Enliven Therapeutics, Inc. · NASDAQ:ELVN
Enliven Therapeutics — Technical Presentation (April 2024)
51 slides from Enliven Therapeutics's technical presentation, Apr 11, 2024
Slide 1: ELVN-001 Initial Proof of Concept Data and the Evolving CML Landscape
ELVN-001 Initial Proof of Concept Data and the Evolving CML Landscape April 11, 2024
Slide 2: Disclaimer
Disclaimer This presentation contains forward-looking statements that involve substantial risks and uncertainties of Enliven Therapeutics, Inc. (“Enliven” or the “Company”). All statements other than statements of historical facts contained in this presentation, including statements regarding our fu
Slide 3: Today's Agenda
Today’s Agenda 1 Introduction 2 The Evolving Chronic Myeloid Leukemia (CML) Landscape & ELVN-001 Preclinical Profile 3 Understanding Clinical Benefit in CML 4 ELVN-001 Phase 1a Initial Proof of Concept Data 5 Discussion with Leading CML Investigator KOLs 6 Q&A 3
Slide 4: The Enliven Story: a Clinical-Stage Precision Oncology Company
The Enliven Story: a Clinical-Stage Precision Oncology Company Discovery process Capital-efficient ELVN-001 and Experienced team rooted in validated Multiple near-term approach on high ELVN-002 supported with a track record biology, milestones in lead potential programs by preclinical of inventing a
Slide 5: Pipeline & Discovery Programs Address New and Emerging Unmet Needs
Pipeline & Discovery Programs Address New and Emerging Unmet Needs Parallel lead product candidates: IND- Next Milestone Program Target Differentiation Disease Regimen Discovery Phase 1 Phase 2 Phase 3 Enabling Milestone Expected Highly selective active site inhibitor w/activity Phase 1a April 11, E
Slide 6: On Today's Call
On Today’s Call Fabian Lang, M.D. Michael J. Mauro, M.D. Sam Kintz, M.B.A. Helen Collins, M.D. Damiette Smit, M.D. Senior Physician of Leader of the Co-founder, Chief Executive Chief Medical Officer of VP of Clinical Development Hematology/Oncology at Myeloproliferative Officer of Enliven Enliven Th
Slide 7: CML Landscape & ELVN-001 Introduction
CML Landscape & ELVN-001 Introduction
Slide 8: CML is Now a Long-Term Condition
CML is Now a Long-Term Condition As patients live longer on treatment, quality of life and tolerability have become important treatment goals CML 10-Year Survival Rate Over Time Estimated Prevalence of CML in the US Over Time Number of patients living with 10-year survival rate CML has more than dou
Slide 9: Significant Need Remains for Better Treatment Options for CML
Significant Need Remains for Better Treatment Options for CML Challenges with Current Standard of Care Switching Dynamics Demonstrate Unmet Need • Approximately 1 in 5 patients switch therapy within the first year Rationale for Switching Treatment and ~40% of patients switch in the first 5 years (1L
Slide 10: Poor Selectivity Limits Tolerability & Efficacy of 1st, 2nd & 3rd Gen Agents
Poor Selectivity Limits Tolerability & Efficacy of 1st, 2nd & 3rd Gen Agents T315I Off Target(s) & Treatment-Emergent, Drug & Administration Annualized Compound Company 1L Efficacy Coverage Non-Hematologic Adverse Events (All Gr / Gr 3+) Requirements Sales (USD)‡ c-KIT, Imatinib Peripheral Edema (20
Slide 11: Review of Asciminib (Scemblix), 4th Generation Allosteric TKI
Review of Asciminib (Scemblix®), 4th Generation Allosteric TKI Scemblix’s Robust Launch Continues to Demonstrate Observations Patient Need for More Effective and Tolerable Agents • Asciminib’s strong launch demonstrates the large market size and need for better agents US 3L+ Approval Q4 2021 • Howev
Slide 12: Asciminib has the Potential to Disrupt Early Line Standard of Care
Asciminib has the Potential to Disrupt Early Line Standard of Care CML Patient Population CML Treatment Landscape 1% 4% NEWLY DIAGNOSED ANNUALLY 1L 28% ~50% of patients are 46% ON 1L (49k) treated with imatinib, 1L 15k and the other ~50% 20% with 2nd Gen TKIs SWITCH ANNUALLY 5% 2% (1L to 2L) 20% 9%
Slide 13: ELVN-001 is Well Positioned to Follow Asciminib in Future CML Treatment Paradigm
ELVN-001 is Well Positioned to Follow Asciminib in Future CML Treatment Paradigm Limitations of Current Treatment Paradigm Future Treatment Paradigm Market Insights & Assumptions (if data supports) (if data supports) Asciminib could capture significant 1L Selective TKIs 1st Gen TKI 4th Gen TKI marke
Slide 14: ELVN-001 is a Selective Active Site, Active Form Inhibitor of BCR::ABL1
ELVN-001 is a Selective Active Site, Active Form Inhibitor of BCR::ABL1 ATP-BINDING SITE BINDING Key Attributes of ELVN-001: DRUG CONFORMATION • Type 1 small molecule inhibitor of BCR::ABL1 ELVN-001 Active targeting the ATP-binding site of the ABL1 BOSUTINIB Active kinase domain that binds to a uniq
Slide 15: ELVN-001 is Highly Selective for ABL1
ELVN-001 is Highly Selective for ABL1 • ELVN-001 has a very selective kinase profile • Clean against key off-target kinases in cells compared to 2nd and 3rd Gen TKIs • 372 kinases screened at 1 µM compound (100 µM ATP) ELVN-001 (100 µM ATP) • Kinases with >50% inhibition selected for IC50 determinat
Slide 16: ELVN-001 Potentially Affords an Improved Therapeutic Index
ELVN-001 Potentially Affords an Improved Therapeutic Index Target Coverage at Cave vs. 1L MMR Therapeutic Index vs. NHP Safety Margin 3 20 Fold above pCRKL IC50 at Cave Human (approved dose) Fold above pCRKL IC50 at Cave Non human primate (MTD) Dasatinib 15 2 Bosutinib Nilotinib ~10x 10 1 5 Imatinib
Slide 17: BCR::ABL1 Mutations Conferring Resistance to Asciminib (ASCEMBL)
BCR::ABL1 Mutations Conferring Resistance to Asciminib (ASCEMBL) ELVN-001 maintains activity against the emerging BCR::ABL1 mutations known to confer resistance to asciminib and activity against T315I similar to ponatinib Emerging BCR-ABL mutations upon discontinuation due to lack of efficacy or pro
Slide 18: ELVN-001 Clinical Focus and Target Product Profile
ELVN-001 Clinical Focus and Target Product Profile Phase 1a/b: Dose Escalation in Late Line Our Opportunity • Patients with CML who have exhausted all available treatment options • Seek to demonstrate improved therapeutic window & efficacy (BCR::ABL1 transcript level reductions) in Drive Deeper Impr
Slide 19: Understanding Clinical Benefit in CML
Understanding Clinical Benefit in CML
Slide 20: The Standard Clinical Endpoint in CML is Molecular Response
The Standard Clinical Endpoint in CML is Molecular Response • Measured by blood test and physical examination Hematologic • Normalization of white blood cell and platelet count without immature cells, 1 Response such as blasts, in peripheral blood • No signs or symptoms of disease, including resolut
Slide 21: Molecular Response Milestones
Molecular Response Milestones BCR::ABL1 Molecular Relevance Transcript Level Response ≤ 10% MR1 • Even in 3L+ setting insufficient for optimal survival • Equivalent to complete cytogenetic remission (absence of ≤ 1% MR2 Philadelphia chromosome) by bone marrow biopsy > 1 log reduction • ≥ MR3 is also
Slide 22: Switching TKIs is Usually Due to Lack of Efficacy or Intolerance
Switching TKIs is Usually Due to Lack of Efficacy or Intolerance • Often used interchangeably with resistance or loss of efficacy, is assessed based on molecular parameters Lack of − 1L/2L: switching is recommended after failure to meet specific molecular milestones at 3, 6 and 12 Efficacy months, l
Slide 23: Phase 1 Data in Late-Line CML from Most Recently Approved TKIs
Phase 1 Data in Late-Line CML from Most Recently Approved TKIs Asciminib Phase 1 (2019) Bosutinib Phase 1 (2012) 1 2 (2%) 1 0% Demographics 2 30 (27%) 2 115 (97%) (Prior TKIs) ≥3 81 (72%) ≥3 3 (3%) Cumulative MMR by 6 months 37/99 (37%) Cumulative MMR (median f/up 28 mo.) 16/105 (15%) Efficacy TKI-R
Slide 24: Asciminib vs. Bosutinib in Late-Line CML (ASCEMBL)
Phase 1 Data Predicted Pivotal Trial Data Asciminib vs. Bosutinib in Late-Line CML (ASCEMBL) Percent MMR at 24 Weeks Probability of MMR Over Time 20% 6/30 Bosutinib Third Line Probability of MMR (%) 29.3% 24/82 Asciminib 13.8% 4/29 Fourth Line 25% 11/44 Represents most of the patients enrolled in th
Slide 25: ELVN-001 Phase 1a Initial Proof of Concept Data in CML
ELVN-001 Phase 1a Initial Proof of Concept Data in CML
Slide 26: ELVN-001 Phase 1 Trial Design
ELVN-001 Phase 1 Trial Design Phase 1a: Dose Escalationa n=3 120 mg QD n=6 EXPLORE n ≤ 10 80 mg QD Primary endpoint: n=8 EXPLORE n ≤ 10 • Safetyb Key eligibility criteria: 40 mg QD • Chronic Phase n=7 EXPLORE n ≤ 10 CML (CP-CML) 20 mg QD Key secondary • Failed, intolerant to, n=3 EXPLORE n ≤ 10 MTD
Slide 27: ELVN-001 Phase 1a Enrolled a Heavily Pretreated Patient Population
ELVN-001 Phase 1a Enrolled a Heavily Pretreated Patient Population 70% of patients had ≥ 3 prior TKIs 70% patients have received prior ponatinib and/or prior asciminib Number of different prior TKIs (% of patients enrolled) Patient treatment status by previous TKI (% of patients enrolled) 1 prior TK
Slide 28: Median Time on ELVN-001 at Cutoff was 18 Weeks
Median Time on ELVN-001 at Cutoff was 18 Weeks (~4 months) 89% (24/27) of Patients Remain on Treatment 1 2 3 x 4 5 6 • Protocol allows re-enrollment and 7 8 intra-subject dose escalation* 9 x − 6 patients had intra-subject 10 x dose escalation 11 12 − 2 patients re-enrolled at 13 higher dose levels
Slide 29: Evaluation of Efficacy by Major Molecular Response by 12 Weeks (n=16)
Evaluation of Efficacy by Major Molecular Response by 12 Weeks (n=16) 1 2 3 x 4 5 MMR 6 atypical 7 MMR 8 >10% to MR1 (now MR2) • 43.8% (7/16) cumulative MMR by 9 x 12 weeks 10 x T315I • 2 additional patients with an 11 12 improvement in molecular 13 T315I response level 2 (re-enrolled) MMR • Exclude
Slide 30: ELVN-001 Early Data Compares Favorably to Precedent Phase 1 Trials
ELVN-001 Early Data Compares Favorably to Precedent Phase 1 Trials Asciminib Phase 1 Bosutinib Phase 1 ELVN-001 Phase 1a (2019) (2012) 1 2 (2%) 0% 1 (4%) 2 30 (27%) 115 (97%) 7 (26%) Demographics 3 41 (36%) 3 (3%)1 9 (33%) (Prior TKIs) More heavily pre- 4 32 (28%) 3 (11%) treated patients ≥5 9 (8%)
Slide 31: Stable or Improved BCR::ABL1 Transcripts in all Evaluable Patients by 12 Weeks
Stable or Improved BCR::ABL1 Transcripts in all Evaluable Patients by 12 Weeks (n=16) Baseline BCR::ABL1 transcript >1-log decrease MR5 MR4.5 MR4 MR3 MR2 MR1 Stable ≤ 0.001 >0.001 to 0.0032 to >0.01 to >0.1 to 1 >1 to 10 >10 0.0032 0.01 0.1 Loss of efficacy (N=0) (N=0) (N=1) (N=4) (N=5) (N=1) (N=5)
Slide 32: Safety and Tolerability of ELVN-001
Safety and Tolerability of ELVN-001 • Well tolerated to date • Maximum tolerated dose has not been reached • No dose reductions • No ≥ Grade 3 non-hematologic treatment-related AEs; no Grade 1/2 >11% • No obvious relationship between dose/exposure and AEs • 2 discontinuations due to AEs within the f
Slide 33: Hematologic Treatment Emergent Adverse Events
Hematologic Treatment Emergent Adverse Events Hematologic TEAE Regardless of Relatedness Dose 10 mg 20 mg 40 mg 80 mg 120 mg Total N 3 7 8 6 3 27 Grade 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 Neutropenia 2 (66.7%) 2 (18.6%) 4 (14.8%) Thrombocytopenia 1 (33.3%) 2 (28.6%) 1 (16.7%) 2 (7.4%) 2
Slide 34: Non-Hematologic Treatment-Related AEs Reported in ≥ 2 patients
Non-Hematologic Treatment-Related AEs Reported in ≥ 2 patients (5%) Non-Heme TRAEs in ≥ 2 Patients Dose 10mg 20mg 40mg 80mg 120mg Total N 3 7 8 6 3 27 Grade 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 1/2 3/4 Lipase increased 1 (33.3%) 1 (14.3%) 1(12.5%) 3 (11.1%) Headache 1 (14.3%) 1 (16.7%) 2 (7.4%) H
Slide 35: Summary
Summary • Presented today is the initial clinical data from the Phase 1a portion of our ongoing ELVN-001 Phase 1 trial • Early anti-CML activity was observed in this late line patient population − Cumulative MMR rate of 44% by 12 weeks is favorable compared to cumulative MMR rates observed in the Ph
Slide 36: Patient Vignettes
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Slide 37: Deepening of Response in Heavily Pretreated Patient
Deepening of Response in Heavily Pretreated Patient MR5 after 7 prior TKIs @ 20mg QD ELVN-001 Patient Background Relevant past Hypertension medical history Imatinib (LOE), nilotinib (pruritis), dasatinib (LOE), Prior therapy bosutinib (diarrhea), nilotinib (pruritis), asciminib (LOE), (reason for sw
Slide 38: Intolerant to 5 Prior TKIs, Including Asciminib
Intolerant to 5 Prior TKIs, Including Asciminib: >10% à <1% by 6 Mo. MR2 after 6 prior TKIs @ 20mg QD ELVN-001 Patient Background Relevant past Young patient with no medical history medical history Imatinib (LOE), bosutinib (GI tox), nilotinib Prior therapy (heme/hepatic/pancreatic tox), dasatinib (
Slide 39: 1L Asciminib Resistant Patient: MR5 with > 1-log decrease
1L Asciminib Resistant Patient: MR5 with > 1-log decrease MR5 post-Asciminib @ 40mg QD ELVN-001 Patient Background Relevant past Hyperlipidemia medical history Prior therapy Asciminib (LOE), ponatinib (LOE) (reason for switch) Mutations A337T and V506M (mutation detected locally) Safety G1 rash (R)
Slide 40: ELVN-001 PK Profile & Target Coverage
ELVN-001 PK Profile & Target Coverage
Slide 41: ELVN-001's PK Profile Supports Once Daily Dosing with Flexible Administration
ELVN-001’s PK Profile Supports Once Daily Dosing with Flexible Administration Requirements 120mg ELVN-001 (single dose) • Linear PK observed in healthy volunteers (HV) and patients 1000 − No time-dependent PK observed in either HVs or cancer Fasted patients Fed Plasma (ng/mL) − Both Cmax and AUC inc
Slide 42: ELVN-001 Achieved Superior Target Coverage Compared to 2nd Gen TKIs
ELVN-001 Achieved Superior Target Coverage Compared to 2nd Gen TKIs Cave Target Coverage vs. 1L MMR at 12 mo. Cave Target Coverage vs. Active Site TKIs (1L) Cave / K562 pCRKL IC50 100% human serum 3 10 8 Target Coverage at Cave Target Coverage at Cave Dasatinib 2 Bosutinib 6 Nilotinib 4 1 2 Imatinib
Slide 43: ELVN-001 Achieved Similar Target Coverage Compared to Asciminib
ELVN-001 Achieved Similar Target Coverage Compared to Asciminib Cave Target Coverage vs. All TKIs (Late Line) Cave Target Coverage vs. Asciminib (Phase 1) Cave / K562 pSTAT5 IC90 PPB adjusted Cave / K562 GI50 PPB adjusted 8 Cave / K562 pSTAT5 IC90 PPB adjusted 6 Target Coverage at Cave 6 Target Cove
Slide 44: Summary & Next Steps
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Slide 45: Summary
Summary CML Opportunity ELVN-001 Initial Proof of Concept Data • CML is a chronic condition, often requiring decades of daily • As a highly selective, active site, active form inhibitor of therapy BCR::ABL1, ELVN-001 represents a complimentary MOA compared to asciminib • Despite generics, the commer
Slide 46: Next Steps for ELVN-001
Next Steps for ELVN-001 2Q 2024 2025 2025 Year End Initiate Phase 1b and Phase 1b data with ~60-100 Initial regulatory continue ongoing patients across various lines interactions with the aim of exploration in Phase 1a of therapy with significant achieving regulatory path follow-up clarity regarding
Slide 47: Appendix
Appendix
Slide 48: 5 Patients that Maintained MMR by 12 Weeks
5 Patients that Maintained MMR by 12 Weeks Reason for Discontinuation ELVN-001 Resistant to Baseline # Prior TKIs Ponatinib Asciminib Last Prior TKI By 12 Weeks Dose other prior TKIs MR Status 2/5 patients 20mg 6 Intolerant LOE Intolerant (P) I, D, B MR4 MR5 improved MR category by 40mg 2 LOE LOE LO
Slide 49: Scemblix (asciminib) USPI: Warnings and Precautions
Scemblix (asciminib) USPI: Warnings and Precautions • Myelosuppression: Severe thrombocytopenia and neutropenia events may occur. Monitor complete blood counts regularly during therapy and manage by treatment interruption or dose reduction. • Pancreatic Toxicity: Monitor serum lipase and amylase. In
Slide 50: Scemblix (asciminib) USPI: Adverse Reactions (≥ 10%) in Patients with CML in ASCEMBL
Scemblix (asciminib) USPI: Adverse Reactions (≥ 10%) in Patients with CML in ASCEMBL Table 3 Abbreviations & Footnotes: Ph+ CML in CP, Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP); TKIs, tyrosine kinase inhibitors. aUpper respiratory tract infection inclu
Slide 51: Asciminib and Bosutinib: Adverse Events Over Time in ASCEMBL
Asciminib and Bosutinib: Adverse Events Over Time in ASCEMBL Figure 8. Adverse events over time: proportion of patients with on-treatment AEs occurring during the first 8 weeks of treatment, and newly occurring between weeks 8-24 of treatment. Denominators are the number of patients on treatment at
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