Objective: To evaluate neurologic measures of efficacy of intravenous AAVrh.10hFXN (LX2006) gene therapy in adults with Friedreich ataxia, based on data from the SUNRISE-FA study and the Weill Cornell Medicine/NHLBI HL151355 first-in-human trial.

Background: Friedreich ataxia (FA) is a rare, hereditary, multisystem disease, with cardiac complications being the leading cause of death.  While cardiomyopathy (CM) drives mortality, neuromuscular manifestations affect individuals with FA and contribute to the quality-of-life burden.  LX2006 is a cardiotropic vector designed to deliver human FXN gene with a ubiquitous promoter to restore mitochondrial function, with potential for the vector to transduce other tissues as demonstrated preclinically. Evaluating neurologic outcomes offers the opportunity to assess additional therapeutic potential of this therapy.

Method: Adult participants (n=17) with genetically confirmed FA and cardiomyopathy received an IV dose of AAVrh.10hFXN (LX2006) in 3 dose cohorts (1.8×10¹¹, n=6; 5.6×10¹¹, n=7 1.2×10¹² vg/kg, n=4). The primary neurologic outcome was evaluated using the Modified Friedreich Ataxia Rating Scale (mFARS), in at least 6-month intervals contextualized with a propensity score–matched natural-history comparator generated from the UNIFAI study (a global Friedreich’s Ataxia Natural history study)

Results: mFARS assessments demonstrated stabilization or improvement over the observation period, driven by improvements in upper limb coordination subscore across participants with more than 6-months of follow up (n=16). Exploratory propensity score–matched (PSM) analyses, confirmed that treated individuals diverged from the expected course observed in the matched UNIFAI natural-history cohort.

Conclusion: Single-dose intravenous LX2006 was associated with early stabilization or improvement in mFARS, driven by upper limb function results. Beyond the effect on FA-CM, these findings highlight the potential of LX2006 to address the neurologic manifestations of the disease and support ongoing and future clinical evaluation of the gene therapy candidate as a disease-modifying therapy. Albeit background omavalexolone was present, there was no clear interaction with LX2006 effect in this study. Interpretation is limited by the small sample size and the absence of a concurrent on-study control.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intravenous-aavrh-10hfxn-lx2006-gene-therapy-in-friedreich-ataxia-early-neurologic-assessment-from-two-phase-1-and-2-studies/