nisevokitug (NIS793) / Novartis, Ligand - LARVOL DELTA

ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis. (PubMed, Blood Adv) - P1/2 | "Forty-four patients were enrolled in Part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821."

Journal • Hematological Disorders • Myelofibrosis • Neutropenia • Thrombocytopenia • GDF15

ADA assays for high-dose biologics: redefining drug tolerance through clinical insights. (PubMed, Bioanalysis) - "Early and ongoing collaboration with health authorities supported alignment of clinically relevant performance criteria and interpretation strategies. Ultimately, this patient-oriented strategy guarantees ADA results that inform patient safety and treatment effectiveness for high-dose biologic therapies."

Journal • Oncology

Biomarker analysis from patients with metastatic PDAC treated with TGFβ antibody, NIS793, plus abraxane+gemcitabine vs. abraxane+gemcitabine alone in a phase II, open label, randomized study. (PubMed, Clin Cancer Res) - P2 | "NIS793 effectively inhibited TGFβ signaling and led to stroma remodeling but failed to improve outcomes in metastatic PDAC. These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC. Future strategies should consider context-dependent effects of TGFβ inhibition(NCT04390763)."

Biomarker • IO biomarker • Journal • P2 data • Fibrosis • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ACTA2 • TGFB1

daNIS-3: A phase II platform study of NIS793 and anti–PD-1 combined with standard of care (SoC) anti-cancer therapy for the second-line (2L) treatment (tx) of microsatellite-stable colorectal cancer (MSS CRC). (ASCO 2026) - P2 | "The daNIS-3 study (NCT04952753) evaluated efficacy and safety of anti-TGFß monoclonal antibody NIS793 (NIS) and anti-PD1 tislelizumab (TISLE) with SoC as 2L tx for MSS CRC patients (pts). This open-label, multicenter study included safety run-in (SRI) Arm 1a: NIS + SoC (bevacizumab [Bev] + FOLFIRI), Arm 1b: NIS + SoC (Bev + mFOLFOX6) followed by Arm 2a: NIS + TISLE + SoC (Bev + FOLFIRI), Arm 2b: NIS + TISLE+ SoC (Bev + mFOLFOX6) to determine NIS recommended phase 2 dose (RP2D) for expansion phase (EP)... Overall AEs were comparable, but a higher incidence of grade ≥3 AEs vs SoC were observed. NIS arms showed a deleterious PFS outcome in MSS CRC pts. *SoC+FOLFIRI/mFOLFOX6 presented together due to similar efficacy."

Clinical • P2 data • Colorectal Cancer • Oncology • Solid Tumor

Evaluation of targeted and immune combination therapies in a rat model of hormone receptor-positive breast cancer. (PubMed, Proc Natl Acad Sci U S A) - "Here, we evaluated targeting candidates from this signature KMT5B/C and IKBKE using inhibitors A-196 and IKBKEi respectively, alongside anti-estrogen (fulvestrant) and a TGFβ blocking antibody (NIS793), both individually and in combination with αPD-L1, within this rat model. Comprehensive tumor profiling through polychromatic flow cytometry and single-cell RNA sequencing revealed that A-196 induced a luminal-to-basal shift in tumor epithelial cells, enhancing antigen presentation, whereas epithelial-to-mesenchymal transition was linked to fulvestrant resistance. Our findings underscore the value of the rat mammary tumor model for preclinical studies in ER-positive breast cancer and advocate for the further validation and potential clinical development of KMT5B/C inhibitors to enhance the efficacy and broaden the applicability of ICI therapy in cancer patients."

IO biomarker • Journal • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • IKBKE • TGFB1

ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - P1/2 | N=45 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; Sponsor Decision

Trial termination • Myelofibrosis

daNIS-3: Study of NIS793 and Other Novel Investigational Combinations With SOC Anti-cancer Therapy for the 2L Treatment of mCRC (clinicaltrials.gov) - P2 | N=204 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; The study was terminated early due to the halt of NIS793 treatment and urgent safety measures issued in July and August 2023, respectively, as continued evaluation of Standard of Care alone will not support the trial's purpose.

Trial termination • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor

daNIS-3: Study of NIS793 and Other Novel Investigational Combinations With SOC Anti-cancer Therapy for the 2L Treatment of mCRC (clinicaltrials.gov) - P2 | N=204 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Solid Tumor

ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - P1/2 | N=45 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Myelofibrosis

Transforming Growth Factor-β Blockade in Pancreatic Cancer Enhances Sensitivity to Combination Chemotherapy in Mice (AACRPanCa 2024) - " We evaluated the TGFβ- blocking antibody NIS793 in combination with gemcitabine/nanoparticle (albumin-bound)- paclitaxel or FOLFIRINOX (folinic acid [FOL], 5-fluorouracil [F], irinotecan [IRI] and oxaliplatin [OX]) in orthotopic pancreatic cancer models. TGFβ regulates pancreatic cancer cell plasticity between classical and basal cell states. TGFβ blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with FOLFIRINOX or gemcitabine/nanoparticle (albumin-bound) paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens."

Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CASP3 • CD8 • TGFB1

Study of Efficacy and Safety of NIS793 in Combination With Standard of Care (SOC) Chemotherapy in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) - daNIS-2 (clinicaltrials.gov) - P3 | N=511 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

FOLFIRINOX + NIS793 in Pancreatic Cancer (clinicaltrials.gov) - P1 | N=4 | Terminated | Sponsor: Colin D. Weekes, M.D., PhD | N=50 ➔ 4 | Trial completion date: May 2025 ➔ Jul 2023 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Jul 2023; NIS793 is no longer being developed

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

daNIS-3: Study of NIS793 and Other Novel Investigational Combinations With SOC Anti-cancer Therapy for the 2L Treatment of mCRC (clinicaltrials.gov) - P2 | N=204 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: May 2024 ➔ Sep 2024

Metastases • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Phase Ib Study of Select Drug Combinations in Patients With Lower Risk MDS (clinicaltrials.gov) - P1 | N=33 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Business reasons

Trial termination • Hematological Malignancies • Myelodysplastic Syndrome • Neutropenia • Oncology

daNIS-1: Study of Efficacy and Safety of NIS793 (With and Without Spartalizumab) in Combination With SOC Chemotherapy in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) (clinicaltrials.gov) - P2 | N=164 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; The study was early terminated following the NIS793 treatment halt and urgent safety measure issued in July 2023, as the continued evaluation of Standard of Care alone will not support the original purpose of this phase 2 clinical trial.

Combination therapy • Metastases • Trial termination • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

daNIS-3: Study of NIS793 and Other Novel Investigational Combinations With SOC Anti-cancer Therapy for the 2L Treatment of mCRC (clinicaltrials.gov) - P2 | N=204 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Sep 2024 ➔ May 2024

Metastases • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

daNIS-3: Study of NIS793 and Other Novel Investigational Combinations With SOC Anti-cancer Therapy for the 2L Treatment of mCRC (clinicaltrials.gov) - P2 | N=205 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: May 2024 ➔ Sep 2024

Metastases • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - P1/2 | N=45 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2024 ➔ Jul 2024

Trial completion date • Myelofibrosis

Study of Efficacy and Safety of NIS793 in Combination With Standard of Care (SOC) Chemotherapy in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) - daNIS-2 (clinicaltrials.gov) - P3 | N=511 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jan 2026 ➔ Jun 2024 | Trial primary completion date: Jan 2026 ➔ Jun 2024

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Phase I/Ib, open-label, multicenter, dose-escalation study of the anti-TGF-β monoclonal antibody, NIS793, in combination with spartalizumab in adult patients with advanced tumors. (PubMed, J Immunother Cancer) - P1 | "In patients with advanced solid tumors, proof of mechanism of NIS793 is supported by evidence of target engagement and TGF-β pathway inhibition."

Combination therapy • Journal • Metastases • P1 data • Colorectal Cancer • Dermatology • Fatigue • Gastrointestinal Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pruritus • Renal Cell Carcinoma • Solid Tumor • TGFB1

Phase I/Ib, open-label, multicenter, dose-escalation study of the anti-TGF-β monoclonal antibody, NIS793, in combination with spartalizumab in adult patients with advanced tumors (J Immunother Cancer) - P1/1b | N=120 | NCT02947165 | Sponsor: Novartis Pharmaceuticals | "Sixty patients were treated in dose escalation, 11 with NIS793 monotherapy and 49 with NIS793 plus spartalizumab, and 60 patients were treated in dose expansion (MSS-CRC: n=40; NSCLC: n=20). No dose-limiting toxicities were observed....Overall 54 (49.5%) patients experienced ≥1 treatment-related adverse event, most commonly rash (n=16; 13.3%), pruritus (n=10; 8.3%), and fatigue (n=9; 7.5%). Three partial responses were reported: one in renal cell carcinoma (NIS793 30 mg/kg Q2W plus spartalizumab 400 mg Q4W), and two in the MSS-CRC expansion cohort. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood."

Biomarker • P1 data • Colorectal Cancer • Non Small Cell Lung Cancer • Renal Cell Carcinoma

TGFβ blockade in pancreatic cancer enhances sensitivity to combination chemotherapy (SITC 2023) - P1, P2, P3 | "This study provides scientific rationale for evaluation of NIS793 with either FOLFIRINOX or gemcitabine/n(ab)paclitaxel chemotherapy backbone in the clinical setting (NCT04390763, NCT04935359, NCT05546411, NCT05417386). We also support the concept of manipulating cancer cell plasticity to increase efficacy of combination therapy regimens."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CASP3 • CD8 • TGFB1

A Trial of NIS793 With FOLFIRINOX in Pancreatic Cancer (clinicaltrials.gov) - P2 | N=8 | Terminated | Sponsor: Kimberly Perez, MD | Trial completion date: Dec 2027 ➔ Oct 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2027 ➔ Aug 2023; Novartis, the drug manufacturer of NIS793, notified Dana Farber Cancer Institute that they are stopping all clinical development of NIS793 in pancreatic cancer, effective immediately.

Combination therapy • Trial completion date • Trial primary completion date • Trial termination • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Phase Ib Study of Select Drug Combinations in Patients With Lower Risk MDS (clinicaltrials.gov) - P1 | N=33 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=90 ➔ 33 | Trial completion date: Sep 2024 ➔ May 2024 | Trial primary completion date: Sep 2024 ➔ May 2024

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Hematological Malignancies • Myelodysplastic Syndrome • Neutropenia • Oncology

daNIS-1: Study of Efficacy and Safety of NIS793 (With and Without Spartalizumab) in Combination With SOC Chemotherapy in First-line Metastatic Pancreatic Ductal Adenocarcinoma (mPDAC) (clinicaltrials.gov) - P2 | N=151 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Nov 2023 ➔ Apr 2024 | Trial primary completion date: Nov 2023 ➔ Apr 2024

Combination therapy • IO biomarker • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD8 • PD-L1