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While the 2017 approval of Luxterna to treat an inherited retinal disorder of the RPE65 gene heralded the promise of gene therapy for many orphan diseases, numerous clinical development challenges remain. Innovative approaches have already been proposed for providing the necessary ‘substantial evidence’ for rare indications including reframing the alternative hypothesis testing framework across levels of evidence and Bayesian borrowing from alternative data sources (RWD, natural history studies, sister diseases) to augment clinical trial data.
But can we do better earlier on the development curve to identify the optimal biological dose which balances safety and durable efficacy thereby unlocking the potential of this therapeutic modality? Several retinal case studies will be reviewed which will illustrate the specific challenges to gene therapy dose-selection along with conceptual recommendations for how to best to address.
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