iOnctura, a clinical-stage precision oncology company combating neglected and hard-to-treat cancers, today announced the publication of two peer-reviewed articles in Nature Communications revealing new insights into the novel mechanism and clinical profile of roginolisib, the company’s next-generation, conformation-selective PI3Kδ inhibitor:

• PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12
• The conformation-selective PI3Kδ inhibitor roginolisib in patients with advanced or metastatic cancer, including metastatic uveal melanoma: first-in-human clinical trial

Catherine Pickering, CEO and co-founder of iOnctura, said: “These papers address a longstanding challenge in PI3Kδ drug development: how to achieve potent inhibition of the target while maintaining selectivity. By revealing a new way of locking PI3Kδ into an inactive state and pairing that discovery with compelling clinical findings, these studies open an exciting new chapter for selective pathway inhibition. The findings reinforce the potential of roginolisib as a differentiated therapeutic option across multiple cancers with significant unmet need.”

Roginolisib’s novel mechanism: locking PI3Kδ in an inactive state
PI3Kδ has long been recognized as an important therapeutic target in cancer, but previous generations of inhibitors have been severely limited by tolerability issues, associated in part with the way they bind to the enzyme. In this mechanistic study, researchers from the University of Geneva and the Max Planck Institute of Biophysics in Frankfurt used X-ray crystallography, molecular dynamics simulations and hydrogen-deuterium exchange mass spectrometry to investigate how roginolisib interacts with PI3Kδ. They revealed a novel binding mode: roginolisib locks the enzyme into an inactive conformation by uniquely stabilizing its catalytic C-terminal helix kα12.

By inhibiting PI3Kδ, roginolisib cuts production of PIP3, a key cellular signaling molecule that drives cancer.

Researchers from the University of Toulouse then discovered that, compared with PI3Kδ inhibitor idelalisib, roginolisib was associated with more sustained suppression of PIP3 formation in tumor samples from patients with chronic lymphocytic leukemia (CLL). Notably, roginolisib also reduced PIP3 levels in samples from heavily pre-treated, double-refractory patients who were resistant to both ibrutinib and venetoclax, whereas idelalisib did not.

Gerhard Hummer, Director of Theoretical Biophysics at the Max Planck Institute of Biophysics and Professor of Biophysics at Goethe University Frankfurt said, “These findings are exciting because they uncover a novel mechanism for PI3Kδ inhibition. By stabilizing the inactive conformation of PI3Kδ, roginolisib inhibits the kinase in a fundamentally different way than conventional approaches. Our research also suggests the novel binding mode may have meaningful biological consequences beyond the structural level.”

FiH study highlights roginolisib’s favorable tolerability profile and clinical activity, supporting clinical relevance of novel PI3Kδ inhibition mechanism
Key findings of the FiH study, which evaluated continuous daily dosing of roginolisib in 44 patients with advanced solid and hematological malignancies include:

• No dose-limiting toxicities and no dose modifications. Grade ≥3 toxicities considered related to roginolisib were reported in only 3 of 44 patients (6.8%).
• Treatment-associated reductions in regulatory T cells and increases in activated CD8+ T cells and circulating IL-15 were observed, supporting a rebalancing of the immune system towards an antitumor response.
• Median overall survival (OS) of 20.8 months in patients with metastatic uveal melanoma (mUM). A median OS of 7 months was observed in historical controls in patients receiving immunotherapies as second line treatment.¹ This difference in median OS triggered the ongoing randomized Phase II study OCULE-0[1].

The study incorporated an extensive translational research program (partly conducted in collaboration with the Karolinska Institute in Sweden and Radiomics.bio in Liege, Belgium), including radiomic imaging analyses, tumor and cell-free DNA profiling, circulating immune-cell analysis, plasma proteomics, tumor transcriptomics and immunohistochemistry.

Anna Maria Di Giacomo, Professor of Medical Oncology at the University of Siena, Italy, and Head of the Phase I Program at the University Hospital of Siena, Italy, first author of the paper, mentioned: “In this patient population a safe agent like roginolisib is not common and the length of treatment was remarkable from the very beginning.”

Michele Maio, Professor of Medical Oncology at the University of Siena, Italy, Director of the Center for Immuno-Oncology, of the Division of Medical Oncology and Immunotherapy, and of the Department of Medical Oncology at the University Hospital of Siena, Italy, and co-principal investigator on the FiH study, added: “The clear translation of roginolisib’s differentiated biology into the clinic is encouraging. Roginolisib demonstrated favorable tolerability with continuous daily dosing and showed encouraging signs of clinical activity, supporting the potential of this novel approach to PI3Kδ inhibition for patients with uveal melanoma and other difficult-to-treat cancers.”

iOnctura is currently running a comprehensive Phase II program investigating roginolisib alone or in combination with standard of care treatments, such as immune checkpoint, kinase, BCL-2 inhibitors and chemotherapy:

• Phase II OCULE-01 study in patients with mUM (NCT06717126)
• Phase II in patients with NSCLC in combination with chemotherapy and the PD-1 inhibitor dostarlimab (NCT06879717)
• Phase I/II in patients with myelofibrosis who no longer respond to JAK inhibitors, in combination with a JAK inhibitor (NCT06887803)

In addition, investigator-sponsored studies are ongoing in CLL patients who no longer respond to BTK inhibitors (NCT06644183); in peripheral T-cell lymphoma (PTCL) patients who have progressed on prior treatments (NCT07018752); and in mUM in combination with tebentafusp (NCT07203391).

References

[1] Rantala et al., Melanoma Res., 2019 Dec 29(6):561-568