BSP 0001: A novel SOD1 antisense therapy for SOD1-linked and sporadic ALS

Loren L Flynn¹,²,³, Doris Tomas⁴, Nozomi Hara¹,², Robert Smith¹,², Craig Metz³, Steve D Wilton¹,², Bradley Turner⁴, and P Anthony Akkari¹,²,³,⁵

¹Perron Institute for Neurological and Translational Science, Perth, Australia, ² Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia, ³ Black Swan Pharmaceuticals, Durham, USA, ⁴Florey Institute of Neuroscience and Mental Health, Melbourne, Australia, ⁵Department of Neurology, Duke University, Durham, USA

Limitations of current SOD1-targeted therapies:

While targeted antisense therapies to suppress superoxide dismutase (SOD1) expression have shown some therapeutic promise for SOD1 mutation positive ALS patients, the clinical benefit of recently conditionally approved Tofersen is limited. Results from the Phase 3 VALOR trial failed to demonstrate an improvement in ALSFRS-R and meet the clinical endpoint, suggesting that alternative therapies with greater SOD1 modulation potential may lead to improved outcomes. Tofersen dosing is restricted by dose limiting toxicity, a common observation for the phosphorothioate class of antisense drugs, with myelitis and hydrocephalus more frequently reported for CNS delivered phosphorothiate compounds. While Tofersen has shown promise for SOD1 patients, novel compounds with improved safety profiles could be used to overcome dose limiting toxicity, leading to greater efficacy.

A novel solution:

We report a novel antisense therapy targeting SOD1 suppression, BSP 0001, utilising the phosphorodiamidate morpholino (PMO) chemistry, not known to have any reported safety concerns otherwise associated with the phosphorothioate class. Due to their safety, PMOs can be administered at higher doses to mediate improved and sustained target modulation, expected to result in greater clinical benefit. Drug safety is key to pre-symptomatic patient treatment for those carrying known SOD1 mutations, as well as for expansion into the broader sporadic disease population.

BSP 0001 has potential for greater SOD1 suppression compared to other efforts, expected to result in improved clinical benefit for SOD1-mutation positive and sporadic ALS patients.