iOnctura's roginolisib gets dual Nature Communications papers

iOnctura has published two peer-reviewed papers in Nature Communications that together advance the scientific and clinical case for roginolisib, its conformation-selective PI3Kδ inhibitor, as Phase II readouts approach for the drug in metastatic uveal melanoma and non-small cell lung cancer.

The mechanistic paper, produced by 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 characterise how roginolisib engages its target. The key finding is that the compound stabilises the catalytic C-terminal helix kα12, locking PI3Kδ in an inactive conformation rather than competing directly with ATP. That allosteric approach is structurally distinct from earlier-generation inhibitors, including idelalisib, which bind the active site. Researchers from the University of Toulouse further showed that roginolisib produced more sustained suppression of PIP3, a pro-tumour signalling lipid, than idelalisib in chronic lymphocytic leukaemia patient samples, and retained activity in samples from ibrutinib-and-venetoclax-refractory patients where idelalisib did not.

Clinical findings

The companion paper covers the first-in-human study, which enrolled 44 patients with advanced solid and haematological malignancies on continuous daily dosing. Grade 3 or higher toxicities considered related to the drug occurred in only three patients, roughly 6.8% of the cohort, and no dose-limiting toxicities or dose modifications were required. Translational analyses recorded reductions in regulatory T cells alongside increases in activated CD8+ T cells and circulating IL-15, consistent with a shift towards an anti-tumour immune environment.

The headline efficacy signal came from the metastatic uveal melanoma subset, where median overall survival reached 20.8 months. A 2019 analysis by Rantala and colleagues reported a median OS of around seven months in patients receiving immunotherapy as second-line treatment in this indication, making the comparison a roughly threefold difference. That signal was sufficient to trigger iOnctura's randomised Phase II OCULE-01 trial, which completed enrolment in December 2025. A second randomised Phase II study, PULMO-01 in NSCLC in combination with chemotherapy and the PD-1 inhibitor dostarlimab, finished enrolment in January 2026.

Gerhard Hummer, Director of Theoretical Biophysics at the Max Planck Institute and Professor at Goethe University Frankfurt, said: "By stabilizing the inactive conformation of PI3Kδ, roginolisib inhibits the kinase in a fundamentally different way than conventional approaches."

Market context

PI3Kδ inhibition has had a troubled history. Idelalisib, approved in 2014, carried a black-box warning for serious and fatal immune-mediated toxicities, leading to restricted use and several programme discontinuations across the class. Umbralisib was withdrawn from the US market in 2022 after its sponsor voluntarily pulled it amid safety concerns. The tolerability data for roginolisib, if confirmed in randomised trials, could meaningfully rehabilitate interest in the target, which sits at the intersection of oncology and immunology and is relevant across both haematological and solid-tumour settings.

iOnctura also has investigator-sponsored studies under way in CLL patients who no longer respond to BTK inhibitors, in peripheral T-cell lymphoma and in uveal melanoma in combination with tebentafusp, the T-cell receptor bispecific approved in 2022. The company is backed by Syncona, M Ventures, Inkef Capital and several other specialist institutional investors, though it has not disclosed the total capital raised to date.

With both pivotal Phase II trials now fully enrolled, the near-term news flow for iOnctura will be driven by readout timing. The company has not disclosed when it expects top-line data from OCULE-01 or PULMO-01, and those releases will be the critical test of whether the Phase I OS signal and the novel binding mechanism translate into randomised benefit.