VAL-1221 FOR THE TREATMENT OF PATIENTS WITH LAFORA DISEASE: STUDY PROTOCOL FOR A SINGLE-ARM, OPEN-LABEL CLINICAL TRIAL

Abstract

ABSTRACTIntroductionLafora 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 analysisThe 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 disseminationThe 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 RegistrationEuropean Union Clinical Trials Register (EudraCT number 2023-000185-34).ARTICLE SUMMARYStrengths And Limitations Of This StudyThis was the first approved study protocol developed for a potential disease-modifying drug in Lafora diseaseThe study will be open label due to the serious and life-threatening nature of the disease and its rarityGiven the lack of a control group in this study, the exploratory endpoints observed will be baseline-controlled and compared with natural history studiesThe rationale for VAL-1221 dose and schedule comes from experience in Pompe disease clinical trials and expanded access programs