Slides
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company presentation LEAP THERAPEUTICS J.P . Morgan 43rd Annual Healthcare Conference January 15, 2025
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Forward looking statements 2 This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, clinical trials, collaborations and partnerships, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements within the meaning of U.S. securities laws. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. These and other risk factors are listed from time to time in reports filed with the Securities and Exchange Commission, including, but not limited to, our Annual Reports on Form 10-K and our Quarterly Reports on Form 10-Q. We assume no obligation to update any forward-looking statements, except as required by applicable law. This presentation does not constitute an offer to sell, or the solicitation of an offer to buy, any securities.
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Developing biomarker-targeted antibody therapies for cancer patients 3 Lead clinical stage antibody program – sirexatamab (DKN-01) targeting DKK1 Multiple upcoming milestones from two randomized clinical trials Biomarker strategy, focus on GI cancers Cash runway to Q2 2026 with $62.8M cash at September 30, 2024
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Pipeline 4 Treatment:Indication: Preclinical Phase 2 Phase 3Phase 1 sirexatamab (DKN-01) Anti-DKK1 antibody tislelizumab + chemotherapy bevacizumab + chemotherapy pembrolizumab Gastric cancer Colorectal cancer Endometrial cancer FL-501 Anti-GDF-15 antibody
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SIREXATAMAB (DKN-01) Anti-DKK1 monoclonal antibody
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The role of DKK1 in cancer 6 Tumor CKAP4 Angiogenesis Akt PI3K Cancer cell Cancer cells DKK1 is produced and secreted by cancer cells, and functions on several tumor pathways and nearby immune cells. Enhances the suppressive activity of MDSCs and M2 macrophages. Reduces NK cell activity and T-cell infiltration. Promotes angiogenesis by increasing the number and size of blood vessels. Promotes activation of Akt by direct signaling through CKAP4 and PI3 kinase. Cancer cell DKK1
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DKK1 production from multiple sources can drive tumor growth 7 Tumor DKK1 DKK1 Bone DKK1 lowDKK1 high Blood vessel ELISA Enzyme-Linked Immunosorbent Assay DKK1 RNA from the tumor is measured by RNAscope DKK1 protein in circulation is measured by ELISA
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Activity of sirexatamab (DKN-01) to treat cancer 8 CKAP4 Angiogenesis Akt PI3K Cancer cell Cancer cells Tumor Cancer cell DKK1 Sirexatamab(DKN-01) treatment neutralizes DKK1 and stimulates an immune mediated anti-tumor response. sirexatamab (DKN-01) Activates NK cells, reprograms macrophages into the tumor-attacking M1 subtype and promotes T cell infiltration. Reduces MDSCs and tumor suppressive M2 macrophages in the TME. Reduces angiogenesis and inhibits pro- oncogenic PI3K/AKT signaling.
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SIREXATAMAB(DKN-01) Colorectal cancer development
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Colorectal cancer background • Includes right colon (cecum, ascending and transverse colon) and left colon (descending colon, sigmoid, and rectum) • When symptoms appear, such as rectal bleeding, anemia, or abdominal pain, most patients already have advanced stage disease where cancers are aggressive and incurable • Third most frequent cancer globally and the second leading cause of cancer-related death • Globally, nearly 2,000,000 new cases in 2020, with nearly 1,000,000 deaths. • In the US, estimated that there will be approximately 150,000 cases each year, resulting in more than 50,000 deaths. 10 Source: WHO Globocan 2020, American Cancer Society
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Bevacizumab benchmark studies demonstrate need for new options for today’s heterogeneous second-line patient population ML18147 404 5.4% E3200 286 22.7% SLAVE 228 25.7% Bevacizumab + Chemo Bevacizumab + Chemo Bevacizumab + Chemo* *SLAVE included N=198 left sided CRC patients. This subgroup has an ORR of 22.7% Bevacizumab- experienced Bevacizumab- naïve EGFR- experienced Treatment Study ORR Population PFS OS 11.2 5.7 7.3 7.1 16.212.9 Significant unmet needs in 2L patients 11
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DeFianCe Part A study design 12 Randomized phase 2 study of FOLFIRI/FOLFOXand bevacizumab +/- sirexatamab (DKN-01) as second-line treatment of advanced colorectal cancer Primary objective: PFS, left-side and all Key eligibility criteria: • One prior 5-FU based therapy for advanced colorectal adenocarcinoma • RECIST v1.1 measurable disease • MSS and absence of BRAFV600 mutation 2L CRC sirexatamab (DKN-01) + bevacizumab + chemotherapy Overall Response Rate Progression-Free Survival Duration of Response N=33 Safety sirexatamab(DKN-01) + SOC chemotherapy (FOLFIRI or mFOLFOX6) + bevacizumab Overall Response Rate Progression-Free Survival Duration of Response Second-line:
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Overall response rate exceeded 20% target with high disease control rate 13 ORR in RE patients: 9/27 = 33% DCR in RE patients: 25/27 = 93% Objective Response Rate (%) Disease Control Rate (%) Partial Response n (%) Stable Disease n (%) Progressive Disease n (%) Overall, n=27 33 93 9 (33) 16 (59) 2 (7) As of October 1, 2024 2L CRC sirexatamab (DKN-01) + bevacizumab + chemotherapy
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• Median DoR: 9.92 months 14 Duration of response 2L CRC sirexatamab (DKN-01) + bevacizumab + chemotherapy
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15 Best overall response based on tumor sidedness 2L CRC sirexatamab (DKN-01) + bevacizumab + chemotherapy Overall, n=27 Objective Response Rate (%) Disease Control Rate (%) Partial Response n (%) Stable Disease n (%) Progressive Disease n (%) Left (n=21) 38 100 8 (38) 13 (62) 0 (0) Right (n=6) 17 67 1 (17) 3 (50) 2 (33) As of October 1, 2024
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• Median PFS in left-sided tumors: 8.6 months 16 Longer progression-free survival in patients with left-sided tumors 2L CRC sirexatamab (DKN-01) + bevacizumab + chemotherapy
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Best overall response based on prior bevacizumab exposure 17 2L CRC sirexatamab (DKN-01) + bevacizumab + chemotherapy As of October 1, 2024 Overall, n=27 Objective Response Rate (%) Disease Control Rate (%) Partial Response n (%) Stable Disease n (%) Progressive Disease n (%) No Prior Bev (n=15) 53 93 8 (53) 6 (40) 1 (7) Prior Bev (n=12) 8 83 1 (8) 10 (83) 1 (8)
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Progression-free survival Bevacizumab exposure subgroup 18 Median PFS in bevacizumab naïve subgroup exceeds prior bevacizumab treated: 8.05 vs 5.98 months 2L CRC sirexatamab (DKN-01) + bevacizumab + chemotherapy
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DeFianCe Part B study design 19 Randomized phase 2 study of FOLFIRI/FOLFOXand bevacizumab +/- sirexatamab (DKN-01) as second-line treatment of advanced colorectal cancer 2L CRC sirexatamab (DKN-01) + bevacizumab + chemotherapy Primary objective: PFS, left-side and all Secondary objectives: – ORR – DoR – OS sirexatamab (DKN-01) + SOC chemotherapy (FOLFIRI or mFOLFOX6) + bevacizumab SOC chemotherapy (FOLFIRI or mFOLFOX6) + bevacizumab N=94 N=94 Key eligibility criteria: • One prior 5-FU based therapy for advanced colorectal adenocarcinoma • RECIST v1.1 measurable disease • MSS and absence of BRAFV600 mutation N=188 1:1
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SIREXATAMAB(DKN-01) Gastric сancer development
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DisTinGuish Part C study design 21 sirexatamab (DKN-01) + tislelizumab + SOC chemotherapy (XELOX or mFOLFOX6) tislelizumab + SOC chemotherapy (XELOX or mFOLFOX6) N=85 N=85 Stratification factors: • DKK1 expression (TPS ≥ 20% vs < 20%) • PD-L1 (CPS ≥5 vs < 5) Key eligibility criteria: • No prior therapy for unresectable locally advanced or metastatic gastric/GEJ adenocarcinoma • RECIST v1.1 measurable disease • Her2 negative N=170 1:1 Primary objective: PFS, DKK1-high and all Secondary objectives: – ORR – DoR – OS 1L GEJ/GC sirexatmab (DKN-01) + tislelizumab + chemotherapyRandomized phase 2 study of FOLFIRI/FOLFOXand tislelizumab +/- sirexatamab (DKN-01) as first-line treatment of advanced GEJ/gastric cancer
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22 ORR (%) (95% CI) DOR months (95% CI) PFS months (95% CI) OS months (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) All Patients 40.5% (36.2%, 45.0%) 47.3% (42.9%, 51.8%) 6.2 (5.6, 6.9) 6.9 (5.7, 7.2) 12.9 (12.1, 14.1) 15.0 (13.6, 16.5) 8.6 (7.9, 11.0) 7.2 (6.0, 8.5) ControlTislelizumab + Chemo Rationale-305 study: tislelizumab + chemotherapy in 1L GEJ/GC patients N= 501 N= 496 0.80 (0.69, 0.92) 0.78 (0.67, 0.90) 31.5% (23.4%, 40.4%) 5.0 (3.9, 6.7) 7.5 (4.4, 12.0) North America & Europe N= 125 10.5 (8.1, 12.1) 11.0 (8.4, 13.9) 5.4 (4.3, 5.9) 5.6 (4.4, 7.0) 36.0% (27.6%, 45.1%) ControlTislelizumab + Chemo 34.9% (21%, 50.9%) 18 (2.8, NA) 11.8 (4.3, NA) N= 274 N= 272 13.8 (10.2, 17.8) 15.4 (8.4, 16.5) 6.9 (5.6, 15) 7.9 (5.6, 9.7) 44.9% (32.9%,57.4%) CPS < 1PD-L1 ControlTislelizumab + Chemo 0.71 (0.54, 0.94) 0.84 (0.63, 1.11) 0.87 (0.54, 1.41) 0.98 (0.64, 1.50) N= 124 All patients and PD-L1 < TAP 1 from September 26, 2024 FDA Briefing Document North American & Europe as presented at ASCO GI 2024
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FL-501 Anti-GDF-15 monoclonal antibody
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GDF-15 Blood stream Stressed сells Cancer cachexia GDF-15 expression leads to an immuno- suppressive TME Heart failure Decline in renal function Hyperemesis gravidarum GFRAL GDF-15 Other GDF-15 related diseases Circulating GDF-15 triggers its effects by binding to its receptor (GFRAL) in the hindbrain Immuno- suppression in cancers GDF-15 expression leads to an immuno- suppressive TME Respiratory diseases The role of GDF-15 in cachexia and cancer 24
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GDF-15 Blood stream Stressed сells Weight gain, normal appetite, improved muscle mass Cardioprotective effects Renoprotective effects Improved maternal health GFRAL Immuno stimulation in tumor microenvironment Pulmonary improvement FL-501 FL-501 mechanism of action 25
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CORPORATE
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2025 Corporate Milestones 27 • Sirexatamab (DKN-01) • Initial data disclosure from both randomized controlled clinical trials expected in Q1 2025 • DisTinGuish study in first-line gastric cancer: ORR and PFS in all patients, DKK1-high and PD-L1 low subgroups • DeFianCe study in second-line colorectal cancer: ORR in all patients, left-side and bevacizumab-naïve subgroups • Identify the Phase 3 development strategy • FL-501 • Manufacturing development initiated with goal of initiating a clinical trial in H1 2026 • Preclinical data presentation expected in early Q2 2025