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Item 1. Business

2025-03-26 compared with 2024-03-18 · 106 added, 244 removed, 336 unchanged (51% of the section changed)

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(“Macrocure”), a publicly held, clinical-stage biotechnology company based in Petach Tikva, Israel.

In connection with the merger, we applied to be listed on the Nasdaq Global Market.

In connection with the merger, Macrocure became our wholly owned subsidiary and we applied to be listed on the Nasdaq Global Market.

Nasdaq approved the listing, and trading in our common stock commenced on January 24, 2017, under the trading symbol “LPTX.” On February 1, 2017, Macrocure’s name was changed to Leap Therapeutics Ltd.

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Our strategy is to identify, acquire, and develop molecules that will rapidly translate into high impact therapeutics that generate durable clinical benefit and enhanced patient outcomes.

Our lead clinical stage program is DKN-01, a monoclonal antibody that inhibits Dickkopf-related protein 1 (“DKK1”).

We are currently studying DKN-01 in multiple ongoing clinical trials in patients with esophagogastric cancer, gynecologic cancers, or colorectal cancer.

Our second clinical stage program is FL-301, a monoclonal antibody that targets cells that express Claudin18.2 on their cell surface.

We also have two preclinical antibody programs, FL-302 and FL-501.

Our lead clinical stage drug candidate is sirexatamab (DKN-01), a monoclonal antibody that inhibits Dickkopf-related protein 1 (“DKK1”).

We are currently studying sirexatamab in a clinical trial in patients with colorectal cancer.

We also have a preclinical program to develop a proprietary monoclonal antibody that we call FL-501.

FL-501 works by inhibiting the GDF-15 protein.

We intend to apply our extensive experience identifying and developing transformational products to build a pipeline of programs that have the potential to change the practice of cancer medicine.

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Over 16 million people in the United States have cancer.

The National Cancer Institute (NCI), estimated that approximately 2.0 million people developed cancer and that nearly 610,000 people died of cancer in 2023.

The National Cancer Institute (“NCI”) estimated that over 2.0 million people developed cancer and that nearly 612,000 people died of cancer in 2024.

While progress has been made from the War on Cancer to the Human Genome Project, and despite advances in early detection and new cancer cell targeted treatments, cancer generally remains an incurable disease.

Esophagogastric Cancer (EGC)

Esophageal cancer (“EC”), and gastric cancer (“GC”), are malignancies of the digestive tract.

According to the GLOBOCAN database in 2020, there were about 18,300 new patients diagnosed in the United States with EC and 26,300 new patients with GC each year.

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.

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 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.

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 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, 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.

According to the World Health Organization (“WHO”), there will be over 2 million new cases of CRC in 2025, 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.

According to the American Cancer Society (“ACS”), in the United States, there will be 154,270 newly diagnosed cases of CRC and 52,900 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.

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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.

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

Endometrial cancer is a malignancy arising in the inner lining of the uterus.

In 2024, according to the American Cancer Society, 67,880 new cases of endometrial cancer will be diagnosed and 13,250 women will die from the disease.

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 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.

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.

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

● altering cell signaling pathways that promote tumor growth and spreading;

● stimulating the immune cells that could attack the tumor;

● inhibiting immune suppression that would prevent an attack on the tumor;

● targeting cancer-specific cell surface markers to facilitate direct cancer cell killing.

Altering cell signaling.

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.

Changes in these pathways can lead to the expression of several cancer-causing genes and factors associated with cell growth, angiogenesis, and metastasis.

We believe that a monoclonal antibody that reduces free DKK1 could shift signaling to healthier levels, thereby resulting in an anti-tumor effect as well as a local anti-angiogenic effect in the diseased tissue.

These mechanisms could enhance or complement the anti-tumor mechanisms used by chemotherapies or other therapies targeted at different cell signaling pathways.

Enhancing anti-tumor immune cells.

A potential way to enhance an immune response against a tumor is by activating tumor-attacking immune cells, such as natural killer cells (“NK cells”) or T lymphocytes (“T cells”).

This strategy is expected to overcome mechanisms that would prevent these immune cells from attacking a tumor.

Preclinical data has shown that DKK1 suppresses the activity of NK cells in the tumor microenvironment and that inhibition of DKK1 can enhance NK cell activity.

Our preclinical antibody, FL-302, is a bi-specific antibody designed to activate T cells in the tumor microenvironment to enhance their anti-tumor activity.

Antibodies that enhance the immune system have the potential to be combined with chemotherapy or checkpoint inhibitors to generate a more robust anti-tumor immune response.

Inhibiting immune suppression.

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 (“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.

In addition, cancer cells promote these suppressor cells by producing anti-inflammatory molecules, such as DKK1.

We believe that monoclonal antibodies that reduce the levels of anti-inflammatory molecules, such as DKK1, in the tumor microenvironment could result in the inhibition of immune suppressor cells and create a pro-inflammatory environment to enhance the immune system activity against the tumor.

Targeting cancer-specific cell surface molecules.

Certain types of cancer cells have cell surface markers that are distinct from those found on normal, non-cancerous cells.

These cell surface markers can be the targets for therapies that will selectively kill the cells bearing those markers while sparing cells that do not bear those markers.

The expression of Claudin18.2 is very limited in normal tissue, as it is typically buried in the tight junction complex of gastric mucosal cells.

In the development of cancer, however, cells lose their polarity and structure.

As a result, Claudin18.2 may be exposed and accessible as a target for cancer therapy and is highly expressed on gastric cancer and pancreatic cancer cells.

Our antibodies FL-301 and FL-302 work to selectively target and kill those cancer cells which bear Claudin18.2 while sparing normal cells.

By targeting novel pathways, immune cell types, and biomarkers, our therapies are designed to combine with existing drugs and have the potential to significantly increase the survival and quality of life of cancer patients.

In 2024, according to company estimates, there were roughly 45,000 and 265,000 first-line treated patients and roughly 30,000 and 160,000 second-line treated patients for advanced CRC in the United States and top 7 non-US markets, respectively.

We estimate that roughly 50% of second-line treated patients did not receive first-line anti-VEGF therapy.

We also estimate that the relevant DKK1-high population would be 25% of second-line CRC patients.

Our Product and Clinical Studies

Sirexatamab (DKN-01)

DKK1 is a cell secreted protein that research has found plays a crucial role in embryonic development.

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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 pancreatic cancer.

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

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

In addition, elevated DKK1 is associated with worse overall survival or time to treatment discontinuation for patients with CRC 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 MDSC.

DKK1 has been shown to activate the suppressive effects of myeloid–derived suppressor cells (“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 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.

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

Through these multiple activities, research has shown that DKK1 helps protect the cancer cells from being targeted by the immune system.

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We believe that the more selective and local the activity is to the tumor, the more likely a drug will be safe and well tolerated and a potential combination partner to other anti-cancer drugs.

Further, our preclinical and clinical data suggests that DKN-01 upregulates PD-L1, suggestive of synergy in combination with an anti-PD-1/PD-L1 therapy.

DKN-01 is a high affinity, neutralizing monoclonal antibody targeting DKK1.

We have shown that DKN-01 reduces free DKK1 levels and has demonstrated an anti-tumor effect in preclinical models.

The FDA granted orphan drug designation to DKN-01 for the treatment of gastric and gastroesophageal junction cancer.

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 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 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 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

Twenty-five first-line GEA patients were treated with DKN-01 in combination with tislelizumab, capecitabine and oxaliplatin (CAPOX) in Part A.

DKN-01 and tislelizumab plus CAPOX was well tolerated in first-line treatment for advanced GEA patients, with a safety profile consistent with previous reports for each of the therapies.

The most common DKN-01-related adverse events (AEs), were low grade (Grade 1 or 2):

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

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 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 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 of DKN-01.

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

The most common DKN-01-related AEs were low grade (Grade 1 and 2):

fatigue and nausea.

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

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:

6 PR, 2 SD, 3 PD, 1 NE), median PFS was 7.7 months, with median OS having not been reached.

In DKK1-high/PD-L1 negative patients, the ORR was 27% (n=11:

3 PR, 1 SD, 7 PD), median PFS was 1.4 months, and median OS was 3.9 months.

In DKK1-high/PD-L1 medium patients with vCPS between 1 and 10, the ORR was 8% (n=18:

1 PR, 3 SD, 9 PD (irPR), 5 NE), median PFS was 1.4 months PFS, and median OS was 5.2 months.

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

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 EGC.

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

In a presentation at the ESMO 2022 Annual Congress, DKN-01 at 300 mg or 600mg every 2 weeks in combination with atezolizumab was considered safe.

No dose-limiting toxicity was observed, and no formal maximum tolerated dose was reached.

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 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.

The ORR was 10%, with an additional 4 patients (40%) having SD.

In the preliminary analysis, elevated baseline DKK1 expression (TPS > 20%) may be associated with clinical response, as the 4 DKK1-high patients had an ORR of 25% (1 PR, 1 SD, 1 PD, 1 NE).

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

Further, our preclinical and clinical data suggests that sirexatamab upregulates PD-L1, suggestive of synergy in combination with an anti-PD1/PD-L1 therapy.

Sirexatamab is a high affinity, neutralizing monoclonal antibody targeting DKK1.

We have shown that sirexatamab reduces free DKK1 levels and has demonstrated an anti-tumor effect in preclinical models.

The FDA granted orphan drug designation to sirexatamab for the treatment of gastric and gastroesophageal junction cancer.

In addition, on September 24, 2020, the FDA granted Fast Track designation to sirexatamab 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 currently developing sirexatamab in a clinical trial in patients with colorectal cancer and have also conducted clinical trials in patients with gastric/gastroesophageal junction cancer and endometrial cancer patients.

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 have evaluated sirexatamab in multiple preclinical CRC models.

Sirexatamab 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 sirexatamab 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.

Supportive of anti-angiogenic activity, preclinical models have also shown fewer and smaller blood vessels in response to sirexatamab treatment, and an additive effect of sirexatamab + bevacizumab at reducing xenograft tumor size.

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 188-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 primary objective is progression-free survival (“PFS”).

Secondary objectives include overall response rate (“ORR”), duration of response (“DoR”), and overall survival (“OS”), including in the exploratory populations of patients with high DKK1 and who have had no prior anti VEGF therapy.

In January 2025, we presented updated ORR and PFS data from Part A of DeFianCe.

In the 27 response-evaluable patients, the ORR was 33% and the disease control rate (“DCR”) was 93%.

Of these responding patients, the median DoR experienced was 9.92 months.

The 21 patients with CRC originating on the left side of the colon or rectum experienced an ORR of 38%, a DCR of 100%, and median PFS of 8.64 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

We conducted study P204, a Phase 2 basket study of DKN-01 as a monotherapy and in combination with paclitaxel in patients with advanced epithelial endometrioid cancer (“EEC”), epithelial ovarian cancer (“EOC”), and carcinosarcoma.

The study consisted of 6 dosing groups and enrolled 111 patients.

The primary objective in each independent study group was to determine the ORR.

Secondary objectives were to determine additional measurements of efficacy, such as OS and PFS, and to evaluate the safety of the study treatment regimen.

The study was designed to enroll at least 50% of patients whose tumors have predefined activating mutations or signaling alterations in the Wnt pathway.

Twenty-nine EEC patients, who had previously received 1 to 10 lines of therapy, enrolled in DKN-01 monotherapy.

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 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.

The DKK1-high patients experienced PFS of 4.3 months, compared to the DKK1-low patients who experienced PFS of 1.8 months.

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) 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.

Investigator-Sponsored Trial in Second Line Patients Combination with Keytruda (pembrolizumab)

An investigator-initiated trial of DKN-01 in combination with pembrolizumab is being conducted at M.D.

Anderson Cancer Center and the University of Alabama, Birmingham Cancer Center.

The study is an open-label, Bayesian design, Phase 2 trial and will initially enroll 15 patients each into DKK1-high and DKK1-low cohorts.

If the efficacy criteria is met in either or both of the 15 patient cohort(s), then the cohort(s) will be expanded by an additional 15 patients.

The primary objective of the study is ORR.

Secondary objectives include clinical benefit rate, PFS, OS, and DOR.

Merck is providing pembrolizumab for the study.

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

It is a key component of the tight junction for cell polarity and sealing the spaces between adjacent cells.

In normal tissue, expression of Claudin18.2 is very limited and largely inaccessible, as it is typically buried in the tight junction complex of gastric mucosal cells.

In the development of cancer, however, cells lose their polarity and structure.

As a result, Claudin18.2 may become exposed during tumorigenesis and accessible as a target for cancer therapy.

Claudin18.2 is highly expressed on gastric cancer and pancreatic cancer cells and can also be present in esophageal, lung, and ovarian cancers.

The expression pattern makes Claudin18.2 a highly selective biomarker for targeted cancer therapies.

Claudin18.2 is a validated target for cancer therapy, as randomized clinical trials from Astellas of their chimeric anti-Claudin18.2 antibody zolbetuximab have shown a survival benefit in combination with chemotherapy in first-line gastric cancer patients whose tumors express high (75% or greater) and intense levels of Claudin18.2.

However, since Claudin18.2 expression in tumors is heterogenous, expansion to patients with lower expression and improved efficacy in patients with higher expression would benefit from an antibody with higher affinity and improved killing activity.

FL-301 is a fully human monoclonal antibody that binds to and blocks Claudin18.2.

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.

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.

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

A bispecific antibody contains binding sites directed to two different targets or two different locations on one target.

CD137 (4-1BB) is an activating receptor found on T cells.

FL-302 is able to bind simultaneously both Claudin18.2 on tumor cells and CD137 on T cells and enhance the anti-tumor activity of T cells in the tumor microenvironment.

We believe that there is an opportunity to improve the activity of Claudin18.2 targeting antibodies through bispecific binding to T cell activation markers and generate additional synergy when used in combination with other immunotherapies, including immune checkpoint inhibitors and potentially DKN-01.

FL-302 is being developed through an exclusive license from NovaRock Biotherapeutics for territories excluding China.

FL-501 is a monoclonal antibody in preclinical development that targets growth and differentiation factor 15 (GDF15), which is a cytokine that is produced at elevated levels in response to various stresses, including chronic inflammation, obesity, cardiovascular diseases, cancers, and chemotherapy treatment.

In the 15 patients who had never received prior bevacizumab, the ORR was 53%, the DCR was 93%, and their median PFS was 8.05 months.

On March 26, 2025, we reported updated preliminary clinical data from Part B of the randomized and controlled DeFianCe Study.

In patients with high circulating DKK1 plasma levels (upper quartile as measured by the SomaLogic SomaScan platform, n=44), the sirexatamab experimental Arm has improved ORR, by both investigator-assessment (“IA”) and blinded independent central review (“BICR”), PFS and OS compared to the control arm:

Experimental Arm

Patients remaining on study drug

● In patients with high circulating DKK1 plasma levels (upper median as measured by the SomaLogic SomaScan platform, n=88), the sirexatamab experimental arm has improved ORR, by both IA and BICR, PFS, and OS compared to the control arm:

Experimental Arm

Patients remaining on study drug

In patients who had not received prior anti-VEGF therapy (n=95), the sirexatamab experimental arm (n=49) has improved ORR, PFS and OS compared to the Control Arm:

Experimental Arm

Patients remaining on study drug

Across the intent-to-treat (ITT) population with second-line MSS CRC (n=188), the sirexatamab experimental arm had improved ORR compared to the control arm, with PFS and OS still to mature due to the high number of patients remaining on study drug:

Experimental Arm

Patients remaining on study drug

DKK1 levels correlated with increasing clinical benefit in those patients receiving DKN-01 compared to Control patients in the control arm who did not.

In addition, patients in the experimental arm with lung metastases had an ORR advantage relative to patients with lung metastases in the control arm (36% vs 13%, n=90) and patients in the experimental arm with liver metastases had an ORR

advantage relative to patients with liver metastases in the control arm (37% vs 28%, n=136).

Prior immunotherapies have been shown to typically perform poorly in treating patients with lung metastases or liver metastases.

Gastric / Gastroesophageal Junction Cancer

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

In collaboration with BeiGene, we conducted 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 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 was to determine the effect of adding DKN-01 on the endpoint of median PFS in DKK1-high patients (defined as DKK1 TPS > 20) and in all patients.

Secondary objectives of Part C included 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.

In January 2025, we reported results of Part C.

While demonstrating activity in biomarker populations, the study did not generate a clear positive signal and we believe the study will be negative on the primary PFS endpoints when it completes, resulting in the decision not to move forward with Phase 3 studies in gastric cancer.

Across the Intent-to-Treat (“ITT”) population (n=170), patients treated with sirexatamab plus tislelizumab and chemotherapy (experimental arm, n=85) had a confirmed ORR of 52% by both IA and BICR, while patients treated with tislelizumab and chemotherapy alone (control arm, n=85) had a confirmed ORR of 56% by IA and 42% by BICR.

By BICR, patients in the experimental arm with DKK1-high tumors (n=22) had a confirmed ORR of 59%, compared to 36% in the control arm (n=22) and patients in the experimental arm with PD-L1-negative tumors (n=18) had a confirmed ORR of 44% compared to 32% in the control arm (n=19).

In the ITT population, preliminary median PFS in the experimental arm was 9.72 months by BICR and 7.66 months by IA compared to 11.99 months by BICR and 10.41 months by IA in the control arm.

The median PFS for tislelizumab plus chemotherapy in the Phase 3 Rationale-305 study was 6.9 months (95% CI:

In the DKK1-high population, preliminary median PFS in the experimental arm was 7.72 months by BICR and 7.43 months by IA compared to 7.79 months by BICR and 11.14 months by IA in the control arm.

The hazard ratio for PFS by BICR was 0.68, representing a trend in favor of the experimental arm in the overall time to event analysis.

Sirexatamab plus tislelizumab and chemotherapy was well tolerated, without additive toxicity to the standard of care.

FL-501 is a potential best in class monoclonal antibody in preclinical development that targets growth and differentiation factor 15 (GDF15), which is a cytokine that is produced at elevated levels in response to various stresses, including chronic inflammation, obesity, cardiovascular diseases, cancers, and chemotherapy treatment.

High GDF15 expression is associated with cachexia including loss of appetite, nausea and weight loss, and is also a validated target with a successful randomized clinical trial from Pfizer.

We are particularly interested in the role of GDF15 in promoting an immunosuppressive tumor micro-environment, much like DKK1, and the broad range of cancers including gastric, colorectal, pancreatic and prostate, where elevated GDF15 also correlates with poor prognosis.

FL-501 is being developed through the collaboration agreement with Adimab.

FL-501 was engineered for higher target affinity and a longer plasma half-life compared to competing therapies.

In preclinical cachexia models, FL-501 increased body weight and restored muscle mass.

In addition, we are interested in the role of GDF15 in promoting an immunosuppressive tumor micro-environment, much like DKK1, and the broad range of cancers including gastric, colorectal, pancreatic and prostate, where elevated GDF15 also correlates with poor prognosis.

FL-501 is being developed through a collaboration agreement with Adimab.

Intellectual Property

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and to operate without infringing on the valid and enforceable patents and proprietary rights of third parties.

Our ability to prevent third parties from making, using, selling, offering to sell or importing competing products to ours, including a competitor to DKN-01 or FL-301, depends on the validity, enforceability and/or scope of our patents.

We have several patents and patent applications relating to DKN-01 and its therapeutic uses, and possess substantial know- how relating to the development and commercialization of DKN-01.

We are the licensee of patents and patent applications relating to DKN-01 and FL-301.

Our ability to prevent third parties from making, using, selling, offering to sell or importing competing products to ours, including a competitor to sirexatamab depends on the validity, enforceability and/or scope of our patents.

We have several patents and patent applications relating to sirexatamab and its therapeutic uses, and possess substantial know-how relating to the development and commercialization of sirexatamab.

We are the licensee of patents and patent applications relating to sirexatamab.

We cannot be sure that any of our pending patent applications or future patent filings will lead to the issuance of new patents, nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be adequate to protect our market.

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We exclusively license from Eli Lilly and Company (“Lilly”), rights under 25 issued patents and 2 pending patent applications, all of which belong to the same patent family.

The patents and applications in this patent family are directed to the composition of matter and use of DKN-01, and include (i) one issued U.S.

The patents and applications in this patent family are directed to the composition of matter and use of sirexatamab, and include (i) one issued U.S.

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

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We own one issued U.S.

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

Patent, granted patents in Japan, Korea, Mexico, and Israel 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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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 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.

We also own another patent family directed to the treatment of colorectal cancer using combination therapy comprising sirexatamab and additional therapeutic agents.

Applications are pending in the following jurisdictions:

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

Any patent that may issue in the United States based on the pending U.S.

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 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.

In addition, we exclusively license from NovaRock Biotherapeutics, Ltd.

(“NovaRock”), the rights under one issued patent and pending patent applications, all of which belong to the same patent family.

The patents and applications in this patent family are directed to the composition of matter and use of FL-301, and include (i) one issued U.S.

Patent, and (ii) pending applications in the following jurisdictions:

Australia, Canada, Eurasia, Europe, Japan, South Korea, Singapore, and the United States of America .

The granted US patent and any additional patents that may issue in the United States based on the pending U.S.

Application will expire in 2040, absent any terminal disclaimer, patent term adjustment due to administrative delays by the 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 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.

We also own two U.S.

Provisional applications directed to the treatment of colorectal cancer using combination therapy comprising sirexatamab and additional therapeutic agents in specific subpopulations of patients.

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

Provisional patent application referenced above are filed in 2025, any patent that may issue from such applications will expire no earlier than 2045 absent any terminal disclaimer.

Any patents issued in foreign jurisdictions will likewise expire in 2045.

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Some foreign jurisdictions, including Europe, have patent extension provisions (e.g., supplementary protection certificates), which allow for extension of the protection of a patent that covers a drug approved by the applicable foreign regulatory agency.

In the future, if and when DKN-01 or any of our other products receives FDA approval, we expect to apply for patent term extension to extend the protection of one of our U.S.

In the future, if and when sirexatamab or any of our other products receives FDA approval, we expect to apply for patent term extension to extend the protection of one of our U.S.

patents covering the product, its use, or a method of manufacturing this product.

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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.

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.

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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The Lilly Agreement also contains certain standard representations and warranties and certain standard confidentiality and indemnification provisions.

Lonza License Agreement

On May 28, 2015, we entered into a license agreement with Lonza Sales AG (the “Lonza Agreement”), pursuant to which Lonza granted us a world-wide, non-exclusive license for certain intellectual property rights relating to a gene expression system, solutions of nutrients used in mammalian cell culture and related know-how and patent rights to use, test, develop, manufacture, market, sell, offer for sale, distribute, import and export DKN-01.

Such license includes a right to sublicense to (i) a competing contract manufacturer solely for the purpose of such manufacturer producing DKN-01 and (ii) our affiliates and strategic partners solely for undertaking commercial activities.

In exchange for the license and sublicense described above, we agreed to pay to Lonza a low single-digit royalty calculated as a percentage of net sales on DKN-01.

In addition, in connection with DKN-01 manufactured by Lonza, or a strategic partner of Lonza, we agreed to pay (i) an annual payment to Lonza beginning on the date of initiation of Phase 1 clinical trials for DKN-01 and (ii) an increased annual payment to Lonza beginning on the date of initiation of Phase 2 clinical trials for DKN-01, for so long as Lonza, or a strategic partner of Lonza, manufactures DKN-01.

In connection with DKN-01 manufactured by any other party, we agreed to pay (i) an annual amount to Lonza per sublicense beginning on the commencement date of such sublicense and continuing for so long as the sublicense exists and (ii) a low single- digit royalty calculated as a percentage of net sales of DKN-01.

All royalty amounts are subject to certain adjustments if, on a country-by -country basis, the manufacture and/or sale of DKN-01 are not protected by a valid claim.

All royalty obligations will expire on a country-by-country basis upon the later of (i) the expiration, revocation or complete rejection of all valid claims covering product in such country or (ii) ten (10) years from first commercial sale of DKN-01 in such country.

NovaRock License Agreement

On August 13, 2021, we entered into a strategic partnership and license agreement with NovaRock Biopharmaceuticals, Inc.

(the “NovaRock Agreement”), pursuant to which NovaRock granted us a world-wide, excluding the People’s Republic of China, Hong Kong, Macau, and Taiwan, exclusive license for certain intellectual property rights relating to FL-301 and FL-302.

Such license includes a right to sublicense.

Pursuant to the NovaRock Agreement, we agreed to pay NovaRock milestones upon the completion of development, regulatory and sales milestones for up to three different products (FL-301, FL-302 and potentially one additional target), along with a royalty in the mid-single digits of net sales of each product in the territory during the applicable royalty term, with certain adjustments to be made to the royalty rate in connection with the lack of coverage by a valid claim in the NovaRock patents, sales of biosimilar products, and third party intellectual property licenses.

We have not yet paid any royalties to NovaRock pursuant to this agreement.

The royalty term, with respect to each country in which a product is sold, on a country -by-country and product-by-product basis, begins on the first commercial sale of the product in the country and the later of (i) the expiration of the last-to-expire issued patent included within the patents licensed under the NovaRock Agreement having a valid claim covering the sale of the product in such country, and (ii) the tenth anniversary of the first date of commercial sale of the product in the territory.

The term of the NovaRock Agreement began on August 13, 2021, and, unless earlier terminated pursuant to the termination provisions described below, will continue on a product-by-product and country-by-country basis until we have no remaining royalty or other payment obligations in a specific country.

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

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.

Either party may terminate the NovaRock Agreement with immediate effect if the other party enters into bankruptcy or takes similar action.

In the event of termination of the NovaRock by either party, all rights under the licensed intellectual property rights will terminate and immediately and automatically revert to NovaRock.

The NovaRock Agreement also contains certain standard representations and warranties and certain standard confidentiality and indemnification provisions.

Adimab Collaboration Agreement

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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.

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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Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

For example, Novartis, Merck, Amgen, and Pfizer are all currently developing or have previously been developing anti-DKK1 monoclonal antibodies.

In addition, Astellas, Zai Labs, Amgen, Transcenta, and Elevation Oncology, among other companies, are all currently developing or have developed antibodies targeting Claudin18.2.

For example, Novartis, Merck, Amgen, Pfizer, Junshi Biosciences and Twist Biosciences are all currently developing or have previously been developing anti-DKK1 monoclonal antibodies.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

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We depend on third-party contract manufacturers (“CMOs”), for the production of clinical trial material for our studies.

Our DKN-01 bulk drug substance (“DS”), is produced at our CMO, ThermoFisher Scientific, which is required to comply with the FDA’s Current Good Manufacturing Practice (“cGMP”) regulations.

Our sirexatamab bulk drug substance (“DS”), is produced at our CMO, ThermoFisher Scientific, which is required to comply with the FDA’s Current Good Manufacturing Practice (“cGMP”) regulations.

Our finished drug product is produced at a contract fill/finisher provider, which is also required to comply with cGMP regulations.

Our FL-301 clinical trial material was manufactured at WuXi Biologics, a global CMO.

We have personnel with significant technical, manufacturing, analytical, quality and project management experience to oversee our third-party CMOs and to manage manufacturing and quality data and information for regulatory compliance purposes.

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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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● Phase 2 — Controlled studies are conducted in limited subject populations with a specified disease or condition to evaluate preliminary efficacy, identify optimal dosages, dosage tolerance and schedule, possible adverse effects and safety risks, and expanded evidence of safety.

● Phase 3 — These adequate and well-controlled clinical trials are undertaken in expanded subject populations, generally at geographically dispersed clinical trial sites, to generate enough data to provide statistically significant evidence of clinical efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product.

provide adequate information for the labeling of the product.

Typically, two Phase 3 trials are required by the FDA for product approval.

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The FDA also may require submission of a risk evaluation and mitigation strategy, or REMS, to ensure that the benefits of the biologic outweigh the risks.

The REMS plan could include medication guides, physician communication plans, and elements to assure safe use, such as restricted distribution methods, patient registries, or other risk minimization tools.

The REMS plan could include medication guides, physician communication plans, and elements to assure

safe use, such as restricted distribution methods, patient registries, or other risk minimization tools.

An assessment of the REMS must also be conducted at set intervals.

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In some cases, a Fast Track product may be eligible for accelerated approval or priority review.

On September 24, 2020, the FDA granted Fast Track designation to DKN-01 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.

On September 24, 2020, the FDA granted Fast Track designation to DKN-01 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.

The FDA may give a priority review designation to products that are intended to treat serious conditions and, if approved, would provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions.

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We make these reports available as soon as reasonably practicable after they are filed with or furnished to the SEC.

The information contained on, or that can be accessed through our website is not a part of or incorporated by reference into this Annual Report on Form 10-K.

The information contained on, or that can be accessed through our

website is not a part of or incorporated by reference into this Annual Report on Form 10-K.

We will also provide to any person without charge, upon request, a copy of any of the foregoing materials.

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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