Clinical-stage oncology company Immuneering, presented positive pharmacokinetic (PK), pharmacodynamic (PD) and safety data from the Phase 1 data that supports the company’s investigational drug IMM-1-104 to potential to address a broad population of patients with RAS mutant tumors. IMM-1-104 aims to achieve universal-RAS activity that selectively impacts cancer cells to a greater extent than healthy cells, through deep cyclic inhibition of the MAPK pathway with once-daily dosing.

The data, presented at the presented at the annual meeting of the  American Association for Cancer Research (AACR), held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida, shows that the drug was well tolerated without dose limiting toxicities (DLTs) or serious adverse events (SAEs).

The results presented are the first to demonstrate novel deep cyclic inhibition mechanism in humans, with IMM-1-104 achieving:

  • Significant PK Cmax levels of over 2,000 ng/mL (or approximately 1 uM drug free-fraction at 160 mg once daily oral dose)
  • Greater than 90 percent PD inhibition of phosphorylated extracellular signal-regulated kinase (pERK) compared to pretreatment baseline for patients at the third dose level (160 mg once daily oral)
  • A median plasma half-life (t1/2) of 1.94 hours across the first three dose levels evaluable (40 mg, 80 mg and 160 mg once daily oral), in patients with pancreatic and colorectal cancer with different RAS mutations, including KRAS-G12D, the most common mutation present in pancreatic cancer.
Ben Zeskind, Ph.D., MBA, Co-founder, and Chief Executive Officer of Immuneering.

These results support potential to evaluate preliminary efficacy sooner than expected, allowing researchers to accelerate the study’s timeline with the recommended Phase 2 dose (RP2D) expected in early 2024.

“We are very pleased to share initial PK, PD and safety data from our Phase 1 trial of IMM-1-104 in patients with advanced RAS mutant solid tumors, ahead of schedule,” noted Ben Zeskind, Ph.D., MBA, Co-founder, and Chief Executive Officer of Immuneering.

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“We believe these data from the first patients dosed in our study demonstrate the PK, PD and safety profile necessary for deep cyclic inhibition – the proprietary and novel mechanism through which our therapies are designed to selectively impact cancer cells to a greater extent than healthy cells, regardless of the specific RAS mutation driving the tumor.”

The data show that we were able to reach significant levels of PK Cmax with the aim of breaking tumor addiction to the MAPK pathway, then rapidly clearing out drug with IMM-1-104’s short half-life. These results position us to accelerate the dose escalation portion of our study, reaching potentially therapeutic levels of IMM-1-104 earlier than previously planned,” Zeskind added.

Major milestone
“These initial PK and PD Phase 1 data with IMM-1-104 mark a major milestone for Immuneering, and for patients affected by RAS mutant tumors. It is the first time IMM-1-104 has shown the profile we believe is necessary for deep cyclic inhibition in humans. Prior therapies have often suffered from steep increases in drug half-life in humans when compared to preclinical models. In contrast, initial clinical results for IMM-1-104 are in line with our preclinical modeling, which we believe helps to de-risk an important element of our universal-RAS program,” explained Brett Hall, Ph.D., Chief Scientific Officer of Immuneering.

“With today’s results showing an approximate two-hour half-life coupled with reaching target Cmax values faster than expected plus encouraging pharmacodynamic, safety and tolerability results observed, we are accelerating the remaining dose-escalation portion of our trial. We now have an opportunity to assess potential preliminary efficacy earlier than anticipated,” Hall noted.

“We are highly encouraged by the initial safety and tolerability data generated to date. IMM-1-104 has been well tolerated with no DLTs or SAEs observed,” said Scott Barrett, M.D., Chief Medical Officer of Immuneering.

Study design
The Phase 1/2a clinical trial is an open-label study was designed to evaluate the safety, tolerability, PK and preliminary efficacy of IMM-1-104 in patients with advanced RAS mutant solid tumors.

The Phase 1 portion of the study, which is being conducted at five clinical sites in the United States, is evaluating IMM-1-104 following a Bayesian mTPI-2 escalation design, which includes a dose escalation phase and dose evaluation phase to establish an optimized RP2D candidate. Following selection of the RP2D candidate, the team at Immuneering expects to conduct a Phase 2a dose expansion phase to assess the safety and efficacy of IMM-1-104 at the RP2D in RAS mutated pancreatic, melanoma, lung and colorectal cancers.

Other data
In addition, IMM-1-104 was evaluated in humanized 3D preclinical tumor models displaying diverse mitogen‑activated protein kinase (MAPK) pathway activation events. The MAPK pathway consists of a series of protein kinases such as RAS, RAF, MEK and ERK that are involved in many important cellular processes including cell proliferation, differentiation and survival.

The antitumor activity of IMM-1-104 was evaluated in 132 tumor models spanning 12 distinct tumor types in a proprietary humanized 3D tumor growth assay (3D-TGA) conducted in Immuneering’s labs in San Diego.

Based on drug-response sensitivity and resistance profiles, a biomarker signature for IMM-1-104 was developed to project potential therapeutic response in more than 100,000 cancer patients found in the AACR Project GENIE® database. Mutational landscapes of patients within GENIE helped identify preclinical models that represent patient profiles likely to be encountered in the clinic. These results were utilized in prioritizing indications for the planned Phase 2a clinical trial.

Clinical trials
A Phase 1/2a Study of IMM-1-104 in Participants With Previously Treated, RAS-Mutant, Advanced or Metastatic Solid Tumors – NCT05585320

[1] Nair P, Funt J, Kolitz S, De Jong J, King PJ, Yamamura A, Johnson M, Kang S, Zhang J, Fowler KD, Travesa A, Brothers J, Axel A, Walker C, Barrett S, Zeskind BJ, Hall BM Humanized 3D tumor models that are mutationally aligned with AACR GENIE patients predict IMM-1-104 activity in RAS-addicted tumors. In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract nr. #4265

Featured image: New Orleans, LA – The AACR 2016 Annual Meeting. Photo courtesy © 2016 AACR/Todd Buchanan. Used with permission.

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