the approved dosing regimen for trofinetide.
Trial Registration
NCT01703533, NCT02715115, NCT04181723.
Plain Language Summary
Trofinetide is the first approved treatment for people living with Rett syndrome, a rare genetic condition affecting brain development. This approval was based on the findings of clinical studies in which trofinetide showed significant improvements in the symptoms of Rett syndrome. In this study researchers were looking to see if the level of trofinetide in the blood was related to the level of improvement in symptoms observed in clinical studies. Information on the effectiveness of trofinetide was obtained from the phase 3 LAVENDER study which used doses of trofinetide according to body weight. Trofinetide’s effectiveness was assessed on the basis of clinical measurements of key Rett syndrome symptoms. All the information on trofinetide dose, blood levels, and how much symptoms changed (i.e., effectiveness of trofinetide) was then used to develop models to predict symptom responses in the observed population. Researchers found that as the blood levels of trofinetide increased the symptom improvement also increased. When the blood levels were at the recommended level that was achieved in the LAVENDER study, the model predicted that symptom improvement was up to seven times greater with trofinetide than having no treatment (i.e., placebo). This study shows a positive relationship between trofinetide blood levels and improvement in the symptoms of Rett syndrome. Trofinetide was effective within the recommended blood level range in the LAVENDER study using the approved weight-based dosing.
PDF
