roginolisib (IOA-244) / iOnctura - LARVOL DELTA

The selective PI3Kδ inhibitor roginolisib synergizes with ruxolitinib against progenitor cells from naïve and JAK inhibitor-refractory/resistant patients with myelofibrosis (ASH 2025) - P1/2 | "We also evaluated combinations of suboptimal IOA-244 (0.5-1 µM) and Momelotinib (Mome, 5-50nM) doses. At the maximal dose, reductions were statistically significant (p<0.05)for IL-10 (-53%), IL-18 (-41.3%), IL-1β (-52.5%), IL-2 (-49.2%), IL-6 (-76.1%), IL-8 (-58.8%), TNF (-44.3%), CCL1(-67.9%), CCL4 (-39.8%), and CXCL10 (-84.2%).CONCLUSIONS. These findings support efficacy of IOA-244, a selective PI3Kδ inhibitor, in primary MFcells, especially when combined with JAK2 inhibitors, providing a rationale for the ongoing phase 2 HEMA-MED clinical trial (NCT06887803)."

Clinical • Hematological Malignancies • Myelofibrosis • CALR • CD34 • CXCL10 • CXCL8 • IL10 • IL18 • IL1B • IL2 • IL6 • PIK3CD

Trial in progress: A study of roginolisib in combination with ruxolitinib in patients with myelofibrosis who are unresponsive to JAK inhibitors (HEMA-MED) (ASH 2025) - P1, P1/2 | "In contrast to the first generation PI3K inhibitors, suchas parsaclisib and umbralisib, roginolisib is a novel, oral, non-ATP competitive, allosteric small moleculeinhibitor of PI3Kδ. The study is currentlyactively enrolling at 8 sites in Italy and Spain.Conclusions. Given the safety profile of roginolisib in patients of the FiH dose study, the combination ofruxolitinib and roginolisib is expected to provide a safe combination treatment in patients with MF whoare no longer responding to JAK inhibition."

Clinical • Combination therapy • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Myelofibrosis • Solid Tumor • Thrombocytosis • PIK3CD

PlatΤform: A multicenter, multi-arm, academic platform trial evaluating novel agents and combinations in relapsed or refractory peripheral T-cell lymphomas (ASH 2025) - P1/2 | "Each sub-study has additional and specific inclusion and exclusion criteria.Sub-Studies: Two sub-studies are currently open:GolcAza: evaluates the combination of golcadomide and oral azacitidine in R/R follicular helper T-celllymphoma. PlaTform represents a novel academic initiative dedicated to R/R PTCL, designed toaccelerate therapeutic innovation in this underserved population.Acknowledgement: We wish to thank the patients and their families for their participation in the clinicaltrials, iOnctura for providing access to roginolisib, and Bristol-Myers Squibb for providing access togolcadomide and azacitidine."

Clinical • B Cell Lymphoma • Cutaneous T-cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoblastic Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • T-Cell Large Granular Lymphocyte Leukemia • PIK3CD

Roginolisib (IOA-244), an orally bioavailable, selective PI3Kδ inhibitor, in combination with venetoclax and rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) (ASH 2025) - P1, P1/2 | "Our group has previously shown promising clinical activity with the combination of thefirst-generation PI3K inhibitor duvelisib and venetoclax, albeit hampered by PI3Ki-related adverse events.In contrast to the first generation PI3K inhibitors, roginolisib is a novel, oral, non-ATP competitive,allosteric small molecule inhibitor of PI3Kδ with a unique safety profile. At the timeof submission of the Abstract , the first dose level cohort of patients in Phase 1 was enrolled.ConclusionsFirst generation PI3K inhibitors have had limitations in patients with hematologic malignancies. Novelnon-ATP competitive, highly selective inhibitors may provide a tailored safe therapy targeting a keybiologic pathway in CLL and enable combinations with standard of care treatments in relapsed/refractoryCLL."

Clinical • Combination therapy • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Lymphoma • Solid Tumor • PIK3CD

iOnctura initiates Phase I/II trial in patients with myelofibrosis ahead of new non-clinical data at ASH (PRNewswire) - "These data demonstrate monotherapy activity of roginolisib against MF cell lines and in vitro models of primary MF cells. Further, roginolisib and JAK inhibition (ruxolitinib or momelotinib) exerts a synergistic anti-cancer effect. These data support the rationale behind the ongoing HEMA-MED clinical trial...In addition to the two posters related to MF, trials in progress posters for the ongoing investigations of roginolisib in peripheral T-cell lymphoma and chronic lymphocytic leukemia (CLL) will also be presented at ASH."

Clinical data • Preclinical • Trial status • Chronic Lymphocytic Leukemia • Myelofibrosis • Peripheral T-cell Lymphoma

HEMA-MED: A Study of Roginolisib in Combination With Ruxolitinib in Patients With Myelofibrosis (MF) Who Are Unresponsive to JAK Inhibitors (clinicaltrials.gov) - P1/2 | N=26 | Recruiting | Sponsor: iOnctura | Initiation date: May 2025 ➔ Nov 2025

Trial initiation date • Myelofibrosis

Novel Pi3kδ Inhibitor Roginolisib Synergizes with the Bcl-2 Inhibitor Venetoclax in Hematological Malignancies (ASH 2023) - "To further validate this finding, the combination of roginolisib with venetoclax or with another bcl-2 inhibitor S55746 was tested in a broad range of lymphoma cell lines including GRANTA519, JVM2, SP49 (MCL); FARAGE, TMD8 (diffuse large B cell lymphoma); MEC1 (chronic lymphocytic leukemia); MJ (cutaneous T cell lymphoma); and YT (NK lymphoma)...Other BCRi such as idelalisib, duvelisib and acalabrutinib were used at 5 μM concentrations as positive controls...In addition, roginolisib synergized with venetoclax in lymphoma cell lines and CLL patient samples. Our data support extending this combination strategy to clinical trials in hematological malignancies."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • BCL2L1 • MCL1 • PIK3CD

Roginolisib a Highly Selective Allosteric Modulator of the Phosphoinositide 3-Kinase Delta (PI3Kδ) in Patients with Refractory/Relapsed Follicular Lymphoma (ASH 2023) - P1 | "ConclusionsThe safety profile of roginolisib in pts with r/r FL appears to match that in pts with solid malignancies. In contrast to other PI3Kδ inhibitors, roginolisib is highly selective for binding to PI3Kδ, favoring an inactive confirmation of PI3Kd and functions as a non-ATP competitive inhibitor."

Clinical • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Respiratory Diseases • Solid Tumor • PIK3CD

INIBITION OF PI3K BY ROGINOLISIB (IOA-244) AS A POTENTIAL THERAPEUTIC STRATEGY FOR MYELOFIBROSIS (SIE 2025) - "This study reports the investigation of Roginolisib (IOA-244), a first-in-class non-ATP-competitive PI3Kδ inhibitor, for the treatment of MF, both alone and in combination with Ruxolitinib (Ruxo). Drug combination effects were analyzed using the Chou-Talalay method to calculate the combination index (CI), where CI<1 indicates synergy. The aforementioned combinations all resulted in synergistic activity, with CI values of 0.25, 0.25, 0.5 and 0.5 for CFU-GM and 0.36, 0.51, 0.37 and 0.5 for BFU-E.In summary, our findings demonstrate efficacy of IOA-244 in MF CD34+ cells; furthermore, the concurrent inhibition of PI3Kδ and JAK2 pathways by IOA-244 and Ruxo leads to enhanced activity in in vitro MF models."

Myelofibrosis • CD34 • PIK3CD

TRIUMPH: Tebentafusp and Roginolisib in Uveal Melanoma to Prolong T-cell Homeostasis (clinicaltrials.gov) - P1 | N=8 | Recruiting | Sponsor: St Vincent's Hospital, Sydney

New P1 trial • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

The PI3Kδ inhibitor roginolisib (IOA-244) preserves T cell function and activity (CICON 2025) - "In summary, roginolisib functions as an effective PI3K inhibitor on leukemic cells, while being able to preserve T cell functions. Thus, roginolisib shows less immune toxicity compared to idelalisib, and pose as an attractive alternative to currently used therapeutic PI3K inhibitors."

Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • CD4 • CD8 • PIK3CD

iOnctura Expands Roginolisib Trials to the US, Advancing Multi-Indication Strategy in Oncology (PRNewswire) - "Several US trial sites are now enrolling patients in the OCULE-01 Phase II study in metastatic uveal melanoma....Dana-Farber Cancer Institute launches new trial of roginolisib for Chronic Lymphocytic Leukemia, backed by Department of Defense grant."

Trial status • Uveal Melanoma

Roginolisib (IOA-244) With Venetoclax and Rituximab for Refractory/Relapsed Chronic Lymphocytic Leukemia (CLL) (clinicaltrials.gov) - P1/2 | N=64 | Recruiting | Sponsor: Jennifer R. Brown, MD, PhD | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology

Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies. (PubMed, Haematologica) - "These findings support proof of concept for roginolisib development in hematological malignancies as a single agent or in combination with venetoclax. A clinical trial of roginolisib with venetoclax and an anti-CD20 antibody is initiating in CLL."

IO biomarker • Journal • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • BCL2 • MCL1 • PIK3CD

A Platform Trial Evaluating New Drugs or Combination in R/R Peripheral T-cell Lymphomas (clinicaltrials.gov) - P1/2 | N=49 | Not yet recruiting | Sponsor: The Lymphoma Academic Research Organisation

New P1/2 trial • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

A phase II randomised study to evaluate the antitumour activity of roginolisib, a novel non-ATP competitive and allosteric modulator inhibiting PI3Kδ, in patients with metastatic uveal melanoma (OCULE-01). (ASCO 2025) - P2 | "A final analysis will be performed to assess efficacy after 72 patients become evaluable. Study Centres are currently being opened for enrolment."

Clinical • IO biomarker • Metastases • P2 data • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • PIK3CD

iOnctura starts randomised phase 1/2 trial in lung cancer treatment (PharmaTimes) - "iOnctura has begun a randomized phase 1/2 study investigating its lead asset, roginolisib, in combination with dostarlimab, with or without docetaxel, in advanced non-small cell lung cancer (NSCLC). The first patient has been dosed in the study, which aims to evaluate the safety of the drug combination and its potential in overcoming resistance to standard immunotherapy."

Trial status • Non Small Cell Lung Cancer

PULMO-01: A Study of Roginolisib (IOA-244) in Combination With Dostarlimab With or Without Docetaxel in Metastatic Non Small-cell Lung Cancer (NSCLC) Patients (clinicaltrials.gov) - P1/2 | N=45 | Recruiting | Sponsor: iOnctura | Not yet recruiting ➔ Recruiting

Enrollment open • IO biomarker • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL7R

HEMA-MED: A Study of Roginolisib in Combination With Ruxolitinib in Patients With Myelofibrosis (MF) Who Are Unresponsive to JAK Inhibitors (clinicaltrials.gov) - P1/2 | N=26 | Recruiting | Sponsor: iOnctura | Not yet recruiting ➔ Recruiting

Enrollment open • Myelofibrosis

Molecular profiling of the PI3Kδ inhibitor roginolisib in metastatic uveal melanoma and its correlation with clinical outcomes (AACR 2025) - P1 | "These findings highlight the importance of immune modulation, PI3K/mTOR signaling, and GPCR gene expression in potentially driving treatment outcomes, and encourage further evaluation of Roginolisib in a Phase 2 randomized study."

Clinical • Clinical data • IO biomarker • Metastases • Tumor mutational burden • Cutaneous Melanoma • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • CCL2 • CCL22 • CD8 • ENTPD1 • GPRC6A • IFNAR2 • IL15 • PD-1 • PIK3CD • TMB

HEMA-MED: A Study of Roginolisib in Combination with Ruxolitinib in Patients with Myelofibrosis (MF) Who Are Unresponsive to JAK Inhibitors (clinicaltrials.gov) - P1/2 | N=26 | Not yet recruiting | Sponsor: iOnctura

New P1/2 trial • Myelofibrosis

PULMO-01: A Study of Roginolisib (IOA-244) in Combination with Dostarlimab with or Without Docetaxel in Metastatic Non Small-cell Lung Cancer (NSCLC) Patients (clinicaltrials.gov) - P1/2 | N=45 | Not yet recruiting | Sponsor: iOnctura

New P1/2 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL7R

iOnctura commences randomized Phase II study in metastatic uveal melanoma (PRNewswire) - "iOnctura...today announces it has dosed the first patient in the randomized Phase II OCULE-01 study investigating lead asset roginolisib in patients with metastatic uveal melanoma (UM), a rare cancer of the eye...The Phase II open label, randomized, parallel-arm OCULE-01 study (NCT06717126), has been designed to assess roginolisib as a monotherapy with the primary objective to evaluate overall survival in patients. The study will have multiple sites across Europe and the US, enrolling approximately 85 patients with metastatic UM, who have progressed following at least one prior therapy."

Trial status • Uveal Melanoma

OCULE-01: A Randomised Phase II Study of Roginolisib in Patients with Advanced/metastatic Uveal Melanoma (clinicaltrials.gov) - P2 | N=85 | Recruiting | Sponsor: iOnctura | Not yet recruiting ➔ Recruiting

Enrollment open • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

iOnctura reaches new clinical milestones in uveal melanoma (PRNewswire) - P1 | N=210 | NCT04328844 | Sponsor: iOnctura | "iOnctura...provides a clinical update on its lead asset, roginolisib. Results from the completed Phase I DIONE-01 study are due to be presented at the European Society for Medical Oncology Immuno-Oncology (ESMO-IO) annual congress tomorrow, 12 December at 12:30 CET (presentation 164P)....Median overall survival (OS) was 16 months for the 29 patients with UM treated with roginolisib, who had previously received a median of two prior therapies. This exceeds the median OS of 7 months observed in historical controls in patients receiving immunotherapies as second line treatment. Median progression free survival (PFS) was 5 months for patients treated with roginolisib versus less than 3 months for historical controls."

P1 data • Uveal Melanoma