Immuneering Stock

Immuneering Corporation operates as a clinical-stage oncology company developing medicines for broad populations of cancer patients.

The company’s initial aim is to develop a universal-RAS therapy, an approach designed to include patients with solid tumors driven by any mutation in KRAS, NRAS, or HRAS. The company’s inclusive approach differentiates the company from narrowly targeted precision therapies, which are limited to patients with tumors harboring select mutations.

The company is evaluating its lead product candidate, IMM-1-104, in a Phase 1/2a clinical trial in patients with advanced solid tumors harboring RAS mutations. IMM-1-104 is being developed as a once-daily oral monotherapy that aims to achieve universal-RAS activity through deep cyclic inhibition of the MAPK pathway. Deep cyclic inhibition is a novel mechanism that aims to deprive tumor cells of the sustained proliferative signaling required for rapid growth, while sparing healthy cells through a cadenced, normalized level of signaling. This mechanism was engineered using the company’s proprietary informatics-based discovery platform. The development of the company’s pipeline is translationally guided by the company’s proprietary, human-aligned 3D tumor modeling platform that the company combine with bioinformatics-driven patient profiling, which has the potential to increase the probability of success in clinical development versus traditional drug development approaches. The company’s second product candidate, IMM-6-415, aims to achieve universal-MAPK activity with an accelerated twice-daily oral dosing cadence, also through deep cyclic inhibition of the MAPK pathway. IMM-6-415 is in Investigational New Drug application, or IND, enabling studies. The company’s pipeline also includes Trifecta MEK, RAS modulators, and other small molecule drug discovery programs.

In November 2022, the company commenced dosing in its Phase 1/2a clinical trial of IMM-1-104 for the treatment of advanced RAS mutant solid tumors. The Phase 1/2a clinical trial is designed to assess the safety, tolerability, pharmacokinetics, or PK, pharmacodynamics, or PD, and preliminary anti-tumor activity of IMM-1-104. The Phase 1 portion of the clinical trial includes a dose escalation and expansion portion and will evaluate IMM-1-104 using a Bayesian modified toxicity probability interval, or mTPI-2, statistical design to establish an optimized recommended Phase 2 dose in solid tumor patients with evidence of any RAS mutation. The planned Phase 2a portion will evaluate IMM-1-104 at the recommended Phase 2 dose in an expanded cohort of solid tumor patients with certain RAS mutated cancers, including potentially pancreatic, melanoma, colorectal and lung. IMM-1-104 is in the dose escalation portion of the trial. The company anticipates reporting initial PK and safety data from the Phase 1 portion of the clinical trial in mid-2023, and initial PD modeling and additional PK and safety data in the second half of 2023. Subject to the results from the Phase 1 portion of the trial, including safety and tolerability data, the company anticipates initiating the Phase 2a portion of the trial in mid-2024.

Wholly Owned Pipeline

The company’s oncology programs target clinically validated pathways, while seeking to improve patient outcomes across a wide range of solid tumor types through the company’s differentiated programs. The company’s pipeline of product candidates and discovery programs is depicted below.

Universal-RAS Program (IMM-1-104)

The company’s lead product candidate, IMM-1-104, is being developed as a once-daily oral monotherapy in RAS mutant tumors. IMM-1-104 is designed to achieve a unique pharmacokinetic, or PK, profile: it aims for a manyfold higher CMax to provide stronger inhibition of the MAPK pathway than has been observed with first and second generation MEK inhibitors, followed by a complete release of the MAPK pathway through a near-zero drug trough. This deep cyclic inhibition may enable broad universal-RAS activity with improved tolerability and limit the development of adaptive resistance.

IMM-1-104 was observed to bind to mitogen-activated protein kinase kinase, or MEK, and acts as a highly selective inhibitor of mitogen-activated protein kinase kinase kinase, or ERK, activation (i.e., phosphorylation), with a ‘Dual MEK’ function that is designed to block the CRAF-bypass feedback to prevent MAPK pathway reactivation. IMM-1-104 is designed with a short plasma half-life that reduces sustained pathway inhibition (as depicted below). IMM-1-104 is also designed to prevent RAF-mediated activation of MEK, such as CRAF-bypass, by engagement of the RAF activation loop on MEK, and at elevated levels further disrupt the kinase suppressor of RAS 1 and 2, or KSR. This method of pathway inhibition has the ability to normalize cancer cell signaling dynamics and limits unnecessary harm to normal healthy cells. Collectively, these qualities differentiate IMM-1-104 from other treatment options for RAS mutant and other MAPK-addicted tumors, as well as from known MEK inhibitors, by potentially enabling IMM-1-104 to reduce drug resistance while improving tolerability.

In preclinical studies, the company observed that IMM-1-104 inhibited MEK and ERK across a wide range of human and murine solid tumor models, including those with activating mutations in KRAS, NRAS, HRAS and BRAF. In addition, in head-to-head preclinical studies, the company evaluated IMM-1-104 in murine-based KRAS, NRAS, and BRAF mutant solid tumor models representing lung, colon, pancreas and skin cancer, and observed tumor stasis or regression with insignificant body weight loss, or BWL, when compared to certain FDA-approved MEK inhibitors at reported human dose equivalent dose and schedules. Given the data observed in these preclinical studies, IMM-1-104 has the potential to deliver clinical benefit as monotherapy and, in the future, if approved, may potentially be administered in select drug combinations for patients with RAS mutant solid tumors who have limited treatment options.

In September 2022, the FDA cleared the company’s IND for IMM-1-104 and in November 2022 the company commenced dosing in a Phase 1/2a clinical trial for IMM-1-104. IMM-1-104 is in the dose escalation portion of the trial. The company anticipates reporting initial PK and safety data from the Phase 1 portion of the clinical trial in mid-2023, and initial PD modeling and additional PK and safety data in the second half of 2023. Subject to the results from the Phase 1 portion of the trial, including safety and tolerability data, the company anticipates initiating the Phase 2a portion of the trial in mid-2024.

Universal-MAPK Program (IMM-6-415)

The company’s second program, which the company refers to as its Universal-MAPK program, is focused on developing innovative allosteric MEK inhibitors that drive deep cyclic inhibition of the MAPK pathway with an even shorter plasma half-life and accelerated pharmacokinetic cadence relative to IMM-1-104. The company’s product candidate for this program is designated as IMM-6-415. In a scientific poster presented at the Society for Immunotherapy of Cancer Annual Meeting in November 2022, the company presented preclinical data demonstrating that IMM-6-415 inhibited the growth of RAF and RAS mutant tumors as a monotherapy across multiple human and murine solid tumor models and could be administered in combination with select immune modulators (e.g., checkpoint inhibitors) for the treatment of certain solid tumors, which are often poorly immunologically accessible. IMM-6-415 is designed to target MEK in a way that disrupts the MAPK pathway at ERK through reduction of MEK activation. The company designed IMM-6-415 to have a unique PK and pharmacodynamic, or PD, profile that may be optimized for distinct solid tumors, potentially including a broad range of MAPK-driven tumors as a monotherapy, as well as for normalizing the patient’s immune response and promoting maximal antitumor responses when administered in combination with select immune modulators. IMM-6-415 is in IND-enabling studies and the company plan to submit an IND for IMM-6-415 to the FDA in the fourth quarter of 2023.

Additional Oncology Discovery Research Programs

The company is leveraging its platform to continue expanding the company’s oncology pipeline by targeting the MAPK pathway and other relevant signaling pathways representing critical tumor-addicted pathways in novel ways. The company also continues to evaluate and prioritize its pipeline, including the company’s earlier stage discovery pipeline. The company has three additional programs at various stages of drug discovery focused on targeting these pathways through novel pharmacological approaches. The company recently streamlined the number of the company’s early discovery programs to three in order to focus the company’s efforts and resources on the most promising near-term areas of development and enable the greatest pipeline synergies. To that end, the company has deprioritized and paused the company’s covalent MEK and PI3K programs and combined the company’s RAS inducer and RAS inhibitor program into a RAS modulators program. The company has also suspended its neuroscience programs to sharpen the company’s focus on its core oncology programs.

Strategy

The company is a clinical-stage oncology company developing medicines for broad populations of cancer patients. The company’s initial aim is to develop a universal-RAS therapy, an approach designed to include patients with solid tumors driven by any mutation in KRAS, NRAS, or HRAS. The company’s platform allows the company to leverage human biological data to generate insights that are not constrained by the inherent limitations of conventional approaches or prevailing scientific views. The company is developing novel product candidates that aim to optimize safety, efficacy, and durability of response for diseases with suboptimal treatment options.

The key elements of the company’s strategy are to advance the company’s Universal-RAS Program, IMM-1-104, through Clinical Development; advance the company’s Universal-MAPK Program, IMM-6-415, into clinical development; progress the company’s pipeline of additional MAPK and other pathway programs to IND-enabling studies; and continue to grow and advance the company’s platform.

Trifecta-MEK Program

The company is developing novel product candidates that are designed to uniquely engage MEK and inhibit the upstream activation events of MEK and the downstream activation events of ERK in MEK itself, for the treatment of solid tumors. The inhibition of upstream and downstream activation events of MEK and ERK bypass MAPK pathway reactivation events (i.e., contributing to drug resistance). The company’s investigational Trifecta- MEK program inhibitors are designed to be differentiated from IMM-1-104 and IMM-6-415 due to their potential mechanism of target engagement, novel potential to allosterically inhibit MEK and KSR disruption, along with a unique PK design approach. The potential dosing intervals, potency and mechanisms of target engagement of the company’s investigational Trifecta-MEK program inhibitors may broaden the application of these inhibitors to metabolically diverse RAS and RAF mutant tumors. The company is designing its investigational Trifecta-MEK program inhibitors to be administered as monotherapy to provide potentially better alternatives to combination therapies inhibiting MEK and RAF in BRAF mutant tumors.

The company has evaluated one of the company’s investigational Trifecta-MEK program inhibitors head-to-head against binimetinib and encorafenib in a cell-based potency study to observe comparisons in the reduction of activated MEK and ERK in KRASG12S and BRAFV600E mutant tumor models. In the KRAS mutant tumor model, the company’s investigational Trifecta-MEK program inhibitor provided greater inhibition of activated MEK and ERK as compared to binimetinib and encorafenib. In the BRAF mutant tumor model, the company’s investigational Trifecta-MEK program inhibitor displayed greater inhibition of activated MEK and ERK as compared to binimetinib, and greater activated ERK inhibition as compared to encorafenib. The company’s Trifecta-MEK program is in the drug discovery stage of development.

RAS Modulators Program

The company is developing investigational mutation agnostic RAS modulators that are designed to bind to a unique, undisclosed site on RAS for the treatment of solid tumors. The company’s investigational RAS modulators have the potential to disrupt RAS biology and therapeutically disrupt MAPK signaling in patients with various RAS mutant tumors, which represent approximately 20% of all cancer patients. Although drugs in this class have begun targeting RAS mutations, such as KRASG12C and KRASG12D, a majority of KRAS mutations, which the company is designing its RAS modulators to target, will remain unaddressed.

In the humanized 3D-TGA tumor model, the company observed a half maximal tumor inhibitor concentration, or IC50, of less than 0.1 µM for twelve of the company’s investigational RAS modulators. A low IC50 value means that a drug may be effective at low concentrations and may provide lower systemic toxicity when administered to the patient because of the low concentration required to generate therapeutic activity. Based on these tumor models, the company’s investigational RAS modulators may achieve RAS signaling disruption when administered at low concentrations, providing the potential for improved tolerability as compared to other FDA-approved MAPK pathway drugs. The company’s RAS program is in the drug discovery stage of development.

Additional Early Discovery Drug Programs

In addition to the discovery programs described above, the company is pursuing drug discovery efforts towards an undisclosed but validated oncology target. The company continues to periodically evaluate its drug discovery efforts and are focused on developing and advancing the company’s early pipeline by addressing validated oncology targets in new ways that may better address unmet clinical needs. The company’s proprietary platforms are central to the company’s discovery and translational efforts, and the company continues to prioritize and de-prioritize early discovery drug programs that demonstrate (or fail to demonstrate) clear, targetable patterns of oncogenic addiction that are therapeutically responsive to deep, cyclic target inhibition. This approach ensures that the company advances drug programs with potential for broad activity and improved overall tolerability.

To that end, the company has deprioritized and paused the company’s covalent MEK and PI3K programs. The company also suspended its neuroscience programs to sharpen the company’s focus on its core oncology programs.

Intellectual Property

As of February 27, 2023, the company had one issued U.S. patent; five pending U.S. patent applications; 20 pending patent applications outside the U.S.; three U.S. provisional applications; and one Patent Cooperation Treaty, or PCT, application that has not entered national stage. These patents and patent applications relate to subject matter, including the company’s lead product candidate, IMM-1-104, the company’s Universal-MAPK candidate, IMM-6-415, the company’s DCT, and Fluency. Excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable; the company’s owned issued U.S. patent and any patents that may issue from the company’s owned pending U.S. patent applications are expected to expire in February 2039 or January 2041; any patents that may issue from the company’s owned pending foreign patent applications are expected to expire in January 2041, and any patents that may issue from national phase filings from the company’s PCT application are expected to expire in January, 2043.

With respect to IMM-1-104, as of February 27, 2023, the company had one pending U.S. patent application and 20 pending patent applications outside the U.S. This U.S. patent application, and these pending patent applications outside the U.S., include pending claims directed to compounds, pharmaceutical compositions, and methods of use. Any patent that may issue, based upon these pending applications related to IMM-1-104, is expected to expire in January 2041, excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable.

With respect to IMM-6-415, as of February 27, 2023, the company had one pending provisional U.S. application and one pending PCT application. Any patent that may issue, based upon this provisional U.S. application related to IMM-6-415, is expected to expire in November, 2043 and any patent that may issue based upon the pending PCT application is expected to expire in January, 2043, excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable.

With respect to the company’s DCT, as of February 27, 2023, the company had one issued U.S. patent and one pending U.S. patent application. The issued claims of this U.S. patent and the pending claims of this U.S. patent application are directed to methods (processes) and systems. The company’s issued U.S. patent related to the company’s DCT and any patent that may issue from the company’s pending patent application related to the company’s DCT are expected to expire in February 2039, excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable.

With respect to Fluency, as of February 27, 2023, the company had three pending U.S. patent applications. The pending claims of these U.S. patent applications are directed to methods (processes) and systems. Any patent that may issue from the company’s pending patent application related to Fluency is expected to expire in February 2039, excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable.

As of February 27, 2023, the company owned certain trademark registrations and pending applications for trademark registration, for the marks FLUENCY, DISEASE CANCELLING and IMMUNEERING in the United States and/or certain foreign jurisdictions.

Government Regulation

Among others, the FDA, U.S. Department of Health and Human Services Office of Inspector General, the Centers for Medicare and Medicaid Services and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial and burdensome requirements upon companies involved in the preclinical and clinical development, manufacture, marketing and distribution of drugs, such as those the company is developing.

Research and Development

The company’s research and development expenses were approximately $36.3 million for the year ended December 31, 2022.

History

Immuneering Corporation was founded in 2008. The company was incorporated under the laws of the state of Delaware in 2008.