New research reveals how a novel approach could finally unlock the full potential of PI3Kδ inhibition
iOnctura’s allosteric modulator of PI3Kδ, roginolisib, is actively being investigated in five clinical trials across a range of solid and hematological malignancies. But how is this approach different to what came before? A new collaborative study between iOnctura, the Institute for Cancer Research in Oslo, Norway, and the Center for Translational Research in Onco-Hematology, University of Geneva provides important insights into how this novel strategy to PI3Kδ inhibition may overcome long‑standing challenges with this class of inhibitors.
Traditional PI3Kδ inhibitors, including the approved molecule idelalisib, have demonstrated meaningful anti‑tumor activity across a number of hematological malignancies, but at the cost of severe immune‑related toxicities. These toxicities have limited long‑term clinical use of the drug class.
Roginolisib (IOA‑244), heralds a new archetype for PI3Kδ inhibition. The non‑ATP‑competitive inhibitor modulates PI3Kδ via an allosteric mechanism. This new binding modality results in highly selective inhibition of just the delta isoform.
Roginolisib has a distinct biological mechanism compared to idelalisib
The study compared the action of roginolisib with idelalisib on human T‑cell subsets in primary chronic lymphocytic leukemia (CLL) samples. The results showed that both agents suppressed PI3Kδ signaling in CLL cells and reduced leukemic viability to a comparable extent, yet they diverged in their impact on T‑cell function and differentiation.
PI3Kδ inhibitors are known to reduce regulatory T‑cell levels, and this effect was observed with both idelalisib and roginolisib.
However, CD4⁺ T‑cell differentiation remained more balanced under roginolisib treatment compared to idelalisib treatment.
At higher concentrations, idelalisib drove increases in Th1, Th2, and Th17 subsets, whereas roginolisib did not.
Th17 activity has been associated with toxicity to PI3Kδ inhibitors whilst Th1 drives IFNg and Th2 drives IL-4/IL-13 driven inflammatory pathways. Therefore, this transition towards a Th1/Th2/Th17 phenotype is consistent with a destabilization of immune homeostasis and subsequent toxicity.
In addition, across multiple T‑cell readouts, roginolisib preserved CD8⁺ cytotoxic activity and proliferation more effectively than idelalisib. CD8+ T-cells recognize tumor-associated antigens and induce cancer-cell death. They are therefore an important contributor to anti-tumor immunity.
Although the underlying mechanisms are still being explored, these findings support the hypothesis that the differentiated clinical safety profile of roginolisib relative to earlier PI3Kδ inhibitors may partly arise from its distinct biological effects on T cells. Specifically, roginolisib preserved CD8+ T-cells to a better degree than idelalisib, without skewing the CD4 population towards an anti-inflammatory phenotype
Why this matters
Historically, PI3Kδ inhibitors have been constrained by immune‑related adverse effects.
These data support the view that roginolisib combines anti‑tumor activity with a more favorable T‑cell functional profile than idelalisib, specifically better CD8+ cell cancer-cell killing and less Th1/Th2/Th17 mediated immune-related toxicity.
We postulate this new footprint – activity without immune toxicity – could be clinically beneficial to patients.
Why this is exciting
Roginolisib is entering an exciting phase of its development.
It is now being evaluated across a broad clinical program, including a randomized Phase II study in uveal melanoma (UM), randomized Phase I/II trials in non‑small cell lung cancer (NSCLC) and CLL, and additional Phase I/II studies in myelofibrosis and peripheral T‑cell lymphoma (PTCL).
More than 170 patients have been treated so far, without the immune-related side effects seen with other available PI3Kδ inhibitors, giving us a growing and meaningful body of evidence.
In earlier Phase I work, roginolisib delivered encouraging signs of activity, including a doubling of overall survival versus historical controls in UM – a rare and aggressive cancer with limited treatment options.
If these early signals of favorable tolerability and activity are confirmed in larger Phase III trials, this new class‑defining approach to PI3Kδ inhibition has the potential to reshape treatment paradigms and improve outcomes for patients worldwide.
Source:
“The PI3Kδ inhibitor roginolisib (IOA-244) preserves T-cell function and activity” Solli et al., Molecular Oncology, 22 Jan 2026
