modakafusp alfa (TAK-573) / Takeda - LARVOL DELTA

Randomized Phase 2 Dose Optimization Trial of Modakafusp Alfa in Relapsed/Refractory Multiple Myeloma (RRMM) (ASH 2024) - P1/2 | "Patients were randomized to receive modakafusp alfa q4w at 240 mg or 120 mg intravenously over 1 hour, with corticosteroid use limited to dexamethasone 20 mg as premedication with each dose of modakafusp alfa. Our results confirm the efficacy of single-agent modakafusp alfa in patients with RRMM. The 240 mg dose appears to have resulted in both a higher ORR and higher rates of toxicity, which were primarily hematologic."

Clinical • P2 data • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia

Targeted interferon therapy with modakafusp alfa for relapsed or refractory multiple myeloma. (PubMed, Blood) - P1/2 | "Modakafusp alfa resulted in anti-tumor activity and immune activation in patients with multiple myeloma. Adverse events were primarily hematologic."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia

Dose escalation of a phase 1b/2 study of modakafusp alfa, an immune-targeting attenuated cytokine, in patients (pts) with metastatic solid tumors. (ASCO 2022) - P1b/2 | "Modakafusp alfa had a manageable safety profile in the dose range 0.1–1.5 mg/kg in pts with solid tumors. Proof of mechanism was validated. The recommended phase 2 dose was determined as 1.0 mg/kg Q3W based on assessment of holistic data and will be tested in combination with a checkpoint inhibitor in selected tumor types."

Clinical • P1/2 data • Cutaneous Melanoma • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Hypertension • Melanoma • Multiple Myeloma • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • IFNA1

Final Results from the First-in-Human Phase 1/2 Study of Modakafusp Alfa, an Immune-Targeting Attenuated Cytokine, in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) (ASH 2022) - P1/2 | "As dexamethasone (dex) is part of standard of care in MM, but could counteract the immune activation elicited by modakafusp, additional cohorts at 0.4 mg/kg Q3W and 1.5 mg/kg Q4W in combination with 40 mg dex QW were opened. Conclusions Modakafusp alfa has a novel mechanism of action, a manageable safety profile, and encouraging anti-myeloma activity at 1.5 mg/kg Q4W, independent of peripheral blood immune cell CD38 expression. A randomized phase 2 study to compare fixed-dose levels of 120 and 240 mg (equivalent to 1.5 and 3.0 mg/kg) Q4W and to define the single-agent dose with the optimal benefit/risk profile is currently enrolling."

Clinical • IO biomarker • P1/2 data • Anemia • Hematological Malignancies • Immune Modulation • Infectious Disease • Inflammation • Multiple Myeloma • Neutropenia • Pneumonia • Respiratory Diseases • Thrombocytopenia • IFNA1

A phase Ib/II study of modakafusp alfa alone and in combination with pembrolizumab in patients with advanced or metastatic solid tumors. (PubMed, Front Oncol) - P1/2 | "High immunogenicity and the potentially limited treatment effect of the interferon MoA may have contributed to limited efficacy in these patients. https://clinicaltrials.gov/study/NCT04157517, identifier NCT04157517."

Journal • P1/2 data • Cutaneous Melanoma • Fatigue • Hematological Disorders • Hematological Malignancies • Melanoma • Multiple Myeloma • Neutropenia • Oncology • Pain • Solid Tumor • Thrombocytopenia

Atypical hemolytic uremic Syndrome Triggered by malignancy and drug exposure: A systematic review and meta-analysis (ASH 2025) - "Tacrolimus was the mostreported drug trigger (n=6)followed by gemcitabine (n=5), vincristine (n=5), bevacizumab (n=3), carfilzomib (n=3), 6-mercaptopurine(n=2), methotrexate (n=2), and mitomycin (n=2). Aflibercept, bactrim, bleomycin, capecitabine, cisplatin, cyclophosphamide, cytarabine,dasatinib, deferasirox, dinutuximab, estarylla, ketoprofen, L-asparaginase, modakafusp alfa, PEG-asparaginase, sunitinib, syntheticpsychoactive drugs, tamoxifen, and topotecan were reported as potential triggers for aHUS in one patient each...The pooled rate of treatment with eculizumab was 74% (95% CI, 0.629-0.842, p < 0.01, I2 = 72%),and the pooled rate of renal recovery was 65% (95% CI, 0.525-0.761, p < 0.01, I2 = 55%)...AKI and hematological abnormalities in these patients should prompt an emergent work-up and treatment. Current evidenceis primarily derived from case reports, so prospective trials are necessary to establish the incidence, associations, triggers, and outcomes..."

Retrospective data • Review • Acute Kidney Injury • Acute Lymphocytic Leukemia • Anemia • Atypical Hemolytic Uremic Syndrome • B Acute Lymphoblastic Leukemia • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Complement-mediated Rare Disorders • Genito-urinary Cancer • Hematological Malignancies • Hepatocellular Cancer • Hodgkin Lymphoma • Leukemia • Lung Cancer • Lymphoma • Multiple Myeloma • Nephrology • Neuroblastoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Renal Disease • Solid Tumor • Thrombocytopenia • Urothelial Cancer

Modakafusp Alfa Demonstrates Type I Interferon-Mediated Innate and Adaptive Immune Enhancement in a Phase 1/2 Study in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM) (ASH 2023) - P1, P1/2 | "Follow-up analyses of the correlation of biomarkers with clinical response are in progress and will be presented. Further clinical trials are underway (iinnovate-2, NCT05556616; iinnovate-3, NCT05590377) to evaluate moda's novel immune activating mechanism in combination with standard of care anti-myeloma therapies."

Clinical • IO biomarker • P1/2 data • Hematological Malignancies • Multiple Myeloma • Oncology • CD40LG • CD68 • CD69 • CD8 • CD86 • FOXP3 • GZMB • IFNA1 • PD-1 • TIGIT

iinnovate-1: A Study of Modakafusp Alfa on Adult Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=272 | Terminated | Sponsor: Takeda | Completed ➔ Terminated; Terminated by the sponsor for strategic reasons

Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

A phase Ib/II study of modakafusp alfa alone and in combination with pembrolizumab in patients with advanced or metastatic solid tumors (Frontiers) - "In phase Ib, 7 patients had a best response of stable disease (SD); in phase II, 1 patient had a confirmed complete response, 1 had a confirmed partial response, and 7 had SD. All immunogenicity-evaluable patients were anti-drug antibodies (ADAs) positive following treatment with modakafusp alfa; neutralizing ADAs were reported in 82.4% and 90.9% of patients in phases Ib and II, respectively, which was associated with drug exposure reduction."

P1/2 data • Melanoma • Solid Tumor

iinnovate-2: A Study of Modakafusp Alfa in Adult Participants With Multiple Myeloma (clinicaltrials.gov) - P1 | N=15 | Terminated | Sponsor: Takeda | Completed ➔ Terminated; Due to strategic reasons (no safety concerns).

Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

iinnovate-3: A Study of Modakafusp Alfa Together With Daratumumab Adults With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=15 | Terminated | Sponsor: Takeda | Completed ➔ Terminated; After completion of Phase 1 Dose Escalation of this study the sponsor decided not to proceed with Phase 2a due to strategic reasons. Thus, no participants were enrolled for Phase 2a and the study was terminated early.

Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

Population Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Modeling of Serum M-Protein Response for Modakafusp Alfa in a Phase 1/2 Study of Patients With Relapsed or Refractory Multiple Myeloma. (PubMed, Clin Transl Sci) - "Serum MP data from patients evaluable at baseline were adequately characterized using the Claret tumor growth inhibition and drug resistance model, with antitumor drug effect using an Emax model. The population PK and PK-PD modeling results supported model-informed drug development for modakafusp alfa, including the switch from weight-based to fixed dosing and the selection of two fixed doses for the randomized dose extension (Part 3) phase of the trial to inform future optimal dose selection, which is consistent with the Project Optimus paradigm."

Clinical • IO biomarker • Journal • P1/2 data • PK/PD data • Hematological Malignancies • Multiple Myeloma • Oncology

A phase 2 randomized study of modakafusp alfa as a single agent in patients with relapsed/refractory multiple myeloma. (PubMed, Blood) - P1/2 | "Pharmacokinetic studies showed a ~2-fold greater exposure with 240 vs 120 mg. Our results confirm the efficacy of single-agent modakafusp alfa in patients with RRMM."

Journal • P2 data • Developmental Disorders • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia

A Study of Modakafusp Alfa (TAK-573) Given by Itself and Together With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=45 | Terminated | Sponsor: Takeda | Completed ➔ Terminated; Study was terminated early due to futility.

Trial termination • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF • CTLA4

iinnovate-2: A Study of Modakafusp Alfa in Adult Participants With Multiple Myeloma (clinicaltrials.gov) - P1 | N=15 | Completed | Sponsor: Takeda | Trial primary completion date: Jan 2024 ➔ Jun 2024

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

iinnovate-1: A Study of Modakafusp Alfa on Adult Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=272 | Completed | Sponsor: Takeda | Trial primary completion date: Feb 2024 ➔ Jul 2024

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

iinnovate-1: A Study of Modakafusp Alfa on Adult Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=272 | Completed | Sponsor: Takeda | Active, not recruiting ➔ Completed

Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

iinnovate-3: A Study of Modakafusp Alfa Together With Daratumumab Adults With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=15 | Completed | Sponsor: Takeda | Active, not recruiting ➔ Completed | N=58 ➔ 15 | Trial completion date: Mar 2025 ➔ May 2024 | Trial primary completion date: Mar 2025 ➔ May 2024

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

iinnovate-2: A Study of Modakafusp Alfa in Adult Participants With Multiple Myeloma (clinicaltrials.gov) - P1 | N=15 | Completed | Sponsor: Takeda | Active, not recruiting ➔ Completed | N=120 ➔ 15

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

iinnovate-2: A Study of Modakafusp Alfa in Adult Participants With Multiple Myeloma (clinicaltrials.gov) - P1 | N=120 | Active, not recruiting | Sponsor: Takeda | Trial completion date: Jan 2028 ➔ Jun 2024 | Trial primary completion date: Jul 2025 ➔ Jan 2024

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

Modakafusp alfa shows intratumoral immune pharmacodynamics (PD) in a subset of patients (pts) in a phase 1b study in advanced/metastatic solid tumors (AACR 2024) - P1/2 | "PD biomarker data from this phase 1/2 trial in pts with advanced solid tumors demonstrated that moda enhances innate and adaptive immune activation in PB and within tumors. The presence of a differential intratumoral PD response in a subset of pts with elevated CD38+ cells highlights that tumor intrinsic factors may play a role in driving moda's activity in tumors."

Clinical • IO biomarker • Metastases • P1 data • PK/PD data • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • CD14 • CD69 • CD8 • FOXP3

New Therapies on the Horizon for Relapsed Refractory Multiple Myeloma. (PubMed, Hematol Oncol Clin North Am) - "Venetoclax is a B-cell lymphoma 2 (Bcl-2) inhibitor with activity in patients with t(11;14) and/or Bcl-2 expression. Iberdomide and mezigdomide are cereblon E3 ligase modulators with higher potency, immunomodulatory, and antiproliferative activity compared with lenalidomide and pomalidomide...Modakafusp alfa is an immunocytokine that targets interferons to CD38+ cells. It has demonstrated single agent activity in relapsed/refractory MM in the phase 1 setting."

IO biomarker • Journal • Review • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Targeted Protein Degradation • CD38 • CRBN

Takeda drops cancer candidates, axing immunocytokine and CAR-Ts amid shifting treatment landscape (Fierce Pharma) - "Takeda’s vision of becoming a leader in oncology ran into more trouble Thursday when the drugmaker axed (PDF) a midphase immunocytokine and three early-stage CAR-T cell therapy prospects from its R&D pipeline...Takeda pushed modakafusp alfa out of the door as part of a pipeline clear-out that also hit three phase 1 autologous CAR-T candidates. Two of the prospects, GPC3-targeted TAK-102 and mesothelin-directed TAK-103, were in development in solid tumors. The third asset, TAK-940, was a CD19-directed, Memorial Sloan Kettering Cancer Center-partnered program that used the 1XX domain to try to enhance efficacy....While Takeda axed a clutch of cancer candidates, Plump said the company 'remains committed to oncology and will continue to develop therapies across hematologic and solid tumors.'"

Discontinued • Hematological Malignancies • Oncology • Solid Tumor

iinnovate-1: A Study of Modakafusp Alfa on Adult Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=336 | Active, not recruiting | Sponsor: Takeda | Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

iinnovate-3: A Study of Modakafusp Alfa Together With Daratumumab Adults With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=58 | Active, not recruiting | Sponsor: Takeda | Recruiting ➔ Active, not recruiting

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