Improved development practices are translating to better results in the clinic
The phosphatidylinositol 3-kinase (PI3K) signalling pathway is one of the most commonly dysregulated pathways in cancer. PI3Kδ is one of four isoforms of the catalytic subunit of PI3K kinase. Whilst its expression is normally restricted to immune cells such as regulatory T cells and myeloid-derived suppressive cells, some cancers express high levels of PI3Kδ which acts to promote tumor growth and survival.
Some accelerated approvals for first-generation PI3Kδ drugs in hematological cancers were withdrawn by regulators because, despite initial advantages in progression-free survival (PFS) shown in smaller clinical trials, they did not show a benefit to overall survival over time in larger trials. Despite the withdrawal of some accelerated approvals, PI3Kδ inhibitors remain available as options for chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL). The US FDA’s Oncologic Drugs Advisory Committee (ODAC) vote on April 2022 required that future approvals of PI3K drugs for hematological cancers should be supported by randomized data focusing on overall survival as an endpoint, rather than just PFS. The toxicity of first-generation PI3K inhibitors likely contributed to their lack of overall survival benefit, prompting the FDA to request more dose-finding studies early in drug development.
Improved practices during drug development are now translating into better results in the clinic, as issues with the first-generation drugs are corrected. iOnctura’s roginolisib is a novel PI3Kδ inhibitor with a unique chemical structure and differentiated allosteric binding mechanism. Allosteric modulation changes the 3D structure of a protein thereby affecting its activity. Roginolisib has exquisite selectivity over other isoforms and highly favourable pharmaceutical properties. It is being developed for indications burdened by immune mediated resistance and a high expression of PI3Kδ in cancer cells and tumor-infiltrating immune cells.
iOnctura’s roginolisib is a novel PI3Kδ inhibitor with a unique chemical structure and differentiated allosteric binding mechanism.
Roginolisib’s lead indication is uveal melanoma (UM), a rare cancer of the eye with limited treatment options. Although disease control can be achieved in patients with localized UM, approximately 50% of patients eventually develop metastatic disease (mUM). These patients are typically treated with immunotherapies with limited success and after therapy failure the median overall survival of these patients is less than 8 months. In this second line setting, roginolisib demonstrated long-term safety and promising efficacy with sustained disease stabilisation over many months in a Phase Ib clinical study. A randomized Phase II study to confirm these findings will commence later in 2024.
The successful mUM data reported so far, combined with a rich preclinical data package, support the rationale to expand into other solid tumor indications. iOnctura plans to commence trials in other cancer indications, including non-small cell lung cancer and primary myelofibrosis, later in 2024.
