What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2023-03-06 compared with 2022-03-10 · 373 added, 450 removed, 493 unchanged (63% of the section changed)

We aim to improve patient outcomes by advancing a unique pipeline of oncology and neuroscience product candidates developed using our translational bioinformatics platform.

We have more than a decade of experience applying translational bioinformatics to generate insights into drug mechanism of action and patient treatment response.

Building on this experience, our disease-agnostic discovery platform enables us to create product candidates based on 1) biological insights that are both counterintuitive and deeply rooted in data, and 2) novel chemistry.

Our lead product candidate IMM-1-104 is designed to be a highly selective dual-MEK inhibitor that further disrupts KSR to modulate the signaling dynamics of the MAPK pathway.

Specifically, it is designed to use deep cyclic inhibition to deprive tumor cells of the sustained proliferative signaling required for rapid growth, while providing a cadenced, moderate level of signaling sufficient to spare healthy cells.

IMM-1-104 is being developed to treat advanced solid tumors in patients harboring RAS mutant tumors, guided by our proprietary, human-aligned 3D tumor modeling platform combined with translational bioinformatics and expertise in translational planning.

In addition to IMM-1-104, we have six other oncology programs in the discovery stage that are designed to target either the MAPK or mTOR pathway, and two neuroscience programs in the discovery stage.

We plan to submit an Investigational New Drug application (an “IND”) to the Food and Drug Administration (“FDA”) for IMM-1-104 in the third quarter of 2022.

In addition, we anticipate filing an IND for IMM-6-415, our MEK-io candidate, in 2023, and plan to file an additional IND for another oncology program in 2024.

Our platform is enabled by our ability to efficiently analyze high-throughput molecular-level biochemical assays, including transcriptomics, genomics and/or proteomics, collectively referred to as Omics data.

These different types of biochemical assays each provide us with unique information about the molecular mechanisms of disease biology and drug response.

We are a clinical-stage oncology company developing medicines for broad populations of cancer patients.

Our 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.

Our inclusive approach differentiates us from narrowly targeted precision therapies, which are limited to patients with tumors harboring select mutations.

We are currently evaluating our 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 our proprietary informatics-based discovery platform.

The development of our pipeline is translationally guided by our proprietary, human-aligned 3D tumor modeling platform that we combine with bioinformatics-driven patient profiling, which we believe has the potential to increase the probability of success in clinical development versus traditional drug development approaches.

Our 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 currently in Investigational New Drug application, or IND, enabling studies.

Our pipeline also includes Trifecta MEK, RAS modulators, and other small molecule drug discovery programs.

In November 2022, we commenced dosing in our 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 currently in the dose escalation portion of the trial.

We anticipate 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, we anticipate initiating the Phase 2a portion of the trial in mid-2024.

Our platform is enabled by two key elements:

● Bioinformatics:

our ability to efficiently analyze high-throughput molecular-level biochemical assays, including transcriptomics, genomics and/or proteomics, collectively referred to as Omics data;

● 3D Tumor Modeling:

our ability to conduct in vitro studies in our own labs using proprietary humanized 3D tumor growth assays that we believe predict in vivo activity more accurately than traditional 2D cell culture models.

These different types of biochemical and 3D tumor growth assays each provide us with unique information about the molecular mechanisms of disease biology and drug response and help to guide our translational planning and development.

Since our inception, we have partnered with industry-leading pharmaceutical and biotechnology companies to perform a variety of analyses that utilize our expertise in translational bioinformatics.

4 unchanged sentences

● leverage insights from human data to identify disease transcriptional profiles we aim to counteract;

● identify novel biology, specifically evaluating new ways to drug an existing target by utilizing our proprietary Disease Cancelling Technology, or DCT, and analyze mechanisms of existing drugs;

● generate novel chemistry that overcomes MAPK-feedback loops to achieve optimal signaling dynamics;

● profile IMM-1-104 in a large number of 3D models using our own translational planning to identify the types of cancer most likely to be sensitive to the product candidate.

Our current oncology programs target mutations of the RAS/RAF/MEK/ERK, or MAPK, and the PI3K/AKT/mTOR, or mTOR, pathways.

The MAPK and mTOR signaling pathways run parallel to each other, and in over half of all cancers, one or both of these pathways are inappropriately activated (as depicted below).

Existing drugs targeting these pathways are limited by toxicity, resistance and/or are narrowly focused on subpopulations with specific mutations.

The MAPK and mTOR pathways function to drive cell proliferation, differentiation, survival and a variety of other cellular functions that are critical for the formation of tumors.

● identify novel biology, specifically evaluating potential new ways to drug an existing target by utilizing our proprietary Disease Cancelling Technology, or DCT, and analyze mechanisms of existing drugs;

● generate novel chemistry that is designed to overcome MAPK-feedback loops and other adaptive resistance mechanisms to achieve optimal signaling dynamics;

● profile IMM-1-104 and any other product candidates in a large number of proprietary humanized 3D tumor growth assays using our own translational planning to identify the types of cancer we believe most likely to be sensitive to the product candidate.

Our current oncology programs are focused on tumors driven by mutations of the RAS/RAF/MEK/ERK, or MAPK pathway, and other relevant signaling pathways.

Existing drugs targeting the MAPK pathway are limited by toxicity, resistance and/or are narrowly focused on subpopulations with specific mutations.

The MAPK pathway functions to drive cell proliferation, differentiation, survival and a variety of other cellular functions that are critical for the formation and progression of tumors.

Fundamental Cancer Signaling Cellular Pathways

MAPK and mTOR

Each of the programs in our oncology pipeline is designed to cause cyclical disruption of abnormal activation of the MAPK and mTOR signaling pathways while limiting drug-related toxicity.

Traditional drug approaches have been designed to sustain pathway inhibition, which can cause on-target drug-related toxicity and limit clinical durability as a result of drug holidays or treatment discontinuation.

Based on insights derived from our translational bioinformatics platform, our differentiated approach is to design drugs with short half-lives that provide enhanced mechanistic control of the target of interest and break tumor addiction, which is the tumor’s ability to indefinitely self-replicate, metastasize and evade the host’s immune system, among other capabilities, through deep cyclic disruption of these pathways (i.e., signaling dynamics).

By cyclically disrupting these core oncogenic signaling pathways in cancer cells, we believe we can create novel therapeutics that maximize therapeutic activity in broad patient populations while providing an improved tolerability profile (as depicted below).

We believe we are pioneers in this unique approach of leveraging signaling dynamics against tumor addiction.

Signaling Dynamics:

Traditional Sustained Inhibition Versus Our Cyclic Approach

Deep Cyclic Inhibition of Cancer Signaling Pathways Challenges the Prevailing Chronic Ablation Approach

Each of the programs in our oncology pipeline is designed to drive cyclical disruption of abnormal activation of the MAPK signaling pathway or other relevant signaling pathways, with the goal of maximizing antitumor therapeutic effects while limiting drug-related toxicity and adaptive resistance.

Traditional targeted oncology drug development generally seeks to chronically sustain pathway inhibition, by prioritizing drugs with long to moderate half-lives and dosing them at intervals that maintain a sufficient level of drug, even at trough, to maintain target occupancy.

This prevailing chronic ablation approach can cause on-target drug-related toxicity and limit clinical durability as a result of drug holidays, treatment discontinuation, and/or adaptive resistance.

By contrast, our differentiated approach, based on counterintuitive insights derived from our translational bioinformatics platform, is to design novel drugs with at least three key aims:

1) achieve a manyfold higher C Max , 2) display a short plasma drug half-

life, and 3) endow drugs with the ability to block feedback loops that would otherwise be susceptible to pathway reactivation.

This design aims to provide enhanced mechanistic control of the target of interest and break tumor addiction, to prevent tumors from indefinitely self-replicating, metastasizing and evading the host’s immune system, among other capabilities.

By cyclically disrupting these core oncogenic signaling pathways in cancer cells (i.e., imposing normalized signaling dynamics), we believe we can create novel therapeutics that maximize therapeutic activity in broad patient populations while providing an improved tolerability profile and improved durability through reduced pressure stemming from adaptive resistance.

We believe we are pioneers in this unique approach of therapeutically leveraging signaling dynamics against tumor addiction.

Pharmacokinetic Conceptual Visualization:

Traditional Sustained Pathway Attenuation Versus Deep, Cyclic Inhibition

Our Wholly Owned Pipeline

Our oncology programs target clinically validated pathways, but we seek to improve patient outcomes across a wide range of addressable solid tumor types through our differentiated programs.

In addition to our oncology pipeline, we are also leveraging our platform to build a neuroscience pipeline initially focusing on Alzheimer’s disease, or AD.

Our oncology programs target clinically validated pathways, while seeking to improve patient outcomes across a wide range of solid tumor types through our differentiated programs.

Our current pipeline of product candidates and discovery programs is depicted below.

Dual-MEK Program

Our dual mitogen-activated protein kinase kinase, or MEK, product candidate, IMM-1-104, is designed to be a highly selective inhibitor of mitogen-activated protein kinase kinase kinase, or ERK, activation (i.e., phosphorylation), prevent MAPK pathway reactivation and have a short plasma half-life that reduces sustained pathway inhibition (as depicted below).

Unlike MEK inhibitors approved by the U.S.

Food and Drug Administration, or the FDA, IMM-1-104 is designed to prevent RAF-mediated activation of MEK by engagement of the RAF activation loop on MEK, such as CRAF-bypass, and further disrupt the kinase suppressor of RAS 1 and 2, or KSR.

Additionally, with a short plasma half-life, IMM-1-104 can achieve deep cyclic inhibition of the MAPK pathway.

We believe this innovative method of pathway inhibition normalizes cancer cell signaling dynamics and prevents further damage to normal healthy cells.

Collectively, we believe these qualities differentiate IMM-1-104 from known MEK inhibitors by potentially enabling IMM-1-104 to avoid drug resistance while improving tolerability.

Dual-MEK Inhibition Prevents Activation of MEK and Downstream Activation of ERK

Universal-RAS Program (IMM-1-104)

Our 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 C Max 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.

We believe 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.

We believe this innovative method of pathway inhibition has the ability to normalize cancer cell signaling dynamics and limits unnecessary harm to normal healthy cells.

Collectively, we believe 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, we 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, we 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 current FDA- approved MEK and BRAF inhibitors.

Given the data observed in these preclinical studies, we believe that IMM-1-104 has the potential to deliver clinical benefit as monotherapy and, in the future, may potentially be administered in select drug combinations for patients with RAS and/or RAF mutant solid tumors who currently have limited treatment options.

IMM-1-104 is currently undergoing Investigational New Drug, or IND, enabling studies.

We plan to submit an IND for IMM-1-104 to the FDA in the third quarter of 2022.

We intend to enroll our first patient in our first-in-human Phase 1 clinical trial of IMM-1-104 in the fourth quarter of 2022 for the treatment of advanced solid tumors in patients harboring RAS mutant tumors, if our IND for IMM-1-104 is accepted.

MEK-Immuno-Oncology

Our MEK-immuno-oncology, or MEK-io, program is focused on developing innovative allosteric MEK inhibitors to be administered in combination with select immune modulators (e.g., checkpoint inhibitors) for the treatment of “cold” solid tumors, which are immunologically inaccessible.

Our investigational MEK-io program inhibitors were designed to target MEK in a way that disrupts the MAPK pathway at ERK and to also reduce baseline MEK activation.

We designed these inhibitors with unique pharmacokinetic, or PK, and pharmacodynamic, or PD, profiles that may enhance cycle inhibition time of MEK and ERK to optimize the patient’s immune response and promote maximal antitumor responses when administered in combination with select immune modulators.

We recently selected a development candidate, IMM-6-415, for the MEK-io program, and initiated IND-enabling studies in the first quarter of 2022.

We observed an initial in vivo proof-of-concept for our MEK-io program, from a related analogue compound to IMM-6-415, in a widely utilized syngeneic murine model.

We evaluated this analogue compound as monotherapy and in combination with a checkpoint inhibitor and compared to vehicle to observe tumor growth inhibition in tumor-bearing BALB/C mice.

Neither treatment alone altered tumor growth as compared to vehicle.

However, when we administered our analogue MEK-io program inhibitor in combination with the checkpoint inhibitor, we observed greater than 50% tumor growth inhibition after two weeks of dosing as compared to vehicle treated mice.

IMM-6-415 may enhance responses to checkpoint inhibitors in tumors that have been responsive to these class of agents.

We observed single agent activity in the Colon-26 syngenetic colorectal tumor model and are evaluating IMM-6-415 as monotherapy or in combination with checkpoint inhibitors in CT26 and MC-38 syngeneic models.

We plan to submit an IND for IMM-6-415 to the FDA in 2023.

Given the data observed in these preclinical studies, we believe that 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 currently have limited treatment options.

In September 2022, the FDA cleared our IND for IMM-1-104 and in November 2022 we commenced dosing in a Phase 1/2a clinical trial for IMM-1-104.

IMM-1-104 is currently in the dose escalation portion of the trial.

We anticipate 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, we anticipate initiating the Phase 2a portion of the trial in mid-2024.

Universal-MAPK Program (IMM-6-415)

Our second program, which we refer to as our 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.

Our 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, we 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.

We 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 currently in IND-enabling studies and we plan to submit an IND for IMM-6-415 to the FDA in the fourth quarter of 2023.

Additional Oncology Discovery Research Programs

We are leveraging our platform to continue expanding our oncology pipeline by targeting the MAPK and mTOR pathways in novel ways.

We have five additional programs in various stages of drug discovery focused on targeting these pathways through novel pharmacological approaches.

We expect to file an IND for at least one of these programs in 2024.

Neuroscience Programs

AD is the most common form of dementia and one in three adults over the age of 65 succumb to AD-related dementia or another form of dementia.

We believe there are specific subgroups of AD that can be stratified through gene expression and brain pathology.

To identify AD subgroups, we have leveraged our platform to employ a patient-centric, data-driven approach.

AD is a neurodegenerative disorder of uncertain cause and pathogenesis characterized by memory impairment and further cognitive decline that can ultimately affect the patient’s behavior, speech, visuospatial orientation and motor system.

AD is a complex multifactorial disease driven by genetic and environmental causes that affects older adults and is one of the leading sources of morbidity and mortality in the aging population.

The estimated total healthcare costs for the treatment of AD were approximately $305 billion in 2020, with the cost expected to increase to more than $1 trillion by 2050.

Our neuroscience programs are in the early stages of drug discovery, and we are evaluating undisclosed targets to pursue a unique approach to treating AD.

Our focus is to slow the progression of AD by developing targeted therapies for distinct biological mechanisms that we have identified in specific AD subgroups.

Our platform and expertise in neurology and neuroscience have allowed us to determine biological differences in AD patients to help develop novel product candidates that may potentially address the significant unmet needs of this underserved patient population.

We are leveraging our platform to continue expanding our oncology pipeline by targeting the MAPK pathway and other relevant signaling pathways representing critical tumor-addicted pathways in novel ways.

We also continue to evaluate and prioritize our pipeline, including our earlier stage discovery pipeline.

We currently have three additional programs at various stages of drug discovery focused on targeting these pathways through novel pharmacological approaches.

We recently streamlined the number of our early discovery programs to three in order to focus our efforts and resources on

what we believe represent the most promising near-term areas of development and enable the greatest pipeline synergies.

To that end, we have deprioritized and paused our covalent MEK and PI3K programs and combined our RAS inducer and RAS inhibitor program into a RAS modulators program.

We have also suspended our neuroscience programs to sharpen our focus on our core oncology programs.

We were founded in 2008 by our Chief Executive Officer and President, Benjamin J.

Zeskind, Ph.D., and the Chairman of our board of directors, Robert J.

Carpenter, with the goal of leveraging translational bioinformatics to generate insights into the mechanisms that cause certain patients to respond to specific medicines across multiple therapeutic areas.

Our multi-disciplinary team brings together experts across translational bioinformatics, preclinical and clinical development in both oncology and neuroscience and includes individuals with extensive experience at some of the leading pharmaceutical companies, including Johnson & Johnson, AstraZeneca, Merck and Incyte.

Our multi-disciplinary R&D team is led by our Chief Scientific Officer, Dr.

Brett Hall, who was the translational lead for Sylvant® (siltuximab) and Imbruvica® (ibrutinib) throughout clinical development, and our Chief Medical Officer, Dr.

Scott Barrett, an accomplished medical oncologist and R&D expert with more than 30 years of clinical and research experience.

Under their leadership, our R&D team brings together expertise across translational bioinformatics, preclinical and clinical development in oncology and includes individuals with extensive experience at some of the leading pharmaceutical companies, including Johnson & Johnson, AstraZeneca, Merck and Incyte.

Our company is built on more than a decade of experience in translational bioinformatics.

Since our founding in 2008, we have utilized this experience to generate insights into the mechanisms that cause certain patients to respond to specific medicines across therapeutic areas by analyzing Omics data.

Our computational biology services business has helped us to better understand how translational bioinformatics can contribute to each stage of drug development, from early drug discovery to clinical development and through commercialization.

Our computational biology services business helped us to better understand how translational bioinformatics can contribute to each stage of drug development, from early drug discovery to clinical development and through commercialization.

However, we recognized the limitations of applying translational bioinformatics in isolation to specific stages of the drug development process and realized that bioinformatics could be even more helpful if applied continuously throughout the drug development process.

Over time, we have developed a proprietary technology platform to facilitate that process and, in early 2018, we began applying the extensive insights from and capabilities of our platform and approach to create a wholly owned pipeline of drug programs, initially focusing on oncology.

Our mission is to develop novel therapies by utilizing our disease-agnostic platform to address areas of high unmet medical need, initially in cancer and neurologic diseases.

Over time, we have developed a proprietary technology platform to facilitate that process and, in early 2018, we began applying the extensive counterintuitive insights from and capabilities of our platform and approach to create a wholly owned pipeline of novel small molecule drug programs, initially focusing on oncology.

We are a clinical-stage oncology company developing medicines for broad populations of cancer patients.

Our 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.

Our platform allows us to leverage human biological data to generate insights that are not constrained by the inherent limitations of conventional approaches or prevailing scientific views.

We are developing novel product candidates that aim to optimize both safety and efficacy for diseases with suboptimal treatment options.

We are developing novel product candidates that aim to optimize safety, efficacy, and durability of response for diseases with suboptimal treatment options.

To achieve our mission, we are executing a near-term strategy with the following key elements:

● Advance IMM-1-104 into Clinical Development .

● Advance our Universal-RAS Program, IMM-1-104, through Clinical Development .

We believe that IMM-1-104 has the potential to treat broad populations of solid tumor patients, specifically those with inappropriate activation of the MAPK pathway.

IMM-1-104 has been specifically designed to overcome MAPK-feedback loops and, combined with its intentionally short half-life, could have the potential to provide broader therapeutic activity and an improved tolerability profile relative to known MEK inhibitors.

We believe IMM-1-104 has the potential to target patients with a wide spectrum of mutations in KRAS and NRAS, as well as other mutations that activate the MAPK pathway.

IMM-1-104 is currently in IND-enabling studies, and we expect to submit an IND in the third quarter of 2022.

● Advance IMM- 6-415 through IND-Enabling studies.

We recently commenced IND-enabling studies for IMM-6-415 and plan to submit an IND in 2023.

IMM-6-415 is a dual-MEK inhibitor that has drug-like properties optimized for immune modulation, and may enhance and/or expand clinical responses to checkpoint inhibitors in tumors that have proved historically challenging to immune modulating therapies.

In addition, we may target patient populations with RAS and RAF mutations who have observed low rates of clinical responses to checkpoint inhibitors.

● Progress Our Pipeline of Additional MAPK and mTOR Pathway Programs to IND-Enabling Studies .

Other key programs in our oncology pipeline also leverage our knowledge of the MAPK and mTOR pathways, translational bioinformatics and signaling dynamics.

For example, we are advancing programs which modulate the formation of RAS dimers to kill RAS-driven tumors while sparing healthy cells.

We are also applying our platform to other relevant pathways and have initiated a program targeting PI3Kα in the mTOR pathway.

We intend to develop other programs for the mTOR pathway, as well as other oncogenic pathways.

We anticipate submitting an IND for at least one of these programs in 2024.

● Utilize Our Platform to Advance Our Neuroscience Programs.

In addition to our extensive oncology pipeline, we have built a neuroscience pipeline initially focused on AD, which leverages key components of our platform.

We have identified subgroups of AD with distinct molecular drivers and have identified unique undisclosed targets for these specific subgroups.

Currently, we are developing investigational small molecules to inhibit these undisclosed targets, which we intend to continue advancing towards IND-enabling studies.

IMM-1-104 has been specifically designed to provide deep cyclic inhibition of the MAPK pathway with a once-daily oral dosing cadence.

IMM-1-104 was designed to overcome MAPK-feedback loops and to have an intentionally short plasma half-life, which we believe could enable it to provide deep cyclic inhibition.

Collectively, we believe IMM-1-104 has the potential to provide broader therapeutic activity and an improved tolerability profile relative to known MEK inhibitors and that IMM-1-104 has the potential to target patients with solid tumors driven by any mutation in KRAS, NRAS, or HRAS .

IMM-1-104 is currently being evaluated as a monotherapy in a Phase 1/2a clinical trial.

● Advance our Universal-MAPK Program, IMM- 6-415, into Clinical Development.

IMM-6-415 has been specifically designed to provide deep cyclic inhibition of the MAPK pathway with an accelerated cadence relative to IMM-1-104, and we predict that its characteristics will be optimal for twice-daily (BID) administration in humans.

We believe that this accelerated cadence will be differentiated from IMM-1-104 for monotherapy activity in a variety of tumors including those with RAF or RAS mutations, as well as enhanced activity in combination with checkpoint inhibitors.

IMM-6-415 is currenetly in IND-enabling studies and we plan to submit an IND to the FDA in the fourth quarter of 2023.

● Progress Our Pipeline of Additional MAPK and other Pathway Programs to IND-Enabling Studies .

Other key programs in our pipeline leverage our deep understanding of the MAPK and other relevant signaling pathways, and are grounded in translational bioinformatics and signaling dynamics.

For example, we are advancing programs designed to directly modulate RAS activity through novel mechanisms with the aim of killing RAS-driven tumors while sparing healthy cells.

We also actively apply our platform to other relevant pathways as new opportunities arise that may strengthen our pipeline.

● Continue to Grow and Advance Our Platform .

We have built a biopharmaceutical company that fully integrates bioinformatics across all aspects of drug discovery and development.

We currently utilize our bioinformatics platform for our drug discovery efforts in oncology and neuroscience, and as we advance our product candidates into and through the clinic, we plan to utilize data and insights from our bioinformatics platform to not only guide future clinical development but to also provide key learnings back to our earlier stage programs.

Lastly, we continue to iterate on our existing technology and processes, and develop new technologies for our platform, all aimed at creating the most efficient process for the development of product candidates that we believe have the potential to optimize both safety and efficacy in broad patient populations with high unmet medical needs.

We have built a clinical-stage oncology company that fully integrates bioinformatics and translational planning across all aspects of drug discovery and development.

We currently utilize our bioinformatics platform for our drug discovery efforts in oncology, which efforts are translationally guided by our proprietary, human-aligned 3D tumor models, and as we advance our product candidates into and through the clinic, we plan to utilize data and insights from our bioinformatics platform and proprietary humanized 3D tumor models to not only guide future clinical development but to also provide key learnings back to our earlier stage programs.

Our Bioinformatics Approach

Leveraging our history in translational bioinformatics, we have built a biopharmaceutical company that incorporates our expertise into every step of our process to discover and develop novel product candidates.

Leveraging our history in translational bioinformatics, we have built a clinical-stage oncology company that incorporates our expertise into every step of our process to discover and develop novel product candidates.

Our goal is to meaningfully improve patient outcomes as compared to drugs developed through traditional drug discovery approaches.

Our integrated approach has already yielded programs that have exhibited preclinical tumor growth inhibition against a broad range of clinically challenging solid tumors, which are advancing towards the clinic.

Our Dual-MEK and MEK-io drug programs are currently in IND-enabling studies, while the rest of our programs are in earlier stage preclinical studies.

expanded our team of experts, including drug discovery and clinical development experts, to develop a pipeline of product candidates by leveraging our translational bioinformatics expertise (as depicted below).

Our Bioinformatics Expertise Leveraged Through All Stages of Drug Discovery and Development

Our lead product candidate IMM-1-104 is currently being evaluated in a phase 1/2a clinical trial and our IMM-6-415 product candidate is currently in IND-enabling studies, while the rest of our programs are in earlier stages of discovery.

We have expanded our team of experts, including drug discovery and clinical development experts, to develop a pipeline of product candidates by leveraging our translational bioinformatics expertise.

Cancer Overview

Cancer is the second most common cause of death worldwide with approximately 10 million deaths annually and an incidence of approximately 19.3 million new cases in 2020.

Cancer is defined as a collection of diseases in which abnormal cells divide uncontrollably and can invade nearby tissues.

Cancer is defined as a collection of diseases in which abnormal cells divide uncontrollably and can invade nearby and distant tissues.

The uncontrollable division of abnormal cells typically results in a malignant tumor (i.e., cancerous) or benign tumor (i.e., non-cancerous).

5 unchanged sentences

Tumor survival is dependent on certain of these capabilities (i.e., tumor addiction).

MAPK and mTOR Pathways

MAPK Pathway and Beyond

In all cells, signaling pathways govern how cells regulate themselves as well as direct activities in relation to other cells in the body.

Two of the most commonly altered signaling pathways in cancer are the MAPK and mTOR pathways.

MAPK and mTOR are both oncogenic signaling pathways that run parallel to each other.

RAS is a family of related oncogenes found upstream in each pathway that codes for four highly related protein isoforms, HRAS, NRAS, KRAS4A and KRAS4B.

In over half of all cancers, one or both of these pathways are inappropriately activated, often through mutations in the key members of the pathway, including RAS, RAF and PI3Kα.

When RAS is switched “on” through the activation of the membrane-bound receptor tyrosine kinase, or RTK, the MAPK and mTOR pathways function to drive cell proliferation, differentiation, survival and a variety of other cellular functions that are critical for the formation of tumors.

In addition, the membrane-bound RTKs can separately activate the mTOR pathway without the assistance of RAS.

Through widespread adaptation of molecular profiling, we now recognize that up to one in two cancer patients harbor tumors which are inappropriately activated through the MAPK pathway, and an additional one in three display alterations that impact the mTOR pathway.

One of the most commonly altered signaling pathways in cancer is the MAPK pathway.

RAS is a family of related oncogenes found upstream in the MAPK pathway that codes for four highly related protein isoforms, HRAS, NRAS, KRAS4A and KRAS4B.

In many solid tumors, the MAPK pathway is inappropriately activated, often through mutations in the key members of the pathway, including RAS.

When RAS is switched “on” through the activation of the membrane-bound receptor tyrosine kinase, or RTK, the MAPK pathway functions to drive cell proliferation, differentiation, survival and a variety of other cellular functions that are critical for the formation of tumors.

Through widespread adaptation of molecular profiling, we now recognize that up to one in two cancer patients harbor tumors which are inappropriately activated through the MAPK pathway.

Many of these patients display tumors with activation mutations in RAS or RAF, which lie upstream of MEK and ERK.

Because inappropriate activation of the MAPK and/or mTOR pathways supports many of the core tumor capabilities described above, efforts to create new therapeutics to target these pathways has been a high priority in cancer drug research.

However, therapeutics that target the MAPK and mTOR pathways have not lived up to the expectations of effectively disrupting these pathways with high patient tolerability.

Nearly all targeted therapeutics against the MAPK and mTOR pathways have been designed for sustained pathway suppression, which has resulted in on-target drug-related toxicity that limits clinical durability and potential drug-drug combinations.

Furthermore, sustained irreversible covalent inhibition of these pathways may lead to treatment resistance, as highlighted in a recently published study in the New England Journal of Medicine.

Because inappropriate activation of the MAPK pathway supports many of the core tumor capabilities described above, efforts to create new therapeutics to target this pathway have been a high priority in cancer drug research.

However, to date nearly all therapeutics that target the MAPK pathway have been limited to narrow patient subpopulations and have struggled to balance tolerability, durability of response, and efficacy.

Nearly all targeted therapeutics against the MAPK pathway have been designed for sustained pathway suppression, which has resulted in on-target drug-related toxicities that limit clinical durability and potential drug-drug combinations.

Furthermore, sustained irreversible covalent inhibition of these pathways may lead to treatment resistance, as highlighted in a recent study in the New England Journal of Medicine (N Engl J Med 2021;

384:2382-2393).

The study focused on patients treated with adagrasib, an irreversible covalent inhibitor of KRAS G12C , and reported that 45% of patients (17 patients out of 38) in the study receiving adagrasib monotherapy developed resistance.

Of these patients, many resistance mechanisms were observed involving non-G12C variations in KRAS, variations in NRAS or BRAF, or other resistance mechanisms related to the MAPK and mTOR pathways.

A second study published in Nature (November 10, 2021) evaluated 43 patients treated with sotorasib, an irreversible covalent inhibitor of KRAS G12C , and reported 27 patients with multiple treatment-emergent resistance alterations.

Of these, 15 patients reported resistance mechanisms involving RAS/RAF mutations.

Developing novel therapeutics to effectively and safely target these pathways may provide clinical benefit in large patient populations with significant unmet needs.

In addition, although these two pathways represent two of the most active areas in cancer drug discovery and development, targeted therapeutics that more effectively and safely normalize, but not ablate, ERK and mTOR signaling may uncouple drug activity and tolerability, while optimizing both.

Our oncology pipeline is designed to non-chronically disrupt molecular pathways that enable tumor addiction while limiting drug-related toxicity of normal healthy cells that also rely, to a lesser degree, on these pathways.

Our Programs Target Aggressive Solid Tumors That Display High RAS/RAF Mutations

Our Differentiated Approach to Tackling Some the Most Challenging Cancers

We are leveraging our platform to target the MAPK and/or mTOR pathway.

Our differentiated approach is to design drugs with short half-lives that provide enhanced mechanistic control of the target of interest and break tumor addiction through deep cyclic disruption of these pathways (i.e., signaling dynamics).

We believe we are pioneers in this approach of leveraging signaling dynamics against tumor addiction, and our insights derived from our translational bioinformatics platform supports our belief that this approach may result in novel therapies targeting these pathways.

Traditional drug approaches have been designed to sustain pathway inhibition, which leads to on-target drug-related toxicity and becomes

limiting for clinical durability as a result of drug holidays or treatment discontinuation.

The mutational activation and/or overexpression of the signaling components that activate the MAPK pathway are well-known, and MEK has been previously validated as a therapeutic target.

We believe our programs, as compared to FDA-approved treatments targeting the MAPK pathway, have the potential to be differentiated by their unique target engagement and PK and PD profiles.

For example, our lead product candidate, IMM-1-104, is designed to inhibit ERK, prevent MAPK- pathway reactivation and have a short plasma half-life that reduces sustained pathway inhibition compared to other drugs targeting the same mechanistic pathway.

By cyclically disrupting these core oncogenic signaling pathways in cancer cells, we believe we can create novel therapeutics in oncology that maximize therapeutic activity in broad patient populations while providing an improved tolerability profile as compared to other FDA-approved treatments for cancers caused by MAPK pathway activation.

Our Oncology Pipeline

Our current development programs in oncology are focused on providing treatments for patients with solid tumors caused by mutations of the MAPK and mTOR pathways.

Our Dual-MEK product candidate, IMM-1-104, and our MEK-io product candidate, IMM-6-415 are currently being evaluated in IND-enabling studies and are complemented by multiple earlier- stage programs that also target the MAPK and mTOR pathways.

Of these patients, many resistance mechanisms were observed involving non-G12C variations in KRAS, variations in NRAS or BRAF, or other resistance mechanisms related to the MAPK pathway.

A second recent study published in Nature (November 10, 2021) evaluated 43 patients treated with sotorasib, an irreversible covalent inhibitor of KRAS G12C , and reported 27 patients with multiple treatment-emergent resistance alterations.

Of these, 70% (19 out of 27) patients reported resistance mechanisms involving RAS/RAF mutations (Nature 2021;

599:679-683).

Developing novel therapeutics to effectively, broadly and safely target this pathway may provide clinical benefit in large patient populations with significant unmet needs.

In addition, although this pathway represents one of the most active areas in cancer drug discovery and development, targeted therapeutics that more effectively and safely normalize, but not chronically ablate, ERK signaling may uncouple drug activity and tolerability, while optimizing both.

Our pipeline is designed to disrupt molecular pathways in a pulsatile way that undermines tumor addiction while limiting drug-related toxicity of normal healthy cells that are less reliant on a sustained high level of signaling along these pathways

Our Differentiated Approach to Tackling Some of the Most Challenging Cancers

We are leveraging our platform to target tumors driven by the MAPK pathway and other relevant signaling pathways.

Our differentiated approach is to design drugs that can achieve high C max levels through short half-lives and provide enhanced mechanistic control of the target of interest and break tumor addiction through deep, cyclic disruption of these pathways (i.e., regulate signaling dynamics and reduce adaptive resistance).

We believe we are pioneers in therapeutically leveraging signaling dynamics against tumor addiction, and our insights derived from our translational bioinformatics platform supports our belief that this approach may result in novel therapies targeting this pathway and potentially other pathways.

Traditional drug approaches have been designed to sustain pathway inhibition, which leads to on-target drug-related toxicity and becomes limiting for clinical durability as a result of drug holidays, treatment discontinuation, or the development of adaptive resistance.

Mutational activation and/or overexpression of key signaling components that activate the MAPK pathway are well-known, and MEK has been previously validated as a therapeutic target.

We believe our programs, as compared to FDA-approved treatments targeting the MAPK pathway, have the potential to be differentiated by their unique potential combination of target engagement, PK and PD profile.

For example, our lead product candidate, IMM-1-104, is designed to inhibit ERK and MEK, prevent MAPK pathway reactivation and have a short plasma half-life, which would reduce sustained pathway inhibition compared to other drugs targeting the same mechanistic pathway.

compared to other FDA-approved treatments and treatments currently being developed for cancers caused by MAPK pathway activation.

Our current development programs in oncology are focused on providing treatments for patients with solid tumors caused by mutations of the MAPK pathway or other relevant signaling pathways.

Our Universal-RAS product candidate, IMM-1-104, is currently being evaluated in a Phase 1/2a clinical trial, and our Universal-MAPK product candidate, IMM-6-415 is currently being evaluated in IND-enabling studies.

IMM-1-104 and IMM-6-415 are complemented by multiple earlier stage programs that are designed to uniquely target the MAPK pathway or other relevant signaling pathways.

The following table summarizes our oncology pipeline:

Overview of Our Lead Program:

Universal-RAS, IMM-1-104

Background of MEK Inhibitors

Activating mutations of RAS and/or RAF in the MAPK pathway are observed in approximately 30% of all cancer patients, and inappropriate activation of this pathway is observed in up to 50% of all tumors and represents one of the most highly utilized signaling pathways in oncologic drug discovery.

In aggressive solid tumors of the pancreas, skin, lungs and colon, mutations in RAS and/or RAF are even more common.

For example, approximately 40% of lung cancers and approximately 90% of pancreatic cancers are due to RAS and/or RAF mutations.

To date, FDA-approved MEK inhibitors have been ineffective at treating RAS mutant tumors when compared to BRAF mutant tumors because of a well-known mechanism of resistance, CRAF- mediated MEK activation, or the CRAF-bypass.

In addition, a well-known limitation of current FDA- approved MEK inhibitors are their high rates of serious drug-related adverse events, most often in over 50% of treated patients, which results in drug intolerability.

The longer half-life of these drugs (e.g., up to 2 to 4 days), or

moderate half-life (e.g., 3 to 6 hours) with increased dosing frequency, contributes to high rates of adverse events because these drugs systemically circulate for an extended period of time destroying healthy normal cells, which also rely on the pathway for survival.

Our goal in developing IMM-1-104 is to address these shortcomings to potentially provide patients with better outcomes, improved tolerability, durability and expand drug-drug combination opportunities (as depicted below).

Designed to be a Highly Differentiated Dual-MEK Inhibitor

In addition, a well-known limitation of current FDA approved MEK inhibitors are high rates of serious drug-related adverse events, or SAE’s, most often observed in over 50% of treated patients, which leads to drug intolerability.

The longer half-life of these drugs (e.g., up to 2 to 4 days) with once per day or less frequent dosing, or moderate half-life (e.g., 3 to 6 hours) with increased dosing frequency, contributes to high rates of adverse events because these drugs systemically circulate for an extended period of time harming healthy normal cells, which also rely on the pathway for survival.

Our goal in developing IMM-1-104 is to address these shortcomings and potentially provide patients with better outcomes, improved tolerability, durability and expand drug-drug combination opportunities (as depicted below).

Designed for Universal-RAS Activity as a once-daily oral monotherapy

Our Solution:

We have leveraged our platform to develop our lead product candidate, IMM-1-104, which is designed to be a highly selective dual-MEK inhibitor that promotes additional scaffold-related disruption of KSR.

We are developing IMM-1-104 to treat patients with cancer, including pancreatic, melanoma, colorectal and non-small cell lung cancer, or NSCLC, caused by mutations of RAS and/or RAF.

In order to overcome MAPK-feedback and CRAF-mediated MEK activation, a well-known limitation of current FDA-approved MEK inhibitors, we developed IMM-1-104 to allosterically inhibit MEK by targeting the site lying adjacent to the binding pocket of adenosine triphosphate, or ATP, which results in downstream inhibition of ERK.

In addition, unlike FDA-approved MEK inhibitors, IMM-1-104 is designed to prevent RAF-mediated activation of MEK by unique engagement of MEK that further disrupts KSR.

We believe the bypass of these drug resistance mechanisms will provide for better patient outcomes by enhancing therapeutic activity throughout the course of treatment.

By reducing steady state drug trough levels, we also designed IMM-1-104 to limit or reduce high rates of serious drug-related adverse events that are observed in current FDA-approved MEK inhibitors (e.g., ranging from 45% to 69%), most often given in combination with a RAF inhibitor, which contribute to discontinuation rates of up to 10% to 15%.

With a goal of improving the tolerability profile of our MEK inhibitor, we designed IMM-1-104 to have a short plasma half-life, resulting in a near-zero steady state drug trough concentration that enables deep cyclic inhibition of the MAPK pathway.

We have leveraged our platform to develop our lead product candidate in our Universal-RAS program, IMM-1-104, which is designed to be a highly selective dual-MEK inhibitor, to inhibit ERK and MEK, and to promote additional scaffold-related disruption of KSR at elevated drug levels.

We are developing IMM-1-104 to treat patients with cancer, including pancreatic, melanoma, colorectal and non-small cell lung cancer, or NSCLC, caused by mutations of RAS.

In addition, unlike FDA-approved MEK inhibitors, IMM-1-104 is designed to prevent MEK activation through a unique target engagement to prevent RAF or KSR-mediated activation of MEK.

We believe that bypassing pathway reactivating drug resistance mechanisms would provide for better patient outcomes by enhancing therapeutic activity throughout the course of treatment.

By reducing or eliminating steady state drug trough levels, we also designed IMM-1-104 to limit or reduce high rates of serious drug-related adverse events that have been observed in current FDA-approved MEK inhibitors (e.g., which can range from 45% to 69%), most often given in combination with a RAF inhibitor, which contributes to discontinuation rates of up to 10% to 15%.

With a goal of improving tolerability, we designed IMM-1-104 to have a short plasma half-life, to result in a near-zero steady state drug trough concentration to enable deep, cyclic inhibition of the MAPK pathway.

We believe this method of drug cadence-driven pathway inhibition has the potential to normalize cancer cell signaling dynamics and prevent further damage to normal healthy cells.

Collectively, we believe these qualities may differentiate IMM-1-104 from known MEK inhibitors by potentially allowing IMM-1-104 to avoid drug resistance while improving tolerability due to its dual allosteric inhibition of MEK, KSR disruption and short plasma half-life.

Collectively, we believe these dosing attributes may differentiate IMM-1-104 from known MEK inhibitors by potentially allowing IMM-1-104 to reduce drug resistance while improving tolerability due to its design to allosterically inhibit MEK, be uniquely resistant to MAPK pathway reactivation and to enable deep, cyclic inhibition stemming from a short plasma half-life.

Preclinical Studies Overview:

In multiple preclinical studies, we observed that IMM-1-104 inhibited activated MEK (i.e., pMEK) and activated ERK (i.e., pERK) across a wide range of murine and humanized 3D solid tumor models, including those with activating mutations in KRAS, NRAS, HRAS and BRAF.

In addition, in head-to-head preclinical studies, we evaluated IMM-1-104 in murine-based KRAS, NRAS, and BRAF mutant solid tumor models representing lung (i.e., A549), colon (i.e., Colon-26), pancreas (i.e., MIA PaCa-2) and skin cancer (i.e., A375 and SK-MEL-2), and observed tumor stasis or regression with insignificant BWL when compared to current FDA-approved MEK inhibitors, including selumetinib, binimetinib, encorafenib and AMG-510 (now known as sotorasib).

Given the data observed in our previously conducted preclinical studies, we believe that IMM-1-104 has the potential to deliver clinical benefit as monotherapy and, in the future, may potentially be administered in select drug combinations for patients with RAS and/or RAF mutant solid tumors who currently have limited treatment options.

In multiple preclinical studies, we observed that IMM-1-104 inhibited activation of MEK (i.e., pMEK) as well as activation of ERK (i.e., pERK) across a wide range of murine and humanized 3D solid tumor models, including those with MAPK pathway activating mutations in KRAS, NRAS, HRAS and BRAF.

CAPAN-2) and skin cancer (i.e., A375 and SK-MEL-2), and observed superior antitumor activity with insignificant body weight loss, or BWL, when compared to certain FDA-approved MEK inhibitors and superior to non-inferior antitumor activity when compared to certain FDA-approved KRAS-G12C and BRAF inhibitors at reported human dose equivalent dose and schedules.

Given the data observed in our previously conducted preclinical studies, we believe that IMM-1-104 has the potential to deliver clinical benefit as monotherapy and, in the future, may potentially be administered in select drug combinations for patients with RAS mutant solid tumors who currently have limited treatment options.

Preclinical Studies:

Maximum Tolerated Dose and Therapeutic Effect

Maximum Tolerated Dose and Therapeutic Effect Data

In our early maximum tolerated dose, or MTD, studies, we observed that oral administration of IMM-1-104 twice a day of up to 150 mg/kg/dose was well-tolerated in mice.

2 unchanged sentences

Preclinical Studies:

Pharmacogenomics

Pharmacogenomics Data

In a pharmacogenomics study utilizing a colorectal KRAS G12D tumor model in BALB/c mice, we evaluated downstream ERK inhibition of the MAPK pathway after IMM-1-104 treatment.

1 unchanged sentence

The tumors were collected across distinct BALB/c mice and RNAseq changes were evaluated using statistical analysis software.

Consistent with IMM-1-104’s designed short plasma half-life, we observed deep, cyclic inhibition of most of the top genes in the ERK transcriptome, as noted by the differences of the dark and light blue bars, which we believe may improve tolerability by allowing healthy normal cells to regenerate before the next dose is administered.

Consistent with IMM-1-104’s designed short plasma half-life, we observed deep, cyclic inhibition of most of the top genes in the ERK transcriptome, as noted by the differences of the dark and light blue bars, which we believe suggests the potential for improved tolerability by allowing healthy normal cells to regenerate before the next dose is administered.

For example, Erg1 and Spry4 were both downregulated over 16-fold at 2 hours after receiving the first dose on day 18 of the study, and at 12 hours after the first dose, which was prior to the second dose, both genes were approaching their baseline state when compared to vehicle treated tumors (as depicted below).

2 unchanged sentences

Head-to-Head Comparison of IMM-1-104 Against Selumetinib Using a Colon-26 Syngeneic Tumor Model:

Deep Cyclic Inhibition of the ERK Transcriptome

Deep Cyclic Inhibition of the ERK Transcriptome Observed

* Adjusted p-value < 0.05, for each treatment versus vehicle (n = 3-4 independent tumors per group)

Preclinical Studies:

Resistance to CRAF-bypass

Resistance to CRAF-bypass Observed

We evaluated IMM-1-104 head-to-head against four FDA-approved MEK inhibitors for CRAF-bypass resistance in a KRAS mutant NSCLC tumor model.

We exposed the tumor cells with 100 nM of each drug for 2 hours and evaluated MEK and ERK activation levels.

We observed that IMM-1-104 was able to reduce overall activity of the MAPK pathway at ERK and pathway reactivation at MEK through a decrease in MEK and ERK activation, resulting in CRAF-bypass resistance.

We observed that IMM-1-104 reduced overall activity of the MAPK pathway at ERK and pathway reactivation at MEK through a decrease in MEK and ERK activation, resulting in CRAF-bypass resistance.

In contrast, we observed that all four FDA-approved MEK inhibitors displayed an increase in activated MEK, resulting in CRAF-bypass (as depicted below).

2 unchanged sentences

Preclinical Studies:

Tumor Regression and Body Weight Loss

Tumor Regression and Body Weight Loss Observed

We evaluated IMM-1-104 head-to-head against binimetinib and selumetinib in an aggressive murine colorectal tumor model (i.e., Colon-26), which expresses mutant KRAS G12D .

3 unchanged sentences

Head-to-Head Comparison of IMM-1-104 Against Binimetinib and Selumetinib Using a Colon-26 Syngeneic Tumor Model:

Body Weight Loss and Tumor Volume

Body Weight Loss and Tumor Volume Observed

After observing the results of the Colon-26 tumor study, we completed two follow-up in vivo studies, where we evaluated IMM-1-104 head-to-head against binimetinib or encorafenib, a BRAF inhibitor, as monotherapy plus the combination of binimetinib with encorafenib in BALB/c mice tumor models with RAS and RAF mutations.

It should be noted that when encorafenib is used to treat KRAS mutant tumors that are wild type for BRAF, it can paradoxically activate the MAPK pathway and antagonize the effects of binimetinib.

In addition, the drug doses and schedules used for binimetinib and encorafenib in these studies were consistent with what was provided in their NDAs to the FDA.

We evaluated IMM-1-104 head-to-head against binimetinib monotherapy and in combination with encorafenib in the KRAS G12S human NSCLC tumor model (i.e., A549).

In addition, the drug doses and schedules used for binimetinib and encorafenib in these studies were consistent with or exceeded what was provided in their NDAs to the FDA for human-relevant exposures in rodent models.

We evaluated IMM-1-104 head-to-head against binimetinib monotherapy and in combination with encorafenib in the KRAS G12S human NSCLC xenograft tumor model (i.e., A549).

When comparing IMM-1-104 to binimetinib monotherapy, we observed that IMM-1-104 had greater tumor growth inhibition (as depicted below).

1 unchanged sentence

Head-to-Head Comparison of IMM-1-104 Against Binimetinib +/- Encorafenib Using a A549 Xenograft Tumor Model:

We also evaluated IMM-1-104 head-to-head against binimetinib and encorafenib monotherapy and the combination of binimetinib with encorafenib in a BRAF V600E human melanoma tumor model.

We also evaluated IMM-1-104 head-to-head against binimetinib and encorafenib monotherapy and the combination of binimetinib with encorafenib in a BRAF V600E human melanoma xenograft model.

It should be noted that the administered combination of binimetinib and encorafenib for BRAF mutant melanoma, such as BRAF V600E/K , is an FDA-approved combination.

1 unchanged sentence

However, when we compared IMM-1-104 to binimetinib monotherapy, we observed that IMM-1-104 had greater tumor growth inhibition (as depicted below).

We believe the greater single agent MEK inhibitor activity provides an opportunity to expand IMM-1-104 into drug-drug combinations with other MAPK pathway inhibitors, such as encorafenib, to treat RAF mutant cancers, such as BRAF V600E/K , among other MAPK pathway mutations.

While our initial focus is on monotherapy of RAS mutant disease, we believe the greater single agent MEK inhibitor activity observed with our deep cyclic inhibition approach demonstrates the potential of IMM-1-104 (and/or IMM-6-415, which has an accelerated cadence of deep cyclic inhibition) in drug-drug combinations with other MAPK pathway inhibitors, such as encorafenib, to treat RAF mutant cancers, such as BRAFV600E/K, among other MAPK pathway mutations.

Head-to-Head Comparison of IMM-1-104 Against Binimetinib +/- Encorafenib Using a A375 Xenograft Tumor Model:

In a further in vivo study based on humanized 3D tumor model data, we evaluated IMM-1-104 head-to-head against AMG-510 (sotorasib) and gemcitabine alone, and IMM-1-104 in combination with AMG-510, for 21 days in the KRAS G12C mutant tumor model (i.e., MIA PaCa-2).

In a previous study conducted by a third-party, AMG-510 demonstrated sensitivity to this pancreatic tumor model.

Comparing IMM-1-104 alone, against AMG-510 and in combination with AMG-510, we observed tumor regressions with insignificant BWL (i.e., within 3% of baseline), which we believe indicates activity, durability and tolerability of IMM-1-104 against a KRAS G12C mutant pancreatic cancer model (as depicted below).

Head-to-Head Comparison of IMM-1-104 +/- AMG-510 (sotorasib) and Gemcitabine Using a MIA PaCa-2 Xenograft Tumor Model:

In a further in vivo study based on humanized 3D tumor model data, we evaluated IMM-1-104 head-to-head against sotorasib (AMG-510) and gemcitabine alone, and IMM-1-104 in combination with sotorasib, for 21 days in the KRAS G12C xenograft model (i.e., MIA PaCa-2).

In a previous study conducted by a third-party, sotorasib demonstrated sensitivity to this pancreatic tumor model.

Comparing IMM-1-104 alone, against sotorasib and in combination with sotorasib, we observed tumor regressions with insignificant median BWL (i.e., within 3% of baseline), which we believe indicates activity, durability and tolerability of IMM-1-104 against a KRAS G12C mutant pancreatic cancer model (as depicted below).

Head-to-Head Comparison of IMM-1-104 +/- sotorasib (AMG-510) Using a MIA PaCa-2 Xenograft Tumor Model:

In an in vivo study based on humanized 3D tumor model data, we evaluated IMM-1-104 monotherapy as compared to binimetinib for 21 days in the NRAS Q61R mutant tumor model (i.e., SK-MEL-2).

We observed better tumor growth inhibition relative to binimetinib (as depicted below).

We observed superior tumor growth inhibition relative to binimetinib (as depicted below).

Head-to-Head Comparison of IMM-1-104 Against Binimetinib Using a SK-MEL-2 Xenograft Tumor Model:

In a further in vivo study based on humanized 3D tumor model data, we evaluated IMM-1-104 monotherapy as compared to vehicle for 21 days in the NRAS Q61R mutant tumor model (i.e., SK-MEL-2).

We observed midcycle tumor regressions in mice treated with IMM-1-104, which we believe indicates activity and durability of IMM-1-104 against an NRAS Q61R mutant melanoma cancer model (as depicted below).

We observed midcycle tumor regressions in mice treated with IMM-1-104, which demonstrated activity and durability of IMM-1-104 against an NRAS Q61R mutant melanoma cancer model (as depicted below).

Evaluation of IMM-1-104 as Compared to Vehicle Using a SK-MEL-2 Xenograft Tumor Model:

In a study described in our June 2022 ASCO abstract, we utilized a Capan-2 PDAC xenograft animal model to evaluate single agent activity of IMM-1-104 (100, 150 mg/kg BID p.o.) vs.

sotorasib and adagrasib (30 and 100 mg/kg QD p.o.

each) for 21 days treatment after tumors had reached volumes of 150 to 200 mm3.

A head-to-head comparison in vivo demonstrated no Tumor Growth Inhibition (TGI) by sotorasib or adagrasib in KRAS-G12V mutant Capan-2 PDAC tumors, while IMM-1-104 prompted TGIs up to 84% at 150 mg/kg BID po.

Preclinical Studies:

3D Tumor Growth Models

3D tumor growth models mimic the tumor microenvironment, or TME, more closely than 2D models, and we believe the 3D model more accurately reflects human tumor biology and complexity when evaluating pharmacological data of MAPK pathway inhibition in vivo .

We have established and evaluated over 60 humanized 3D tumor models that display mutations in the RAS isoforms, amongst other altered MAPK pathway targets, including BRAF, CRAF, NF1 and ERK, to evaluate their sensitivities to IMM-1-104.

In general, we observed that tumor models with KRAS or NRAS mutations and certain molecular profiles were most sensitive to IMM-1-104, followed closely by tumor models with BRAF mutations.

For example, the IC 50 of IMM-1-104 ranged from 68.7 nM in NRAS Q61K to 214.7 nM in NRAS G12D , whereas the IC 50 of IMM-1-104 ranged from 814.7 nM to greater than 10,000 nM in BRAF V600E and certain RAS mutants, respectively.

More specifically, our 3D tumor modeling data suggested that KRAS mutant pancreatic cancer and NRAS mutant melanoma may be particularly sensitive to single agent IMM-1-104.

To further examine the translational opportunity in KRAS mutant pancreatic cancer and NRAS mutant melanoma, we evaluated several of these cancer mutations utilizing real-world data through a pan-cancer registry, the Genomics Evidence Neoplasia Information Exchange, or GENIE.

3D tumor growth models mimic the tumor microenvironment, or TME, more closely than 2D culture models, and we believe humanized 3D models more accurately reflect human tumor biology and complexity when translating pharmacological data of MAPK pathway inhibition in vivo .

We have established and evaluated over 130 humanized 3D tumor models, a majority of which display activating mutations in the RAS isoforms, amongst other altered MAPK pathway targets, including BRAF, CRAF, NF1 and ERK, to evaluate their sensitivities to IMM-1-104.

In general, we observed that tumor models with KRAS or NRAS mutations and certain molecular profiles were sensitive to IMM-1-104, including tumor models displaying BRAF mutations.

For example, IMM-1-104 IC 50 dose-response values in 3D assays as low as 23.7 nM were observed in tumor models that expressed NRAS mutants such as Q61L, Q61R, G12D, Q61K, among others.

Similarly, KRAS mutant tumor models were sensitive to IMM-1-104 treatment, with IC 50 dose responses as low as 66.7 nM when displaying mutations including Q61H, G12C, G12V, G13D, G12D, G12R, among others.

Certain tumor models with BRAF mutations were also found to be sensitive to IMM-1-104 with IC 50 dose responses in 3D assays as low as 54.2 nM for V600E (class 1) and G464E (class 2) mutations.

A clear driver mutation in RAS or RAF was generally predictive of IMM-1-104 response, but a smaller number of RAS or RAF mutant models displaying certain oncogenic mutation profiles were found to be insensitive to IMM-1-104 and displayed IC 50 dose response values of over 10,000 nM.

We observed that IMM-1-104 broadly displays universal-RAS activity with additional responses in MAPK pathway addicted tumors.

Also, our 3D tumor modeling data suggested that KRAS mutant pancreatic cancer and NRAS mutant melanoma may be particularly sensitive to single agent IMM-1-104, followed by KRAS mutant lung and colon cancers.

To further examine the translational opportunity in KRAS mutant pancreatic cancer, NRAS mutant melanoma, KRAS mutant non-small cell lung cancer and KRAS mutant colorectal cancer, we evaluated several of these cancer mutations utilizing real-world data through a pan-cancer registry, the Genomics Evidence Neoplasia Information Exchange, or GENIE (Cohort v13.0-public:

The AACR Project GENIE Consortium.

AACR Project GENIE:

Powering Precision Medicine Through An International Consortium, Cancer Discov.

2017 Aug;7(8):818-831).

The total number of patients in the analysis are depicted below in blue and the percentage of patients with a known mutation in KRAS or NRAS are shown as a percentage of the total patients (depicted below in black).

Biomarker sensitive profiles (depicted below in green) and biomarker resistant profiles (depicted below in red) are projected subsets of patients with mutated KRAS or NRAS that may be sensitive or resistant to IMM-1-104.

We observed that the overwhelming majority of pancreatic cancers associated with KRAS mutations (i.e., 92%) and melanoma associated with NRAS mutations (i.e., 73%) are found to harbor a biomarker profile that may be sensitive to IMM-1-104 (as depicted below).

Translational Profiling for KRAS Mutant Pancreatic Cancer and NRAS Mutant Melanoma Utilizing a Pan-Cancer Registry, GENIE

Biomarker sensitive profiles (depicted below in green) and putative biomarker resistant profiles (depicted below in red) are projected subsets of patients with mutated KRAS or NRAS that may be sensitive or resistant to IMM-1-104 monotherapy.

We found the overwhelming majority of pancreatic cancers associated with KRAS mutations (i.e., 93%) and melanoma associated with NRAS mutations (i.e., 78%) are found to harbor a biomarker profile that may be sensitive to IMM-1-104 (as depicted below).

Additionally, KRAS mutant non-small cell lung cancer (i.e., 66%) is favorable, but KRAS mutant colorectal cancer (i.e., 22%) may benefit from further biomarker stratification.

Translational Profiling for KRAS Mutant Pancreatic Cancer, NRAS Mutant Melanoma, KRAS Mutant Non-Small Cell Lung Cancer and KRAS Mutant Colorectal Cancer Utilizing a Pan-Cancer Registry, GENIE

Clinical Development Overview:

IMM-1-104 is currently undergoing IND-enabling studies.

We plan to submit an IND for IMM-1-104 to the FDA in the third quarter of 2022.

We continue to expand our preclinical pharmacology models, including research to further understand sensitivity and resistance biomarkers related to IMM-1-104.

We have conducted 28-day good laboratory

practices, or GLP, orally dosed safety and toxicology studies in rats and dogs prior to initiating our Phase 1 clinical trial of IMM-1-104.

We intend to enroll the first patient in our first-in-human Phase 1 clinical trial of IMM-1-104 in the fourth quarter of 2022 for the treatment of advanced solid tumors in patients harboring RAS mutant tumors if our IND for IMM-1-104 is accepted.

The Phase 1 clinical trial of IMM-1-104 is being designed to primarily evaluate its safety and tolerability, and to also identify dose-limiting toxicities.

Our clinical development plan for IMM-1-104 will initially focus on indications selected by our translational data.

Additional indications will be based on future preclinical studies and clinical trial outcomes.

Our goal is to further expand the development of IMM-1-104 in indications, including a broad range of RAS and/or RAF mutant tumors.

In addition, we plan to evaluate IMM-1-104 in combination with FDA-approved MAPK and adjacent pathway inhibitors to treat certain cancers in the future.

MEK-io Program

We are developing innovative investigational allosteric MEK inhibitors to be administered in combination with select immune modulators (e.g., checkpoint inhibitors) for the treatment of “cold” solid tumors.

Our investigational MEK-io program inhibitors are designed to target MEK in a way that disrupts the MAPK pathway at ERK and to also reduce baseline MEK activation.

We are designing these inhibitors with unique PK and PD profiles that may enhance cycle inhibition time of MEK and ERK to optimize the patient’s immune response and promote maximal antitumor responses when administered in combination with select immune modulators.

KRAS mutant tumors impact approximately 15% of patients globally and include cold or “non-inflamed” tumors.

Cold tumors are immunologically inaccessible, meaning the patient’s immune system cannot provide an appropriate antitumor response because the lack of T-cell infiltration in the tumor, which is required for the immune system (i.e., T-cells) to find, target and attack the tumor.

Checkpoint inhibitors work by helping to reactivate and enhance the patient’s immune system by allowing T-cells to better provide an appropriate antitumor response.

If a cold tumor were to become “hot” or “inflamed,” this would create an inflammatory process enabling T-cells to infiltrate the tumor and allow them to recognize and attack the tumor (i.e., an antitumor response).

We believe our investigational MEK-io program inhibitors have the potential to turn a cold tumor hot, and when administered in combination with a checkpoint inhibitor, could provide an innovative approach to treat patients with cold solid tumors by providing MEK/ERK inhibition and optimizing antitumor response, which would not typically be seen in these patients.

We observed an initial in vivo proof-of-concept for our MEK-io program, with a related analogue to our MEK-io product candidate IMM-6-415, in a widely utilized syngeneic murine model.

We evaluated it as monotherapy and in combination with a checkpoint inhibitor as compared to vehicle to observe tumor growth inhibition in tumor-bearing BALB/C mice.

Neither treatment alone altered tumor growth as compared to vehicle.

However, when we administered in combination with the checkpoint inhibitor, we observed greater than 50% tumor growth inhibition (TGI) after two weeks of dosing as compared to vehicle treated mice.

Our MEK-io product candidate, IMM-6-415, is currently in IND-enabling studies.

IMM-6-415 may enhance responses to checkpoint inhibitors in tumors that have been poorly responsive to these class of agents.

We observed dose-dependent, tumor growth inhibition by IMM-6-415 in a syngeneic Colon-26 animal model following oral administration of the drug to identify maximum tolerated dose in a once per day, or QD, schedule (TGI after 8 days at 175 mg/kg = 46%) or twice per day, or BID, schedule (TGI after 8 days at 150 mg/kg = 74%).

Current preclinical studies are evaluating IMM-6-415 as monotherapy or in combination with checkpoint inhibitors in CT26 and MC-38 syngeneic models.

We plan to submit an IND for IMM-6-415 to the FDA in 2023.

In September 2022 the FDA cleared our IND for IMM-1-104, and in November 2022, we commenced dosing in a first-in-human , phase 1/2a clinical trial of IMM-1-104.

The Phase 1/2a clinical trial is an open-label study designed to evaluate the safety, tolerability, clinical pharmacology, and preliminary efficacy of IMM-1-104 when dosed as monotherapy, once daily, in participants with advanced RAS mutant solid tumors, following at least one line of systemic, standard-of-care therapy.

The Phase 1 ( dose exploration ) study consists of both dose escalation and dose expansion portions and may enroll up to 42 patients across five clinical sites within the United States.

● Dose Escalation follows a Bayesian (mTPI-2) statistical design.

This streamlined design is designed to allow for the most efficient approach to optimize dose escalation.

● Dose Expansion will further evaluate and refine selected dose-level candidates for recommended phase 2 dose, or RP2D, in accordance with guidance provided by FDA under its Project Optimus initiative.

The final RP2D selection will be based upon composite review of data related to safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activity accumulated during Phase 1.

Once a final RP2D has been determined, the Phase 2a portion of the trial may commence, evaluating the monotherapy activity and safety of IMM-1-104 within selected tumor-specific indications, which we currently plan to expand in parallel.

Based upon our internally developed and proprietary bioinformatics platform and translational modeling, we have initially identified four potential indications for phase 2a expansion:

RAS mutant pancreatic cancer, RAS mutant melanoma, KRAS mutant non-small cell lung cancer, and KRAS mutant (APC wild type ) colorectal cancer.

Each of these will be evaluated using a Simon 2-stage statistical design and independently considered for further indication-specific development.

The final indication selection and design of the Phase 2a portion of the study is subject to change based on information learned in the Phase 1 portion.

IMM-1-104 is currently in the dose escalation portion of the trial.

We anticipate reporting initial PK and safety data from the Phase 1 portion of the clinical trial in mid-2023, and additional safety and PK and initial PD modeling data in the second half of 2023.

Based on results from the Phase 1 portion of the trial, including safety and tolerability data, we anticipate initiating the Phase 2a portion of the trial in mid-2024

In addition to the above, we also may engage in appropriate IMM-1-104 anchored combination studies dosed at the RP2D.

Specific combination partners and indications will be selected based-upon pooled discovery and clinical proof of concept data accumulated by that time.

Universal-MAPK, IMM-6-415 Program

Our second program, which we refer to as our Universal-MAPK program, is focused on developing innovative allosteric MEK inhibitors that drive deep cyclic inhibition of the MAPK pathway with a shorter plasma half-life and accelerated cadence relative to IMM-1-104.

Our product candidate for this program is designated as IMM-6-415.

As described, in a poster presentation of results from preclinical studies at the SITC 2022 Annual Meeting in November 2022, IMM-6-415 inhibited the growth of RAF and RAS mutant tumors as a monotherapy in human and murine solid tumor models, and was administered in combination with select immune modulators (e.g., checkpoint inhibitors) for the treatment of “cold” solid tumors, which are immunologically inaccessible.

IMM-6-415 was designed to target MEK in a way that disrupts the MAPK pathway at ERK and to also reduce baseline MEK activation.

We designed IMM-6-415 to have a unique PK and PD profile that may be optimized for distinct tumors, potentially including a broad range of MAPK-driven tumors as monotherapy and to optimize the patient’s immune response and promote maximal antitumor responses when administered in combination with select immune modulators.

We plan to submit an IND for IMM-6-415 to the FDA in the fourth quarter of 2023.

Preclinical Studies:

Resistance to CRAF-bypass

We evaluated IMM-6-415 head-to-head against two FDA-approved MEK inhibitors to assess their control of pMEK, pERK and CRAF-bypass in a NRAS, HRAS, NF1 and BRAF mutant melanoma tumor models.

We exposed the tumor cells with 100 nM of each drug for 2 hours and evaluated MEK and ERK activation levels.

We observed that IMM-6-415 reduced overall activity of the MAPK pathway at ERK and pathway reactivation at MEK through a decrease in MEK and ERK activation, resulting in CRAF-bypass resistance.

In contrast, we observed that both FDA-approved MEK inhibitors displayed an increase in activated MEK, resulting in CRAF-bypass in RAS and NF1 mutant tumors (as depicted below).

Head-to-Head Comparison of IMM-6-415 against Two FDA-Approved MEK Inhibitors Using a Panel of Nine Melanoma Tumor Models:

Observed Activity in RAS and RAF Mutant Tumors and Prevented Downstream Activation of ERK (↓ pERK) and Inhibited Activation of MEK (↓ pMEK)

Tumor cell lines were acquired from ATCC, ECACC and DSMZ.

3D-Tumor Growth Assay (3D-TGA) sensitivity (green fill) defined as IC 50 < 10uM in 72-hour ECM-based assay with %EdU readout, and IC 50 ≥10uM considered resistant.

Cell-based 2D in vitro molecular assays were performed to assess cellular levels of phosphorylated and total ERK and MEK across 9 melanoma models (100 nM drug for 2-hours followed by quantitative Western blot analysis for pERK, total ERK, pMEK and total MEK);

Binimetinib & selumetinib were commercially purchased (MAPK pathway reactivation observed, pMEK);

= not yet tested

Preclinical Studies:

Maximum Tolerated Dose and Therapeutic Effect Data

In our early maximum tolerated dose, or MTD, studies, we observed that oral administration of IMM-6-415 twice a day of up to 175 to 180 mg/kg/dose was well-tolerated in mice.

In other preclinical studies, we observed that the maximum therapeutic effect of IMM-6-415 was reached when administered orally twice a day between 150 and 180 mg/kg/dose.

These dosing studies provided the basis of IMM-6-415’s dosing schedule in subsequent preclinical studies.

Preclinical Studies:

Tumor Regression and Body Weight Loss Data

We evaluated IMM-6-415 against vehicle and historic responses from IMM-1-104 in an aggressive murine colorectal tumor model (i.e., Colon-26), which expresses mutant KRAS G12D .

We observed that IMM-6-415 demonstrated robust tumor growth inhibition at top effective doses of 150 and 175 mg/kg BID p.o., with multiple mice experiencing tumor regression during the first 7 days of dosing (as depicted below), with good tolerability, and evidenced limited (-8.61% to to +3.34% vs.

vehicle group) changes in median BWL at doses in the range of 25 to 175 mg/kg BID p.o.

While IMM-6-415 displayed a plasma half-life in mice of only a 0.3 to 0.4 hours (0.5 to 0.7 in non-human primates), IMM-6-415 led to comparable tumor growth inhibition of that observed with IMM-1-104, a molecule that has been observed to have a 1.3 hour half-life in mice (i.e., 3 to 4 times longer than IMM-6-415 in the same species), which was previously observed to be superior in a head-to-head comparison against binimetinib and selumetinib in the same model (as described previously).

Evaluation of IMM-6-415 as Compared to Vehicle Using a Colon 26 Syngeneic Rodent Tumor Model:

Colon 26 (KRAS G12D ) syngeneic colorectal tumor model in immune competent BALB/c mice.

Tumor Growth Inhibition (TGI) % = [1 – (Ti – T0)/(Ci – C0)]x100%;

Maximum Antitumor Effective Dose Range for IMM-6-415 in mice is 150 mg/kg to 175-180 mg/kg BID p.o.

We evaluated IMM-6-415 against vehicle treatment as well as historic IMM-1-104 responses in the KRAS G12S human NSCLC xenograft tumor model (i.e., A549).

When comparing IMM-6-415 to previous studies with IMM-1-104 (shown previously), we observed similar and sustained tumor growth inhibition with IMM-6-415 treatment at top effective doses of 150 to 175 mg/kg BID p.o.

(as depicted below), and an IMM-6-415 dose range of 60 to 180 mg/kg BID p.o.

was well-tolerated with each group gaining 4.77% to 10.75% body weight (similar to vehicle) over the 21 day study.

Unlike IMM-1-104, which is being developed as a once-daily monotherapy, we project a shorter human plasma half-life for IMM-6-415.

We believe that this would enable twice per day (BID) dosing schedules while still achieving deep, cyclic inhibition for IMM-6-415.

Evaluation of IMM-6-415 as Compared to Vehicle Using a A549 Xenograft Tumor Model:

A549 (KRAS G12S ) human NSCLC xenograft tumor model in athymic nude BALB/c mice.

Tumor Growth Inhibition (TGI) % = [1 – (Ti – T0)/(Ci – C0)]x100%;

Maximum Antitumor Effective Dose Range for IMM-6-415 in mice is 150 mg/kg to 175-180 mg/kg BID p.o.

In a further in vivo study based on the positive and negative impact of MAPK pathway activation in antitumor responses, we evaluated IMM-6-415 head-to-head against PD1 and CTLA4 checkpoint inhibitors alone, and IMM-6-415 in combination with each, for 28 days in the KRAS G12D mutant syngeneic tumor model (i.e., CT-26).

Historically, this KRAS mutant colorectal tumor mouse model has demonstrated greater sensitivity to CTLA4 over PD1/PDL1 checkpoint inhibition.

Comparing IMM-6-415 alone at moderated doses below the maximum cytoreductive levels described above, against anti-PD-1 or anti-CTLA4 treatments and in each combination with IMM-6-415 (e.g., QD, BID at multiple dose levels), we observed superior survival through 28 days with insignificant median BWL (i.e., median body weight gain observed in all groups), which we believe indicates the potential for activity, durability and tolerability of IMM-6-415 against a KRAS G12D mutant colorectal cancer model in immune competent rodents (as depicted below).

Head-to-Head Comparison of IMM-6-415 +/- anti-PD-1 and anti-CTLA4 Using a CT-26 Syngeneic Tumor Model:

Probability of Survival Based on Tumor Volume Limits

CT-26 (KRAS G12D ) syngeneic colorectal tumor model in immune competent BALB/c mice (note:

monotherapy and combinations were inactive in athymic nude CT-26 model – data not shown).

Translational Preclinical Studies:

Humanized 3D Tumor Assays

IMM-6-415 has been evaluated for response/non-response profiles in over 60 humanized 3D tumor models that display a wide range of mutations in the MAPK and other pathways.

These include and are enriched for activation mutations in KRAS, NRAS, HRAS and BRAF.

While IMM-1-104 generally demonstrates more potent head-to-head responses in RAS mutant models, IMM-6-415 displayed more comparable potency, based on IC 50 values, to IMM-1-104 in BRAF mutant models.

Given the increased cadence of IMM-6-415 BID (versus.

QD for IMM-1-104) as projected for the clinic, we believe that IMM-6-415 has the potential to afford differentiated treatment options for certain cancer patients with RAS or RAF mutant disease as monotherapy and in potential future drug-drug combinations.

Deep, cyclic MEK inhibition can potentially help optimize antitumor immune responses, prevent adaptive resistance to enhance durability and reshape signaling dynamics that focus drug activity against the tumor compartment.

Trifecta-MEK Program

We are 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.

We believe the inhibition of upstream and downstream activation events of MEK and ERK bypass MAPK pathway reactivation events (i.e., drug resistance).

Our 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 allosteric inhibition of MEK and KSR disruption, along with a unique PK approach.

The potential dosing intervals, potency and mechanisms of target engagement of our investigational Trifecta-MEK program inhibitors may broaden the application of these inhibitors to

metabolically diverse RAS and RAF mutant tumors.

We believe the inhibition of upstream and downstream activation events of MEK and ERK bypass MAPK pathway reactivation events (i.e., contributing to drug resistance).

Our 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 our investigational Trifecta-MEK program inhibitors may broaden the application of these inhibitors to metabolically diverse RAS and RAF mutant tumors.

We are designing our 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.

4 unchanged sentences

Head-to-Head Comparison of One of Our Investigational Trifecta-MEK Program Inhibitors Against Encorafenib and Binimetinib Using A549 and A375 Xenograft Tumor Models

KRAS4B Program

We are developing investigational mutation agnostic KRAS4B inhibitors that are designed to bind to a unique, undisclosed site on KRAS4B for the treatment of solid tumors.

We believe our investigational KRAS4B inhibitors have the potential to disrupt RAS nanocluster biology and prevent MAPK signaling in patients with KRAS mutant tumors, which represent approximately 15% of all cancer patients.

Although drugs in this class have begun targeting RAS mutations, such as

KRAS G12C , we believe a majority of KRAS mutations, which we are designing our KRAS4B inhibitors to target, will remain unaddressed.

In an in vitro tumor model, we observed a half maximal tumor inhibitor concentration, or IC 50 , of 1 μM for one of our investigational KRAS4B inhibitors.

A low IC 50 value means that a drug is 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 this tumor model, we believe our investigational KRAS inhibitors may achieve KRAS4B inhibition when administered at low concentrations, providing a potentially improved tolerability profile as compared to other FDA-approved MAPK pathway inhibitors.

Our KRAS4B program is currently in the drug discovery stage of development.

RAS Induction Program

We are developing investigational RAS inducers that are designed to hyperactivate the MAPK pathway to potentially induce tumor cell death.

Our RAS inducers are designed to be agnostic to known activating mutations of any oncogene of the MAPK pathway, providing the potential clinical opportunity to effectively treat any patient with an activated MAPK pathway, which represents over 50% of all cancer patients globally.

A study by Leung et al (Mol Can Res 2019) supports this novel pharmacological approach by demonstrating that the hyperactivation of the MAPK pathway in tumor cells that express mutant RAS or RAF are intolerant to further increases in activity at the level of ERK and induce tumor cell death.

This approach was further validated by clinical observations of secondary tumor reductions in some patients when targeted agents that inhibit the MAPK pathway were discontinued.

In an in vitro KRAS mutant tumor model, we observed cell-based induction of the MAPK pathway at activated ERK of 844% when administering 30 μM of one of our RAS inducers.

Additional in vivo modeling is required to validate this pharmacologic strategy, but we believe that, if successful, short pulsatile target induction will be critical.

Our RAS induction, or RASi, program is currently in the drug discovery stage of development.

Covalent-MEK Program

We are developing investigational irreversible allosteric inhibitors of MEK by attacking one of three critical amino acids lying adjacent to the binding pocket.

We believe the covalent, or irreversible inhibition, fully disrupts MEK enzymatic activity completely avoiding any potential drug resistance from MAPK pathway reactivation events.

Covalent-MEK’s novel pharmacological approach provides scaled attenuation of the MAPK pathway disruption that is anchored to the half-life of MEK itself, which has been reported to be approximately 12 to 14 hours.

Our Covalent-MEK program is in the drug discovery stage of development and builds on our dynamic portfolio of novel and mechanistically distinct MEK inhibitors.

PI3K-alpha Program

We are developing investigational allosteric PI3Kα inhibitors designed to target PI3Kα agnostically in common mutations and further disrupt upstream activation events of the mTOR pathway.

Similar to IMM- 1-104, we intend to design our PI3Kα inhibitors with a short plasma half-life to potentially normalize tumor signaling dynamics while retaining healthy normal cells.

While still in the early drug discovery stage of development, we envision our PI3K-alpha program will be able to address significant unmet clinical needs in certain subsets of cancer, as well as reaching a broader patient population in combination with one or more of our MEK or RAS drug programs, where the mTOR pathway may synergistically work in tandem with MAPK pathway inhibition.

Our Neuroscience Programs

In addition to our extensive oncology pipeline, we are also leveraging our platform to build a neuroscience pipeline initially focusing on AD.

Our neuroscience programs are in the early stages of drug discovery, and we are evaluating undisclosed targets to pursue a unique approach to treating AD.

We believe by treating AD- related neuroinflammation, rather than treating amyloid beta protein, or β-amyloid, and hyperphosphorylated tau deposition in the brain, we may be able to slow the progression of AD.

We believe our platform and expertise in neurology and neuroscience has allowed us to determine

biological differences in AD patients to help develop novel product candidates that have the potential to address the significant unmet needs of this underserved patient population.

Alzheimer’s Disease Overview

AD is a neurodegenerative disorder of uncertain cause and pathogenesis and is the most common form of dementia.

AD is characterized by memory impairment and further cognitive decline that can ultimately affect the patient’s behavior, speech, visuospatial orientation and motor system.

AD is a complex multifactorial disease driven by genetic and environmental causes that affects older adults and is one of the leading sources of morbidity and mortality in the aging population.

Established risk factors for AD include age, family history of dementia, rare dominantly inherited mutations in genes that impact β-amyloid in the brain (as described below) and apolipoprotein E epsilon 4 allele (as described below).

The disease is most often categorized into three different groups:

early-onset AD, late-onset AD and familial AD.

Late-onset AD, also referred to as sporadic AD, is the most common form of the disease representing approximately 90% of the patients, and is classified in patients who present with symptoms at older ages (i.e., ≥ 65 years), while early-onset AD is classified in patients who present with symptoms at younger ages (i.e., < 65 years).

Familial AD is an inherited form of AD (i.e., genetic) and patients with early-onset AD most often have some inherited form of the disease.

In contrast, sporadic AD most often involves common and rare genetic risk factors, as well as environmental factors.

Available data supports a worldwide prevalence of AD of approximately 35 million people, or approximately 6 million people in the United States.

The prevalence of AD is known to increase exponentially with age, essentially doubling every 5 years after the age of 65.

Diagnosis of AD is typically only considered after symptoms manifest and while the diagnosis of AD can be based on clinical criteria or detection of certain biomarkers, such as β-amyloid and tau, a postmortem histopathologic examination is required to confirm the diagnosis.

Recent emerging evidence supports that neurological changes may occur years before patients start to experience early clinical manifestations of AD, which is most often memory impairment.

Limitations of Current Targeted Therapies for Alzheimer’s Disease

Since 2003, only two new treatments for AD have been approved by the FDA, representing a significant unmet medical need.

Despite clinical trials of numerous agents over a wide range of mechanisms, there are currently only six FDA-approved treatments for AD, and none of these treatments has been shown to do anything more than briefly and modestly improve AD symptoms, ultimately failing to prevent or slow disease progression.

Patients may develop AD irrespective of β amyloid deposition.

Without a disease-modifying treatment that targets the underlying cause of AD, many AD patients require daily supportive care from their families or other caregivers.

Pathogenesis of Alzheimer’s Disease

While the pathogenesis of AD remains unclear, the genetic basis for early-onset and familial AD is understood most clearly.

Most AD patients appear to have an overproduction and/or decreased clearance of β-amyloid, which is neurotoxic.

This explanation of AD is otherwise known as the “amyloid hypothesis.” β-amyloid is produced by the cleavage of a protein translated from the amyloid precursor protein gene, or APP , and cleaved by α-secretase, β-secretase, and γ-secretase.

Presenilin is a sub-component of γ-secretase and is partially responsible for cleaving APP .

Mutations in presenilin 1 gene, or PSEN1 , or presenilin 2, or PSEN2 , and APP result in overproduction of β-amyloid and are known to cause familial AD in greater than 95% of patients.

In addition, the pathogenesis of AD is believed to involve a second protein, tau.

Tau plays a role in stabilizing the biological mechanisms required for facilitating neuronal activity and communication.

In patients suffering from AD, observations have shown that tau accumulates and causes neurotoxicity as a result of its hyperphosphorylation.

In addition, transmission of pathologic forms of tau between neurons has been proposed to account for the spread of AD in the brain.

There are several other important and potentially overlapping pathways that are considered to be involved in AD.

For example, the strongest association of sporadic AD involves human apolipoprotein E gene, or APOE .

APOE is involved in multiple cellular processes, including cholesterol transport and immune regulation, amongst others.

APOE is known to

have three alleles, including epsilon 4, or APOE4 .

Carriers of one APOE4 are two to three times more likely to develop AD as compared to noncarriers, and those with two APOE4 are at approximately 8 to 12 times more likely to develop AD.

Despite APOE4 ’s strong link to sporadic AD, some carriers of APOE4 never develop any cognitive decline.

Unlike familial and early-onset AD, the genetic basis for sporadic AD is complex and poorly understood, and often involves environmental factors.

Pathology of Alzheimer’s Disease

The hallmark neuropathologic changes of AD are diffuse and neuritic plaques, marked by extracellular β-amyloid deposition and neurofibrillary tangles, comprised of the intracellular accumulation of hyperphosphorylated tau (as depicted below).

The pathology of AD is characterized by the widespread death of neurons in the brain and follows a destructive trajectory starting at the hippocampus, which is responsible for learning and memory.

As AD progresses, the pathology gradually spreads to other important regions of the brain further causing cognitive decline.

Among AD patients, the levels of brain atrophy vary and the underlying cause of this is unknown.

Healthy Brain Compared to an AD Patient’s Brain with β-Amyloid and Tau Deposition

Heterogeneity Among Alzheimer’s Disease Patients

A growing body of evidence suggests that AD is a heterogeneous group of diseases, which may partially explain the lack of consistent clinical data, including clinical trials.

The cardinal symptoms of AD are cognitive impairment, including memory impairment, loss of executive function, impaired judgement and problem solving, behavioral and psychological problems, and visuospatial impairment.

While nearly all AD patients struggle with cognitive decline, there is no prescribed pattern or progression of symptoms.

For example, some AD patients have significant β-amyloid and hyperphosphorylated tau deposition, but experience little or no cognitive impairment.

The pattern of memory impairment in patients suffering from AD is distinctive.

Memory of events occurring at a particular time and place is often profoundly affected in these patients.

These memory deficits develop insidiously and progress slowly over time, evolving to include deficits of semantic memory (i.e., general knowledge accumulated throughout life) and immediate recall.

Impairments of procedural memory (i.e., how to perform certain actions and skills) appear only in the late stages of AD.

In addition, behavioral and psychologic symptoms become more common in the middle to late course of the disease.

These can begin with relatively subtle symptoms including apathy, social disengagement and irritability.

However, emergence of behavioral disturbances such as agitation, aggression, wandering and psychosis are seen as well.

Approximately 11% of AD patients suffer from some form of psychosis and at least 75% of AD patients deal with agitation, aggression and wandering.

Although the signs and symptoms of AD are understood, the underlying cause of the disease, including progression of certain aspects of the disease, still remain unknown and provide an opportunity

for the development of disease-modifying treatments that would address significant unmet needs in the underserved AD patient population.

Our Approach to Alzheimer’s Disease

We believe there are specific subgroups of AD that can be stratified through gene expression and brain pathology.

To identify AD subgroups, we have leveraged our platform to employ a patient-centric, data-driven approach through:

● Patient Data .

Categorizing and quality controlling postmortem patient data available from multiple public repositories.

● Patient Stratification .

Using a combination of different types of data, such as brain pathology and gene expression, to stratify patients into certain groups.

● Our Expertise .

Leveraging our computational biology expertise to develop machine learning algorithms to detect patterns across biological data and find subgroups based on distinct patterns.

Our approach to stratify AD patients based off specific subgroups and discover therapies that may benefit these patients is depicted in the image below.

AD Patient Subgroup Stratification and Application of Our Drug Discovery Platform

We believe our platform and expertise in neurology and neuroscience has allowed us to determine biological differences in AD patients to help develop novel product candidates that have the potential to address the significant unmet needs of this underserved patient population.

Through postmortem patient data, we have determined multiple subgroups of AD with varying degrees of neuropathology and cognitive deficiencies, differences in brain gene expression irrespective of β-amyloid or tau deposition, and inclusion or lack of high levels of gene expression resulting in neuroinflammation of the brain.

We categorize the subgroup of patients with high levels of gene expression resulting in neuroinflammation of the brain as “Type I AD.”

Through our next-generation approach for AD drug discovery (as depicted above), we have been able to develop a streamlined strategy for identifying novel product candidates by utilizing the following elements of our platform:

● Novel Biology .

Leveraging DCT to identify robust novel targets using gene expression signatures from each AD subgroup.

Characterizing mechanisms of action in central nervous system, or CNS, cell types for target assessment.

● Novel Chemistry .

Employing our Fluency technology to accelerate the identification of small molecules that selectively bind to a target of interest.

● Proprietary Translational Planning.

Utilizing the AD subgroup data that we have generated to select ideal preclinical models to improve clinical translation, including AD subgroup-specific induced pluripotent stem cell, or iPSC, lines, and defined existing and novel biomarkers specific to these patients.

By leveraging our data-driven discoveries, we believe we have a unique advantage to develop a targeted strategy for patient selection and to increase response rates by treating the underlying biology of the AD subgroups.

Our Neuroscience Pipeline

Our current neuroscience programs are dedicated to providing treatments for patients classified in a specific AD subgroup for which there are significant unmet needs and underserved patient populations.

Our neuroscience programs are currently in the early stages of drug discovery and we are focused on advancing these programs into lead optimization.

The following table summarizes our neuroscience pipeline:

Our Neuroscience Programs—Rationale for Treating Neuroinflammation

We believe treating neuroinflammation in Type I AD patients will slow the progression of the disease.

Previous academic studies have shown that neuroinflammation is a possible cause of AD pathology.

In addition, other studies have determined that neuroinflammation is an early AD event that precedes β-amyloid and/or tau deposition in AD patients, and is necessary for AD patients to progress from mild cognitive symptoms to more severe cognitive impairment leading to diagnosis of AD.

In a meta-analysis review of peripheral inflammatory markers in AD, an academic group reviewed 175 studies that enrolled over 26,000 patients and observed that AD patients have elevated inflammatory markers, including IL-1β and IL-6.

In another study, IL-1β was associated with a faster rate of decline on executive functioning in older adults and IL-6 was associated with a faster decline of verbal memory.

These observations are in agreement with our studies that identified subgroups of AD patients with elevated levels of neuroinflammatory gene expression.

Collectively, through our own research and publicly available literature, we believe that treating neuroinflammation earlier in Type I AD patients may be able to slow the progression of the disease in these patients.

Our Solution:

We are developing investigational small molecule inhibitors against an undisclosed target, or AO.01, for our IMM-ALL-01 program, which is currently in early stages of discovery.

We believe that inhibition of AO.01 will decrease AD-related neuroinflammation by reducing the activation of microglia.

Microglia are innate immune cells that have been observed to significantly increase AD-related neuroinflammation.

Our preclinical studies in cultured microglia have demonstrated that 50 μM treatment with our AO.01 inhibitors decrease the release of IL-6 (as depicted in figure B below), an inflammatory marker that drives AD-related neuroinflammation, while promoting anti-inflammatory IL-10 expression (as depicted in figure A below).

In Vitro Observation of AO.01 Inhibitors Decreasing the Release of IL-6 and Promoting IL-10 Expression

DCT revealed AO.01 as a target involved in AD-related neuroinflammatory mechanisms dysregulated in the brains of Type I AD patients.

Through our bioinformatics analysis of independent study data, we observed that gene expression of AO.01 is significantly increased in activated microglia.

In our in vitro studies, knockdown of AO.01 gene expression suppressed the neuroinflammatory behavior of primary microglia.

Our RNAseq analysis of our internal microglia experiment confirmed reduced expression of neuroinflammatory pathway genes after AO.01 knockdown.

Based on these studies, we observed that knockdown of AO.01 directly correlates with a decrease in neuroinflammatory markers.

We further observed that knockdown of AO.01 gene expression decreased neuronal hyperphosphorylated tau deposition in a tau cell model.

We believe this suggests that AO.01 inhibition may block multiple independent AD-related neuroinflammatory pathways by inhibiting and/or suppressing the release of neuroinflammatory markers, including IL-6, and decreasing tau deposition.

We plan to improve the in vitro potency of our AO.01 inhibitors by focusing on a resolved catalytic pocket of AO.01 to further reduce the proinflammatory activity of microglia.

While our preliminary studies demonstrate high cell permeability for our current AO.01 inhibitors, we plan to focus on optimizing blood brain barrier penetrance during lead optimization to provide desirable activity in the brain.

Our goal is to increase translatability by exploring the effect of our AO.01 inhibitors on inflammation in human microglia derived from acquired iPSC lines of Type I AD patients.

Our Solution:

We are developing investigational small molecule inhibitors against an undisclosed target, or AO.03, for our IMM-ALL-03 program, which is currently in the early stages of discovery.

We leveraged Fluency to identify and rank initial hits against the AO.03 protein and screened a subset of hits with drug-like properties through a cell-free assay.

The screening assays confirmed several Fluency hits from different chemical classes to AO.03, and subsequent modification of our AO.03 hits significantly improved inhibition of AO.03’s activity (as depicted in figure A below).

Our preclinical studies in activated microglia have demonstrated that 10 and 50 μM treatment with our AO.03 inhibitors decrease the release of IL-6 (as depicted in figure B below).

In addition, in our preliminary studies, we have observed high cell permeability for our current AO.03 inhibitors.

We plan to optimize blood brain barrier penetrance during lead optimization to provide desirable activity in the brain.

Fluency Platform Identifies Small Molecules Designed to Inhibit AO.03 and In Vitro Observation of AO.03 Inhibitors Decreasing the Release of IL-6

Biological Relevance of AO.03

Through our platform, we have discovered that AO.03 is a target that is involved in aberrant inflammatory pathways in Type I AD pathogenesis, and that reduced AO.03 gene expression corrects the expression of genes related to Type I AD biology.

In our in vitro studies, we observed that stimulation of microglia into a proinflammatory state triggered significant increases in AO.03 gene expression, whereas reduction of AO.03 gene expression had a causative effect in converting microglial behavior from a proinflammatory state to an anti-inflammatory state.

Similar to AO.01, we also observed that lower AO.03 gene expression blocked neuronal tau deposition in a tau cell model, including phosphorylation of tau at a protein site called Threonine 181, or p181 (as depicted below).

Based upon literature, there is strong evidence that p181 phosphorylation occurs early in AD progression and is positively correlated to the age of onset, suggesting early prevention of p181 phosphorylation may significantly delay AD symptoms.

While in vitro analysis of stimulated microglia after AO.03 and AO.01 knockdown revealed non-identical, overlapping changes in cytokine release, RNAseq analyses have revealed that the targeted pathways of AO.03 and AO.01 are different.

Concretely, reduction of AO.01 gene expression reduced expression of signaling genes for oxidation phosphorylation and the pentose phosphate pathway, whereas reduction of AO.03 gene caused a reduction of genes widely known to be involved in neuroinflammatory pathways in AD, including the IL-6 and toll-like receptor signaling pathways (as depicted below).

We believe this represents unique opportunities for regulating several neuroinflammatory pathways in Type I AD patients.

The Biological Effect of Reducing AO.03 Gene Expression on Inflammation and Tau Deposition, and Pathway Analysis of AO.01 versus AO.03

RAS Modulators Program

We are developing investigational mutation agnostic RAS modulators that are designed to bind to a unique, undisclosed site on RAS for the treatment of solid tumors.

We believe our 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 KRAS G12C and KRAS G12D , we believe a majority of KRAS mutations, which we are designing our RAS modulators to target, will remain unaddressed.

In the humanized 3D-TGA tumor model, we observed a half maximal tumor inhibitor concentration, or IC 50 , of less than 0.1 μM for twelve of our investigational RAS modulators.

A low IC 50 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, we believe our 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.

Our RAS program is currently in the drug discovery stage of development.

Additional Early Discovery Drug Programs

In addition to the discovery programs described above, we are also pursuing drug discovery efforts towards an undisclosed but validated oncology target.

We continue to periodically evaluate our drug discovery efforts and are focused on developing and advancing our early pipeline by addressing validated oncology targets in new ways that may

better address unmet clinical needs.

Our proprietary and we believe, innovative, platforms are central to our discovery and translational efforts, and we continue 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 we advance drug programs with potential for broad activity and improved overall tolerability.

To that end, we have deprioritized and paused our covalent MEK and PI3K programs.

We also suspended our neuroscience programs to sharpen our focus on our core oncology programs.

Consistent with our approach of weaving bioinformatics and computational biology into every stage of the drug development process, we have developed a proprietary disease-agnostic platform that allows us to leverage human biological data to generate insights that are not constrained by the inherent limitations of conventional approaches or prevailing scientific views.

4 unchanged sentences

● Novel Biology.

Identify novel targets and new ways to drug existing targets using DCT and/or our insights into mechanisms of response.

Identify potential novel targets and new ways to drug existing targets using DCT and/or our insights into mechanisms of response.

● Novel Chemistry.

Rapidly identify small molecules that selectively bind to a target of interest using our proprietary Fluency technology, and/or engineer PK to achieve optimal signaling dynamics.

Identify small molecules that selectively bind to a target of interest using our proprietary Fluency technology, and/or engineer PK to achieve optimal signaling dynamics.

● Proprietary Translational Planning.

Use humanized preclinical models and bioinformatics to prioritize indications and identify sensitive subpopulations.

Use proprietary, humanized 3D preclinical models and bioinformatics to prioritize indications and identify sensitive subpopulations.

Underlying each of these elements is our rigorous quality control and ability to analyze complex biological datasets.

2 unchanged sentences

Our platform is not limited to a single aspect or pathology;

rather, it is disease-agnostic, which we believe enables us to identify, develop and evaluate product candidates across multiple disease areas simultaneously, with our initial focus in

oncology and neuroscience.

rather, it is disease-agnostic, which we believe enables us to identify, develop and evaluate product candidates across multiple disease areas simultaneously, with our current focus in oncology.

While we currently have an emphasis on transcriptomic data, our platform is not limited to a single data type and thus we believe it will be able to evolve as new datasets emerge.

2 unchanged sentences

Insights from Human Data

Our analyses often begin by comparing existing transcriptomic data from two groups of patients (e.g.

from those whose tumors have metastasized versus those whose tumors have not) to help elucidate the biological mechanisms underlying a particular aspect of disease which we seek to counteract.

Our analyses often begin by comparing existing transcriptomic data from two groups of patients (e.g., from those whose tumors have metastasized versus those whose tumors have not) to help elucidate the biological mechanisms underlying a particular aspect of disease which we seek to counteract.

As another example, we may analyze existing data from patients with differences in response to an existing therapy, in order to better understand what is happening in responders versus non-responders.

34 unchanged sentences

The platform uses patient data as a starting point, rather than artificial 2D in vitro models.

For example, our neuroscience program uses gene expression data from AD patient subsets as an input to DCT.

We have presented data at American Association for Cancer Research and other conferences demonstrating how cell lines fail to capture the heterogeneity of patient tumors, and our discovery team’s experience in the 3D tumor modeling field has also highlighted the limitations of 2D in vitro data.

12 unchanged sentences

It also makes predictions about the target binding location for all compounds, which allows us to filter the library for drug candidates that are the most likely to affect a specific region of interest on the desired target.

Fluency accelerates our drug development process by allowing us to go from millions of potential compounds down to what Fluency selects as the best hundred drug candidates within a single work day.

Fluency accelerates our drug development process by allowing us to go from millions of potential compounds down to what Fluency selects as the best hundred drug candidates within a single workday.

This allows us to quickly advance only those select candidates to medicinal chemistry and experimental validation (as depicted below), increasing our capital efficiency.

2 unchanged sentences

To illustrate both the ease of use, as well as the power of Fluency to identify promising drug candidates, we constructed a test screen of Tukysa® (tucatinib), a recently FDA-approved drug for the treatment of advanced breast cancer in combination with trastuzumab and capecitabine.

Tukysa® is a tyrosine kinase inhibitor of human epidermal growth factor

receptor 2, or HER2 (also referred to as ERBB2).

Tukysa® is a tyrosine kinase inhibitor of human epidermal growth factor receptor 2, or HER2 (also referred to as ERBB2).

We created a test compound library by placing Tukysa® in a diverse chemical library of 17.8 million drug-like molecules and evaluated whether or not Fluency could identify it as a promising drug candidate against ERBB2 (depicted in the first panel below).

8 unchanged sentences

Fluency Test Screen Output Example

Fluency has been used to screen for potential drug candidates within our early-stage oncology and neuroscience programs.

We have a dedicated team of AI experts who continue to evolve Fluency and are embedded in our end-to-end preclinical drug development processes.

Fluency has been used to screen for potential drug candidates within our early-stage oncology programs.

Our team includes AI specialists with expertise in Fluency who are embedded in our end-to-end preclinical drug development processes.

We continue to seek new ways to apply our AI expertise to develop novel product candidates and potentially improve the lives of patients.

6 unchanged sentences

Proprietary Translational Planning

Humanized Models .

Humanized 3D Tumor Models .

In oncology, we are deeply experienced in advanced, humanized 3D-based tumor growth models, which based on peer reviewed research by members of our team and others, more accurately predict drug response in animal models, and we believe in patients, compared to standard models.

1 unchanged sentence

Thus, we believe our deep expertise in 3D tumor models enables us to more accurately stratify patients likely to benefit from our potential product candidates.

In neuroscience, we similarly seek to use human iPSC based models that more faithfully represent the biology of a heterogeneous patient population than more traditional cell lines.

3D-TGA Background and Utility

Although two-dimensional, or 2D, tissue culture has dominated cell-based preclinical oncology research for over 70 years, successful translation and regulatory approval of new oncology drugs are amongst the lowest of all therapeutic areas.

Innovations in cell-based platform technologies, such as matrix-based humanized 3D Tumor Growth Assay, or 3D-TGA, tumor models, offer the promise to enrich preclinical drug discovery and improve overall clinical translational success.

Our company and leadership have a strong history in research and translation of drug response using patient-derived tumor models (e.g., patient-derived xenografts and 3D ex vivo models) and translational bioinformatics using public and internal patient data.

Our team has built on previous ex vivo tumor modeling experience and patient-alignment model selection approaches to identify models that better reflect molecular profiles of target patient populations.

We believe this effort will help improve translational success of our pipeline and help ensure that established 3D-TGA models perform well as a core platform for innovative oncology drug R&D.

By leveraging over two decades of humanized modeling expertise, our translational and discovery teams have built, characterized, and interrogated a large set of 3D-TGA tumor models from commonly used human tumor cell lines (i.e., currently at over 130 tumor models).

The cohort of 3D-TGA tumor models span at least 12 major tumor types, including:

breast, colorectal, lung, pancreas, melanoma, ovary, liver, stomach, prostate, neuroblastoma, rhabdomyosarcoma, and thyroid.

Over time, additional 3D-TGA models may be developed to add new indications or expand existing indications to better test emerging discovery or translational hypotheses.

A large, proprietary 3D-TGA collection ensures that new drug candidates, identified as active in one cohort, could be quickly tested for broader tumor activity in additional tumor types.

The established collection of 3D-TGA tumor models can also be used to perform novel drug screens and develop novel chemical entities (NCE’s) that demonstrate drug activity.

Prioritize Indications and Identify Sensitive Subpopulations

9 unchanged sentences

DCT was then utilized to identify targets and intervention time points, otherwise known as biological perturbations, that could counteract cachexia.

Among the highest ranked perturbations were multiple MEK, inhibitors, but only the gene expression profiles induced by these MEK inhibitors at early time points (i.e., at 3 and 6 hours) were ranked highly for cancelling the disease-associated signals according to our technology.

In contrast, the gene expression signals induced by MEK inhibitors at a later time point (i.e., at 24 hours) amplified or mimicked the transcriptomic signatures associated with diseases.

2 unchanged sentences

The BALB/c mice were orally administered 100 mg/kg of selumetinib twice a day for 18 days.

when we examined a set of genes known to be downstream of ERK and activated by the MAPK pathway, we saw reduced downregulation of the pathway following selumetinib treatment.

Notably, when we examined a set of genes known to be downstream of ERK and activated by the MAPK pathway, we saw reduced downregulation of the pathway following selumetinib treatment.

There was very little difference between the degree of MAPK pathway downregulation at the 2 hour time point and the 12 hour time point, demonstrating that the inhibition achieved by a typical MEK inhibitor with a non-zero drug trough was both static and limiting in a chronic setting.

6 unchanged sentences

We utilize Fluency, the novel chemistry element of our platform, to rapidly identify small molecule hits for a targeted region of a protein for many of the earlier stage programs in our oncology pipeline.

Fluency is being utilized to accelerate the advancement of our RAS and PI3K-alpha programs.

For example, Fluency is being utilized to accelerate the advancement of our RAS modulator program.

In addition, these earlier stage programs also utilize our platform’s ability to generate novel biology by characterizing mechanisms of response to address these targets in new ways.

In the case of our RAS modulators, this involves targeting the process of RAS dimerization.

In the case of our RAS modulators, this includes targeting the process of RAS dimerization.

Finally, we are also leveraging novel chemistry in the form of PK changes with the goal of achieving optimal signaling dynamics and deep cyclic inhibition to maximize therapeutic activity in broad populations while improving tolerability.

We plan to evaluate each of our programs in humanized 3D models and leverage bioinformatics to prioritize indications and identify sensitive patient subgroups.

Our Platform and Our Neuroscience Programs

Our neuroscience programs began with our platform’s ability to identify insights from human data, specifically by methodically analyzing challenging datasets by assessing the robustness of various publicly available AD datasets.

Given the lack of disease-modifying therapies and AD patient heterogeneity, robust analysis of data is a motivating factor to drive our success in this space.

We applied our platform’s capability to stratify patients into previously undiscovered subsets, identifying new subpopulations of AD patients with strikingly different molecular biology and distinct gene expression profiles.

We then applied our platform’s ability to identify novel biology by leveraging DCT to identify and rank novel targets for specific subsets of AD patients.

Two of these undisclosed AD targets, AO.01 and AO.03, have been identified in vitro and have gone on to become the focus of our two lead neuroscience programs, IMM-ALL-01 and IMM-ALL-03, respectively.

Once those targets had been identified and experimentally confirmed, we utilized Fluency to rapidly identify small molecules that are designed to selectively bind to the targets, and such selective binding has since been observed in vitro .

We also leveraged our platform’s capabilities for characterizing mechanisms of response to assess the biological impact of those hits, and we are preparing for proprietary translational planning by using iPSC models to confirm the differences in response we expect to see in specific AD patient subgroups.

The pharmaceutical and biotechnology industries are characterized by rapid advancement of novel technologies, significant competition and a strong defense of intellectual property rights.

2 unchanged sentences

Key factors that would affect our ability to effectively compete with other therapeutics include safety, efficacy, ease of administration, pricing, brand recognition and availability of reimbursement and coverage by third party payors.

Our Oncology and Neuroscience Programs

Our Oncology Programs

The current FDA-approved treatment options that target MAPK pathway cancers are either MEK inhibitors limited by their high rates of serious drug-related adverse events that result in drug intolerability and drug resistance through MAPK-feedback loops, or KRAS inhibitors limited to patients with specific KRAS mutations.

We expect that our oncology programs targeting the MAPK pathway may compete with current FDA-approved therapies or clinical programs targeting KRAS mutant tumors that are being advanced by certain pharmaceutical and biotechnology companies.

There are currently only five FDA-approved treatments for AD, and these treatments are widely considered to only briefly and modestly improve AD symptoms, ultimately failing to prevent or slow disease progression.

We expect that our neuroscience programs that are initially focused on treating neuroinflammation in AD may compete with products or programs being advanced by certain pharmaceutical and biotechnology companies.

We expect that our oncology

programs targeting the MAPK pathway may compete with current FDA-approved therapies or clinical programs targeting KRAS mutant tumors that are being advanced by certain pharmaceutical and biotechnology companies.

Intellectual Property

1 unchanged sentence

We rely on a combination of intellectual property protection strategies, including patents, trademarks, copyrights, trade secrets, license agreements, confidentiality policies and procedures, non-disclosure agreements, invention assignment agreements and technical measures designed to protect the intellectual property and confidential information and data used in our business.

As of March 3, 2022, we have:

As of February 27, 2023, we have:

one issued U.S.

two pending U.S.

five pending U.S.

patent applications;

provisional application;

20 pending patent applications outside the 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:

our lead product candidate, IMM-1-104, our MEK-io candidate, IMM-6-415, our DCT, and Fluency.

our lead product candidate, IMM-1-104, our Universal-MAPK candidate, IMM-6-415, our 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;

1 unchanged sentence

patent and any patents that may issue from our owned pending U.S.

patent applications are expected to expire in February, 2039;

and any patents that may issue from our owned pending foreign patent applications or PCT applications are expected to expire in January, 2041.

With respect to IMM-1-104, as of March 3, 2022, we have one pending U.S.

provisional application and one pending PCT application.

The pending U.S.

provisional application is directed to, among other things, combination claims with respect to IMM-1-104.

provisional application would need to be converted to a non-provisional application by January 6, 2023.

Any patent that may issue, based upon this provisional U.S.

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.The pending PCT application has not yet entered the national stage;

its pending claims are directed to compounds, pharmaceutical compositions, and methods of use.

Any patent that may issue, based upon this pending PCT application 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 March 3, 2022, we have one pending provisional U.S.

this application would need to be converted to a non-provisional application by January 6, 2023.

patent applications are expected to expire in February, 2039 or January 2041;

any patents that may issue from our owned pending foreign patent applications are expected to expire in January, 2041, and any patents that may issue from national phase filings from our PCT application are expected to expire in January, 2043.

With respect to IMM-1-104, as of February 27, 2023, we have one pending U.S.

patent application and 20 pending patent applications outside the 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, we have 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 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 our DCT, as of March 3, 2022, we have one issued 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 our DCT, as of February 27, 2023, we have one issued U.S.

patent and one pending U.S.

5 unchanged sentences

patent related to our DCT and any patent that may issue from our pending patent application related to our 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 March 3, 2022, we have one pending U.S.

patent application.

The pending claims of this U.S.

patent application are directed to methods (processes) and systems.

With respect to Fluency, as of February 27, 2023, we have 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 our 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.

2 unchanged sentences

In the United States, a patent’s term may, in certain cases, be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming a common inventor and having an earlier expiration date.

We cannot be sure that our pending patent applications that we have filed or may file in the future will result in issued patents, and we can give no assurance that any patents that have issued or might issue in the future will protect our current or future products, will provide us with any competitive advantage, and will not be challenged, invalidated, or circumvented.

We cannot be sure that our pending patent applications that we have filed or may file in the future will result in issued patents, and we can give no assurance that any patents that have

issued or might issue in the future will protect our current or future products, will provide us with any competitive advantage, and will not be challenged, invalidated, or circumvented.

In the United States, the patent term of a patent that claims an FDA-approved drug or biologic may also be eligible for patent term extension, which permits patent term restoration as compensation for the patent term lost during FDA regulatory review process.

10 unchanged sentences

In addition to our reliance on patent protection for our inventions, products, and technologies, we also seek to protect our brand through the procurement of trademark rights.

As of March 3, 2022, we have certain trademark registrations and pending applications for trademark registration, for the marks DISEASE CANCELLING and IMMUNEERING in the United States and/or certain foreign jurisdictions.

As of February 27, 2023, we own 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.

Furthermore, we rely on trade secrets, know-how, unpatented technology and other proprietary information, to strengthen our competitive position.

12 unchanged sentences

Generally, our activities in other countries will be subject to regulation that is similar in nature and scope as that imposed in the United States, although there can be important differences.

Additionally, some significant aspects of regulation in the European Union, or EU, are addressed in a centralized way, but country-specific regulation remains essential in many respects.

Additionally, some significant

aspects of regulation in the European Union, or EU, are addressed in a centralized way, but country-specific regulation remains essential in many respects.

Drug Development Process

14 unchanged sentences

An IND is a request for authorization from the FDA to administer an investigational new drug product to humans.

central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies.

The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies.

Some preclinical testing may continue even after the IND is submitted.

7 unchanged sentences

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical study.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

Clinical trials are conducted under protocols detailing, among other

things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.

22 unchanged sentences

When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain FDA regulatory requirements in order to use the study as support for an IND or application for marketing approval.

Specifically, the FDA has promulgated regulations governing the acceptance of foreign clinical trials not conducted under an IND, establishing that such studies will be accepted as support for an IND or application for marketing approval if the study was conducted in accordance with GCP, including review and approval by an independent ethics committee, or IEC, and use of proper procedures for obtaining informed consent from subjects, and the FDA is able to validate the data from the study through an on-site inspection if the FDA deems such inspection necessary.

Specifically, the FDA has promulgated regulations governing the acceptance of foreign clinical trials not conducted under an IND, establishing that such studies

will be accepted as support for an IND or application for marketing approval if the study was conducted in accordance with GCP, including review and approval by an independent ethics committee, or IEC, and use of proper procedures for obtaining informed consent from subjects, and the FDA is able to validate the data from the study through an on-site inspection if the FDA deems such inspection necessary.

The GCP requirements encompass both ethical and data integrity standards for clinical studies.

17 unchanged sentences

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, preclinical and other non-clinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product.

Data may come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of

alternative sources, including studies initiated by investigators.

Data may come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including studies initiated by investigators.

To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the investigational drug product to the satisfaction of the FDA.

5 unchanged sentences

This review typically takes twelve months from the date the NDA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision after it the application is submitted.

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review.

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they

are sufficiently complete to permit substantive review.

The FDA may request additional information rather than accept an NDA for filing.

21 unchanged sentences

Under PREA, original NDAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver.

The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the

product is safe and effective.

The sponsor or the FDA may request a deferral of pediatric clinical trials for some or all of the pediatric subpopulations.

3 unchanged sentences

Orphan designation must be requested before submitting an NDA.

After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

After the FDA grants orphan designation, the identity

of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

14 unchanged sentences

Any product candidate submitted to the FDA for approval, including a product candidate with a fast track designation or breakthrough therapy designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

An NDA for a product candidate is eligible for priority

review if it has the potential to provide significant improvement in treatment, diagnosis or prevention of a serious disease or condition compared to marketed products.

An NDA for a product candidate is eligible for priority review if it has the potential to provide significant improvement in treatment, diagnosis or prevention of a serious disease or condition compared to marketed products.

The FDA will attempt to direct additional resources to the evaluation of an application for a new drug designated for priority review in an effort to facilitate the review.

2 unchanged sentences

Drug products intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product candidate has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

As a condition of approval, the FDA may require that a sponsor of a drug

receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

The FDA may withdraw accelerated approval if, among other things, the confirmatory study fails to verify clinical benefit;

49 unchanged sentences

Pediatric exclusivity is another type of marketing exclusivity available in the United States.

Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to another period of exclusivity if a sponsor conducts

clinical trials in children in response to a written request from the FDA.

Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to another period of exclusivity if a sponsor conducts clinical trials in children in response to a written request from the FDA.

The issuance of a written request does not require the sponsor to undertake the described clinical trials.

2 unchanged sentences

Such regulation may constrain the financial arrangements and relationships through which we research, develop, and ultimately, sell, market and distribute any products for which we obtain marketing approval.

Such laws include, without limitation, federal and state anti-kickback, fraud and abuse, and false claims laws, such as the federal Anti-Kickback Statute and the federal Civil False Claims Act, as well as federal and state data privacy and security laws and regulations, and transparency laws and regulations addressing drug pricing and payments and other transfers of value made by pharmaceutical manufacturers to physicians and other healthcare providers, such as the federal Physician Payment Sunshine Act.

Violations of any of such laws or any other governmental regulations that apply may result in significant penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations, integrity oversight and reporting obligations to resolve allegations of noncompliance, exclusion from participation in federal and state healthcare programs, such as Medicare and Medicaid, and imprisonment.

Such laws include, without limitation, federal and state anti-kickback, fraud and abuse, and false claims laws, such as the federal Anti-Kickback Statute and the federal Civil False Claims Act, as well as federal and state transparency laws and regulations with respect to drug pricing and payments and other transfers of value made by pharmaceutical manufacturers to physicians and other healthcare providers, such as the federal Physician Payment Sunshine Act.

Violations of any of such laws or any other governmental regulations

that apply may result in significant penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations, integrity oversight and reporting obligations to resolve allegations of noncompliance, exclusion from participation in federal and state healthcare programs, such as Medicare and Medicaid, and imprisonment.

Coverage and Reimbursement

26 unchanged sentences

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare.

Other legislative changes have been proposed and adopted since the ACA was enacted, including aggregate reductions of Medicare payments to providers of 2% per fiscal year, which went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, will stay in effect through 2030, with the exception of a temporary suspension from May 1, 2020 through March 31, 2022 unless additional action is taken by Congress.

In addition, the American Taxpayer Relief Act of 2021, effective January 1, 2024, would eliminate the statutory cap on rebate amounts owed by drug manufacturers under the Medicaid Drug Rebate Program, or MDRP, which is currently capped at 100% of the AMP for a covered outpatient drug.

In the future, there may be additional challenges and/or amendments to the ACA.

Other legislative changes have been proposed and adopted since the ACA was enacted, including aggregate reductions of Medicare payments to providers, which went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, will stay in effect through 2032, with the exception of a temporary suspension from May 1, 2020 through March 31, 2022 unless additional action is taken by Congress.

In addition, the American Rescue Plan, effective January 1, 2024, would eliminate the statutory cap on rebate amounts owed by drug manufacturers under the Medicaid Drug Rebate Program, or MDRP, which is currently capped at 100% of the AMP for a covered outpatient drug.

Moreover, there has been heightened governmental scrutiny recently over the manner in which manufacturers set prices for their marketed products, which have resulted in several recent Congressional inquiries and proposed and enacted legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for pharmaceutical products.

On August 16, 2022, the Inflation Reduction Act of 2022, or IRA, was signed into law.

Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap;

imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023);

and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025).

The IRA permits the Secretary of the Department of Health and Human Services (HHS) to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

For that and other reasons, it is currently unclear how the IRA will be effectuated.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

4 unchanged sentences

In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws and consumer protection laws and regulations govern the collection, use, disclosure, and protection of health-related and other personal information.

In addition, certain foreign laws govern the privacy and security of personal data, including health-related data.

For example, the GDPR imposes strict requirements for processing the personal data of individuals within the European Economic Area, or the EEA.

Companies that must comply with the GDPR face increased compliance obligations and risk, including more robust regulatory enforcement of data protection requirements and potential fines for noncompliance of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater.

Further, from January 1, 2021, companies have had to comply with the GDPR and also the UK GDPR, which, together with the amended UK Data Protection Act 2018, retains the GDPR in UK national law.

The UK GDPR mirrors the fines under the GDPR, i.e.

, fines up to the greater of €20 million (£17.5 million) or 4% of global turnover.

In addition, certain foreign

laws govern the privacy and security of personal data, including health-related data.

Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts, and can result in investigations, proceedings, or actions that lead to significant civil and/or criminal penalties and restrictions on data processing.

18 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business