Gilead Sciences snf ImmunoGen have agreed to jointly evaluate the safety and anti-leukemia activity of pivekimab sunirine (IMGN632), a CD123 (Interleukin-3 alpha chain/IL-3 Rα) -targeting antibody-drug conjugate, in combination with magrolimab, a potential, first-in-class, investigational CD47 inhibitor, in patients with relapsed or refractory (R/R) CD123-positive acute myeloid leukemia (AML).[1]

The outlook for patients diagnosed with R/R acute CD123-positive myeloid leukemia (AML) remains poor, with conventional chemotherapeutic treatments often associated with unacceptable toxicities, including severe infections due to profound myelosuppression.[1]

CD123 is a cell surface marker and attractive therapeutic target for many myeloid malignancies whose cells ubiquitously overexpress CD123.[1] The target is expressed on multiple myeloid and lymphoid cancers including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myeloproliferative neoplasms. Because of limited expression on normal hematopoietic cells, rapid internalization, and expression on AML leukemia stem cells, CD123 is a clinically validated therapeutic target.[2]

Development of CD123 targeting agents
Therapeutic strategies targeting CD123 including antibody-drug conjugates (ADC), bispecific T-cell engagers (BiTE), and chimeric antigen receptor T-cells (CAR-T) based cellular therapies are currently undergoing evaluation in clinical studies including many myeloid malignancies.

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These ongoing studies included single as well as combination therapies with other classes of targeted agents (i.e. BCL2 inhibitors) having the potential to change the treatment paradigm for patients with this historically difficult-to-treat malignancy.

Magrolimab is a potential, first-in-class investigational monoclonal antibody against CD47 and a macrophage checkpoint inhibitor that is designed to interfere with recognition of CD47 by the SIRPα receptor on macrophages, with the goal of blocking the “don’t eat me” signal used by cancer cells to avoid being ingested by macrophages.

The investigational drug is being developed in several hematologic cancers, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) as well as solid tumor malignancies.

Pivekimab sunirine
Pivekimab sunirine is in clinical development for the treatment of hematological malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), and other CD123+ hematologic malignancies.

The investigational agent is being evaluated as monotherapy for patients with BPDCN, as a doublet with the investigational drug magrolimab (being developed by Gilead Sciences) in patients with relapsed/refractory AML, and as a triplet with azacitidine) and venetoclax in patients with frontline AML.

Pivekimab sunirine includes a humanized IgG1 antibody with high affinity to CD123 linked one of ImmunoGen’s novel indolinobenzodiazepine (IGN) payloads, which alkylate DNA and cause single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells. This payload has been observed in preclinical studies and clinical trials to have less toxicity to normal marrow progenitors than other DNA-targeting payloads.

Common form of leukemia
“AML is the most common form of acute leukemia among adults and accounts for the largest number of deaths from leukemia in both the United States and Europe,” said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen.

“Given the potentially complementary mechanisms of action, the limited overlap in safety profiles, and the encouraging data seen with each agent in combinations to date, we are excited to explore this novel doublet in patients with relapsed/refractory AML, where few effective treatment options exist.”

Trial schedule
Expected to initiate in 2023, the collaboration will be a new cohort in ImmunoGen’s 802 study and will evaluate pivekimab in combination with magrolimab in up to 42 patients with R/R CD123-positive AML. The primary endpoint for this cohort is complete response (CR) rate.

ImmunoGen’s 802 study is an open-label, multicenter, Phase 1b/2 trial to determine the safety and tolerability of pivekimab and assess the anti-leukemia activity of the agent when administered in combination with azacitidine (Vidaza®; Bristol Meyers Squibb/Celgene) and venetoclax (Venclexta®/Venclyxto®; AbbVie Inc. and Genentech) in patients with relapsed and frontline CD123-positive AML.

Clinical trials
Study of IMGN632 in Patients With Untreated BPDCN and Relapsed/Refractory BPDCN – NCT03386513
IMGN632 as Monotherapy or With Venetoclax and/or Azacitidine for Patients With CD123-Positive Acute Myeloid Leukemia – NCT04086264
A Study of the Drug IMGN632 in Children With Leukemia That Has Come Back After Treatment or is Difficult to Treat – NCT05320380

Highlights of prescribing information
Azacitidine (Vidaza®; Bristol Meyers Squibb/Celgene) [Prescribing Information]
Venetoclax (Venclexta®/Venclyxto®; AbbVie Inc. and Genentech) [Prescribing Information]

[1] Kovtun Y, Jones GE, Adams S, Harvey L, Audette CA, Wilhelm A, Bai C, Rui L, Laleau R, Liu F, Ab O, Setiady Y, Yoder NC, Goldmacher VS, Chari RVJ, Pinkas J, Chittenden T. A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells. Blood Adv. 2018 Apr 24;2(8):848-858. doi: 10.1182/bloodadvances.2018017517. PMID: 29661755; PMCID: PMC5916008.
[2] DiPippo AJ, Wilson NR, Pemmaraju N. Targeting CD123 in BPDCN: an emerging field. Expert Rev Hematol. 2021 Nov;14(11):993-1004. doi: 10.1080/17474086.2021.1988848. Epub 2021 Oct 29. PMID: 34607517.

Featured image: Contract. Courtesy: © 2010 – 2022 Fotolia. Used with permission.

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