SP-101 - a novel inhaled AAV gene therapy to treat CF
Previous attempts to treat CF with AAV gene therapies were well tolerated but hampered by poor efficacy. Spirovant’s lead candidate SP-101 is optimized to overcome historical barriers. SP-101 is composed of a novel AAV capsid, AAV2.5T, that has been selected for its high tropism to the apical side of cultured human airway epithelial cells (Excoffon KJ, et al. Proc Natl Acad Sci U S A. 2009;106(10):3865-3870), which is present on the luminal side of the airways targeted by the inhalation route. It further contains a human CFTR minigene (hCFTR∆R) with regulatory elements (Ostedgaard LS, et al. Proc Natl Acad Sci U S A. 2002;99(5):3093-3098 Yan Z, et al. Hum Gene Ther. 2015;26(6):334-346) that efficiently drive hCFTR∆R expression in human airway epithelial cells.
Preclinical data indicate that the co-administration of doxorubicin, a small molecule chemotherapeutic and proteasome inhibitor, is critical for the correction of CF. Doxorubicin has been shown to strongly increase the production of functional CFTR protein by facilitating the translocation of AAV genomes into the cell nucleus (Yan Z, et al. J Virol. 2004;78(6):2863-2874 Zhang LN, et al. Mol Ther. 2004;10(6):990-1002). Inhaled administration of SP-101 and doxorubicin to CF ferrets resulted in efficient pulmonary hCFTR∆R expression, suggesting that accumulated mucus is not an additional barrier to SP-101. In addition, hCFTR∆R expression increased with increasing doses of SP-101 and doxorubicin and was durable (NACFC 2021 poster and presentation). Spirovant is the only company developing inhaled AAV gene therapy in concert with a small molecule transduction augmenter. The US and EMA granted SP-101 orphan drug designation and additionally, the US granted SP-101 rare pediatric disease designation.