Slides
Page 1
Extending the Boundaries of Targeted Cancer Therapies with Radio-DARPins and Next-Gen Immune Cell Engagers May 16, 2025 Nasdaq, SIX Swiss Exchange: MOLN
Page 2
Disclaimer This presentation contains forward looking statements. Any statements contained in this presentation that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, as amended, including without limitation: implied and express statements regarding the clinical development of Molecular Partners’ current or future product candidates; expectations regarding timing for reporting data from ongoing clinical trials or the initiation of future clinical trials; the potential therapeutic and clinical benefits of Molecular Partners’ product candidates and its RDT and Switch-DARPin platforms; the selection and development of future programs; Molecular Partners’ collaboration with Orano Med including the benefits and results that may be achieved through the collaboration; and Molecular Partners’ expected business and financial outlook, including anticipated expenses and cash utilization for 2025 and its expectation of its current cash runway and the expected use of proceeds from the October 2024 offering. These statements may be identified by words such as “aim”, "anticipate",“expect”, “guidance”, “intend”, “outlook”, “plan”, “potential”, “will” and similar expressions, and are based on Molecular Partners’ current beliefs and expectations. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements. Some of the key factors that could cause actual results to differ from Molecular Partners’ expectations include its plans to develop and potentially commercialize its product candidates; Molecular Partners’ reliance on third party partners and collaborators over which it may not always have full control; Molecular Partners’ ongoing and planned clinical trials and preclinical studies for its product candidates, including the timing of such trials and studies; the risk that the results of preclinical studies and clinical trials may not be predictive of future results in connection with future clinical trials; the timing of and Molecular Partners’ ability to obtain and maintain regulatory approvals for its product candidates; the extent of clinical trials potentially required for Molecular Partners’ product candidates; the clinical utility and ability to achieve market acceptance of Molecular Partners’ product candidates; the potential that Molecular Partners’ product candidates may exhibit serious adverse, undesirable or unacceptable side effects; the impact of any health pandemic, macroeconomic factors and other global events on Molecular Partners’ preclinical studies, clinical trials or operations, or the operations of third parties on which it relies; Molecular Partners’ plans and development of any new indications for its product candidates; Molecular Partners’ commercialization, marketing and manufacturing capabilities and strategy; Molecular Partners’ intellectual property position; Molecular Partners’ ability to identify and in-license additional product candidates; unanticipated factors in addition to the foregoing that may cause Molecular Partners’ actual results to differ from its financial and business projections and guidance; and other risks and uncertainties set forth in Molecular Partners’ Annual Report on Form 20-F for the year ended December 31, 2024 and other filings Molecular Partners makes with the SEC from time to time. These documents are available on the Investors page of Molecular Partners’ website at www.molecularpartners.com. In addition, this presentation contains information relating to interim data as of the relevant data cutoff date, results of which may differ from topline results that may be obtained in the future. Any forward-looking statements speak only as of the date of this presentation and are based on information available to Molecular Partners as of the date of this release, and Molecular Partners assumes no obligation to, and does not intend to, update any forward-looking statements, whether as a result of new information, future events or otherwise. 2
Page 3
Molecular Partners at a Glance Extending the Boundaries of Targeted Cancer Therapies DARPin Designed Ankyrin Repeat Protein Target Our Pipeline: Patient Value • Differentiated Assets with focus in Oncology, • Targeted radiotherapy / MP0712 and next-gen immune cell engagers / MP0533 for patients across indications with high unmet medical need Our Company: MOLN • Clinical-stage biotech company pioneering DARPin therapeutics for patients • Operations & listing in Switzerland (SIX, 2014) and US (Nasdaq, 2021), founded 2004 • Well financed into 2027 through key value inflection points (CHF ~149 M*) Our Capabilities: Technology, Team, Collaborations • Proprietary DARPin Platforms, including Radio-DARPins and Switch / T cell engagers • Strong international team to execute up to clinical POC • Global partnerships to access technology & capabilities (Orano Med) 3*Financials as per December 31, 2024.
Page 4
r/r AML and AML/MDS CD33 x CD123 x CD70 x CD3 Advanced Solid Tumors FAP x CD40 Ovarian 212Pb - MSLN Solid Tumors SCLC & NECs 212Pb - DLL3 Pipeline RESEARCH PRE-CLINICAL PHASE 1 PHASE 2 PHASE 3 Radio-DARPin Therapy (RDT) CANDIDATEMODALITY MP0712 (DLL3) RDT x MSLN Undisclosed Programs MP0533 MP0317 HSCT cKit x CD16a x CD47 Co-development* Up to 8 programs* CD3 x costim x TAAs *The co-development agreement with Orano Med includes up to 10 RDT programs, including MP0712. AML, acute myeloid leukemia; DLL3, Delta-like ligand 3; HSCT, hematopoietic stem cell transplant; MDS, myelodysplastic syndrome; MSLN, mesothelin; NET, neuroendocrine cancer; r/r, relapsed/refractory; SCLC, small cell lung cancer; TAA, tumor-associated antigen. Co-development* Next-Gen Immune Cell Engagers MP0621 (Switch-DARPin) Switch-DARPin T Cell Engager 4
Page 5
The DARPin Modality and Molecular Partners’ Strategy • New class of therapeutics: Designed Ankyrin Repeat Proteins (DARPins) • DARPins close the gap between small molecules and antibodies • 7 clinical-stage compounds, >2500 patients treated What we invented • Unique DARPin solutions, not addressable by antibody designs • Demonstrate true patient value with early clinical readouts • Combine our capabilities with world-class partners 15 kDa 150 kDa DARPin Antibody Multi-DARPin How we apply it 5
Page 6
Our Lead Programs & DARPin Platforms to Build Therapeutics MP0533 & Next-Gen Immune Cell Engagers MP0712 & Radio-DARPin Therapy MALIGNANT CELL T CELL MEDIATED KILLING RADIOACTIVITY- MEDIATED DNA DAMAGE SOLID TUMOR CELLS 6
Page 7
MP0712 & Radio-DARPin Therapy Custom-engineered to create vectors ideal for radiopharmaceuticals
Page 8
MP0712, the first 212Pb-DLL3 Targeted Radiotherapeutic for SCLC SCLC: critical unmet need, limited treatment options • Median progression free survival (mPFS) ~3 months1,2 • 5y overall survival (OS) ~3%1,2 DLL3: a validated target for SCLC • Expressed in >85% of SCLC patients3 and in neuroendocrine cancers • No expression in healthy tissues • Tarlatamab4, approved DLL3 targeting drug (T cell engager) – ORR ~40%, DOR 9.7 months, PFS 4.3 months MP0712: targeted delivery of alpha radiation with 212Pb • DLL3 DARPin optimized for selective delivery of payload to tumor • 212Pb payload: high energy alpha emissions in short time frame, works with low target copy number • Potential for combinations with immunotherapy MP0712 product composition 1.Treatment of refractory and relapsed small cell lung cancer, UpToDate; 2. SEER; 3. Rojo et al., Lung Cancer 2020; 4. Phase 2 DeLLphi-301 study (NCT05060016). DOR, duration of response; HLE, half-life extension; ORR, overall response rate; SCLC, small cell lung cancer. + αDLL3 DARPin 212Pb Albumin binding HLE 8
Page 9
MP0712: Potent Efficacy at Clinically-Relevant Dose Efficacy study in NCI-H82 s.c. tumor model / MP0712 and negative control injected 4 x 10μCi at 0.01mg/kg or 8 x 5μCi at 0.01mg/kg every 1; 10 μCi = 370 kBq • MP0712 reached T:K ratios > 2 in mouse model matching clinically relevant DLL3 expression levels • MP0712 induces complete and durable tumor regression in NCI-H82 tumor model at 10µCi injected every week 0 10 20 30 40 50 60 70 80 0 500 1000 1500 2000 Days since cell injection Tumor Volume (mm3) average ± SEM MP0712 (4x10µCi) MP0712 (8x5µCi) Negative control (4x10µCi) Buffer Steiner et al, TRP 2024 (oral presentation) 9 Mice xenografted i.v. with NCI-H82 tumor cells NCI-H82 tumors hDLL3-MC38 tumors Human SCLC tumors DLL3 expression & distribution by IHC NCI-H82 i.v. mouse model: 212Pb-DOTAM-DARPin - single injection - dose : 10 µCi (0.01 mg/kg) Croset et al, EANM 2024 (oral presentation) Lizak et al, SNMMI 2024 (oral presentation)
Page 10
Phase 2s • 1–2L combination with IO SCLC • PoC in NEPC patients Outline of MP0712 Clinical Development Strategy • Patients: Focus on Small Cell Lung Cancer (SCLC), secondly on Neuro Endocrine Prostrate (NEPC) • Imaging and dosimetry on-going, initial data* expected by YE 2025 • Phase 1 study to start in H2 2025, initial safety and efficacy data in 2026 Registration study 2L+ SCLC patients PHASE 1/2a STUDY RP2D, recommended phase 2 dose; YE, year-end. 10 Phase 1: 212Pb Dose Escalation, Main objective: Safety, RP2D; N = 15–20 patients Phase 1 includes an imaging and dosimetry step with 203Pb Phase 2a – Dose Expansion and PoC – SCLC+NEC; Main objective: Efficacy signals, confirm RP2D; N = 30 patients *Molecular Partners has received and accepted a request from Nuclear Medicine Research Infrastructure (NuMeRI) in South Africa to provide MP0712 for imaging use under the legal framework in South Africa for compassionate care (also referred to as Section 21 of the Medicines and Related Substances Act). This approach enables the generation of first images applying MP0712 labelled with 203Pb in patients with SCLC. While the decision of where and how to share data from the image work under Section 21 remains at the discretion of NuMeRI, the Company anticipates providing an update on MP0712 in H2 2025.
Page 11
212Pb x MSLN Targeted Radio-DARPin for Ovarian Cancer Combining distinctive DARPin features with the power of 212Pb for next-gen targeted alpha therapy Ovarian Cancer (OC): high medical need and marginal progress • > 50% patients die within 5y post-diagnosis (diagnosis often in late stage) • Poor treatment options: ~80% recurrence rate post 1L chemo, limited 2L options (FR-alpha targeted Tx relevant for only 40% patients) Mesothelin (MSLN): a promising target for OC as 1st indication • Highly expressed in OC (>80% prevalence), expression maintained in metastases • Shed MSLN detected in serum of OC patients, might limit efficacy of MSLN- targeted therapies1,2,3,4 (e.g., CAR T/NK, ADC, TCE in development) RDT x MSLN: targeted delivery of alpha radiation with 212Pb • MSLN DARPin targets membrane-proximal epitope (and not shed MSLN) • 212Pb payload: high energy alpha emissions in short time frame • Potential for combinations with immunotherapy (incl. next-gen TCEs) 1. Awuah et al. 2016; 2..Zhang et al. 2011; 3.Smith et al. 2024 (ASCO poster); 4.Pastan et al, 2024. 11 Product composition αMSLN DARPin 212Pb HLE Tumor cell Shed MSLN Membrane-proximal epitope Full-length MSLN cleavage +
Page 12
DARPin activity is maintained despite shed MSLN Tumor cell Shed MSLN Membrane-proximal epitope Full-length MSLN cleavage “Distal” DARPin “Proximal” DARPin 10-1 101 102 103 104 0 20 40 60 80 100 OVCAR-8 Cell binding competition assay 100nM DARPin with increasing concentration of shed MSLN shed MSLN [nM] Normalized binding (%) 0 Proximal DARPin Distal DARPin Binding maintained in presence of shed MSLN Binding inhibited in presence of shed MSLN 12 Preclinical update on MSLN at AACR 2025
Page 13
Global Partnership to Develop 212Pb Radio-DARPin Therapeutics Combining DARPin versatility with the power of 212Pb for next-gen Targeted Alpha Therapy 13 4 Radio-DARPin programs 50:50 cost and share split 4 MP-owned programs 2 MP-owned programs with opt-in option for OM for 50:50 cost:share split Pipeline of Ten 212Pb Radiotherapy products MP0712 (212Pb x DLL3) 212Pb x MSLN TEXAS, US: Preclinical development GMP supply for early clinical phases INDIANA, US: Industrial scale manufacturing Global shipping hub ATLab US FRANCE: 212Pb starting material ATLab Europe SWITZERLAND: Preclinical assessment DARPin engine, fast & high throughput World class technologies & capabilities combined MOLECULAR PARTNERS PIONEERS of DARPIN THERAPEUTICS ORANO MED PIONEERS of TARGETED ALPHA THERAPY FULL VALUE CHAIN PARTNERSHIP 1 2 3 4 5 6 7 8 9 10 212PbDARPin
Page 14
DARPin: IDEAL VECTOR FOR RADIOPHARMACEUTICALS • Proven selective targeting • High affinity, tumor retention • Broad target space • Small size Radio-DARPins as Versatile Therapeutic Candidates Combining versatile DARPin features with the power of 212Pb for next-gen Targeted Alpha Therapy + HLE 212Pb: ALPHA-EMITTING THERAPEUTIC ISOTOPE • Proven clinical efficacy • Fast & high energy deposition • Safe profile • Ideal waste management LINKER & CHELATOR • Established DOTAM SURFACE ENGINEERING • High stability • Reduce kidney accumulation HALF-LIFE EXTENDER • Half-life tuning • Promote tumor uptake 14
Page 15
Orano Med – Pioneer of Targeted Alpha Therapy 1. Zimmermann, J Nucl Med, 2023. 2. Li et al., Materials 2021. Targeted Alpha Therapy with 212Pb: • Alpha therapy: • High cytotoxicity: DNA double-strand break, high energy deposition, no need for receptor internalization • Targeted effect: short range of action with potential to target microlesions, less impact on healthy tissues • Lead-212 (212Pb): • Short-half life (~11h): out-patient administration, easy waste management, high-dose rate, flexible dosing • Clean decay with single alpha emission and effective chelating agent, limiting circulation of free daughter isotopes Orano Med as Pioneer of 212Pb Targeted Alpha Therapy: • Unique, independent supply of 212Pb as alpha emitting therapeutic isotope • Large scale GMP manufacturing capabilities • Fully integrated research and preclinical development platform • Clinical capabilities demonstrated with 212Pb and lead program AlphaMedixTM, outlicensed to Sanofi in Sept 2024, in Phase 2 • Strong collaboration partner with MP since early 2023 Decay chain of 212Pb [2] 15
Page 16
16 MP0533 Tetra-specific T-cell Engager for AML
Page 17
17 MP0533 Enables Avidity-Driven Selective Killing of AML Cells • MP0533 designed to induce T cell-mediated killing preferentially when 2 or 3 AML-associated antigens are co-expressed • Potential to kill all AML cells (blasts and LSCs) despite heterogeneity, ensuring long-term disease control MP0533: avidity-driven selectivity and T cell-mediated killing • AML bears a high risk of relapse due to persistent LSCs • AML cell population is heterogeneous → differentiation from healthy cells (e.g., HSCs) feasible through their co-expression of CD33, CD123, CD70 HSA Half-life extender HSA CD33 Target localizers CD123 CD70 CD3 Immune activator AML cells Healthy cells AML cellHealthy cell killing AML, acute myeloid leukemia; HSC, hematopoietic stem cell; HSA, human serum albumin; LSC, leukemic stem cells. AML-associated antigens are also expressed on healthy cells T cell T cell HSA CD33 CD123 CD70 HSA
Page 18
18 MP0533 Phase 1/2a Study in Patients with R/R AML/MDS Protocol amendment to optimize MP0533 exposure ADA, anti-drug antibody; DR, dose regimen. Amended Dosing SchemeInitial Protocol Dose Escalation (DR 1–7) • Limited clinical activity • Target-mediated drug disposition (TMDD) = low exposure • Loss of exposure (LoE) in some patients (ADA) Intermediate densification (DR 8) • Additional Day 12 dose allows steeper & faster dose escalation (step-up-dosing), addressing TMDD Further dose densification (DR 9–10) • High dose frequency for 1st cycle • Premedication for LoE mitigation
Page 19
19 DR 5 DR 6 DR 2 DR 3 DR 4 DR 1 DR 7 Data cut-off: 16 December 2024 Preliminary data as study is ongoing, subject to final data validation. 1. Döhner et al. Blood 2022;140(12)1345-77. CR, complete response; CRi, CR with incomplete hematologic recovery; ELN, European LeukemiaNet; MLFS, morphologic leukemia-free state. MP0533 Administration Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 MP0533 Treatment and Clinical Response DR 8 MDS / AML MDS / AML MDS / AML MDS / AML AML AML AML AML AML AML MP0533 Administration Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 DR 1–7: 4 responders reported, manageable safety DR 8: 3 responders and manageable safety reported to-date, evaluation on-going DR 9+ (further dose densification): update in 2025 Arrows at the top indicate MP0533 administration at D1, D5, D8, D12 (DR 8 only), D15 and weekly thereafter Step-up dosing at DR 1–7 D12 dose at DR 8 Color changes in grey: start of a new 28-day cycle Response (2022 ELN1) was assessed every 4 weeks until disease progression and results are presented as: CR CRi MLFS No ELN response Patients with ongoing treatment at data cut-off Patients who discontinued treatment Legend Dose Escalation (DR 1–7) Intermediate densification (DR 8) AML MDS / AML MDS / AML MDS / AML MDS / AML MDS / AML MDS / AML MDS / AML MDS / AML MDS / AML MDS / AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML AML 0 1 mo 4 mo 5 mo Time (mo)2 mo 3 mo 0 1 mo 4 mo 5 mo Time (mo)2 mo 3 mo
Page 20
20 Blasts at Screening Low (<20% Blast) High (>=20% Blast) Cohort Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 Cohort 8 Best Response Complete Remission (CR) CR with incomplete hematologic recovery (CRi) Morphologic leukemia-free state (MLFS) 550 600 CR MLFS CRi CR CRi MLFS MLFS 50% -50% -150 -100 -50 0 50 100 150 Best relative change from baseline in BM blasts [%] Encouraging Blast Reduction Observed, Particularly in Patients with Lower Disease Burden at Baseline* *Lower disease burden defined as patients with baseline blast <20% in bone marrow. BM, bone marrow. Data cut-off: 16 Dec 2024; cohort 8 ongoing. ➢ Improved response rate and depth observed to-date in Cohort 8
Page 21
21 Improved MP0533 exposure at DR 8 with steeper and denser step-up dosing regimen C1D12 n=4 n=4 n=2 n=4 n=6 Predicted therapeutic range Overlay of DR6 and DR8 geometric mean Cycle 1 –– DR 6 –– DR 8 n = number of evaluable patients at data cut-off.Data cut-off: 3 December 2024 Preliminary data as study is ongoing, subject to final data validation.
Page 22
22 MP0533 Phase 1/2a Study in Patients with R/R AML/MDS Protocol amendment to optimize MP0533 exposure Objectives of protocol amendment: • To improve the exposure profile of MP0533 in patients • To increase the rate, depth and duration of clinical responses How: • Dose densification may overcome target-mediated drug disposition (TMDD) • Premedication with B cell depleting agent may mitigate loss of exposure (LoE) Outlook: • Full DR 8 clinical data at EHA 2025 • Initial data from DR 9 in H2 2025 DR, dose regimen. Amended Dosing Scheme Intermediate densification (DR 8) • Additional Day 12 dose allows steeper & faster dose escalation (step-up-dosing), addressing TMDD Further dose densification (DR 9–10) • High dose frequency for 1st cycle • Premedication for LoE mitigation
Page 23
23 Switch-DARPin Platform Next-generation T cell engagers
Page 24
24 Binding to TAAs releases CD3 Switch-DARPin CD3 DARPin masked by 2-in-1 Switch in absence of TAAs OFF ON Immune cell-mediated killing CD3 Switch-DARPin for Next-gen TCEs with Enhanced Function Tackling current limitations of TCEs in solid tumors Healthy Cell EpCAM (TAA 1) α-CD3 MSLN (TAA 2) CD3 CD2 (co-stim) T-Cell Killing TumorT-Cell CD3 CD2 MSLN No immune cell engagement ➢ TCE is silent and inactive in circulation ➢ TCE is activated to kill the tumor cell ➢ TCE is stimulated (no exhaustion) TAA, tumor associated antigen; TCE, T cell engager. Preclinical update on CD3 Switch T cell engager at AACR 2025
Page 25
25 Outlook
Page 26
26 2025 Outlook and Upcoming Milestones Switch-DARPin • MSLN preclinical update at AACR 2025, therapeutic candidate selection • Additional 212Pb x RDT programs nominated, in collaboration with Orano Med • First-in-Human studies to start in 2025 (Phase 1) • Initial clinical data by end 2025 (imaging & dosimetry) • Initial efficacy and safety data in H1 2026 CHF ~131 million cash* (incl. short-term time deposits) ensures funding well into 2027 *Financials as per March 31, 2025. IND, investigational new drug. MP0533 MP0712 • Comprehensive clinical data from Phase 1 cohort 8 at EHA 2025 • Protocol implementation of improved dosing regime, H1 2025 • Data from additional cohorts on amended dosing scheme in H2 2025 Radio-DARPin Therapy (RDT) • Preclinical update on CD3 Switch T cell engager at AACR 2025 • Evaluation of partnering opportunities with Switch platform, including MP0621 (cKit) & T-cells
Page 27
Twenty Years of Pioneering DARPin Therapeutics for Patients Thank You