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| Item 7.01 | Regulation FD Disclosure. |
As previously announced, Repare Therapeutics Inc. (the “Company”) will host a conference call and live audio webcast today, October 13, 2023 at 5:30 p.m., Eastern Time, to discuss the presentation of positive initial data from Modules 1 and 2 of its ongoing Phase 1 MYTHIC clinical trial evaluating lunresertib alone and in combination with camonsertib, at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, including a discussion of new, updated data of its product candidate lunresertib (RP-6306) in combination with camonsertib since the September 5, 2023 data cut-off date of the 2023 AACR-NCI-EORTC presentation.
The live audio webcast may be accessed through the “Events & Presentations” page in the “Investors and Media” section of the Company’s website at ir.reparerx.com. Alternatively, participants may dial (877) 870-4263 (U.S. and Canada) or (412) 317-0790 (international). A copy of the presentation to be used by the Company during the conference call is furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.
Additionally, on October 13, 2023, the Company posted an updated corporate presentation to its website. The corporate presentation is available under the “Events & Presentations” tab in the “Investors & Media” section of the Company’s website, located at www.reparerx.com. The Company intends to use this presentation in meetings with analysts, investors and others from time to time. A copy of the presentation is furnished as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated herein by reference.
The information contained in Item 7.01 of this Current Report on Form 8-K, including Exhibits 99.1 and 99.2 attached hereto, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or the Exchange Act, or otherwise subject to the liabilities of that section, and shall not be deemed incorporated by reference into any of the Company’s filings under the Securities Act of 1933, as amended, or the Exchange Act, whether made before or after the date hereof, regardless of any general incorporation language in such filing, except as shall be expressly set forth by specific reference in such filing.
The Company’s website and any information contained on the Company’s website are not incorporated into this Current Report on Form 8-K.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits
Exhibit No. |
Description | |
| 99.1 | Conference Call Presentation dated October 13, 2023 | |
| 99.2 | Company Presentation dated October 2023 | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
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.
| REPARE THERAPEUTICS INC. | ||||||
| Date: October 13, 2023 | By: | /s/ Lloyd M. Segal | ||||
| Lloyd M. Segal | ||||||
| President and Chief Executive Officer | ||||||
Insight that enriches. Precision that empowers. Lunresertib MYTHIC Clinical Trial Update October 13, 2023 Exhibit 99.1
Agenda Welcome & Introduction Lloyd M. Segal, President & CEO Lunresertib Preliminary MYTHIC Monotherapy & Combination Therapy Clinical Trial Results Timothy Yap, MBBS, PhD, FRCP, Principal Investigator, MYTHIC Trial Conclusions & Lunresertib Development Plan Maria Koehler, MD, PhD, Chief Medical Officer Upcoming Catalysts Lloyd M. Segal, President & CEO Q&A Repare Therapeutics Leadership & Dr. Yap
Disclaimer Statements contained in this presentation regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Words such as "anticipates," "believes," "expects," "intends," “plans,” “potential,” "projects,” “would” and "future" or similar expressions are intended to identify forward-looking statements. Each of these forward-looking statements involves substantial risks and uncertainties that could cause actual results to differ significantly from those expressed or implied by such forward-looking statements. Forward-looking statements contained in this presentation include, but are not limited to, statements regarding the initiation, timing, progress and results of our current and future preclinical studies and clinical trials, including specifically our clinical trials of lunresertib (RP-6306) and camonsertib; the expected timing of program updates and data disclosures; the timing of filing INDs and other regulatory documents; the timing and likelihood of seeking regulatory approval for our product candidates; the competitive landscape for our product candidates; our ability to identify and develop additional product candidates using our SNIPRx platform; and our estimates regarding expenses, future revenue, capital requirements, cash runway and needs for additional financing. These forward-looking statements reflect our current beliefs and expectations. Many factors may cause differences between current expectations and actual results, including the duration and impact of the COVID-19 pandemic on our business and market volatility, unexpected safety or efficacy data observed during preclinical or clinical studies, clinical site activation rates or clinical trial enrollment rates that are lower than expected, changes in expected or existing competition, changes in the regulatory environment, and unexpected litigation or other disputes. These and other risks are described more fully in our filings with the Securities and Exchange Commission (“SEC”), including the “Risk Factors” section of our Quarterly Report on Form 10-Q filed with the SEC on August 9, 2023, and other documents we subsequently filed with or furnished to the SEC. All forward-looking statements contained in this presentation speak only as of the date on which they were made. Except as required by law, we assume no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and growth and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. Neither we nor any other person makes any representation as to the accuracy or completeness of such data or undertakes any obligation to update such data after the date of this presentation. In addition, projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. Solely for convenience, the trademarks and trade names in this presentation may be referred to without the ® and ™ symbols, but such references should not be construed as any indicator that their respective owners will not assert their rights thereto.
Differentiated and expanding clinical-stage pipeline Lunresertib: First-in-class oral PKMYT1 inhibitor (Phase 1/2) Camonsertib: ATR inhibitor (Partnered with Roche) Additional near-term clinical programs Potential across multiple tumor types Proprietary CRISPR-enabled SNIPRx platform Focused on genomic instability and DNA damage repair within cancer cells Multiple clinical catalysts expected in 2023 and 2024 Cash runway into 2026 Developing Next-Generation Precision Oncology Therapeutics
Lunresertib: First-in-class, oral, small molecule, PKMYT1 inhibitor Combination therapy achieved strong anti-tumor activity across multiple tumor types and tested genotypes; 33% overall response at preliminary RP2D (N=18) 50% RECIST response observed in camonsertib combination in largest cohort (gynecological tumors) at preliminary RP2D (N=10) Proof of concept established for monotherapy and camonsertib combination in MYTHIC Phase 1 trial Validated preclinical synergy hypothesis and patient selection approach from proprietary SNIPRx platform Large, genomically defined potential patient population ~90K addressable population including CCNE1, FBXW7 and PPP2R1A Encouraging safety and tolerability profile observed for oral monotherapy and combination therapy RP2D, recommended phase 2 dose
~90K patients across tumor types; ~65K among top tumors CCNE1 amplification or inactivating mutations in FBXW7 and PPP2R1A Genetic alterations largely mutually exclusive Addressing unmet need in critical patient populations Top Tumors (New Advanced Cases, US+UK/EU4) Top Tumors (New Advanced Cases, US+UK/EU4) Tumor Type Prevalence of Genes of Interest Eligible Patients Uterine 7,000 Ovarian 6,300 Stomach 9,000 Colorectal 24,500 Bladder 6,200 Cervical 1,300 Esophageal 4,500 Sarcoma1 1,200 Lung Squamous2 5,300 * Based on estimated number of pts treated in 1st line, advanced setting for diagnosed and new recurrent patients (CancerMPact®, Treatment Architecture, United States, 2021; accessed 5/19/23) and lesion prevalence (TCGA). 1 Soft Tissue Sarcoma only; 2 Squamous subtype of Non-Small Cell Lung Cancer only CCNE1 FBXW7 PPP2R1A Multiple
Lunresertib Preliminary Monotherapy & Combination Therapy Clinical Trial Results Timothy Yap, MBBS, PhD, FRCP, Principal Investigator, MYTHIC Trial
Study principal investigator: Timothy Yap, MBBS, PhD, FRCP Medical Oncologist and Physician-Scientist at the University of Texas, MD Anderson Cancer Center Professor, Department for Investigational Cancer Therapeutics (Phase 1 Program) Vice President, Head of Clinical Development in the Therapeutics Division Primary research focuses on the first-in-human and combinatorial development of molecularly targeted agents and immunotherapies, and their acceleration through clinical studies using novel predictive and pharmacodynamic biomarkers Main interests include the targeting of the DNA damage response with novel therapeutics, such as ATR and PARP inhibitors, as well as the development of novel immuno-therapeutics BSc degree in Immunology and Infectious Diseases and MD from Imperial College London, UK
Speaker disclosures: Timothy Yap, MBBS, PhD, FRCP I have the following relevant financial relationships to disclose: Employee of: University of Texas MD Anderson Cancer Center, where I am Vice President, Head of Clinical Development in the Therapeutics Discovery Division, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios) Consultant for: AbbVie, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Astex, AstraZeneca, Athena, Atrin, Avenzo, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, BioCity Pharma, Blueprint, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Clovis, Cybrexa, Daiichi Sankyo, Dark Blue Therapeutics, Diffusion, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Ellipses Pharma, EMD Serono, Entos, F-Star, Genesis Therapeutics, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Ideaya Biosciences, Idience, Ignyta, I-Mab, ImmuneSensor, Impact Therapeutics, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, Merck, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys, Nimbus, Novocure, Odyssey, OHSU, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Pegascy, PER, Pfizer, Piper-Sandler, Pliant Therapeutics, Prolynx, Radiopharma Theranostics, Repare, resTORbio, Roche, Ryvu Therapeutics, SAKK, Sanofi, Schrodinger, Servier, Synnovation, Synthis Therapeutics, Tango, TCG Crossover, TD2, Terremoto Biosciences, Tessellate Bio, Theragnostics, Terns Pharmaceuticals, Tolremo, Tome, Thryv Therapeutics, Trevarx Biomedical, Varian, Veeva, Versant, Vibliome, Voronoi Inc, Xinthera, Zai Labs and ZielBio Grant/Research support from: Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Boundless Bio, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, Ideaya ImmuneSensor, Insilico Medicine, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tango, Tesaro, Vivace and Zenith Stockholder in: Seagen
PKMYT1 was identified as a strong synthetic lethal partner to CCNE1 amplification1 1Gallo et al. CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Nature. 2022; 604 (7907): 749-756. SNIPRx SL hits are LoF mutations that are essential for fitness in CCNE1-O/E cells but not their wild type counterparts. STEP2 (SNIPRx Targeted Expansion of Patient Populations ) hits are LOF mutations that are essential for fitness in lunresertib treated cells but not the vehicle treated controls. PKMYT1, protein kinase, membrane associated tyrosine/threonine 1; SNIPRx, SyNthetic Lethal Interactions for Precision Therapeutics platform; PP2A, protein phosphatase 2A. Chemogenomic screen identified novel sensitizers to PKMYT1i FBXW7 PPP2R1A Inactivating mutations in FBXW7, E3 ubiquitin ligase, increase cyclin E levels and replication stress. Hotspot inactivating mutations in PP2A phosphatase increase replication stress. Cyclin E overexpression (O/E) drives premature S-phase entry, overloads the DNA replication machinery, resulting in genome instability Synthetic lethal score (CCNE1-O/E cells) Essentiality score (RPE1 WT cells) PPP2R1A FBXW7 PKMYT1i sensitivity score PKMYT1i sensitivity score Genome-wide CRISPR-Cas9 screen
Lunresertib: Potent and selective first-in-class PKMYT1 inhibitor Potency Enzyme potency (IC50, nM) 3 HCC1569 CDK1 T14 phosphorylation (IC50, nM) 20 HCC1569 cell viability (EC50, nM) 19 PKMYT1 selectivity over WEE1 (cell-based ) >100-fold ADME Properties CYP inh (3A4, 2D6, 2C9, 1A2, 2C19) all >30 µM Hepatocytes: rat, dog, human Clint (µL/min/106cells) 28, <6, <6 Human plasma protein binding 79% Rat PK (%F, t1/2) 44%, 2.6h Dog PK (%F, t1/2) 74%, 5.5h Lunresertib profile: Highly potent and selective inhibitor PanLabs Lead Profiling screen on 68 assays showed no significant activity at 10 µM No activity (>100 µM) in patch clamp assays for hERG, hNaV1.5, and hCaV1.2 ion channels Favorable pre-clinical PK profile Low potential for clinical drug-drug interactions Parameter Lunresertib ADME, absorption, distribution, metabolism, excretion; CDK, cyclin-dependent kinase; cClint , intrinsic clearance CYP inh, cytochrome P inhibition; EC50, half maximal effective concentration; F, bioavailability; h, hour; IC50, half-maximal inhibitory concentration; min, minute; PK, pharmacokinetics; PKMYT1, protein kinase, membrane associated tyrosine/threonine 1; Thr, threonine.
Lunresertib monotherapy inhibits xenograft growth across doses and schedules HCC1569 CCNE1 amplified Breast Cancer CDX model 5-on/2-off, 5 days on / 2 days off; BID, twice daily; Lunre, lunresertib.
PKMYT1 and ATR inhibitors synergize to enhance anti-tumor activity1 Lunresertib-sensitizing alterations engage ATR through replication stress Combination of ATR and PKMYT1 inhibition enhances CDK1 activation and premature mitosis 1ANE poster B057: Gallo et al. Preclinical development of PKMYT1 and ATR inhibitor combinations. ATR, ataxia telangiectasia and Rad-3 related; CDC25, cell division cycle-25; CDK, cyclin-dependent kinase; CHK1, checkpoint kinase 1; PKMYT1, protein kinase, membrane associated tyrosine/threonine 1.
Lunresertib and camonsertib combination treatment is active in CCNE1 amplified or FBXW7 altered tumor models Combination treatment drives tumor regressions at sub-efficacious single-agent doses *Additional internal Repare data, not shown. Free drug exposure of 5-10 mg/kg dose in mouse (AUC or Cmin) are comparable to that at the respective human RP2Ds. 5-on/2-off, 5 days on / 2 days off; 3-on/4-off, 3 days on / 4 days off; AUC, area under the curve; BID, twice daily; Cam, camonsertib; Lunre, lunresertib; QD, once daily; RP2D, recommended phase 2 dose. DLD1 Colorectal Cancer FBXW7 Knockout CDX model OVCAR3 Ovarian Cancer CCNE1 amplified CDX model Camonsertib alone has limited activity in CCNE1 and FBXW7 altered PDX models*
MYTHIC: PKMYT1 inHIbition for the treatment of Cancers (N=126) Module 1: Single agent lunresertib Primary endpoints: Safety and tolerability RP2D, schedule Other endpoints: PK PD in paired tumor biopsies Preliminary antitumor activity Kinetics of ctDNA Module 1 initiated Apr 2021 Data snapshot Sept 5, 2023 Module 2: Lunresertib with camonsertib Module 2 initiated May 2022 Study is ongoing NCT04855656 Patients ≥12 y with solid tumors resistant/intolerant to standard therapy Local NGS report (tissue or plasma)* Tumors with CCNE1 amplification**, deleterious FBXW7 or PPP2R1A alterations*** ECOG PS of 0-2 Hgb ≥ 9 g/dL Platelets ≥ 100 K/uL ANC ≥ 1.5 K/uL Inclusion criteria: 67 patients 59 patients * NGS report centrally reviewed and annotated by Precision Oncology Decision Support (PODS) Group at MDACC. ** CCNE1 amplification (Copy number ≥6). *** Up to 5 patients with endometrial cancer without these alterations were eligible in Module 1. ANC, absolute neutrophil count; ctDNA, circulating tumor DNA; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Hgb, hemoglobin; NGS, next generation sequencing; PD, pharmacodynamics; PK, pharmacokinetics; RP2D, recommended phase 2 dose.
MYTHIC: Patient demographics Parameter (Lun alone) N=67 (Lun + Cam) N= 59 Sex, n (%) Male Female 17 (25.4) 50 (74.6) 15 (25.4) 44 (74.6) Age (years) Median (range) ≥65 years, n (%) 60 (15, 81) 25 (37.3) 65 (16, 81) 30 (50.8) ECOG PSa, n (%) 0 1/2 21 (31.3) 44 (65.7) /1 (1.5) 23 (39.0) 35 (59.3) / 0 Prior lines of therapy, n (%) 0 1-2 3-4 ≥5 1 (1.5) 21 (31.3) 25 (37.3) 20 (29.9) 0 24 (40.7) 24 (40.7) 11 (18.6) Prior platinum, n (%) 58 (86.6) 51 (86.4) Parameter (Lun alone) N=67 (Lun + Cam) N=59 Tumor types, n (%) Endometrialb Colorectal Ovarian Breast Lung Otherc 23 (34.3) 11 (16.4) 11 (16.4) 3 (4.5) 0 19 (28.4) 17 (28.8) 13 (22.0) 11 (18.6) 3 (5.1) 3 (5.1) 12 (20.3) Most common genotypesd, n (%) CCNE1 FBXW7 PPP2R1A PPP2R1A and CCNE1 PPP2R1A and FBXW7 FBXW7 and CCNE1 Unselected endometriale 31 (46.3) 21 (31.3) 12 (17.9) 0 1 (1.5) 0 2 (3) 20 (33.9) 23 (39.0) 13 (22.0) 1 (1.7) 1 (1.7) 1 (1.7) 0 Similar patient characteristics in monotherapy and combination therapy cohorts aOne each, pediatric patient in monotherapy and combination with Lansky Performance Status score 80 and 90, respectively. bIncludes uterine serous carcinoma, carcinosarcoma, clear cell carcinoma, endometrioid cOther tumor types in monotherapy: esophageal (n=2), head and neck (n=3), leiomyosarcoma (n=2), osteosarcoma (n=3) and one each (bladder, brain, cervical, gallbladder, GI, gastroesophageal junction, kidney, melanoma, vulvar); combination therapy: gastroesophageal (n=2), bile duct (n=2), pancreatic (n=2), one each (cervical, liver, melanoma, osteosarcoma, upper GI, and vulvar). d4 patients in lun + cam cohort also had ATRi-sensitizing alterations: 2 biallelic and 2 of unknown allelic status. eEndometrial patients without CCNE1, FBXW7, or PPP2R1A mutation. Cam, camonsertib; ECOG PS, Eastern Cooperative Oncology Group Performance Status; GI, gastrointestinal; Lun, lunresertib.
Multiple doses/schedules of lunresertib tested Adaptive BOIN design, sufficient cohort sizes to establish MTD/RP2D QD dose tested first, once half-life known, BID dose was then tested Continuous and intermittent schedules showed similar activity in preclinical efficacy models DLT: reversible rash Intermittent weekly schedule minimized rash** Exposure with and without food was similar at preliminary RP2D 5mg to 600mg QD Continuous daily N=34 60mg & 80mg BID Continuous daily N=20 60mg to 140mg BID Intermittent weekly* N=13 80mg to 100mg BID Intermittent weekly* N=8 Preliminary RP2D range * 5 days on/2 days off and 3 days on / 4 days off were evaluated. ** Investigation of the mechanism of rash ongoing BID, twice daily; BOIN, bayesian optimal interval; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; QD, once daily; RP2D, recommended phase 2 dose
TRAEs in ≥15% of patients, n (%) All Grades G3 G4 All Grades G3 G4 Rash* 23 (34.3) 5 (7.5) 0 4 (50.0) 0 0 Nausea/Vomiting 21 (31.3) 1 (1.5) 0 2 (25.0) 0 0 Anemia 15 (22.4) 4 (6.0) 0 1 (12.5) 0 0 Fatigue 15 (22.4) 1 (1.5) 0 3 (37.5) 0 0 Lunresertib monotherapy: Treatment related adverse events (TRAEs) Safety profile encouraging Infrequent Grade 3 and no reported Grade 4 TRAEs across all doses evaluated Preliminary RP2D range (80-100mg BID, intermittent) demonstrates encouraging tolerability profile Favorable tolerability, with manageable AEs Dose reductions limited to 14.9% of patients Rash* improves, as early as 48 hours, with supportive care or lunresertib interruption * Rash terms included: dermatitis contact, eczema, erythema, flushing, pruritis, rash, rash erythematous, rash maculopapular, rash pruritic, skin exfoliation. BID-I, twice daily, intermittent; G, grade; RP2D, recommended phase 2 dose. All Patients N=67 Limited and reversible low-grade toxicity in monotherapy is encouraging for combination therapies Preliminary RP2D 80-100mg BID-I N=8
Target PK exposures achieved with lunresertib Human lunresertib PK is linear up to daily doses of 160-240 mg with a half-life of ~9 hours PK exposures similar between QD and BID schedules and exceeded the target exposure for inhibition of pCDK1 BID, twice daily; Conc, concentration; pCDK1, phosphorylated cyclin dependent kinase 1; PK, pharmacokinetic; QD, once daily; RP2D, recommended phase 2 dose. Cycle 1 - Day 1 PK at 80 and 100 mg BID Cycle 1 - Day 1 PK at 240 mg QD
Lunresertib monotherapy mechanism of action confirmed in paired biopsies pCDK1-Thr14 (Direct Target Inhibition IHC, pCDK1 target -50%*) ƔH2AX (Induction of DNA Damage IHC, ƔH2AX target 2-fold) ƔH2AX PKMYT1 CDK1 Lunre Thr14 DNA damage Pretreatment vs. On-treatment (n=17; p=0.003) Pretreatment vs. On-treatment (n=25; p=0.022) *Due to assay differences, IHC ~50% target inhibition corresponds to ~80% inhibition by ELISA when maximal tumor growth inhibition in preclinical models was recorded. P-values generated using paired samples with Wilcoxon sign rank test comparing +3% pCDK1 and ƔH2AX positive cells pre-treatment vs on-treatment. CDK1, cyclin-dependent kinase 1; ELISA, enzyme linked immunosorbent assay; IHC, immunohistochemistry; Lunre, lunresertib; pCDK1, phosphyorylated cyclin-dependent kinase 1; PKMYT1, protein kinase, membrane associated tyrosine/threonine 1; Thr, threonine. Relative change from baseline (%) 50% 0 −20 −40 −60 −80 −100 Enrollment gene CCNE1 FBXW7 Unselected Enrollment gene FBXW7 PPP2R1A CCNE1 Unselected Relative change from baseline (%) 2-Fold 2000 −250 1250 1000 750 500 250 0 1750 1500
Anti-tumor activity with lunresertib monotherapy FBXW7 PPP2R1A Baseline Left external iliac chain LN TA #1 – Week 6 Overall response: cPR (RECIST) RECIST target lesion decrease -41% Received therapy for 8.3 months Female 73 years old Metastatic recurrent uterine carcinosarcoma & One RECIST responder Mutations Further, 7 patients with <30% tumor shrinkage, and 2 patients with PFS > 6 and 14 months, respectively Lunresertib: 80mg BID-I Right paratracheal LN BID-I, twice daily, intermittent; cPR, confirmed partial response; LN, lymph node; RECIST, Response Evaluation Criteria in Solid Tumors; PFS, progression free survival; RP2D, recommended phase 2 dose; TA, tumor assessment. 3 prior lines of therapy
MYTHIC: PKMYT1 inHIbition for the treatment of Cancers (N=126) Module 1: Single agent lunresertib Primary endpoints: Safety and tolerability RP2D, schedule Other endpoints: PK PD in paired tumor biopsies Preliminary antitumor activity Kinetics of ctDNA Module 1 initiated Apr 2021 Data snapshot Sept 5, 2023 Module 2: Lunresertib with camonsertib Module 2 initiated May 2022 Study ongoing NCT04855656 Patients ≥12 y with solid tumors resistant/intolerant to standard therapy Local NGS report (tissue or plasma)* Tumors with CCNE1 amplification**, deleterious FBXW7 or PPP2R1A alterations ECOG PS of 0-1 Hgb ≥ 10 g/dL Platelets ≥ 100 K/uL ANC ≥ 1.5 K/uL Inclusion criteria: 67 patients 59 patients * NGS report centrally reviewed and annotated by Precision Oncology Decision Support (PODS) Group at MDACC. ** CCNE1 amplification (Copy number ≥6). ANC, absolute neutrophil count; ctDNA, circulating tumor DNA; ECOG, Eastern Cooperative Oncology Group; Hgb, hemoglobin; NGS, next generation sequencing; PD, pharmacodynamics; PK, pharmacokinetics; RP2D, recommended phase 2 dose.
Lunresertib with camonsertib dose escalation † Tested doses derived from single agent exposures values. * Of the 59 patients, 57 were given 80mg and 2 patients received 120mg of camonsertib. ** One patient started at the daily dose of lunresertib 80mg QD 3 d on/ 4d off and was later escalated to 80mg BID. BID, twice daily; d, days; QD, once daily; RP2D, recommended phase 2 dose Thorough dose/schedule evaluation RP2D/schedule optimization 120mg QD Continuous N=6 40mg BID Continuous N=5 80mg BID 3d on /4d off 240mg QD 3d on/4d off N=12 80mg BID 3d on/4d off N=21** Camonsertib 80mg QD 3d on /4d off 80mg* QD 3d on /4d off Preliminary RP2D: N=20 Camonsertib Lunresertib† Lunresertib + + 60mg BID 3d on/4d off N=15
Lunresertib + camonsertib: Treatment related adverse events (TRAEs) TRAEs in ≥15% of patients, n (%) All Grades G3 G4 All Grades G3 G4 Anemia 40 (67.8) 25 (42.4) 0 13 (65.0) 9 (45.0) 0 Nausea/Vomiting 38 (64.4) 0 0 9 (45.0) 0 0 Fatigue 24 (40.7) 0 0 5 (25.0) 0 0 Rash* 23 (39.0) 1 (1.7) 0 7 (35.0) 0 0 Leukopenia 12 (20.3) 2 (3.4) 0 3 (15.0) 0 0 Neutropenia 11 (18.6) 7 (11.9) 2 (3.6) 3 (15.0) 2 (10.0) 0 Headache 9 (15.3) 0 0 3 (15.0) 0 0 All Patients N=59 Preliminary RP2D N=20 At the preliminary RP2D: No Grade 4 TRAEs Anemia was the most common TRAE Likely due to synergy and ATRi effect1 Grade 3 anemia detected early (< 6w) in patients with high-risk features†; others had later onset (> 6w) Did not lead to discontinuations Usually improved with 1w drug hold Nausea/vomiting, alleviated with food Combination therapy DLT: anemia, rash/mucositis, and neutropenia Preliminary RP2D: lunresertib 80 mg BID + camonsertib 80 mg QD; both 3d on/ 4d off Weekly or 2 weeks on / 1 week off — schedule optimization ongoing Dose of camonsertib is ~50% lower than the monotherapy RP2D 1 Rosen et al. Development of a practical nomogram for personalized anemia management in patients treated with ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib. [in press: Clinical Cancer Research 2023]. *Rash terms included: dermatitis contact, eczema, erythema, flushing, pruritis, rash, rash erythematous, rash maculopapular, rash pruritic, skin exfoliation. † median values at entry: Hb = 10.7g/dl, previous therapies = 4, median age = 59 y, ATRi, ataxia telangiectasia and Rad3-related inhibitor; BID, twice daily; G, grade; Hbg, hemoglobin; QD, once daily; RP2D, recommended phase 2 dose; TRAE, treatment-related adverse events; w, week.
Direct target inhibition (pCDK1-Thr14) is enhanced with combination treatment *Due to assay differences, IHC ~50% target inhibition corresponds to ~80% inhibition by ELISA when maximal tumor growth inhibition in preclinical models was recorded. ATR, ataxia telangiectasia and Rad-3 related; Cam, camonsertib; CDK1, cyclin-dependent kinase 1; Lunre, lunresertib; pCDK1, phosphyorylated cyclin-dependent kinase 1; PKMYT1, protein kinase, membrane associated tyrosine/threonine 1; Thr, threonine. More tumors had a 50% pCDK1 reduction with combination (69%, 11/16) compared to monotherapy (47%, 8/17) Lunresertib monotherapy (n=17) Lunresertib and camonsertib (n=16) PKMYT1 CDK1 cancer cell Thr14 DNA damage ATR Lunre Enrollment gene CCNE1 FBXW7 PPP2R1A 50% Relative change from baseline (%) 20 −100 −80 −60 −40 −20 0 Relative change from baseline (%) 50% 0 −20 −40 −60 −80 −100 Enrollment gene CCNE1 FBXW7 Unselected Cam
Responses to combination observed across tumor types and lunresertib-sensitizing alterations * One response evaluable patient became uPR and four patients had responses confirmed after the Sept. 5, 2023 cutoff, data as of Oct. 6, 2023. Relevant patient tumor co-mutations †BRCA1 rearrangement and ‡BRCA2 biallelic loss. +Treatment ongoing. BL, baseline; cPR, confirmed partial response; RECIST, Response Evaluation Criteria in Solid Tumors; TL, target lesion; Tx, treatment; uPR, unconfirmed partial response. RECIST and tumor marker responses occurred early despite heavily pre-treated, relapsed/refractory patient population Tumor type Genotype Response Best % change in TL from BL Therapy (weeks) Lines of prior Tx/ prior platinum Endometrial PPP2R1A/FBXW7 cPR -55.9 30.4 3/Y PPP2R1A/CCNE1 cPR -53.0 18.1 2/Y FBXW7 cPR* -100.0 11.1+ 3/Y FBXW7 uPR -39.6 16.0 3/Y FBXW7 uPR* -44.7 11.4+ 3/Y Ovarian CCNE1 cPR* -70.2 21.4+ 2/Y CCNE1† cPR* -30.8 12.6+ 3/Y CCNE1 CA-125 -16.9 29.0+ 9/Y CCNE1 CA-125 -23.1 37.0+ 2/Y CCNE1 CA-125 13.6 12.9+ 5/Y Cervical PPP2R1A cPR* -44.4 11.0+ 1/Y Colorectal FBXW7 cPR -43.3 27.6 3/Y Bile duct CCNE1 cPR -35.0 28.1 2/Y Breast FBXW7‡ uPR -43.8 18.1 2/N
*Efficacy evaluable patients only (≥1 post-baseline tumor assessment). Other tumor types include cervical (n=1), esophageal (n=1), GI (n=1), liver (n=1), lung (n=3), melanoma (n=1), osteosarcoma (n=1), pancreatic (n=2), and upper GI (n=1). CBR: overall response or time on treatment ≥ 16 wk w/o progression; CRC, colorectal cancer; RECIST, Response Evaluation Criteria in Solid Tumors (RECIST) Gynecologic Cancer InterGroup (GCIG); MRR, molecular response rate; OR, overall response based on RECIST or GCIG CA-125 response; RP2D, recommended phase 2 dose. Frequent and deep tumor reductions with lunre + cam combination across multiple tumor types In evaluable patients*, across all tumors/doses: OR: 23.6% (n=55) CBR: 41.8% (n=55) MRR: 50.0% (n=24) At preliminary RP2D, across all tumors: OR: 33.3% (n=18) CBR: 50.0% (n=18) CA-125 response Treatment ongoing + Tumor type: Ovarian Endometrial CRC Bile Duct Breast Other Best change from baseline in tumor size (%) 100 −80 80 60 40 20 0 −20 −40 −60 −100
Most patients with gynecologic cancers had tumor reductions with combination treatment * Gynecologic cancers: ovarian, endometrial, and cervical cancers. Data represent the efficacy evaluable population (≥1 post-baseline tumor assessment). CBR, clinical benefit rate; OR, overall response based on RECIST or GCIG CA-125 response; MRR, molecular response rate; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors ; Gynecological Cancer InterGroup (GCIG); RP2D, recommended phase 2 dose. Across all doses (n=26): Overall response: 38.5%; RECIST Response: 26.9% CBR: 57.7%; MRR: 8/10 (80%) At preliminary RP2D (n=10): Overall response: 60%; RECIST Response: 50% CBR: 70% Patients had 1-9 prior therapies (median=3); treatment ongoing in 11 patients; enrollment in expansion cohorts at RP2D continues Meaningful tumor reductions and durable clinical benefit observed in heavily pre-treated patients PR Tumor marker response Treatment ongoing Gynecologic cancers* Efficacy evaluable patients Weeks of treatment 0 4 8 12 16 20 24 28 32 36 40 Best change from baseline in tumor size (%) CA-125 response Treatment ongoing + 60 40 20 0 −20 −40 −60 −80 −100 At preliminary RP2D
Meaningful tumor reductions across lunresertib-sensitizing alterations # patients with lunresertib-sensitizing co-alterations: 1 each (FBXW7/CCNE1, PPP2R1A/CCNE1, and PPP2R1A/FBXW7). Data represent the efficacy evaluable patient population with ≥ 1 post-baseline tumor assessment. CBR, clinical benefit rate; MRR, molecular response rate; OR, overall response based on RECIST or GCIG CA-125 response. OR across all genotypes: 33.3% in CCNE1 (n=18) 17.4% in FBXW7 (n=23) 21.4% in PPP2R1A (n=14) CBR is promising across genotypes: 44% in CCNE1 (n=18) 35% in FBXW7 (n=23) 50% in PPP2R1A (n=14) MRR: 40% in CCNE1 (n=10) 44% in FBXW7 (n=9) 80% in PPP2R1A (n=5)
Clinical benefit: Combination treatment across lunresertib-sensitizing alterations and doses OR across all genotypes: 33.3% in CCNE1 (n=18) 17.4% in FBXW7 (n=23) 21.4% in PPP2R1A (n=14) CBR is promising across genotypes: 44% in CCNE1 (n=18) 35% in FBXW7 (n=23) 50% in PPP2R1A (n=14) Treatment ongoing in 16 patients Efficacy and tolerability assessments continue to optimize RP2D in tumor- and alteration-selected expansions # patients with lunresertib-sensitizing co-alterations : 1 each (FBXW7/CCNE1, PPP2R1A/CCNE1, and PPP2R1A/FBXW7). Data represent the efficacy evaluable patient population (≥ post-baseline tumor assessment). CBR, clinical benefit rate; OR, overall response based on RECIST or GCIG CA-125 response; PR, partial response; TL, target lesion; RP2D, recommended phase 2 dose. PR Tumor marker response Treatment ongoing, best % change in TL Tumor genomic alteration: CCNE1 FBXW7 PPP2R1A -1.0 -23.1 -16.9 -20.0 -79.2 -0.7 -38.9 -7.3 -7.3 -8.3 13.6 -30.8 -14.9 -12.8 -100 -17.4 Weeks of treatment Efficacy evaluable patients 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 # # #
Significantly higher molecular responses confirm the benefit of combination treatment Molecular responses were observed across lunresertib-sensitizing molecular alterations1 1ANE poster B057: Gallo et al. Molecular response: ≥ 50% decline in mVAF assessed by Tempus xF and Tempus xF+ gene panels for patients with detectable somatic alterations in monotherapy and combination therapy, respectively; best mVAFR capped at +100%. p-value of monotherapy vs. combination therapy determined using chi-squared test. MRR, molecular response rate; mVAFR, mean variant allele frequency ratio. Lunresertib + camonsertib Lunresertib monotherapy Molecular response rate in combination therapy was significantly higher than with monotherapy (p=0.003) CCNE1 FBXW7 PPP2R1A MRR: 12/24 (50%) MRR: 3/30 (10%) CCNE1 FBXW7 PPP2R1A Unselected Best mVAFR (%) 100 50 0 −50 −100 Best mVAFR (%) 100 50 0 −50 −100
Early response in recurrent FBXW7 mutated colorectal adenocarcinoma FBXW7 Male 63 years old Recurrent colorectal adenocarcinoma Mutation Lunre 240mg QD 3/4 Cam 80mg QD 3/4 Overall response: cPR (RECIST) RECIST target lesion decrease -43.3% Received therapy for 27.6 weeks Left para-aortic lymph node Baseline TA - 6 weeks TA - 12 weeks Pre-treatment On-treatment ctDNA Dynamics pCDK1-Thr14 ƔH2AX Gene alteration: ALK p.L1118F APC p.A1485fs APC p.E984* FANCA p.L1167F FBXW7 p.R505C H3F3A p.HA114HG TP53 p.R213* Allele frequency Time on treatment (days) 3/4, 3 days on/4 days off; cPR, confirmed partial response; ctDNA, circulating tumor DNA; RECIST, Response Evaluation Criteria in Solid Tumors; QD, once daily; RP2D, recommended phase 2 dose; TA, tumor assessment; Thr, threonine. 3 prior lines of therapy TP53 mut
Gradual response heralded by CA-125 decrease; recurrent CCNE1 amplified ovarian cancer Overall response: cPR (RECIST) RECIST target lesion decrease -70.2% Therapy ongoing for >21 weeks Female 56 years old High grade serous ovarian carcinoma Amplification RP2D: Lunre 80mg BID 3/4 Cam 80mg QD 3/4 CCNE1 Baseline 6 wks 12 wks T01 Peritoneum T02 Peritoneum Pelvis 18 wks Tumor assessment Size Size Size Images not available in RECIST report Images not available in RECIST report No visible lesion reported No visible lesion reported ctDNA dynamics Allele frequency Time on treatment (days) ARID1B p.Q122_Q128dup CIC p.N1133fs RET p.EV62DL TP53 p.R280* Gene alteration: CA-125 dynamics 3/4, 3 days on/4 days off; cPR, confirmed partial response; ctDNA, circulating tumor DNA; RECIST, Response Evaluation Criteria in Solid Tumors; QD, once daily; RP2D, recommended phase 2 dose. 2 prior lines of therapy TP53 mut
Prompt response in recurrent cervical carcinosarcoma with a PPP2R1A mutation Female 66 years old Recurrent cervical carcinosarcoma Mutation RP2D: Lunre 80mg BID 3/4 Cam 80mg QD 3/4 T01 Lymph node external iliac left PPP2R1A Baseline 6 weeks 12 weeks Tumor assessment CA-125 dynamics Overall response: cPR (RECIST) RECIST target lesion decrease -44.4% Therapy ongoing at 11 weeks 3/4, 3 days on/4 days off; BID, twice daily; CN, copy number; cPR, confirmed partial response; RECIST, Response Evaluation Criteria in Solid Tumors; QD, once daily; RP2D, recommended phase 2 dose; TA, tumor assessment. 1 prior line of therapy MYC amp TP53 mut
Conclusions & Lunresertib Development Plan Maria Koehler, MD, PhD, Chief Medical Officer
Lunresertib: MYTHIC Preliminary Phase 1 Trial Results (M1: Monotherapy) (M2: Camonsertib Combination Therapy) MONOTHERAPY Safe, well tolerated, and anti-tumor activity established (N=67) Recommended Phase 2 dose: 80 to 100mg twice daily in intermittent schedule CAMONSERTIB COMBINATION THERAPY Safe, well tolerated, and promising anti-tumor activity across tumors and lunresertib-sensitizing genomic alterations (N=59) 23.6% OR; 41.8% CBR in efficacy-evaluable patients (N=55) 33.3% OR; 50.0% CBR at preliminary RP2D range, across all tumors (N=18) 38.5% OR; 57.7% CBR in patients with heavily pre-treated gynecologic cancers (N=26); 50% RECIST response at preliminary RP2D (N=10) Preliminary recommended Phase 2 dose: Lunresertib 80mg twice daily and camonsertib 80mg once daily, dose/schedule optimization ongoing OR, overall response; CBR, clinical benefit rate; RP2D, recommended phase 2 dose.
Lunresertib + camonsertib combination therapy (additional data) MYTHIC is a dose finding Phase 1 study: Preliminary RP2D range identified, schedule optimization ongoing. RP2D is important; only 18 pts were treated at preliminary RP2D range. Anemia is the primary tolerability issue to alleviate. Our experience* and our emerging understanding of the anemia promises a range of simple solutions for patients. Gynecological cancers are the largest trial population with strongest signal so far. We expect a robust signal at refined dose and schedule with increasing patient numbers. We are highly interested in multiple other tumors. Numerous opportunities and nothing is off the table. *Rosen et al. Development of a practical nomogram for personalized anemia management in patients treated with ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib. [in press: Clinical Cancer Research 2023]. RP2D, recommended phase 2 dose.
Gynecologic cancers provide most robust example of criticality of sufficient exposure Treatment at preliminary RP2D increases efficacy Gynecologic Cancers Only: N (%) RP2D (N=10) Non-RP2D (N=16) Overall Response (RECIST/CA-125) 6 (60.0%) 4 (25.0%) RECIST response (confirmed+unconfirmed) ** 5 (50.0%) 2 (12.5%) CBR 7 (70.0%) 8 (50.0%) Therapy Ongoing Without PD 5 (50%) 5 (31.3%) *Efficacy evaluable patients (>=1 post-baseline tumor assessment); Sept 5 database; Gyn includes endometrial, ovarian, and cervical. ** additional endometrial cancer with uPR after data base lock for total of 6 RECIST responders. Most doses were below daily RP2D exposure More patients still ongoing at RP2D level Patient split between RP2D and Non-RP2D reflects thorough dose finding; only most recent patients at RP2D exposures. Enrollment now open in multiple tumor expansions with RP2D optimization
Anemia likely a result of synergistic combination effect Mostly a sole, manageable event, suggestive of narrow bone marrow effect Dose optimization and individualized patient management now in place: Maintain RP2D weekly in patients without anemia Early onset: schedule adjustment Late onset: “on demand” modifications Gr 3 anemia at RP2D reflects higher risk population 8/9 pts w Gr3 anemia entered study with anemia; median Hb=10.7g/dL Median age 59y, 3 were >70 years old Median previous therapies was 4 Assessment of this approach and dose/schedule optimization is ongoing Anemia patterns understood and manageable Worst Grade of Treatment-Related Anemia No treatment-related anemia No treatment-related anemia or Grade 1 Grade 3 Grade 2 Shorter time to peak anemia (cycles 1-2) Longer time to peak Anemia (cycles 3+) Grade 3 Grade 2 840 720 560 480 360 Lunre weekly dose <=10-11 11-11.9 12-12.9 >=13 Baseline Hgb G3 Gr2 Gr 1/ no anemia Treatment-Related Anemia Lunre Baseline 1 2 3 4 5 6 7+ Lunre Baseline 1 2 3 4 5 6 7+ Cycle Cycle Cycle Lunre Baseline 1 2 3 4 5 6 7+ Camonsertib dose evaluated was 80mg in all patients *Rosen et al. Development of a practical nomogram for personalized anemia management in patients treated with ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib. [in press: Clinical Cancer Research 2023].
Most patients with gynecologic cancers had tumor reductions with combination treatment * Gynecologic cancers: ovarian, endometrial, and cervical cancers. Data represent the efficacy evaluable population (≥1 post-baseline tumor assessment). CBR, clinical benefit rate; OR, overall response based on RECIST or GCIG CA-125 response; MRR, molecular response rate; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors ; Gynecological Cancer InterGroup (GCIG); RP2D, recommended phase 2 dose. Across all doses (n=26): Overall response: 38.5%; RECIST Response: 26.9% CBR: 57.7%; MRR: 8/10 (80%) At preliminary RP2D (n=10): Overall response: 60%; RECIST Response: 50% CBR: 70% Patients had 1-9 prior therapies (median=3); treatment ongoing in 11 patients; enrollment in expansion cohorts at RP2D continues Meaningful tumor reductions and durable clinical benefit observed in heavily pre-treated patients PR Tumor marker response Treatment ongoing Gynecologic cancers* Efficacy evaluable patients Weeks of treatment 0 4 8 12 16 20 24 28 32 36 40 Best change from baseline in tumor size (%) CA-125 response Treatment ongoing + 60 40 20 0 −20 −40 −60 −80 −100 At preliminary RP2D
Small #pts in 11 different tumors 1/3 of patients with NSCLC have 10m PFS 1/3 of patients with upper GI cancer have 10m PFS 1/2 of patients with cholangio: cPR 1/3 of patients with breast cancer: uPR, continuous target lesion shrinkage Opportunity across multiple tumor types: emerging signals from Phase 1 trial – non gynecologic tumors Time on treatment by tumor type (>=1 post-baseline tumor assessment) Multiple development options: Additional investigation ongoing Multiple PPP2R1A FBXW7 CCNE1 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 Breast Melanoma Lung Lung Pancreatic Upper GI Esophageal Bone Pancreatic Bile Duct Liver Breast Breast Bile Duct Lung Gastric PR, confirmed PR, unconfirmed Ongoing Tumor CRC of keen interest: N=13, only 4 at RP2D, one cPR, 4 treated >16 weeks, including one for >1 year
Evolving broad trial program: sponsored and collaborative PPP2R1A FBXW7 Recurrent solid tumors Key inclusion criteria: CCNE1 amplification or inactivating mutations Determine RP2D dose / schedule Progress to late-stage trials MAGNETIC: + Gemcitabine MYTHIC: + Camonsertib MINOTAUR: + FOLFIRI IST: + CCTG1 IST: + Carbo/paclitaxel2 Lunresertib Combination Therapy Selected tumors with FBXW7 loss Tumors with high rate of sensitivity genes Basket trial 1 Canadian Clinical Trial Group (CCTG) collaborations include NCT05605509 and NCT05601440. 2 SOC for 1st line ovarian cancer is carbo/paclitaxel (6 cycles) + PARPi maintenance therapy or carbo/paclitaxel with bevacizumab + bev maintenance therapy; this IST supports future potential 1st line combination studies as triplet therapy in patients with CCNE1 amplified tumors. Selected tumors with amplified CCNE1 Ovarian, Lung, Esophageal / Gastric Future Opportunities CRC, Other GI, Pan Tumor Endometrial, Bladder Breast, Sarcoma, Bile Duct 4 collaboration trials in advanced discussion
Oncology and patient communities taking high interest in emerging data accelerating the expansion of lunresertib development as MYTHIC moves ahead MYTHIC trial: Key takeaways and next steps Validated lunresertib mechanism of action and SNIPRx preclinical patient selection approach Safety, tolerability, early efficacy signals confirmed in camonsertib combination therapy 50% RECIST response observed in camonsertib combination in 10 pts in largest cohort (gynecological tumors) at preliminary RP2D, underscoring high opportunity in other tumor types we are now enrolling MYTHIC trial expanded to evaluate combination therapy in patients with select tumor types and genomic alterations; Expect to report additional data in 2H 2024 Clear understanding of anemia pattern facilitates patient friendly, simple management; Update 2024
Upcoming Catalysts Lloyd M. Segal, President & CEO
Upcoming milestones 2H 2024 2H 2023 1H 2024 Camonsertib Phase 2 TAPISTRY trial initiation Lunresertib + carboplatin/paclitaxel combination Phase 1 IST initiation RP-1664 and RP-3467 (Polθi) focused investor event RP-1664 clinical trial initiation Initial lunresertib + FOLFIRI combination Phase 1 data RP-3467 (Polθi) clinical trial initiation Lunresertib + gemcitabine combination Phase 1 data Lunresertib + camonsertib combination Phase 1 data (expansion cohorts)
Q&A Lloyd M. Segal President & CEO Timothy Yap, MBBS, PhD, FRCP Principal Investigator, MYTHIC Trial Maria Koehler, MD, PhD Chief Medical Officer Steve Forte, CPA Chief Financial Officer Mike Zinda, PhD Chief Scientific Officer
Insight that enriches. Precision that empowers. Lunresertib MYTHIC Clinical Trial Update October 13, 2023
Insight that enriches. Precision that empowers. Corporate Presentation October 2023 Exhibit 99.2
Disclaimer Statements contained in this presentation regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Words such as "anticipates," "believes," "expects," "intends," “plans,” “potential,” "projects,” “would” and "future" or similar expressions are intended to identify forward-looking statements. Each of these forward-looking statements involves substantial risks and uncertainties that could cause actual results to differ significantly from those expressed or implied by such forward-looking statements. Forward-looking statements contained in this presentation include, but are not limited to, statements regarding the initiation, timing, progress and results of our current and future preclinical studies and clinical trials, including specifically our clinical trials of lunresertib (RP-6306) and camonsertib; the expected timing of program updates and data disclosures; the timing of filing INDs and other regulatory documents; the timing and likelihood of seeking regulatory approval for our product candidates; the competitive landscape for our product candidates; our ability to identify and develop additional product candidates using our SNIPRx platform; and our estimates regarding expenses, future revenue, capital requirements, cash runway and needs for additional financing. These forward-looking statements reflect our current beliefs and expectations. Many factors may cause differences between current expectations and actual results, including the duration and impact of the COVID-19 pandemic on our business and market volatility, unexpected safety or efficacy data observed during preclinical or clinical studies, clinical site activation rates or clinical trial enrollment rates that are lower than expected, changes in expected or existing competition, changes in the regulatory environment, and unexpected litigation or other disputes. These and other risks are described more fully in our filings with the Securities and Exchange Commission (“SEC”), including the “Risk Factors” section of our Quarterly Report on Form 10-Q filed with the SEC on August 9, 2023, and other documents we subsequently filed with or furnished to the SEC. All forward-looking statements contained in this presentation speak only as of the date on which they were made. Except as required by law, we assume no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and growth and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. Neither we nor any other person makes any representation as to the accuracy or completeness of such data or undertakes any obligation to update such data after the date of this presentation. In addition, projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. Solely for convenience, the trademarks and trade names in this presentation may be referred to without the ® and ™ symbols, but such references should not be construed as any indicator that their respective owners will not assert their rights thereto.
Differentiated and expanding clinical-stage pipeline Lunresertib: First-in-class oral PKMYT1 inhibitor (Phase 1/2) Camonsertib: ATR inhibitor (Partnered with Roche) Additional near-term clinical programs Potential across multiple tumor types Proprietary CRISPR-enabled SNIPRx platform Focused on genomic instability and DNA damage repair within cancer cells Multiple clinical catalysts expected in 2023 and 2024 Cash runway into 2026 Developing Next-Generation Precision Oncology Therapeutics
Targeting the un-targetable through synthetic lethality Current Treatment Paradigm Genetic Alterations in Cancer Next Generation Therapeutics Specifically targeting and disrupting genes essential for cancer cell survival SNIPRx identifies and targets necessary genes to induce synthetic lethality Highly targeted & tumor-type agnostic approach Exploiting cancer cell genomic instability, including DNA damage repair Platform validated with established and expanding clinical-stage pipeline Targetable Gain-of-function ~29% Un-targetable Loss-of-function ~54% Un-targetable Gain-of-function ~17%
Enabling target identification & patient insights through SNIPRx® Predicted non-responders DRUG TARGET Small molecule inhibitor (clinical candidate) POTENTIAL SL DRUG TARGETS Viable VALIDATION NORMAL CELL CANCER-ASSOCIATED GENETIC LESION Predicted responders DRUG TARGET Viable Lethal SL genetic lesion STEP2 genetic alterations Lethal Select tumor lesion of interest Execute SNIPRx® CRISPR-Cas9 enabled screen campaign in isogenic cell lines Prioritize, select and validate druggable targets Develop potent and selective inhibitors Perform SNIPRx® Targeted Expansion of Patient Populations (STEP2) screens Conduct clinical trials in an enriched patient population
Expanding pipeline of precision oncology therapeutics PROGRAM TUMOR LESION DRUG TARGET PRECLINICAL PHASE 1 PHASE 2 PHASE 3 RIGHTS Camonsertib (RP-3500/ RG6526) ATM + 16 STEP2 lesions ATR Lunresertib (RP-6306) CCNE1, FBXW7 + others PKMYT1 RP-1664 Undisclosed Undisclosed RP-3467 Polθ Inhibitor BRCA1/2 + others Polθ SNIPRx® Platform Additional SL targets in advanced stages of development Discovery and validation of new SL precision oncology targets Ph2 TAPISTRY Ph1b/2 Morpheus-Lung Ph1/2 TRESR: Mono + PARP (talazoparib) Combo Ph1/2 ATTACC: PARP (olaparib/niraparib) Combo Ph1/2 TRESR: Gemcitabine Combo Ph2 CCTG ISTs Ph1 MYTHIC: Mono + Camonsertib Combo Ph1 MAGNETIC: Gemcitabine Combo Ph1 MINOTAUR: FOLFIRI Combo Ph1 Carboplatin/paclitaxel Combo IST
Driving shareholder value through strategic collaborations Global development and commercialization collaboration for Camonsertib Multi-target discovery collaboration leveraging SNIPRx® discovery platform $135M upfront ~$1.2B potential milestones High single-digit to high-teens royalties 50/50 U.S. co-development, profit/cost share and co-promotion option $65M upfront ~$3B potential milestones Royalties Both SL targets and “undruggable” targets outside our focus
Proven experience in drug discovery and development Leadership Team Scientific Founders Steve Forte, CPA Chief Financial Officer Michael Zinda, PhD Chief Scientific Officer Maria Koehler MD, PhD Chief Medical Officer Cameron Black, PhD Head of Discovery Philip Herman Chief Commercial, Portfolio Development Officer Daniel Bélanger Head of Human Resources Lloyd M. Segal President & CEO Kim A. Seth, PhD Chief Business Officer Daniel Durocher, PhD Developed CRISPR SL platform Deep DNA repair knowledge Lunenfeld-Tanenbaum Research Institute (LTRI) & professor at University of Toronto Agnel Sfeir, PhD DDR and cancer pathway investigator Pioneer in Polθ, genome instability Professor, MSKCC Frank Sicheri, PhD Globally recognized structural biologist, expert in eukaryotic cell signaling, drug mechanism of action LTRI & professor at University of Toronto
Lunresertib (RP-6306)
Lunresertib: First-in-class, oral, small molecule, PKMYT1 inhibitor Combination therapy achieved strong anti-tumor activity across multiple tumor types and tested genotypes; 33% overall response at preliminary RP2D (N=18) 50% RECIST response observed in camonsertib combination in largest cohort (gynecological tumors) at preliminary RP2D (N=10) Proof of concept established for monotherapy and camonsertib combination in MYTHIC Phase 1 trial Validated preclinical synergy hypothesis and patient selection approach from proprietary SNIPRx platform Large, genomically defined potential patient population ~90K addressable population including CCNE1, FBXW7 and PPP2R1A Encouraging safety and tolerability profile observed for oral monotherapy and combination therapy RP2D, recommended phase 2 dose
Lunresertib: The only clinical-stage therapeutic targeting PKMYT1 Protein Kinase within the Wee1 kinase family Regulates cell cycle and is part of DNA damage repair-related signaling Inactivates CDK1 via phosphorylation of threonine14 (T14) holding the cell in S phase until ready to undergo mitosis CCNE1 amp or deleterious mutations in FBXW7 and PPP2R1A result in an extended S phase and reliance on PKMYT1 activity Inhibiting PKMYT1 in these genomic backgrounds may result in cell death via mitotic catastrophe STEP2 screen identified additional genes (FBXW7 and PPP2R1A) Initially identified CCNE1 amplification sensitive to PKMYT1 inhibition
~90K patients across tumor types; ~65K among top tumors CCNE1 amplification or inactivating mutations in FBXW7 and PPP2R1A Genetic alterations largely mutually exclusive Addressing unmet need in critical patient populations Top Tumors (New Advanced Cases, US+UK/EU4) Top Tumors (New Advanced Cases, US+UK/EU4) Tumor Type Prevalence of Genes of Interest Eligible Patients Uterine 7,000 Ovarian 6,300 Stomach 9,000 Colorectal 24,500 Bladder 6,200 Cervical 1,300 Esophageal 4,500 Sarcoma1 1,200 Lung Squamous2 5,300 * Based on estimated number of pts treated in 1st line, advanced setting for diagnosed and new recurrent patients (CancerMPact®, Treatment Architecture, United States, 2021; accessed 5/19/23) and lesion prevalence (TCGA). 1 Soft Tissue Sarcoma only; 2 Squamous subtype of Non-Small Cell Lung Cancer only CCNE1 FBXW7 PPP2R1A Multiple
Evolving broad trial program: sponsored and collaborative PPP2R1A FBXW7 Recurrent solid tumors Key inclusion criteria: CCNE1 amplification or inactivating mutations Determine RP2D dose / schedule Progress to late-stage trials MAGNETIC: + Gemcitabine MYTHIC: + Camonsertib MINOTAUR: + FOLFIRI IST: + CCTG1 IST: + Carbo/paclitaxel2 Lunresertib Combination Therapy Selected tumors with FBXW7 loss Tumors with high rate of sensitivity genes Basket trial 1 Canadian Clinical Trial Group (CCTG) collaborations include NCT05605509 and NCT05601440. 2 SOC for 1st line ovarian cancer is carbo/paclitaxel (6 cycles) + PARPi maintenance therapy or carbo/paclitaxel with bevacizumab + bev maintenance therapy; this IST supports future potential 1st line combination studies as triplet therapy in patients with CCNE1 amplified tumors. Selected tumors with amplified CCNE1 Ovarian, Lung, Esophageal / Gastric Future Opportunities CRC, Other GI, Pan Tumor Endometrial, Bladder Breast, Sarcoma, Bile Duct 4 collaboration trials in advanced discussion
Lunresertib: MYTHIC Preliminary Phase 1 Trial Results (M1: Monotherapy) (M2: Camonsertib Combination Therapy) MONOTHERAPY Safe, well tolerated, and anti-tumor activity established (N=67) Recommended Phase 2 dose: 80 to 100mg twice daily in intermittent schedule CAMONSERTIB COMBINATION THERAPY Safe, well tolerated, and promising anti-tumor activity across tumors and lunresertib-sensitizing genomic alterations (N=59) 23.6% OR; 41.8% CBR in efficacy-evaluable patients (N=55) 33.3% OR; 50.0% CBR at preliminary RP2D range, across all tumors (N=18) 38.5% OR; 57.7% CBR in patients with heavily pre-treated gynecologic cancers (N=26); 50% RECIST response at preliminary RP2D (N=10) Preliminary recommended Phase 2 dose: Lunresertib 80mg twice daily and camonsertib 80mg once daily, dose/schedule optimization ongoing OR, overall response; CBR, clinical benefit rate; RP2D, recommended phase 2 dose.
Anti-tumor activity with lunresertib monotherapy FBXW7 PPP2R1A Baseline Left external iliac chain LN TA #1 – Week 6 Overall response: cPR (RECIST) RECIST target lesion decrease -41% Received therapy for 8.3 months Female 73 years old Metastatic recurrent uterine carcinosarcoma & One RECIST responder Mutations Further, 7 patients with <30% tumor shrinkage, and 2 patients with PFS > 6 and 14 months, respectively Lunresertib: 80mg BID-I Right paratracheal LN BID-I, twice daily, intermittent; cPR, confirmed partial response; LN, lymph node; RECIST, Response Evaluation Criteria in Solid Tumors; PFS, progression free survival; RP2D, recommended phase 2 dose; TA, tumor assessment. 3 prior lines of therapy
PKMYT1 and ATR inhibitors synergize to enhance anti-tumor activity1 Lunresertib-sensitizing alterations engage ATR through replication stress Combination of ATR and PKMYT1 inhibition enhances CDK1 activation and premature mitosis 1ANE poster B057: Gallo et al. Preclinical development of PKMYT1 and ATR inhibitor combinations. ATR, ataxia telangiectasia and Rad-3 related; CDC25, cell division cycle-25; CDK, cyclin-dependent kinase; CHK1, checkpoint kinase 1; PKMYT1, protein kinase, membrane associated tyrosine/threonine 1.
Responses to combination observed across tumor types and lunresertib-sensitizing alterations * One response evaluable patient became uPR and four patients had responses confirmed after the Sept. 5, 2023 cutoff, data as of Oct. 6, 2023. Relevant patient tumor co-mutations †BRCA1 rearrangement and ‡BRCA2 biallelic loss. +Treatment ongoing. BL, baseline; cPR, confirmed partial response; RECIST, Response Evaluation Criteria in Solid Tumors; TL, target lesion; Tx, treatment; uPR, unconfirmed partial response. RECIST and tumor marker responses occurred early despite heavily pre-treated, relapsed/refractory patient population Tumor type Genotype Response Best % change in TL from BL Therapy (weeks) Lines of prior Tx/ prior platinum Endometrial PPP2R1A/FBXW7 cPR -55.9 30.4 3/Y PPP2R1A/CCNE1 cPR -53.0 18.1 2/Y FBXW7 cPR* -100.0 11.1+ 3/Y FBXW7 uPR -39.6 16.0 3/Y FBXW7 uPR* -44.7 11.4+ 3/Y Ovarian CCNE1 cPR* -70.2 21.4+ 2/Y CCNE1† cPR* -30.8 12.6+ 3/Y CCNE1 CA-125 -16.9 29.0+ 9/Y CCNE1 CA-125 -23.1 37.0+ 2/Y CCNE1 CA-125 13.6 12.9+ 5/Y Cervical PPP2R1A cPR* -44.4 11.0+ 1/Y Colorectal FBXW7 cPR -43.3 27.6 3/Y Bile duct CCNE1 cPR -35.0 28.1 2/Y Breast FBXW7‡ uPR -43.8 18.1 2/N
*Efficacy evaluable patients only (≥1 post-baseline tumor assessment). Other tumor types include cervical (n=1), esophageal (n=1), GI (n=1), liver (n=1), lung (n=3), melanoma (n=1), osteosarcoma (n=1), pancreatic (n=2), and upper GI (n=1). CBR: overall response or time on treatment ≥ 16 wk w/o progression; CRC, colorectal cancer; RECIST, Response Evaluation Criteria in Solid Tumors (RECIST) Gynecologic Cancer InterGroup (GCIG); MRR, molecular response rate; OR, overall response based on RECIST or GCIG CA-125 response; RP2D, recommended phase 2 dose. Frequent and deep tumor reductions with lunre + cam combination across multiple tumor types In evaluable patients*, across all tumors/doses: OR: 23.6% (n=55) CBR: 41.8% (n=55) MRR: 50.0% (n=24) At preliminary RP2D, across all tumors: OR: 33.3% (n=18) CBR: 50.0% (n=18) CA-125 response Treatment ongoing + Tumor type: Ovarian Endometrial CRC Bile Duct Breast Other Best change from baseline in tumor size (%) 100 −80 80 60 40 20 0 −20 −40 −60 −100
Most patients with gynecologic cancers had tumor reductions with combination treatment * Gynecologic cancers: ovarian, endometrial, and cervical cancers. Data represent the efficacy evaluable population (≥1 post-baseline tumor assessment). CBR, clinical benefit rate; OR, overall response based on RECIST or GCIG CA-125 response; MRR, molecular response rate; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors ; Gynecological Cancer InterGroup (GCIG); RP2D, recommended phase 2 dose. Across all doses (n=26): Overall response: 38.5%; RECIST Response: 26.9% CBR: 57.7%; MRR: 8/10 (80%) At preliminary RP2D (n=10): Overall response: 60%; RECIST Response: 50% CBR: 70% Patients had 1-9 prior therapies (median=3); treatment ongoing in 11 patients; enrollment in expansion cohorts at RP2D continues Meaningful tumor reductions and durable clinical benefit observed in heavily pre-treated patients PR Tumor marker response Treatment ongoing Gynecologic cancers* Efficacy evaluable patients Weeks of treatment 0 4 8 12 16 20 24 28 32 36 40 Best change from baseline in tumor size (%) CA-125 response Treatment ongoing + 60 40 20 0 −20 −40 −60 −80 −100 At preliminary RP2D
Early response in recurrent FBXW7 mutated colorectal adenocarcinoma FBXW7 Male 63 years old Recurrent colorectal adenocarcinoma Mutation Lunre 240mg QD 3/4 Cam 80mg QD 3/4 Overall response: cPR (RECIST) RECIST target lesion decrease -43.3% Received therapy for 27.6 weeks Left para-aortic lymph node Baseline TA - 6 weeks TA - 12 weeks Pre-treatment On-treatment ctDNA Dynamics pCDK1-Thr14 ƔH2AX Gene alteration: ALK p.L1118F APC p.A1485fs APC p.E984* FANCA p.L1167F FBXW7 p.R505C H3F3A p.HA114HG TP53 p.R213* Allele frequency Time on treatment (days) 3/4, 3 days on/4 days off; cPR, confirmed partial response; ctDNA, circulating tumor DNA; RECIST, Response Evaluation Criteria in Solid Tumors; QD, once daily; RP2D, recommended phase 2 dose; TA, tumor assessment; Thr, threonine. 3 prior lines of therapy TP53 mut
Gradual response heralded by CA-125 decrease; recurrent CCNE1 amplified ovarian cancer Overall response: cPR (RECIST) RECIST target lesion decrease -70.2% Therapy ongoing for >21 weeks Female 56 years old High grade serous ovarian carcinoma Amplification RP2D: Lunre 80mg BID 3/4 Cam 80mg QD 3/4 CCNE1 Baseline 6 wks 12 wks T01 Peritoneum T02 Peritoneum Pelvis 18 wks Tumor assessment Size Size Size Images not available in RECIST report Images not available in RECIST report No visible lesion reported No visible lesion reported ctDNA dynamics Allele frequency Time on treatment (days) ARID1B p.Q122_Q128dup CIC p.N1133fs RET p.EV62DL TP53 p.R280* Gene alteration: CA-125 dynamics 3/4, 3 days on/4 days off; cPR, confirmed partial response; ctDNA, circulating tumor DNA; RECIST, Response Evaluation Criteria in Solid Tumors; QD, once daily; RP2D, recommended phase 2 dose. 2 prior lines of therapy TP53 mut
Prompt response in recurrent cervical carcinosarcoma with a PPP2R1A mutation Female 66 years old Recurrent cervical carcinosarcoma Mutation RP2D: Lunre 80mg BID 3/4 Cam 80mg QD 3/4 T01 Lymph node external iliac left PPP2R1A Baseline 6 weeks 12 weeks Tumor assessment CA-125 dynamics Overall response: cPR (RECIST) RECIST target lesion decrease -44.4% Therapy ongoing at 11 weeks 3/4, 3 days on/4 days off; BID, twice daily; CN, copy number; cPR, confirmed partial response; RECIST, Response Evaluation Criteria in Solid Tumors; QD, once daily; RP2D, recommended phase 2 dose; TA, tumor assessment. 1 prior line of therapy MYC amp TP53 mut
Camonsertib (RP-3500 / RG6526)
Camonsertib: Potential best-in-class ATR inhibitor Expanded potential with combination therapy Proof of concept established in Phase 1/2 monotherapy trial Durable antitumor activity in combination with PARP inhibitors and gemcitabine; meaningful clinical benefit in ovarian cancer Demonstrated synthetic lethal interaction of ATR and a network of genes identified by SNIPRx and STEP2 process Global development and commercialization collaboration with Roche; Initially advancing TAPISTRY Phase 2 and Morpheus Lung Phase 1b/2 trials
Potential across additional patient populations Top 10 Tumor Types* with Highest Prevalence of ATM Deficiency Top 10 Tumor Types* with Highest Prevalence of ATM Deficiency or STEP2 Genomic Alterations Source: *TCGA; Not weighted for tumor prevalence
Expanding clinical development through Roche collaboration Note: Camonsertib monotherapy TRESR Module 2 expansion phase to be integrated into partnered clinical development plans under Roche IND Repare Trials Roche Collaboration TRESR Phase 1/2 Monotherapy (M1) + Talazoparib (M3) + Gemcitabine (M4) ATTACC Phase 1/2 + Olaparib / Niraparib TAPISTRY Phase 2 (Initiation expected 2H 2023) Morpheus Lung Phase 1b/2 Robust clinical program potential
Camonsertib: TRESR & ATTACC Phase 1/2 Trial Results MONOTHERAPY Favorable safety profile (N=120) Proof-of-concept established in ovarian cancer 25% OR; 75% CBR; 8+ months PFS Clinical benefit in patients with BRCA1/2 mutations COMBINATION THERAPY Clinically meaningful anti-tumor activity in combination with all leading PARP inhibitors Confirmed efficacy in platinum- and PARPi-resistant cancers 48% overall CBR (N=90) 32% OR; 58% CBR; ~7 months PFS in advanced ovarian cancer (N=19) OR, overall response; CBR, clinical benefit rate; PFS, progression free survival
Anti-tumor activity in ovarian cancer with monotherapy *Platinum refractory/resistant: progression on platinum or a platinum-free interval of <6 mo. CBR: OR or ≥16w on therapy without progression 25% Overall response (5/20*) 35w Median PFS 75% Clinical benefit rate (CBR) 90% (18/20) patients had prior PARPi 85% (17/20) patients platinum refractory/ resistant* Time on Treatment (wk) – Ovarian Time to Disease Progression or Death – Ovarian
Time on Treatment (wk) – BRCA1/BRCA2 Module 1 subjects with > 100mg/day dose levels Percent change from baseline in target lesions (BRCA1/BRCA2) Module 1 subjects > 100mg/day dose levels Clinically relevant benefit in patients with BRCA1/2 mutations with monotherapy CBR (OR or ≥16w on therapy without progression) was 48% for BRCA1 population, and 36% for BRCA2 14% Overall response in BRCA1/2 (RECIST, 5/37) 43% CBR for BRCA1/2 tumors 48% CBR for post-PARPi BRCA1/2 tumors
Durable clinical benefit observed with combination therapy Similar benefit observed in patients with platinum-resistant tumors (ORR 12%, CBR 49%) and non-platinum-resistant tumors (ORR 13%, CBR 46%) Benefit observed across multiple tumors, regardless of previous PARPi treatment 48% overall CBR (N=90) Included patients from efficacy analysis set. ORR is based on overall response as best response of confirmed or unconfirmed CR or PR per RECIST v1.1 criteria or confirmed CA-125 response per Gynecological Cancer Intergroup; CBR is based on overall response or ≥16 weeks on treatment without progression; MRR is based on ctDNA molecular response as >50% decline in mVAF assessed by GuardantINFINITY or Tempus xF gene panel for patients with detectable somatic alterations. CBR, clinical benefit rate; CR, complete response; PR, partial response; ORR, overall response rate; RECIST, Response Evaluation Criteria in Solid Tumors.
Upcoming milestones 2H 2024 2H 2023 1H 2024 Camonsertib Phase 2 TAPISTRY trial initiation Lunresertib + carboplatin/paclitaxel combination Phase 1 IST initiation RP-1664 and RP-3467 (Polθi) focused investor event RP-1664 clinical trial initiation Initial lunresertib + FOLFIRI combination Phase 1 data RP-3467 (Polθi) clinical trial initiation Lunresertib + gemcitabine combination Phase 1 data Lunresertib + camonsertib combination Phase 1 data (expansion cohorts)
Developing Next-Generation Precision Oncology Therapeutics Differentiated and expanding clinical-stage pipeline Lunresertib: First-in class oral PKMYT1 inhibitor (Phase 1/2) Camonsertib: ATR inhibitor (Partnered with Roche) Additional near-term clinical programs Potential across multiple tumor types Proprietary CRISPR-enabled SNIPRx platform Focused on genomic instability and DNA damage repair within cancer cells Multiple clinical catalysts expected in 2023 and 2024 Cash runway into 2026
Insight that enriches. Precision that empowers. Corporate Presentation October 2023