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Item 1. Business

2024-02-15 compared with 2023-02-09 · 298 added, 332 removed, 800 unchanged (44% of the section changed)

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and its wholly owned subsidiaries.

We are a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of small molecule and cell therapies based on the modulation of cellular protein levels as a novel treatment approach for cancer and other challenging diseases.

We are a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of innovative small molecules and antibody therapies based on the modulation of cellular protein levels as a novel treatment approach for cancer, inflammatory conditions and other challenging diseases.

Leveraging our extensive expertise in E3 ligases together with our proprietary DNA-encoded libraries, we have built DELigase, an integrated discovery platform to identify and advance novel drug candidates targeting E3 ligases, a broad class of enzymes that can modulate proteins within the cell.

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Our wholly owned, clinical stage pipeline includes targeted protein degraders of Bruton’s tyrosine kinase (BTK), a B-cell signaling protein, and inhibitors of Casitas B-lineage lymphoma proto-oncogene B (CBL-B), an E3 ligase that regulates activation of multiple immune cell types including T cells and NK cells.

Our partnered drug discovery pipeline consists of ten programs under collaboration agreements with Sanofi S.A.

(Sanofi) and Gilead Sciences, Inc.

(Gilead), within which we retain options for co-development and co-commercialization rights in the United States for up to four drug candidates.

Our partnered drug discovery pipeline consists of multiple programs under collaboration agreements with Gilead Sciences, Inc.

(Gilead), Sanofi S.A.

(Sanofi) and Seagen Inc.

(now a part of Pfizer Inc.) (Pfizer), within which we retain certain options for co-development, co-commercialization and profit sharing in the United States for multiple drug candidates.

Our Clinical Development Pipeline

Our wholly owned pipeline of Targeted Protein Modulation drug candidates comprises four clinical stage programs in our Targeted Protein Degradation and Targeted Protein Elevation portfolios.

Our wholly owned pipeline of Targeted Protein Modulation (TPM) drug candidates comprises three clinical stage programs in our Targeted Protein Degradation (TPD) and Targeted Protein Elevation (TPE) portfolios.

These two portfolios demonstrate our ability to either decrease or increase protein levels in cells through the modulation of E3 ligases.

The following chart summarizes our clinical pipeline and ongoing clinical studies:

Table of Content

MOA , mechanism of action;

IND , investigational new drug;

DAC , degrader-antibody conjugates;

I&I , inflammation and immunology

Targeted Protein Degradation

Our portfolio of targeted protein degraders of BTK, a B‑cell signaling protein, comprises NX‑2127, an orally bioavailable BTK degrader for the treatment of relapsed or refractory B‑cell malignancies, and NX‑5948, an orally bioavailable BTK degrader for the treatment of relapsed or refractory B-cell malignancies and potentially autoimmune diseases.

We are currently enrolling patients in a Phase 1 trial for patients with relapsed or refractory B-cell malignancies which comprises a Phase 1a dose-escalation study and a Phase 1b cohort expansion study.

We have initiated the first of several potential Phase 1b expansion cohorts for patients with relapsed chronic lymphocytic leukemia (CLL), and enrollment continues in the Phase 1a dose-escalation portion of the trial for patients with several types of non-Hodgkin lymphoma (NHL).

We are currently enrolling patients in the Phase 1a portion of a Phase 1a/1b dose-escalation and cohort expansion study in patients with relapsed or refractory B-cell malignancies.

Our portfolio of targeted protein degraders of BTK, a B‑cell signaling protein, comprises NX‑5948, an orally bioavailable BTK degrader for the treatment of relapsed or refractory B-cell malignancies and potentially autoimmune diseases, and NX‑2127, an orally bioavailable BTK degrader that also degrades cereblon neosubstrates IKZF1 (Ikaros) and IKZF3 (Aiolos) for the treatment of relapsed or refractory B‑cell malignancies.

We are currently treating patients in a Phase 1a/1b dose-escalation and cohort expansion study in patients with relapsed or refractory B-cell malignancies.

In January 2024, the U.S.

Food and Drug Administration (FDA) granted Fast Track designation for NX-5948 for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two lines of therapy, including a BTK inhibitor (BTKi) and a B-cell lymphoma 2 (BCL2) inhibitor.

We are currently treating patients in a Phase 1a/1b dose-escalation and cohort expansion study of NX-2127 in patients with relapsed or refractory B-cell malignancies.

We have initiated Phase 1b expansion cohorts for patients with relapsed CLL, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

Enrollment of new patients in this clinical trial is paused pending resolution of a partial clinical hold, which was implemented by the FDA in late October 2023.

Patients already enrolled who are receiving clinical benefit may continue treatment.

Targeted Protein Elevation

Our portfolio of inhibitors of CBL-B, an E3 ligase that regulates the activation of multiple immune cell types including T cells and NK cells, comprises NX-1607, an orally bioavailable CBL-B inhibitor for immuno-oncology indications, and NX-0255, for ex vivo use to enhance adoptive T-cell therapy including our drug-enhanced tumor infiltrating lymphocyte (TIL) therapy, DeTIL-0255.

We are currently enrolling patients in the Phase 1a portion of a Phase 1a/1b dose-escalation and cohort expansion study in patients with solid tumors and lymphomas.

Our targeted protein elevation program includes NX-1607, an orally bioavailable an inhibitor of CBL-B, an E3 ligase that regulates the activation of multiple immune cell types including T cells and NK cells.

NX-1607 is targeted for immuno-oncology indications.

We are currently treating patients in a Phase 1a/1b dose-escalation and cohort expansion study of NX-1607 in patients with a range of oncology indications.

This study also includes a cohort within the Phase 1a dose escalation study testing NX-1607 in combination with paclitaxel, a taxane chemotherapy commonly used across a range of relapsed and refractory solid tumor indications.

NX-1607 was awarded an Innovative Passport from the UK Medicines and Healthcare products Regulatory Agency to accelerate time to market and facilitate patient access to novel drugs to treat serious and life-threatening diseases.

We completed the safety run-in portion of a Phase 1 trial in patients with advanced gynecologic malignancies, which included three patients with advanced epithelial ovarian cancer (EOC) who have been dosed with DeTIL-0255 and have cleared the initial safety evaluation.

The timing of the expansion of the Phase 1 trial will be established following a determination regarding the potential inclusion of NX-1607 in future cohorts.

Drug Discovery Pipeline

In addition to our clinical stage drug candidates, we are extending our protein modulation portfolio, both on our own and with partners by developing new targeted protein degraders and ligase inhibitors for a number of targets for which we believe the protein modulation modality can be clinically advantageous over existing therapies.

These existing and future programs may have the potential to address diseases with significant unmet need, including cancer and other challenging diseases.

We have entered into several revenue generating collaborations with large biopharmaceutical companies to leverage our DELigase platform for drug discovery.

In December 2019, we entered into a global strategic collaboration with Sanofi, which was subsequently expanded and amended in January 2021, to discover, develop and commercialize a pipeline of innovative targeted protein degradation drugs for patients with challenging diseases in multiple therapeutic areas.

In June 2019, we entered into a global strategic collaboration with Gilead to discover, develop and commercialize innovative targeted protein degradation drugs for a wide range of diseases including cancer.

Both collaborations allow us to further advance our future pipeline with ten currently identified targets included in these collaborations.

These existing and future programs may have the potential to address diseases with significant unmet need, including cancer, autoimmunity, inflammation, and other challenging diseases.

We have entered into several revenue generating collaborations with large biopharmaceutical companies, including with Gilead, Sanofi and Seagen (now a part of Pfizer), to leverage our DELigase platform for drug discovery.

These collaborations allow us to further advance our future pipeline with multiple currently identified targets included in these collaborations.

In aggregate, we have received $413.0 million in non-dilutive financing from our collaborators to date, and as of November 30, 2023, we are eligible to receive up to $8.1 billion in potential future fees and milestone payments, as well as royalties on future product sales.

We retain options for co-development and co-commercialization rights in the United States for up to four drug candidates discovered under these collaborations.

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We retain certain options for co-development, co-commercialization and profit sharing in the United States for multiple drug candidates pursuant to these collaborations.

Corporate Strategy

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• Advance our lead programs through clinical development .

We have four drug candidates in Phase 1 clinical development and anticipate the following advancements in 2023.

Enrollment is ongoing in our Phase 1a/1b clinical trial of NX-2127 in adults with relapsed or refractory B-cell malignancies.

We expect to provide a clinical update for the NX-2127 trial in the second half of 2023 and further anticipate defining a regulatory strategy for NX-2127 in the second half of 2023 based on emerging clinical data and feedback from the U.S.

Food and Drug Administration (FDA).

Enrollment is ongoing in our Phase 1a/1b clinical trial of NX-5948 in adults with relapsed or refractory B-cell malignancies.

We anticipate presenting initial clinical data from the Phase 1a portion of the NX-5948 trial in the second half of 2023.

In addition, we seek to define a dose for Phase 1b cohort expansion in the second half of 2023.

Enrollment is ongoing in our Phase 1 trial for NX-1607 in adults with a variety of oncology indications.

We expect to present clinical data from the Phase 1a portion of the NX-1607 trial and to define a dose for Phase 1b cohort expansion in the second half of 2023.

• Enhance and expand our DELigase platform.

We have three drug candidates in Phase 1 clinical development and anticipate the following advancements in 2024.

Enrollment is ongoing in our Phase 1a/1b clinical trial of NX-5948 in adults with relapsed or refractory B-cell malignancies, including CLL.

In 2024, we seek to define doses for Phase 1b cohort expansion in CLL and NHL and accelerate Phase 1 clinical trial enrollment to enable pivotal trials.

We plan to present additional clinical data with higher dose levels and longer treatment duration in mid-2024.

Screening and enrollment of new patients in our Phase 1a/1b clinical trial of NX-2127 in adults with relapsed or refractory B-cell malignancies have been paused due to a partial clinical hold placed on the study by the FDA.

Patients currently enrolled in the clinical study who are deriving clinical benefit may continue to receive treatment in accordance with the ongoing study protocol.

In 2024, we expect to resolve the partial clinical hold to enable the introduction of newly manufactured drug product into the ongoing Phase 1 clinical trial.

Enrollment is ongoing in our Phase 1 trial for NX-1607 in adults with a range of oncology indications.

In 2024, we expect to present data from the Phase 1a dose escalation portion of the trial of NX-1607 and to define dose(s) to enable Phase 1b cohort expansion.

• Advance our portfolio of preclinical programs to generate development candidates for our partners and our proprietary pipeline.

Our research efforts are largely focused on the advancement of multiple programs for our partners Gilead, Sanofi, and Pfizer and for our proprietary pipeline.

These partnered and wholly owned programs are at various stages of DNA-encoded library (DEL) screening, lead optimization and preclinical research.

We aim to advance at least one program to the development candidate stage in 2024.

• Enhance and refine our DELigase platform .

Targeted Protein Modulation is a rapidly emerging therapeutic modality that can provide significant advantages over existing modalities.

Our proprietary DELigase platform enables us to advance an industry-leading approach to either selectively decrease or increase protein levels.

We intend to continue to invest resources in our research and development activities to expand the breadth of our DELigase platform both in terms of the number of ligases available for drug discovery and the scale of our DEL collection.

We plan to leverage our platform capabilities to further enhance our position as a leader in the promising field of protein modulation.

• Discover and develop new targeted protein modulation drug candidates .

We select new targets for which we have evidence that modulation of protein levels may provide a distinct therapeutic advantage over traditional small molecule inhibitors, or which have been considered undruggable by existing modalities.

We have multiple additional wholly owned and partnered targets in DNA-encoded library (DEL) screening, lead optimization and preclinical research.

We plan to use our DELigase platform to continue to explore new targets with potential applications in cancer and other challenging diseases.

We expect to select a new targeted protein degrader development candidate in 2023.

We intend to continue to invest resources in our research and development activities to enhance our DELigase platform both in terms of the number of ligases available for drug discovery and the scale of our DEL collection.

We plan to continue to leverage our platform capabilities to further enhance our position as a leader in the promising field of protein modulation.

• Explore additional strategic collaborations to maximize the commercial potential of our DELigase platform and our drug candidates .

We have received $413.0 million in non-dilutive funding to date from our collaborations to support our research and development activities and to create new targeted protein modulation drugs with our partners.

Under our Sanofi and Gilead collaborations, as of November 30, 2022, we have the opportunity to receive up to $4.8 billion in potential future fees and milestone payments, as well as royalties on future sales while retaining certain commercialization options.

Under our Gilead, Sanofi and Pfizer collaborations, as of November 30, 2023, we have the opportunity to receive up to $8.1 billion in potential future fees and milestone payments, as well as royalties on future sales while retaining certain commercialization options.

We currently retain worldwide development and commercialization rights to our BTK and CBL-B portfolios.

While we intend to become a fully integrated biopharmaceutical company and build a targeted sales force in the United States to support the commercialization of our drug candidates, if approved, we intend to selectively evaluate technology collaborations and commercialization partnerships for our drug candidates with partners whose capabilities complement our own while retaining meaningful commercial rights in key geographic territories.

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Targeted Protein Modulation

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Our DEL collection consists of billions of small molecule compounds used to identify potential binders to ligases and protein targets as critical starting points in our drug discovery process.

The differentiation of our protein modulation platform is in its breadth and versatility, enabling us to alter protein levels either upward or downward for both clinically validated targets, such as BTK, and for targets previously thought to be “undruggable”;

that is, proteins that could not be addressed by conventional pharmacological means, such as CBL-B.

Proteins as targets in treating disease

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One of the most exquisitely ordered cellular systems governing cellular proteins is the ubiquitin proteasome system (UPS).

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As depicted above, the UPS is responsible for regulating and maintaining normal protein levels in the cell.

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• Targeted Protein Degradation (Harnessing E3 ligases).

Targeted protein degradation (TPD) harnesses the natural activity of ligases to remove specific proteins from the cell.

Targeted protein degradation harnesses the natural activity of ligases to remove specific proteins from the cell.

Targeted protein degradation is accomplished by using bifunctional small molecules, which are composed of an E3 ligase binding element, or harness, linked to a target protein binding element.

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• Targeted Protein Elevation (Inhibiting E3 ligases).

By inhibiting the function of E3 ligases in targeted protein elevation (TPE), it is possible to rapidly increase specific protein levels to control biological pathways.

By inhibiting the function of E3 ligases in targeted protein elevation, it is possible to rapidly increase specific protein levels to control biological pathways.

Increasing the levels of distinct sets of proteins could be a powerful approach to blocking pathological processes and restoring normal physiology.

While there is enthusiasm in the scientific community around the therapeutic potential of E3 ligase inhibition, the discovery of such inhibitors has been impeded by the limited understanding of this biochemically and structurally complex class of proteins.

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Targeted Protein Modulation

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Our targeted protein degradation portfolio includes two clinical stage drug candidates that catalyze potent degradation of BTK, a well validated target for B-cell malignancies.

Our two BTK degrader drug candidates, NX-2127 and NX-5948, are oral drug candidates being evaluated for the treatment of relapsed or refractory B-cell malignancies including NHL and CLL.

In addition, NX-5948 has the potential to address B-cell mediated autoimmune indications, due to its specificity for BTK and its ability to cross the blood brain barrier.

In preclinical studies, we have demonstrated the ability of both NX-2127 and NX-5948 to degrade BTK in tumor cell lines harboring either wild type BTK or a variety of clinically relevant mutant forms of BTK that confer resistance to both currently marketed BTK inhibitors and next-generation BTK inhibitors in late-stage development.

In these models, BTK degradation correlated with anti-tumor activity.

In addition to degrading BTK, NX-2127 was also designed to have cereblon mediated immunomodulatory activity through the degradation of neosubstrates Ikaros and Aiolos.

Based on our preclinical data, we believe NX-2127 and NX-5948 have the potential to demonstrate improved clinical benefit over current standard-of-care in multiple oncology indications.

Our targeted protein elevation portfolio includes two clinical stage small molecule drug candidates that inhibit CBL-B, an intracellular orchestrator of the activation of T cells, B cells and NK cells.

In preclinical studies, primary human T cells exposed to our lead oral CBL-B ligase inhibitor drug candidate NX-1607 demonstrated increased T-cell activation in the absence of co-stimulation with CD3 and CD28, a potential advantage in an immune suppressive tumor microenvironment.

Our two BTK degrader drug candidates, NX-5948 and NX-2127, are oral drug candidates being evaluated for the treatment of relapsed or refractory B-cell malignancies including CLL and non-Hodgkin’s lymphoma (NHL).

NX-5948 is designed to solely degrade BTK, and NX-2127 is designed to degrade BTK and the immunomodulatory substrates of Ikaros and Aiolos.

NX-5948 has the potential to address B-cell mediated autoimmune indications due to its specificity for BTK, and neurologic autoimmune indications due to its ability to cross the blood brain barrier.

In preclinical studies and in patient-derived samples, we have demonstrated the ability of both NX-5948 and NX-2127 to degrade BTK in cells harboring either wild type BTK or a variety of clinically relevant mutant forms of BTK that are known to confer resistance to both currently marketed BTK inhibitors and next-generation BTK inhibitors in late-stage development.

Based on our preclinical and clinical data, we believe that both NX-5948 and NX-2127 have the potential to demonstrate unique and improved clinical benefit over the current standard-of-care in multiple oncology indications.

Our targeted protein elevation portfolio includes our lead ligase inhibitor NX-1607, an oral, clinical stage small molecule drug candidate that inhibits CBL-B, an intracellular orchestrator of the activation of T cells, B cells and NK cells.

In preclinical studies, primary human T cells exposed to NX-1607 demonstrated increased T-cell activation in the absence of co-stimulation with CD3 and CD28, a potential advantage in an immune suppressive tumor microenvironment.

In addition, NX-1607 has been shown in preclinical models to increase T‑cell proliferation and result in increased secretion of interleukin-2 (IL-2), a key cytokine involved in immune activation.

We believe that oral delivery of CBL-B inhibitors has the potential to drive immune cell activation and stimulation of localized IL-2 secretion, leading to enhanced anti-tumor response across a wide range of oncology indications.

We have also developed a second CBL-B ligase inhibitor drug candidate, NX‑0255, for ex vivo use.

We believe incorporating NX-0255 into adoptive cell therapy (ACT) has the potential to enhance T‑cell proliferation and improve cellular phenotype to drive greater anti-tumor activity.

NX-0255 has been incorporated into the manufacturing process for the production of therapeutic, drug-enhanced tumor infiltrating lymphocytes (DeTIL) in a safety run-in study we completed in 2022.

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We believe that oral delivery of a CBL-B inhibitor has the potential to drive immune cell activation and stimulation of localized IL-2 secretion, leading to enhanced anti-tumor response across a wide range of oncology indications.

Targeted protein degradation portfolio in clinical trials

We have developed two targeted protein degrader drug candidates that are potent degraders of the BTK protein, a genetically validated signaling factor that drives B-cell activation and proliferation.

Our BTK degraders harness the E3 ligase cereblon, and our lead BTK degrader NX-2127 was engineered to include cereblon-mediated immunomodulatory activity, another well validated mechanism to treat hematologic malignancies.

As such, NX-2127 is a dual degrader of both BTK and Aiolos/Ikaros.

In certain B-cell malignancy indications, we believe dual activity may provide therapeutic advantages that could result in improved outcomes.

Our second BTK degrader development candidate, NX-5948, degrades BTK without degrading Aiolos/Ikaros.

NX-5948 is further differentiated from NX-2127 because it has demonstrated the ability to cross the blood brain barrier in animal models and degrade BTK in both brain-resident tumor cells and normal microglia in the brain.

We are currently enrolling Phase 1 trials for NX-2127 and NX-5948 in patients with relapsed or refractory B-cell malignancies.

We have developed two targeted protein degrader drug candidates that are potent degraders of the BTK protein, a clinically validated signaling factor that drives B-cell activation and proliferation.

Both of our BTK degraders harness the E3 ligase cereblon.

NX-5948 is designed to selectively degrade BTK and has demonstrated the ability to cross the blood brain barrier in animal models and degrade BTK in both brain-resident tumor cells and normal microglia in the brain.

NX-2127 was engineered to degrade both BTK and cereblon neosubstrates Ikaros and Aiolos for the treatment of relapsed or refractory B-cell malignancies.

In several B-cell malignancy indications, and in particular in certain NHL subtypes, we believe dual activity may provide therapeutic advantages not addressable by pure BTK degraders or inhibitors, that could in turn result in improved outcomes for patients.

We are currently treating patients with relapsed or refractory B-cell malignancies in Phase 1 trials for NX-5948 and NX-2127.

BTK’s role in B-cell malignancy

BTK is a key component of the B-cell receptor signaling pathway and has been clinically validated as a target in the treatment of B-cell malignancies.

It is estimated that over 80 thousand people in the United States were diagnosed with NHLs in 2022.

BTK is a key component of the B-cell receptor signaling pathway and has been clinically validated as a target in the treatment of B-cell malignancies, most notably in CLL but also in NHL.

In 2022, it was estimated that over 20 thousand patients were diagnosed with CLL and over 80 thousand patients were diagnosed with NHLs in the United States.

Approximately 85% of NHLs are a result of B-cell malignancies.

The natural progression of NHL varies widely and takes multiple forms, ranging from aggressive subtypes such as diffuse large B-cell lymphoma (DLBCL), to more indolent forms such as follicular lymphoma (FL).

The natural progression of NHL varies widely and takes multiple forms, ranging from aggressive subtypes such as DLBCL, to more indolent forms such as follicular lymphoma (FL).

Background on BTK inhibitors and immunomodulatory drugs for B-cell malignancies

The first generation BTK inhibitor Imbruvica, or ibrutinib, is approved for the treatment of CLL and various forms of NHL, including mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia (WM), and marginal zone lymphoma (MZL).

Second generation BTK inhibitors such as Calquence, or acalabrutinib, is approved for use in CLL and MCL, and Brukinsa, or zanubrutinib, is approved for use in CLL, MCL, WM, and MZL.

In 2021, global sales of BTK inhibitors were approximately $8.4 billion.

The first generation BTK inhibitor Imbruvica, or ibrutinib, is approved for the treatment of CLL, Waldenstrom’s macroglobulinemia (WM), and chronic graft versus host disease (GVHD).

Second generation BTK inhibitors include Calquence, or acalabrutinib, which is approved for use in CLL and MCL, and Brukinsa, or zanubrutinib, which is approved for use in CLL, MCL, WM and marginal zone lymphoma (MZL).

Based on reported sales to date, we estimate that 2023 BTK sales were approximately $8.7 billion.

These BTK inhibitors bind covalently to cysteine C481 of the BTK protein and irreversibly inhibit BTK;

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In addition, acquired resistance, most commonly through mutations in C481, may limit long term efficacy of these first and second generation BTK inhibitors.

A number of noncovalent BTK inhibitors are currently being investigated in clinical trials as potential therapies for patients with relapsed and refractory disease, including Jaypirca, or pirtobrutinib, which was recently approved for use in MCL.

However, the noncovalent inhibitors are also subject to acquired resistance, and treatment with these agents has led to the discovery of a broad range of new resistance mutations.

We believe targeted protein degradation of BTK may be a superior approach to existing covalent or noncovalent BTK inhibitors that only inhibit enzyme activity, particularly in the relapsed and refractory setting, and in the setting of resistance mutations to both covalent and noncovalent inhibitors.

BTK degraders possess several unique properties that offer potential advantages over inhibitors:

• Addresses scaffold function of BTK.

Removal of the BTK protein rather than just inactivating the kinase domain addresses the scaffolding activity of BTK, more completely blocking the signaling activity of both wild type and mutant forms of BTK.

• Event-driven pharmacology.

BTK degraders do not require strong and prolonged binding to BTK to trigger degradation, which increases the ability our degraders to act on mutated BTK and may decrease the probability of forming new resistance mutations.

• Catalytic activity.

A single degrader molecule is able to affect multiple target BTK molecules sequentially without the need to be constantly bound to the target.

We believe that targeted protein degradation of BTK may be a superior approach to existing covalent or noncovalent BTK inhibitors, particularly in the relapsed and refractory setting, and in the setting of resistance mutations to both covalent and noncovalent inhibitors.

The immunomodulatory drugs including Revlimid, or lenalidomide, and Pomalyst, or pomalidomide, are analogs of Thalomid, or thalidomide.

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This may suggest that simultaneous degradation of BTK combined with cereblon-mediated immunomodulatory activity by a single agent could produce an additive or synergistic effect in certain B-cell malignancies.

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Potential advantages of BTK degraders

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We have demonstrated that both NX-5948 and NX-2127 can induce BTK degradation and inhibit tumor growth with oral administration in xenograft mouse models implanted with both wild type and ibrutinib-resistant lymphoma cell lines.

We have specifically designed NX-2127 as a dual degrader of BTK and the cereblon neosubstrates Aiolos and Ikaros, and we have designed NX-5948 to degrade BTK with limited or no degradation of cereblon neosubstrates for potential applications in indications where sparing immunomodulatory activity may be beneficial.

We have also demonstrated the ability of both NX-5948 and NX-2127 to degrade BTK in circulating B-cells of non-human primates and in B-cell lymphoma patients following once daily oral dosing in ongoing Phase 1 trials.

We have specifically designed NX-5948 to degrade BTK with limited or no degradation of cereblon neosubstrates, and we have designed NX-2127 as a dual degrader of BTK as well as the cereblon neosubstrates Aiolos and Ikaros, for potential applications in indications where adding immunomodulatory activity may be beneficial.

We have optimized NX-5948 and NX-2127 to be able to degrade both wild type BTK and the C481S variant of BTK that has been identified as the most common mutation in patients who have become resistant to ibrutinib therapy over time.

Both agents have subsequently demonstrated the ability to degrade additional mutant variants of BTK associated with resistance to BTK inhibitors including L528W, T474I, M437R and V416L.

In the figure below, we show the concentration dependent degradation of both wild-type BTK (top left) and C481S mutant BTK (top right) in a lymphoma cell line (TMD8) for our clinical candidate NX-5948.

We have also demonstrated that NX-5948 induces rapid BTK degradation over time in a lymphoma cell line (Ramos) as compared to a control protein, with nearly complete loss of BTK within one hour of administration as shown in the figure below at the bottom.

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Using a human TMD8, we have demonstrated that both NX-2127 and NX-5948 have an ability to degrade BTK and inhibit growth of tumor cell lines that are resistant to ibrutinib.

As shown in the charts below, our BTK degrader, NX-5948, can inhibit both wild type and ibrutinib-resistant tumor cell line growth, where approved BTK inhibitors ibrutinib and acalabrutinib lose activity against the C481S mutation.

In our model of DLBCL cell line (TM8) harboring the most common resistance mutations, both NX-5948 and NX-2127 retained activity while all tested inhibitors demonstrated a major decrease in activity against at least one resistance mutation.

The figure below shows a heat map of the relative activity of NX-5948 compared to a panel of first and second generation covalent BTK inhibitors and non-covalent BTK inhibitors.

Potent tumor growth inhibition was achieved at varying doses of orally administered NX-2127 in mouse xenograft tumor models with a wild type BTK protein, as shown in the figure below on the top right.

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These target levels of inhibition suggest a potential therapeutic range correlating BTK degradation to tumor growth inhibition.

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In addition to BTK degradation, we have also demonstrated the ability of NX-2127 to degrade both Aiolos (as shown in the figure below on the left) and Ikaros (not shown), proteins targeted by immunomodulatory drugs Revlimid (lenalidomide) and Pomalyst (pomalidomide).

Studies in human T cells comparing NX-2127 to lenalidomide and pomalidomide have shown comparable Aiolos degradation and resultant T-cell activation, as shown in the figure below on the right.

In addition to BTK degradation, we have also demonstrated the ability of NX-2127 to degrade both Aiolos (as shown in the figure below) and Ikaros (not shown), proteins targeted by immunomodulatory drugs Revlimid (lenalidomide) and Pomalyst (pomalidomide).

Studies in human T cells comparing NX-2127 to lenalidomide and pomalidomide have shown comparable Aiolos degradation and resultant T-cell activation, as shown in the figure below.

Based on the clinical data of both ibrutinib and the immunomodulatory drug in B-cell malignancies, we believe that this strategy of targeting both BTK and Aiolos/Ikaros in a single oral treatment may improve anti-tumor activity.

We anticipate that the ability of NX-2127 to degrade both BTK and Aiolos/Ikaros will confer unique anti-tumor activity.

One example is in the preclinical mantle cell lymphoma model (REC-1).

Both BTK inhibitors and immunomodulatory drugs have demonstrated single agent clinical activity in mantle cell lymphoma.

In the REC-1 model shown in the figure below, covalent BTK inhibitors such as ibrutinib demonstrate potent but incomplete activity (below, left).

The same is true for non-covalent inhibitors such as pirtobrutinib (below, right).

Immunomodulatory drugs, such as pomalidomide, demonstrate a more complete cell killing but at higher drug concentrations (below, left).

NX-2127 outperforms these drugs in this cell viability assay, demonstrating both potent activity and complete cell killing.

Clinical development of NX-2127

We are studying the pharmacology, safety and clinical activity of NX-2127 in multiple subtypes of relapsed and refractory B‑cell malignancies, including those in which ibrutinib has shown only modest effects or is ineffective, as in the case of CLL patients with BTK inhibitor resistance mutations.

Furthermore, indications in which immunomodulatory activity could augment responses are of high interest.

These indications include DLBCL, MCL, MZL and FL.

We plan to expedite development in indications where NX-2127 shows evidence of compelling clinical activity and where there is high unmet need.

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As illustrated in the diagram below, we are enrolling patients in the Phase 1a dose-escalation trial in patients with relapsed or refractory NHL and a Phase 1b cohort expansion study of NX-2127 in patients with relapsed or refractory CLL.

The Phase 1a portion is designed as a monotherapy dose escalation trial to investigate the safety and tolerability of NX‑2127 and to identify a maximum tolerated dose for further evaluation.

The Phase 1b portion of the trial is designed as a monotherapy expansion trial in defined cohorts of up to 20 patients each.

We selected a 100 mg dose for a Phase 1b expansion dose in CLL patients and that study is ongoing.

The three other potential cohorts include patients with DLBCL, MCL/MZL/WM, and FL.

Initial clinical findings in patients with CLL

Two presentations at the 64 th American Society of Hematology (ASH) annual meeting in December 2022 described positive data for NX-2127 in patients with CLL and new scientific findings supporting the rationale for BTK degradation as a novel mechanism of action to address the current and emerging unmet need in patients who have failed multiple prior lines of therapy.

The first presentation described a set of clinically emergent BTK mutations that confer resistance to currently approved covalent BTK inhibitors and to unapproved noncovalent BTK inhibitors in development.

These mutations fall into two biochemically defined categories of kinase proficient, which maintain their known enzymatic activity but no longer are fully inhibited by BTK active site inhibitors such as ibrutinib, and kinase dead, which lack the enzymatic activity normally attributed to BTK but still signal tumor growth promotion through the B-cell receptor in the presence of a BTK inhibitor.

Such signaling has been hypothesized to be achieved through a structural, scaffolding function of the BTK protein.

In the figure below, we demonstrate equivalent BTK degradation in clinical samples from patients in our Phase 1 trial independent of baseline mutations.

Montoya et al., ASH 2022, Abstract #750.

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The second presentation included preliminary clinical findings from the ongoing Phase 1 trial for patients with CLL.

Despite a median of five prior lines of treatment and BTK mutations present in 48% of patients, NX-2127 treatment resulted in an objective overall response rate of 33% (5 out of 15).

Tumor shrinkage and clinical responses were observed in patients regardless of prior lines of therapy or baseline BTK mutations.

The trial is ongoing, and we continue to enroll additional CLL patients.

Mato et al., ASH 2022, Abstract #965.

Clinical development studies for NX-5948

We are studying the pharmacology, safety, and clinical activity of NX-5948 in multiple subtypes of relapsed and refractory B-cell malignancies, including those in which ibrutinib has shown only modest effects or is ineffective, as in the case of CLL patients with BTK inhibitor resistance mutations.

As illustrated in the diagram below, we are conducting a Phase 1a/1b dose-escalation and cohort expansion study of NX-5948 in patients with relapsed or refractory NHL and CLL.

As illustrated in the diagram below, we are conducting a Phase 1a/1b dose-escalation and cohort expansion study of NX-5948 in patients with relapsed or refractory CLL and NHL.

The Phase 1a portion is designed as a monotherapy dose escalation trial to investigate the safety and tolerability of NX-5948 and to identify a biologically active dose for cohort expansion and potentially a maximum tolerated dose.

The Phase 1b portion of the trial is designed as a monotherapy expansion trial in up to five potential cohorts.

We are currently enrolling patients at escalating doses in the Phase 1a portion of the study.

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Initial biomarker data from the first dose levels in the ongoing Phase 1a trial shown below demonstrate rapid, robust, and sustained BTK degradation in all patients with once daily oral dosing of NX-5948.

The patients in the study represent a heavily pre-treated population with a variety of previous treatment options.

Some patients also have resistance mutations and other high risk molecular features.

The study is currently enrolling in the United States, the United Kingdom (UK) and the Netherlands.

a Subtypes include:

transformed indolent lymphoma (e.g., grade 3b/transformed FL), Richter-transformed DLBCL, high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements, high-grade B-cell lymphomas NOS;

b Includes patients with secondary CNS involvement;

c Additional lines of therapy include anthracycline for non-GCB DLBCL and BTKi for MCL

Abbreviations:

BCL-2i , B-cell lymphoma-2 inhibitor;

BTKi , Bruton’s tyrosine kinase inhibitor;

CIT , chemo-immunotherapy;

CLL , chronic lymphocytic leukemia;

CNS , central nervous system;

DLBCL , diffuse large B-cell lymphoma;

FL , follicular lymphoma;

GCB , germinal center B-cell;

MCL , mantle cell lymphoma;

LoT , line of therapy;

MZL , marginal zone lymphoma;

NOS , not otherwise specified;

PCNSL , primary central nervous system lymphoma;

SLL , small lymphocytic lymphoma;

WM , Waldenströms macroglobulinemia

Initial clinical findings

Initial clinical findings from the NX-5948 clinical trial were presented at the 65th American Society of Hematology (ASH) annual meeting in December 2023.

Pharmacokinetics (PK) and pharmacodynamics data from the ongoing Phase 1a trial shown below demonstrate dose-dependent PK and rapid, robust, and sustained BTK degradation in all patients with once daily oral dosing of NX-5948, confirming the findings and projections from previous preclinical research.

NX-5948 C1D1 pharmacokinetics BTK degradation in patients receiving NX-5948

BTK , Bruton’s tyrosine kinase;

MFI , mean fluorescence intensity;

SEM , standard error of the mean

Searle et al., ASH 2023, Poster #4473

Results from the first data disclosure of the NX-5948 Phase 1a trial showed that NX-5948 is well tolerated and demonstrates clinical benefit.

Out of 26 patients dosed, there were no dose limiting toxicities and no treatment emergent adverse events (TEAEs) resulting in drug discontinuation.

There were four NX-5948-related grade ≥3 TEAEs and no related serious adverse events (SAEs).

As of the October 17, 2023 data cutoff, in the CLL patient population six out of seven dosed patients showed clinical benefit, including three partial responses (one ongoing over nine months) and three stable disease outcomes (two still on treatment).

In the NHL patient population (19 dosed), durable responses were noted across indications, with eight patients, or almost half of the patient population, continuing treatment.

An expanded data set from a larger number of patients treated at higher doses and for a longer duration of time is expected in 2024.

NX-5948 CLL efficacy

CI , confidence interval;

CLL , chronic lymphocytic leukemia;

CR , complete response;

PD , progressive disease;

PR , partial response;

SD , stable disease

NX-5948 NHL efficacy

CR , complete response;

DLBCL , diffuse large B-cell lymphoma;

FL , follicular lymphoma;

MCL , mantle cell lymphoma;

MZL , marginal zone lymphoma;

NHL , non-Hodgkin’s lymphoma;

PCNSL , primary CNS lymphoma;

PD , progressive disease;

PR , partial response;

SD , stable disease;

WM , Waldenstrom’s macroglobulinemia

Searle et al., ASH 2023, Poster #4473

Clinical development of NX-2127

We are studying the pharmacology, safety and clinical activity of NX-2127 in multiple subtypes of relapsed and refractory B‑cell malignancies, including CLL, DLBCL, MCL, MZL and FL.

We plan to focus development in indications where NX-2127 shows evidence of compelling clinical activity and where there is high unmet need.

As illustrated in the diagram below, the Phase 1a/1b dose-escalation and cohort expansion trial is evaluating doses ranging from 50 mg to 300 mg, and currently includes expansion cohorts for patients with CLL, DLBCL and MCL.

The Phase 1a portion is designed as a monotherapy dose escalation trial to investigate the safety and tolerability of NX‑2127 and to identify a maximum tolerated dose for further evaluation.

The Phase 1b portion of the trial is designed as a monotherapy expansion trial in defined cohorts.

We selected a 100 mg dose for a Phase 1b expansion in CLL patients and selected a 300 mg dose for Phase 1b expansion in MCL and DLBCL patients.

The patient population in the trial was heavily pre-treated and included a sizeable proportion of patients with resistance mutations.

Enrollment of new patients in this clinical trial is currently paused pending resolution of a partial clinical hold.

a Planned number of evaluable patients (i.e., meeting DLT evaluability criteria);

b Planned number of evaluable patients (i.e., meeting efficacy evaluability criteria)

CLL , chronic lymphocytic leukemia;

DLBCL , diffuse large B-cell lymphoma;

DLT , dose-limiting toxicity;

FL , follicular lymphoma;

MCL , mantle cell lymphoma;

MTD , maximum tolerated dose;

MZL , marginal zone lymphoma;

PD , pharmacodynamics;

PK , pharmacokinetics;

PCNSL , primary central nervous system lymphoma;

SLL , small lymphocytic lymphoma;

WM , Waldenstrom's macroglobulinemia

Clinical findings

Updated data from the NX-2127 clinical study presented at the 65th ASH annual meeting in December 2023 described positive data for NX-2127 in patients with NHL and CLL, confirming a manageable safety profile that is consistent with previous reports for BTK-targeted and immunomodulatory therapies.

BTK and Ikaros degradation was demonstrated at all dose levels in patient samples, as shown in the figure below.

Danilov et al., ASH 2023, Poster #4463

The safety findings from the study confirmed the manageable and predictable safety profile.

The most common TEAEs (any grade) were fatigue, neutropenia, hypertension, bruising/contusion, and diarrhea.

The most common grade ≥3 TEAEs were neutropenia, hypertension and anemia.

Atrial fibrillation was observed in six patients (11.1%;

down from 17% reported previously), with three patients (5.6%) having grade ≥3 events.

Twenty-one patients (38.9%) had serious TEAEs, of whom eight (14.8%) had SAEs considered related to NX-2127 treatment.

Two patients experienced dose limiting toxicities (cognitive disturbance, neutropenia;

both at the 300 mg dose).

Efficacy findings showed promising clinical activity:

For patients with NHL encouraging and durable responses were observed, including two complete responses at week eight and two partial responses at week eight.

For patients with CLL despite a median of five prior lines of treatment and BTK mutations present in 36% of patients, NX-2127 treatment resulted in an objective overall response rate of 40.7%, including partial responses in 11 patients, with treatment ongoing in 13 patients.

Tumor shrinkage and clinical responses were observed in patients regardless of prior lines of therapy or baseline BTK mutations.

NX-2127 NHL efficacy

NX-2127 CLL efficacy

Danilov et al., ASH 2023, Poster #4463

Targeted protein elevation portfolio in clinical trials

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CBL-B deficient animal models demonstrate enhanced signal dependent T-cell activation and robust T-cell dependent anti-tumor immunity.

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CBL-B is highly expressed in human CD4+ and CD8+ T cells, with expression tightly regulated by CD28 and CTLA-4 and other co-stimulatory and inhibitory signals.

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The increased secretion of IL-2 is of particular importance in the optimization and development of our CBL-B inhibitors, serves as a key cellular biomarker for measuring successful T-cell activation and is a known therapeutic cytokine in oncology.

We believe that our oral, small molecule CBL-B inhibitors have several potential immunotherapy applications through enhancing T-cell mediated anti-tumor activity by lowering the activation threshold of T cells in a suppressive tumor microenvironment where CBL-B plays a key role in the downregulation of T cells.

Importantly, our CBL-B inhibitors do not appear to activate T cells in the absence of TCR engagement.

We are studying our lead oral CBL-B inhibitor, NX-1607, in a Phase 1a dose escalation trial in multiple solid tumors and lymphoma.

We believe that our oral, small molecule CBL-B inhibitor, NX-1607, has several potential immunotherapy applications through enhancing T-cell mediated anti-tumor activity by lowering the activation threshold of T cells in a suppressive tumor microenvironment where CBL-B plays a key role in the downregulation of T cells.

Importantly, NX-1607 does not appear to activate T cells in the absence of TCR engagement.

We are studying NX-1607 in a Phase 1a dose escalation trial in multiple solid tumors and lymphoma.

Solid tumors represent the vast majority of human cancers.

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However, most patients fail to respond or experience only transient responses.

Pre-clinical development of CBL-B inhibitors

Preclinical development of CBL-B inhibitors

We have developed a series of potent small molecule inhibitors of CBL-B activity that have demonstrated biochemical activity and effects in vitro on human immune cells as well as in mouse tumor models.

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Based on our findings to date, we believe that CBL-B inhibitors may induce an immune cell localized IL-2 secretion that in combination with other immune activation effects will enhance anti-tumor responses.

The precursor compounds shown in the graphs below led to the optimization and selection of NX-1607 and NX-0255 as development candidates in our CBL-B portfolio.

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Clinical development strategy of CBL-B inhibitors

We are focused on three major immunotherapy applications for our CBL-B inhibitors in oncology.

In these applications, our overall strategy is to maximize an anti-tumor effect and clinical benefit of our CBL-B inhibitors by enhancing T cells in vivo or ex vivo .

In the first application, NX-1607, an oral small molecule immunotherapy drug candidate, is intended to be used as a single agent or in combination with other mechanistically complementary oncology therapies.

The second application is the ex vivo use of NX-0255 to create drug-enhanced cell therapy products.

DeTIL-0255 is a drug-enhanced investigational cell therapy product that uses NX-0255 ex vivo to enhance TIL propagation and phenotypic characteristics.

In 2022, we completed a safety run-in portion of a Phase 1 trial in patients.

The third application is the use of orally dosed NX-1607 in combination with potentially any cell therapy, such as DeTIL-0255, to promote engraftment and anti-tumor activity of the transplanted cells.

The precursor compounds shown in the graphs below led to the optimization and selection of NX-1607 as a development candidate.

NX-1607, an oral CBL-B inhibitor for immuno-oncology

NX-1607 is an investigational, orally bioavailable, potent inhibitor of CBL-B.

In vitro studies demonstrated that NX-1607 treatment resulted in a dose-dependent increase in T cells activation in TCR stimulated primary human T cells in the presence and, to a lesser extent, in the absence of CD28 co-stimulation, a potential advantage in a suppressive tumor microenvironment.

In vitro studies demonstrated that NX-1607 treatment resulted in a dose-dependent increase in T cell activation in TCR stimulated primary human T cells in the presence and, to a lesser extent, in the absence of CD28 co-stimulation, a potential advantage in a suppressive tumor microenvironment.

In vitro , NX-1607 has been demonstrated to increase T-cell activation in primary human T cells in the absence of co-stimulation with CD3 and CD28, a potential advantage in a suppressive tumor microenvironment.

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The tumor growth inhibition with oral administration of NX-1607 recapitulates the genetic experiment in mice with a ligase-inactive version of CBL-B which also shows tumor growth inhibition as illustrated in the figure below on the right.

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The in vivo effects of orally administered NX-1607 were further evaluated as a single agent in several mouse models of cancer.

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Without further treatment, all mice in the vehicle group (black line) died by day 60 as a result of disseminated tumor metastases in the lung, liver and brain.

By contrast, animals treated with NX-1607 (blue line) administered as a daily oral dose starting at day 7 and continuing through day 46 demonstrated a highly significant prolongation of survival.

By contrast, animals treated with NX-1607 (blue line) administered as a daily oral dose starting at day seven and continuing through day 46 demonstrated a highly significant prolongation of survival.

In the figure below on the right, oral treatment with NX-1607 (blue squares) significantly reduced the size of tumors and the rate of tumor growth compared to the vehicle group (black circles) in a B-cell lymphoma model.

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Both single agent NX-1607 (blue triangles) and single agent anti-PD-1 (red circles) reduced the number of lung metastases at day 28 compared with the vehicle group (black squares), but the combination of NX-1607 and anti-PD-1 (light blue diamonds) was superior to either single agent.

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Clinical development of NX-1607

We are studying the pharmacology, safety and clinical activity of single-agent NX-1607 in multiple solid tumor indications and lymphoma.

We are studying the pharmacology, safety and clinical activity of single-agent NX-1607 and the combination of NX-1607 with taxane chemotherapy in multiple solid tumor indications and lymphoma.

The solid tumors selected for this initial assessment include three different immune phenotypes:

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As illustrated in the diagram below, we are conducting a Phase 1a/1b dose-escalation and cohort expansion study of NX-1607 in patients with relapsed or refractory solid tumors and lymphoma.

The Phase 1a portion is designed as a monotherapy dose escalation trial to investigate the safety and tolerability of NX-1607, to identify a biologically active dose for cohort expansion and to identify a maximum tolerated dose.

The Phase 1b portion of the trial is designed as a monotherapy expansion trial in eight potential cohorts spanning four immune phenotypes, including immune checkpoint-resistant tumors, highlight suppressive tumor microenvironment indications, low immunogenicity/low antigenicity tumors and hematologic malignancies with T cell dysfunction or post-CAR-T.

We are currently enrolling patients in the Phase 1a dose escalation portion of the trial.

Background on Adoptive Cell Therapies

Adoptive Cell Therapies represent another class of immunotherapy in which T cells are isolated directly from patient tumors, as with TIL, or from patient blood with subsequent genetic modification to recognize specific antigens present on cancer cells, as with CAR-T therapies.

Tumor-reactive T cells are then expanded and infused back into the patient.

Currently, the only FDA-approved ACTs are anti-CD19 CAR-T therapies that are approved for treatment of acute B-cell leukemia and acute B-cell lymphoma and anti-BCMA CAR-T therapies that are approved for the treatment of multiple myeloma.

CAR-T therapies have not yet proven to be effective in solid tumors.

This is due to a number of factors within the tumor microenvironment unique to solid tumors such as the presence of immune checkpoint molecules and suppressive cytokines, and the heterogeneous nature of tumor cells themselves, preventing the identification of uniformly expressed targets for CAR design.

Another ACT is TIL therapy.

TIL is an expanded collection of lymphocytes that have penetrated the stroma of a tumor and contain host T cells that have recognized a variety of tumor antigens.

Ex vivo expanded TIL can be infused into the patient as a therapeutic to amplify the patient’s own immune response to the tumor.

Although existing ACT have delivered encouraging results in certain hematologic malignancies and some solid tumors, most patients fail to respond due to three main issues:

(i) failure to obtain sufficient quantity and/or quality of T cells from the tumor samples or from the blood for a successful production process, (ii) poor engraftment of T cells upon reinfusion to the patient and (iii) lack of a persistent anti-tumor response or relapse.

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CBL-B Inhibitors for Adoptive Cell Therapies

The opportunities to address the above limitations are substantial, and our results to date support the concept that CBL-B inhibitors may address some or all of the current limitations of ACT.

We are advancing several lines of experimentation to refine our understanding of the clinical and commercial opportunities in this area.

We have consolidated these efforts under an initiative we call the Nurix Adoptive Cell Therapy program (NxACT).

Our NxACT initiative includes a drug-enhanced TIL program known as DeTIL, as illustrated in the figure below, and a drug-enhanced CAR-T therapy known as DeCART.

The broader conceptual framework for NxACT is convergence of targeted protein modulation with ACT.

In addition to CBL-B, we expect to explore additional targets for protein modulation that may be useful in the NxACT program.

Based on our preclinical findings to date, we believe CBL-B inhibition using NX-0255 ex vivo during the isolation and expansion of TIL can address some of the issues that have limited the success of existing ACT.

We believe the use of NX-0255 ex vivo can address these limitations by producing not only more T cells, but also T cells with favorable characteristics including greater numbers of CD8+ T cells with an enhanced central memory phenotype, a profile that has been associated with better clinical outcomes.

In our preclinical ACT research program, we expanded TIL from human tumor samples ex vivo and measured the effects of drug enhancement by NX-0255 on TIL production.

Compared to TIL isolated and expanded in the presence of IL-2, TIL isolated and expanded with NX-0255 and IL-2 (DeTIL-0255) demonstrated greater proliferation, less exhaustion, increased cytotoxicity and increased central memory T-cell population.

The DeTIL-0255 investigational product under development is an autologous cell therapy consisting of T cells derived from a patient’s tumor expanded in culture with IL-2 + NX-0255.

Although NX-0255 has limited oral bioavailability, we have demonstrated inhibition of CBL-B both biochemically and in ex vivo T-cell culture, making it well suited for the ex vivo creation of new ACT products.

DeTIL-0255 is designed to be a single administration autologous TIL therapy infused following non-myeloablative chemotherapy.

We believe DeTIL-0255 could allow a broader application of TIL therapy, potentially providing long term benefit to patients with multiple types of cancer.

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Preclinical development of DeTIL-0255

We have tested NX-0255 in a mouse model of ACT shown below to determine if culture of tumor specific T cells ex vivo in the presence of a potent CBL-B inhibitor can confer a superior anti-tumor effect as compared to standard culture conditions using IL-2 alone.

We have demonstrated that even a short, three-day ex vivo exposure of T cells to NX-0255, either alone or in combination with IL-2, conferred a lasting anti-tumor phenotype upon transfer of the cells into a tumor-bearing animal as compared to controls.

We have also demonstrated that those cells cultured under standard conditions with IL-2 alone resulted in superior conditional survival of the mice relative to controls, but not as good as either group treated with NX-0255 as shown in the figure below.

We have further preclinically explored ACT by including an oral dosing regimen of NX-1607 in combination with NX‑0255 ex vivo treated T cells.

The results shown below illustrate that the combination with NX‑1607 yields more substantial anti-tumor effect and subsequent conditional survival than with ex vivo NX‑0255 ACT alone.

These data support our plan to explore the combination of oral NX‑1607 and ex vivo NX-0255 ACT in a future clinical trial.

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Clinical development of DeTIL-0255

We recently completed the safety run-in portion of the DeTIL-0255 Phase 1 trial for patients with relapsed and refractory gynecologic cancers.

For this trial, we worked with contract manufacturing organizations (CMOs) with experience in TIL product development for the development of the DeTIL-0255 process and manufacturing.

The primary objective of the study is to evaluate the safety and tolerability of DeTIL-0255 autologous cell therapy.

Secondary objectives include an exploratory evaluation of efficacy.

Other exploratory objectives include characterization of DeTIL-0255 phenotypes utilizing a variety of T-cell markers, identification of potential mechanisms of response or resistance to DeTIL-0255 including repertoire analysis and persistence of the autologous cell therapy in the patient.

The safety run-in portion of the trial included three patients with advanced EOC who have been dosed with DeTIL-0255 and have cleared the initial safety evaluation.

The timing of the expansion of the Phase 1 trial will be established following a determination regarding the potential inclusion of NX-1607 in future cohorts.

We are currently enrolling patients in the Phase 1a dose escalation portion of the monotherapy trial.

Our DELigase platform

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DEL technology is well suited to finding new binders for targets thought to be undruggable, which include the vast majority of proteins encoded in the human genome including E3 ligases.

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DEL technology taps enormous chemical space to overcome “druggability” limits

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We have also developed machine learning and high throughput methods for nanoscale hit resynthesis and affinity selection mass spectroscopy that allow a more comprehensive and industrialized process for finding the best chemical starting points for future pipeline programs.

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Leveraging the Nurix DEL Database for clear classification of enriched DEL ligands

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This automation enables us to sample unprecedented chemical space and allows for faster design test cycles which accelerates drug discovery projects.

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• Harnessing our data generation pipelines with Machine Learning.

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We have expanded the universe of E3 ligases available for therapeutic manipulation from the two predominantly used in the field, cereblon and VHL, by screening over 60 additional E3 ligases to date.

We have carefully selected these E3 ligases for use in drug discovery across our four core areas of therapeutic expertise:

oncology, immuno-oncology, adoptive cell therapy and immune disorders.

We have carefully selected these E3 ligases for use in drug discovery across our three core areas of therapeutic expertise:

oncology, immuno-oncology and immune disorders.

We consider the unique biological function of each ligase and the therapeutic requirements of the disease state for inhibitor programs.

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Our substantial expertise in E3 ligase biochemistry and biology has allowed us to identify and develop potent inhibitors of E3 ligases that play pivotal roles in T-cell signaling and immune cell function.

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Drug candidate identification and selection process

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Collaborations and License Agreements

Sanofi Collaboration and License Agreement

In June 2019, we entered into a global strategic collaboration agreement with Gilead (as subsequently amended, the Gilead Agreement) to discover, develop and commercialize a pipeline of targeted protein degradation drugs for patients with cancer and other challenging diseases using our DELigase platform to identify novel agents that utilize E3 ligases to induce degradation of five specified drug targets.

In August 2019 and September 2022, we entered into the First Amendment and the Second Amendment, respectively, to the Gilead Agreement to clarify certain language of the Gilead Agreement.

Under the Gilead Agreement, Gilead has the option to license drug candidates directed to up to five targets resulting from the collaboration and is responsible for the clinical development and commercialization of drug candidates resulting from the collaboration.

We retain the option to co-develop and co-promote, under a profit share structure, up to two drug candidates in the United States, provided that we may only exercise such option once per licensed product and Gilead retains the right to veto our option selection for any one drug candidate of its choice.

The collaboration excludes our current internal protein degradation programs for which we retain all rights, and also excludes our future internal programs, provided that we have distinguished future programs as excluded from the scope of the collaboration.

In March 2023, Gilead exercised the option to exclusively license one target (Gilead License Option Exercise), the first development candidate resulting from the Gilead Agreement.

Pursuant to the Gilead Agreement, we received a license option exercise payment of $20.0 million in April 2023 for the Gilead License Option Exercise.

Over time, Gilead may elect to replace the initial drug targets with other drug targets.

For drug targets that are subject to the collaboration, we are obligated to use commercially reasonable efforts to undertake a research program in accordance with a research plan agreed to by the parties and established on a target-by-target basis.

We have primary responsibility under the Gilead Agreement for performing preclinical research activities (including target validation, drug discovery, identification or synthesis) pursuant to a research plan.

Each party will bear its own costs in the conduct of research activities.

Gilead will be responsible for any development, commercialization and manufacturing activities, unless we exercise our co-development and co-promotion option.

For those programs that we exercise our option to co-develop and co-promote, we and Gilead will split U.S.

development costs as well as U.S.

profits and losses evenly, and we will be eligible to receive royalties on net ex-U.S.

sales and reduced milestone payments.

Upon signing the Gilead Agreement, Gilead paid us an upfront payment of $45.0 million, plus $3.0 million in additional fees.

In addition, from the signing of the Gilead Agreement to November 30, 2023, we received payments of $47.0 million for research milestones and additional payments and $20.0 million for a license option exercise payment.

As of November 30, 2023, we are eligible to receive up to approximately $2.3 billion in total additional payments based on certain additional fees, payments and the successful completion of certain preclinical, clinical, development and sales milestones.

We also are eligible to receive mid-single digit to low tens percentage tiered royalties on annual net sales from any commercial products directed to the optioned collaboration targets, subject to certain reductions and excluding sales in the United States of any products for which we exercise our option to co-develop and co-promote, for which the parties share profits and losses evenly.

Subject to earlier expiration in certain circumstances, the Gilead Agreement expires on a licensed product-by-licensed product and country-by-country basis upon the later of (1) the expiration of the last to expire patent with a valid claim covering the applicable licensed product in the applicable country, (2) the expiration of any regulatory exclusivity for the applicable licensed product in the applicable country or (3) ten years after the first commercial sale of the applicable licensed product in the applicable country covered by the Gilead Agreement, provided that the term for any profit-shared licensed product in the United States will expire upon the expiration or termination of the applicable profit-share term as set forth in an applicable profit-share agreement to be negotiated upon our exercise of our option to co-develop and co-promote such licensed product.

If Gilead does not exercise an option to license a drug candidate, then the Gilead Agreement will terminate at the end of the last to expire option period.

In December 2019, we entered into a strategic collaboration with Genzyme Corporation, a subsidiary of Sanofi, which became effective in January 2020 (as subsequently expanded and amended, the Sanofi Agreement), to discover, develop and commercialize a pipeline of targeted protein degradation drugs for patients with challenging diseases in multiple therapeutic areas using our DELigase platform to identify small molecules designed to induce degradation of three specified initial drug targets.

In January 2021, as part of the existing Sanofi Agreement, Sanofi paid us $22.0 million to exercise its option to expand the number of targets in the Sanofi Agreement from three to a total of five targets.

Over time and subject to certain limitations, Sanofi may elect to replace the drug targets with other reserved targets.

In January 2021, we entered into the First Amendment to the Sanofi Agreement to modify the research term on all targets.

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In July 2022, we entered into the Third Amendment to the Sanofi Agreement to further extend the substitution deadline on certain targets.

The extensions of the substitution deadline had no impact on revenue recognition.

Also in July 2022, Sanofi elected to replace certain drug targets, and the substitution extended the research term of those targets by one year to 5.25 years and increased overall forecasted costs, which had an immaterial impact on revenue recognition.

In August 2022, we entered into the Fourth Amendment to the Sanofi Agreement to modify the research plan for a certain target, which had no impact on revenue recognition.

Also in July 2022, Sanofi elected to replace certain drug targets, and the substitution extended the research term of those targets by one year to 5.25 years.

In August 2022 and November 2023, we entered into the Fourth Amendment and Fifth Amendment, respectively, to the Sanofi Agreement to modify the research plan for certain targets.

Under the Sanofi Agreement, Sanofi has exclusive rights and is responsible for the clinical development, commercialization and manufacture of drug candidates resulting from the collaboration while we retain the option to co-develop, co-promote and co-commercialize all drug candidates in the United States directed to up to two targets, one of which must be selected from a list of targets designated at the execution of the Sanofi Agreement or any replacement of such targets, and one of which must be selected from targets identified by Sanofi as part of their January 2021 expansion.

Our right to exercise our option to co-develop, co-promote and co-commercialize a given target is dependent on our ability to demonstrate, within a given timeframe, that we have sufficient cash resources and personnel to commercialize the product.

The collaboration excludes our current internal protein degradation programs for which we retain all rights, and also excludes our future internal programs, provided that we distinguished future programs as excluded from the scope of the collaboration.

For drug targets that are subject to the collaboration, we have primary responsibility for conducting preclinical research activities (including target validation, drug discovery, identification or synthesis) in accordance with the applicable research plan agreed to by the parties and established on a target-by-target basis.

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net sales and reduced milestone payments on such optioned products.

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Upon signing the Sanofi Agreement, Sanofi paid us an upfront payment of $55.0 million.

Subsequently in January 2021, Sanofi paid us an additional $22.0 million to exercise its option to expand the number of targets beyond the initial targets included in the collaboration.

We are eligible to receive additional payments if Sanofi exercises an option to extend the license term with respect to a particular target.

In addition, from the signing of the Sanofi Agreement to November 30, 2023, we received payments of $7.0 million for research milestones.

As of November 30, 2022, we are eligible to receive up to approximately $ 2.5 billion in total payments, including payments of up to $ 496.0 million upon the achievement of specified development milestones, up to $ 625.0 million upon the achievement of specified regulatory milestones and up to $ 1.3 billion upon the achievement of certain sales milestones, as well as up to $ 126.5 million in certain additional fees related to target licensing and reservation.

In addition, we are eligible to receive tiered royalties ranging from mid-single digit to low teen percentages on annual net sales of any commercial products that may result from the collaboration, subject to certain reductions and excluding sales in the United States of any products for which we exercise our option to co-develop and co-promote, for which we share profits and losses evenly.

Subject to earlier expiration in certain circumstances, the Sanofi Agreement expires on a licensed product-by-licensed product or profit-shared licensed product-by-profit-shared licensed product basis and country-by-country basis upon on the later of the expiration of (i) the last-to-expire patent with a valid claim covering the applicable licensed product in the applicable country, (ii) the expiration of any regulatory exclusivity for the applicable licensed product in the applicable country or (iii) ten years after the first commercial sale of the applicable licensed product in the applicable country covered by the Sanofi Agreement.

Gilead Collaboration, Option and License Agreement

In August 2019 and September 2022, we entered into the First and Second Amendment, respectively, to the Gilead Agreement to clarify certain language of the Gilead Agreement.

We retain the option to co-develop and co-promote, under a profit share structure, up to two drug candidates in the United States under certain conditions.

Additionally, we achieved two research milestones in November 2023 and received payments totaling $4.0 million in January 2024 as a result.

As of November 30, 2023, we are eligible to receive up to approximately $2.5 billion in total additional payments based on certain additional fees, payments and the successful completion of certain research development, regulatory and sales milestones, as well as mid-single digit to low teen percentage tiered royalties on annual net sales of any commercial products that may result from the collaboration, subject to certain reductions and excluding sales in the United States of any products for which we exercise our option to co-develop and co-promote, for which the parties share profits and losses evenly.

Subject to earlier expiration in certain circumstances, the Sanofi Agreement expires on a licensed product-by-licensed product or profit-shared licensed product-by-profit-shared licensed product basis and country-by-country basis upon on the later of (1) the expiration of the last-to-expire patent with a valid claim covering the applicable licensed product in the applicable country, (2) the expiration of any regulatory exclusivity for the applicable licensed product in the applicable country or (3) ten years after the first commercial sale of the applicable licensed product in the applicable country covered by the Sanofi Agreement.

In September 2023, we entered into a strategic collaboration with Seagen Inc.

(now a part of Pfizer Inc.) (the Pfizer Agreement) to develop a suite of targeted protein degraders against multiple targets nominated by Pfizer that are suitable for antibody conjugation.

Pfizer will be responsible for conjugating these degraders to antibodies to make Degrader-Antibody Conjugates (DACs), a new class of medicines for use in cancer treatment, and advancing these DAC drug candidates through preclinical and clinical development and commercialization.

Under the Pfizer Agreement, Pfizer has the option to obtain exclusive licenses to develop and commercialize certain degraders, while we retain an option for U.S.

profit sharing and co-promotion on two products arising from the collaboration.

Over time, Gilead may elect to replace the initial drug targets with other drug targets.

Each party will bear its own costs in the conduct of research activities.

Gilead will be responsible for any development, commercialization and manufacturing activities, unless we exercise our co-development and co-promotion option.

For those programs that we exercise our option to co-develop and co-promote, we and Gilead will split U.S.

development costs as well as U.S.

profits and losses evenly, and we will be eligible to receive royalties on ex-U.S.

net sales and reduced milestone payments.

Upon signing the Gilead Agreement, Gilead paid us an upfront payment of $45.0 million, plus $3.0 million in additional fees.

In addition, from the signing of the Gilead Agreement to November 30, 2022, we have received payments of $ 34.5 million for research milestones and additional payments.

As of November 30, 2022, we are eligible to receive up to approximately $ 2.3 billion in total additional payments, including up to $ 667.5 million upon the achievement of specified development milestones, up to $ 1.5 billion upon the achievement of specified sales milestones, subject to reduction for any product for which we exercise our option to co-develop and co-promote, and up to $ 136.8 million in certain additional fees related to target licensing, reservation and selection and research term extensions.

In addition, we are eligible to receive tiered royalties from mid-single digit to low tens percentages on annual net sales from any commercial products directed to the optioned collaboration targets, subject to certain reductions and excluding sales in the United States of any products for which we exercise our option to co-develop and co-promote, for which we share profits and losses evenly.

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Subject to earlier expiration in certain circumstances, the Gilead Agreement expires on a licensed product-by-licensed product and country-by-country basis upon on the later of (i) the expiration of the last-to-expire patent with a valid claim covering the applicable licensed product in the applicable country, (ii) the expiration of any regulatory exclusivity for the applicable licensed product in the applicable country or (iii) ten years after the first commercial sale of the applicable licensed product in the applicable country covered by the Gilead Agreement, provided that the term for any profit-shared licensed product in the United States will expire upon the expiration or termination of the applicable profit-share term as set forth in an applicable profit-share agreement to be negotiated upon our exercise of our option to co-develop and co-promote such licensed product.

If Gilead does not exercise an option to license a drug candidate, then the Gilead Agreement will terminate at the end of the last-to-expire option period.

For the targets nominated by Pfizer under the collaboration, we shall use commercially reasonable efforts to identify, synthesize, characterize and deliver targeted protein degraders that selectively bind to and degrade such targets.

Development of licensed degraders, with the exception of licensed products for which we exercised our profit-share options, will be at Pfizer’s sole cost and expense.

For the profit-share products, the parties will share net profits and net losses and global development costs, and we will be eligible to receive royalty and milestone payments on such optioned products.

Under the terms of the Pfizer Agreement, we received an upfront payment of $60.0 million.

We are eligible to receive up to approximately $3.4 billion in contingent payments based on specified research, development, regulatory and commercial milestones across multiple programs, and are eligible for mid-single to low double digit percentage tiered royalties on future sales.

Subject to the exceptions described in the Pfizer Agreement, the Pfizer Agreement expires upon the first to occur of (1) the expiration of the last-to-expire option exercise period under the Pfizer Agreement if no such option has been exercised prior to such expiration and (2) the expiration of the last-to-expire royalty term under the Pfizer Agreement.

Manufacturing and Supply

We do not own or operate, and currently have no plans to establish, any facilities for product manufacturing, packaging, storage and distribution, or testing.

We rely on and expect to continue to rely on contract manufacturing organizations (CMOs) for both drug substance and finished drug product, and ACT product.

We rely on and expect to continue to rely on contract manufacturing organizations (CMOs) for both drug substance and finished drug product.

We have personnel or engaged consultants with extensive technical, manufacturing, analytical and quality experience and good project management to oversee contract manufacturing and testing activities.

We have engaged third-party manufacturers to supply the drug substance for NX-2127, NX-5948 and NX-1607 and to develop and manufacture finished drug product for use in our Phase 1 clinical trials.

We have also engaged a third-party manufacturer to supply the drug substance for NX-0255 and to develop and manufacture the cell therapy product DeTIL-0255.

We currently obtain our supplies from these manufacturers on a purchase order basis and do not have long-term supply arrangements in place.

Because TIL and CAR-T therapies are manufactured on a patient-by-patient basis, they involve complex manufacturing and we anticipate that we will have to rely on third-party manufacturers to manufacture our ACT products for pre-clinical studies and clinical trials.

We have engaged third-party manufacturers to supply the drug substances for NX-5948, NX-2127 and NX-1607 and to develop and manufacture finished drug products for use in our clinical trials.

Should any of these manufacturers become unavailable to us for any reason, we believe that there are a number of potential replacements, although we may incur some delay in identifying and qualifying such replacements.

All of our drug candidates are organic compounds of low molecular weight, generally called small molecules, but which are larger than traditional small molecule therapeutics.

We have selected these compounds not only on the basis that they could have potentially favorable efficacy and safety profiles, but also for their ease of synthesis and reasonable cost of their starting materials.

We have selected these compounds not only on the basis that they could have potentially favorable efficacy and safety profiles, but also for their ease of synthesis and the reasonable cost of their starting materials.

In particular, our lead drug candidates are manufactured using reliable and reproducible synthetic processes from readily available starting materials.

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Moreover, our industry is characterized by the existence of large numbers of patents and frequent allegations of patent infringement.

Our platform and product focus is the discovery and development of protein modulation therapies using our chimeric small molecules and ligase inhibitors.

Other companies researching chimeric small molecules for protein degradation include Arvinas, Inc., BeiGene, Ltd., BioTheryX, Inc., C4 Therapeutics, Inc., Cullgen Inc., Foghorn Therapeutics Inc., Kymera Therapeutics, Inc.

Our focus is the discovery and development of innovative small molecules and antibody therapies designed to modulate protein levels, including targeted protein degraders.

Other companies that primarily focus on developing small molecules that degrade target proteins include, but are not limited to, Arvinas, Inc., BioTheryX, Inc., C4 Therapeutics, Inc., Cullgen Inc., Foghorn Therapeutics Inc., Kymera Therapeutics, Inc.

and Monte Rosa Therapeutics.

Further, several large pharmaceutical companies have disclosed preclinical investments in this field, including Amgen Inc., AstraZeneca plc, Bayer AG, Bristol-Myers Squibb Company, Genentech, Inc., GlaxoSmithKline plc and Novartis International AG.

Furthermore, we are aware of several biotech companies focused on developing TIL therapies for the treatment of cancer, including Instil Bio, Inc.

and Iovance Biotherapeutics, Inc.

Moreover, we also compete with current and future therapeutics developed at universities and other research institutions.

In addition to competition from other protein modulation therapies, any products that we develop may also face competition from other types of therapies, such as small molecule, antibody, vaccine or gene therapies.

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Our lead drug candidates target hematologic cancers and immune-mediated diseases including immuno-oncology and cell-based therapeutics for cancer.

Drug candidates from our BTK degrader and CBL-B inhibitor programs may face competition from drugs with similar mechanisms of action.

We are aware of clinical-staged BTK degraders currently in development by AbbVie Inc., Accutar Biotechnology, Inc., BeiGene, Ltd, Haisco Pharmaceutical Group Co., Ltd.

and Ubix Therapeutics, Inc.

In addition, we are aware of a clinical-staged CBL-B inhibitor currently in development by HotSpot Therapeutics, Inc.

Our lead drug candidates target hematologic cancers and immune-mediated diseases.

The most common methods of treating patients in oncologic indications are surgery, radiation and drug therapy, including chemotherapy, hormone therapy and targeted drug therapy.

A new class of therapies for treatment of oncology patients are ACTs including CAR-T cell therapies and TIL cell therapies.

There are a variety of available drug therapies marketed for cancer, including hematologic cancers.

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Our policy is to seek to protect our proprietary position by, among, other methods, pursuing patent protection in the United States and in jurisdictions outside of the United States related to our proprietary technology, inventions, improvements, platforms and drug candidates that are important to the development and implementation of our business.

Our patent portfolio, including pending priority applications and Patent Cooperation Treaty (PCT) applications, is intended to cover, but is not limited to, our technology platforms, drug candidates and components thereof and their methods of use, and any other inventions that are commercially important to our business.

However, the portfolio covering our drug candidates is at an early stage and is currently comprised of only applications and we do not currently own or license any issued patents.

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Our patent portfolio is intended to cover, but is not limited to, our technology platforms, drug candidates and components thereof and their methods of use, and any other inventions that are commercially important to our business.

We also rely on trade secret protection of our confidential information and know-how relating to our proprietary technology, platforms and drug candidates and continuing innovation to develop, strengthen and maintain our position in our DELigase platform and drug candidates.

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We believe that we have a strong global intellectual property position and substantial know how and trade secrets relating to our DELigase platform and drug candidates.

As of December 31, 2022, we have four U.S.

As of December 31, 2023, we have five U.S.

patents, 22 U.S.

patent applications and 80 foreign applications that we own, and three pending U.S.

patent applications, one foreign patent and 103 foreign applications that we own, and one U.S.

patent, four pending U.S.

patent applications and 26 foreign patent applications that we co-own with Gilead.

The expected expirations for issued patents and patents that may issue from pending applications covering our clinical candidates are 2039-2042 for NX-2127 and NX-5948;

2040-2042 for NX-1607;

and 2040 for DeTIL-0255.

The expected expirations for issued patents and patents that may issue from pending applications covering our clinical candidates are between the years 2039 and 2042 for NX-5948 and NX-2127;

and between 2040 and 2043 for NX-1607.

The term of individual patents depends upon the laws of the countries in which they are obtained.

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For more information, please see the sections titled “Risk Factors—Risks Related to Our Intellectual Property” and “Risk Factors—Risks Related to Regulatory Approval and Marketing of Our Drug Candidates.”

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Government Regulation

The processes for obtaining regulatory approvals in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

FDA approval process

In the United States, biological and pharmaceutical products are subject to extensive regulation by the FDA.

The processes for obtaining approval in the United States, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

The Federal Food, Drug, and Cosmetic Act (FDCA), Public Health Service Act (PHSA), and other federal and state statutes and regulations govern, among other things, the research, development, testing, manufacture, quality control, packaging, storage, recordkeeping, approval, labeling, promotion, advertising and marketing, distribution, post-approval monitoring and reporting, sampling, tracking and tracing and import and export of biological and pharmaceutical products.

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patients and subsequent protocol amendments must be submitted to the FDA as part of the IND.

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The FDA may order the temporary or permanent discontinuation of a clinical trial at any time, as a clinical hold or partial clinical hold, or impose other sanctions, if it believes that the clinical trial either is not being conducted in accordance with FDA requirements or presents an unacceptable risk to the clinical trial patients.

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In a Phase 3 trial, the drug or biological product is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy or potency and purity, and safety, of the product for approval or licensure, to establish the overall risk benefit profile of the product, and to provide adequate information for the labeling of the product.

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In most cases the FDA requires at least two adequate and well-controlled Phase 3 clinical trials to demonstrate the efficacy or potency of the drug.

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The FDA is not bound by the recommendation of an advisory committee, but it generally follows such recommendations.

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Before approving an NDA or BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

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If a Member State does not recognize the marketing authorization, the disputed points are eventually referred to the European Commission, whose decision is binding.

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Since the United Kingdom (UK) has left the EU, Great Britain is no longer covered by centralized marketing authorizations.

Since the UK has left the EU, Great Britain is no longer covered by centralized marketing authorizations.

This is not the case for Northern Ireland as under the Northern Ireland Protocol, centralized marketing authorizations continue to be recognized in Northern Ireland.

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A separate application is, however, still required.

The UK government reached a new agreement with the EU, the “Windsor Framework,” which aims to replace the Northern Ireland protocol.

According to the Windsor Framework, medicinal products intended for the UK market including Northern Ireland will be authorized by the MHRA and will bear a “UK only” label.

This means that medicinal products placed on the market in Northern Ireland will no longer need to be compliant with EU law.

These new measures will be implemented beginning January 1, 2025.

The MHRA has ceased to participate in the assessment of any centralized procedures since January 1, 2021.

Since then, the MHRA has launched the Innovative Licensing and Access Pathway (ILAP), a new accelerated assessment procedure for marketing authorization applications that enables companies to enter the UK market faster.

On January 1, 2024, the MHRA launched an International Recognition Procedure for Great Britain (England, Scotland and Wales) marketing authorization applications whereby the MHRA will, when considering such applications, recognize the approval of medicines by trusted reference regulators in Australia, Canada, Switzerland, Singapore, Japan, United States and EU following its own abbreviated assessment.

Clinical trials regulation and data sharing in the EU

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Pursuant to the Northern Ireland Protocol, the EU pharmaceutical legal framework acquis continues to apply in Northern Ireland and medicines can only be placed in the Northern Ireland market if they comply with EU law.

The UK government is however currently trying to renegotiate the Northern Ireland Protocol.

The UK government reached a new agreement with the EU, the “Windsor Framework,” which aims to replace the Northern Ireland protocol.

According to the Windsor Framework, medicinal products intended for the UK market including Northern Ireland will be authorized by the MHRA and will bear a “UK only” label.

This means that medicinal products placed on the market in Northern Ireland will no longer need to be compliant with EU law.

These new measures will be implemented beginning January 1, 2025.

Expedited approval pathways

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In May 2014, the FDA published a final Guidance for Industry titled “Expedited Programs for Serious Conditions Drugs and Biologics,” which provides guidance on the FDA programs that are intended to facilitate and expedite development and review of new drug or biological product candidates as well as threshold criteria generally applicable to concluding that a product candidate is a candidate for these expedited development and review programs.

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The FDA may designate a product for Fast Track review if it is intended, whether alone or in combination with one or more other products, for the treatment of a serious or life threatening disease or condition, and nonclinical or clinical data demonstrate the potential to address unmet medical needs for such a disease or condition.

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In addition, all promotional materials for drugs and biological products approved under accelerated regulations are subject to prior review by the FDA.

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The EU and UK operate accelerated evaluation and assessment schemes, which include, at EU level, PRIME (PRIority MEdicines) scheme and, at UK level, the Early Access to Medicines Scheme (EAMS), which may be granted in exceptional cases, often when there is unmet medical need for a life-threatening or serious debilitating condition and existing data show a positive benefit/risk balance that means the medicinal product is of a major public health interest.

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In the UK, the MHRA has launched the Innovative Licensing and Access Pathway (ILAP), a new accelerated assessment procedure for marketing authorization applications that enables companies to enter the UK market faster, available since January 1, 2021.

Under the Orphan Drug Act, the FDA may grant Orphan Drug Designation to drugs or biological products intended to treat a rare disease or condition—generally a disease or condition that affects fewer than 200,000 individuals in the United States.

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It is noted that the general pharmaceutical legislative framework, as well as the framework applicable to orphan and pediatric medicinal products in the EU, is under review.

The European Commission expects to publish its position on this in the second quarter of 2023.

Although the final proposals are not yet known, it is expected that there will be a reduction in applicable regulatory exclusivities which will significantly affect all medicinal products that will be authorized after the legislative changes have taken effect.

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On April 26, 2023, the European Commission adopted a proposal for a new Regulation set to replace Regulation (EC) No 726/2004 and a new Directive to replace Directive 2001/83 on the Community Code relating to medicinal products for human use.

If made into law, this proposal will revise the existing general pharmaceutical legislation and may reduce applicable regulatory exclusivities which will significantly affect all medicinal products that will be authorized after the legislative changes have taken effect.

Post-approval requirements

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The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off label uses, and a company that is found to have improperly promoted off label uses may be subject to significant liability.

In addition, the distribution of prescription drug products is subject to the Prescription Drug Marketing Act (PDMA) which regulates the distribution of drugs and drug samples at the federal level, and sets minimum standards for the registration and regulation of drug distributors by the states.

Both the PDMA and state laws limit the distribution of prescription drug product samples and impose requirements to ensure accountability in distribution.

In addition, the distribution of prescription drug and biological products is subject to the Prescription Drug Marketing Act (PDMA) which regulates the distribution of drugs, biological products and drug or biological product samples at the federal level, and sets minimum standards for the registration and regulation of drug and biological product distributors by the states.

Both the PDMA and state laws limit the distribution of prescription drug and biological product samples and impose requirements to ensure accountability in distribution.

Many jurisdictions, including the EU and the UK, require each marketing authorization holder, national competent authority and the EMA to operate a pharmacovigilance system to ensure that the safety of all medicines is monitored throughout the lifetime of a medicinal product.

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Applicable obligations extend to all activities consisting of procuring, holding, supplying or exporting medicinal products to the public and may therefore be incumbent upon importers, distributors and other economic operators in the supply chain.

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Abbreviated new drug applications for generic drugs

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Generic and hybrid medicinal products of reference medicinal products authorized via the centralized procedure have automatic access to the centralized procedure.

Generic and hybrid products can refer to the complete dossier (i.e.

the quality, pre-clinical and clinical data) of the reference medicinal product in their marketing authorization application, by demonstration of bioequivalence, usually through the submission of the appropriate bioavailability studies after the period of regulatory data protection (also called “data exclusivity”) has expired, namely eight years after the grant of the marketing authorization of the reference medicinal product.

Generic and hybrid products can refer to the complete dossier (i.e., the quality, preclinical and clinical data) of the reference medicinal product in their marketing authorization application, by demonstration of bioequivalence, usually through the submission of the appropriate bioavailability studies after the period of regulatory data protection (also called “data exclusivity”) has expired, namely eight years after the grant of the marketing authorization of the reference medicinal product.

Applicants will be able to cross-refer to the dossier of the reference medicinal product, as long as the data protection period has expired.

This abridged application procedure avoids the requirement to repeat trials and allows generic applicants a faster entry to the market.

If a biosimilar of a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical studies or clinical trials relating to these conditions must be provided.

If a biosimilar of a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate preclinical studies or clinical trials relating to these conditions must be provided.

The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I of Directive 2001/83 as amended and the related detailed guidelines.

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Upon approval of a drug, each of the patents listed in the application for the drug is then published in the FDA’s Orange Book.

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When an ANDA applicant files its application with the FDA, the applicant is required to certify to the FDA concerning any patents listed for the reference product in the Orange Book, except for patents covering methods of use for which the ANDA applicant is not seeking approval.

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Complexities associated with the larger, and often more complex, structures of biological products, as well as the processes by which such products are manufactured, pose significant hurdles and have slowed implementation of the BPCIA by the FDA.

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Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA.

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Under the European Pediatric Regulation (Regulation (EC) No 1901/2006), which has also been reflected in and retained by UK law, applicants must submit to the national competent authority or the EMA data from pediatric studies in compliance with an agreed PIP for the validation or acceptance of a marketing authorization application, unless the medicine is exempt because of a deferral or waiver.

The conduct of the paediatric studies in accordance with the agreed PIP will result in the grant of a reward (period of protection) which will depend on the type of product (i.e., orphan medicinal product will benefit from an extension of the orphan exclusivity by two years, bringing it to 12 years of marketing exclusivity;

The conduct of the pediatric studies in accordance with the agreed PIP will result in the grant of a reward (period of protection) which will depend on the type of product (i.e., orphan medicinal product will benefit from an extension of the orphan exclusivity by two years, bringing it to 12 years of marketing exclusivity;

or an extension of the supplementary protection certificate by six months).

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Patent term extension

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The EU GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies and obtain compensation for damages resulting from violations of the EU GDPR.

The EU GDPR grants individuals various data protection rights (e.g., the right to erasure of personal data) and imposes stringent data protection requirements on U.S.-based companies, such as ours, which fall within its scope, including inter alia:

(i) accountability, data treatment and transparency requirements;

and (ii) obligations to report certain personal data breaches to the supervisory authority without undue delay (and no later than 72 hours where feasible).

In addition, the EU GDPR prohibits the transfer of personal data from the EEA to the United States and other jurisdictions that the European Commission does not recognize as having “adequate” data protection laws unless a data transfer mechanism has been put in place.

In July 2020, the Court of Justice of the European Union limited how organizations could lawfully transfer personal data from the EEA to the United States by invalidating the EU-U.S.

Privacy Shield for purposes of international transfers and imposed further restrictions on use of standard contractual clauses (SCCs) (i.e., EU-style data transfer agreements) including, a requirement for companies to carry out a transfer privacy impact assessment, which among other things, assesses laws governing access to personal data in the recipient country and considers whether supplementary measures that provide privacy protections additional to those provided under SCCs will need to be implemented to ensure an essentially equivalent level of data protection to that afforded in the EEA.

Moreover, new versions of the SCCs (new EU SCCs) have recently been published requiring additional compliance and implementation efforts.

However, in October 2022, President Biden signed an Executive Order to facilitate a new Trans-Atlantic Data Privacy Framework which will act as a successor to the invalidated EU-U.S.

Privacy Shield.

Following this, in December 2022, the European Commission released a draft adequacy decision for the United States, reflecting its belief that the Executive Order and Framework address the transfer issues raised when the EU-U.S.

Privacy Shield was invalidated.

If finalized, the agreement will facilitate the transatlantic flow of personal data and provide additional safeguards (in addition to the new SCCs) for companies transferring personal data from the EU to the United States.

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Relatedly, following the UK’s withdrawal from the EU (Brexit), the EU GDPR has been implemented in the UK (UK GDPR).

The UK GDPR sits alongside the UK Data Protection Act 2018, which implements certain derogations in the EU GDPR into UK law.

The requirements of the UK GDPR are (at this time) largely aligned with those under the EU GDPR and as such, may lead to similar compliance and operational costs with potential fines for non-compliance of up to £17.5 million or 4% of annual worldwide turnover.

As a result, we are potentially exposed to two parallel data protection regimes, each of which authorizes fines and the potential for divergent enforcement actions.

In terms of international data transfers, the UK also imposes obligations on entities transferring personal data outside of the UK, in a similar manner to the EU.

The UK’s data protection authority (ICO), has released its own version of the SCCs, the International Data Transfer Agreement (IDTA).

We note that companies have the choice to use either the IDTA or the new EU SCCs along with a “UK Addendum” for any restricted international data transfers.

In addition, the UK has published its own transfer privacy impact assessment called the Transfer Risk Assessment (TRA) tool, although again parties may conduct the EU style transfer impact assessment instead of adopting the TRA tool.

Reimbursement of medicines in Europe

In the EU, pricing and reimbursement methods can differ in each Member State.

Some Member States and the UK may require that health technology assessments (HTA) be completed to obtain reimbursement or pricing approval.

Some Member States and the UK may require that health technology assessments (HTA) be completed for the product to be recommended for funding under the NHS.

The outcome of HTAs is decided on a national basis and some Member States may decide not to reimburse the use of medicines or may reduce the rate of reimbursement.

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The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively, the ACA) amended the intent element of the federal Anti-Kickback Statute to clarify that a person or entity need not have actual knowledge of the statute or specific intent to violate it in order to commit a violation.

Among others, this statute applies to arrangements between pharmaceutical and biological product manufacturers on the one hand and prescribers, purchasers and formulary managers on the other, including, for example, consulting/speaking arrangements, discount and rebate offers, grants, charitable contributions and patient support offerings.

Among others, this statute applies to arrangements between pharmaceutical and biological product manufacturers on the one hand and prescribers, pharmacies, purchasers and formulary managers on the other, including, for example, consulting/speaking arrangements, discount and rebate offers, grants, charitable contributions and patient support offerings.

A conviction for violation of the federal Anti-Kickback Statute can result in criminal fines and/or imprisonment and requires mandatory exclusion from participation in federal health care programs.

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Although there are a number of statutory exceptions and regulatory safe harbors protecting certain common activities from prosecution or other regulatory sanctions under the law, the exceptions and safe harbors are drawn narrowly and practices that involve remuneration intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they do not qualify for an exception or safe harbor.

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The federal civil False Claims Act prohibits, among other things, any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to the federal government, or knowingly making, or causing to be made, a false record or statement material to a false claim.

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The law also prohibits avoiding, decreasing or concealing an obligation to pay money to the federal government.

The government can bring claims directly or through a civil whistleblower or qui tam action, and potential liability includes mandatory treble damages and significant per claim penalties currently set at $12,537 up to $25,076 per false claim or statement for penalties assessed after May 9, 2022.

The government can bring claims directly or through a civil whistleblower or qui tam action, and potential liability includes mandatory treble damages and significant per claim penalties currently set at $13,946 up to $27,894 per false claim or statement for penalties assessed after January 15, 2024.

Numerous pharmaceutical and other healthcare companies have been prosecuted under these laws for allegedly inflating drug or biological product prices they report to pricing services, which in turn were used by the government to set Medicare and Medicaid reimbursement rates, and for allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product.

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While a final rule has not yet been issued, if adopted, these proposed changes may require us to update our policies and procedures to comply with the new requirements.

In addition, many state laws govern the privacy and security of health information and other personal information in certain circumstances (such as the California Consumer Privacy Act of 2018 and the Virginia Consumer Data Protection Act, and similar forthcoming state privacy laws in Colorado, Connecticut and Utah), and these state laws may differ from each other in significant ways and may not have the same effect.

In addition, many state laws govern the privacy and security of health information and other personal information in certain circumstances (such as the California Consumer Privacy Act of 2018, the Virginia Consumer Data Protection Act, and similar state privacy laws in Colorado, Connecticut and Utah, along with health privacy focused laws such as the Washington My Health My Data Act), and these state laws may differ from each other in significant ways and may not have the same effect.

These laws are rapidly evolving and may impose additional regulatory compliance burden and legal risks on our operations.

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Failure to submit required information may result in civil monetary penalties.

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In addition, several states require prescription drug and biological product companies to report certain expenses relating to the marketing and promotion of drug and biological products and to report gifts and payments to individual healthcare practitioners in these states.

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Companies that breach these laws may incur substantial fines and imprisonment.

In the EU, payments made to healthcare professionals must be publicly disclosed under applicable transparency provisions and agreements with healthcare professionals must be the subject of prior notification and approval by the healthcare professional’s employer.

In the EU and the UK, payments made to healthcare professionals must be publicly disclosed under applicable transparency provisions and agreements with healthcare professionals must be the subject of prior notification and approval by the healthcare professional’s employer.

Such requirements are set out in national laws, industry codes or professional codes of conduct, applicable in the EU Member States and in the UK.

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pharmaceutical industry.

The ACA, among other things, (i) proscribed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs and therapeutic biologics that are inhaled, infused, instilled, implanted or injected, (ii) increased the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extended the rebate program to individuals enrolled in Medicaid managed care organizations, (iii) established annual nondeductible fees and taxes on manufacturers of certain branded prescription drugs and therapeutic biologics, apportioned among these entities according to their market share in certain government healthcare programs, (iv) established a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer what are now 70% point of-sale discounts off negotiated prices of applicable brand drugs and therapeutic biologics to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs and therapeutic biologics to be covered under Medicare Part D, (v) expanded eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals and by adding new mandatory eligibility categories for individuals with income at or below 138% of the federal poverty level, thereby potentially increasing manufacturers’ Medicaid rebate liability, (vi) expanded the entities eligible for discounts under the 340B Public Health program, (vii) required annual reporting of certain information regarding drug samples that manufacturers and distributors provide to licensed practitioners, (viii) created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in and conduct comparative clinical effectiveness research, along with funding for such research, and (ix) established a Center for Medicare Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.

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The ACA, among other things, (i) proscribed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs and therapeutic biologics that are inhaled, infused, instilled, implanted or injected, (ii) increased the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extended the rebate program to individuals enrolled in Medicaid managed care organizations, (iii) established annual nondeductible fees and taxes on manufacturers of certain branded prescription drugs and therapeutic biologics, apportioned among these entities according to their market share in certain government healthcare programs, (iv) expanded eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals and by adding new mandatory eligibility categories for individuals with income at or below 138% of the federal poverty level, thereby potentially increasing manufacturers’ Medicaid rebate liability, (v) expanded the entities eligible for discounts under the 340B Public Health program, (vi) required annual reporting of certain information regarding drug samples that manufacturers and distributors provide to licensed practitioners, (vii) created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in and conduct comparative clinical effectiveness research, along with funding for such research, and (viii) established a Center for Medicare Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.

Some of these cost-savings pilots and projects, such as the Enhancing Oncology Model, are directed specifically at oncology.

The ACA and certain of its provisions have been subject to judicial challenges as well as legislative and regulatory efforts to repeal or replace them or to alter their interpretation or implementation.

For example, the Tax Cuts and Jobs Act (TCJA), among other things, included a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment, or penalty, imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” Further, the Bipartisan Budget Act of 2018, among other things, amended the ACA, effective January 1, 2019, to increase from 50% to 70% the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole.” Additionally, the Further Consolidated Appropriations Act of 2020, signed into law December 20, 2019, fully repealed the ACA’s “Cadillac Tax” on certain high-cost employer-sponsored insurance plans (for tax years beginning after December 31, 2019), the annual fee imposed on certain health insurance providers based on market share (for calendar year 2021) and the medical device excise tax on non-exempt medical devices.

In December 2018, a federal district court in Texas ruled that the ACA’s individual mandate, without the penalty that was repealed effective January 1, 2019, was unconstitutional and could not be severed from the ACA.

As a result, the court ruled the remaining provisions of the ACA were also invalid.

The Fifth Circuit Court of Appeals affirmed the district court’s ruling that the individual mandate was unconstitutional, but it remanded the case back to the district court for further analysis of whether the mandate could be severed from the ACA (i.e., whether the entire ACA was therefore also unconstitutional).

The Supreme Court of the United States granted certiorari on March 2, 2020 and heard oral argument on November 10, 2020.

On June 17, 2021, the Supreme Court dismissed the lawsuit without ruling on the merits of the constitutionality arguments.

On June 17, 2021, the U.S.

Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states who argued that, without the individual mandate, the entire ACA was unconstitutional.

The Supreme Court’s dismissal of the lawsuit did not specifically rule on the constitutionality of the ACA.

On March 11, 2021, Congress enacted the American Rescue Plan Act of 2021, which included among its provisions a sunset of the ACA’s cap on pharmaceutical manufacturers’ rebate liability under the Medicaid Drug Rebate Program.

Under the ACA, manufacturers’ rebate liability was capped at 100% of the average manufacturer price for a covered outpatient drug.

Effective January 1, 2024, manufacturers’ MDRP rebate liability will no longer be capped, potentially resulting in a manufacturer paying more in MDRP rebates than it receives on the sale of certain covered outpatient drugs.

Effective January 1, 2024, manufacturers’ MDRP rebate liability is no longer capped, potentially resulting in a manufacturer paying more in MDRP rebates than it receives on the sale of certain covered outpatient drugs.

The American Rescue Plan Act also temporarily increased premium tax credit assistance for individuals eligible for subsidies under the ACA for 2021 and 2022 and removed the 400% federal poverty level limit that otherwise applies for purposes of eligibility to receive premium tax credits.

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Other legislative changes have been proposed and adopted in the United States since the ACA was enacted to reduce healthcare expenditures.

These changes include the Budget Control Act of 2011, which, among other things, led to aggregate reductions of Medicare payments to providers of up to 2% per fiscal year that started in 2013 and, due to subsequent statutory amendments, will remain in effect into 2031 unless additional Congressional action is taken, with the exception of a temporary suspension from May 1, 2020 through July 1, 2022 due to the COVID-19 pandemic.

Following the end of the temporary suspension, the law provided for 1% Medicare sequestration in the second quarter of 2022, with the full 2% sequestration going into effect thereafter until 2031.

To offset the temporary suspension during the COVID-19 pandemic, in 2030, the sequestration will be 2.25% for the first half of the year, and 3% in the second half of the year.

These changes include the Budget Control Act of 2011, which, among other things, led to aggregate reductions of Medicare payments to providers of up to 2% per fiscal year that started in 2013 and, due to subsequent statutory amendments, will remain in effect through the first six months of the FY 2032 sequestration order unless additional Congressional action is taken, with the exception of a temporary suspension from May 1, 2020 through July 1, 2022 due to the COVID-19 pandemic.

The American Taxpayer Relief Act of 2012 made other changes, including the reduction of Medicare payments to several types of providers and an increase in the statute of limitations period for the government to recover overpayments to providers from three to five years.

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and, beginning in 2026, establishes a “maximum fair price” for a fixed number of pharmaceutical and biological products covered under Medicare Parts B and D following a price negotiation process with the CMS.

CMS has also taken steps to implement the IRA, including:

on June 30, 2023, issuing guidance detailing the requirements and parameters of the first round of price negotiations, to take place during 2023 and 2024, for products subject to the “maximum fair price” provision that would become effective in 2026;

on August 29, 2023, releasing the initial list of ten drugs subject to price negotiations;

on November 17, 2023, releasing guidance outlining the methodology for identifying certain manufacturers eligible to participate in a phase-in period where discounts on applicable products will be lower than those required by the Medicare Part D Manufacturer Discount Program;

and on December 14, 2023, releasing a list of 48 Medicare Part B products that had an adjusted coinsurance rate based on the inflationary rebate provisions of the IRA for the time period of January 1, 2024 to March 31, 2024.

If federal spending is further reduced, anticipated budgetary shortfalls may also impact the ability of relevant agencies, such as the FDA or the NIH to continue to function at current levels.

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These reductions may also impact the ability of relevant agencies to timely review and approve research and development, manufacturing, and marketing activities which may delay our ability to develop, market and sell any products we may develop.

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Additionally, the cost of prescription pharmaceuticals and biological products has recently been the subject of considerable discussion in the United States.

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In its announcement, the administration noted that its new goals under the initiative include addressing inequities in order to ensure broader access to cutting-edge cancer therapeutics and investing in a robust pipeline for new treatments.

In alignment with President Biden’s Cancer Moonshot initiative, on June 27, 2023, the Center for Medicare Innovation at CMS announced a new model, the Enhancing Oncology Model, that is designed to make high-quality cancer care more affordable to both patients and Medicare.

On September 12, 2022, President Biden issued an Executive Order to promote biotechnology and biomanufacturing innovation.

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At the state level, legislatures are increasingly passing legislation and implementing 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, to encourage importation from other countries and bulk purchasing.

Most recently, on January 5, 2024, the FDA approved Florida’s importation plan to allow pharmacists and wholesalers in the state to import certain medications from Canada.

The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize any product that is ultimately approved, if approved.

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Human Capital

As of November 30, 2022, we had 297 full-time employees, of which approximately 34% have earned an M.D.

As of November 30, 2022, 260 of our full-time employees are engaged in research and development.

As of November 30, 2023, we had 284 full-time or part-time employees, of which approximately 40% have earned an M.D.

As of November 30, 2023, 249 of our full-time or part-time employees are engaged in research and development.

From time to time, we retain independent contractors to support our organization.

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We consider the intellectual capital of our employees to be an essential driver of our business.

Our workforce expanded during fiscal year 2022;

new employees were hired to support our clinical and preclinical pipeline, with additions in our research, clinical development, operations and general and administrative functions.

We continually evaluate our business needs and opportunities and strive to balance inhouse expertise and capacity with outsourced expertise and capacity.

We continually evaluate our business needs and opportunities and strive to balance in-house expertise and capacity with outsourced expertise and capacity.

Currently, we outsource substantially all clinical trial work to clinical research organizations and drug substance and finished drug product manufacturing to contract manufacturers.

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Competitive pay and benefits

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Biotechnology and pharmaceutical companies both large and small compete for a limited number of qualified applicants to fill specialized positions.

We monitor our compensation programs closely and provide what we consider to be a very competitive mix of compensation, insurance and wellness benefits for all our employees, as well as participation in our equity and enhanced maternity and paternity programs.

To attract qualified applicants, we offer a total rewards package consisting of a base salary and cash target bonus, a comprehensive benefits package and equity compensation for all full-time employees.

Bonus opportunity and equity compensation increase as a percentage of total compensation based on level of responsibility.

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Recruitment, hiring, development, training, compensation and advancement at our company is based on qualifications, performance, skills and experience without regard to gender, race and ethnicity.

As of November 30, 2022, approximately 52% of our full-time employees were self-reported as female.

As of November 30, 2023, approximately 52% of our full-time and part-time employees were self-reported as female.

Of our vice president-level and above employees, approximately 42% were self-reported as female.

In addition, as of November 30, 2023, approximately 57% of our full-time employees were self-reported as ethnic or racial minorities in the United States, with 42% Asian, 2% Black or African American, 8% Hispanic or Latino and 6% of other minority groups or two or more races.

Of our vice president-level and above employees, 24% were self-reported as ethnic or racial minorities in the United States, with 17% Asian, 3% Black or African American and 3% Hispanic or Latino.

Of our vice president-level and above employees, 25% were self-reported as ethnic or racial minorities in the United States, with 17% Asian and 8% Black or African American.

Employee development and training

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Employees are encouraged to attend scientific, clinical and technological meetings and conferences and have access to broad resources they need to be successful.

The safety and health of our employees is a top priority.

For example, in response to the COVID-19 pandemic, we implemented safety protocols including clear policies to address actual and suspected COVID-19 cases and potential exposure, weekly COVID-19 testing, shift work scheduling to reduce the number of people in our facilities at a given time, requirements for the wearing of masks and for social distancing, and increased cleaning procedures.

These protocols were designed to comply with health and safety standards as required by federal, state and local government agencies, taking into consideration the guidelines of the Centers for Disease Control and Prevention and other public health authorities.

We continue to monitor developments regarding health pandemics or other health concerns, including COVID-19, and will implement any additional safety protocols that may become necessary in the future.

Board of Directors oversight

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Our Board’s Nominating and Corporate Governance Committee is responsible for developing and recommending to the Board any company program relating to corporate responsibility and sustainability, including environmental, social and governance matters.

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Corporate Information

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The mark “Nurix” is our registered trademark in Canada, France, Germany, Italy, Japan, Mexico, Spain, the United Kingdom and the United States.

The marks “DELigase,” “DeTIL” and “NxACT” are our registered trademarks in the United States.

The mark “DELigase” is our registered trademarks in the United States.

The Nurix logo is our common law trademark.

All other service marks, trademarks and trade names appearing in this Annual Report on Form 10-K are the property of their respective owners.

Solely for convenience, the trademarks and tradenames referred to in this Annual Report on Form 10-K appear without the ® and ™ symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights, or the right of the applicable licensor to these trademarks and tradenames.

Solely for convenience, the trademarks and trade names referred to in this Annual Report on Form 10-K appear without the ® and ™ symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights, or the right of the applicable licensor to these trademarks and trade names.

Additional Information

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Also available on our website is information relating to corporate governance at Nurix and our Board, including our Corporate Governance Guidelines;

our Code of Business Conduct and Ethics (for our directors, officers and employees), and our Board Committee Charters.

We will provide any of the foregoing information without charge upon written request to our Corporate Secretary, Nurix Therapeutics, Inc., 1700 Owens Street, Suite 205, San Francisco, CA 94158.

our Code of Business Conduct and Ethics (for our directors, officers and employees);

and our Board Committee Charters.

We will provide any of the foregoing information without charge upon written request to our Corporate Secretary, Nurix Therapeutics, Inc., 1700 Owens Street, Suite 205, San Francisco, California 94158.

We use our Investor Relations website (http://ir.nurixtx.com) as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD promulgated by the SEC.

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Our references to the URLs for websites are intended to be inactive textual references only.

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What changed 10-K

Item 1. Business