UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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| Item 7.01 | Regulation FD Disclosure |
On September 5, 2023, Acrivon Therapeutics, Inc. (the “Company”) issued a press release regarding ACR-2316, its internally developed small molecule development candidate. The Company has also updated its corporate presentation. The presentation provides, among other things, an update regarding the Company’s pipeline, including ACR-2316, disclosure regarding the Company’s cash and marketable securities as of June 30, 2023 and confirmation of its projected cash runway into 2025.
Copies of the Company’s press release and corporate presentation are attached hereto as Exhibit 99.1 and Exhibit 99.2 and are 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 | Press release, dated September 5, 2023 | |
| 99.2 | 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: September 5, 2023 | By: | /s/ Peter Blume-Jensen | ||||
| Name: | Peter Blume-Jensen, M.D., Ph.D. | |||||
| Title: | Chief Executive Officer and President | |||||
Exhibit 99.1
Acrivon Therapeutics Announces ACR-2316, a Novel Dual WEE1 and PKMYT1 Inhibitor Development Candidate, Designed Using Acrivon’s AP3 Platform to Achieve Potent Single Agent Activity, as Demonstrated in Preclinical Studies
Acrivon’s Predictive Precision Proteomics (AP3) platform is a proprietary, broadly applicable, next-generation precision oncology platform at the forefront of the next wave of biology-driven drug discovery, in addition to its previously demonstrated utility in clinical development for treating patients based on predicted drug sensitivity
ACR-2316 is a novel, internally developed small molecule development candidate, rationally designed through advanced co-crystallography and the AP3 platform to achieve optimal target potency and selectivity delivering potent single agent anti-tumor activity across in vitro and in vivo preclinical studies, compared to benchmark WEE1 and PKMYT1 inhibitors
The AP3 platform has uniquely enabled the rapid generation of this novel dual inhibitor optimized to potentially overcome resistance mechanisms induced by WEE1 and PKMYT1 single inhibitors, and other mechanism-based liabilities
The company is prioritizing advancement of this molecule, with planned IND submission by the fourth quarter of 2024, to initiate clinical monotherapy development in tumor types predicted responsive to ACR-2316 through prior AP3-derived OncoSignature indication finding and subsequent treatment of patients based on OncoSignature-predicted sensitivity
WATERTOWN, Massachusetts, September 5, 2023 – Acrivon Therapeutics, Inc. (“Acrivon” or “Acrivon Therapeutics”) (Nasdaq: ACRV), a clinical stage biopharmaceutical company developing precision oncology medicines that it matches to patients whose tumors are predicted to be sensitive to each specific medicine by utilizing its proprietary proteomics-based patient responder identification platform, today announced a novel, internally developed clinical candidate, ACR-2316, a dual WEE1 and PKMYT1 inhibitor. The company plans to prioritize Investigational New Drug (IND) enabling studies for ACR-2316 to be ready for IND submission by the fourth quarter of 2024.
“The rapid generation and optimized design of ACR-2316 further demonstrates the broad utility of the AP3 platform in drug discovery, in addition to its applications in clinical development,” said Kristina Masson, Ph.D., M.B.A., co-founder, executive vice president, and site head of Acrivon AB, Acrivon Therapeutics’ wholly-owned drug discovery and phosphoproteomics subsidiary in Medicon Village, Lund, Sweden. “This dual inhibitor development candidate is yet another powerful validation of our AI-enabled AP3 platform, which has been instrumental for the identification of this compound, optimized for strong single agent activity compared to existing WEE1 and PKMYT1 inhibitors.”
“Previously, we have shown how AP3 can be used to develop drug-tailored predictive OncoSignature tests for effective identification of patients likely to respond to a given therapy, as we have done for our clinical stage CHK1/2 inhibitor, ACR-368,” said Peter Blume-Jensen, M.D., Ph.D., chief executive officer, president, and founder of Acrivon Therapeutics. “We now believe that we have shown how AP3 can be used to go beyond the limitations of traditional drug discovery methods by enabling biological pathway-based rational design of development candidates with optimal target selectivity profile and potency, with ACR-2316 being the first example. This novel dual WEE1/PKMYT1 inhibitor has the potential to address significant unmet needs across many solid tumor types based on its compelling preclinical profile, with the potential for monotherapy development in tumors predicted to be sensitive to ACR-2316 using our OncoSignature patient selection approach.”
Based on the emerging favorable preclinical profile of ACR-2316, the company has entered into IND-enabling studies. The compound is designed for high selectivity towards WEE1 and PKMYT1, exhibiting single-digit nM IC50 potency in a carefully predetermined ratio to ensure strong single agent anti-tumor activity, as demonstrated in tumor-bearing rodent models and other preclinical analyses. Using AP3 for unbiased quantitative high-resolution measurement of the effects of ACR-2316 on the human tumor cell phosphoproteome, this compound has been further optimized for potent induction of mitotic catastrophe, which is key to its strong single agent activity in preclinical models and potentially favorable clinical profile for monotherapy development.
“The preclinical data we have generated thus far is consistent with potential clinical advantages and possible differentiation compared to current single inhibitors of WEE1 and PKMYT1, both critically important cell cycle regulators with demonstrated clinical activity,” said Erick Gamelin, M.D., Ph.D., chief medical officer of Acrivon. “We are particularly encouraged by its compelling target selectivity and preclinical potency profile. With ACR-2316, we have demonstrated that the company’s data-driven, streamlined AP3 approach can generate molecules with desirable preclinical properties tailored for clinical monotherapy development.”
Additional information regarding ACR-2316 can be found in the company’s updated corporate presentation, which can be found on the company’s website using this link.
About Acrivon Therapeutics
Acrivon is a clinical stage biopharmaceutical company developing precision oncology medicines that it matches to patients whose tumors are predicted to be sensitive to each specific medicine by utilizing Acrivon’s proprietary proteomics-based patient responder identification platform, Acrivon Predictive Precision Proteomics, or AP3. The AP3 platform enables the creation of drug-specific proprietary OncoSignature companion diagnostics that are used to identify the patients most likely to benefit from Acrivon’s drug candidates. Acrivon is currently advancing its lead candidate, ACR-368, a selective small molecule inhibitor targeting CHK1 and CHK2 in a potentially registrational Phase 2 trial across multiple tumor types. The company has received fast track designation from the Food and Drug Administration, or FDA, for the investigation of ACR-368 as monotherapy based on OncoSignature-predicted sensitivity in patients with platinum-resistant ovarian or endometrial cancer. Acrivon’s ACR-368 OncoSignature test, which has not yet obtained regulatory approval, has been extensively evaluated in preclinical studies, including in two separate, blinded, prospectively-designed studies on pretreatment tumor biopsies collected from past third-party Phase 2 trials in patients with ovarian cancer treated
with ACR-368. In addition to ACR-368, Acrivon is also leveraging its proprietary AP3 precision medicine platform for developing its internally-discovered preclinical stage pipeline programs, consisting of its development candidate, ACR-2316, a selective, dual WEE1/PKMYT1 inhibitor, and additional programs targeting these two critical nodes in the DNA Damage Response, or DDR, pathways.
Forward-Looking Statements
This press release includes certain disclosures that contain “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 about us and our industry that involve substantial risks and uncertainties. All statements other than statements of historical facts contained in this press release, including statements regarding our future results of operations or financial condition, business strategy and plans and objectives of management for future operations, are forward-looking statements. 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,” “possible,” “predict,” “project,” “should,” “target,” “will,” or “would” or the negative of these words or other similar terms or expressions. Forward-looking statements are based on Acrivon’s current expectations and are subject to inherent uncertainties, risks and assumptions that are difficult to predict. Factors that could cause actual results to differ include, but are not limited to, risks and uncertainties that are described more fully in the section titled “Risk Factors” in our reports filed with the Securities and Exchange Commission. Forward-looking statements contained in this press release are made as of this date, and Acrivon undertakes no duty to update such information except as required under applicable law.
Investor and Media Contacts:
Adam D. Levy, Ph.D., M.B.A
alevy@acrivon.com
Alexandra Santos
asantos@wheelhouselsa.com
Exhibit 99.2 Acriv Acrivon on Thera Therapeutics peutics ACRIVON PREDICTIVE PRECISION PROTEOMICS (AP3): DRUG-TAILORED PATIENT SELECTION FOR CLINIC AL SUCCESS CORPORATE PRESENTATION SEPTEMBER 2023
FORWARD -LOOKING STATEMENTS 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 ACRIVON THERAPEUTICS
ACRIVON THERAPEUTICS: DRUG -TAILORED PATIENT SELECTION AIMING TO OVERCOME THE KEY ATTRITION FACTOR PREVENTING CLINICALLY ACTIVE DRUGS FROM REACHING MARKET AP3 Platform OncoSignature Test ACR-368 (Prexasertib) Pipeline - Acrivon’s proprietary - Clinically active (15-20% - Monotherapy candidate - Our proprietary predictive proteomics-based predictive ORR) Phase 2 DNA Damage ACR-2316, a selective, dual drug-tailored biopsy test precision medicine platform Response (DDR) inhibitor WEE1/PKMYT1 inhibitor, in - Extensively evaluated in licensed from Eli Lilly & Co. IND-enabling studies - Applied where NGS/genetics prospective preclinical studies, is insufficient and for our - Now being developed with - Additional co-crystallography including on blinded internal pipeline OncoSignature patient programs leveraging AP3 to pretreatment tumor biopsies selection for increased ORR optimize target selectivity from past trials with registrational intent profile and indication finding DNA for monotherapy 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) OROR RR == 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 3 ACRIVON THERAPEUTICS Tumor fractional change
ACCOMPLISHED LEADERSHIP TEAM Rasmus Holm-Jorgensen Erick Gamelin, M.D., Ph.D. Kristina Masson, Ph.D., M.B.A Peter Blume-Jensen, M.D., Ph.D. Eric Devroe, Ph.D. Site Head Acrivon AB, Co-Founder Chief Financial Officer Chief Medical Officer CEO, President, Founder Chief Operating Officer EVP Business Operations • Novo Nordisk Finance and IR • Founder and CEO, Opsonix • Executive Serono, Merck & Co., • Professor, CEO, large national • Cross-functional Leadership • Synageva pipeline expansion • Business executive MD Anderson Daiichi Sankyo cancer center and hospital Merrimack Pharmaceuticals, and $9bn sale to Alexion Cancer Center and Metamark • CSO Metamark - Marketed • Executive Amgen, Pfizer, Dynavax, MIT/BROAD ® • Kiniksa founding team, IPO • EIR Wyss Institute, Harvard prostate proteomic test ProMark MacroGenics; CMO STEP Pharma • Founder and CEO, OncoSignature AB and commercial launch • Associate, Flagship Pioneering • Inventor AP3 pt. selection platform • Led >100 ph 1-3 oncology trials (acquired by Acrivon Therapeutics) John van Duzer, Ph.D. Joon Jung, Ph.D. Katie Peterson, C.P.A. David Proia, Ph.D. Adam Levy, Ph.D., M.B.A. SVP, CMC VP, Head, Data VP, Finance and VP, Drug Discovery and SVP, Investor Relations Science Accounting Biology and Corporate Affairs Mary-Alice Miller, J.D. Praveen Marapaka, Ph.D. Bruce Close Parvin Miah Monica Phadnis Michail Shipitsin, Ph.D. SVP, General Counsel SVP, Global Regulatory VP, Quality and VP, Head, Human VP, Clinical VP, Biomarker Affairs Compliance Resources Operations Development 4 ACRIVON THERAPEUTICS
ACRIVON THERAPEUTICS AT A GLANCE Development Site (Boston) Precision-Proteomics Site (Lund/Copenhagen) • Drug and clinical biomarker assay development • Early pipeline drug programs • Clinical trials • BM identification and drug profiling • Market access pending approval • Mass spectrometry HQ LOCATED IN BOSTON - ACCESS TO LEADING PROTEOMIC HUB LOCATED IN MEDICON DRUG DISCOVERY, BIOTECH, AND PHARMA VALLEY - NORTHERN EUROPE`S LEADING LIFE SCIENCE CLUSTER Peter Blume-Jensen Jesper V. Olsen Kristina Masson CEO, President, EVP, Bus Ops, Academic Co-Founder. Co-Founder Novo-Nordisk Foundation Site Head and Co-Founder Protein Center, Cph. Founded 2018, IPO November 2022 (NASDAQ: ACRV) For more information, please visit https://acrivon.com 5 ACRIVON THERAPEUTICS
ACRIVON PREDICTIVE PRECISION PROTEOMICS, AP3 DNA Genomic Biomarkers are useful for patient selection in the smaller subset of cancers (<10%) with single gene driver mutations or known synthetic lethal context* RNA Protein P Dysregulated CANCER IS CAUSED BY DYSREGULATED PROTEIN ACTIVITY Protein Drug P Acrivon’s AP3 platform directly measure the disease-driving, dysregulated proteins and is designed to enable an exact match with the drug mechanism-of-action independent of genetic alterations Dysregulated Pathways (Acrivon meaning: “Exact, Accurate”) CANCER *Oncogenic Kinase Signaling: Blume-Jensen, P. and Hunter, T. Nature (2001) Synthetic lethality as an engine for cancer drug target discovery: Huang, A. et al. NatRevDrugDisc (2020) 6 ACRIVON THERAPEUTICS
AP3 PLATFORM ADDRESSES HIGH UNMET NEED BEYOND NGS -BASED PRECISION MEDICINE Acrivon Positioned to Increase Precision Oncology Market Size Current Precision Oncology Approaches Only Scratching the Surface 72 unique approvals Precision Oncology 1.0 51 drugs 31 genomic indications Approved indications: Approved indications: 18 cancer types HER2+ Breast Cancer CML (BCR-ABL) Only 5% of patients respond st HER2+ Gastric Cancer Ph+ ALL 1 Gen Precision Oncology Currently Unaddressed Precision Oncology 2.0 Solid Tumors (NTRK)) IDH mutation in AML NSCLC (NTRK) and NSCLC (KRAS G12C) CRC (ROS1, ALK) Class II and III BRAF 95% of patients are currently unaddressed by Bladder (FGFR3) Solid Tumors (NRG1) kinase alterations: N/A traditional genetics-based precision oncology Predictive Precision Proteomics Aiming to make targeted therapeutic solutions available to broader group of cancer patients Sources: Company Filings, ACS, CDC, NCI, Wall Street Research 7 ACRIVON THERAPEUTICS
AP3 PLATFORM: DRUG RESPONSE PREDICTION IN INDIVIDUAL PATIENTS PROPRIETARY WORKFLOW INTEGRATING PROVEN TECHNOLOGIES STEP 1 STEP 2 STEP 3 THERAPEUTIC PACKAGE PATIENT RESPONDERS BIOMARKER IDENTIFICATION Predicted Predicted Acrivon drug with predictive BM assay Optimal indications and combinations Non-responder Responder CLASS 1 BM 3 AP DRUG PROFILING HIGH RES PROTEOMICS BY MS CLASS 2 BM Resistant Sensitive + AI-DRIVEN No benefit Benefit ® OncoSignature CLASS 3 BM CLINICAL SIGNATURE ASSAY PROSPECTIVE RESPONSE PREDICTION ON PRETREATMENT BIOPSY 3-6 BIOMARKERS BIOMARKER VALIDATION Patients without biomarkers critical CELL LINES, PDX, HUMAN TISSUE for drug sensitivity efficiently excluded “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 \ 8 ACRIVON THERAPEUTICS
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 ACR-368 Endometrial Cancer 2H 2023 (CHK1/CHK2) LDG Combination ACR-368 Monotherapy Bladder Cancer LDG Combination + Option to Initiate Additional Trials in HPV SCC (H&N, Anal, Cervical) and sarcomas OncoSignature- ACR-2316 IND-Enabling Predicted Monotherapy IND Filing in Q4 2024 (WEE1/ PKMYT1) Studies Sensitive Tumors Additional Development AP3-driven co-crystallography Candidates programs 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 9 ACRIVON THERAPEUTICS
ACR -368: A CLINICALLY ACTIVE PHASE 2 CHK1/2 INHIBITOR • ATP-competitive inhibitor of CHK1 (0.9 nM) and CHK2 (8 nM) • Good ADME properties, minimal drug-drug interaction (DDI) potential • Discovered by Array Biopharma, acquired by Eli Lilly & Company • CoM patent exp. Oct., 2030; Salt-form exp. Apr., 2037 ACR-368 (MW): 365.4 M G 1 G1/S-defective cancers Defective G1/S rely on CHK1-regulated Cancer Checkpoint G2/M Checkpoint cell cycle checkpoints Cell Cycle CHK1 pauses cell cycle to S Phase CHK1 G S 2 Checkpoint enable DNA repair CHK1 • Durable monotherapy activity: Platinum-resistant ovarian and squamous cell cancers (Anal and H&N) • Large safety database, favorable safety profile: >1,000 patients treated (~50% mono, ~50% in combination) • Ideal for AP3 method: Proven clinical activity, but requires patient responder identification to achieve sufficient ORR 10 ACRIVON THERAPEUTICS
CLINICAL OVERVIEW OF ACR -368 MONOTHERAPY (PAST DATA) # Indication Trial ORR (confirmed) Median DoR° Reference HGSOC* (BRCA wild type, primarily Phase 2 single center 29% >10 months^ Lee et al, Lancet platinum-resistant) (NCI) Oncology, 2018 HGSOC (BRCA wild type and mutant; Phase 2 multi-center 12.1% (platinum-resistant) 5.6 months Konstantinopoulos platinum-resistant and refractory) (Lilly) et al; Gynec. Oncol.: 2022 Squamous cell cancer (anal cancer, Phase 1b multi-center 19% HPV+ H&N 7 months (HPV+ H&N) Hong et al, CCR, head & neck cancer [H&N]) (Lilly) 15% anal cancer 12 months anal cancer 2018 Dosing and Administration 2 • IV q14d (RP2D = 105 mg/m ) Safety summary • Acceptable safety profile in >1,000 patients - No clinical or regulatory holds imposed across all clinical studies to date • Primary adverse events ≥ grade 3 were hematological (manageable neutropenia and thrombocytopenia) • Limited ≥ grade 3 non-hematological toxicities (≤7% for all AEs) • Drug-related discontinuations <1-2% # *High grade serous ovarian cancer; ^Updated post-publication; Overall response rate; °Duration of Response 11 ACRIVON THERAPEUTICS
PAST PHASE 2 TRIALS IN HIGH GRADE SEROUS OVARIAN CANCER NCI single-center Phase 2 study (N=28) Lilly-sponsored multi-center (46 center, 8 country) Phase 2 study (N=169) • Heavily pre-treated patients; median 5 prior lines • All lines of prior therapy, BRCA wt and mt, incl. prior PARPi • Pretreatment tumor biopsies mandated • Pretreatment tumor biopsies mandated RESULTS RESULTS • ORR 29%; mDoR >10 months (post-publication) • ORR 12.1% (excl. unconfirmed); mDoR =5.6 months mut mut • No genetic correlation with p53 , DDR , or CCNE1 • No correlation with genetic alterations 100 N = 169 PATIENTS COHORT DESCRIPTION PERCENT CONFIRMED ORR (95 % C.I.) Best response 50 Cohort 1 (53) Plat resistant BRCA wt; ≥3 lines of 11.3 (4.3 to 23.0) (N = 24 evaluable patients) prior therapy 0 Cohort 2 (46) Plat resistant BRCA wt; < 3 lines of 13.0 (4.9 to 26.3) prior therapy (50) Cohort 3 (41) Plat resistant BRCA mt, any line of 12.2 (4.1 to 26.2) therapy (must include prior PARPi ) Cohort 4 (29) Plat refractory, any BRCA, any line of 6.9 (0.8 to 22.8) (100) therapy Platinum-sensitive Platinum-resistant Platinum-refractory Still on study Study ID Lee et al; Lancet Oncology: 2018 Konstantinopoulos et al; Gynec. Oncol.: 2022 10 14 36 48 7 42 5 46 6 24 35 38 33 23 47 28 17 41 4 31 1 37 40 29 Number of previous lines of therapy 2 5 5 2 5 1 2 3 5 5 6 3 5 6 3 4 4 5 2 13 1 6 5 4 PFS (months) 2.0 2.0 2.0 2.0 2.0 9.5 2.0 2.0 8.0 4.0 8.5 3.0 16.0 4.0 7.5 10.0 13.0 3.5 9.0 7.5 9.0 13.5 12.5 16.5 Mutations in DDR genes CCNE1 gene amplification ü Past trials suggest unenriched all-comer ORR in HGS ovarian cancer is ~15-20% CCNE1 mRNA upregulation ü Durable clinical activity in most responders CCNE1 protein overexpression* ü No predictive biomarkers identified, need for alternative biomarker approach (ideal for AP3) Positive Negative Amplification Copy number gain Upregulation 12 ACRIVON THERAPEUTICS Best response (%)
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 DMSO 4NQO 4NQO+Prex OncoSignature 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 13 ACRIVON THERAPEUTICS
ONCOSIGNATURE TESTS: USAGE IN THE CLINIC Pretreatment Treatment decision tumor biopsy based on patient stratification Predicted Predicted Sample processing Responder Non-responder 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 14 ACRIVON THERAPEUTICS
CONSISTENT ACR -368 ONCOSIGNATURE PERFORMANCE ACROSS PRECLINICAL STUDIES Tissue ID. BM1 BM2 BM3 Fov060265 0.69 0.79 0.73 Fov050855 0.94 0.71 0.67 Fov041300 0.89 0.23 0.55 Fov060380 0.95 0.62 0.51 Fov060050 0.85 0.23 0.51 Fov041285 0.69 0.19 0.5 Fov100142 0.47 0.76 0.47 Fov050764 0.82 0.22 0.47 Fov041267 0.4 0.36 0.36 Fov100146 0.84 0.57 0.26 Fov060382 0.44 0.45 0.22 Fov041269 0.37 0.21 0.2 Fov060302 0.29 0.22 0.15 Fov020067 0.89 0.38 0.09 Fov100003 0.9 0.89 0.08 Fov050700 0.17 0.17 0.07 • Prediction of the fraction of human tumors sensitive to Fov050139 0.63 0.66 0.05 Fov041138 0.36 0.11 0.05 Fov060152 0.24 0.3 0.03 Fov030062 0.57 0.14 0.02 Fov060133 0.94 0.43 0.01 Fov050666 0.93 0.38 0.01 Fov060371 0.88 0.93 0 Fov020497 0.61 0.43 0 Fov010706 0.54 0.14 0 single agent ACR-368 Fov020386 0.11 0.09 0.12 Fov050734 0.11 0.06 0.08 Fov040872 0.23 0.04 0.36 Fov050659 0.29 0.01 0.02 Fov060293 0.42 0 0 Fov060210 0.1 0.1 0 Fov050840 0.07 0.29 0.01 Fov040855 0.05 0 0.22 o Selection rate 30-40% across lead indications Fov050816 0.04 0.33 0.12 Fov060355 0.04 0.27 0 Fov010252 0.03 0.17 0.02 Fov010682 0.03 0.03 0 Fov060553 0.03 0.02 0.03 71768C3 0.02 0 0 Fov150230 0 0.36 0.12 Fov060308 0 0 0 • Identification of additional human tumor types predicted sensitive to single agent ACR-368 o Endometrial and bladder cancer • Prediction of treatment outcome in human PDX models o ORR enrichment to ≥ 55%; AUC of 0.88 and 0.9 • Two separate, prospectively designed, blinded studies of biopsies from past Phase 2 trials with ACR-368 in patients with platinum-resistant ovarian cancer o ORR enrichment to 47% (NCI) and 58% (Lilly multi-center) 15 ACRIVON THERAPEUTICS
ACR -368 ONCOSIGNATURE PREDICTION OF DRUG SENSITIVITY: BIOMARKER QUANTITATION ACROSS HUMAN CANCER PATIENT SAMPLES Class 1 BM Class 2 BM Class 3 BM Tissue ID. BM1 BM2 BM3 Fov060265 0.69 0.79 0.73 Fov050855 0.94 0.71 0.67 Fov041300 0.89 0.23 0.55 Fov060380 0.95 0.62 0.51 Fov060050 0.85 0.23 0.51 Patient Fov041285 0.69 0.19 0.5 Fov100142 0.47 0.76 0.47 High Fov050764 0.82 0.22 0.47 Fov041267 0.4 0.36 0.36 Fov100146 0.84 0.57 0.26 Fov060382 0.44 0.45 0.22 Fov041269 0.37 0.21 0.2 Fov060302 0.29 0.22 0.15 Predicted Responder Fov020067 0.89 0.38 0.09 Fov100003 0.9 0.89 0.08 Patient with drug target dependency Fov050700 0.17 0.17 0.07 Fov050139 0.63 0.66 0.05 Fov041138 0.36 0.11 0.05 Fov060152 0.24 0.3 0.03 Fov030062 0.57 0.14 0.02 Fov060133 0.94 0.43 0.01 Fov050666 0.93 0.38 0.01 Fov060371 0.88 0.93 0 Fov020497 0.61 0.43 0 Fov010706 0.54 0.14 0 Class 1 BM Class 2 BM Class 3 BM Fov020386 0.11 0.09 0.12 Fov050734 0.11 0.06 0.08 Fov040872 0.23 0.04 0.36 Fov050659 0.29 0.01 0.02 Fov060293 0.42 0 0 Fov060210 0.1 0.1 0 Patient Fov050840 0.07 0.29 0.01 Fov040855 0.05 0 0.22 Low Fov050816 0.04 0.33 0.12 Fov060355 0.04 0.27 0 Fov010252 0.03 0.17 0.02 Fov010682 0.03 0.03 0 Fov060553 0.03 0.02 0.03 71768C3 0.02 0 0 Predicted Non-Responder Fov150230 0 0.36 0.12 Fov060308 0 0 0 Patient with no drug target dependency efficiently excluded 16 ACRIVON THERAPEUTICS
BIOPSY STUDY 1: SUBSTANTIAL RESPONSE AND PFS BENEFIT IN PREDICTED RESPONDERS (BLINDED, PROSPECTIVELY DESIGNED STUDY) • Available pretreatment tumor biopsies from past phase 2 trials at NCI with ACR-368 in platinum-resistant ovarian cancer were obtained rd • OncoSignature scores were generated blinded to treatment outcome at Acrivon and analyzed by 3 party biostatistician in prospectively designed study PR OncoSignature Prediction: OncoSignature Prediction: SD Non-Responders Responders 1.2 PR SD PR 0.9 PR SD SD mPFS Predicted Responders 0.6 PR mPFS = 7.9 months (days) PR SD All Predicted R 238.0 SD 0.3 All Predicted NR 66.5 SD SD in predicted R 238.0 PR SD in predicted NR 108.0 PD 0.0 mPFS in R SD SD (0.3) SD Predicted Non-Responders SD PD mPFS = 2.2 months (0.6) PD ORR = 0% ORR = 47% PD mPFS in NR PD (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 0 100 200 300 400 500 600 700 Duration (days) Result: ORR ~47%; mPFS = 7.9 months 17 ACRIVON THERAPEUTICS Tumor fractional change
TWO ADDITIONAL HIGH UNMET NEED SOLID CANCERS PREDICTED ACR -368 -SENSITIVE THROUGH HUMAN TUMOR SAMPLE SCREENING HGS Ovarian Sq. NSCLC Bladder cancer Endometrial cancer Tissue ID BM1 BM2 BM3 Tissue ID BM1 BM2 BM3 Tissue ID BM1 BM2 BM3 Tissue ID BM1 BM2 BM3 Fov010719 0.96 0.68 0.78 Rln020132 0.17 0.26 0.02 Fur021904 0.16 0.38 0.86 Ubd040512 0.99 0.48 0.65 Fov060075 0.54 0.51 0.38 Rln010099 0.08 0.06 0.01 Fur021989 0.86 0.17 0.71 Fov020069 0.31 0.30 0.38 Ubd040016 0.30 0.58 0.63 Fov010809 0.94 0.16 0.36 Rln020029 0.48 0.28 0.00 Fur021785 0.14 0.55 0.69 Fov030970 0.93 0.28 0.33 Rln020005 0.34 0.06 0.00 Ubd040039 0.43 0.33 0.54 Fur021984 0.87 0.62 0.63 Fov010892 0.95 0.72 0.32 Rln010095 0.28 0.02 0.00 Fov040102 0.98 0.23 0.29 Fur021937 0.81 0.65 0.61 Ubd030040 0.88 0.73 0.45 Fov050734 0.95 0.22 0.25 Rln020051 0.11 0.01 0.14 Fur022037 0.12 0.22 0.54 Fov040164 0.94 0.69 0.21 Ubd040287 0.63 0.34 0.40 Rln010167 0.14 0.00 0.00 Fur130035 0.55 0.48 0.50 Fov020776 0.60 0.18 0.19 Fov050764 0.77 0.35 0.17 Rln020284 0.09 0.00 0.00 Fur030113 0.90 0.65 0.31 Ubd040151 0.65 0.72 0.34 Fov060380 0.98 0.58 0.17 Rln020141 0.05 0.18 0.00 Fur020288 0.60 0.26 0.30 Fov010172 0.85 0.51 0.17 Ubd040225 0.76 0.64 0.33 Rln020032 0.05 0.01 0.00 Fov100051 0.92 0.21 0.16 Fur020281 0.21 0.57 0.27 Fov100142 0.58 0.82 0.14 Rln010199 0.05 0.06 0.03 Fur130010 0.79 0.75 0.27 Ubd040282 0.27 0.16 0.26 Fov020160 0.58 0.30 0.14 Rln020197 0.04 0.00 0.00 Fur021781 0.75 0.31 0.26 Fov010252 0.96 0.21 0.14 Ubd060279 0.29 0.13 0.16 Fov050617 0.61 0.76 0.14 Rln020250 0.04 0.00 0.00 Fur140135 0.72 0.35 0.25 Fov060302 0.24 0.29 0.13 Rln020190 0.04 0.00 0.00 Ubd030229 0.79 0.39 0.15 Fur150643 0.61 0.73 0.22 Fov050836 0.79 0.28 0.13 0.02 0.00 0.01 Fov060050 0.86 0.25 0.12 Rln020243 Fur021558 0.61 0.33 0.22 Ubd040104 0.84 0.58 0.15 Fov041285 0.50 0.15 0.11 Rln020012 0.02 0.41 0.07 Fur020131 0.73 0.57 0.18 Fov030109 0.97 0.39 0.10 Rln010148 0.02 0.05 0.06 Ubd040056 0.79 0.83 0.14 Fov020386 0.58 0.08 0.09 Fur021367 0.30 0.55 0.18 Fov020067 0.96 0.44 0.08 Rln020006 0.01 0.00 0.02 Ubd070017 0.62 0.40 0.14 Fur020506 0.94 0.68 0.17 Fov110030 0.92 0.39 0.08 Rln020296 0.01 0.00 0.00 Fur020163 0.23 0.33 0.12 Fov041267 0.44 0.39 0.06 Ubd040204 0.12 0.76 0.12 Rln020186 0.01 0.02 0.02 Fov100004 0.95 0.36 0.05 Fur130009 0.18 0.69 0.10 Fov060003 0.78 0.24 0.05 Rln020166 0.01 0.05 0.01 Ubd040131 0.95 0.81 0.10 Fur021197 0.35 0.70 0.09 Fov020061 0.87 0.20 0.05 Rln020208 0.01 0.01 0.00 Fov041269 0.70 0.38 0.04 Fur010587 0.18 0.34 0.08 Ubd040142 0.84 0.62 0.09 Fov010873 0.97 0.53 0.03 Rln020327 0.01 0.00 0.00 Fur140260 0.77 0.51 0.07 Fov041300 0.90 0.27 0.03 Rln020343 0.01 0.00 0.01 Ubd030138 0.54 0.11 0.09 Fov060152 0.63 0.59 0.02 Fur021980 0.30 0.70 0.06 Rln020233 0.01 0.04 0.06 Fov060265 0.48 0.38 0.02 Ubd040043 0.65 0.92 0.08 Fur020831 0.18 0.45 0.04 Fov100146 0.66 0.63 0.01 0.00 0.26 0.00 Rln020007 Fov060382 0.28 0.37 0.01 Fur020809 0.36 0.58 0.00 Rln020138 0.00 0.01 0.01 Ubd050077 0.72 0.46 0.08 Fov010706 0.87 0.70 0.01 Fur030068 0.41 0.63 0.00 Fov060133 0.93 0.69 0.01 Rln020321 0.00 0.00 0.01 Ubd020464 0.73 0.63 0.07 Fur030131 0.50 0.68 0.00 Fov020059 0.97 0.27 0.01 Rln020231 0.00 0.00 0.01 Fov010682 0.85 0.59 0.01 Fur021437 0.98 0.37 0.00 Ubd040177 0.89 0.84 0.04 Rln020088 0.00 0.00 0.00 Fov100220 0.69 0.18 0.00 Fur021620 0.41 0.10 0.33 Fov010750 0.98 0.81 0.00 Rln020169 0.00 0.16 0.00 Ubd040214 0.29 0.17 0.03 Fov060434 0.91 0.56 0.00 Fur020073 0.29 0.06 0.21 Rln020164 0.00 0.00 0.00 Fov050840 0.16 0.23 0.00 Fur020115 0.56 0.02 0.00 Ubd040128 0.77 0.29 0.03 Fov040044 0.81 0.54 0.00 Rln030301 0.00 0.18 0.00 Fur020107 0.68 0.00 0.17 Fov030062 0.10 0.17 0.00 Rln020083 0.00 0.00 0.00 Ubd050035 0.17 0.33 0.02 Fov010563 0.71 0.58 0.00 Fur020703 0.05 0.27 0.00 Rln020086 0.00 0.00 0.00 Fov010903 0.82 0.09 0.00 Ubd080024 0.18 0.28 0.01 Fur021233 0.05 0.66 0.00 Fov050139 0.40 0.57 0.00 Rln020160 0.00 0.00 0.00 Fov020262 0.91 0.09 0.00 Fur021561 0.04 0.01 0.14 0.00 0.00 0.00 Ubd040101 0.26 0.31 0.01 Rln020096 Fov060553 0.84 0.08 0.00 Fur020837 0.04 0.06 0.04 Fov050417 0.72 0.26 0.00 Rln020140 0.00 0.00 0.00 Ubd030151 0.79 0.61 0.00 Fur020266 0.04 0.40 0.03 Fov050855 0.92 0.61 0.00 Rln020302 0.00 0.00 0.00 Fov060371 0.81 0.82 0.00 Fur020280 0.03 0.42 0.25 Ubd040098 0.35 0.40 0.00 Fov040694 0.59 0.81 0.00 Rln020253 0.00 0.00 0.00 Fur030193 0.03 0.10 0.02 Fov030128 0.99 0.68 0.00 0.00 0.00 0.08 Rln020331 Ubd040008 0.75 0.90 0.00 Fov020497 0.83 0.59 0.00 Fur021641 0.02 0.30 0.01 Rln020002 0.00 0.00 0.00 Fov050700 0.37 0.25 0.00 Ubd040162 0.97 0.10 0.00 Fur020121 0.02 0.14 0.01 Fov060210 0.48 0.22 0.00 Rln020415 0.00 0.00 0.00 Fov020106 0.95 0.07 0.11 Fur030025 0.01 0.03 0.01 Rln020298 0.00 0.00 0.00 Ubd040341 0.19 0.09 0.03 Fov041138 0.27 0.06 0.00 Fur021248 0.01 0.32 0.05 Rln010086 0.00 0.00 0.00 Fov020002 0.57 0.06 0.08 Ubd070027 0.20 0.08 0.01 Fur021721 0.01 0.35 0.00 Fov020111 0.16 0.05 0.11 Rln020361 0.00 0.11 0.00 Fov040872 0.31 0.04 0.01 Fur021423 0.01 0.35 0.04 Rln020383 0.00 0.01 0.06 Ubd040030 0.95 0.07 0.01 Fov050666 0.99 0.03 0.00 Fur020604 0.01 0.02 0.00 Fov050659 0.81 0.03 0.00 Rln020386 0.00 0.03 0.00 Ubd040067 0.81 0.06 0.03 71768C3 0.44 0.03 0.05 Fur020155 0.01 0.09 0.07 Rln020248 0.00 0.00 0.00 Fov050555 0.20 0.02 0.01 Ubd040074 0.60 0.03 0.10 Fur020408 0.01 0.39 0.02 Rln020221 0.00 0.00 0.00 Fov020193 0.69 0.02 0.00 Fov031530 0.81 0.01 0.10 Fur020821 0.00 0.22 0.08 Rln020184 0.00 0.00 0.01 Ubd040213 0.85 0.02 0.15 Fov030763 0.59 0.01 0.29 0.00 0.00 0.05 Fur030114 0.00 0.73 0.00 Rln010119 Fov021215 0.52 0.01 0.07 Ubd040055 0.07 0.03 0.02 Fov040855 0.11 0.01 0.04 Rln020380 0.00 0.00 0.02 Fur021562 0.00 0.07 0.00 Fov050706 0.12 0.01 0.00 Fur020786 0.00 0.00 0.00 Rln020244 0.00 0.00 0.00 Ubd040050 0.06 0.58 0.00 Fov030120 0.70 0.01 0.00 Fur021353 0.00 0.00 0.00 Fov030286 0.10 0.00 0.00 Rln020324 0.00 0.00 0.00 Ubd020068 0.05 0.11 0.18 Fov020132 0.03 0.00 0.01 Rln010122 0.00 0.00 0.00 Fur021216 0.00 0.21 0.04 Fov020486 0.03 0.00 0.00 Rln010079 0.00 0.03 0.00 Ubd040144 0.03 0.57 0.00 Fur021372 0.00 0.08 0.40 Fov050816 0.03 0.25 0.00 Fov020263 0.01 0.29 0.06 Rln020282 0.00 0.00 0.00 Fur021334 0.00 0.04 0.01 Ubd040242 0.00 0.05 0.00 Fov050388 0.01 0.00 0.05 Rln020249 0.00 0.00 0.00 Fur021642 0.00 0.38 0.01 Fov010181 0.00 0.00 0.00 Ubd040256 0.00 0.17 0.01 Rln020255 0.00 0.00 0.00 Fur021075 0.00 0.19 0.07 Fov150230 0.00 0.06 0.19 OncoSignature-positive = 30% OncoSignature-positive = 0% OncoSignature-positive = 30-50% OncoSignature-positive = 30-40% (ORR in past trials: 12+% and 29%) (ORR in past trial: 0%) 18 ACRIVON THERAPEUTICS
TWO ATTRACTIVE ACR -368 -SENSITIVE CANCER TYPES IDENTIFIED Bladder cancer patient samples Endometrial patient samples Pa Pta ie tint ent 1 1 LO LO W W P Pa at tiie ent nt 2 2 H HIG IGH H PP aa ttie ient nt 1 1-L LO OW W P Paattiieent nt 22 -H HIG IG H H Class 1 BM Class 1 BM CHK1 S296 Class 2 BM Class 2 BM KAP1 S473 Class 3 BM Class 3 BM CCNE1 Predicted Predicted Predicted Predicted Non-Responders Responders Non-Responders Responders ACR-368 OncoSignature screening of human cancer samples 19 ACRIVON THERAPEUTICS
A SUBSET OF ENDOMETRIAL AND BLADDER PDX MODELS ARE HIGHLY SENSITIVE TO ACR -368 Bladder PDX Endometrial PDX 1,500 2,000 2,000 BL001 2,000 BL002 Endo 1 Endo 2 1,500 1,500 1,000 ACR-368-sensitive 1,000 1,000 1,000 500 responders 500 500 0 0 0 0 0 5 10 15 20 25 30 0 7 14 21 0 7 14 21 28 0 5 10 15 20 25 30 PDX-L PDX-H Day Study Days Study Days Day 2,000 1,500 2,500 3,000 BL003 BL004 Endo 3 Endo 4 2,000 2,250 1,000 BM1 1,500 1,500 1,000 1,000 500 750 500 0 0 0 0 0 7 14 0 5 10 15 20 25 30 0 5 10 15 20 25 30 0 7 14 21 28 Study Days Study Days Day Day 3,000 3,500 1,500 1,500 BL005 BL006 Endo 5 Endo 6 BM2 2,250 2,625 1,000 1,000 1,500 1,750 500 500 750 875 0 0 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 0 7 14 0 7 14 21 BM3 Study Days Study Days Day Day 2,000 2,000 2,000 2,500 BL007 BL008 Endo 7 Endo 8 2,000 1,500 1,500 1,000 1,000 1,000 1,000 500 500 Predicted Predicted 0 0 0 0 0 7 14 21 28 35 0 7 14 21 28 Responders Non-Responders 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Day Day Study Days Study Days 20 ACRIVON THERAPEUTICS Tumor Volume (mm3) Tumor Volume (mm3) Tumor Volume (mm3) Tumor Volume (mm3) Tumor Volume (mm3) Tumor Volume (mm3) Tumor Volume (mm3) Tumor Volume (mm3) Cubic Millimeters Cubic Millimeters Cubic Millimeters Cubic Millimeters Cubic Millimeters Cubic Millimeters Cubic Millimeters Cubic Millimeters
AP3 UNCOVERS ACTIONABLE ACR -368 RESISTANCE MECHANISMS UNBIASED AND INDEPENDENT OF GENETIC INFORMATION 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 21 ACRIVON THERAPEUTICS
ULTRA -LOW DOSE GEMCITABINE SENSITIZES OVARIAN CANCER CELL LINES TO ACR -368 OVCAR3-Parental Gemcitabine alone in Ovarian-Parental OVCAR3-Resistant Ovarian-Resistant Gemcitabine alone OVCAR3-P and OVCAR3-R 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 EC50 Prexasertib Abs EC50 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 22 ACRIVON THERAPEUTICS % Cell viability realtive to DMSO % Cell viability realtive to DMSO % Cell viability realtive to DMSO
ENROLLING AND DOSING ACR -368 IN THREE HIGH UNMET NEED INDICATIONS: OVARIAN, ENDOMETRIAL AND BLADDER CANCER • RP2D of ACR-368 based on OncoSignature+ Single Arm Simon 2 Stage Monotherapy predicted sensitivity using our Phase 2b with Registrational Intent ACR-368 OncoSignature Assay Stage 1 St a g e 2 run by our CDx partner (N= 23 per cohort) (N= 48 per cohort) Ovarian Endometrial 1 • 45 sites currently activated Bladder Single Arm Phase 1b/2 Exploratory OncoSignature- Combination with Low Dose Gemcitabine • Key opinion leaders, some with extensive experience using Phase 2 Expansion Phase 1b (N= ~21) (N= 33 per cohort) ACR-368 from previous trials are actively participating FDA Fast Track Designation granted May 8, 2023 for ACR-368 monotherapy in OncoSignature- positive patients with Platinum-Resistant Ovarian Cancer and Endometrial Cancer 1 https://clinicaltrials.gov/ct2/show/NCT05548296 23 ACRIVON THERAPEUTICS
WEE1 AND PKMYT1 VALIDATED CANCER TARGETS: IDEAL FOR AP3 APPROACH • 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: – Adavosertib (AstraZeneca) – Debio0123 (Debiopharm) – Azenosertib (Zentalis Pharmaceuticals) Ghelli Luserna di Rorà et al. J. Hematol Oncol, 2020 – SGR-3515 (preclinical, Schrödinger) – Lunresertib (Repare Therapeutics) ü Single agent clinical activity (WEE1 and PKMYT1) ü Synergy identified with dual inhibition, potential for strong monotherapy clinical activity ü Correlation with genetic alterations challenging, CCNE1 association being explored by others ü Acrivon intends to leverage OncoSignature for optimal patient selection 24 ACRIVON THERAPEUTICS
INTERNAL PIPELINE: ADVANCING DEVELOPMENT CANDIDATE ACR -2316 AND OTHER DDR PROGRAMS - LEVERAGING AP3 Rationale • Leveraging our AP3 patient selection platform for high clinical POS • Potentially optimal profile for monotherapy clinical development and for AP3-identified rational drug combinations High throughput AP3 profiling ACR-2316 and other DDR programs Global analysis Pairwise analysis Volcanoplot, FDR=0.05 > 10 k p-sites. ANOVA, HA, FDR=0.05 • >39 high resolution co-crystals (1.5-3.1 Å) and AP3-driven SAR • Novel WEE1- and PKMYT1-selective structural series and lead candidates • Optimal selectivity profiles generated based on AP3 profiling Causal networks Activity analysis Motifs ACR-2316 in IND-enabling studies • High resolution co-crystals with WEE1 and PKMYT1 • Novel, potent dual inhibitor (single digit nM potency) Kinase score GSEA • Designed to overcome WEE1 and PKMYT1 single inhibitor resistance • Potent single agent activity AP3 used for biologically relevant selectivity profiling 25 ACRIVON THERAPEUTICS
Phosphosites AP3 PLATFORM: PROPRIETARY PIPE FOR AUTOMATED ANALYSES WITH ACTIONABLE RESULTS IN ONE DAY Proprietary machine learning algorithms applied to state-of-the-art AP3 MS-based phosphoproteomics for all compound projects Unbiased PD marker identification High throughput MS Dose-response of target engagement AP3 profiles of WEE1 inhibitors Plate 1 – Compound 1 Pathway mapping Plate 2 – Compound 2 Mechanism of action Plate 3 – Compound 3 Agonist Inhibitor pEC50 Increased Decreased Activity Activity pEC50 = -log10(EC50) 26 ACRIVON THERAPEUTICS
AP3: TIGHT, HIGH -RESOLUTION DATA WITH DEEP COVERAGE 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 ü Acrivon proprietary compound data (~20 million data points per experiment); dozens of compounds profiled ü Miniaturized, high throughput, scalable: One week turn-around, automated AI computational analyses in 1 day ü Actionable results: Resistance mechanisms, rational combinations, drug-tailored OncoSignature patient selection 27 ACRIVON THERAPEUTICS
AP3 REVEALS DRUG -REGULATED KINASE ACTIVITY IN INTACT CELLS NOT DETECTABLE BY STANDARD METHODS KinomeScan @ 1µM Substrate motif-inferred kinase activity* ACR-2316 ACR-2316 ACR-2743 ACR-2743 (previous lead candidate) MAPK3K4 PRKCE GAK PKMYT1 PLK1 PLK2 WEE2 PLK3 WEE1 YSK4 Time : 60 minutes Dose : 20 nM * Kinase activity based on proprietary PTM-SEA hybrid method 28 ACRIVON THERAPEUTICS
AP3 RECIPROCAL QUENCHING REVEALS OPTIMAL TARGET POTENCY PROFILE FOR DUAL WEE1/PKMYT1 INHIBITOR Sensitive Resistant Sensitive Resistant WEE1i and PKMYT1i dual inhibition synergy Target substrates Target substrate of ACR-368 Target substrate of PKMYT1i Target substrates Optimal potency ratio results in significant synergy WEE1i and ACR-368 Centered log2FC (treated vs. DMSO) 4 -4 1043 p-sites from 298 proteins 29 ACRIVON THERAPEUTICS HCL, Euclidean PKMYT1i WEE1i PKMYT1i WEE1i PKMYT1i WEE1i PKMYT1i WEE1i
DUAL WEE1/PKMYT1 INHIBITOR ACR -2316 DEMONSTRATES STRONG POTENCY AND SELECTIVITY KinomeScan (106 kinases @ 1000 nM) Benchmark WEE1 inhibitor WEE1 Benchmark Dual inhibitor show potent cell cycle effects compared to benchmark inhibitors PKMYT1 inhibitor PKMYT1 DMSO ACR-2316 (Dual) G1 100 nM, 24 hour Dual inhibitor G2/M S ACR-2316 PKMYT1 WEE1 1N 2N DNA content 30 ACRIVON THERAPEUTICS
ACR -2316 DEMONSTRATES POTENT MONOTHERAPY ANTI - TUMOR ACTIVITY IN TUMOR -BEARING MICE ACR-2316 anti-tumor activity (QDx7; PO) ACR-2316 anti-tumor activity (5d on/2d off; PO) ACR-2316 causes tumor regression, in contrast to the highest tolerated doses of benchmark WEE1 and PKMYT1 inhibitors, which only result in tumor inhibition 31 ACRIVON THERAPEUTICS
ACR-2316 FAVORABLE PRECLINICAL PROFILE Target ACR-2316 MOA • AP3 phosphoproteomics-based, optimized MOA; selective, dual WEE1/PKMYT1 inhibition ü Potency • In vitro kinase activity, IC ≤ 10 nM ü 50 • Potent target engagement in optimized ratio ü • Activity across sensitive human tumor cell lines, CC <100 nM ü 50 ü Selectivity • Kinase panel profiling – highly selective (kinome selectivity) ü • AP3 profiling confirms desirable CDK and PLK activation for mitotic catastrophe/apoptosis ü ADME/PK • Orally bioavailable ü • T½ suitable for once/day dosing ü In vitro safety • Low in vitro hERG (>10 µM) and CYP inhibition and induction (>1 µM) Solubility • > 50 µM for active compounds ü PPB • < 90% ü In vivo efficacy • Demonstrated potent target engagement intratumorally in vivo ü • Potent single agent activity in CDX models ü 32 ACRIVON THERAPEUTICS
ACR-2316 DEVELOPMENT: NEXT STEPS • Completion of IND-enabling studies • ACR-2316 OncoSignature generation • OncoSignature indication finding and prioritization for clinical development • Planned IND filing Q4 2024, pending IND-enabling studies, in preparation for monotherapy clinical development with OncoSignature patient selection 33 ACRIVON THERAPEUTICS
AP3: BROAD APPLICABILITY AND UNTAPPED POTENTIAL DELIVERABLES Patient responder Indication Rational drug Resistance Pharmacodynamic (PD) identification finding combinations mechanisms biomarkers AP3 Patient selection for Patient selection for novel Continued in-licensing Rational drug design SAR broadly applicable drugs targets and drugs (druggable drivers, drug MOA, (active drugs, no patient rational drug combinations (CDK4/6, K-RAS, ADCs) (CRISPR, degraders, epigenetic) selection path) APPLICATIONS 34 ACRIVON THERAPEUTICS
AP3 GENERATES VALUE ACROSS MULTIPLE DIMENSIONS Next-Generation Proteomics-Based Precision Medicine Clinical Biomarkers Potential for Predictive Signature Assays Paradigm Shift for Patient Outcomes AP3 Drug Discovery SAR Platform Selectivity Optimization Indication Finding AI + ML enabled Intellectual Property Informs in-licensing Extends Exclusivity PD Markers Resistance Mechanisms Rational Drug Combinations 35 ACRIVON THERAPEUTICS
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 36 ACRIVON THERAPEUTICS
FINANCIAL HIGHLIGHTS AS OF Q2 2023 Cash and marketable securities Projected runway into Fully Diluted Shares Outstanding $151.0M 27.0M 2025 Balance sheet Current operating plan, assuming Shares and equity grants 30-June-2023 no additional financing outstanding 30-June-2023 Unaudited. 37 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. 38 ACRIVON THERAPEUTICS 0 0 100000 100000 200000 300000 200000 400000 500000 300000
APPENDIX 39 ACRIVON THERAPEUTICS
TEAM HAS PIONEERED OUTCOME-PREDICTIVE QUANTITATIVE PROTEOMIC MULTIPLEX IN SITU TEST Prostate cancer 8-marker biopsy test developed and launched by Founding team Raw Image Epithelium Classified Nuclei Classified ROI: Malignant Epithelium A B C D Protein Current Ideal test multiplex CDx in situ test tests Quantitative and automated ✓ (✓) Channel 1 Channel 2 Channel 3 Validated Abs and reagents ✓ (✓) ROI 2: Sub-cellular G. BM 3 Analysis F. BM 2 Analysis E. BM 1 Analysis Tumor Compartment Drug target and pathway E G F H ✓ activation context Biomarkers measured in ✓ relevant region on tumor biopsy Channel 5 Channel 4 Channel 6 Imaging algorithm (tissue ✓ pattern) • ProMark®: Marketed, automated in situ proteomic test for Addresses tumor ✓ human outcome prediction included under NCCN guidelines heterogeneity • Founding team: Has pioneered p-proteomics and quantitative Double-blinded, prospective multiplex imaging including double-blinded clinical validation* ✓ (✓) validation *Blume-Jensen et al: Development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer. Clinical Cancer Research (2015) 40 ACRIVON THERAPEUTICS
PROOF -OF -CONCEPT FOR PROTEIN BIOMARKER SIGNATURE: MARKETED, OUTCOME -PREDICTIVE MULTIPLEX CANCER TEST (2015) • Third-party blinded clinical validation, bioinformatic analysis (U. Montreal) • Validation of locked ProMark™ test on single institution biopsy cases (N=274) • Secondary validation on multi-center biopsy cohort (N=359) for clinical use indication • Marketed test included under NCCN Guidelines and Medicare coverage 41 ACRIVON THERAPEUTICS
PIONEERING PHOSPHO -PROTEOMICS STUDY IDENTIFIES NOVEL PI3’K PATHWAY INHIBITOR BIOMARKERS Sci Transl Med 2: 1-14 (2010) Editorial Highlights: TOWARD CUSTOMIZING TUMOR TREATMENT Just as our view of Earth has become increasingly global, cells are now seen as complex networks of interacting and intersecting signaling pathways rather than a collection of regulated genes. A discovery strategy for novel cancer biomarkers 42 ACRIVON THERAPEUTICS
OLSEN LAB -EXAMPLES OF DEEP PROTEOMICS DRUG PROFILING Science Signaling (2018) Nature Communications (2020) Cell Systems (2017) Highest throughput, sensitivity, and scalability to date ALK-i : LDK378, TAE684, crizotinib, lorlatinib. Deepest proteome resolution of a human cell to date Cell Reports (2018) SHP2-i: SHP099 -allosteric inhibitor. Nature Communications (2021) Subcellular compartmental proteomics Cell (2019) Functional mapping of differential signaling by RPTK mutants Cell Reports (2017) Nature Communications (2021) CHK1-i: SCH900776, ATM-i: KU55933 Clinically actionable resistance mechanisms ONGOING (MULTICENTER): Profiling of DDR and core kinase pathway inhibitors (>45) Cell Reports (2017) CDK7-i: THZ-1 ATR CHK1 ATM DNAPK p38a JNK 43 ACRIVON THERAPEUTICS
ADVISORS AND COLLABORATORS SAB David Berman, M.D., Ph.D. George Demetri, M.D., Robert Abraham, Ph.D. Timothy Yap, M.B.B.S., FACP, FASCO, FAACR Ph.D., F.R.C.P. Professor, Director, EVP, Head Cancer Biology, Queen’s Cancer Res. Inst., Professor, Harvard Med. Associate Prof., MD Odyssey Therapeutics Ontario Canada Anderson Cancer Center, School, Dir. Dana-Farber Adj. Prof. , Burnham Inst. Medical Director, Inst. for Cancer Institute & Ludwig Adj. Prof. UCSD Applied Cancer Science Center, Boston • Expert on DDR accelerated • GU Pathologist; bladder cancer • Leader in Precision Oncology • Expert in signal transduction- expert clinical development and • Key contributor to based R&D • Expert on protein biomarkers predictive biomarkers development and rapid • Previously SVP and WW Head, and quantitative tissue imaging • Previously oncologist Royal approvals of Gleevec, Sutent, Oncology R&D, Pfizer Marsden, London and Inst. • Academic lead on ProMark® Stivarga, Zelboraf, Votrient, • VP, Oncology Res., Wyeth Cancer Res, London and Yondelis • Professor, Burnham Institute • Lead/P.I. on numerous DDR • Professor, Duke University trials Jesper V. Olsen, Ph.D. Jung-Min Lee, M.D. Academic Co-Founder NCI Collaborator Professor, Novo-Nordisk Investigator, Lasker Foundation Protein Clinical Research Center, Cph. University Scholar, NCI • Recognized pioneer and • Expert on women’s cancers and leading authority in DNA damage response (DDR) phosphoproteomics and • Lead and co-PI on numerous proteomic systems analyses HGSOC &TNBC trials • Top 0.1% most cited scientist • Lead PI on ACR-368 platinum- in protein sciences resistant ovarian trials 44 ACRIVON THERAPEUTICS
AP3 IS APPLICABLE ACROSS DRUG DEVELOPMENT STAGES 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 45 ACRIVON THERAPEUTICS
OPTIMIZED DUAL INHIBITORS SHOW SHARED AND DIFFERENTIATED PATHWAY EFFECTS Optimized dual WEE1 and PKMYT1 inhibitors affect cell cycle and canonical MAPK pathways in desirable manner Benchmark* WEE1 + PKMYT1 Substrate motif-inferred ACR-2743 ACR-2316 Inhibitors in combination kinase activities Kinase activity based on proprietary PTM- Activity (NES) SEA-based hybrid workflow and analyses -5 0 5 *Clinical-stage selective WEE1 and PKMYT1 inhibitors 46 ACRIVON THERAPEUTICS
AP3 -DERIVED DUAL POTENCY OPTIMIZATION TO OVERCOME WEE1 INHIBITOR RESISTANCE: RECIPROCAL QUENCHING Cell cycle and cancer Protein set name PUJANA_CHEK2_PCC_NETWORK DNA DNA damage homology Sensitive responses Resistant repair PKMYT1i WEE1i PUJANA_BRCA1_PCC_NETWORK Mitotic regulation WEE1i PKMYT1i REACTOME_CELL_CYCLE REACTOME_SEPARATION_OF_SIST Protein set size ER_CHROMATIDS 500 5 EC75 Enrichment Score (NES) Comprehensive annotation, Induced Suppressed weighted for protein set size 47 ACRIVON THERAPEUTICS
AP3 REVEALS SINGLE AGENT SENSITIVITY CONTEXT AND RATIONAL DRUG COMBINATIONS INDEPENDENT OF GENETIC INFORMATION 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 48 ACRIVON THERAPEUTICS
ELI LILLY ACR -368 HIGH LEVEL LICENSE TERMS • In-licensing completed 27 January 2021 – WW exclusive rights with rights to sub-license – $5M up front and low single digit percentage equity subject to ordinary dilution going forward – Aggregate development and commercial milestone payments of up to $168M, of which $5M is due prior to NDA – Tiered percentage royalty on annual net sales ranging from low single-digit up to a maximum of 10% subject to certain specified reductions – Drug product as well as drug substance sufficient to treat several hundred patients – Limited right of first negotiation expiring 45 days upon completion of certain clinical milestones 49 ACRIVON THERAPEUTICS