In an interview with PharmaShots, Douglas Onsi, CEO and President of Leap Therapeutics shares insights on the clinical data of DKN-01 along with its mechanism. He also highlights the company's growth, plans, goal etc.

Shots:

• DKK1 is a secreted protein that modulates cell signaling pathways known as the Wnt signaling pathways, as well as the PI3 kinase and AKT pathway
• DKN-01 demonstrated clinical responses and longer progression-free survival in patients with Wnt signaling alterations and high tumoral DKK1 expression
• The company is planning to develop DKN- 01 in other indications that could lead to better treatment options for patients

Tuba: Briefly give an overview of the novel mechanism of DKN-01?

Douglas: DKK1 is a secreted protein that modulates cell signaling pathways known as the Wnt signaling pathways, as well as the PI3 kinase and AKT pathway. In cancer, DKK1 has been implicated in facilitating tumor growth and metastasis, as well as promoting immunosuppression in the tumor microenvironment through the activation of myeloid-derived suppressor cells and the suppression of natural killer cell anti-tumor activity. In addition, some patients tumors have mutations in their Wnt signaling pathways that lead to higher levels of DKK1 being produced by the tumor cells.

We are developing an antibody that binds and inhibits the activity of DKK1 known as DKN-01. We have evaluated DKN-01 in a variety of preclinical and clinical studies. We believe that DKN-01 has both direct anti-tumor activity and contributes to the activation of the innate immune system in the tumor micro-environment.

Tuba: Please provide detail on the P-II P204 study design and the key findings of the P204 study?

Douglas:  Basket study evaluating DKN-01 as monotherapy or in combination with paclitaxel in advanced gynecologic malignancies. The primary objective of this study is to determine the overall response rate and to explore genetic mutations in the Wnt signaling pathway and tumoral DKK1 expression as predictive biomarkers. Eligible patients who have recurrent epithelial endometrial cancer (EEC), Recurrent platinum-resistant/refractory epithelial ovarian cancer (EOC), or carcinosarcoma (MMMT), have received at least one prior therapy, and at least 50% in each group are required to have tumors with Wnt signaling alterations. In the study, 52 patients received DKN-01 monotherapy and the second group of 59 patients each received a combination therapy of DKN-01 and Paclitaxel. The monotherapy patients in group 1 were made up of 29 EEC patients, 14 EOC patients, and 9 MMMT patients. The combo therapy patients in group 2 were made up of 25 EEC patients, 19 EOC patients, and 15 MMMT patients.

The Key findings are the following:

• Greater and more durable clinical activity in EEC patients with Wnt signaling alterations: 1 CR, 1 PR (ORR 10%), and 8 SD (ODCR 50%) vs 1 SD (ODCR 17%)
• Higher tumoral expression of DKK1 is associated with greater clinical activity: DKK1-high: ORR 14.3%; ODCR: 57.1% vs DKK1-low: ORR: 0%; ODCR: 8.3%
• Longest PFS in patients with Wnt activating mutations compared to those without Median 5.5 months (95% CI: 1.0, 11.1) vs 1.8 months (95% CI: 1.4, 2.3)
• Longest OS in patients with Wnt activating mutations compared to those without Median not reached (NR) vs 12.2 months (95% CI: 3.3, NE)
• Higher tumoral expression of DKK1 is associated with longer PFS than DKK1-low (3.0 vs 1.8 months)
• EEC has a high prevalence of patients with Wnt signaling alterations (72%), including a subgroup with Wnt activating mutations (~30%)

Tuba:  When can we expect the initiation of the P-III study assessing DKN-01 in Gynecologic Cancers?

Douglas:

We are currently evaluating the final data from our study of DKN-01 in gynecologic cancer and are considering the following development strategies:

• Monotherapy: DKN-01 in in previously treated DKK1-high or Wnt Activating Mutation Patients
• Proof-of-Concept Data: 14.3% ORR, 57.8% DCR, 3 months PFS in DKK1- high Patients
•  Proof-of-Concept Data: 5.5 months PFS, NR OS (> 20 months) with Wnt Activating Mutations

PD-1 Combination: DKN-01 plus anti-PD-1 antibody in previously treated DKK1- high or Wnt Activating Mutation Patients

• Proof-of-Concept Data: Esophagogastric Cancer Data, Single Agent Activity

Additional biomarker data analysis is ongoing and expected to be presented in    Q1 2021

• CKAP4-PI3K-AKT Pathway biomarkers

Tuba:  Leap Therapeutics is evaluating DKN-01 as a combination regimen in multiple cancer indications in collaboration with other global companies. Please describe each partnership and the different indications?

Douglas:  

BeiGene has the rights to DKN-01 in Asia (excluding Japan), Australia, and New Zealand. The deal is described more below.

Leap is running two company-sponsored studies:

• Esophagogastric Cancer DKN-01 + BeiGene's anti-PD-1 antibody, tislelizumab, in patients with DKK1-high 2L gastroesophageal junction (GEJ) and gastric cancer (GEJ/GC) and + CAPOX in 1L GEJ/GC
• Gynecologic Cancer DKN-01 ± paclitaxel in EEC, EOC & MMT

Leap has four investigator-sponsored studies:

• Prostate Cancer NYU: DKN-01 ± docetaxel in DKK1+/Wnt activated 2L+
• Biliary Tract Cancer (50% funded by BMS) Massachusetts General Hospital: DKN-01 + nivolumab 2L
• Esophagogastric Cancer (100% funded by Roche) Royal Marsden Hospital in the United Kingdom: DKN-01 + atezolizumab 2L
• Hepatocellular Cancer University of Mainz in Germany: DKN-01 ± sorafenib in Wnt activated 1L
• Neither BMS or Roche have any rights to DKN-01.

Tuba:  Are you looking for more collaborations to assess the potential of DKN-01 in other cancer indications?

Douglas:  As a company committed to patient outcomes, we are always looking to develop DKN- 01 in other indications that could lead to better treatment options for patients. We continue to have ongoing discussions internally and externally about the opportunities    that are out there for DKN-01 and new, potential opportunities.

Tuba: Briefly discuss Leap's second candidate TRX518? How does it work and discuss its potential in treating advanced solid tumors?

Douglas:  TRX518 is a novel, fully humanized agylcosyl IgG1 anti-GITR mAb. GITR is a member of the tumor necrosis factor receptor family expressed on T, B, & NK cells, and antigen presenting cells. GITR is expressed at high levels by Tregs and up-regulated following T cell activation; minimally expressed by na?ve CD4+ and CD8+ T cells. Signaling through GITR abrogates Treg mediated suppression and enhances CD4+ and CD8+ T cell proliferation and TCR stimulation. GITR signaling may enhance host immune responses against tumor and aid in tumor rejection. We have deprioritized TRX518 to give DKN-01 our full attention. We saw promising results in TRX518 in the treatment of advanced solid tumors, and we continue to look for opportunities to develop it.

Tuba:  Please add any additional information about the company's growth, future plans, etc.?

Douglas:  

Leap-BeiGene strategic partnership remains to be our priority

The upfront payment of $8 million was a $3 million option fee and a $5 million equity investment. This gave them exclusive rights to Asia (excluding Japan), Australia, and New Zealand. The deal also includes a greater than $10 million option exercise fee based on data from DKN-01 plus tislelizumab combination study, $132 million total option exercise, clinical, regulatory, and commercial milestones, and high-single digit to mid-teen double digit royalties. After option exercise, BeiGene will be responsible for all of the costs of development, manufacturing, and commercialization in their territory.

Cash Position

We are very well funded to reach our goals and with our most recent public offering in June we raised $51.75 million. We ended the third quarter with $58 million in cash that will enable us to reach the milestones we have set for ourselves and carry us well into 2022.

Data Readouts

• Final readout data in Q1 of 2021 on gynecologic cancer study with DKN-01 +/- paclitaxel

• Initial data readout in Q2 of 2021 on NYU prostate study with DKN-01 +/- docetaxel

• Initial data readout in 2H of 2021 on BeiGene gastric cancer study with DKN-01 + tislelizumab

About Author:

Doug Onsi has served as Leap's Chief Financial Officer, Treasurer, and Secretary since 2011 and became the President & CEO in April of 2020. Doug received his JD from the University of Michigan Law School and his BS in biological sciences from Cornell University.

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