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Item 7.01 Regulation FD Disclosure
Acrivon Therapeutics, Inc. (the “Company”) will host an investor event taking place virtually on May 1, 2023 beginning at 11:00 a.m. EST. The Company has updated its corporate presentation to be used in connection with its discussion with investors during the event. The presentation includes, among other things, an update regarding the Company’s pipeline and AP3 platform, disclosure regarding the Company’s cash and marketable securities as of March 31, 2023 and confirmation of its projected cash runway into at least the fourth quarter of 2024.
A copy of the Company’s corporate presentation is attached hereto as Exhibit 99.1 and is hereby incorporated by reference herein.
The information furnished under Item 7.01 of this Current Report on Form 8-K, including Exhibit 99.1, is being furnished and shall not be deemed to be “filed” for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as shall be expressly set forth by specific reference in such a filing.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits:
| Exhibit Number | Exhibit Description | |
| 99.1 | Acrivon Therapeutics, Inc. Presentation | |
| 104 | Cover Page Interactive Data File (formatted as Inline XBRL). | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Acrivon Therapeutics, Inc. | ||||||
| Dated: May 1, 2023 | By: | /s/ Peter Blume-Jensen | ||||
| Name: | Peter Blume-Jensen, M.D., Ph.D. | |||||
| Title: | Chief Executive Officer and President | |||||
Exhibit 99.1 A Acr criv ivon on T T h h e e r r a a p p e e u u t t ii c c s s ACRIVON PREDICTIVE PRECISION PROTEOMICS (AP3): DRUG-TAILORED PATIENT SELECTION FOR CLINIC AL SUCCESS INVESTOR EVENT MAY 01, 2023
F O R W A R D - L O O K I N G S T A T E M E N T S Certain information contained in this presentation includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 regarding our future results of operations or financial condition, business strategy and plans and objectives of management for future operations. In some cases, you can identify forward-looking statements because they contain words such as “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” or “would” or the negative of these words or other similar terms or expressions. Our forward-looking statements are based primarily on our current expectations and projections about future events and trends that we believe may affect our business, financial condition and results of operations. The outcome of the events described in the forward-looking statements is subject to risks and uncertainties, including the factors described in our filings with the U.S. Securities and Exchange Commission. New risks and uncertainties emerge from time to time, and it is not possible for us to predict all risks and uncertainties that could have an impact on the forward-looking statements contained in this presentation. The results, events, and circumstances reflected in the forward-looking statements may not be achieved or occur, and actual results, events, or circumstances could differ materially from those described in the forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of the date of this presentation. We undertake no obligation to update any forward-looking statements or to reflect new information or the occurrence of unanticipated events, except as required by law. 2 A C R I V O N T H E R A P E U T I C S
O U T L I N E • Company overview • Acrivon Predictive Precision Proteomics (AP3) platform update • Preclinical pipeline update • Clinical trial enrollment progress • Corporate updates • Q & A 3 A C R I V O N T H E R A P E U T I C S
A C R I V O N T H E R A P E U T I C S : D R U G - T A I L O R E D P A T I E N T S E L E C T I O N AIMING TO OVERCOME THE KEY ATTRITION FACTOR PREVENTING CLINICALLY ACTIVE DRUGS FROM REACHING MARKET ® AP3 Platform OncoSignature ACR-368 (Prexasertib) Pipeline - Acrivon’s proprietary - Clinically active (15-20% - Two co-crystallography- and - Our proprietary predictive proteomics-based predictive ORR) Phase 2 DNA Damage AP3-driven preclinical drug-tailored biopsy test precision medicine platform Response (DDR) inhibitor programs targeting WEE1 - Extensively evaluated in licensed from Eli Lilly & Co. and PKMYT1, proximal and - Applied where NGS/genetics prospective preclinical studies, redundant DDR nodes - Now being developed with is insufficient and for our including prediction on OncoSignature patient - Single digit nM inhibitors, internal pipeline blinded pretreatment tumor selection for increased ORR wholly-owned, opportunity biopsies from past trials with registrational intent for AP3 patient selection and DNA resulting in ORR 47% and 58% pipeline combinations OncoSignature Prediction: OncoSignature Prediction: Predicted Predicted Non-Responders Responders 1.2 RNA Non-Responders Responders 0.9 Protein 0.6 P Dysregulated Protein 0.3 P Drug 0.0 Dysregulated (0.3) Pathways (0.6) ORR ORR == 0% 0% ORR OR = R 4 = 47 7%% CANCER (0.9) PD SD PD PD PD SD SD SD PD SD SD SD SD SD SD SD PR PR PR PR PR PR PR 4 A C R I V O N T H E R A P E U T I C S Tumor fractional change
ACRIVON PIPELINE Anticipated Preclinical Phase 1 Phase 2 Phase 3 Next Milestone Single-Arm Trials Based on OncoSignature Prediction ACR-368 Monotherapy Platinum-Resistant Ovarian Cancer LDG Combination ACR-368 Monotherapy Initial Clinical Readouts in Endometrial Cancer Second Half 2023 LDG Combination ACR-368 (CHK1/CHK2) ACR-368 Monotherapy Bladder Cancer LDG Combination Staggered Development Under Same Master Protocol Trial Design + ACR-368 Monotherapy HPV SCC (anal, H&N Option to Initiate in 2023 and cervical cancer) LDG Combination IND-enabling studies WEE1 Inhibitor in 2023 IND-enabling studies PKMYT1 Inhibitor in 2023 Notes ACR-368 Monotherapy Registrational intent Phase 2 single arm trials based on predicted sensitivity to ACR-368 monotherapy in OncoSignature-positive patients LDG Combination Exploratory Phase 1b/2 single arm trials of ACR-368 in combination with low dose gemcitabine, or LDG, in OncoSignature-negative patients 5 A C R I V O N T H E R A P E U T I C S
AP3 PLATFORM: DRUG RESPONSE PREDICTION IN INDIVIDUAL PATIENTS ® P R O P R I E T A R Y 3 - S T E P W O R K F L O W I N T E G R A T I N G P R O V E N T E C H N O L O G I E S Drug OncoSignature S T E P 3 S T E P 1 S T E P 2 Predicted Predicted THERAPEUTIC PACKAGE PATIENT RESPONDERS BIOMARKER IDENTIFICATION Non-responder Responder Acrivon drug with predictive BM assay Optimal indications and combinations CLASS 1 BM CLASS 2 3 AP DRUG PROFILING BM HIGH RES PROTEOMICS BY MS Resistant Sensitive + No benefit Benefit ® CLASS 3 OncoSignature BM CLINICAL SIGNATURE ASSAY PROSPECTIVE RESPONSE PREDICTION ON PRETREATMENT BIOPSY 3-6 BIOMARKERS Patients without biomarkers critical BIOMARKER VALIDATION for drug sensitivity efficiently excluded CELL LINES, PDX, HUMAN TISSUE “Disease Pathway-Based Method to Generate Biomarker Panels Tailored to Specific Therapeutics for Individualized Treatments”: EP 2 229 589, issued June 10, 2015; US2017/0067877A9, pending. OncoSignature® is a Registered Trademark: US Reg. No. 5,718,472; Int. Cl. 5, 42. Intl. Reg. 1382289 \ 6 A C R I V O N T H E R A P E U T I C S
A P 3 I S A P P L I C A B L E A C R O S S D R U G D E V E L O P M E N T S T A G E S Approval & Target ID Hit ID Lead Opt IND Enabling Early Clinical Late Clinical Commercialization ID druggable AP3 drug profiling: AP3 is also applicable in preclinical phase driver targets Unbiased drug target engagement & PD biomarkers Resistance Mechanisms Rational Combinations Indication Finding: ® OncoSignature patient sample screening ® OncoSignature patient responder identification 7 A C R I V O N T H E R A P E U T I C S
A P 3 R E V E A L S S I N G L E A G E N T S E N S I T I V I T Y C O N T E X T A N D R A T I O N A L D R U G C O M B I N A T I O N S I N D E P E N D E N T O F G E N E T I C I N F O R M A T I O N Using spatial phosphoproteomics (Nat. Commun., 2021) Acrivon’s AP3 platform can uncover single agent sensitivity and rational drug combinations for targets with complicated mechanism of action Cell Reports, August 9, 2022 8 A C R I V O N T H E R A P E U T I C S
E X A M P L E : D R U G G A B L E C D C 7 I N H I B I T O R R E S I S T A N C E M E C H A N I S M ( 5 1 4 2 P - S I T E S S I G N I F I C A N T L Y R E G U L A T E D ) Enriched kinase motif p-value CDK1,2,4,6 kinase substrate motif 1.65E-08 Cdc2 kinase substrate motif 8.29E--09 CDK kinase substrate motif 9.99E-07 Calmodulin-dependent protein kinase II alpha substr. 7.71E-05 Enriched kinase motif p-value Calmodulin-dependent protein kinase II alpha substr. 3.20E-29 14-3-3 domain binding motif 9.73E-26 PKC kinase substrate motif 2.11E-25 PKC epsilon kinase substrate motif 3.87E-23 PAK2 kinase substrate motif 5.40E-23 PKA kinase substrate motif 5.01E-19 Phosphorylase kinase substrate motif 2.07E-14 MAPKAPK1 kinase substrate motif 3.48E-10 Akt kinase substrate motif 1.25E-10 p70 Ribosomal S6 kinase substrate motif 1.57E-07 Calmodulin-dependent protein kinase IV substr. 2.27E-07 Aurora-A kinase substrate motif 3.95E-07 Chk1 kinase substrate motif 1.77E-06 Pim1 kinase substrate sequence 1.94E-06 Enriched kinase motif p-value GSK-3, ERK1, ERK2, CDK5 substrate motif 4.53E-07 WW domain binding motif 4.53E-07 Enriched kinase X motif p-value CDK1,2,4,6 kinase substrate motif 1.04E-50 Cdc2 kinase substrate motif 2.14E-50 CDK kinase substrate motif 1.98E-38 Enriched kinase motif p-value ERK1,2 kinase substrate motif 7.59E-08 Significant Kinase X response/cell cycle arrest after 24h in the non-responders Enriched kinase motif p-value Casein kinase I substrate motif 3.49E-12 indicate a CDC7i resistance mechanism that could be targeted with X-inhibitor Casein kinase II substrate motif 4.51E-11 combinations BARD BRCT domain binding motif 1.77E-10 phosphosite Z-score B-Adrenergic Receptor kinase substrate motif 2.23E-09 -3 3 9 A C R I V O N T H E R A P E U T I C S
A P 3 U N C O V E R S A C T I O N A B L E A C R -368 R E S I S T A N C E M E C H A N I S M S U N B I A S E D A N D I N D E P E N D E N T OF G E N E T I C I N F O R M A T I O N T-test significant Proteins, FDR<0.05 Unsupervised Hierarchical Clustering Resistant Parental G1/S CELL CYCLE Upregulated in ACR-368 Resistant Cells Downregulated in ACR- DNA DAMAGE REPAIR 368 Resistant Cells Data suggest that gemcitabine might be a rational combination to overcome DDR suppression 10 A C R I V O N T H E R A P E U T I C S
U L T R A - L O W D O S E G E M C I T A B I N E S E N S I T I Z E S O V A R I A N C A N C E R C E L L L I N E S T O A C R -368 OVCAR3-Parental Gemcitabine alone in OVCAR3-Resistant Ovarian-Parental Ovarian-Resistant OGe VCAR3m -P ac ndi t Oa VCbi ARne 3-R alone 150 150 150 No Gem No Gem 0.53 nM Gem 0.53 nM Gem OVCAR3-P 2.7 nM Gem 2.7 nM Gem OVCAR3-R 100 100 100 Relative IC (uM) 50 Prexasertib Abs EC 50 Prexasertib Abs EC 50 OVCAR3-P: 0.005 + 0 nM Gem: 15 nM + 0 nM Gem: >10 uM OVCAR3-R: 0.011 + 0.53 nM Gem: 2.7 nM + 0.53 nM Gem: 100 nM + 2.7 nM Gem: 0.2 nM + 2.7 nM Gem: 6 nM 50 Absolute IC (uM) 50 50 50 OVCAR3-P: >10 OVCAR3-R: 0.836 0 0 0 -10 -8 -6 -4 -10 -8 -6 -4 -10 -8 -6 -4 Gemcitabine Log10 (M) Prexasertib Log10(M) Prexasertib Log10(M) Gemcitabine Log10 (M) ACR-368 Log10 (M) ACR-368 Log10 (M) Bliss Synergy score: o <-10: Drug interaction is likely antagonistic o -10 to 10: Drug interaction is likely additive o >10: Drug interaction is likely synergistic 11 A C R I V O N T H E R A P E U T I C S % Cell viability realtive to DMSO % Cell viability realtive to DMSO % Cell viability realtive to DMSO
INTERNAL PIPELINE: WEE1 AND PKMYT1 - LEVERAGING AP3 Rationale • Complement to in-licensing, leveraging our AP3 patient selection platform for high clinical POS • Potential within DDR drug target class to pursue combinations (ACR-368, WEE1, and PKMYT1 inhibitors) High throughput AP3 profiling WEE1 and PKMYT1 programs Lead optimization ongoing in several prioritized series based Global analysis Pairwise analysis Volcanoplot, FDR=0.05 > 10 k p-sites. ANOVA, HA, FDR=0.05 on high resolution co-crystals (WEE1: 1.5-2.6 Å; PKMYT1: 1.65-2.1 Å) • Potent target inhibition (IC <10 nM) 50 • Confirmed target engagement in cells • Multiple novel structural series Causal networks Activity analysis • Kinase selectivity (IVKA and AP3 profiling) Motifs • PK studies ongoing Kinase score GSEA WEE1 IC50 = 4.6 nM PKMYT1 IC50 = 2.4 nM AP3 used for biologically relevant selectivity profiling PKMYT1 IC50 = 10 nM PKMYT1 co-crystallized with a candidate compound 12 ACRIVON THERAPEUTICS
W E E 1 A N D P K M Y T 1 P R O G R A M S : I D E A L F O R A P 3 A P P R O A C H • WEE1 and PKMYT1 regulate S and G2-M cell cycle checkpoints to ensure proper DNA replication and mitotic completion through phosphorylation and inhibition of CDK2 and CDK1 and CDK1, respectively • WEE1 inhibition propagates genomic instability by premature DNA replication and cell cycle progression, resulting in mitotic catastrophe • PKMYT1 inhibition results in premature mitotic entry and cell death • Strong preclinical data and emerging clinical data: – AZD1775/MK1775/adavosertib (AstraZeneca) – Debio0123 (Debiopharm) – ZN-c3 (Zentalis Pharmaceuticals) – SGR-XXX (preclinical, Schrödinger) Ghelli Luserna di Rorà et al. J. Hematol Oncol, 2020 – RP-6306 (Repare Therapeutics) ✓ Clinical activity (WEE1 single agent) ✓ Correlation with genetic alterations challenging, CCNE1 association being explored ® ✓ Acrivon intends to leverage OncoSignature for optimal patient selection 13 A C R I V O N T H E R A P E U T I C S
® DEVELOPMENT OF AP3-BASED PATIENT SELECTION ONCOSIGNATURE TESTS Technical Validation Functional Validation P-proteomics Cellular MOA (Intended use tissue) (Intended use tissue) Human cancer screening: Quantitative mapping Dose response, BM antibody validation ID of drug-sensitive >20,000 p-sites; knockdowns, drug by quantitative IF on cancers and proportions 25% drug-related combinations human and PDX of responders samples Final Drug-regulated OncoSignature® 4NQO DMSO 4NQO+Prex phospho-sites and OVCAR3 Assay biological processes A2780 Prediction of drug sensitivity in cancer cell lines and PDX models Target engagement, Pathway visualization cell assays, imaging and reconstitution Patient responder Border: Most regulated Significant Not identified -14 -4 0 4 14 Log2 Intensity ratio prediction on pre- treatment tumor biopsies Literature and database mining Initial biomarker candidates 14 A C R I V O N T H E R A P E U T I C S
P R O F I L E S O F B E N C H M A R K W E E 1 A N D P K M Y T 1 I N H I B I T O R S Assays WEE1 inhibitor A WEE1 inhibitor B WEE1 inhibitor C PKMYT1 inhibitor Target IC50 1.2 nM 2.0 nM 1.0 nM 9.8 nM Target Engagement IC50 18.6 nM 15.9 nM 109.0 nM 10 nM Cell Viability IC50 31.9 nM 49.2 nM 318.0 nM 87 nM Kinome Selectivity Score @ 1uM 0.172 0.101 0.082 0.121 Eurofins Discovery panel (106 kinases) Traditional drug discovery profiling methods yield limited information 15 A C R I V O N T H E R A P E U T I C S
I N V I T R O K I N A S E P R O F I L I N G D O E S N O T N O T P R E D I C T D R U G - R E G U L A T E D K I N A S E A C T I V I T Y I N I N T A C T C E L L S PTM-SEA – 60min & 200nM Not Active Active ompound 1 ompound 1 ompound 2 KinomeScan Kinase Activity* ompound 2 ompound ompound Time : 60 minutes Eurofins Discovery KinomeScan Dose : 200 nM 16 A C R I V O N T H E R A P E U T I C S
Phosphosites P R O P R I E T A R Y P I P E F O R A U T O M A T E D A P 3 D A T A A N A L Y S E S Proprietary machine learning algorithms applied to state-of-the-art AP3 MS-based phosphoproteomics for all compound projects Unbiased PD marker identification • Automated quantitation of EC50s for 5- 6,000 PD markers in each MS run High throughput MS Dose-response of target engagement AP3 profiles of WEE1 inhibitors • deep, multi-parameter analyses • Ex: Phosphorylation of CDK1 Y15 • WEE1 inhibitors are very differentiated (time, dose, cell type) Plate 1 – Compound 1 Pathway mapping • Unbiased compound-specific effects on disease-driving signaling pathways 0 0.32 1.6 8 40 200 1000 5000 nM Plate 2 – Compound 2 Mechanism of action 0 0.32 1.6 8 40 200 1000 5000 nM • Pathway activity modulation by WEE1 inhibitors Plate 3 – Compound 3 Agonist Inhibitor pEC50 Increased Decreased Activity Activity 0 0.32 1.6 8 40 200 1000 5000 nM pEC50 = -log10(EC50) 17 A C R I V O N T H E R A P E U T I C S
T I G H T , H I G H - R E S O L U T I O N D A T A W I T H D E E P C O V E R A G E 25,800 p-sites 16,456 p-sites QC Consensus Data Clean Volcano Hierarchical Kinase Pathway Functional Network QC MS Data Processed Sequence Biomarkers Up Plots Clustering Inference Enrichment Annotation Mapping Data Motif • Filter >60% in at least on condition • Normalization: LOESS • Imputation: SLSA 18 A C R I V O N T H E R A P E U T I C S
WEE1 INHIBITORS ARE MORE DIFFERENT THAN SIMILAR Drug-regulated phosphorylation sites Pathway enrichment analysis Unique and shared drug-regulated sites (unsupervised hierarchical cluster) Cell cycle Mitosis apoptosis Shared on target mechanisms Clinically actionable drug-specific effects FDR < 0.5 & abs(Fold Change) > 1.5; Time : 60 minutes; Dose : 200 nM Pathway over-representation analysis: Wikipathway and Reactome; FDR < 0.00005; Significance = -log10(FDR) 19 ACRIVON THERAPEUTICS
W E E 1 I N H I B I T O R - R E G U L A T E D G L O B A L P H O S P H O P R O T E O M E R E V E A L H I G H L Y D I F F E R E N T I A T E D E F F E C T S Drug-regulated phosphosites Compound 1 Compound 2 Compound 3 Mean log2FC -5 0 5 FDR < 0.5 & abs(Fold Change) > 1.5 Differentiated WEE1 inhibitor-specific effects provide opportunity for tailored patient responder identification Time : 60 minutes; Dose : 200 nM 20 A C R I V O N T H E R A P E U T I C S
F U N C T I O N A L P A T H W A Y N E T W O R K E F F E C T S B Y W E E 1 A N D P K M Y T 1 I N H I B I T O R S A R E H I G H L Y D I S T I N C T Compound 1 Compound 2 Compound 3 Compound 4 Sensitive tumor cell RTK-MAPK axis Phosphoinositides Mitotic regulation Cell cycle TLR Insensitive and signaling cancer tumor cell mTOR HDR MYC/MAX signaling WNT p value Significant Not significant Compounds 1 and 4 demonstrate opposite effects on HDR in sensitive cells Enrichment Score (NES) Induced Suppressed 21 A C R I V O N T H E R A P E U T I C S
B E N C H M A R K W E E 1 I N H I B I T O R S H A V E D I F F E R E N T I A T E D C O M P O U N D - S P E C I F I C D I S E A S E P A T H W A Y M O D U L A T I O N Drug regulation of pathway activity states Drug-regulated phosphorylation sites (substrate consensus motif enrichment analysis) (unsupervised hierarchical clustering) Z-score Pathway Pvalue Cell Cycle, Mitotic 1.9E-09 -3 0 3 Cdc2 kinase substrate motif 3.3E-10 Mitotic Prometaphase 2.3E-08 CDK kinase substrate motif 6.7E-10 GSK-3, ERK1, ERK2, CDK5 substrate motif 3.1E-05 CDK1,2,4,6 kinase substrate motif 3.3E-09 Mitotic Anaphase 2.3E-05 DMSO CMP 3 CMP2 CMP 1 Resolution of Sister Chromatid Cohesion 1.1E-04 positive regulation of sequestering of triglyceride 2.4E-11 SUMOylation of DNA replication proteins 1.4E-04 RNA splicing, via transesterification reactions with bulged adenosine as nucleophile 9.8E-11 nuclear mRNA splicing, via spliceosome 9.8E-11 Shared upregulated Cell Cycle 1.8E-11 WW domain binding motif 3.1E-45 Cell Cycle, Mitotic 3.2E-09 GSK-3, ERK1, ERK2, CDK5 substrate motif 3.1E-45 Regulation of TP53 Activity 8.5E-09 Cdc2 kinase substrate motif 1.6E-28 CDK1,2,4,6 kinase substrate motif 1.6E-28 RIG-I-like receptor signaling pathway 1.1E-09 ERK1,2 kinase substrate motif 1.3E-22 CDK kinase substrate motif 2.0E-16 Signaling by Rho GTPases 1.2E-13 CDK5 kinase substrate motif 1.2E-13 Cell Cycle 1.2E-11 Cell Cycle 2.3E-12 SUMO E3 ligases SUMOylate target proteins 1.2E-11 Cell Cycle, Mitotic 3.6E-11 TGF-beta signaling pathway 2.4E-11 M Phase 3.5E-07 Cell Cycle, Mitotic 1.4E-10 Angiopoietin-like protein 8 regulatory pathway 3.1E-09 Apoptotic cleavage of cellular proteins 1.0E-09 ATM signaling in development and disease 1.9E-08 Apoptotic execution phase 1.0E-09 Integrated breast cancer pathway 2.0E-08 MAPKAPK1 kinase substrate motif 1.9E-08 4-hydroxytamoxifen, Dexamethasone, and Retinoic Acids Regulation of p27 Expression 2.0E-08 Target of rapamycin (TOR) signaling 2.2E-08 Nuclear Envelope Breakdown 2.7E-08 Pathways affected in adenoid cystic carcinoma 4.1E-07 SUMO E3 ligases SUMOylate target proteins 2.7E-08 Cell Cycle 4.3E-07 Mitotic Prophase 2.7E-08 Signaling by Rho GTPases 4.3E-07 Chromatin modifying enzymes 4.3E-07 Apoptotic execution phase 4.8E-07 Shared downregulated Signaling by Rho GTPases 5.3E-10 EGF/EGFR signaling pathway 3.5E-10 Cell Cycle 1.1E-08 VEGFA-VEGFR2 signaling pathway 1.2E-07 Membrane Trafficking 2.6E-08 MET in type 1 papillary renal cell carcinoma 2.2E-07 Androgen receptor signaling pathway 4.7E-08 ErbB signaling pathway 2.9E-07 Brain-derived neurotrophic factor (BDNF) signaling pathway 4.7E-08 Signaling by Rho GTPases 3.0E-07 22 A C R I V O N T H E R A P E U T I C S
D I F F E R E N T I A L W E E 1 I N H I B I T O R - R E G U L A T E D P A T H W A Y A C T I V I T Y Shared on target CDK1/2 activation and compensatory activation of CHK1 and ATR Substrate motif-inferred kinase activities Compound 1 Compound 2 Compound 3 1 2 Activity (NES) -3 0 3 Time : 60 minutes Dose : 200 nM 23 A C R I V O N T H E R A P E U T I C S
W E E 1 I N H I B I T O R R E G U L A T I O N O F P A T H W A Y A C T I V I T Y ( 4 H ) Drug-regulated kinase activities calculated based on consensus motif enrichment analysis * = FDR < 0.05 ** = FDR < 0.01 ***= FDR < 0.005 0.32 1.6 8 40 200 1000 0.32 1.6 8 40 200 1000 0.32 1.6 8 40 200 1000 Compound 3 Compound 1 Compound 2 Compound 2 shows possible PLK1 inhibition and less pronounced CDK activation: Could counteract mitotic catastrophe Compound 3 shows upregulation of MAPK and PI3K: Could be single agent resistance mechanisms Upregulated kinase activities are color-coded in red with the corresponding false discovery rate (FDR) denoted with “*” 24 A C R I V O N T H E R A P E U T I C S
D I F F E R E N T I A L R E G U L A T I O N O F P L K 1 A C T I V I T Y – P O T E N T I A L I M P A C T O N P A T I E N T T R E A T M E N T O U T C O M E (4 hours) Compound 3 Compound 1 Compound 2 WEE1 WEE1 WEE1 CDK1 CDK1 CDK1 AURKA AURKA AURKA PLK1 PLK1 PLK1 Mitotic Mitotic Possible catastrophe catastrophe tumor survival PLK1 inhibition might counteract mitotic catastrophe and has been associated with adverse events 25 A C R I V O N T H E R A P E U T I C S
ACR-368 (nM) ACR-368 (nM) ACR -368 IS SYNERGISTIC WITH AND OVERCOMES RESISTANCE TO WEE1 INHIBITOR WEE1 inhibitor 125 1000 nM 333 nM 100 111 nM 37 nM Human 12.3 nM 75 Combo synergy correlates to 4.12 nM endometrial 1.37 nM WEE1 inhibitor resistance 50 tumor cell 0 nM line 15 25 r = 0.93 0 0 p = 0.0078 0.01 0.1 1 10 100 1000 10000 10 ACR-368 conc (nM) 5 WEE1 inhibitor 125 1000 nM 333 nM 100 111 nM 0 37 nM Human 12.3 nM 75 4.12 nM ovarian -5 1.37 nM tumor 0 1 2 3 50 0 nM Log IC50, WEE1 inhibitor cell line 25 0 0 0.01 0.1 1 10 100 1000 10000 ACR-368 conc (nM) 26 ACRIVON THERAPEUTICS WEE1 inhibitor (nM) WEE1 inhibitor (nM) % Viability % Viability ACR-368&WEE1 inhibitor Synergy
A C T I O N A B L E F I N D I N G S A N D C O N C L U S I O N S • AP3 enables unbiased measurement of compound-specific on- and off-target effects • WEE1 inhibitors all demonstrate activation of CDK1/2 and cell cycle machinery • Benchmark WEE1 inhibitor AP3 profiles can be leveraged for rational drug design and SAR (‘dialing’ in and out wanted and unwanted pathway effects) • Differential actionable resistance mechanisms, e.g. WEE1 and CHK combination • WEE1inhibitor-treated patients predicted to still be sensitive to ACR-368 27 A C R I V O N T H E R A P E U T I C S
W E E 1 A N D P K M Y T P R O G R A M S T A T U S • Hundreds of compounds designed and synthesized across multiple lead series • High resolution co-crystal structures generated for >30 compounds in complex with Wee1 or PKMYT1 (resolution from about 1.5Å to <3Å) Crystal structure of adavosertib:Wee1 Crystal structure of RP-6306:PKMYT1 Zhu et al, J. Med. Chem. 2017 60:7863–7875 (PDP: 5V5Y) Szychowski et al, J. Med. Chem. 2022; 65:10251–10284 (PDP 8D6E) 28 A C R I V O N T H E R A P E U T I C S
E X E M P L A R Y P K M Y T 1 A N D W E E 1 A N D D U A L - S E L E C T I V E L E A D C O M P O U N D P R O F I L E S Compound CMPD-2655 CMPD-2714 CMPD-2707 CMPD-2743 (A) Wee1 IC 451 nM 251 nM 410 nM 1.3 nM 50 PKMYT1 IC 6.5 nM 2.9 nM 1.8 nM 20.6 nM 50 17 nM (Wee1) TE EC 118 nM (PKMYT1) 47.1 nM (PKMYT1) 56 nM (PKMYT11) 50 233 nM (PKMYT1) hERG IC (in vitro) TBD >100 µM 760 µM 1.4 µM 50 Hu microsomal Clint (µl/min/mg) 17 13 <10 102 Rat microsomal Clint (µl/min/mg) 17 16 <10 TBD Mu t½ (IV); Vdss (L/kg); %F 0.9 hr; 2.71; 50% 1.8 hr; 3.19; 75% 0.9; 1.43; 64% 1.5 hr; 4.4; 25.3% Compound CMPD-2743 CMPD-2736 CMPD-2804 CMPD-2858 Wee1 IC 1.3 nM 1.25 nM 2.5 nM 2.1 nM 50 PKMYT1 IC 20.6 nM 45.8 nM 91% @ 10 µM 84% @ 10 µM 50 TE EC 17 nM (Wee1) 15 nM (Wee1) 9.9 nM (Wee1) 47.9 (Wee1) 50 Cell viability IC 25 nM 33 nM N.D. N.D. 50 hERG IC (in vitro) 1.4 µM >100 µM 3.0 µM 4.0 µM 50 Rat microsomal Clint (µl/min/mg) TBD <10 - TBD Rat PO AUC/dose (h/L*kg) 0.185 0.05 0.09 0.21 Mu t½ (IV); Vdss (L/kg); %F 1.5 hr; 4.4; 25.3 N.D. N.D. N.D. 29 A C R I V O N T H E R A P E U T I C S
A C R - 3 6 8 C L I N I C A L T R I A L • We reconfirm our guidance and timeline of initial clinical readouts of our Phase 2 3 Cohorts: and Phase 1b/2 clinical trial in H2 2023 Ovarian, Endometrial, Bladder Single-Arm Trial Single-Arm Trial OncoSignature • Enrolling and dosing patients at the Subject Selection on Fresh Tumor ARM 1 OncoSignature Positive ARM 2 OncoSignature Negative Biopsy (≤12 weeks) Monotherapy Combination Therapy RP2D of ACR-368 based on predicted Phase 2 Simon 2-Stage Phase 1b / 2 sensitivity using our ACR-368 Stage 1 Phase 1b (N= 23 per cohort) (N= ~21) OncoSignature Assay run by our CDx 2 ACR-368 (105 mg/m ) + LDG 2 ACR-368 monotherapy (105 mg/m ) (dose escalation) partner Stage 2 Phase 2 Exploratory Study (N= 48 per cohort) (N= 33 per cohort) 1 2 • 19 sites currently activated ACR-368 (105 mg/m ) + LDG at RP2D • Key opinion leaders with extensive experience using ACR-368 from previous trials are actively participating 1 https://clinicaltrials.gov/ct2/show/NCT05548296 30 A C R I V O N T H E R A P E U T I C S
® ONCOSIGNATURE TESTS: USAGE IN THE CLINIC Pretreatment Treatment decision tumor biopsy based on patient stratification Predicted Predicted Sample processing Responder Non-responder ® OncoSignature test Biopsy in Automated tumor FFPE Region-of-Interest block biomarker scoring • Pretreatment tumor biopsy test • Compatible with 5 business days turn-around • Offered by CDx partner under exclusive license from Acrivon 31 A C R I V O N T H E R A P E U T I C S
FINANCIAL HIGHLIGHTS Cash and marketable securities Projected runway at least into Fully Diluted Shares Outstanding $159.5M 27.0M Q4’24 Balance sheet Current operating plan assuming no Shares and equity grants 31-March-2023 additional financing outstanding 31-March-2023 Unaudited. 32 ACRIVON THERAPEUTICS
ACRIVON ADDRESSABLE MARKETS (US & EU INCIDENCE) Prioritized indications for single agent ACR-368 Prioritized indications Bladder Cancer (N=742,000) * Endometrial Cancer * + Potential additional HPV SCC 12% indications Ovarian cancer *Currently enrolling * (N = 634,000) and dosing Sarcoma 10% Other cancers Potential additional indications for single agent ACR-368 predicted to have ~45% DDR stress Colorectal Cancer Pancreatic Cancer All cancers US and Europe Est. >6.3M cases/year • ~30% (N = 223,000) of prioritized indications predicted sensitive to single agent ACR-368 • WEE1 and/or PKMYT1 inhibitor combinations with ACR-368 might further expand addressable fraction within sensitive tumor types US cancer stats are based on ACS 2022 publication and subtype estimation from literature; EU cancer stats are based on IARC 2020 publication and subtype estimation from literature. Cancers with DDR stress are estimated to be 67% which is calculated from MSK-IMPACT patient samples with DDR relevant mutations and CNVs, such as TP53, KRAS, CCNE1, etc. 33 ACRIVON THERAPEUTICS 0 0 100000 100000 200000 300000 200000 400000 500000 300000
THE AP3 APPROACH IS MODALITY AND DISEASE AGNOSTIC Therapeutic Oligo/RNA modalities Antibody Bifunctional ADC molecule Small molecule Cancers with DDR stress Oncology Therapeutic Fibrotic and areas inflammatory Autoimmune Current focus Infectious, CNS, and other diseases 34 ACRIVON THERAPEUTICS