What changed in this filing

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Item 1. Business

2024-03-18 compared with 2023-03-24 · 90 added, 91 removed, 490 unchanged (27% of the section changed)

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GLOBOCAN estimates that there were over 604,000 EC patients and 1,090,000 GC patients diagnosed worldwide in 2020, with a majority of the prevalence in Eastern Asia.

EC patients have difficulty swallowing and often have pain while swallowing.

EGC patients have difficulty swallowing and often have pain while swallowing.

Substantial weight loss can result from reduced appetite, poor nutrition and having an active cancer.

Pain may be severe, occur almost daily, and be worsened by swallowing any form of food.

The disruption of normal swallowing can lead to aspiration of food content, nausea, vomiting and an increased risk of pneumonia.

The disruption of normal swallowing and digestion can lead to aspiration of food content, nausea, vomiting and an increased risk of pneumonia.

The tumor itself may be irritable and bleed, which can either cause spitting up with blood or blood in the bowels.

Compression of local structures in the esophagus occurs in advanced disease, leading to problems such as upper airway obstruction.

Many people diagnosed with EGC have late-stage disease, because people usually do not have significant symptoms until the tumor is fairly large.

In advanced stages, the cancer frequently spreads into the liver or lungs.

In 2021, the anti-PD-1 antibody nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy was approved by the US FDA in first-line EGC with a 47% overall response rate (“ORR”), 7.7 month median progression free survival (“PFS”), and 13.8 month overall survival (“OS”).

In 2021, the anti-PD-1 antibody nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy was approved by the US FDA in first-line GC with a 47% overall response rate (“ORR”), 7.7 month median progression free survival (“PFS”), and 13.8 month overall survival (“OS”).

In addition, nivolumab in combination with chemotherapy was approved in Europe for patients with PD-L1 expression designated by a combined positive score (“CPS”), greater than or equal to 5.

In the Rationale-305 study, tislelizumab, an anti-PD-1 antibody being developed by BeiGene and Novartis, in combination with chemotherapy demonstrated statistically significant benefit over chemotherapy alone in patients with CPS greater than or equal to 5, with a 50.4% ORR, 7.2 months PFS, and 17.2 months OS.

Despite this progress, overall survival expectations for newly diagnosed advanced gastric cancer patients is poor at less than 2 years, and better outcomes are particularly needed for patients with low PD-L1 expression.

In the Rationale-305 study, tislelizumab, an anti-PD-1 antibody being developed by BeiGene, in combination with chemotherapy demonstrated statistically significant benefit over chemotherapy alone in patients with CPS greater than or equal to 5, with a 50.4% ORR, 7.2 months PFS, and 16.4 months OS.

For all patients regardless of PD - L1 expression, the ORR was 47.3%, 6.9 months PFS, and 15.0 months OS.

In the same study, the full study subset of European and North American patients demonstrated a 36.0% ORR, 5.6 months PFS, and 11.0 months OS suggesting that these patients experience poorer outcomes to anti-PD-1 therapy.

Despite this progress, overall survival expectations for newly diagnosed advanced EGC patients is poor, and better outcomes are particularly needed for patients with low PD-L1 expression.

Colorectal Cancer

Colorectal cancer (“CRC”), is the third most frequent cancer globally and the second leading cause of death.

According to the World Health Organization (“WHO”), there were nearly 2 million new cases of CRC in 2020, with nearly 1 million deaths.

CRC includes colon cancer (57.5%), rectal cancers (35%), and anal cancer (2.5%).

According to the NCI, in the United States, there were about 153,020 newly diagnosed cases of CRC and 52,550 estimated deaths from CRC.

When the symptoms of CRC appear, such as rectal bleeding, anemia, or abdominal pain, most patients are already in the advanced stage where cancers are aggressive, malignant, and metastatic.

Mutations in the pathways modulated by DKK1, such as APC, and activation of the Wnt pathway are highly prevalent in CRC patients.

CRCs belonging to the consensus molecular subtype 2 (“CMS2”) are specifically characterized by hyperactivation of Wnt signaling.

CMS2 is most seen in cancers in the distal colon and rectum.

For patients who have non-microsatellite instability-high (“MSI-H”) colorectal cancer, and who do not have a specific mutation that can be targeted with approved therapies, outcomes are extremely poor for patients who have progressed on first-line therapy.

A clinical trial of the antibody bevacizumab in combination with chemotherapy generated a response rate of approximately 5% and PFS of 5.7 months.

Endometrial Cancers

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There are currently very few treatment options for these patients, typically consisting of chemotherapy, local radiation therapy, and hormonal agents, and poor treatment outcomes.

Patients with endometrioid cancers have a high frequency of mutations in a protein known as beta-catenin, with alterations estimated at approximately 30% of cases according to The Cancer Genome Atlas.

Patients with endometrial cancers have a high frequency of mutations in a protein known as β-catenin, with alterations estimated at approximately 30% of cases according to The Cancer Genome Atlas.

These β-catenin mutations are often driver mutations leading to rapid disease progression and poor outcomes.

Recently, the anti-programmed cell death-1 (“PD-1”), antibody dostarlimab-gxly was granted accelerated approval by the FDA for endometrial cancer patients with microsatellite instability high (“MSI-H”), or mismatch repair deficient, (“dMMR”), disease who had progression on or after a chemotherapy regimen.

In July 2023, the anti-PD-1 antibody dostarlimab-gxly was approved by the FDA for adult endometrial cancer patients with mismatch repair deficient, (“dMMR”) advanced or recurrent disease who had progression on or after a chemotherapy regimen.

In addition, the combination of lenvatinib and pembrolizumab was approved in second line non-MSI-H or mismatch repair proficient endometrial carcinoma patients with a 30% response rate, 6.6 month median PFS, and 17.4 month median OS.

However, this combination has been associated with significant toxicity with an 89% rate of grade 3 or higher treatment-emergent adverse events, including a 6% rate of fatal adverse events.

Colorectal Cancer

Colorectal cancer (“CRC”), is the third most frequent cancer globally and the second leading cause of death.

According to the WHO, there were nearly 2 million new cases of CRC in 2020, with nearly 1 million deaths.

CRC includes colon cancer (57.5%), rectal cancers (35%), and anal cancer (2.5%).

When the symptoms of CRC appear, such as rectal bleeding, anemia, or abdominal pain, most patients are already in the advanced stage where cancers are aggressive, malignant, and metastatic.

Mutations in the pathways modulated by DKK1, such as APC, and activation of the Wnt pathway are highly prevalent in CRC patients.

For patients who have non-MSI-H colorectal cancer, and who do not have a specific mutation that can be targeted with approved therapies, outcomes are extremely poor for patients who have progressed on first-line therapy.

A clinical trial of the antibody bevacizumab in combination with chemotherapy generated a response rate of approximately 5% and PFS of 5.7 months.

Our approach to treating cancer patients seeks to enhance the effectiveness of approved chemotherapies and immune checkpoint inhibitors by:

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Altering cell signaling.

An important set of signaling pathways in cancer cells are known as the canonical and non-canonical Wnt pathways and the PI3 kinase—AKT pathway.

The canonical and non-canonical Wnt pathways and the PI3 kinase—AKT pathway are important signalling pathways in cancer cells.

DKK1 serves as one of the inhibitors of the canonical Wnt signaling pathway, modulates the non-canonical Wnt signaling pathways, and directly activates the PI3 kinase—AKT pathway.

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The human immune system has the ability to recognize and protect its own cells and tissues.

Certain kinds of white blood cells, such as T regulatory cells and myeloid-derived suppressor cells, serve to prevent other cells from attacking the body.

Certain kinds of white blood cells, such as T regulatory cells and myeloid-derived suppressor cells (“MDSC”), serve to prevent other cells from attacking the body.

In the case of cancer, these cells may fail to recognize the danger posed by the tumor and suppress the activity of potentially tumor-fighting white blood cells.

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DKK1 also has a role in suppressing the immune system from effectively targeting and clearing the cancer.

Published data, including from TCGA and real world evidence from our collaboration with Tempus, indicate that DKK1 expression levels are significantly higher or have an important high DKK1 population in many cancers, including EGC, non-small cell lung cancer (“NSCLC”), endometrial cancer, CRC, and prostate cancer.

In addition, elevated DKK1 expression is associated with worse overall survival or time to treatment discontinuation for patients with EGC, NSCLC, endometrial cancer, CRC, prostate cancer, and other cancers.

In addition, elevated DKK1 expression is associated with worse overall survival or time to treatment discontinuation for patients with EGC and several other cancers.

Researchers have shown that when the DKK1 protein is added in certain animal models, the cancer grows larger.

Publications have also demonstrated a role for DKK1 in maintaining an environment around a tumor that suppresses the immune system’s ability to clear the tumor and to prevent metastasis.

DKK1 has been shown to activate the suppressive effects of myeloid-derived suppressor cells (“MDSC”), a type of white blood cell that can potently block other immune system cells.

DKK1 has been shown to activate the suppressive effects of MDSC.

Other published data has shown that metastatic tumor cells with stem cell-like features avoid the immune system by overexpressing DKK1 and secreting it out of the cell.

Secreted DKK1 can then down-regulate certain molecules on tumor cells known as natural killer cell activating ligands (“NK cell ligands”), that would activate the immune system, causing these cancer cells to remain invisible to NK cells and evade the immune system.

Secreted DKK1 can then down-regulate certain molecules on tumor cells known as NK cell activating ligands, that would activate the immune system, causing these cancer cells to remain invisible to NK cells and evade the immune system.

We have also identified DKK1 as being involved with the activity of T regulatory cells that can suppress anti-tumor T cells.

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Preclinical studies that we and others have conducted demonstrated that using an anti-DKK1 antibody can lead to clinical benefits in xenograft cancer models.

The anti-DKK1 antibody is believed to shift cell signaling in multiple cell types, thereby resulting in an

anti-tumor immune effect.

The anti-DKK1 antibody is believed to shift cell signaling in multiple cell types, thereby resulting in an anti-tumor immune effect.

In these models, researchers demonstrated that an anti-DKK1 antibody allowed the immune system to recognize and attack the cancer cells.

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In addition, on September 24, 2020, the FDA granted Fast Track designation to DKN-01 in combination with BeiGene’s tislelizumab for the treatment of patients with gastric and gastroesophageal junction adenocarcinoma whose tumors express high DKK1, following disease progression on or after prior fluoropyrimidine- and platinum- containing chemotherapy and if appropriate, human epidermal receptor growth factor (HER2)/neu-targeted therapy.

We are developing DKN-01 in clinical trials in three different indications:

gastric cancer, endometrial cancer, and colorectal cancer.

Gastric Cancer

We are currently developing DKN-01 in clinical trials in three different indications:

gastric/gastroesophageal junction cancer, colorectal cancer, and endometrial cancer.

Gastric / Gastroesophageal Junction Cancer

DisTinGuish Study

In collaboration with BeiGene, we are conducting P205, the DisTinGuish study, a three-part Phase 2 study of DKN-01 in combination with tislelizumab in patients with inoperable, locally advanced, gastric and gastroesophageal junction adenocarcinoma (“GEA”).

Part A enrolled 25 patients with first-line, HER2-negative gastric cancer who received DKN-01 in combination with tislelizumab and oxaliplatin and chemotherapy, also known as standard of care (“SOC”) chemotherapy.

Part A enrolled 25 patients in the United States with first-line, HER2-negative gastric cancer who received DKN-01 in combination with tislelizumab and oxaliplatin and chemotherapy, also known as standard of care (“SOC”) chemotherapy.

Part B enrolled 52 patients with second-line, DKK1-high gastric cancer who received DKN-01 in combination with tislelizumab.

Part C is enrolling approximately 160 first-line, HER2-negative patients.

Patients will be randomized 1:1 to evaluate DKN-01 in combination with tislelizumab and SOC chemotherapy, compared to tislelizumab and SOC chemotherapy.

The primary objective is progression-free survival (“PFS”) in DKK1-high patients.

Secondary objectives of Part C include PFS in all patients regardless of DKK1 expression, as well as overall survival and objective response rate as measured by RECIST v1.1 in DKK1-high and all patients.

Part C enrolled 170 first-line, HER2-negative patients in the United States, Republic of Korea, and Germany.

Patients were randomized 1:1 to evaluate DKN-01 in combination with tislelizumab and SOC chemotherapy, compared to tislelizumab and SOC chemotherapy.

The primary objective is progression-free survival (“PFS”) in DKK1-high patients and in all patients.

Secondary objectives of Part C include overall survival (“OS”) and objective response rate (“ORR”) as measured by RECIST v1.1 in DKK1-high and all patients.

Part A –– First Line Combination with tislelizumab, capecitabine and oxaliplatin

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fatigue, nausea, diarrhea, neutrophil count decrease, and platelet count decrease.

As of July 31, 2022, the data cut-off date for our presentation at the European Society for Medical Oncology (ESMO) 2022 Annual Congress, the ORR among the 22 patients who received a full cycle of DKN-01 therapy was 68%, including 1 complete response (“CR”), and 14 partial responses (“PRs”).

As presented at the American Society for Clinical Oncology (“ASCO”) 2023 Annual Congress, the ORR among the 22 patients who received a full cycle of DKN-01 therapy was 73%, including 1 complete response (“CR”), and 15 partial responses (“PRs”).

The DKK1-high patient subgroup had a 90% response rate, with 9 PRs and 1 patient non-evaluable, while the DKK1-low subgroup had a 67% response rate, with 1 CR, 5 PRs and 3 patients with a best response of stable disease (“SD”).

The median PFS was 11.3 months for the overall population, with the DKK1-high subgroup experiencing 11.3 months PFS and the DKK1-low subgroup experiencing 12.0 months PFS.

The median duration of response (“DoR”) in DKK1-high patients was 10.7 months and 7.9 months in DKK1-low patients.

OS was not yet mature.

The median OS was 19.5 months for the overall population, with the DKK1-high subgroup experiencing 16.9 months OS and the DKK1-low subgroup experiencing 24.4 months OS.

Patients with low PD-L1 expression, defined as having a vCPS (visually-estimated Combined Positive Score, also known as Tumor Area Positivity (TAP) score - Ventana Medical Systems) of less than 5, had a response rate of 86% while patients with high PD-L1 expression, defined as having a vCPS of greater than or equal to 5, had a response rate of 67%.

All 6 of the patients who were DKK1-high and PD-L1-low had responses.

The median PFS was 11.6 months for the PD-L1-high subgroup and the PD-L1-low subgroup experiencing 10.7 months PFS.

OS was not yet mature.

The median PFS was 11.6 months for the PD-L1-high subgroup and the PD-L1-low subgroup experienced 10.7 months PFS.

The median OS was 22.0 months for the PD-L1-high subgroup and the PD-L1-low subgroup experienced 18.7 months OS.

Part B –– Second Line DKK1-high patients tislelizumab combination

Fifty-two second-line, DKK1-high GEA patients were treated with DKN-01 in combination with tislelizumab in Part B.

The combination of DKN-01 and tislelizumab has been well tolerated with manageable toxicity across both the 300 mg and 600 mg doses

The combination of DKN-01 and tislelizumab has been well tolerated with manageable toxicity across both the 300 mg and 600 mg doses of DKN-01.

The higher DKN-01 dose at 600mg was not associated with higher frequency of AEs.

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There were no Grade 5 treatment-emergent AEs (TEAE) and no TEAEs leading to study drug discontinuation or dose reduction.

As of August 31, 2022, the data cut-off date for our presentation at the Society for Immunotherapy in Cancer (“SITC”), Annual Meeting, the ORR for evaluable anti-PD-1/PD-L1 antibody naïve patients was 27%, median PFS was 1.4 months, and median OS was 7.7 months.

As presented at the Society for Immunotherapy in Cancer (“SITC”), Annual Meeting, the ORR for evaluable anti-PD-1/PD-L1 antibody naïve patients was 27%, median PFS was 1.4 months, and median OS was 7.7 months.

In the dual biomarker-high (DKK1-high/PD-L1 high with vCPS > 10) patients, the ORR was 55% ORR (n=12:

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Part C –– First Line Randomized Controlled Trial combination with tislelizumab and SOC chemotherapy

Part C of the DisTinGuish study will enroll approximately 160 first-line, HER2-negative GEA patients.

Patients will be randomized to receive either DKN-01 in combination with tislelizumab and SOC chemotherapy or to receive tislelizumab and SOC chemotherapy.

The primary objective is to determine the effect of adding DKN-01 on the endpoint of median PFS in DKK1-high patients.

Secondary objectives of Part C include PFS in all patients regardless of DKK1 expression, as well as OS and ORR as measured by RECIST v1.1 in DKK1-high and all patients.

Enrollment began in October 2022.

We currently anticipate completion of enrollment of the 160 patient study late this year, with initial response rate data being available year end 2023/early 2024 and PFS data in 2024.

Part C of the DisTinGuish study enrolled 170 first-line, HER2-negative GEA patients.

Patients were randomized to receive either DKN-01 in combination with tislelizumab and SOC chemotherapy or to receive tislelizumab and SOC chemotherapy.

The primary objective is to determine the effect of adding DKN-01 on the endpoint of median PFS in DKK1-high patients and in all patients.

Secondary objectives of Part C include OS and ORR as measured by RECIST v1.1 in DKK1-high and all patients.

Enrollment began in October 2022 and was completed in December 2023.

We currently expect to have the initial ORR data from Part C in the middle of 2024 and preliminary PFS data in the second half of 2024.

WAKING Study – Investigator-Sponsored Trial in Second and Third Line Patients Combination with Tecentriq

The Royal Marsden Hospital in the United Kingdom is conducting the WAKING study that is evaluating DKN-01 in combination with Roche’s Tecentriq ® (atezolizumab) in patients with microsatellite stable esophagogastric cancer.

Roche is providing atezolizumab drug supply and funding the study as part of its imCORE network.

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No treatment-related deaths occurred, and no dose reductions were required.

As of August 16, 2022, the time of the data cut off, 18 patients were enrolled in the study, and 12 patients that were treated in the initial phase were presented.

As of August 16, 2022, the time of the data cut off, 18 patients were enrolled in the study, and 12 patients who were treated in the initial phase were presented.

Ten patients were response evaluable at the time of data cut-off, and 1 patient had a PR and a DKK1 expression of 81% tumor-percentage score, which is a very high level of DKK1 expression.

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Translational analyses and assessment of PD-L1 status are ongoing.

Colorectal Cancer

We have evaluated DKN-01 in multiple preclinical CRC models.

DKN-01 showed additive activity with 5-fluorouracil (5-FU) chemotherapy, which is commonly used in CRC patients, and in two CRC models that were resistant to 5-FU therapy.

Treatment with DKN-01 can result in tumor regressions as a monotherapy and can overcome 5-FU-resistance to have further activity in combination with 5-FU chemotherapy.

We believe that these 5-FU-resistant models are reflective of the second-line CRC population currently being recruited in the DeFianCe clinical study.

DeFianCe Study –Second Patients Combination with bevacizumab and chemotherapy

The DeFianCe study is a Phase 2, randomized, open-label, multicenter study of DKN-01 in combination with standard of care bevacizumab and chemotherapy in patients with advanced CRC who have received one prior systemic therapy.

Part A of the study enrolled 33 patients.

Based on the results of these first 33 patients, the study expanded into a 130-patient randomized controlled trial against bevacizumab and standard of care chemotherapy.

The primary objective is PFS.

Secondary objectives include ORR, DoR and OS.

At ASCO GI 2024, we presented the initial ORR and PFS data from Part A of DeFianCe.

In the initial 27 response-evaluable patients, the ORR was 30% and the DCR was 93%.

The 21 patients with CRC originating on the left side of the colon or rectum experienced an ORR of 33%, a DCR of 100% and median PFS of 8.3 months.

The rectal/rectosigmoid subgroup experienced an ORR and DCR of 46% and 100%, respectively, and a median PFS of 9.43 months, with six patients continuing on study therapy, as of the data cutoff date.

As of March 15, 2024, 80 patients have enrolled in Part B of the DeFianCe study.

We expect to complete enrollment in the middle of 2024.

Endometrial Cancer

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Tumoral DKK1 expression data was available for 23 patients.

In the group of 8 patients with DKK1-high tumors, one patient (12.5%) has had a CR for over 4.5 years, 1 patient (12.5%) had a PR, 3 patients (37.5%) had SD, and 3 patients (37.5%) had PD, representing an ORR of 25.0% and a Disease Control Rate (“DCR”), of 62.5%.

In the group of 8 patients with DKK1-high tumors, one patient (12.5%) has had a CR for over 5.5 years, 1 patient (12.5%) had a PR, 3 patients (37.5%) had SD, and 3 patients (37.5%) had PD, representing an ORR of 25.0% and a DCR of 62.5%.

In the group of 15 patients with DKK1-low tumors, 1 patient (6.7%) had SD, 11 patients (93.3%) had PD, and 3 patients were non-evaluable.

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In the group of 24 EEC patients treated with DKN-01 plus paclitaxel, 72% of whom had received 3 or more prior systemic therapies, DKK1-high patients had improved median PFS (5.4 months vs.

1.8 months [HR 0.34;

0.12, 0.97]) compared to DKK1-low patients.

1.8 months) compared to DKK1-low patients.

One patient with carcinosarcoma treated with DKN-01 and paclitaxel experienced a CR approximately two years on therapy, while another DKK1-high patient with carcinosarcoma treated with DKN-01 and paclitaxel experienced a PR.

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Merck is providing pembrolizumab for the study.

Colorectal Cancer

We have evaluated DKN-01 in multiple preclinical CRC models as a monotherapy, in combination with chemotherapy, and in combination with an anti-PD-1 antibody.

DKN-01 showed additive activity with 5-fluorouracil (5-FU) chemotherapy, which is commonly used in CRC patients, and in two CRC models that were resistant to 5-FU therapy.

Treatment with DKN-01 can result in tumor regressions as a monotherapy and can overcome 5-FU-resistance to have further activity in combination with 5-FU chemotherapy.

We believe that these 5-FU-resistant models are reflective of the second-line CRC population currently being recruited in the DeFianCe clinical study.

In addition, DKN-01 as monotherapy or in combination with an anti-PD-1 antibody has generated tumor regressions in a CT26 syngeneic CRC model.

In this model, DKN-01 treatment increased PD-L1 expression, promoted substantial tumor necrosis, which was associated with a robust immune cell infiltrate, and generated a tumor immune infiltrate that contained a substantial number of CD3+ and CD8+ cells, implying the presence of an adaptive immune response to tumor antigen.

DeFianCe Study –Second Patients Combination with bevacizumab and chemotherapy

The study is designed with an initial 20 patient cohort and is expected to expand into a 130-patient randomized controlled trial against bevacizumab and standard of care chemotherapy.

The primary objective is PFS.

Secondary objectives include ORR, DoR and OS.

We expect to complete enrollment in Part A of the DeFianCe study in the coming weeks and have initial data from Part A in the middle of 2023.

The cell surface molecule Claudin18.2 regulates barrier properties and contributes to cell-to-cell adhesion.

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In nonclinical models presented at the American Association for Cancer Research (“AACR”) 2020 Annual Meeting, FL-301 was shown to have 10-20x higher affinity to Claudin18.2 than zolbetuximab and specificity to both gastric and pancreatic tumors.

Through Fc engineering, FL-301 has been

designed with enhanced antibody dependent cellular cytotoxicity, complement dependent cytotoxicity, and antibody dependent cellular phagocytosis, which are three mechanisms that can lead to improved cancer cell killing and greater potency relative to zolbetuximab in nonclinical models.

Through Fc engineering, FL-301 has been designed with enhanced antibody dependent cellular cytotoxicity, complement dependent cytotoxicity, and antibody dependent cellular phagocytosis, which are three mechanisms that can lead to improved cancer cell killing and greater potency relative to zolbetuximab in nonclinical models.

Food and Drug Administration has granted orphan drug designation to FL-301 for the treatment of gastric and gastroesophageal junction cancer and for the treatment of pancreatic cancer.

FL-301 is being developed through an exclusive license from NovaRock Biotherapeutics for territories excluding China and is currently in a Phase 1 clinical trial in cancer patients in China.

We expect to have initial clinical data to present later this year or early next year and intend to use this data to initiate clinically relevant combination studies in biomarker-selected cancer patients at appropriate dose levels.

FL-301 is being developed through an exclusive license from NovaRock Biotherapeutics for territories excluding China.

FL-302 is a Claudin18.2/CD137 (also known as 4-1BB) bispecific antibody that is in preclinical development.

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Patent, (ii) issued patents in the following jurisdictions:

Argentina, Australia, Canada, China, Eurasia, Europe, Gulf Cooperation Council, India, Israel, Japan, Lebanon, Macao, Mexico, New Zealand, Pakistan, Singapore, South Africa, Taiwan, Ukraine, Hong Kong and South Korea and (iii) pending applications in the following jurisdictions:

Argentina, Australia, Brazil, Canada, China, Eurasia, Europe, Gulf Cooperation Council, India, Israel, Japan, Lebanon, Macao, Mexico, New Zealand, Pakistan, Singapore, South Africa, Taiwan, Ukraine, Hong Kong and South Korea and (iii) pending applications in the following jurisdictions:

Venezuela and Thailand.

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We own one issued U.S.

Patent and pending applications directed to the use of a biomarker in patients receiving DKN-01 therapy in the following jurisdictions:

Patent, one Japanese Patent and pending applications directed to the use of a biomarker in patients receiving DKN-01 therapy in the following jurisdictions:

Australia, Brazil, Canada, China, Europe, Hong Kong, India, Israel, Japan, Korea, Mexico, New Zealand, Russia, Singapore and the United States.

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Application will expire in 2037, absent any terminal disclaimer, patent term adjustment due to administrative delays by the United States Patent and Trade Office (“USPTO”) or patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman Act or Hatch-Waxman Amendment, and provided that all required maintenance fee payments are timely paid.

Any patents that may issue in foreign jurisdictions will likewise expire in 2037, provided that all required annuities are timely paid.

The Japanese Patent and any other patents that may issue in foreign jurisdictions will likewise expire in 2037, provided that all required annuities are timely paid.

We also own two additional patent families both directed to the treatment of cancer using DKN-01 in specific subpopulations of patients.

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Applications are pending in the following jurisdictions:

the United States of America, China, Japan, South Korea, Australia, New Zealand, Canada, Hong Kong, Mexico, Brazil, Israel, India, Europe and Singapore.

the United States of America, China, Japan, South Korea, Australia, New Zealand, Canada, Hong Kong, Mexico, Brazil, Israel, Europe and Singapore.

In the second patent family, the patient subpopulation is defined as harboring a specific genetic mutation.

Applications are pending in the following jurisdictions:

the United States of America, China, Japan, South Korea, Australia, New Zealand, Canada, Mexico, Brazil, Israel, Europe and Singapore.

the United States of America, China, Japan, South Korea, Australia, New Zealand, Canada, Hong Kong, Mexico, Brazil, Israel, Europe and Singapore.

Any patents that may issue in the United States based on the applications in these two patent families will expire in 2040, absent any terminal disclaimers, patent term adjustment due to administrative delays at the USPTO or patent term extension under the Hatch-Waxman Act, and provided that all required maintenance fee payments are timely paid.

Any patents that may issue in foreign jurisdictions will likewise expire in 2040, provided that all required annuities are timely paid.

We also own one U.S.

Provisional patent application directed to treatment of colorectal cancer using combination therapy comprising DKN-01 and additional therapeutic agents.

If non-Provisional patent applications claiming the benefit of the pending U.S.

Provisional patent application referenced above are filed in 2023, any patent that may issue from such applications will expire no earlier than 2043 absent any terminal disclaimer.

We also own one pending international patent application filed under the Patent Cooperation Treaty (“PCT”) directed to treatment of colorectal cancer using combination therapy comprising DKN-01 and additional therapeutic agents.

The PCT is an international patent law treaty that provides a unified procedure for filing a single initial patent application to seek patent protection for an invention simultaneously in each of the member states.

Although a PCT application is not itself examined and cannot issue as a patent, it allows the applicant to seek protection in any of the member states through national - phase applications.

Any patents that may issue in the United States based on the PCT application will expire no earlier than 2043 absent any terminal disclaimer.

Any patents issued in foreign jurisdictions will likewise expire in 2043.

We jointly own with BeiGene a pending international application filed under the PCT directed to the combination of DKN-01 and tislelizumab.

Any patents that may be issued in the United States based on the pending application will expire in 2042, absent any terminal disclaimers, patent term adjustment due to administrative delays at the USPTO or patent term extension under the Hatch-Waxman Act, and provided that all required maintenance fee payments are timely paid.

Any patents that may be issued in the United States based on the pending international application will expire in 2042, absent any terminal disclaimers, patent term adjustment due to administrative delays at the USPTO or patent term extension under the Hatch-Waxman Act, and provided that all required maintenance fee payments are timely paid.

Any patents that may issue in foreign jurisdictions will likewise expire in 2042, provided that all required annuities are timely paid.

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Any patents that may issue in foreign jurisdictions will likewise expire in 2040, provided that all required annuities are timely paid.

We also exclusively license from NovaRock, the rights under one pending international application filed under the PCT and directed to the composition of matter and use of the FL - 302 bispecific antibody (CLDN 18.2 and CD137).

Any patents that may issue in the United States based on the PCT application will expire no earlier than 2042 absent any terminal disclaimer.

Any patents issued in foreign jurisdictions will likewise expire in 2042.

The base term of a U.S.

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Lilly may terminate the agreement (i) upon our material breach of the Lilly Agreement upon ninety (90) days written notice to us, unless we cure such breach or violation during such ninety day period or (ii) if we challenge, or materially assist any third person to challenge, the validity or enforceability of the licensed intellectual property that is the subject of the Lilly Agreement upon thirty (30) days written notice to us, unless we cure such breach or violation during such thirty (30) day period.

acquired by us during the term of the Lilly Agreement that relate to the Lilly licensed intellectual property, (iv) subject to certain limitations, we will be required to grant to Lilly an irrevocable, non-exclusive, perpetual, fully paid up license to the results of data from all preclinical and clinical studies of any compound or product covered by the Lilly Agreement, (v) subject to certain limitations, we will be required to take all steps necessary to permit Lilly to commence marketing product covered by the Lilly Agreement, and (vi) we will be required to assign or re-assign to Lilly all Lilly patents covered by the Lilly Agreement and that were assigned by Lilly to us.

If Lilly terminates the Lilly Agreement or if we terminate the Lilly Agreement without cause, (i) all rights under the licensed intellectual property rights will terminate and immediately and automatically revert to Lilly, (ii) any sublicense will be assigned by us to Lilly so that such sublicense becomes a direct license between Lilly and such sublicensee, (iii) subject to certain limitations, we will be required to grant to Lilly an irrevocable, non-exclusive, perpetual, fully paid up license under all patent rights developed or acquired by us during the term of the Lilly Agreement that relate to the Lilly licensed intellectual property, (iv) subject to certain limitations, we will be required to grant to Lilly an irrevocable, non-exclusive, perpetual, fully paid up license to the results of data from all preclinical and clinical studies of any compound or product covered by the Lilly Agreement, (v) subject to certain limitations, we will be required to take all steps necessary to permit Lilly to commence marketing product covered by the Lilly Agreement, and (vi) we will be required to assign or re-assign to Lilly all Lilly patents covered by the Lilly Agreement and that were assigned by Lilly to us.

If we terminate the Lilly Agreement for material breach by Lilly or Lilly’s bankruptcy, the licenses will remain in full force and effect and we will remain liable for the payment of all royalty obligations under the Lilly Agreement.

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Upon expiration in a given country, the licenses granted with respect to such country shall become fully paid up, perpetual and irrevocable.

notice to NovaRock, unless NovaRock cures such breach or violation during such sixty (60) day period, which shall be shortened to a thirty (30) day cure period for breaches of payment obligations.

We may terminate the NovaRock Agreement on a product-by-product basis (i) at any time without cause upon ninety (90) days written notice to NovaRock or (ii) upon material breach of the NovaRock Agreement by NovaRock upon sixty (60) days written notice to NovaRock, unless NovaRock cures such breach or violation during such sixty (60) day period, which shall be shortened to a thirty (30) day cure period for breaches of payment obligations.

NovaRock may terminate the agreement on a product-by-product basis upon our material breach of the NovaRock Agreement upon sixty (60) days written notice to us, unless we cure such breach or violation during such sixty-day period, which shall be shortened to a thirty (30) day cure period for breaches of payment obligations.

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The biotechnology and pharmaceutical industries are characterized by continuing technological advancement and significant competition.

While we believe that our product candidates, technology, knowledge, experience and scientific resources provide us with competitive advantages, we face competition from major pharmaceutical and biotechnology companies, academic institutions,

governmental agencies and public and private research institutions, among others.

Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.

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In addition, manufacturers of biopharmaceutical products participating in Medicaid and Medicare are required to comply with mandatory price reporting, discount, and rebate requirements.

The processes for obtaining regulatory approvals in the United States and in foreign countries, along with subsequent compliance with applicable statutes and

regulations, require the expenditure of substantial time and financial resources.

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

The following is a summary of the primary government regulations applicable to our business.

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Clinical Trials

provide their informed consent in writing for their participation in any clinical trial, as well as review and approval of the study by an IRB.

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with federal regulations and GCP requirements, which include the requirements that all research subjects provide their informed consent in writing for their participation in any clinical trial, as well as review and approval of the study by an IRB.

Investigators must also provide certain information to the clinical trial sponsors to allow the sponsors to make certain financial disclosures to the FDA.

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In this event, the application must be resubmitted with the additional information.

The resubmitted application is also

subject to review before the FDA accepts it for filing.

The resubmitted application is also subject to review before the FDA accepts it for filing.

Once the submission is accepted for filing, the FDA begins an in-depth substantive review.

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Manufacturers must also verify that purchasers of the manufacturers’ products are appropriately licensed.

subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious health consequences or death.

Further, under this legislation, manufacturers will have product investigation, quarantine, disposition, and notification responsibilities related to counterfeit, diverted, stolen, and intentionally adulterated products that would result in serious adverse health consequences or death to humans, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious health consequences or death.

Similar requirements additionally are and will be imposed through this legislation on other companies within the biopharmaceutical product supply chain, such as distributors and dispensers.

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

What changed 10-K

Item 1. Business