IMGN779 / Jazz, AbbVie - LARVOL DELTA

Synergistic Anti-Leukemic Activity of PARP Inhibition Combined with IMGN632, an Anti-CD123 Antibody-Drug Conjugate in Acute Myeloid Leukemia Models (ASH 2018) - P1; "...Our laboratory has previously demonstrated that the Poly ADP Ribose (PARP) inhibitor, olaparib, synergistically enhances the activity of the CD33-targeted ADC, IMGN779, in preclinical AML models (Portwood S et al, ASH 2016). Based on the hypothesis that PARP inhibition will synergize with DNA damaging mechanism of IMGN632, we investigated the ability of olaparib and other PARP inhibitors (PARPi) in clinical development (talazoparib, niraparib, rucaparib, and veliparib) to enhance the therapeutic efficacy of IMGN632 across diverse human AML cell lines and primary relapsed/refractory AML samples...Further studies investigating this novel combinatorial approach in specific molecular subtypes of AML with variable baseline sensitivities to PARPi are currently ongoing. Our results strongly support future investigation of PARPi as a novel class of agents with the potential to significantly enhance the efficacy of DNA-alkylating ADCs and/or cytotoxic chemotherapy for...

PARP Biomarker • Acute Myelogenous Leukemia • Biosimilar • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

IMGN779, a Next Generation CD33-Targeting ADC, Combines Effectively with Cytarabine in Acute Myeloid Leukemia (AML) Preclinical Models, Resulting in Increased DNA Damage Response, Cell Cycle Arrest and Apoptosis In Vitro and Prolonged Survival In Vivo (ASH 2017) - P1; "IMGN779 and cytarabine are a highly effective and well tolerated combination in preclinical models of AML. Mechanistically, the IMGN779 plus cytarabine combination increased DNA damage response, cell cycle arrest, and apoptosis in vitro, which lead to increased survival in vivo. Interestingly, cytarabine increased cell surface CD33 levels on AML cells, indicating a novel mechanism by which cytarabine may potentiate IMGN779 uptake and possibly efficacy."

Acute Myelogenous Leukemia • Biosimilar

Maturing Clinical Profile of IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Acute Myeloid Leukemia (ASH 2018) - P1; "IMGN779 continues to display manageable tolerability and antileukemia activity in patients with relapsed or refractory AML, characterized by an adverse event profile that is consistent with the underlying disease and/or comorbidity. PK exposures and PD CD33 saturation continue to increase with dose and support further escalation of both Q2W and QW dosing schedules, which is ongoing. Figure 1."

Clinical • Acute Myelogenous Leukemia • Biosimilar • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Neutropenia • Oncology • Pain

Synergistic antileukemic activity of the antibody-drug conjugate (IMGN779) combined with PARP inhibition in preclinical human acute myeloid leukemia models (AACR 2018) - "Here we assessed the efficacy of multiple PARPi (olaparib, niraparib, rucaparib, veliparib, and talazoparib) alone and in combination with IMGN779 for AML therapy.Materials and Human AML cell lines (HEL, HL60) were characterized for CD33 expression using flow cytometry after staining with antibody-linked fluorescent QuantiBrite Beads. Our results demonstrate that PARP inhibitors as a class exert dose-dependent antitumor activity against human CD33+ AML cells. Moreover, PARPi consistently induce in vitro synergistic antileukemic effects against human AML cells when combined with the anti-CD33 ADC (IMGN779). Studies evaluating the mechanisms of action and the efficacy of combinatorial therapy in primary AML cells are under way."

PARP Biomarker • Preclinical • Acute Myelogenous Leukemia

CD33-Targeted Therapies: Beating the Disease or Beaten to Death? (PubMed, J Clin Pharmacol) - "Gemtuzumab ozogamicin was the first and only CD33-directed antibody-drug conjugate to be US Food and Drug Administration approved for AML...Promising new strategies include cellular therapy mechanisms and linker molecules. This is an exciting target that requires a considerable amount of precision to yield clinical benefit."

Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Immunogen reports recent progress and second quarter 2018 operating results (Immunogen Press Release) - "ANTICIPATED UPCOMING EVENTS [1] Report initial findings from the FORWARD II expansion cohort [NCT02606305] of mirvetuximab in combination with pembrolizumab (Keytruda) for 35 patients with medium or high FRα expression at the European Society for Medical Oncology (ESMO) 2018 Congress in October [2] Report additional data from IMGN779 Phase 1 dose finding study [NCT02674763] in 4Q 2018 [3] Report initial data from IMGN632 Phase 1 dose finding study [NCT03386513] in 4Q 2018 [4] Advance ADAM9 ADC program into IND-enabling activities before year-end..."

IND • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology • Ovarian Cancer

Early T precursor acute lymphoblastic leukaemia/lymphoma shows differential immunophenotypic characteristics including frequent CD33 expression and in vitro response to targeted CD33 therapy. (PubMed, Br J Haematol) - "Notably, targeted anti-CD33 therapy with IMGN779 resulted in significant growth inhibition and increased apoptosis in ETP-ALL cells in vitro...In summary, identification of ETP-ALL might be enhanced by using an 11-marker T-ALL immunophenotype score. CD33 expression is frequent in ETP-ALL, and in vitro data suggest that exploring anti-CD33 therapy in ETP-ALL is warranted."

Journal • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

ImmunoGen reports second quarter fiscal year 2016 financial results and provides corporate update (Immunogen Press Release) - "[Immunogen]...intends to present initial biomarker data from [the 20-patient Phase 1 expansion cohort for mirvetuximab soravtansine] at a medical meeting in 2Q2016 in addition to reporting mature data from the 40-patient Phase 1 cohort in this disease at the meeting....Patient enrollment in a Phase 2 trial assessing IMGN529 in combination with rituximab is expected to begin early this year. Enrollment in a Phase 2 trial assessing coltuximab ravtansine in a different combination regimen is expected to begin in 2H2016....ImmunoGen is preparing to initiate Phase 1 testing of IMGN779 for the treatment of acute myeloid leukemia in 1H2016."

Anticipated conference • Anticipated enrollment status • Anticipated new P1 trial • Anticipated P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

ImmunoGen, Inc. announces 2015 outlook for product pipeline (Immunogen Press Release) - "Expected 2015 events [for IMGN529] include selection of recommended P2 dose in 1H 2015, start of initial efficacy testing, including as a treatment for relapsed/refractory DLBCL and for CLL in 2Q/3Q 2015 and presentation of updated clinical data in 2H 2015....2015 expectations [for IMGN289 include initiation of a] dose-finding P1 clinical testing for the treatment of EGFR-positive solid tumors....[Anticipated] Submission of Investigational New Drug Application (IND) [for IMGN779] 2H 2015."

Anticipated clinical data • Anticipated IND • Anticipated new P1 trial • Pipeline update • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

ImmunoGen reports fourth quarter and fiscal year 2016 financial results and provides quarterly business update (Immunogen Press Release) - "Following positive meeting with FDA, Phase 3 FORWARD I study of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer on track to begin before year end. Mirvetuximab soravtansine plus Avastin combination regimen advanced to Phase 2 in FORWARD II trial...Initial clinical data from [P1 trial of IMGN779 in AML is] expected to be presented in 2017."

Anticipated new P3 trial • Anticipated P1 data • New P2 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology • Ovarian Cancer

ImmunoGen completes strategic review to strengthen the organization and drive long-term growth (Businesswire) - "the Company has prioritized its portfolio and aligned its resources to deliver on key development milestones and drive innovation in oncology, including...Accelerating its earlier-stage portfolio of highly innovative IGN programs – IMGN779, IMGN632..."

Clinical • Oncology

Jazz Pharmaceuticals and ImmunoGen, Inc. announce a strategic collaboration and option agreement to develop and commercialize antibody-drug conjugate products (Jazz Pharma Press Release) - "Jazz Pharmaceuticals...and ImmunoGen...announced that the companies have entered into a collaboration and option agreement granting Jazz Pharmaceuticals exclusive, worldwide rights to opt into development and commercialization of two early-stage, hematology-related antibody-drug conjugate (ADC) programs, as well as an additional program to be designated during the term of the agreement.  The programs covered under the agreement include IMGN779, a CD33-targeted ADC for the treatment of acute myeloid leukemia (AML) in Phase 1 testing, and IMGN632, a CD123-targeted ADC for hematological malignancies expected to enter clinical testing before the end of the year."

Licensing / partnership • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

ImmunoGen to present new data on novel antibody-drug conjugates at 59th ASH Annual Meeting (Businesswire) - "In a poster presentation...will report updated data evaluating the safety and anti-leukemia activity from...the IMGN779 first-in-human trial...preclinical data...of repeated dosing of IMGN779 and cytarabine in combination using in vitro and in vivo human AML preclinical models will be reported. Lastly, preclinical data...of IMGN632 on ALL cells will be presented in a poster presentation."

Clinical data • Preclinical • Hematological Malignancies • Oncology

ImmunoGen presents data from phase I study of IMGN779 in acute myeloid leukemia (Immunogen Press Release) - "The first-in-human data demonstrate the safety and tolerability of IMGN779 across seven dose levels, with no dose limiting toxicities (DLTs), as well as evidence of dose-dependent biological and anti-leukemia activity...Preclinical data for IMGN779 were also presented at EHA showing the agent is highly active in multiple AML xenograft models and is well-tolerated in preclinical repeat dosing regimens."

P1 data • Preclinical • Oncology

IMGN779: "Antileukemia activity was seen at doses ≥0.39 mg/kg in both schedules in seven patients with poor prognostic features" (Immunogen) - ASH 2017

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

IMGN779: “IMGN779 displays tolerability with repeat dosing across a wide range of doses in patients with relapsed AML”; Acute myeloid leukemia (Immunogen) - ASH 2018: “IMGN779 demonstrates anti-leukemia activity in 41% (12 of 29) patients with evaluable bone marrows (≥0.39 mg/kg), although with limited CR/CRis at doses examined to date”

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Open-label Study of IMGN779 in Adult Patients With Relapsed/Refractory CD33-positive Acute Myeloid Leukemia (clinicaltrials.gov) - P1; N=124; Not yet recruiting; Sponsor: ImmunoGen, Inc.

New P1 trial • Acute Myelogenous Leukemia • Biosimilar • Hematological Malignancies • Leukemia • Oncology

ImmunoGen announces recent product program advancements and anticipated 2016 events in advance of J.P. Morgan Healthcare Conference (Immunogen Press Release) - "Events anticipated in 2016: [1] Advancing Phase 2 combination trial and potentially other program updates for IMGN529; [2] Disclosure of combination regimen to be assessed in 1H2016 and initiation of Phase 2 combination study midyear for coltuximab ravtansine; [3] Initiation of Phase 1 testing [of IMGN779] for the treatment of AML in 1H2016."

Anticipated new P1 trial • Anticipated new P2 trial • Acute Myelogenous Leukemia • Oncology

IMGN779: “No DLTs have been observed at doses up to 0.54 mg/kg” (Immunogen) - EHA 2017: “Favorable PK/PD reveal prolonged exposure and CD33 saturation in cohorts 6+7”

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

ImmunoGen: J. P. Morgan Healthcare Conference (35th Annual J.P. Morgan Healthcare Conference, Immunogen) - Anticipated data from P1 trial (NCT02674763) in AML in mid-2017

Anticipated P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

ImmunoGen: J. P. Morgan Healthcare Conference (35th Annual J.P. Morgan Healthcare Conference, Immunogen) - Anticipated data from P1 trial (NCT02674763) in AML in mid-2017

Anticipated P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

ImmunoGen reports financial results for quarter ended September 30 and reviews business highlights (Immunogen Press Release) - "Preclinical data from the IMGN779 and IMGN632 programs will be presented at the ASH Annual Meeting in December, which will include an oral presentation for IMGN632. A Phase 1 trial of CD33-targeting IMGN779 in acute myeloid leukemia (AML) is ongoing with the first clinical data expected to be reported in 2017."

Anticipated conference • Anticipated P1 data • Anticipated preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology

ImmunoGen presents new data highlighting potential of novel ADCs in oral presentations at ASH Annual Meeting (Businesswire) - "ImmunoGen...today announced that new data from the ongoing Phase 1 studies of IMGN632 and IMGN779...in patients with relapsed or refractory adult acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) will be presented during an oral session at the 60th American Society of Hematology (ASH) Annual Meeting in San Diego. Preclinical data for IMGN632 as a monotherapy in BPDCN patient-derived xenografts, as well as in combination with a PARP inhibitor in AML models, will also be presented at the conference."

P1 data • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Open-label Study of IMGN779 in Adult Patients With Relapsed/Refractory CD33-positive Acute Myeloid Leukemia (clinicaltrials.gov) - P1; N=62; Completed; Sponsor: ImmunoGen, Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion

Synthesis of Highly Potent N-10 Amino-Linked DNA-Alkylating Indolinobenzodiazepine Antibody-Drug Conjugates (ADCs). (PubMed, ACS Med Chem Lett) - "Indolinobenzodiazepine DNA alkylators (IGNs) are the cytotoxic payloads in antibody-drug conjugates (ADCs) currently undergoing Phase I clinical evaluation (IMGN779, IMGN632, and TAK164). Here, we present an alternative strategy for the IGNs, linking through a carbamate at the readily available N-10 amine present in the monoimine containing dimer. As a result, we have designed a series of N-10 linked IGN ADCs with a wide range of in vitro potency and tolerability, which may allow us to better match an IGN with a particular target based on the potential dosing needs."

Journal