IMGN779 Demonstrates Favorable Safety Profile with repeat Dosing and no Dose-limiting Toxicities

The first-in-human data demonstrate the safety and tolerability of IMGN779, being developed by ImmunoGen, across seven dose levels, with no dose limiting toxicities (DLTs), as well as evidence of dose-dependent biological and anti-leukemia activity.The data also showed Adverse Events that were generally consistent with the underlying disease.

IMGN779 is an investigational drug for the treatment of patients with relapsed or refractory adult acute myeloid leukemia or AML whose tumors express CD33.

These results were presented in a poster presentation on Saturday, June 24, 2017, at the 22nd Congress of the European Hematology Association (EHA) in Madrid, Spain. [1][2]

ADC Bio
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Drug design
The investigational drug IMGN779 is designed as the next generation targeting antibody-drug conjugate or ADC, and combines a high-affinity, humanized anti-CD33 antibody via a cleavable – N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (s-SPDB) – desulfide linker with one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells. The novel drug is designed to maximize anti-AML activity and preclinical safety.

Highly active
In multiple AML xenograft models, including models with poor prognostic factors, IMGN779 is highly active and well-tolerated in pre-clinical repeat dosing regimens. An additional benefit was achieved with a fractionating the dosing regimen over a single high dose.

The data presented comes from the ongoing Phase I study evaluating single agent IMGN779.

Safety, pharmacokinetic (PK), and pharmacodynamic (PD) data, as well as initial anti-leukemia activity for IMGN779 through dose level seven were presented at EHA.

The key findings presented included:

  • No DLTs have been observed through dose level seven, with reported adverse events consistent with the underlying disease.
  • No increase in the nature, frequency, or severity of any treatment-emergent adverse event has been reported with escalating doses and no evidence of cumulative toxicity has been observed with repeated dosing.
  • Favorable PK/PD reveal prolonged exposure and CD33 saturation at dose levels six and seven.
  • Initial anti-leukemia activity was observed at dose levels six and seven in patients who failed intensive frontline therapy.

The Phase I trial is designed to establish the maximum tolerated dose of MTD and determine the recommended Phase II dose for IMGN779 administered as monotherapy. The trial is also intended to evaluate safety and tolerability and characterize PK, PD, and preliminary anti-leukemia activity in relapsed or refractory AML. Dose escalation continues.

Ultra potent
These results provide the foundation for the clinical evaluation of IMGN779 in AML.

“We have designed our DNA-alkylating IGNs to be ultra-potent while providing the tolerability necessary for ongoing retreatment,” said Richard Gregory, Ph.D., executive vice president and chief scientific officer of ImmunoGen.

“We believe that by combining IGNs with our ADC technology, we may be able to treat a number of additional cancers that don’t respond to existing ADC therapies. These data suggest favorable tolerability and encouraging activity in patients with AML, and we look forward to determining the recommended dose for IMGN779 and moving quickly into later-stage development,” Gregory added.

Foundation for clinical evaluation
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.

Findings from the preclinical evaluation provided the foundation for the clinical evaluation of IMGN779 in AML.