Tryp Therapeuatics (TRYPF) Coverage Report

Mouse studies have shown that psilocybin increases spine density and spine size in frontal cortical pyramidal cells, and these contribute to the density and strength of neuronal connections (Neuron. 2021; 109(16): 2535). Research into specific brain areas, such as the claustrum, suggests that it may play in regulating the psilocybin-induced changes in both the DMN and task-positive networks and contribute to the subjective effects of psilocybin (Neuroimage. 2020; 218: 116980). Another brain region, the amygdala, in clinical studies with psilocybin and healthy volunteers showed a relationship between decreased amygdala reactivity during emotion processing and an increase in positive mood (Biol Psychiatry. 2015; 78:572). Exhibit 11: Psilocybin’s three levels of activity Source: Cell. 2020;181(1): 24 With metabolism comes variability, as Tryp looks to develop TRP-8803. After oral administration, psilocybin is predominately dephosphorylated by alkaline phosphatase in the intestine and liver to psilocin and can also be dephosphorylated in the stomach due to the acidic environment. Psilocin is then further metabolized by liver monoamine oxidase (MAO) or aldehyde dehydrogenase, to other metabolites. However, an important step in the metabolism process involves the glucuronidation of psilocin-to-psilocin O -glucuronide via UDP-glucuronosyltransferases (UGT)1A10 in the small intestine and UGT1A9 once absorbed into circulation. The glucuronidation makes the metabolite more stable (Forensic Sci Int. 2014 Apr;237:1-6.) and is the main form of psilocin (80%) that is eliminated by the urine (Drug Metab Rev. 2017; 49(1): 84). Psilocybin’s clinical pharmacokinetics and variability. In human studies, psilocybin is detected in the plasma 20-40 min after oral administration and peak plasma levels are reached at 80-100 min. The half-life of psilocybin is 160 min and for psilocin is 50 min. The effects of the drug last for about four-to-six hours (Drug Metab Rev. 2017; 49(1): 84). In a study at UW-Madison, researchers evaluated the PK of escalating oral psilocybin doses (0.3, 0.45, and 0.6 mg/kg) that were dosed at monthly intervals in a controlled setting with subjects monitored for 24 hours (Clin Pharmacokinet. 2017;56(12): 1543). Researchers observed that the dose-normalized psilocybin AUC and C max’s varied between patients. The least squared regression lines held steady despite increasing doses, but the variability in PK levels increased at higher doses. Michael Higgins 212.409.2074 Tryp Therapeutics, Inc. (TRYPF) Page 19