Mechanistic target of rapamycin (mTOR) is an evolutionarily conserved kinase that serves as the catalytic center of two distinct protein complexes, mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2).

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These complexes serve as fundamental regulators of incoming environmental and nutritional signals, and finely regulate anabolic and catabolic functions to maintain healthy cellular homeostasis.

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In healthy individuals, mTORC1 and mTORC2 are in balance.  However, in certain disease states mTORC1 becomes hyperactivated, leading to dysregulation of multiple physiologic processes including protein synthesis, cellular growth and signaling.

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Our lead indication, tuberous sclerosis complex, is a rare genetic disorder resulting from mutations in the genes TSC1 or TSC2, leading to loss of function of the normal physiological role of the TSC protein complex in downregulating the activity of mTORC1. In TSC patients, overactivation of mTORC1 has severe clinical consequences that can often include medically intractable epilepsy which is extremely difficult to manage with currently available treatments.

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Rapamycin and its previously developed analogs functionally result in nonselective inhibition of mTORC1 and mTORC2, and this nonselective profile has been associated with tolerability issues that limit their use in TSC and other disorders of selective mTORC1 overactivation. The nonselective mTORC1/mTORC2 inhibitor everolimus has demonstrated a partial degree of efficacy in TSC epilepsy, but its clinical use has been limited due to dose-limiting toxicities likely stemming from its undesirable off-target inhibition of mTORC2. These often result in dose reductions or interruptions which in turn limit achievable efficacy. The suboptimal safety and efficacy profile of nonselective mTORC1/mTORC2 inhibitors has resulted in a significant ongoing unmet medical need for a next-generation treatment able to achieve improved safety and efficacy by selectively targeting the mTORC1 overactivation associated with TSC. As such, we believe TSC is an exceptionally clear and compelling precision medicine target for AV078, our first-in-class CNS-penetrant selective inhibitor of mTORC1.