The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for IMGN632, a novel CD123-targeting Antibody-drug Conjugate (ADC), for the treatment of patients with relapsed or refractory blastic plasmacytoid dendritic cell neoplasm (BPDCN). The investigational drug is being developed by ImmunoGen, using the company’s indolino-benzodiazepine (IGN) payloads.
IGN payloads have been designed to have high potency against AML blasts, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads, enable continued patient treatment. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of healthy cells.
A rare form of blood cancer
BPDCN is a rare form of blood cancer that has features of both leukemia and lymphoma, with characteristic skin lesions, lymph node involvement, and frequent spread to the bone marrow. This aggressive cancer requires intense treatment often followed by stem cell transplant.
Despite the recent approval of a CD123-targeting therapy, the unmet need remains high for patients, particularly in the relapsed/refractory setting.
IMGN632 is in clinical development for hematological malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), and acute lymphocytic leukemia (ALL).
The investigational agent is currently being evaluated in multiple cohorts, including monotherapy for patients with BPDCN and minimal residual disease positive (MRD+) AML following frontline induction therapy and in combinations with the hypomethylating agent azacitidine (Vidaza®; Bristol Meyers Squibb/Venclexta®; AbbVie/Genentech) for patients with relapsed/refractory AML.) and the BCL-2 inhibitor venetoclax (
In clinical trials, IMGN632 has shown a favorable safety profile and complete remissions as a monotherapy in patients with relapsed/refractory AML and BPDCN (NCT03386513).
“We are pleased FDA has granted Breakthrough Therapy designation for IMGN632 as it underscores the urgent need for effective and well-tolerated treatments for patients with this rare and aggressive cancer,” said Mark Enyedy, ImmunoGen’s President and Chief Executive Officer.
“We look forward to continuing to work with FDA to further define the development path for IMGN632 in BPDCN, in addition to pursuing our ongoing evaluation of IMGN632 in AML and other hematological malignancies.”
Breakthrough Therapy designation
According to FDA guidelines, Breakthrough Therapy designation is designed to expedite the development and review of drugs that are intended to treat a serious condition and have generated preliminary clinical evidence that the drug may demonstrate substantial improvement over available therapy.
Breakthrough Therapy designation was granted for IMGN632 based on the findings from the BPDCN cohort of the first-in-human study of IMGN632, for which initial data were presented in an oral session at the American Society of Hematology (ASH) Annual Meeting in 2019.
Updated data from the IMGN632 monotherapy BPDCN dose-expansion cohort will be presented during the annual meeting of the American Society of Hematology (ASH) in December 2020.
Study of IMGN632 in Patients With Relapsed/Refractory AML, BPDCN, ALL, Other CD123+ Hem Malignancies – NCT03386513
 Miller ML, Fishkin NE, Li W, Whiteman KR, Kovtun Y, Reid EE, Archer KE, Maloney EK, Audette CA, Mayo MF, Wilhelm A, Modafferi HA, Singh R, Pinkas J, Goldmacher V, Lambert JM, Chari RV. A New Class of Antibody-Drug Conjugates with Potent DNA Alkylating Activity. Mol Cancer Ther. 2016 Aug;15(8):1870-8. doi: 10.1158/1535-7163.MCT-16-0184. Epub 2016 May 23. PMID: 27216304.
 Kuruvilla VM, McCarthy R, Zhang Q, Sloss CM, Zweidler-McKay PA, Romanelli A, Adams S, Konopleva MY. IMGN632, a CD123-Alkylating ADC Bearing a DNA-Alkylating IGN Payload, Combines Effectively with Azacitidine and Venetoclax In Vivo, Prolonging Survival in Preclinical Models of Human Acute Myeloid Leukemia (AML) Blood (2019) 134 (Supplement_1): 1375. https://doi.org/10.1182/blood-2019-124963