Restoration of Nusinersen Levels Following Treatment Interruption in People With Spinal Muscular Atrophy: Simulations Based on a Population Pharmacokinetic Model.

BACKGROUND: Nusinersen is approved for the treatment of spinal muscular atrophy. The most common approved dosing regimen is four intrathecal loading doses of nusinersen 12 mg; the first three are administered at 14-day intervals followed by a fourth dose 30 days later, and then 12-mg maintenance doses are administered every 4 months thereafter. Interruption of nusinersen treatment in the maintenance dosing phase might occur for a number of clinical reasons. OBJECTIVE: The objective of this report is to describe dosing regimens that allow for the most rapid restoration of steady-state concentrations of nusinersen in the cerebrospinal fluid (CSF) following a treatment interruption during maintenance dosing. METHODS: Population pharmacokinetic models using integrated pharmacokinetic data from ten nusinersen clinical trials that included a broad range of participants with spinal muscular atrophy treated with intrathecal nusinersen were used to investigate different durations of treatment interruptions during maintenance treatment. Potential dosing regimens for re-initiation of nusinersen were evaluated, with the goal of achieving the quickest restoration of steady-state nusinersen CSF concentrations without exceeding maximal CSF exposures observed during the initial loading period. RESULTS: Our pharmacokinetic modeling indicates the following regimen will lead to optimal restoration of nusinersen CSF levels after treatment interruption: two doses of nusinersen should be administered at 14-day intervals following treatment interruptions of ≥ 8 to < 16 months since the last dose, and three doses of nusinersen at 14-day intervals for treatment interruptions of ≥ 16 to < 40 months since the last maintenance dose, with subsequent maintenance dosing every 4 months in both instances. After treatment interruptions of ≥ 40 months, the full loading regimen will rapidly restore nusinersen CSF levels. CONCLUSIONS: Prolonged treatment interruptions lead to suboptimal CSF levels of nusinersen. The optimal regimen to restore nusinersen CSF levels depends on the interval since the last maintenance dose was administered.

Nusinersen is a drug used to treat people of all ages who have spinal muscular atrophy. Nusinersen is injected with a thin needle into the lower back, a procedure known as a lumbar puncture. People initially receive three doses of nusinersen 12 mg each 14 days apart. They receive a fourth dose 1 month later, and then injections every 4 months (known as maintenance dosing). This treatment plan allows nusinersen to build up to effective levels in the fluid surrounding the spinal cord and brain. Some people may miss dose(s) or may stop nusinersen treatment at some point during maintenance dosing and then may want to continue treatment. This study used information from ten clinical trials to find out the best way to restart treatment to build up nusinersen to effective levels. People with a treatment break of ≥ 8 to < 16 months since the last dose need two doses of nusinersen at 14-day intervals before receiving maintenance dosing. People with a treatment break of ≥ 16 to < 40 months since the last dose need three doses of nusinersen at 14-day intervals before receiving maintenance dosing. If people stopped treatment for ≥ 40 months, they would need four doses before starting maintenance treatment. Results from this study showed that the number of doses that people needed before starting maintenance treatment depended on how long the treatment break was.

Targeting Huntingtin Expression in Patients with Huntington's Disease.

BACKGROUND: Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. METHODS: We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF. RESULTS: Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively). CONCLUSIONS: Intrathecal administration of HTTRx to patients with early Huntington's disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02519036.).

Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations.

Nusinersen is an antisense oligonucleotide intended for the treatment of spinal muscular atrophy. The pharmacokinetics of nusinersen, following intrathecal administrations, in the cerebrospinal fluid (CSF) and plasma of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across 5 clinical trials was analyzed via population-based modeling. With sparse data in the CSF and profile data in the plasma, a linear 4-compartment model simultaneously described the time-concentration profiles in both matrices. The typical population parameters were: Qp = 0.572 L/h, QCSF = 0.069 L/h, CLp = 2.50 L/h, CLCSF = 0.133 L/hr, VCSF = 0.441 L, Vp = 32.0 L, Vsystemic_tissue = 429 L, and VCNS_tissue = 258 L. A full covariate modeling approach identified baseline body weight to be a statistically and clinically relevant covariate on VCSF , Vp , and CLp . The model predicted that the CSF volume of distribution increased steadily with age from 0 to 2 years but became relatively steady for children >2 years. Simulations from the final model showed that age-based dosing in children under 2 years ensured a more comparable exposure (peak concentration and area under the concentration-time curve) across subjects in the population relative to a fixed dosing scheme. However, because no dose-limiting toxicity has been reported in any of the trials, a fixed-dose scheme (12 mg across all age groups) was recommended. The median terminal half-life of nusinersen in the CSF was determined from the model to be 163 days, which supported infrequent dosing, once every 4 to 6 months in pediatric patients with spinal muscular atrophy.

Detection of ß-amyloid oligomers as a predictor of neurological outcome after brain injury.

OBJECT: Traumatic brain injury (TBI) is known to be a risk factor for Alzheimer-like dementia. In previous studies, an increase in ß-amyloid (Aß) monomers, such as ß-amyloid 42 (Aß42), in the CSF of patients with TBI has been shown to correlate with a decrease in amyloid plaques in the brain and improved neurological outcomes. In this study, the authors hypothesized that the levels of toxic high-molecular-weight ß-amyloid oligomers are increased in the brain and are detectable within the CSF of TBI patients with poor neurological outcomes. METHODS: Samples of CSF were collected from 18 patients with severe TBI (Glasgow Coma Scale Scores 3-8) and a ventriculostomy. In all cases the CSF was collected within 72 hours of injury. The CSF levels of neuron-specific enolase (NSE) and Aß42 were measured using enzyme-linked immunosorbent assay. The levels of high-molecular-weight ß-amyloid oligomers were measured using Western blot analysis. RESULTS: Patients with good outcomes showed an increase in the levels of CSF Aß42 (p = 0.003). Those with bad outcomes exhibited an increase in CSF levels of ß-amyloid oligomers (p = 0.009) and NSE (p = 0.001). In addition, the CSF oligomer levels correlated with the scores on the extended Glasgow Outcome Scale (r = -0.89, p = 0.0001), disability rating scale scores (r = 0.77, p = 0.005), CSF Aß42 levels (r = -0.42, p = 0.12), and CSF NSE levels (r = 0.70, p = 0.004). Additionally, the receiver operating characteristic curve yielded an area under the curve for ß-amyloid oligomers of 0.8750 ± 0.09. CONCLUSIONS: Detection of ß-amyloid oligomers may someday become a useful clinical tool for determining injury severity and neurological outcomes in patients with TBI.

Gene targeting MRI: nucleic acid-based imaging and applications.

Gene action plays a role in neural cell migration, learning processes, stress response, drug addiction, cancer, mental health, psychiatric and neurological disorders, as well as neurodegenerative diseases. Studies also show that upregulation of certain gene activities in neurons may contribute to the development of Alzheimer's disease and other progressive cognitive disorders many decades after the alteration itself occurs. Endogenous, environmental stress-related, or drug-induced chemical imbalances in the brain affect the homeostasis of gene activities in neurons in specific brain regions and contribute to the comorbidity of mental illness and substance dependence. On the other hand, altered gene activities are also a necessary part of repair processes after brain injury. Our general well-being is governed by the highly regulated gene activities in our brains. A better understanding of gene activities and their relationship to the progression of neurological disease can help the research and medical communities develop necessary measures for early intervention, as well as plan more appropriate interventions or new therapeutic approaches that can benefit a broad spectrum of patients who will be or have been affected by brain diseases. We developed a non-invasive imaging technique that allows real-time assessment of gene transcription profiles in live brains. This imaging method has the potential to provide first-hand information about the progression of neurological disorders by gene targeting and cell typing, and it could elucidate a surrogate marker for therapeutic efficacy for future planning of treatments for human diseases. We have established a workable and reproducible MRI technique in live rodent brains.