Molecular Partners Ag · SIX:MOLN
Molecular Partners — Investor Day (December 2021)
105 slides from Molecular Partners's investor day presentation, Dec 15, 2021
Slide 1: Custom Built Biology for Patients – Oncology Day 2021
Custom Built Biology for Patients 1 Oncology Day 2021 Molecular P artners A G, S witzerland (SIX: MOLN)
Slide 2: Disclaimer
This presentation is not an offer to sell or a solicitation of offers to purchase or subscribe for shares of Molecular Partners AG, nor shall it or any part of it nor the fact of its distribution form the basis of, or be relied on in connection with, any contract or investment decision. This present
Slide 3: R&D Day Speakers (and Intro to Agenda)
R&D Day Speakers (and Intro to Agenda) Patrick Amstutz, PhD Chief Executive Officer, Molecular Partners Michael Stumpp, PhD Chief Operating Officer, Molecular Partners Daniel Steiner, PhD SVP Research, Molecular Partners Anne Goubier, DVM, PhD VP Biology, Molecular Partners Prof. Adrian Ochsenbein,
Slide 4: Pioneering DARPin Therapies to Transform Lives
Pioneering DARPin Therapies to Transform Lives 4 Overview: Pa t ri c k Amstu t z
Slide 5: 2021 in Review: Corporate & Portfolio Growth
2021 in Review: Corporate & Portfolio Growth • Ensovibep (Covid) from Phase 1 to POC data imminent • Activity on all variants of concern, to date • MP0317 (FAP x CD40) into Phase 1 • Initial data anticipated in H2 2022 • Nomination of MP0533 for the treatment of AML • ASH poster; Bern collaboration;
Slide 6: DARPins: A Unique Class of Biologics
DARPins: A Unique Class of Biologics 15 kDa 15 0 k Da Binding regions / specificities MONOCLONAL ANTIBODIES • High affinity and specificity • Large size: 150 kDa • Complex architecture; 4 proteins with 12 domains • Long half - life • Good safety & low immunogenic potential • High affinity and specif
Slide 7: Pipeline
7 Pipeline Oncolo g y Discovery Oncology Op ht halmolo g y Infectious disease Pipeline CANDIDATE / FOCUS RESEARCH PRECLINICAL PHASE 1 PHASE 2 PHASE 3 RIGHTS Ensovibep – Covid Next Gen Covid Covid ambulatory – Empathy Future VoC* AMG506 / MP0310 FAP x 4 - 1BB Solid tumors MP0317 FAP x CD40 Solid tumo
Slide 8: MP Strategy – Building on our Strengths
MP Strategy – Building on our Strengths Our candidates’ design aims to directly change the course of disease biology and allow testing in a model with high translatable value We aim to drive true patient value with early clinical read - outs We leverage the advantages of the DARPin technology to pro
Slide 9: Local Agonists in Oncology: MP0310 & MP0317
Local Agonists in Oncology: MP0310 (FAPx4 - 1BB) & MP0317 (FAPxCD40) • Tumor local activation of immune cells • Wider therapeutic window for combinations • Multi - specific DARPin leading to clustering upon co - engagement • MP0310: Amgen, MP0317: not partnered TECHNOLOGY TARGET PATIENTS BIOLOGY Ear
Slide 10: Targeting Leukemic Stem Cell in AML: MP0533
Targeting Leukemic Stem Cell in AML: MP0533 (CD33+CD70+CD123 x CD3) • Avidity driven targeting of leukemic stem cells • Long - term control of AML • Tri - specific T - Cell engager with optimized binding affinities and geometry • University of Bern – Profs. Ochsenbein and Riether TECHNOLOGY TARGET P
Slide 11: DARPin Radio-Ligand Therapy, DARPin-Drug-Conjugates
DARPin Radio - Ligand Therapy , DARPin - Drug - Conjugates • Deep tumor penetration, low systemic exposure with high - tox payload • Deep response in hard - to - treat tumors • Small sized DARPin with high affinity coupled to a highly toxic payload (radio ligand) Novartis, a leader in the field of R
Slide 12: Pipeline
Pipeline CANDIDATE / FOCUS RESEARCH PHASE 2 PHASE 3 R IG HT S Ensovibep – Covid Next Gen Covid 12 Pipeline Oncolo g y Discovery Oncology Op ht halmolo g y Infectious disease PRECLINICAL PHASE 1 Covid ambulatory – Empathy Future VoC* AMG506 / MP0310 FAP x 4 - 1BB Solid tumors MP0317 FAP x CD40 Solid
Slide 13: Abicipar – what's next?
Abicipar – what's next? 13
Slide 14: Abicipar: Phase 3 Asset, Reviewing Data from AbbVie
Abicipar: Phase 3 Asset, Reviewing Data from AbbVie DARPin Advantage Target Patient Disease Biology Milestones • Growth/leakage of abnormal blood vessels beneath the retina • VEGF - A has been found to be a key molecule in numerous retinal diseases • VEGF - A inhibition has been established as a hig
Slide 15: CEDAR & SEQUOIA Phase 3 using OCT as biomarker
CEDAR & SEQUOIA Phase 3 using OCT as biomarker • Abicipar as effective as Lucentis • 10 injections instead of 25 (2 y) • Fixed Q12w regimen proven • Potential to simplify visits • OCT - ocular coherence tomography, a method to measure the thickness of the retina 15
Slide 16: Reducing Intraocular Inflammation (IOI)
Reducing Intraocular Inflammation (IOI) • CEDAR/SEQUOIA (Phase 3) • Much less IOI in 2 nd year (as Lucentis) • MAPLE (Phase 2, improved purity) • lower severity of IOI reported 16
Slide 17: Type of Syringe Identified as Likely IOI Contributor
Type of Syringe Identified as Likely IOI Contributor in vivo Ophthalmic - use 17
Slide 18: Abicipar Conclusions and Next Steps
Abicipar Conclusions and Next Steps 18 • Increase benefit/risk ratio to address CRL • Plan to discuss with FDA in Q1/2022 • Establish precise need for additional clinical data/study • Further our understanding of potential timelines for re - submission • If proposals are feasible, discuss partnershi
Slide 19: Our Platform and future products
Our Platform and future products 19 Daniel Steiner
Slide 20: MP Strategy – building on our Strengths
MP Strategy – building on our Strengths We strive to collaborate with the best scientists and clinicians in the field from ideation to clinical trials Our candidates’ design aims to directly change the course of disease biology and allow testing in a model with high translatable value We aim to driv
Slide 21: DARPins: The Core of our Drug Engine
DARPins: The Core of our Drug Engine Small size (15 kDa) DARPin KEY PROPERTIES Target p r o tein DAR Pin DARPin ADVANTAGE » Deep tissue penetration » High molar concentration » Turn - key multispecifics » Easy coupling of payloads » Ultra - high binding affinity and selectivity Rigid protein scaffol
Slide 22: Our Platform in Action: Creating Ensovibep
Our Platform in Action: Creating Ensovibep Isolation of 380 neutralizing anti - COVID mono - DARPin Generation of >100 tri - specific DARPin Candidates Functional screening and identification of Ensovibep WEEKS – 0 1 2 3 6 22
Slide 23: Creating MP0533: Unique Avidity-Driven Tumor Selectivity
Creating MP0533: Unique Avidity - Driven Tumor Selectivity • The problem: Address AML tumor heterogeneity and reduce impact on healthy cells • The solution: DARPin platform allows to rapidly screen & iterate 100s of tri - specific T cell engagers to find the potency – selectivity – heterogeneity swe
Slide 24: Multi-DARPins Offering a Broad Spectrum of Unique Solutions
Multi - DARPins are Offering a Broad Spectrum of Unique Solutions Multispecificity enabled possibilities Conditional activation Ensovibep High affinity for deep SARS - Cov - 2 inhibition and prevention of escape MP0310 & MP0317 Tumor localized clustering to activate effector cells in tumor only Immu
Slide 25: Conditional Activation to Unlock full Potential of Potent Effectors
Conditional Activation to Unlock full Potential of Potent Effectors Target binding activated Switch DARPin T - cell engager Tumor protease - activated ProDrug T - cell engager • Local activation via target “X” binding • No need for protease cleavage AACR 2021 • Local activation via protease cleavage
Slide 26: Expanding Multi-DARPins by Programming of Highly Potent Effectors
Expanding Multi - DARPins by Programming of Highly Potent Effectors Multispecificity enabled possibilities Conditional activation Delivery Vectors “radical simplicity” Ensovibep High affinity for deep SARS - Cov - 2 inhibition and prevention of escape MP0310 & MP0317 Tumor localized clustering to ac
Slide 27: Challenges of Standard Delivery Vectors of Potent Payloads
Challenges of Standard Delivery Vectors of Potent Payloads mAB Peptide Size 150 kDa 1 - 2 kDa Affinity high (bivalent) low Specificity high limited High tumor load » concentration at site of action + + Deep tumor penetration » access site of action - + Long tumor retention » maintenance at site of a
Slide 28: Mono-DARPins as Ideal Delivery Vectors for Potent Payloads
Mono - DARPins as Ideal Delivery Vectors for Potent Payloads Efficient tumor targeting with limited systemic exposure t um or D r ug infusion I n f u sion s t opped Small size (15 kDa) fast extravasation & deep tumor penetration Small size (15 kDa) rapid systemic clearance High affinity (< 50 pM) lo
Slide 29: Applying our DARPin Advantages to Address Disease Biology
Multispecificity enabled possibilities Conditional activation Delivery Vectors “radical simplicity” RLT & DDC Small size – ultra high affinity for efficient delivery with limited systemic exposure Applying our DARPin Advantages to Address Disease Biology Ensovibep High affinity for deep SARS - Cov -
Slide 30: Clinical Progress MP0310 & MP0317
Clinical Progress 30 MP0310 & MP0317 Nicolas Leupin
Slide 31: MP Strategy – Building on our Strengths
MP Strategy – Building on our Strengths Our candidates’ design aims to directly change the course of disease biology and allow testing in a model with high translatable value We aim to drive true patient value with early clinical read - outs We leverage the advantages of the DARPin technology to pro
Slide 32: What We Achieved in 2021 – a Very Challenging & Successful Year
• >900 patients dosed across all clinical programs, a new "record" for MP • Ensovibep, MP0310, and MP0317 all progressing well • Thousands of clinical samples analyzed, despite logistical challenges • Both in house and at external providers • ~15 clinical batches produced at various scales (up to >1
Slide 33: Toxicity of 4-1BB & CD40 Antibodies Has Limited Their Activity
Activated APC Toxicity of 4 - 1BB & CD40 Antibodies Has So Far Limited Their Activity CRS Liver To x icity Activated APC Re st i ng APC Tumor S t roma DARPin advantage: Increasing therapeutic window via a tumor - localized approach Systemic activation of immune cells leads to toxicity that limit tre
Slide 34: AMG 506 / MP0310: Localized Activation of 4-1BB
AMG 506 / MP0310: Localized Activation of 4 - 1BB • Patients with solid tumors, low T - cell tumor penetration and positive FAP expression • Patient populations where there are T - cell engagers in development, that can be boosted • Many solid tumors are surrounded by dense stromal tissue in which F
Slide 35: FAP – an Ideal Target for Tumor-localized Activity
FAP – an Ideal Target for Tumor - localized Activity • FAP is expressed on activated cancer associated fibroblasts (CAFs) • Overexpression in the stroma of many solid tumors • Limited expression in normal adult tissues MP0310 (FAP - 4 - 1BB) Phase 1 human biopsy samples FAP is a clinically validated
Slide 36: PD Activity in Paired Biopsies Supports MP0310 MoA
Baseline Post (C1D15) Time point Signature score (log2) 2 3 4 5 6 CD 8 T Cells Cytotoxicity IFN Gamma NK Cells T Ce lls TH1 Cells PD Activity in Paired Biopsies Supports AMG 506 / MP0310 MoA on 4 - 1BB Activation BLOOD TUM O R • In the blood, immune cells remain inactive (CD8 + & CD4 + T - cells, Tr
Slide 37: Objectives of MP0310-CP101 Study
Objectives of MP0310 - CP101 Study Primary Objectives • To define the safety and tolerability of MP0310 as monotherapy (with or without rituximab pre - treatment) in patients with advanced solid tumors • To determine the maximum tolerated dose ( MTD ) AND recommended expansion dose ( RED ) for MP031
Slide 38: MP
MP 0 3 1 7 38
Slide 39: MP0317: Localized Activation of CD40
MP0317: Localized Activation of CD40 • Solid tumor patients with positive FAP expression • Many patients still fail to benefit from current immunotherapy options, or relapse • CD40 is a potent activator of dendritic cells, macrophages, and B cells, and has long been considered an attractive immunoth
Slide 40: Competitive Environment is Favorable for MP0317
Competitive Environment is Favorable for MP0317 Phase II Localized effect w/in Immune system Non - localized approaches, mAB In v i tro In vivo Translational Preclinical Phase I APX005 / sotigalimab (IgG1) 13x ph1 & ph2 RP2D: 0.3 mg/kg (latest CRC neoadj, MEL 2 admin schedules, MEL +PD1+CTLA4) YH003
Slide 41: CD40 Biology and Therapeutic Potential
Can cer Cells Neutrophil CD8+ T - Cell B Cel l Dendriti c Cell M ac roph a ge CD40 Biology and Therapeutic Potential • Cell surface receptor member of the TNFRSF • Expressed broadly on Antigen Presenting Cells (B cells, DC and macrophages) as well as many non - immune cells and a range of tumors • C
Slide 42: MP0317 Activates all APCs in a FAP-dependent Manner in vitro
MP0317 Activates all APCs in a FAP - dependent Manner in vitro anti - human CD40 mAb FAPxCD40 DARPin® - FAP FAPxCD40 DARPin® + FAP MFI CD86 20000 15000 10000 5000 10 - 4 10 - 3 10 - 2 10 - 1 10 0 10 1 10 2 concentration (nM) Monocytes + IL - 4 + GM - CSF DC 6000 40 30 20 10 TNFα (pg/ml) +FAP - F AP
Slide 43: MP0317: Localizes to MC38-FAP Tumors
0 50 40 30 20 10 Time after compound injection (h) % ID/ g mFAP x mCD40 0 50 40 30 20 10 50 µm 50 µm CTRL DARPin ® mFAP x mCD40 Published at AACR 2020 43 DARPin detection in the tumor by IHC SPECT - CT study 4 24 48 72 96 4 24 48 72 96 CTR DARPin Binding HSA but not FAP and CD40 % ID/ g 4 24 48 72 9
Slide 44: MP0317 Shows Therapeutic Activity without Cytokine Release
MC38 - FAP Colorectal cancer Time after tumor inoculation (days) Tumor growth (mm 3 ) MP0317 Shows Therapeutic Activity without Cytokine Release Efficacy Peripheral cytokine release Vehicle Neg. CTRL* mFAP x mCD40 mCD40 Ab Published at AACR 2020 44
Slide 45: ex vivo: mFAPxCD40 Activates DC in the TME
e x - vivo : m F APxCD40 Activates DC i n t he TME CD86 on CD11c (MFI) CD54 on CD11c (MFI) 400000 300000 200000 100000 0 LN Tumor • Upregulation of co - stimulatory molecules on tumor Dendritic cells potential for better T cell activation • Higher activity in Tumor vs LN, in contrast to aCD40 Pres
Slide 46: mFAPxCD40 Increased CD8 T cell Infiltrate in the TME
mFAPxCD40 Increased CD8 T cell Infiltrate in the TME 0 5 1 0 1 5 % CD8+ T cells within total cells Anti - tumor activity Presented at ESMO - IO 2021 46
Slide 47: FAP Expression in Human Tumor Allows CD40 Mediated Immune Activation
FAP Expression in Human Tumor Allows CD40 Mediated Immune Activation a - C D40 mAb CD 16 3 ↓ CD 8 0 ↑ Δ MF I CD 54 Δ M FI Δ MFI B cell activation - CD54 Macrophage repolarisation – inflammatory phenotype (CD80hi CD163lo) MP0317 x Macrophage repolarization is further supported by in vitro data 10 - 2
Slide 48: MP0317-CP101 Biomarker and Safety Trial Design
48 MP0317 - CP101 Biomarker and Safety Trial Design Dose x6 x5 x4 x3 x2 x1 1 - 3pts 1 - 3pts 3 - 6pts 3 - 6 p ts 3 - 6pts 3 - 6pts 15pts Dose - Escalation MP0317 Monotherapy Expansion MP0317 Monotherapy T ime Next recommended dose level A d v anced solid tumors Obj ectives : • Safety • Local activit
Slide 49: Identification and Screening of Potential Tumor Targets from MP0317
Identification and Screening of Potential Tumor Targets from MP0317 • The tumor immune score is correlated to response to aPD1. The FAP threshold is 20% > 2/3 score. + F AP CD40 49
Slide 50: CD40 Open for Multiple Combination Therapies
CD40 Open for Multiple Combination (IO or Other) Tumor • Direct tumor killing • Release of tumor antigens • Debulking aids immune cell access • Timing with immunotherapy is important because immune cells can also be damaged PD - 1 or other IO Therapy T c Tumor • Removes suppression of T - cell respo
Slide 51: Conclusions: Highly Differentiated Multi-Specific IO Assets
Conclusions: Highly Differentiated Multi - Specific IO Assets 51 • Localized activity achieved with MP0310/AMG 506 • No systemic immune activation observed • Tumor local immune stimulation confirmed after 1 st dose • FAP “validated” as target in the TME of many solid tumors for DARPin IO agonists •
Slide 52: AML & MP0533
AML & MP0533 52 Prof. Adrian Ochsenbein, University Hospital Bern Prof. Carsten Riether, University Hospital Bern Dr. Anne Goubier, Molecular Partners
Slide 53: Speaker Biographies
Universitätsklinik für Medizinische Onkologie, Inselspital Bern Prof. Carsten Riether, PhD Head of Research Department Medical Oncology, Inselspital, University Hospital Bern • PhD in Immunology, ETH Zurich • Post - doc in Tumorimmunology in the lab of Prof. A. F. Ochsenbein, University of Bern • Re
Slide 54: RD Day Molecular Partners
RD Day Molecular Partners Adrian Ochsenbein / Carsten Riether
Slide 55: Disclosures
Disclosures Molecular Partners: consultancy Argenx: research funding, consultancy, royalties Universitätsklinik für Medizinische Onkologie, Inselspital Bern
Slide 56: AML: Deadly Disease for About Half of the Patients
AML: Deadly Disease for About Half of the Patients 19,940 patients diagnosed 11,180 patients died US 2020 Patient are either cured or die within 1 - 2 y ea r s ( r api d , a g g r essi v e relapses) unmet need to cure more patients or s u b s t a n tially del a y the relapses MRD+ is driver of relap
Slide 57: AML is a Heterogeneous Disease
Grimwade et al., Blood 2010 AML is a Heterogeneous Disease Universitätsklinik für Medizinische Onkologie, Inselspital Bern
Slide 58: Pathogenesis and Biology of AML
Pathogenesis and Biology of AML Patel, et al., NEJM 2012; TCGA NEJM 2013. 200 clinically annotated cases 23 genes commonly mutated 237 genes mutated in 2 or more cases
Slide 59: 2017 European Leukemia Net Stratification by Genetics
2017 European Leukemia Net Stratification by Genetics Döhner et al. Blood 2017;129:424 - 447. Ge n etic R isk Group Subset Favorable • t(8;21)(q22;q22); RUNX1 - RUNX1T1 • inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB - MYH11 • Mutated NPM1 without FLT3 - ITD (normal karyotype) • Bialleli c m u t a
Slide 60: Treatment for AML patients
Treatment for AML patients Universitätsklinik für Medizinische Onkologie, Inselspital Bern curative intention palliative intention Induction Induction ? « 3 +7» • hypomethylating agents (HMA) • + BCL 2 inhibitor venetoclax Further consolidation or autologous HSCT Allogeneic HSCT
Slide 61: Treatment for AML patients
Treatment for AML patients Universitätsklinik für Medizinische Onkologie, Inselspital Bern curative intention palliative intention Induction Induction ? « 3 +7» • hypomethylating agents (HMA) • + BCL 2 inhibitor venetoclax Further consolidation or autologous HSCT Allogeneic HSCT
Slide 62: History of FDA approved AML therapy
Universitätsklinik für Medizinische Onkologie, Inselspital Bern History of FDA approved AML therapy 2020 2018 Sept. 2020 Azacitidine (maintenance) Nov. 2018 Gilteritinib, V eneto c l a x , Glasdejib July 2018 Ivosidenib 2017 Aug./Sept 2017 Gemtuzumab ozga m ici n , C P X - 351, Enasidenib Apr. 2017
Slide 63: CD33 and CD123 as single therapeutic targets in AML
Universitätsklinik für Medizinische Onkologie, Inselspital Bern CD33 and CD123 as single therapeutic targets in AML Expression: Treatment approaches: CD123 • on blasts and LSCs > 90% patients • on virtually all healthy myeloid and progenitor cells, megakaryocytes, B cell subsets as well as endotheli
Slide 64: CD70/CD27 signaling
Universitätsklinik für Medizinische Onkologie, Inselspital Bern activated lymphocytes dendritic cells MHC C D 70 C D 27 SS T CR B and T cells HSCs S S S S SS • proliferation • anti - apoptotic signals • effector function • memory function . CD70/CD27 signaling ..... .. induces T cell expansion and d
Slide 65: Elevated levels of soluble CD27 correlate with poor prognosis in AML
Universitätsklinik für Medizinische Onkologie, Inselspital Bern Elevated levels of soluble CD27 correlate with poor prognosis in AML Riether et al, J Exp Med 2017; 214:359 – 80 Parameter HR (95% CI) P - value sCD27 2.17 (1.34 – 3.50) 0.0016 Risk group 1.69 (1.29 – 2.38) 0.0024 Age 1.03 (1.01 – 1.05)
Slide 66: Cusatuzumab: Swimmer plot
Universitätsklinik für Medizinische Onkologie, Inselspital Bern Cusatuzumab: Swimmer plot T r an s plant 0 6 12 18 24 C usa tu z u ma b monotherapy EOT due to PD EOT due to AE EOT due to transplant Treatment duration (months) Ongoing Time to response PR CRi CR * Data cut - off: February 2019 PR = pa
Slide 67: Summary I
Universitätsklinik für Medizinische Onkologie, Inselspital Bern • CD70 has a unique expression pattern on activated immune cells and on AML LSCs • Blocking the CD70/CD27 signaling pathway eliminates LSCs • Treatment with HMA upregulates CD70 on LSCs • cusatuzumab monotherapy reduces AML blasts and L
Slide 68: Leukemia: a Paradigmatic Stem Cell Disease
Universitätsklinik für Medizinische Onkologie, Inselspital Bern Leukemia: a Paradigmatic Stem Cell Disease Bonnet et al. Nature Medicine 1997; 3, 730 - 737 • Self - renewing • Therapy - resistant • Quiescent Leukemia Stem Cells Bla s ts Unlimited r egene r a ti o n
Slide 69: Leukemic SC Numbers and Stem Cell Signatures are Negative Predictors
Universitätsklinik für Medizinische Onkologie, Inselspital Bern Leukemic SC Numbers and Stem Cell Signatures are negative Predictors for Survival in AML van Rhenen et al. Clin. Cancer Research 2005; 11:6520 – 6527 Pearce et al. Blood 2006; 107:1166 – 1173. Gentles et al. JAMA 2010; 304:2706 – 2715.
Slide 70: How Can We Study the Effect of a Treatment on LSCs?
Universitätsklinik für Medizinische Onkologie, Inselspital Bern How Can We Study the Effect of a Treatment on LSCs? 1. Colony formation assay (ex vivo) 2. Re - platings assays (ex vivo) 3. Gold - standard : Patient - derived xenograft model 4. Next - generation RNA sequencing analysis
Slide 71: Blockade of CD70/CD27 Signaling reduces Stem Cell Function
Universitätsklinik für Medizinische Onkologie, Inselspital Bern Blockade of CD70/CD27 Signaling reduces Stem Cell Function X αCD70 = F c - d i m i n i s h e d blocking version of cusatuzumab wi th o u t ADCC potential Riether et al. J Exp Med; 214, 359 - 380
Slide 72: Cusatuzumab kills leukemic stem cells
Universitätsklinik für Medizinische Onkologie, Inselspital Bern Cusatuzumab kills leukemic stem cells NCT0303 0 6 1 2 Mean > ***P<0.001 Stem cell frequency (fold change vs. diagnosis) Diagnosis Monotherapy Reduction in leukemic stem cell frequency : *** 1.0 0.8 0.6 0.4 0.2 0.0 Riether et al. Nat Med
Slide 73: Identification of Targets for the Treatment of AML Patients
Universitätsklinik für Medizinische Onkologie, Inselspital Bern Identification of Targets for the Treatment of AML Patients van Rhenen et al. Clin. Cancer Research 2005; 11:6520 – 6527 ; Pearce et al. Blood 2006; 107:1166 – 1173 ; Gentles et al. JAMA 2010; 304:2706 – 2715 ; Eppert et al. Nature Medi
Slide 74: CD33 and CD123 as single therapeutic targets in AML
Universitätsklinik für Medizinische Onkologie, Inselspital Bern CD33 and CD123 as single therapeutic targets in AML Expression: Treatment approaches: CD123 • on blasts and LSCs > 90% patients • on virtually all healthy myeloid and progenitor cells, megakaryocytes, B cell subsets as well as endotheli
Slide 75: MP0533 Reduces Colony Formation of Primary Human LSCs ex vivo
Universitätsklinik für Medizinische Onkologie, Inselspital Bern MP0533 Reduces Colony Formation of Primary Human LSCs ex vivo
Slide 76: Summary II
Universitätsklinik für Medizinische Onkologie, Inselspital Bern • Various targetable surface antigens in AML have been identified (e.g. CD33, CD123, CLL - 1, CD70). • Therapeutic approaches targeting most of these antigens have been shown to reduce leukemia burden and induce remission in a fraction
Slide 77: MP0533 – Anne Goubier
MOLECULAR partners MP0533 Anne Goubier
Slide 78: MP0533: Tri-specific T-cell Engager for AML
MP0533: Tri - specific T - cell Engager for AML DARPin Advantage Target Patient Disease Biology Expected Mi l e s to n es • FIH clinical studies in 2022 • Avidity driven multispecific DARPin, targeting 3 TAA's, engaging CD3 • T cell are activated only when 2 or more TAA's are bound • Should allow fo
Slide 79: Requisites for an Ideal AML Therapeutic Solution
Requisites for an Ideal AML Therapeutic Solution • An ideal AML therapeutic solution should: • Achieve control of the disease by eliminating LSCs • Cover tumor heterogeneity by targeting multiple antigens • Increase the therapeutic window: optimal dose levels with limited side effects • Limited kill
Slide 80: The DARPin Solution: a Trispecific CD3 Engager
The DARPin Solution: a Trispecific CD3 Engager DARPin For Specific killing of all LSCs and blasts via avidity - driven T cell engagement Minimal effect on healthy cells Single targets Low affinity engagement Efficient attack of heterogenous cancer cells CD3 engager : demonstrated potency in hematolo
Slide 81: CD33, CD123 & CD70: Optimal Targets to Maximize Efficacy and Selectivity
CD33, CD123 & CD70: Optimal Targets to Maximize Efficacy and Selectivity • Clinically validated targets • Co - expression pattern of CD70, CD33 and CD123 on LSCs and AML blasts • Differentiates LSCs and AML blasts from healthy cells optimal selectivity • Covers tumor heterogen e ity opti m al ef
Slide 82: CD123/CD70/CD33 co-expression differentiates LSCs and AML Blasts
CD123/CD70/CD33 co - expression differentiates LSCs and AML Blasts Allowing for or avidity - driven specific T cell killing of LSCs and blasts LSCs Blasts HSC Lymphocytes Inflamed EC Myeloid cells pDCs Basophiles CD70 Low Low Neg /Low Variable Neg Neg Neg Neg CD123 High High Low Neg Medium Low/ Medi
Slide 83: From the Idea to MP0533: Exploiting DARPin Platform Versatility
10 12 1 10 10 3 5 100 From the Idea to MP0533: Exploiting DARPin Platform Versatility Allows Screening for Function Sweet Spot Screening of multi - domain DARPins Functional M ulti - D A RPin ca ndida tes Screening of multi - domain DARPins Multi - DARPin lead molecule Library used to generate binde
Slide 84: MP0533: a DARPin Solution for AML Patients?
MP0533: a DARPin Solution for AML Patients? 1. Validation of the avidity - driven T cell mediated killing concept • Can MP0533 induce killing of cells expressing 2 or 3 TAA while sparing cells with 1 TAA? 2. Demonstration of MP0533 efficacy against AML • Is the level of TAA expressed by AML blasts s
Slide 85: MP0533 Induces Specific Killing of AML Cells Expressing 2 or 3 TAAs
10 - 2 10 - 1 10 0 10 1 10 2 10 3 10 4 10 5 0 2 5 5 0 7 5 1 0 0 M P 0 53 3 Concentration [pM] % cell killing CD 3 3 + C D 123 + C D 7 0 + CD33+CD70+ CD123+CD70+ CD33+CD123+ CD33+ C D 12 3 + CD70+ MP0533 Induces Specific Killing of AML Cells Expressing 2 or 3 TAAs TAAs expressed on Molm - 13 cells MO
Slide 86: MP0533 Induces Potent T-Cell Mediated Killing of AML Blasts
MP0553 Induces Potent T - Cell Mediated Killing of AML Blasts As compared to CD123 - DART and CD33 - Bite 10 - 3 10 - 2 10 - 1 5 0 2 5 7 5 1 0 0 BMMC AML - Mean of 3 donors 10 0 10 1 10 2 10 3 10 4 10 5 pM %viable tumor cells CD33 - BITE C D 123 - D A R T MP0533 Primary AML samples + Healthy donor T
Slide 87: MP0533 Induces AML Killing by Patients' Own T Cells
MP0533 Induces AML Killing by Patients’ Own T Cells Despite lower frequency and expected lower quality of T cells *No unspecific killing with NB - CD3 control (not shown) MP0533 CD 12 3 - D A R T First line 87 R e l a pse Primary AML samples ( no addition of healthy T cells ) MP0533 or controls 120
Slide 88: MP0533 Shows in vivo Efficacy Against Established MOLM Tumors
MP0533 Shows in vivo Efficacy Against Established MOLM - 13 Tumors As compared to CD33 - Bite Day - 2 Day 0 Day 8 HuPBMCs M O L M - 13 T reatme n t Start MP0533 3 times per week for 2 weeks (6 injections) CD33 - bite or vehicle daily for 2 weeks (14 injections) 0 50 0 100 0 150 0 200 0 250 0 MOLM -
Slide 89: MP0533 Shows Preferential Killing of CD34+ LSCs over HSC
0 1 0 0 1 0 0 1 0 1 1 0 2 5 5 0 7 5 1 0 0 % colony count M P 0 5 3 3 100 10 C D 1 2 3 - CD 3 DART 100 10 CD 3 3 - C D 3 BiTE 1 [pM] L S C H S C MP0533 Shows Preferential Killing of CD34+ LSCs over HSC Larger therapeutic window as compared to CD123 - DART and CD33 - bite L S C H S C CD 3 3 CD1 2 3 CD
Slide 90: MP0533 Demonstrates Reduced Cytokine Release and Hemotoxicity
MP0533 Demonstrates Reduced Cytokine Release and Hemotoxicity As compared to CD123 - DART Addition of test molecules Blood draw healthy donor C y tokine analysis R o tating wheel Blood sampling 0 - 2 - 4 - 8 - 24h Cell counts 1 1 0 0 150 0 0 300 0 0 450 0 0 I F N γ 0.001 0.01 0.1 nM AUC 0 - 24h 1 1
Slide 91: MP0533: a DARPin Solution for AML Patients
MP0533: a DARPin Solution for AML Patients 1. Validation of the avidity - driven T cell mediated killing concept x • Can MP0533 induce killing of cells expressing 2 or 3 TAA while sparing cells with 1 TAA? 2. Demonstration of MP0533 efficacy against AML x • Is the level of TAA expressed by AML blast
Slide 92: MP0533: a Unique DARPin Solution for AML Patients
MP0533: a Unique DARPin Solution for AML Patients • An ideal AML therapeutic solution should: • Ensure long term control of the disease by eliminating LSCs x • Control tumor heterogeneity by targeting multiple Ag x • Increase the therapeutic window: optimal dose levels for efficacy with limited side
Slide 93: Patrick Amstutz Conclusions
Pa t ri c k Amstu t z 93 Co n clusions
Slide 94: MP Strategy – Building on our Strengths
MP Strategy – Building on our Strengths Our candidates’ design aims to directly change the course of disease biology and allow testing in a model with high translatable value We aim to drive true patient value with early clinical read - outs We leverage the advantages of the DARPin technology to pro
Slide 95: How we Select Targets for Optimized Risk/Reward
How we Select Targets for Optimized Risk/Reward Probability of Success Differentiation OUR PURPOSE: Transform the lives of people with cancer by delivering truly innovative therapies Novel Biology Novel Biology on Validated Targets V alidated Targets 95
Slide 96: Pipeline
Pipeli n e CANDIDATE / FOCUS RESEARCH PHASE 2 PHASE 3 R IG HT S Ensovibep – Covid Next Gen Covid AMG506 / MP0310 FAP x 4 - 1BB MP0317 FAP x CD40 MP0533 CD3 x CD33+CD70+CD123 Abicipar VEGF Radio Ligand Therapy Platform Discovery 96 Pipeline Inflection Points Discovery Oncology Op ht halmolo g y Infec
Slide 97: Pipeline Inflection Points
Pipeline CANDIDATE / FOCUS Ensovibep – Covid Next Gen Covid AMG506 / MP0310 M P0317 M P0533 Abicipar Radio Ligand Therapy Platform Discovery Pipeline Inflection Points Oncolo g y Discovery Oncology Op ht halmolo g y Infectious disease Radical simplicity & Co Additional Infectious D RESEARC H P R E C
Slide 98: My Key Takeaways
My Key Takeaways • DARPin leadership and Product Strategy in place • Strong cross - functional execution: Technology & Biology & Medical • Continued collaboration to leverage outside expertise AND • Creation of molecules where we control our full destiny: » MP0533 = first DARPin with real potential
Slide 99: Wie pee Nc Vow Wire War Wie pee wc Vows
Wie pee Nc Vow Wire War Wie pee wc Vows Ea otcch () tian B BE. 9a oid 0) stM ek das MD. 2 of OF fa Ailes 7% teat Sd eo re TS | po TY ce ty) fea W Ruta 2 “Allee
Slide 100: Molecular Partners AG contact details
Molecular Partners AG Wagistrasse 14 8952 Zürich - Schlieren Switzerland www.molecularpartners.com T +41 44 755 77 00 100
Slide 101: Ensovibep Protects Against Omicron
Ensovibep Protects Against Omicron 101
Slide 102: Covid Pseudotype Inhibition – From Wild-Type to Omicron
Covid Pseudotype Inhibition – From Wilde - Type to Omicron 1 2 0 1 0 0 80 60 40 20 0 0 1 0 - 1 1 0 0 1 0 1 1 0 2 1 0 3 1 0 4 1 0 5 n o v ir u s Concentration (ng/ml) Wild Type Relative infection (%) 1 2 0 1 0 0 80 60 40 20 0 0 1 0 - 1 1 0 0 1 0 1 1 0 2 1 0 3 1 0 4 1 0 5 n o v ir u s Concentration (n
Slide 103: Ensovibep Remains Fully Active Against Omicron Pseudotype
Ensovibep Remains Fully Active Against Omicron Pseudotype 103 Neutralization of ensovibep and a panel of monoclonal antibodies in VSV - pseudotype assays containing the Omicron variant spike protein with >30 substitutions. Wild Type Omicron 1 Compound IC 50 (ng/mL) IC 50 (ng/mL) fold change to wt en
Slide 104: DARPin – Radio-Ligand Therapeutics: New collaboration with Novartis
C onfidential 104 DARPin – Radio - Ligand Therapeutics New collaboration with Novartis
Slide 105: Radio-Ligand Therapeutics Collaboration
105 Radio - Ligand Therapeutics Collaboration • NIBR established as world leader in the RLT field • RLTs - the potential to deliver targeted radiation to tumor cells anywhere in the body • DARPins – small size and high specificity & affinity may offer an advantage in RLT’s, which often require a hig