vopikitug (RG6292) / Roche - LARVOL DELTA

EBV INFECTION OUTCOMES DETERMINED BY MONOCYTE AND T REG -DRIVEN IMMUNE DYNAMICS IN AN EX VIVO PBMC MODEL. (PubMed, bioRxiv) - "Treatment with the Treg-depleting antibody RG6292 suppressed viral transformation in donors that otherwise supported LCL outgrowth, confirming a functional role for Tregs in shaping early EBV infection outcomes. Viral transcript enrichment-seq revealed an upregulation of early lytic and failure to sustain latent gene expression correlating with failure to generate LCL. These findings highlight intact PBMCs as a tractable model to study EBV viral-host interaction in a genetically diverse, human-specific context, and that Tregs play a key determining role in viral transformation."

Journal • Preclinical • Epstein-Barr Virus Infections • Immunology • Infectious Disease • Metabolic Disorders • Oncology • CCR2 • CD4 • CD8 • FOXP3 • IL2RA

A Study to Evaluate the Safety and Tolerability of RO7296682 in Combination With Atezolizumab in Participants With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=49 | Terminated | Sponsor: Hoffmann-La Roche | Completed ➔ Terminated; The sponsor decided to terminate the study early, due to recruitment challenges for Part II and, based on the totality of data generated with a low likelihood of achieving the targeted efficacy, to open Part III.

Trial termination • Oncology • Solid Tumor

Safety and anti-tumor activity of a novel aCD25 Treg depleter RG6292 as a single agent and in combination with atezolizumab in patients with solid tumors. (PubMed, Cancer Res Commun) - P1 | "RG6292 induced a dose-dependent peripheral blood and measurable intratumoral Treg depletion in concordance with the proposed mode of action; however, clinical efficacy as single agent or combined with atezolizumab was insufficient to warrant further exploration in this population."

Journal • Dermatology • Oncology • Pruritus • Solid Tumor • ISG20

Optimizing Early Clinical Investigations in Cancer Immunotherapy: The Translational Journey of RG6292, a Novel, Selective Treg-Depleting Antibody. (PubMed, Clin Pharmacol Ther) - "The first clinical data obtained for RG6292 in patients verified the appropriateness of the described approaches as well as validated the full clinical relevance of the projected safety, PK, and PD profiles from animal to man. This work shows how the integration of mechanistic non-clinical data increases the predictive value for human, allowing efficient transition of drug candidates and optimizations of early clinical investigations."

Journal • Oncology • IL2RA

A Study to Evaluate the Safety and Tolerability of RO7296682 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=76 | Terminated | Sponsor: Hoffmann-La Roche | Completed ➔ Terminated; Halted in order to focus on the ongoing combination of RO7296682 with Atezolizumab, evaluated in study BP42595, as a higher likelihood for efficacy is expected in combination with Atezolizumab as compared to the monotherapy setting.

Metastases • Trial termination • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

A Study to Evaluate the Safety and Tolerability of RO7296682 in Combination With Atezolizumab in Participants With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=49 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | N=180 ➔ 49

Combination therapy • Enrollment change • Metastases • Trial completion • Oncology • Solid Tumor

PLYCOM: A Study Evaluating the Safety and Efficacy of Multiple Treatments in Participants With Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=200 | Recruiting | Sponsor: Hoffmann-La Roche | N=50 ➔ 200 | Trial completion date: Jul 2026 ➔ Dec 2026 | Trial primary completion date: Sep 2023 ➔ Mar 2026

Enrollment change • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

"2 abstracts at #AACR23 on the Treg depleter anti-CD25 MAb RG6292 +/- atezolizumab. Intratumoral and circulating Tregs “profoundly“ depleted. THERE WAS NO CLINICAL EFFECT AND NO IMPACT ON IMMUNE SIGNATURES." (@PDRennert)

Clinical • Oncology

A Study to Evaluate the Safety and Tolerability of RO7296682 in Combination With Atezolizumab in Participants With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=180 | Recruiting | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Oncology • Solid Tumor

CD25 targeting with the afucosylated human IgG1 antibody RG6292 eliminates regulatory T cells and CD25+ blasts in acute myeloid leukemia. (PubMed, Front Oncol) - "In addition, we observed a strong enrichment in the prevalence of CD25 expressing AML cells in patients bearing a FLT3-ITD mutation or treated with a hypomethylating agent in combination with venetoclax. The in-depth characterization of patient samples by proteomic and genomic analyses supported the identification of a patient population that may benefit most by harnessing CD25 Mab's dual mode of action. In this pre-selected patient population, CD25 Mab could lead to the specific depletion of regulatory T cells, in addition to leukemic stem cells and progenitor-like AML cells that are responsible for disease progression or relapse."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • IL2RA

Pharmacokinetic/pharmacodynamic (PK/PD) relationships of the novel Treg depleter RG6292 in Phase Ia and Ib studies in patients with solid tumors (AACR 2023) - P1 | "It has been optimized for ADCC and selective depletion of cells with high CD25 density (Treg).MATERIALS and Adult patients with advanced solid tumors were given RG6292 i.v. Q3W as monotherapy (S1: NCT04158583) or in combination with atezolizumab 1200 mg Q3W (S2: NCT04642365) in a Ph1 dose escalation study. RG6292, consistent with its proposed mechanism of action, induces profound and preferential depletion of Treg cells over CD8+CD25+ in the periphery and in the TME at clinically safe doses between 35-70mg. Further development of RG6292 is currently being explored."

Clinical • IO biomarker • P1 data • PK/PD data • Oncology • Solid Tumor • CD4 • CD8 • CXCL10 • IFNG • IL10 • IL2RA • PD-L1 • STAT5 • STAT5AWqe

Safety and anti-tumor activity of a novel Treg depleter RG6292, as a single agent and in combination with atezolizumab in patients with solid tumors (AACR 2023) - P1 | "Two patients have PR and 19 patients have SD as best overall response.ConclusionRG6292 is well tolerated and has a manageable safety profile as a single agent and in combination with atezolizumab. The preliminary safety and clinical activity from dose-escalation warrant further investigation of RG6292."

Clinical • Combination therapy • Oncology • Solid Tumor • IL2RA • STAT5 • STAT5AWqe

Depletion of regulatory T cells without interruption of IL-2 signaling by antibody against CD25 for enhancing antitumor immunity (AACR 2023) - "This antibody has a medium affinity to CD25 (KD=8.9nM), weaker than Daclizumab (KD=1.5nM) and RG6292 (KD=4.5nM). In the in vivo MC38 murine tumor model with mice whose CD25 was replaced with human CD25, H11E11-2V1 given by I.P. injection suppressed tumor growth with higher efficiency than RG6292. These results suggested that H11E11-2V1 was an excellent candidate therapeutical antibody against CD25 for cancer therapy."

IO biomarker • Oncology • CD4 • FOXP3 • GZMB • IL2 • IL2RA

CD25 Targeting Eliminates Regulatory T Cells and CD25+ Blasts in Acute Myeloid Leukemia (ASH 2022) - P1 | "CD25 Mab (also referred to as RG6292 and RO7296682) is an afucosylated, IL-2 non-blocking human IgG1 antibody, shown to efficiently deplete immunosuppressive regulatory T cells (Tregs) in humans and solid tumour models (Kolben 2021) whilst allowing binding of IL-2 to effector T cells and the induction of anti-tumour adaptive immune responses (Solomon, Amann et al...CD25 Mab is currently being investigated in a phase I dose escalation monotherapy study (NCT04158583) or in combination with atezolizumab (NCT04642365)...CD25 targeting represents an attractive target for the treatment of AML, especially in patients where CD25 is expressed on LSC or immature AML cells. Our study warrants further exploration of CD25 Mab as combinatorial treatment with, for instance, FLT3 inhibitors or venetoclax."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CD34 • FLT3 • IL2 • IL2RA

A Study to Evaluate the Safety and Tolerability of RO7296682 in Combination With Atezolizumab in Participants With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=180 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Oncology • Solid Tumor

A Study to Evaluate the Safety and Tolerability of RO7296682 in Participants With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=76 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed | Trial completion date: Dec 2022 ➔ Jul 2022 | Trial primary completion date: Dec 2022 ➔ Jul 2022

Trial completion • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

CD25-T-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity. (PubMed, Nat Cancer) - "Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies."

Journal • Immune Modulation • Inflammation • Oncology • Solid Tumor • IL2 • IL2RA • STAT5

Therapeutical antibody against CD25 mediating depletion of regulatory T cells without interruption of IL-2 signaling enhances antitumor immunity (AACR 2022) - "At last, these CD25 antibodies were tested in humanized mice whose CD25 was replaced with human CD25, and MC38 tumor cells were transplanted into these mice.H3F1-4V2 completely suppressed tumor growth, while RG6292 also suppressed tumor growth with weaker efficiency and Daclizumab had little effect on tumor growth. These results suggested H3F1-4V2 was the best candidate targeting CD25 for cancer therapy."

Oncology • GZMB • IL2 • IL2RA

A Study to Evaluate the Safety and Tolerability of RO7296682 in Participants With Advanced Solid Tumors. (clinicaltrials.gov) - P1 | N=76 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Mar 2022 ➔ Dec 2022 | Trial primary completion date: Mar 2022 ➔ Dec 2022

Trial completion date • Trial primary completion date • Oncology • Solid Tumor

A Study to Evaluate the Safety and Tolerability of RO7296682 in Participants With Advanced Solid Tumors. (clinicaltrials.gov) - P1; N=76; Active, not recruiting; Sponsor: Hoffmann-La Roche; Recruiting ➔ Active, not recruiting; N=140 ➔ 76

Clinical • Enrollment change • Enrollment closed • Oncology • Solid Tumor

[VIRTUAL] Anti-CD25 Mab: Selective depletion of T-regulatory cells (AACR 2021) - "A dose dependent peripheral Treg depletion was observed as expected from RG6292 design and a significant flux of activated CD8+T cells as well as increase of PDL1 expression and intensity were observed in 3/3 patients in on-treatment biopsies taken 28 days after initiation of treatment. RG6292 at the doses tested was well tolerated in patients with advanced metastatic solid tumors and yielded encouraging PD effects consistent with its mechanism of action."

IO biomarker • Oncology • Solid Tumor • CD8 • IL2 • IL2RA • PD-L1 • STAT5

A Study to Evaluate the Safety and Tolerability of RO7296682 in Combination With Atezolizumab in Participants With Advanced Solid Tumors. (clinicaltrials.gov) - P1; N=160; Recruiting; Sponsor: Hoffmann-La Roche; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Oncology • Solid Tumor

A Study to Evaluate the Safety and Tolerability of RO7296682 in Combination With Atezolizumab in Participants With Advanced Solid Tumors. (clinicaltrials.gov) - P1; N=160; Not yet recruiting; Sponsor: Hoffmann-La Roche

Clinical • Combination therapy • New P1 trial • Oncology • Solid Tumor

A Study to Evaluate the Safety and Tolerability of RO7296682 in Participants With Advanced Solid Tumors. (clinicaltrials.gov) - P1; N=110; Recruiting; Sponsor: Hoffmann-La Roche; Trial completion date: Jun 2022 ➔ Mar 2022; Trial primary completion date: Jun 2022 ➔ Mar 2022

Clinical • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Newly added product (clinicaltrials.gov) - P1, Oncology

Pipeline update