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Part A tested single intrathecal doses of BIIB094 10–150 mg versus placebo; part B tested four doses of 40–120 mg every 4 weeks versus placebo, stratified by LRRK2 variant status. Adverse events were mainly mild to moderate and not dose limiting, with no BIIB094-related serious events. Systemic exposure increased with dose, and CSF LRRK2 and phosphorylated Rab10 decreased up to 59% and 50%, respectively, regardless of variant status. Reductions in lysosomal protein levels suggested a potential mechanism linking LRRK2 therapeutics to PD pathophysiology.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/lrrk2-targeting-antisense-oligonucleotide-in-parkinsons-disease-a-phase-1-randomized-controlled-trial/397394/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/lrrk2-targeting-antisense-oligonucleotide-in-parkinsons-disease-a-phase-1-randomized-controlled-trial/397394.png","ImageObject",300,407,{"name":92,"@type":93},"anakgang17","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-26",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What intervention was tested in the phase 1 REASON trial?","Question",{"text":113,"@type":114},"The trial tested BIIB094 (ION859), an LRRK2-targeting antisense oligonucleotide administered intrathecally to promote degradation of LRRK2 mRNA.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How was dosing structured across the trial parts A and B?",{"text":118,"@type":114},"Part A used single doses of BIIB094 (10–150 mg) or placebo, while part B used four doses of BIIB094 (40–120 mg) or placebo every 4 weeks, stratified by LRRK2 variant status.",{"name":120,"@type":111,"acceptedAnswer":121},"What pharmacodynamic effects were observed in CSF biomarkers?",{"text":122,"@type":114},"CSF LRRK2 and phosphorylated Rab10 levels were lowered by up to 59% and up to 50%, respectively, irrespective of LRRK2 variant status. Concomitant reductions in lysosomal proteins suggested a possible mechanism affecting PD pathophysiology.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},397394,1790560879,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":31,"preview_page_count":4},962090883568,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","nature medicine  \nArticle [https://doi.org/10.1038/s41591-026-04262-4](https://doi.org/10.1038/s41591-026-04262-4)  \nLRRK2-targeting antisense oligonucleotide in Parkinson’s disease: a phase 1 randomized controlled trial  \nReceived: 11 August 2025  \nAccepted: 3 February 2026  \n\n| Published online: 24 March 2026 |\n| --- |\n|  Check for updates |\n\nA list of authors and their affiliations appears atthe end of the paper  \nLRRK2 (encoding leucine-rich repeat kinase 2) variants are the most common genetic cause of Parkinson’s disease (PD). Lowering LRRK2 levels and/or inhibiting LRRK2 activity may modify PD-associated neuropathology. BIIB094 (ION859), an antisense oligonucleotide, targets LRRK2 mRNA for degradation. REASON was a first-in-human randomized phase 1 study investigating the safety, tolerability, pharmacokineticsand pharmacodynamics of intrathecal BIIB094 inpatients with PD. In part A, 40 participants received single doses of BIIB094 10–150 mg or placebo. In part B, 42 participants, stratified by LRRK2 variant status, received four dosesofBIIB094 40–120 mg or placebo every 4 weeks. Adverse events were reported by 64.5%(20/31) of participants in part A and by 84.8%(28/33) of participants in part B. The events were mainly mild to moderate and not dose limiting. No serious adverse events related to BIIB094 were reported in either part A or B. Systemic BIIB094 exposure increased with dose. Cerebrospinal fluid (CSF) LRRK2 and phosphorylatedRab10 levels were lowered by up to 59% and up to 50%, respectively, irrespective ofLRRK2 variant status. Concomitant reductions inCSF lysosomal protein levels suggested a potential mechanism whereby LRRK2 therapeutics may impact underlying PD pathophysiology. ClinicalTrials.gov identifier, NCT03976349; EudraCT number, 2018-002995-42.  \nParkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, affecting up to 4% of the older population, with incidence increasing with age1,2. PD is characterized by motor symptoms, including resting tremor, bradykinesia, muscle rigidity and postural instability, and nonmotor symptoms, including psychiatric, autonomic, cognitive and sleep impairments3–6. These symptoms culminate in severe disability and death for most patients7–9. Current treatment strategies for PD primarily target motor symptom relief through dopaminergic therapies10,11, but these cannot slow disease progression and often lead to complications such as motor fluctuationsand dyskinesia. There remains an unmet need for therapeutic approaches that can slow or halt PD progression.  \nVariants in LRRK2 (encoding leucine-rich repeat kinase 2) have been identified as the most common cause of familial PD and as risk factors for idiopathic PD10,12–14. Several pathogenic LRRK2 variants  \nunambiguously segregate with familial PD (R1441C/G/H, Y1699C, N1437H, N14S7D, I2012T, I2020T and the most prevalent variant G2019S), and genome-wide association studies have revealed additional variants as risk factors for idiopathic PD (for example, S1761R, rs76904798)12,14–18 or protective against PD (R1398H)15,19. LRRK2 variants show incomplete penetrance and age dependence, meaning that carriers have an increasing probability of developing PD with age, although some may not develop clinical manifestations during their lifetime12,13,16,17,20.  \nLRRK2 is a large multi-domain protein that has critical roles in various cellular processes, such as vesicular trafficking, cytoskeletal dynamics, neurotransmission, immune and microglial regulation, and autophagy15,19,21. Although the functions of LRRK2 are not fully understood15,17, one key activity is the phosphorylation of Rab guanosine triphosphatases (Rab proteins), which are involved in  \n[e-mail:](e-mail: omar.mabrouk@biogen.com)[ omar.mabrouk@biogen.com](e-mail: omar.mabrouk@biogen.com)  \nTable 1 | Participant disposition and baseline characteristics  \n\n| Part A: single ascending doses |  |  |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | ","cbCaifhjZvX0hKFk","https://ap.wps.com/l/cbCaifhjZvX0hKFk","pdf",4392799,"English","# Trial design and rationale\n## Safety and tolerability\n## Pharmacokinetics and pharmacodynamics\n## Participant disposition and baseline characteristics","[{\"question\":\"What intervention was tested in the phase 1 REASON trial?\",\"answer\":\"The trial tested BIIB094 (ION859), an LRRK2-targeting antisense oligonucleotide administered intrathecally to promote degradation of LRRK2 mRNA.\"},{\"question\":\"How was dosing structured across the trial parts A and B?\",\"answer\":\"Part A used single doses of BIIB094 (10–150 mg) or placebo, while part B used four doses of BIIB094 (40–120 mg) or placebo every 4 weeks, stratified by LRRK2 variant status.\"},{\"question\":\"What pharmacodynamic effects were observed in CSF biomarkers?\",\"answer\":\"CSF LRRK2 and phosphorylated Rab10 levels were lowered by up to 59% and up to 50%, respectively, irrespective of LRRK2 variant status. Concomitant reductions in lysosomal proteins suggested a possible mechanism affecting PD pathophysiology.\"}]","LRRK2-targeting antisense oligonucleotide in Parkinson’s disease - a phase 1 randomized controlled trial | PDF",1790461474]