Alpelisib

Drug Overview

Alpelisib is a p110-alpha isoform-specific PI3K inhibitor. PI3K signaling plays a fundamental role in
tumorigenesis, governing cell proliferation, survival, and motility, as well as angiogenesis. Mechanisms
that contribute to PI3K dysregulation include aberrant activation of upstream receptors of PI3K,
amplification mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
(PIK3CA) gene that encodes the catalytic subunit of PI3K, as well as inactivation of the phosphatase
and tensin homolog (PTEN) tumor suppressor protein (Massacesi et al., 2013; Wymann et al., 2003).

Analyst Outlook

Novartis is attempting to position its phosphoinositide 3-kinase (PI3K) inhibitors alpelisib and
buparlisib as the standard option for PI3K-mutated breast cancers, which represents the largest
molecular mutation in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-
negative (HER2-) breast cancer patients. By positioning these two drugs at different lines of
treatment, Novartis is attempting to minimize competition between them and to maximize its share
of the PI3K niche market. This will be significant to Novartis, as revenue from its approved mammalian
target of rapamycin complex (mTORC) inhibitor Afinitor (everolimus) is expected to decline in coming
years. However, late-phase data are needed for alpelisib in HR+/HER2- breast cancer to fully
determine the extent of its efficacy and its commercial potential in the market.