Val-1221 for the treatment of patients with lafora disease: study protocol for a single-arm, open-label clinical trial

Introduction Lafora Disease (LD) is an ultrarare fatal progressive myoclonic epilepsy, causing drug-resistant epilepsy, myoclonus, and psychomotor deterioration. LD is caused by mutations in EPM2A or NHLRC1, which lead to the accumulation of polyglucosans in the brain and neurodegeneration. There are no approved treatments for LD. VAL-1221 is a fusion protein comprised of the Fab portion of a cell-penetrating antibody and recombinant human acid alpha glucosidase, and has demonstrated an ability to clear polyglucosans. We hypothesize that intravenous infusion of VAL-1221 might be able to degrade cerebral polyglucosans and stabilize or improve disease outcomes. The aim of this study is to assess the safety and preliminary efficacy of VAL-1221 in patients with LD. Methods and analysis The study is a phase 2, single-arm, open-label, baseline-controlled clinical trial which will be conducted in a single investigational study center in Italy, namely the sponsor “IRCCS Istituto delle Scienze Neurologiche di Bologna - Azienda USL di Bologna”. The study will enroll 6 genetically-confirmed patients with mid- to late stage LD. The global duration of the study for each participant will be 18 months, including screening period, open-label treatment (12 months), and follow-up period. VAL-1221 20 mg/kg will be administered as an intravenous infusion every week for 3 weeks, then every other week. Patients will undergo full clinical assessments at baseline, at an intermediate and at the end-of-treatment visit. The primary objective is to evaluate the safety. The exploratory efficacy endpoints will be related to epilepsy, neuropsychological and motor functions, global assessment and disease burden, in addition to biomarkers. Statistical analyses will be primarily descriptive. Ethics and dissemination The study protocol was approved by the local ethics committee (number 232-2023-FARM-AUSLBO–23020, 22-Mar-2023). The results of this study will be disseminated by the investigators through presentations at international scientific conferences and reported in peer-reviewed scientific journals. Trial Registration European Union Clinical Trials Register (EudraCT number 2023-000185-34). Strengths And Limitations Of This Study ### Competing Interest Statement All authors have completed the ICMJE Form for Disclosure of Potential Conflicts of Interest. FB received consulting fees from Angelini Pharma and Eisai. RM received honoraria for lectures from Eisai, and received support for attending meetings from Angelini Pharma and Eisai. DA is CEO of Parasail LLC, Quincy, MA, USA. LM, LV, MT, SM, CZ declare no conflict. ### Funding Statement Funded by the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS. PNRR-MR1-2022-12376430 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript