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

Abstract

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 comprising the Fab portion of a cell-penetrating antibody and recombinant human acid alpha glucosidase, and has demonstrated an ability to clear polyglucosans. We hypothesise that intravenous infusion of VAL-1221 might be able to degrade cerebral polyglucosans and stabilise 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 centre in Italy, namely the sponsor 'IRCCS Istituto delle Scienze Neurologiche di Bologna-Azienda USL di Bologna'. The study will enrol six 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 March 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 number: European Union Clinical Trials Register (EudraCT 2023-000185-34).

Keywords: Clinical Trial; Epilepsy; PAEDIATRICS.

Figure 1. Schedule of study procedures. Cognition assessments include: Montreal Cognitive Assessment, Leiter International Performance Scale-3, Visual Motor Integration test, Children’s Color Trail Test, NEPSY-II Inhibition subtest, phonemic verbal fluency test, semantic verbal fluency test, WAIS-IV working memory subtest, WAIS-IV vocabulary subtest. Motor function assessments include: 4-stage balance test, timed up and go test, 6-minute walking test, 10-metre walk test, 9-hole peg test, Unified Myoclonus Rating Scale, Scale for Assessment and Rating of Ataxia. Global function and disease burden assessements include: Lafora Disease Performance Scale, Lafora Epilepsy Severity Scale, Barthel Index, Clinical Global Impression-Improvement, Patient Global Impression-Change, Caregiver Global Impression-Change, Vineland Adapative Behavior Scale-II, Burden Scale for Family Caregivers Short Form. V0=screening visit; V1=baseline visit; V2=intermediate evaluation visit; V3=end of treatment visit; V4=follow-up up visit. ¹Females of childbearing potential; ²patients who discontinue study drug prematurely should return to the clinic for an early termination visit 1 week after their final dose, and will be asked to continue to follow the regular schedule of visits for the remainder of the study.