Slide 1: PRMT5: A Precision Therapeutic Target for MTAP-Loss Pancreatic Tumors
PRMT5: A Precision Therapeutic Target for MTAP- Loss Pancreatic Tumors Maxim Pimkin, MD, PhD 30 October 2025
Slide 2: Most cancer targets are not drugged yet
Most cancer targets are not drugged yet SYNTHETIC DNA DAMAGE LETHALITY REPAIR TUMOR Primary approach to SUPPRESSOR targeting tumor GENES suppressor gene loss IMMUNE EVASION • Important drivers of cancer (CoREST) inactivated or deleted in almost all human cancers CRISPR TECHNOLOGY • Not directly drug
Slide 3: ~60K treatable MTAP-del patients/year (US)
~60K treatable MTAP-del patients/year (US) Large unmet need • MTAP deletion confers sensitivity to PRMT5 inhibitors • Large opportunity for development in pancreatic cancer, lung cancer and a histology agnostic group of 13 different cancer types 3 CONFIDENTIAL
Slide 4: PRMT5 and MTAP are a synthetic lethal pair
PRMT5 and MTAP are a synthetic lethal pair MTAP-deleted cancer cell lines are sensitive Rationale for synthetic lethal relationship to PRMT5 knockdown Chromosome 1 Project DRIVE 9p21 deletion 0.5 MTAP 0 MTA MTA MTA accumulation Cell death effect size -0.5 MTA MTA -1 MTAP-intact PRMT5 -1.5 MTAP-delet
Slide 5: Non-MTA-cooperative PRMT5 inhibitors are not synthetic lethal with MTAP deletion
Non-MTA-cooperative PRMT5 inhibitors are not synthetic lethal with MTAP deletion because of their mechanism of action Cancer cells with no MTAP deletion MTAP-deleted cancer cells + MTAP-deleted cancer cells and normal cells MTA-cooperative PRMT5 inhibitor Cytotoxic epigenetic modifiers MTA-cooperati
Slide 6: MTA-cooperative PRMT5 inhibitors are selective for MTAP-deleted cancer cells
MTA-cooperative PRMT5 inhibitors are selective for MTAP- deleted cancer cells Selective activity in MTAP-del cancer cells 143 cancer cell lines from multiple lineages Vopimetostat (TNG462) TNG456 GSK3326595 IC50 4 nM IC50 20 nM IC50 120 nM 45X selective for MTAP deletion 55X selective for MTAP delet
Slide 7: Vopimetostat preclinical activity is not limited by histology
Vopimetostat preclinical activity is not limited by histology Vopimetostat drives deep and durable response Strong efficacy across histologies in xenograft models Multiple histologies • Tumor growth inhibition, stasis or MTAP-null PDX regression in all models (n=22) with no bias for specific histolo
Slide 8: Vopimetostat phase 1/2 study
Vopimetostat phase 1/2 study DOSE ESCALATION DOSE OPTIMIZATION Pancreatic cancer MTAP-del solid tumors Lung cancer Histology agnostic cancers All pancreatic cancers are adenocarcinomas. All lung cancers are non-small cell histology. 8 CONFIDENTIAL
Slide 9: Vopimetostat exposure at 250 mg QD optimizes therapeutic index
Vopimetostat exposure at 250 mg QD optimizes therapeutic index 250 mg QD dose results in optimal Mean steady-state PK profiles (200-300 mg) exposure and target coverage • Preclinical data demonstrate optimal efficacy requires continuous, maximal Anemia threshold PRMT5 inhibition • Vopimetostat (TNG4
Slide 10: Vopimetostat selectively inhibits PRMT5 in tumor cells
Vopimetostat selectively inhibits PRMT5 in tumor cells Selected SDMA IHC cohorts 3-5 SDMA IHC cohorts 1-5 Normal Tumor 80 mg QD 160 mg QD 300 mg QD Pancreatic Mesothelioma Pancreatic Ex8-del MTAP IHC-pos N T N T N T 90% inh 90% inh Cohorts 2-5 Dose dependent tumor-specific SDMA suppression 10 CONFID
Slide 11: Vopimetostat 27% ORR across cancer types
Vopimetostat 27% ORR across cancer types Active doses >6 mo follow-up Key points n=94 • ORR 27% • mPFS 6.4 months • DCR 78% • 37/94 patients ongoing • Active in all tumor types enrolled except sarcoma (ORR 0%, n=9) • Median follow-up 9.4 months ● Patients remaining on treatment Data extract 1 Sept 2
Slide 12: Durable disease control with vopimetostat across cancer types
Durable disease control with vopimetostat across cancer types All tumor evaluable patients at active doses (n=131) Key points • Overall mPFS 6.4 months Partial response − PR pts 11.1 months Stable disease Progressive disease − SD pts 7.3 months − PD pts <2 months • Median time to response 3.5 months
Slide 13: Vopimetostat efficacy matures over time
Vopimetostat efficacy matures over time Vopimetostat phase 1/2 trial Follow-up N ORR Median follow-up Any 127 20% 7.4 mo > 4 mo 114 22% 7.6 mo > 6 mo 85 27% 9.3 mo All patients dosed more than 6 months before data cutoff at 200 mg QD and above Median time to RECIST response 3.5 months Data extract 1
Slide 14: Vopimetostat 250 mg QD has a potential best-in-class safety profile
Vopimetostat 250 mg QD has a potential best-in-class safety profile Related AEs in ≥5% pts (n=84) Key points • Median follow-up 6.1 months • 8% dose reduction • 0% discontinuation for related events • No grade 4-5 related events Grade 1 • Low grade GI side effects Grade 2 Grade 3 Vopimetostat AE pro
Slide 15: Vopimetostat pancreatic cancer cohort
Vopimetostat pancreatic cancer cohort 64 pancreatic cancer patients at active doses* One prior therapy for advanced disease • n=29 pts • 10/29 pts more than 6 months since enrollment (8 pts tumor evaluable) Two or more therapies for advanced disease • n=34 pts • 29/34 pts more than 6 months since en
Slide 16: Vopimetostat mPFS is 7.2 months in 2L pancreatic cancer
Vopimetostat mPFS is 7.2 months in 2L pancreatic cancer Vopimetostat in 2L and 3L+ pancreatic cancer Summary Vopimetistat 2L PDAC • 2L mPFS 7.2 mo 3L+ PDAC • 2L ORR 25% - Overall ORR 15% • Overall DCR 71% • Median follow-up 7.8 mo Time on study (weeks) Chemotherapy historical control trials • 2L mPF
Slide 17: Vopimetostat mPFS in 2L pancreatic cancer more than twice historical SOC trials
Vopimetostat mPFS in 2L pancreatic cancer more than twice historical SOC trials Key points • Vopimetostat 2L mPFS 7.2 mo • SOC chemotherapy mPFS 2-3.5 mo • MTAP deletion likely confers worse prognosis vs WT due to concurrent CDKN2A deletiona • Vopimetostat pivotal study control arm of only MTAP-del
Slide 18: Confirmed partial response to vopimetostat after progression on daraxonrasib
Confirmed partial response to vopimetostat after progression on daraxonrasib in metastatic PDAC Clinical summary • 56 yo male with metastatic pancreatic cancer diagnosed April 2022 • MTAP del, KRAS Q61K • Three prior lines of treatment including ~1 yr daraxonrasib (panRASi) then vopimetostat • Confi
Slide 19: Vopimetostat 49% ORR in histology agnostic cohort
Vopimetostat 49% ORR in histology agnostic cohort Tumor evaluable pts at active doses with >6 months follow-up (n=37) Key points • ORR 49% • mPFS 9.1 months • DCR 89% • 21/37 patients ongoing • Median follow-up 9.5 months • Excludes sarcoma, pancreatic and lung cancer ● Ongoing Cholangiocarcinoma Me
Slide 20: Vopimetostat 9.1 mo mPFS more than twice historical SOC trials
Vopimetostat 9.1 mo mPFS more than twice historical SOC trials in multiple indications mPFS (95% CI) 9.1 months (6.5 – 12.0) Durable activity in multiple late line, difficult to treat cancers provides: • Further evidence of robust single agent activity • Additional optionality for development in lar
Slide 21: Vopimetostat has robust, durable clinical activity in multiple MTAP-del cancer types
Vopimetostat has robust, durable clinical activity in multiple MTAP-del cancer types • Overall response rate (ORR) 27% across cancer types currently best-in-class*, FDA agreement on 250 mg QD go-forward dose • Median progression-free survival (mPFS) 7.2 months and ORR 25% in 2L MTAP-del pancreatic c
Slide 22: Vopimetostat pivotal trial in 2L pancreatic cancer
Vopimetostat pivotal trial in 2L pancreatic cancer Pivotal study start planned 2026 vopimetostat 250mg QD n=150 2L MTAP-del pancreatic cancer SOC chemotherapy n=150 Planning for 2L registration • Rapid enrollment of ~300 patients anticipated given high unmet medical need in this patient population •
Slide 23: Vopimetostat + zoldonrasib has strong preclinical combination benefit
Vopimetostat + zoldonrasib (KRAS G12D) has strong preclinical combination benefit Vopimetostat (TNG462) + zoldonrasib (RMC-9805) Vopimetostat monotherapy KP4 KP4 MTAP-null, KRASG12D/WT PDAC CDX MTAP-null, KRASG12D/WT PDAC CDX • 40% of pancreatic cancers have a KRAS G12D driver mutation • Collaborati
Slide 24: Vopimetostat + RAS(ON) inhibitors may provide chemotherapy free treatment for 1L
Vopimetostat + RAS(ON) inhibitors may provide chemotherapy free treatment for 1L MTAP-del pancreatic cancer Study update DOSE ESCALATION • Cohort 1 complete (n=7) − Exposures in active range for each compound vopimetostat − Both combos well tolerated to date, Any RAS mut + early signs of activity da
Slide 25: Vopimetostat has the potential to be best-in-class and first-to-market
Vopimetostat has the potential to be best-in-class and first-to-market for large patient populations with high unmet need • FDA alignment on 250 mg QD go-forward dose • Strong activity across cancer types − All histologies ORR 27%, mPFS 6.4 months − 2L pancreatic cancer ORR 25%, mPFS 7.2 months − Hi
Slide 26: Acknowledgements
Acknowledgements We would like to thank all the patients, families and caregivers who participated in this study. Thank you to the following investigators who participated in this study: Capucine Baldini, Irene Braña, Phillipe Cassier, Ibiayi Dagogo-Jack, Candace Haddox, Angela Hirbe, Victor Moreno,