SAR439459 / Sanofi - LARVOL DELTA

Clinical and translational study of the TGF-β monoclonal antibody SAR439459 in combination with the PD-1 inhibitor cemiplimab for patients (pts) with advanced solid tumors: Results from the phase 1b TACTIC trial (AACR 2025) - P1, P1b | "In this phase 1b study, SAR439459 and cemiplimab demonstrated a deep and durable RECISTv1.1 PR in a post-PD-1/L1i treated pt with advanced ccRCC. While translational data are limited, these findings support the association of systemic immune activation with response to therapy. Despite this, based on data from another study (NCT03192345), all investigations of SAR439459 were discontinued due to lack of sufficient antitumor activity and the associated bleeding risk."

Clinical • Combination therapy • Metastases • P1 data • Castration-Resistant Prostate Cancer • Clear Cell Renal Cell Carcinoma • Endocrine Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • CD4 • CD8 • CTLA4 • LAG3 • TGFB1 • TIGIT

Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI) (clinicaltrials.gov) - P1 | N=16 | Terminated | Sponsor: Sanofi | N=24 ➔ 16 | Trial completion date: Jun 2025 ➔ Nov 2024 | Recruiting ➔ Terminated | Trial primary completion date: Jun 2025 ➔ Nov 2024; Sponsor decision to prematurely stop the study, not linked to any safety concern.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Genetic Disorders • COL1A1 • COL1A2

Isatuximab in Combination With Novel Agents in RRMM - Master Protocol (clinicaltrials.gov) - P1/2 | N=258 | Recruiting | Sponsor: Sanofi | N=197 ➔ 258

Combination therapy • Enrollment change • Hematological Malignancies • Multiple Myeloma • Oncology

A First-in-human Study of the Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity of SAR439459 Monotherapy and Combination of SAR439459 and Cemiplimab in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=161 | Completed | Sponsor: Sanofi | Terminated ➔ Completed

Combination therapy • Metastases • Monotherapy • Trial completion • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of SAR439459, a TGFβ inhibitor, as monotherapy and in combination with cemiplimab in patients with advanced solid tumors: Findings from a phase 1/1b study. (PubMed, Clin Transl Sci) - "SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients."

Clinical • Combination therapy • Journal • Metastases • Monotherapy • P1 data • P1 data • PK/PD data • Gastrointestinal Cancer • Hematological Disorders • Hepatocellular Cancer • Melanoma • Oncology • Skin Cancer • Solid Tumor • TGFB1

Isatuximab in Combination With Novel Agents in RRMM - Master Protocol (clinicaltrials.gov) - P1/2 | N=197 | Recruiting | Sponsor: Sanofi | Trial completion date: Dec 2027 ➔ Mar 2028 | Trial primary completion date: Dec 2027 ➔ Jun 2027

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

Biomarker and pharmacodynamic activity of the transforming growth factor-beta (TGFβ) inhibitor SAR439459 as monotherapy and in combination with cemiplimab in a phase I clinical study in patients with advanced solid tumors. (PubMed, Clin Transl Sci) - P1 | "SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFβ alteration. However, further studies are needed to identify biomarkers of response."

Biomarker • Combination therapy • Journal • Metastases • Monotherapy • P1 data • PK/PD data • Melanoma • Oncology • Solid Tumor • CXCL10 • TGFB1 • TGFB2

Isatuximab in Combination With Novel Agents in RRMM - Master Protocol (clinicaltrials.gov) - P1/2 | N=197 | Recruiting | Sponsor: Sanofi | N=123 ➔ 197 | Trial completion date: Nov 2028 ➔ Dec 2027 | Trial primary completion date: Nov 2028 ➔ Dec 2027

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

Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI) (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Sanofi | Phase classification: P1b ➔ P1 | Trial completion date: Dec 2024 ➔ Jun 2025

Phase classification • Trial completion date • Genetic Disorders • COL1A1 • COL1A2

Isatuximab in Combination With Novel Agents in RRMM - Master Protocol (clinicaltrials.gov) - P1/2 | N=123 | Recruiting | Sponsor: Sanofi | Trial completion date: Feb 2026 ➔ Nov 2028 | Trial primary completion date: Feb 2026 ➔ Nov 2028

Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

SAR439459 and Cemiplimab for the Treatment of Advanced or Unresectable Solid Tumors, Strategic Alliance, TACTIC TRIAL (clinicaltrials.gov) - P1b | N=3 | Terminated | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Nov 2025 ➔ Dec 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Nov 2025 ➔ Dec 2022; The industry supporter discontinued the study and lead drug, SAR439459, due to toxicity.

IO biomarker • Metastases • Trial completion date • Trial primary completion date • Trial termination • Oncology • Solid Tumor • PD-L1 • TGFB1

Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI) (clinicaltrials.gov) - P1b | N=24 | Recruiting | Sponsor: Sanofi | Trial completion date: Jun 2024 ➔ Dec 2024 | Trial primary completion date: Jun 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Genetic Disorders • COL1A1 • COL1A2

Isatuximab in Combination With Novel Agents in RRMM - Master Protocol (clinicaltrials.gov) - P1/2 | N=123 | Recruiting | Sponsor: Sanofi | N=72 ➔ 123 | Trial completion date: Jun 2028 ➔ Feb 2026 | Trial primary completion date: Jun 2028 ➔ Feb 2026

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

[VIRTUAL] Tumor-derived Extracellular Vesicles (EVs) expressing TGFb as potential biomarkers for anti-TGFb antibody activity and drug activity in liquid biopsy (AACR-II 2020) - P1 | "The EVs released by cells harbor the cargos of their original cells and could be a good tool to follow drug activity.We are developing anti-TGFβ antibody SAR439459 for the treatment of cancer (NCT03192345), and in this vitro study we explore the effect of anti-TGFβ antibody in EVs carrying TGFβ...Finally, using TGFβ Antibody-coated magnetic beads, we demonstrate that intact EVs express TGFβ at their surface.In conclusion, these results suggest that EVs express TGFβ at their surface and carry the active free TGFβ. Finally, the expression of active free TGFβ in EVs is decreased with anti-TGFβ antibody, suggesting that it might be a biomarker for monitoring anti-TGFβ antibody activity in patients by liquid biopsies."

Biomarker • Liquid Biopsy • Oncology

Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI) (clinicaltrials.gov) - P1b | N=24 | Recruiting | Sponsor: Sanofi | Trial completion date: Oct 2023 ➔ Apr 2024 | Trial primary completion date: Oct 2023 ➔ Apr 2024

Trial completion date • Trial primary completion date • Genetic Disorders • COL1A1 • COL1A2

Preliminary biomarker and pharmacodynamic (PD) activity of the TGFβ inhibitor SAR439459, alone or in combination with cemiplimab, in a phase 1 clinical study in patients with advanced solid tumors (SITC 2021) - P1 | "Coupled with CD8+ T cell modulation in TME, these findings suggest the identification of early PD biomarkers impacted by SAR439459 which is consistent with the mechanism of action and biological activity of TGFβ blockade therapy. Trial Registration NCT03192345"

Biomarker • Clinical • Combination therapy • IO biomarker • P1 data • PK/PD data • Colorectal Cancer • Oncology • Solid Tumor • CD8 • FOXP3 • PD-L1 • TGFB1

Safety and efficacy results from the expansion phase of the first-in-human study evaluating TGFβ inhibitor SAR439459 alone and combined with cemiplimab in adults with advanced solid tumors. (ASCO 2022) - P1 | "The NCT03192345 study was discontinued due to a lack of efficacy, and a high bleeding risk particularly in pts with HCC."

Clinical • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hematological Disorders • Hepatocellular Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Urothelial Cancer • TGFB1

Isatuximab in Combination With Novel Agents in RRMM - Master Protocol (clinicaltrials.gov) - P1/2 | N=66 | Recruiting | Sponsor: Sanofi | Trial completion date: Apr 2027 ➔ Oct 2027 | Trial primary completion date: Apr 2027 ➔ Oct 2027

Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Isatuximab in Combination With Novel Agents in RRMM (clinicaltrials.gov) - P1/2 | N=66 | Recruiting | Sponsor: Sanofi | Trial completion date: Aug 2026 ➔ Apr 2027 | Trial primary completion date: Aug 2026 ➔ Apr 2027

Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Liver) (clinicaltrials.gov) - P1/2 | N=280 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jul 2024 ➔ Dec 2024 | Trial primary completion date: Jul 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • PD-L1

Isatuximab in Combination With Novel Agents in RRMM (clinicaltrials.gov) - P1/2 | N=66 | Recruiting | Sponsor: Sanofi | Trial completion date: Feb 2026 ➔ Sep 2026 | Trial primary completion date: Feb 2026 ➔ Sep 2026

Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI) (clinicaltrials.gov) - P1b | N=24 | Recruiting | Sponsor: Sanofi | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • COL1A1 • COL1A2

Isatuximab in Combination With Novel Agents in RRMM (clinicaltrials.gov) - P1/2 | N=66 | Recruiting | Sponsor: Sanofi | N=117 ➔ 66

Combination therapy • Enrollment change • Hematological Malignancies • Multiple Myeloma • Oncology

A First-in-human Study of the Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity of SAR439459 Monotherapy and Combination of SAR439459 and Cemiplimab in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=161 | Terminated | Sponsor: Sanofi | Active, not recruiting ➔ Terminated; Occurrence of objective responses in multiple indications in the Phase 1b was not enough to warrant further exploration in view of competitive landscape and some toxicity (mostly bleeding events).

Combination therapy • Monotherapy • Trial termination • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI) (clinicaltrials.gov) - P1b | N=24 | Not yet recruiting | Sponsor: Sanofi

New P1 trial • Genetic Disorders • COL1A1 • COL1A2