Alpelisib

iOnctura’s PI3K delta inhibitor shows promise in phase 1 study in patients with mostly pre-treated metastatic melanoma. In a head-to-head comparison of patient tumors, iOnctura’s roginolisib outperformed Gilead’s Zydelig (idelalisib) in reducing cancer signaling pathway effectors. The two-part phase 1 study examined the safety and efficacy of roginolisib in 44 patients with advanced solid and hematologic malignancies. Part A was a dose-escalation study done in 24 patients, while part B was a dose expansion for roginolisib as a second-line treatment in 20 patients with metastatic uveal melanoma. In the 44 patients that were dosed with roginolisib, the median overall survival (mOS) was 20.8 months . Although there was no placebo head-to-head comparison in this trial, historically, patients receiving immunotherapies as a second-line treatment have an mOS of seven months . The drug was safe with no dose-limiting toxicities or dose modifications, and grade 3 adverse events were observed in three of the 44 patients. Roginolisib also demonstrated a predictable pharmacokinetic profile, decreased T regulatory cell abundance and increased activated CD8+ T cells. “Patients are progressing very rapidly, even on treatment, and then there is nothing for patients after they've progressed. This is where we believe roginolisib fits perfectly,” iOnctura CEO Catherine Pickering, Ph.D., told Fierce. “We're not adding toxicity. We're not adding [a] burden to patients, but we're extending life—and that's really important for us as a company.” The PI3K signaling pathway is one of the most frequently dysregulated pathways across multiple cancer types, including uveal melanoma. Cancer cells receive an extracellular signal that binds to its receptor to trigger the PI3K cascade, which includes production of a second messenger called PIP3, which subsequently leads to downstream activation of cancer signaling pathways. Uveal melanoma is a rare cancer of the back of the eye and spreads to other organs such as the liver. “As a company, we are really interested in pursuing solid tumor indications, and therefore we selected an indication where we knew that immunosuppression was a driver of the malignancy,” Giusy Di Conza, Ph.D., head of research and translational science at iOnctura, told Fierce. “By relieving immunosuppression, you could reawaken the immune system to fight the tumor.” iOnctura spun out of a pact with Merck KGaA and Cancer Research UK in 2017. Both founding organizations contributed assets designed to modulate immunosuppressive mechanisms that affect the tumor microenvironment, one being Merck KGaA’s roginolisib, which was at the time developed as a lupus drug. Roginolisib is an oral “conformation stabilizer of the inactive form of PI3K delta” designed to revert immunosuppression and inhibit cancer cell growth and proliferation, Pickering explained. It binds into a unique site in the inactive state of PI3K delta and causes a conformational shift, preventing ATP from binding and fueling the enzyme, while also preventing a shift to the activated state. Alongside the phase 1 trial results, iOnctura also published a paper describing the binding mechanism of roginolisib and comparing its efficacy to Gilead’s idelalisib, also a PI3K delta inhibitor. The researchers found that roginolisib was associated with more sustained suppression of PIP3 formation in tumor samples from patients with chronic lymphocytic leukemia. Besides idelalisib, there are a handful of other FDA-approved PI3K-targeting drugs. Secura Bio’s duvelisib is a dual PI3K delta and gamma inhibitor approved for B-cell blood cancers, while Pharming Group’s Novartis-licensed selective PI3K delta inhibitor Joenja is approved for a rare genetic immune disorder. PI3K alpha inhibitors such as Novartis’ Piqray and Roche’s Itovebi are approved in breast cancer. But there are no PI3K delta inhibitors approved for solid tumor indications, which is why iOnctura is pursuing this target in solid tumors, Pickering noted.