Acrivon Therapeutics, Inc. · NASDAQ:ACRV
Acrivon Therapeutics — Corporate Update (November 2023)
56 slides from Acrivon Therapeutics's corporate update, Nov 9, 2023
Slide 1: Acrivon Predictive Precision Proteomics (AP3) Corporate Presentation November 2023
Acrivon T h e r a p e u t i c s ACRIVON PREDICTIVE PRECISION PROTEOMICS (AP3) OV E R C O M I N G L I M I TAT I O N S O F G E N E T I C S—B A S E D P R E C I S I O N M E D I C I N E C O R P O R AT E P R E S E N TAT I O N N OV E M B E R 2 0 2 3
Slide 2: Forward-Looking Statements
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 meaning of information the Privatecontained Securities in Litigation this presentation Reform Act includes of 1995 regarding forward-looking our future statements results of within operations the or some financial cases,condition, you can ident
Slide 3: Acrivon: Next Generation Precision Oncology
A C R I V O N : N E X T G E N E R A T I O N P R E C I S I O N O N C O L O G Y O V E R C O M I N G L I M I T A T I O N S O F G E N E T I C S—B A S E D P R E C I S I O N M E D I C I N E Clinically Actionable ACR-368 (Phase 2) Resistance Mechanisms CHK 1/2 inhibitor in Rational drug combinations regist
Slide 4: Accomplished Leadership Team
A C C O M P L I S H E D L E A D E R S H I P T E A M Peter Blume-Jensen, M.D., Ph.D. Rasmus Holm-Jorgensen Kristina Masson, Ph.D., M.B.A Erick Gamelin, M.D., Ph.D. Eric Devroe, Ph.D. Mary-Alice Miller, J.D. CEO, President, Founder Chief Financial Officer Site Head Acrivon AB, Co-Founder Chief Medical
Slide 5: Acrivon Therapeutics at a Glance
A C R I V O N T H E R A P E U T I C S A T A G L A N C E 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 • Mas
Slide 6: Acrivon Predictive Precision Proteomics, AP3
A C R I V O N P R E D I C T I V E P R E C I S I O N P R O T E O M I C S , A P 3 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 DYSREGUL
Slide 7: AP3 Platform Addresses High Unmet Need Beyond NGS-Based Precision Medicine
A P 3 P L A T F O R M A D D R E S S E S H I G H U N M E T N E E D B E Y O N D N G S—B A S E D P R E C I S I O N M E D I C I N E Current Precision Oncology Approaches Only Scratching the Surface Acrivon Positioned to Increase Precision Oncology Market Size 72 unique approvals 51 drugs Precision Oncol
Slide 8: AP3 Platform: Drug Response Prediction in Individual Patients
AP3 PLATFORM: DRUG RESPONSE PREDICTION IN INDIVIDUAL PATIENTS Predicted Predicted Non-responder Responder CLASS 1 BM CLASS 2 BM AI-DRIVEN CLASS 3 BM Patients without biomarkers critical for drug sensitivity efficiently excluded “Disease Pathway-Based Method to Generate Biomarker Panels Tailored to S
Slide 9: Acrivon Pipeline
A C R I V O N P I P E L I N E Anticipated Preclinical Phase 1 Phase 2 Phase 3 Next Milestone Single-Arm Trials Based on OncoSignature Prediction Platinum-Resistant ACR-368 Monotherapy Fast-Track Designation Ovarian Cancer LDG Combination ACR-368 Monotherapy Fast-Track Designation Clinical Data at Ma
Slide 10: ACR-368: Clinically Active Phase 2 CHK1/2 Inhibitor
A C R—3 6 8 : A C L I N I C A L L Y A C T I V E P H A S E 2 C H K 1 / 2 I N H I B I T O R • 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 e
Slide 11: Clinical Overview of ACR-368 Monotherapy (Past Data)
C L I N I C A L O V E R V I E W O F A C R—3 6 8 M O N O T H E R A P Y ( P A S T D A T A ) 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 a
Slide 12: Past Phase 2 Trials in High Grade Serous Ovarian Cancer
P A S T P H A S E 2 T R I A L S I N H I G H G R A D E S E R O U S O V A R I A N C A N C E R 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
Slide 13: Development of AP3-Based Patient Selection OncoSignature Tests
DEVELOPMENT OF AP3-BASED PATIENT SELECTION ONCOSIGNATURE TESTS Technical Validation Functional Validation P-proteomics Cellular MOA respons Human cancer screening: owns, ID of drug-sensitive inations cancers and proportions of responders inal DMSO 4NQO 4NQO+Prex ignat OVCAR3 ssay A2780 Pathway visua
Slide 14: OncoSignature Tests: Usage in the Clinic
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
Slide 15: Consistent ACR-368 OncoSignature Performance Across Preclinical Studies
C O N S I S T E N T A C R—3 6 8 O N C O S I G N A T U R E P E R F O R M A N C E A C R O S S P R E C L I N I C A L S T U D I E S 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
Slide 16: ACR-368 OncoSignature Prediction of Drug Sensitivity Across Human Cancer Samples
A C R—3 6 8 O N C O S I G N A T U R E P R E D I C T I O N O F D R U G S E N S I T I V I T Y : B I O M A R K E R Q U A N T I T A T I O N A C R O S S H U M A N C A N C E R P A T I E N T S A M P L E S 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
Slide 17: Biopsy Study: Response and PFS Benefit in Predicted Responders
B I O P S Y S T U D Y 1 : S U B S T A N T I A L R E S P O N S E A N D P F S B E N E F I T I N P R E D I C T E D R E S P O N D E R S ( B L I N D E D , P R O S P E C T I V E L Y D E S I G N E D S T U D Y ) • Available pretreatment tumor biopsies from past phase 2 trials at NCI with ACR-368 in platinum
Slide 18: Two Additional High Unmet Need Solid Cancers Predicted ACR-368-Sensitive
T W O A D D I T I O N A L H I G H U N M E T N E E D S O L I D C A N C E R S P R E D I C T E D A C R—3 6 8—S E N S I T I V E T H R O U G H H U M A N T U M O R S A M P L E S C R E E N I N G HGS Ovarian Sq. NSCLC Bladder cancer Endometrial cancer Tissue ID BM1 BM2 BM3 Tissue ID BM1 BM2 BM3 Tissue ID BM
Slide 19: Two Attractive ACR-368-Sensitive Cancer Types Identified
T W O A T T R A C T I V E A C R—3 6 8—S E N S I T I V E C A N C E R T Y P E S I D E N T I F I E D Bladder cancer patient samples Endometrial patient samples Patient 1 LOW Patient 2 HIGH Patient 1 LOW Patient 2 HIGH Class 11 BM 2 Class 2 BM 3 Class 3E BM Predicted Predicted Predicted Predicted Non-Re
Slide 20: Endometrial and Bladder PDX Models Highly Sensitive to ACR-368
A S U B S E T O F E N D O M E T R I A L A N D B L A D D E R P D X M O D E L S A R E H I G H L Y S E N S I T I V E T O A C R—3 6 8 Bladder PDX Endometrial PDX 2,000 BL001 2,000 BL002 1,500 Endo 1 2,000 Endo 2 mm3) mm3) r s rs ( 1,500 ( 1,500 e e e 1,000 mete ACR-368-sensitive um um imet i l l 1,000 i
Slide 21: AP3 Uncovers Actionable ACR-368 Resistance Mechanisms
A P 3 U N C O V E R S A C T I O N A B L E A C R—3 6 8 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 O F 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
Slide 22: Low Dose Gemcitabine Sensitizes Ovarian Cancer Cell Lines to ACR-368
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—3 6 8 Ovarian-Parental Ovarian-Resistant 150 No Gem 150 No Gem 0.53 nM Gem 0.53 nM Gem MSO 2.7 nM Gem O MS 2.7 nM Gem D D to to 100 100 tive ltiv e al a e r Prexasertib Abs EC50 e Prexaserti
Slide 23: Enrolling and Dosing ACR-368 in Three High Unmet Need Indications
E N R O L L I N G A N D D O S I N G A C R—3 6 8 I N T H R E E H I G H U N M E T N E E D I N D I C A T I O N S : O V A R I A N , E N D O M E T R I A L A N D B L A D D E R C A N C E R • RP2D of ACR-368 based on predicted sensitivity using our OncoSignature+ Single Arm Simon 2 Stage Monotherapy Phase 2
Slide 24: Encouraging Initial Clinical Observations
E N C O U R A G I N G I N I T I A L C L I N I C A L O B S E R V A T I O N S • Consistent with the extensive experience and tolerability profile from past trials, drug-related adverse events are primarily hematological, reversible, and manageable • In the limited number of patients evaluated by imagi
Slide 25: WEE1 and PKMYT1 Validated Cancer Targets: Ideal for AP3 Approach
W E E 1 A N D P K M Y T 1 V A L I D A T E D C A N C E R T A R G E T S : I D E A L F O R A P 3 A P P R O A C H • proper WEE1 and DNA PKMYT1 replication regulate and mitotic S and G2 completion -M cell cycle through checkpoints phosphorylation to ensure and inhibition of CDK2 and CDK1 and CDK1, respec
Slide 26: Internal Pipeline: Advancing Development Candidate ACR-2316
I N T E R N A L P I P E L I N E : A D V A N C I N G D E V E L O P M E N T C A N D I D A T E A C R—2 3 1 6 A N D O T H E R D D R P R O G R A M S—L E V E R A G I N G A P 3 Rationale • Leveraging our AP3 patient selection platform for high clinical POS High throughput AP3 profiling • Potentially optima
Slide 27: Executive Summary: ACR-2316 Development Candidate
E X E C U T I V E S U M M A R Y : A C R—2 3 1 6 D E V E L O P M E N T C A N D I D A T E A selective dual WEE1/ PKMYT1 inhibitor optimized using AP3 for potent single agent activity Accelerating IND-enabling studies and planning for monotherapy clinical development • AP3-based SAR optimization facili
Slide 28: Dual WEE1/PKMYT1 Inhibitor ACR-2316 Demonstrates Potency and Selectivity
D U A L W E E 1 / P K M Y T 1 I N H I B I T O R A C R—2 3 1 6 D E M O N S T R A T E S S T R O N G P O T E N C Y A N D S E L E C T I V I T Y KinomeScan (106 kinases @ 1000 nM) Benchmark WEE1 inhibitor WEE1 Benchmark PKMYT1 inhibitor Dual inhibitor show potent cell cycle effects with pronounced S-G2/M
Slide 29: ACR-2316 Shows Superior Activity vs Benchmarks Across Tumor Cell Lines
A C R—2 3 1 6 S H O W S S U P E R I O R A C T I V I T Y VS B E N C H M A R K S A C R O S S A L L H U M A N T U M O R C E L L L I N E S T E S T E D Example: Ovarian human cancer cell lines 19 ovarian and other human tumor cell lines tested to date 29 A C R I V O N T H E R A P E U T I C S
Slide 30: ACR-2316 Highly Potent Across Cell Lines and Patient-Derived Organoids
A C R—2 3 1 6 I S H I G H L Y P O T E N T A C R O S S H U M A N T U M O R C E L L L I N E S A N D P A T I E N T—D E R I V E D O V A R I A N T U M O R O R G A N O I D S Human tumor cell lines Patient-derived tumor organoids CTG-1703 CTG-2884 CTG-3718 CTG-0956 CTG-3383 ACR-2316 CTG-2733 CTG-1448 WEE1i
Slide 31: ACR-2316 Demonstrates Potent Monotherapy Anti-Tumor Activity in Mice
A C R—2 3 1 6 D E M O N S T R A T E S P O T E N T M O N O T H E R A P Y A N T I -T U M O R A C T I V I T Y I N T U M O R—B E A R I N G M I C E ACR-2316 anti-tumor activity (QDx7; PO) ACR-2316 anti-tumor activity (5d on/2d off; PO) ACR-2316 demonstrates potent anti-tumor activity, including tumor reg
Slide 32: ACR-2316 Emerging Safety Profile from Preclinical Studies
A C R—2 3 1 6 E M E R G I N G S A F E T Y P R O F I L E F R O M P R E C L I N I C A L A N I M A L S T U D I E S A P P E A R S P R O M I S I N G Mice: • ACR-2316 is well-tolerated at target doses up to ≤60 mg/kg daily oral dosing resulting in tumor regression in xenograft mouse models • No obvious an
Slide 33: Streamlined AP3-Based Biological SAR Optimization
S T R E A M L I N E D A P 3—B A S E D B I O L O G I C A L S A R O P T I M I Z A T I O N F O R S I N G L E A G E N T A C T I V I T Y O F P R E C L I N I C A L P R O G R A M S Quantitative mapping (>35,000 phospho-sites covering >4,500 proteins) Week 0 OVCAR3 A2780 Non-synchronized OVCAR3 A2780 OVCAR3
Slide 34: AP3: Tight, High-Resolution Data with Deep Coverage
A P 3 : 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 35388 p-sites 15733 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
Slide 35: AP3 Reveals Drug-Regulated Kinase Activity in Intact Cells
A P 3 R E V E A L S 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 N O T D E T E C T A B L E B Y S T A N D A R D M E T H O D S KinomeScan @ 1mM Drug-regulated kinase activity* in intact cells ACR-2316 ACR-2316 Traditional AP3-based selectivity pathway profiling profi
Slide 36: Optimized Dual Inhibitors Show Desirable Pathway Effects
O P T I M I Z E D D U A L I N H I B I T O R S S H O W D E S I R A B L E P A T H W A Y E F F E C T S Optimized dual WEE1 and PKMYT1 inhibitors affect cell cycle and canonical MAPK pathways in desirable manner Substrate motif-inferred Benchmark* WEE1 + PKMYT1 ACR-2316 ACR-2743 kinase activities Inhibi
Slide 37: AP3-Derived Dual Potency Optimization to Overcome WEE1 Inhibitor Resistance
A P 3—D E R I V E D D U A L P O T E N C Y O P T I M I Z A T I O N T O O V E R C O M E W E E 1 I N H I B I T O R R E S I S T A N C E : R E C I P R O C A L Q U E N C H I N G Cell cycle and cancer Protein set name PUJANA_CHEK2_PCC_NETWORK DNA DNA damage homology responses Sensitive Resistant repair PKM
Slide 38: AP3 Reciprocal Quenching Reveals Optimal Target Potency Profile
A P 3 R E C I P R O C A L Q U E N C H I N G R E V E A L S O P T I M A L T A R G E T P O T E N C Y P R O F I L E F O R D U A L W E E 1 / P K M Y T 1 I N H I B I T O R Sensitive Resistant Sensitive Resistant PKMYT1i PKMYT1i PKMYT1i WEE1i PKMYT1i WEE1i WEE1i and PKMYT1i dual inhibition synergy WEE1i WE
Slide 39: ACR-2316 Meets Pre-Specified Development Candidate Criteria
A C R—2 3 1 6 M E E T S P R E—S P E C I F I E D D E V E L O P M E N T C A N D I D A T E C R I T E R I A Target ACR-2316 MOA • AP3 phosphoproteomics-based, optimized MOA; selective, dual WEE1/PKMYT1 inhibition ✓ Potency • In vitro kinase activity, IC50 ≤ 10 nM ✓ • Potent in cell target engagement in
Slide 40: Expediting ACR-2316 Towards Clinical Monotherapy Development
E X P E D I T I N G A C R—2 3 1 6 T O W A R D S C L I N I C A L M O N O T H E R A P Y D E V E L O P M E N T A novel, AP3-enabled, internally discovered dual WEE1 / PKMYT1 inhibitor Rational Design Superior Profile Streamlined Development • Co-crystallography-driven • Demonstrated preclinical • Aimin
Slide 41: AP3: Broad Applicability and Untapped Potential
A P 3 : B R O A D A P P L I C A B I L I T Y A N D U N T A P P E D P O T E N T I A L DELIVERABLES Patient responder Indication Rational drug Resistance Pharmacodynamic (PD) identification finding combinations mechanisms biomarkers AP3 Patient selection for Rational drug design SAR Patient selection f
Slide 42: AP3 Is Broadly Applicable Across Drug Discovery and Development
A P 3 I S B R O A D L Y A P P L I C A B L E A C R O S S D R U G D I S C O V E R Y A N D D E V E L O P M E N T Clinical Biomarkers Indication Finding Predictive OncoSignature tests Sensitive tumor types Drug Discovery SAR Informs in-licensing Optimal target selectivity AP3 AP3 profiling of candidates
Slide 43: The AP3 Approach Is Modality and Disease Agnostic
T H E A P 3 A P P R O A C H I S M O D A L I T Y A N D D I S E A S E A G N O S T I C Therapeutic modalities Antibody ADC Bifunctional Oligo/RNA molecule Small molecule Cancers with DDR stress Oncology Therapeutic areas Fibrotic and inflammatory Autoimmune Current focus Infectious, CNS, and other dise
Slide 44: Financial Highlights
F I N A N C I A L H I G H L I G H T S A S O F Q 3 2 0 2 3 Cash and marketable securities Projected runway into Fully Diluted Shares Outstanding $142.1M H2’25 27.6M Balance sheet Current operating plan, assuming Shares and equity grants 30-Sept-2023 no additional financing outstanding 30-Sept-2023 Un
Slide 45: Acrivon Addressable Markets (US & EU Incidence)
A C R I V O N A D D R E S S A B L E M A R K E T S ( U S & E U I N C I D E N C E ) Prioritized indications for single agent ACR-368 Prioritized indications Bladder Cancer * (N=742,000) Endometrial Cancer * HPV+ SCC Potential additional indications 12% Ovarian cancer * *Currently enrolling Sarcoma and
Slide 46: Appendix
A P P E N D I X 46 A C R I V O N T H E R A P E U T I C S
Slide 47: Team Has Pioneered Outcome-Predictive Multiplex Tests
T E A M H A S P I O N E E R E D O U T C O M E—P R E D I C T I V E A T I M I C X I N psy test unding tea Raw Image Epithelium Classified Nuclei Classified ROI: Malignant Epithelium A B C D Protein Current Ideal test multiplex CDx in situ test tests Channel 1 Channel 2 Channel 3 Quantitative and autom
Slide 48: Proof-of-Concept for Protein Biomarker Signature: Marketed Multiplex Cancer Test
P R O O F—OF—C O N C E P T F O R P R O T E I N B I O M A R K E R S I G N A T U R E : M A R K E T E D , O U T C O M E—P R E D I C T I V E M U L T I P L E X C A N C E R T E S T (2015) • Third-party blinded clinical validation, bioinformatic analysis (U. Montreal) • Validation of locked ProMark™ test o
Slide 49: Pioneering Phospho-Proteomics Study Identifies Novel PI3K Pathway Inhibitor Biomarkers
P I O N E E R I N G P H O S P H O—P R O T E O M I C S S T U D Y I D E N T I F I E S N O V E L P I 3 ’ K P A T H W A Y I N H I B I T O R B I O M A R K E R S Sci Transl Med 2: 1-14 (2010) Editorial Highlights: TOWARD CUSTOMIZING TUMOR TREATMENT Just as our view of Earth has become increasingly global,
Slide 50: Olsen Lab: Examples of Deep Proteomics Drug Profiling
O L S E N L A B—E X A M P L E S O F D E E P P R O T E O M I C S D R U G P R O F I L I N G Science Signaling (2018) Cell Systems (2017) Nature Communications (2020) ALK-i : LDK378, TAE684, crizotinib, lorlatinib. Deepest proteome resolution of a human cell to date Highest throughput, sensitivity, and
Slide 51: Advisors and Collaborators
A D V I S O R S A N D C O L L A B O R A T O R S SAB George Demetri, M.D., Robert Abraham, Ph.D. Timothy Yap, M.B.B.S., David Berman, M.D., Ph.D. FACP, FASCO, FAACR EVP, Head Cancer Biology, Ph.D., F.R.C.P. Professor, Director, Professor, Harvard Med. Queen’s Cancer Res. Inst., Odyssey Therapeutics A
Slide 52: AP3 Is Applicable Across Drug Development Stages
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 engage
Slide 53: AP3 Analysis: ACR-2316 Regulates Cell Cycle and Mitosis More Potently (WEE1)
A P 3 A N A L Y S I S : A C R—2 3 1 6 R E G U L A T E S C E L L C Y C L E A N D M I T O S I S M O R E P O T E N T L Y T H A N B E N C H M A R K W E E 1 I N H I B I T O R 60min WEE1 inhibitor ACR-2316 200nM Tight junction Post-synaptic transmission Autophagy GTPases Sensitive RTK-MAPK Mitotic pathway
Slide 54: AP3 Analysis: ACR-2316 Regulates Cell Cycle and Mitosis More Potently (PKMYT1)
A P 3 A N A L Y S I S : A C R—2 3 1 6 R E G U L A T E S C E L L C Y C L E A N D M I T O S I S M O R E P O T E N T L Y T H A N B E N C H M A R K P K M Y T 1 I N H I B I T O R Tight junction Post-synaptic transmission Autophagy GTPases RTK-MAPK Mitotic pathways HDR p value SREBP Significant Not Cell c
Slide 55: AP3 Reveals Single Agent Sensitivity Context and Rational Drug Combinations
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 sensi
Slide 56: Eli Lilly ACR-368 High Level License Terms
E L I L I L L Y A C R—3 6 8 H I G H L E V E L L I C E N S E T E R M S • 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 mile
Acrivon Therapeutics — Corporate Update (November 2023) on 6ix