New therapeutic strategies for Lafora disease: Evaluation of the safety, efficacy, pharmacokinetics and metabolomic profile of intravenous VAL-1221 treatment.

Lafora disease (LD) is a fatal progressive myoclonus epilepsy that affects previously healthy adolescents and lacks effective treatments. It is caused by pathogenic variants in EPM2A or NHLRC1, leading to the accumulation of polyglucosan in the brain and other tissues. This study is the first to evaluate the administration of a potentially disease-modifying drug - VAL-1221, a glycogen-degrading antibody-enzyme fusion - in LD patients through a 12-month compassionate use program. Five patients (aged 17-24 years; three females) with intermediate to advanced LD received VAL-1221 intravenous infusions (20 ​mg/kg every other week). Safety was monitored through treatment-emergent adverse events (TEAEs), whereas efficacy was assessed using clinical scales, EEG and neuroimaging. Drug concentration profile was studied via liquid chromatography-high resolution mass spectrometry (LC-HRMS) of plasma and cerebrospinal fluid (CSF), and metabolomics via gas chromatography-MS of CSF. Four patients completed the full treatment course: one discontinued after eight months following status epilepticus. VAL-1221 was well tolerated, with five mild infusion-related TEAEs (skin rash in one, hypotension in four). Efficacy measures showed continued disease progression across patients. LC-HRMS analysis revealed no detectable levels of VAL-1221 in CSF. CSF metabolic profiling revealed no difference between untreated and VAL-1221-treated samples. These findings demonstrate that intravenous VAL-1221 is safe but ineffective, providing an important negative result that prevents further patient exposure to this approach and redirects efforts toward direct central nervous system delivery methods. The study also demonstrates the feasibility of assessing disease progression using clinical and neuroimaging measures, providing a valuable framework for clinical trials in LD.