opelkibart elmanitin (MGTA-117) / Dianthus Therap - LARVOL DELTA

Nongenotoxic CD45-ADC-Based Conditioning Maintains Potent Suppression of Plasma Viremia in Nonhuman Primate Model of HIV (ASGCT 2024) - "We have advanced our model of HIV-specific HSPC gene therapy in a clinically relevant model and observe long term persistence of CCR5-edited HSPC and progeny in vivo after targeted conditioning. Myeloablative busulfan, CD117-ADC and CD45-ADC conditioning all supported engraftment without impaired resistance to SHIV. In our model of antiretroviral therapy-suppressed HIV infection, hematopoietic recovery and engraftment of edited cells after CD45-ADC conditioning was comparable to busulfan and achieved tissue-specific depletion of CD45+ cells."

Preclinical • Gene Therapies • Hematological Disorders • Human Immunodeficiency Virus • Infectious Disease • Neutropenia • Oncology • Transplantation • CD34 • KIT • PTPRC

CD117 Antibody-Drug Conjugate Conditioning Allows Efficient Engraftment of Gene-Modified CD34+ Cells with Fertility Preservation in a Rhesus Gene Therapy Model (ASH 2023) - "To investigate the activity of CD117-ADC in non-human primates, we administered a single injection of ADC without HSC infusion, resulting in a >99% depletion of CD34+CD90+ bone marrow cells in cynomolgus macaques (n=2 of 3 in 0.1 mg/kg and n=3 in 0.3 mg/kg); similar to the ablation observed with 4 doses of myeloablative busulfan (Bu) (n=3). The transplanted animals with ADC maintained their fertility. Overall, these data indicate that an ADC-based targeted approach offers safer conditioning and could improve the risk-benefit profile in HSC gene therapy."

Gene therapy • CNS Disorders • Epilepsy • Gene Therapies • Genetic Disorders • Hepatology • Infertility • Mucositis • Pulmonary Disease • Respiratory Diseases • Sexual Disorders • Transplantation • CD34 • KIT • THY1

Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model. (PubMed, Nat Commun) - "Following single-dose CD117-ADC, a >99% depletion of bone marrow CD34 + CD90 + CD45RA- cells without lymphocyte reduction is observed, which results are not inferior to multi-day myeloablative busulfan conditioning. Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans."

Gene therapy • Journal • Gene Therapies • Hematological Disorders • Infertility • Sexual Disorders • CD34 • KIT • THY1

CAREFULLY ENGINEERED CD117 VARIANTS RESULT IN FULL PROTECTION OF SHIELDED HEMATOPOIETIC STEM AND PROGENITOR CELLS FROM A HIGHLY POTENT CD117-DIRECTED ANTIBODY DRUG CONJUGATE IN VIVO (EBMT 2023) - "Since CD117-directed antibody drug conjugates (ADC) result in deeper HSPC depletion than SCF blockade alone, we aimed to test whether CD117 variants also shield from CD117-ADCs... Our data demonstrate that HSPCs can be shielded from a highly potent CD117-targeting ADC. In addition, our data show that for highly potent agents such as CIM058-tes, even weak interaction with the immunotherapy can result in cell depletion. Therefore, for ADCs and other highly effective immunotherapies, variants that completely abolish binding to the depleting agent are preferrable over variants with residual binding."

IO biomarker • Preclinical • Bone Marrow Transplantation • Hematological Disorders • Oncology • Transplantation • CD34 • KIT

Mgta-117, an Anti-CD117-Amanitin Antibody-Drug Conjugate, in Participants with Relapsed/Refractory Adult Acute Myeloid Leukemia (AML) and Myelodysplasia with Excess Blasts (MDS-EB): Safety, Pharmacokinetics, and Pharmacodynamics Initial Findings from a Phase 1/2 Study (TCT-ASTCT-CIBMTR 2023) - P1/2 | "MGTA-117 has been well tolerated with no unexpected safety concerns. It has shown proof-of-mechanism (robust receptor binding, selective target cell depletion) and rapid clearance with in vivo stability. Further dose escalation continues, and progress is being made toward development of MGTA-117 to enable HSCT in AML/MDS and gene therapy indications."

Clinical • P1/2 data • PK/PD data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Constipation • Gastroenterology • Gastrointestinal Disorder • Gene Therapies • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Oncology • Septic Shock • Transplantation • KIT

Mgta-117, an Anti-CD117 Antibody-Drug Conjugated with Amanitin, in Participants with Relapsed/Refractory Adult Acute Myeloid Leukemia (AML) and Myelodysplasia with Excess Blasts (MDS-EB): Safety, Pharmacokinetics and Pharmacodynamics Initial Findings from a Phase 1/2 Study (ASH 2022) - P1/2 | "MGTA-117 has been well tolerated with no unexpected safety concerns. Preliminary data show in vivo stability of the ADC with rapid clearance from blood, robust binding of MGTA-117 on CD117+ cells, and early evidence of single-agent biological activity. The observed PK/PD profile in humans is highly consistent with predictions based on data from studies in preclinical species."

Clinical • P1/2 data • PK/PD data • Acute Myelogenous Leukemia • Anemia • Bone Marrow Transplantation • Cardiovascular • Gene Therapies • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Thrombocytopenia • Transplantation • KIT

Study of MGTA-117 in Patients With Adult Acute Myeloid Leukemia (AML) and Myelodysplasia-Excess Blasts (MDS-EB) (clinicaltrials.gov) - P1/2 | N=22 | Terminated | Sponsor: Magenta Therapeutics, Inc. | N=55 ➔ 22 | Trial completion date: Oct 2023 ➔ Feb 2023 | Recruiting ➔ Terminated | Trial primary completion date: Oct 2023 ➔ Feb 2023; Sponsor Decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • KIT

Magenta Therapeutics Voluntarily Pauses the MGTA-117 Phase 1/2 Dose-Escalation Clinical Trial to Investigate Drug Safety (GlobeNewswire) - "Magenta Therapeutics...announced that the latest participant dosed at the Cohort 3 level (0.08 mg/kg) in the ongoing MGTA-117 Phase 1/2 Dose-Escalation Clinical Trial in relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) experienced a Grade 5 Serious Adverse Event (SAE) (respiratory failure and cardiac arrest resulting in death) deemed to be possibly related to MGTA-117....After consultation with the trial’s safety Cohort Review Committee and with the highest regard for patient safety, Magenta has voluntarily paused dosing in the clinical trial and is working to evaluate the totality of available data and determine next steps for the development of MGTA-117."

Trial status • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Magenta Therapeutics Provides Update for MGTA-117 Phase 1/2 Dose Escalation Clinical Trial (GlobeNewswire) - "Magenta Therapeutics...announces that, per the clinical trial protocol for the MGTA-117 Phase 1/2 Dose Escalation Clinical Trial in relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), it has stopped dosing participants at the Cohort 4 dosing level (0.13 mg/kg) and plans to dose additional participants at the Cohort 3 dosing level (0.08 mg/kg)....Three participants have been dosed in Cohort 4, and dose-limiting toxicities (DLTs) were observed in the second and third dosed participants....The second dosed participant in Cohort 4 experienced a Grade 4 Serious Adverse Event (SAE) (respiratory) considered possibly related to MGTA-117....In accordance with the clinical trial protocol and following the recommendation of the trial’s safety Cohort Review Committee on December 19, 2022, Magenta plans to continue enrollment at the Cohort 3 dose level."

Adverse events • Enrollment status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Encouraging Clinical Data from Two Antibody Drug Conjugates Based on Heidelberg Pharma’s ATAC Technology Presented at the ASH Annual Meeting 2022 (PipelineReview) - P1/2 | N=65 | NCT05223699 | Sponsor: Magenta Therapeutics, Inc. | "...partner Magenta Therapeutics...presented in an oral session preliminary positive safety and initial efficacy data from its clinical trial with the ATAC candidate MGTA-117....Preliminary results from 15 patients across three dose-escalation cohorts showed target cell depletion in the blood and bone marrow, providing evidence of an active dose. Two transplant-ineligible patients became transplant-eligible due to the successful depletion of bone marrow cancer cells. MGTA-117 was well-tolerated in all participants....Currently, the trial is enrolling patients in cohort 4; further data is expected in Q1 2023."

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

The Pharmacokinetic and Pharmacodynamic Characterization of Mgta-117, an Anti-CD117-Amanitin Antibody-Drug Conjugate for Targeted Conditioning Prior to Transplant, in Nonhuman Primates (ASH 2022) - "MGTA-117 demonstrated potent single-agent activity with predictable and consistent PK-PD profile across a wide range of doses in NHPs. The rapid clearance of MGTA-117 from blood was consistent with saturation of CD117 binding and internalization. At doses of 0.3 mg/kg and higher, the observed PD responses within stem cells confirm targeted depletion of CD117 expressing populations, with durable depletion beyond the actual clearance of ADC."

PK/PD data • Bone Marrow Transplantation • Hematological Disorders • Infertility • Oncology • Sexual Disorders • Transplantation • CD34 • KIT • THY1

Magenta Therapeutics to Host Conference Call and Webcast on Tuesday, December 13, 2022, to Review MGTA-117 Clinical Data from Ongoing Phase 1/2 Clinical Trial (GlobeNewswire) - "Magenta Therapeutics...announced that it will host a conference call and webcast at 8:30 a.m. Eastern Time (ET) / 7:30 a.m. Central Time (CT) tomorrow, Tuesday, December 13, 2022 to review the MGTA-117 clinical data from its ongoing Phase 1/2 does escalation clinical trial that will be presented at the 2022 American Society of Hematology (ASH) Annual Meeting."

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Magenta Therapeutics to Present Data at the 2022 American Society of Hematology (ASH) Annual Meeting (GlobeNewswire) - "Magenta Therapeutics...announced that it will make three presentations relating to its ongoing clinical trials at the 2022 American Society of Hematology (ASH) Annual Meeting....Poster presentation characterizing MGTA-117 Pharmacokinetic (PK) and Pharmacodynamic (PD) in Non-Human Primates (NHPs):...All dose levels showed rapid rates of MGTA-117 clearance that, together with evidence showing robust stem cell depletion, supports the potential use of MGTA-117 to deplete target cells prior to a patient’s hematopoietic stem cell transplant or infusion of any ex vivo gene therapy product. To date, the PK and PD data and modeled projections derived from this NHP study have been predictive of MGTA-117’s clinical experience."

PK/PD data • Preclinical • Hematological Malignancies • Oncology

Heidelberg Pharma and Partner Magenta to Present Initial Clinical Data on their Antibody Drug Conjugates at the ASH Annual Meeting 2022 (PharmiWeb) - "Heidelberg Pharma AG...today announced that it will present initial data from the Phase I/IIa clinical trial with HDP-101 at the 64th Annual Meeting of the American Society of Hematology (ASH). In addition, partner Magenta Therapeutics...will present data from its clinical trial with MGTA-117. The conference will take place from December 10 to 13, 2022 in New Orleans, USA."

P1 data • P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

TIP: A phase I/II study of MGTA-117, an anti-CD117 antibody-drug conjugate, in patients with adult acute myeloid leukemia (AML) and myelodysplasia with excess blasts (MDS-EB). (ASCO 2022) - P1/2 | "CD117 receptor occupancy by MGTA-117 will be measured and MSBE dose will be based on safety and receptor occupancy. The study is designed with the possibility that subjects would proceed to HSCT >28 days after MGTA-117 administration, if eligible per the local transplant practices."

Clinical • P1/2 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • KIT

Magenta Therapeutics Reports Third Quarter Financial Results and Recent Program Highlights (GlobeNewswire) - "Magenta Therapeutics...reported financial results for the third quarter ending September 30, 2022, and recent program highlights...Magenta has completed enrollment in Cohort 1 and Cohort 2. In addition, Magenta has enrolled a sufficient number of patients to complete Cohort 3, provided that the patients complete their respective dose-limiting toxicity (DLT) observation periods; Magenta has initiated requests for formal engagement with multiple regulatory authorities for the purpose of transitioning the clinical program into transplant-eligible AML and MDS patients....General and administrative expenses were $6.1 million for the third quarter of 2022, compared with $7.5 million in the third quarter of 2021."

Commercial • Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Magenta Therapeutics to Present Data at the 2022 American Society of Hematology (ASH) Annual Meeting (GlobeNewswire) - P1/2 | N=55 | NCT05223699 | Sponsor: Magenta Therapeutics, Inc. | "Magenta Therapeutics...announced that it will make three presentations relating to its ongoing clinical trials at the 2022 American Society of Hematology (ASH) Annual Meeting....Oral presentation of updated clinical data from ongoing Phase 1/2 dose escalation clinical trial:...The clinical data from the four patients in Cohort 1 showed evidence that MGTA-117 (i) binds to cells expressing CD117 target, (ii) depletes target cells and (iii) clears the body rapidly with no detectable free payload....As described in the abstract, MGTA-117 was well-tolerated with no serious adverse events deemed related to MGTA-117 and no dose-limiting toxicities. As described separately, in addition to the results described in the published abstract, Magenta will present updated available clinical data."

P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

"MGTA-117 - Amanitin ADChttps://www.adcreview.com/drugmap/mgta-117-amanitin-adc/" (@OncoZine)

Review

Non-Genotoxic Restoration of the Hematolymphoid System in Fanconi Anemia. (PubMed, Transplant Cell Ther) - "These results demonstrate the safety and efficacy of several different non-genotoxic mAb-based conditioning strategies in the FA setting. In addition, they show that if sufficient immunosuppression is given to obtain initial donor HSC engraftment, resulting turnover of a majority of the hematolymphoid system can occur likely due to the survival advantage of WT HSCs over FA HSCs. Such non-toxic all antibody-based conditioning strategy could be transformative for FA patients and those with other hematolymphoid diseases."

Journal • Anemia • Bone Marrow Transplantation • Hematological Disorders • Immunology • Transplantation • FANCD2 • KIT

Magenta Therapeutics Reports Second Quarter Financial Results and Recent Program Highlights (GlobeNewswire) - "MGTA-117 Phase 1/2 Clinical Trial Progression and Data Disclosure Expectations...The MGTA-117 clinical trial continues to make progress with additional clinical trial site activations, patient identification, patient screening and enrollment; Magenta expects to report interim clinical data from multiple dose-escalation cohorts from the clinical trial in Q4 2022; Magenta anticipates engagement with regulators in Q4 2022."

P1 data • Regulatory • Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Single Injection of CD117 Antibody-drug Conjugate Allows for Efficient Engraftment of Gene-modified CD34+ Cells in a Rhesus Gene Therapy Model (ASGCT 2022) - "We administered a single injection of CD117-ADC at 0.3 mg/kg (ZL13 and ZJ62) and 0.4 mg/kg (H635 and H96G), compared with busulfan (Bu 5.5 mg/kg x 4 days) (12U018 and 12U020). In summary, we demonstrated that a single dose of CD117-ADC allows for efficient engraftment of gene-modified CD34+ HSCs and robust HbF induction in a rhesus gene therapy model, achieving a similar level as myeloablative Bu conditioning. This targeted approach for safer conditioning could improve the risk-benefit profile in HSC gene therapy."

Gene Therapies • Transplantation • CD34 • KIT

Magenta Therapeutics Reports First Quarter Financial Results, Early Clinical Observations from MGTA-117 Clinical Trial and Other Program Highlights (Businesswire) - P1/2 | N=55 | NCT05223699 | Sponsor: Magenta Therapeutics, Inc. | "Early Clinical Observations from Cohort 1:...Preliminary data from four patients were available for measuring drug clearance. In all patients, MGTA-117 was deemed to be cleared 48 hours after dosing....Magenta expects to report additional progress updates and clinical observations from multiple dose-escalation cohorts in 2022, including providing patient-level data from this clinical trial at a scientific congress later this year....The company anticipates that further data from the current clinical trial showing MGTA-117 at high receptor occupancy levels with well-tolerated cell depletion in the blood and/or bone marrow will be supportive of the planned transition to transplant-eligible patients."

P1/2 data • Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Study of MGTA-117 in Patients With Adult Acute Myeloid Leukemia (AML) and Myelodysplasia-Excess Blasts (MDS-EB) (clinicaltrials.gov) - P1/2 | N=55 | Recruiting | Sponsor: Magenta Therapeutics, Inc. | N=42 ➔ 55

Enrollment change • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • KIT

CD117 Antibody Drug Conjugate-Based Conditioning Enables Efficient Engraftment of Gene-Modified CD34+ Cells in a Rhesus Gene Therapy Model (TCT-ASTCT-CIBMTR 2022) - "As a single agent, CD117-ADC enabled engraftment of gene-modified CD34+ HSCs and robust HbF induction comparable to myeloablative busulfan in a clinically-relevant rhesus gene therapy model. A CD117-ADC targeted conditioning approach could improve the clinical risk benefit profile versus current non-targeted conditioning in HSC gene therapy."

Gene Therapies • Genetic Disorders • Transplantation • CD34 • KIT

"$MGTA to focus on MGTA-117 development and is pausing certain MGTA-145 investments, including MGTA-145 dosing and administration optimization clinical trial in healthy subjects. Workforce reduction of 14%" (@BioStocks)

Clinical