The SIMPATHIC Basket Trial: Targeting Shared Pathomechanisms for Personalized Medicine in Rare Diseases

<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" dir="auto" id="d7207918e143">This project has received funding from the Horizon Europe research and innovation programme under grant agreement No 101080249. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d7207918e145"/><p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d7207918e146">Introduction: Drug repurposing is a key strategy in the development of therapies for patients with rare diseases and high unmet medical needs. The International Consortium SIMPATHIC aims to accelerate drug repurposing for rare neurological, neurometabolic, and neuromuscular disorders (neuro-RD’s) by ‘exploiting SIMilarities in clinical and molecular PAThology’. Moving away from the one-drug-one-disease paradigm, we aim to repurpose existing drugs in neuro-RD’s by targeting shared pathomechanisms and clinical manifestations. In a basket trial, treatment effectiveness can be tested in multiple diseases simultaneously and consequently larger patient populations. Based on high-throughput compound screening and disease model systems, sildenafil citrate was identified as a candidate to be tested clinically in multiple neuro-RD's. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d7207918e148"/><p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d7207918e149">Method: To ensure a solid trial framework, we collaborate with clinicians, translational researchers, regulatory agencies, and patients(representatives). The efficacy and safety of sildenafil citrate will be investigated in a multi-center, randomized, placebo-controlled, crossover basket trial. A master protocol was designed for the basket trial. After sufficient (pre)clinical evidence was provided and reviewed by disease experts, eligible disorders were selected to be included as substudies. Outcome measure hierarchy was determined through consensus by disease experts, researchers, and patient representatives. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d7207918e151"/><p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d7207918e152">Discussion: A basket trial design proposes an efficient route for evidence-based drug repurposing in rare diseases, which accelerates the route to market authorization and patient access. Moreover, the innovative trial design allows generation of high level of evidence on treatment efficacy in small patient populations, which often miss out on treatments due to limited trial opportunities.