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- W4387391987 abstract "ABSTRACTIntroduction SPL84 is an inhaled antisense oligonucleotide (ASO) in development for the treatment of cystic fibrosis (CF) patients carrying the 3849 + 10kb C->T (3849) mutation. To support initiation of the first proof of concept clinical study, a full battery of safety and toxicology studies were performed.Research design and methods SPL84 was administered by inhalation to mice and monkeys, to determine the no observed adverse effect level (NOAEL) and establish sufficient safety margins for the starting clinical doseResults There were no preclinical safety findings with SPL84; no related clinical signs, nor any effect on body weight, food consumption, or clinical pathology. The microscopic changes in the lungs were regarded as non-adverse and reflected a normal clearance process for inhaled compounds. Systemic exposure in both species was low. The NOAEL for mice and monkeys was the highest administered dose in both species, resulting in safety margins ~ 40X the proposed starting clinical dose.Conclusion These successful results supported initiation of a Phase 1/2 clinical study of SPL84 (ongoing), assessing the safety, tolerability, and pharmacokinetics of a single ascending dose in healthy subjects to be followed by assessment of safety, tolerability, pharmacokinetics, and preliminary efficacy of multiple ascending doses in CF patients carrying the 3849 mutation.KEYWORDS: Antisense oligonucleotidecystic fibrosisinhalationsafety profileToxicokineticsLungDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Declaration of Interest:O Barchard-Avitzur, L Friedman, E Ozeri-Galai, A Choen, S Dahan, T Mordechai, and G Hart have been under the employment of SpliSense LTD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer Disclosures:Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.AcknowledgementsThe authors are grateful to Dr. D Kornbrust (Preclinsight), R Wolff (RK Wolff Safety Consulting Inc) for toxicity input and discussion along the project. Monoceros Biosystems LLC for the in silico off target analysis. ImmunXperts (Belgium) for executing PBMC cytokine release assay (CRA). ITR Laboratories and Axolabs GmbH for executing all the toxicological studies.Authorship Contribution Statement:L Friedman and O Barchard-Avitzur contributed equally to the manuscript. O Barchard-Avitzur, was responsible for manuscript organization and writing and carried out the off-target analysis. L Friedman and G Hart: carried out for the overall project design animal studies and tissue analyses, review & editing. E Ozeri-Galai scientific input on specificity and off target analyses. N Ferrari supervised all the toxicological studies, review & editing. A Choen supported all the CMC aspects for this project. S.D and T Mordechai carried out the specificity and in vitro off target analysis.Ethics Statement:The study plans and relevant amendments were reviewed and approved by the Animal CareCommittee (ACC) of ITR. ACC acceptance was maintained on file at ITR. All animals used in the study were cared for in accordance with the principles outlined in the current “Guide to the Care and Use of Experimental Animals” as published by the Canadian Council on Animal Care and the “Guide for the Care and Use of Laboratory Animals”, a NIH publication.Figure 1. Specificity of SPL84 in HNE cells. A-B. Specificity analysis in untreated (NT) or SPL84 treated (200 nM) HNE cells from non-CF healthy volunteers. RNA was extracted and the CFTR splicing pattern of CFTR was analyzed using RT-PCR amplifying a ~400 bp region between exons 22 and 23 (A). The CFTR activity was measured in the Ussing Chamber assay from non-CF HV presented as the median of the absolute ΔIscCFTRInh172 values normalized to NT calculated from 4 filters from one biological experiment (B). C. The CFTR activity was measured in the Ussing Chamber assay of HNE cells derived from a homozygous F508del CF patient treated with SPL84 or a control ASO. The effect of the treatments is presented as the median of the absolute ΔIscCFTRInh172 values calculated from 4 filters from one biological experiment. (D) Specificity analysis in untreated (NT), control ASO or SPL84 treated (200 nM) HNE cells from CF 3849+10 kb C->T heterozygote patient. RNA was extracted and the CFTR splicing pattern of CFTR was analyzed using RT-PCR amplifying a ~400 bp region between exons 22 and 23Display full sizeFigure 2. Representative H&E lung sections from Main Phase control mice (A-C) and SPL84-treated mice (54.4 mg/kg/week, D-F). Alveolar macrophages with basophilic granules (thick arrows).Display full sizeFigure 3. Representative H&E trachea-bronchial lymph node sections from Main Phase control mice (A-C) and SPL84-treated mice (54.4 mg/kg/week, D-F). Alveolar macrophages with basophilic granules (thick arrows).Display full sizeFigure 4. Plasma concentration vs time of SPL84 in mice and monkeys. A. Mean (±SEM) plasma concentration vs time profiles of SPL84 following weekly inhalation administration of SPL84 to mice on Day 1 (Left) and Day 57 (Right) at the following achieved doses: 5.49, 24.2, and 54.4 mg/kg/week (n=2 animals/sex). B. Mean (±SEM) plasma concentration vs time profiles of SPL84 following weekly inhalation administration of SPL84 to monkeys on Day 1 (Left) and Day 57 (Right) at the following doses: 5.9,10.9 and 20.8 mg/kg/week (n=2-5 animals/sex). *These blood samples were collected from the recovery animals of the groups of 10.9 and 20.8 mg/kg/week only on Day 57.Display full sizeFigure 5. Tissue levels of SPL84 in selected mice tissues. Mean (±SEM) tissue concentrations of SPL84 in the lung, liver, and kidney following weekly inhalation administration to mice at the following doses: 5.49,24.2 and 54.4 mg/kg/week (n=4-6 animals).Display full sizeAdditional informationFundingThis paper was funded by SpliSense LTD." @default.
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- W4387391987 title "The safety and toxicity profile of SPL84, an inhaled antisense oligonucleotide for treatment of cystic fibrosis patients with the 3849 +10kb C->T mutation, supports a phase 1/2 clinical study" @default.
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- W4387391987 doi "https://doi.org/10.1080/17425255.2023.2266361" @default.
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