Scalable Expanded Access with Analysis of Neurofilament and Other Biomarkers for Ibudilast in ALS (SEA-NOBI-ALS)

PROJECT SUMMARY/ABSTRACT Current treatment options for amyotrophic lateral sclerosis (ALS) are inadequate, and many patients living with ALS seek access to experimental therapies with the hope that they will be effective. Since most patients are excluded from participation in interventional trials based on restrictive inclusion and exclusion criteria, expanded access programs (EAPs) can bridge an important gap. As such, through an EAP, we are now proposing to offer a promising drug – ibudilast – that is presently in a phase 2/3 trial for ALS. Ibudilast has a well-established favorable safety record and has been approved for asthma and post-stroke symptoms in Japan. Most relevant to our application is the fact that it is able to penetrate the central nervous system and has beneficial pharmacological effects for ALS, such as phosphodiesterase inhibition, increased autophagy, and amelioration of TDP-43 pathology. This EAP will offer ibudilast as an experimental treatment to 200 ALS patients for 6 months. Our project will develop a network of ALS physicians, to be managed by Mayo Clinic and WideTrial, which features self-activation and streamlined workflows with e-consent and enrollment, home-health visit ordering, drug supply ordering, and oversight of safety events and outcomes data capture. Evaluations will be done either in a physician’s office or virtually in the patient’s home to minimize the burden of participation. Safety monitoring will be conducted by the treating physician and through blood drawn in the patient’s home, processed in a central laboratory. We will determine the effect of ibudilast on ALS progression using the gold standard primary clinical trial outcome measure – the ALS functional rating scale revised (ALSFRS-R) – with the emerging biomarker neurofilament light (NfL) as co-primary outcome. Given the urgent need for reliable biomarkers, we will also test other candidates (e.g., TDP-43 markers). Furthermore, to aid in differentiating between ibudilast responders and non-responders, we will use cutting-edge multi-omic sequencing methods. Our usage of long-read whole- genome sequencing enables us to span the full range of genomic variation, and by generating complementary transcriptomic data, we can capture RNA signatures and disease-relevant cell populations. Thus, we strongly believe that our datasets will provide a valuable resource and can possibly assist in patient stratification. In summary, our EAP will offer a promising drug, bring together novel web-based infrastructures, implement novel biomarkers, and obtain multi-omic profiles of responders, thereby allowing tailored personalized therapies and setting the stage for future ALS clinical trials.