Clinical Pharmacology & Therapeutics, Journal Year: 2022, Volume and Issue: 111(4), P. 715 - 717
Published: March 21, 2022
The theme of this issue Clinical Pharmacology & Therapeutics (CPT) encompasses neuroscience in the broad sense to include neurology and psychiatry, nonclinical clinical aspects, novel trial methodologies, modeling simulation approaches applicable central nervous system (CNS) drug development therapy. While naturally last two years have been dominated by coronavirus disease 2019 (COVID-19), it is important not forget that for other indications has stopped, albeit many trials were affected terms delays recruitment collection data. There are numerous rare ultrarare neurological diseases which very limited number patients, combined with lack reliable biomarkers targeted therapies, pose a real challenge traditional development, including appropriate dose-finding studies. Abuasal et al.1 discuss role regulatory flexibility approval new drugs give examples from US Food Drug Administration (FDA) scientific assessment conclusions based on relatively data set, using select optimal dose, extrapolation among populations, or pharmacodynamic biomarkers. authors also provide an optimistic outlook into future regarding expected quantitative systems pharmacology, artificial intelligence, machine learning, as well progression models real-world (Figure 1). Stephenson al.2 whether how innovative designs technologies, multiarm adaptive platform digital health tools monitor like Duchenne muscular dystrophy amyotrophic lateral sclerosis (ALS), can drive advancement treatments common Parkinson’s disease. At same time, excellent insight importance collaborative efforts: Novel platforms containing completed trials, registries, natural history studies, preclinical do only foster sharing but means connectivity sophisticated applications. frequently challenged extensive heterogeneity between patients their survival non-negligible dying during course trial, particularly rapidly progressive ALS. Van Eijk al.3 present overview commonly used strategies address death efficacy end points may implications interpretation study results. Exemplified ALS, review provides guidance define exact research question align its objectives design, analytical strategy handling death, ultimately aid planning analysis. Particularly diseases, initiatives forged advocates play emerging vital role. Romer al.4 moving perspective family-driven pediatric diseases. authors’ journey started months search reasons fact children stopped developing at pace children, followed devastating diagnoses fatal Tay-Sachs GM1 gangliosidosis. describe how—after converting initial anger urgency purpose—they managed mobilize substantial network resources, leading consortia scientists clinicians, gene therapy animal models, finally translation both Since first FDA 2017 voretigene neparvovec-rzyl (Luxturna), treat specific form retinal blindness, raising hopes treating genetic despite setbacks past. In State-of-the-Art article, Flotte Gessler5 cover basic principles, obstacles, directions disorders. diversity CNS disorders calls diverse therapeutic technological presented viral vector recombinant adeno-associated virus, nonviral platforms, oligonucleotide-based therapeutics, editing, cell therapies. Preclinical translational efforts up considerations illustrated different groups spinal atrophy (SMA), lysosomal storage Canavan disease, RPE65 mutation–associated dystrophy. Particular focus placed multiple challenges associated ranging eligible enrolment, safety concerns (particularly context immune responses), definition window, costs. Promising developments field comprise delivery routes beyond intravenous administration. For example, cerebrospinal fluid being evaluated setting onasemnogene abeparvovec (Zolgensma), product SMA. Efforts improve brain intensified recent increasingly available biologic modalities antibodies nucleic acid-based therapeutics (e.g., antisense oligonucleotides). Sadekar al.6 via access routes, e.g., intracerebroventricular, intrathecal-cisterna magna, intrathecal-lumbar, intraparenchymal, intranasal. already successful oligonucleotides (ASOs) delivered intrathecal route, nusinersen (Spinraza), ASO targeting motor-neuron 2 (SMN2) SMA whereas others tominersen (anti-HTT ASO) Huntington’s tofersen (anti-SOD1 ALS failed so far deliver pivotal promising exploratory results still under investigation. De Lange al.7 complement topic outlining blood-brain barrier transport intra-CNS distribution target sites, together methods influence delivery. Zhu al.8 explain rationale behind FDA’s accelerated use aducanumab, antibody against beta-amyloid (Aβ) early Alzheimer’s reduction Aβ plaque brain. By summarizing literature seven anti-Aβ investigated late-phase potential threshold effect. Kesselheim,9 one experts advising procedure, presents counterpart argument. He argues while amyloid marker usefulness surrogate measure never demonstrated, products reduce production, inhibit aggregation, promote disaggregation, increase clearance beta-amyloid. summary, various challenges, variety psychiatric demand pharmacology successfully translate discoveries effective treatments. This special-themed CPT brings extract wealth experimental, translational, diagnostic imaging), computational innovating effort develop treatment
Language: Английский
