Immuneering Announces Positive Initial Phase 1 Data for IMM-1-104 Universal-RAS Program; Accelerates Study Timeline

Immuneering Corporation recently announced positive initial pharmacokinetic (PK), pharmacodynamic (PD), and safety data from the Phase 1 trial of IMM-1-104 (NCT05585320), which was shared in a poster presentation titled Humanized 3D tumor models that are mutationally aligned with AACR GENIE patients predict IMM-1-104 activity in RAS-addicted tumors (abstract #4265) at the American Association for Cancer Research (AACR) annual meeting.

“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,” said Ben Zeskind, PhD, MBA, Co-founder, and Chief Executive Officer of Immuneering. “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 C_max 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.”

“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,” said Brett Hall, PhD, Chief Scientific Officer of Immuneering. “With today’s results showing an approximate two-hour half-life coupled with reaching target C_max 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.”

“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,” added Scott Barrett, MD, Chief Medical Officer of Immuneering. “We are grateful to the patients participating in our trial, and to the investigators. Investigator enthusiasm remains high, which combined with our study’s broad inclusion criteria, gives us confidence in our ability to keep enrolling patients in an expeditious manner.”

The Phase 1/2a clinical trial is an open-label study 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 Company 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.

Highlights of the initial IMM-1-104 Phase 1 PK, PD and safety data presented at AACR include (as of data cut-off date of April 10, 2023, including patients with pancreatic and colon cancer):

• Significant PK C_max levels (plasma concentration of therapy in a specific area of the body) observed with IMM-1-104 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) with IMM-1-104 compared to pretreatment baseline for patients at the third dose level (160 mg once daily oral)
• A median plasma half-life (t_1/2) of 1.94 hours observed with IMM-1-104 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
• IMM-1-104 was well tolerated with no DLTs or SAEs observed and no drug-related adverse events beyond Grade 1 observed

Based on the encouraging initial data presented, Immuneering has updated guidance for the anticipated timing of announcing a RP2D for IMM-1-104 for its Phase 1/2a study. Management now expects to announce the RP2D in early 2024, versus prior guidance of mid-2024.

Other data presented at AACR:

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.

Updated Near-Term Milestone Expectations

IMM-1-104

• Additional trial updates expected on a periodic basis.
• RP2D and additional safety data expected in early 2024.

IMM-6-415

• IND filing expected in the fourth quarter of 2023.

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. IMM-1-104 is currently being evaluated in a Phase 1/2a study in patients with advanced solid tumors harboring RAS mutations (NCT05585320).

Immuneering is a clinical-stage oncology company developing medicines for broad populations of cancer patients with an initial aim to develop a universal-RAS therapy. The company aims to achieve universal activity through deep cyclic inhibition of the MAPK pathway, impacting cancer cells while sparing healthy cells. Immuneering’s lead product candidate, IMM-1-104, is in a Phase 1/2a study in patients with advanced solid tumors harboring RAS mutations. The company’s development pipeline also includes IMM-6-415, a universal-MAPK program, as well as several early stage programs. For more information, visit www.immuneering.com.