MOMA-313 is a potent and selective inhibitor of the Polθ DNA helicase domain for the treatment of HR-deficient tumors

MOMA-313 is a potent and selective inhibitor of the Polθ DNA helicase domain for the treatment of HR-deficient tumors Jordan Krall, Michael Reutershan, Vinny Motwani, Kelly McGlynn, Yonghong Bai, Christopher Quinn, Manaswni Dhingra, Cen Gao, David Waller, Salah Nabhan, Marc Ballas, Timothy Guzi, Peter Hammerman and Erica Evans MOMA Therapeutics, Cambridge, Massachusetts, USA MOMA-313 displays dose-dependent and complete inhibition of Polθ-mediated TMEJ in tumor xenografts Basal 0 0.1 0.3 1 3 10 0 10 20 30 40 TMEJ Repair Product (percent of edited reads) [MOMA-313] mg/kg BID Dox-induced DNA DSB No Dox Polθ-independent DNA repair 0 7 14 21 28 -20 -10 0 10 20 Time (d) Body weight [% change from day 0] Vehicle olaparib (100 mg/kg QD) MOMA-313 (0.3 mg/kg BID) + olaparib MOMA-313 (1 mg/kg BID) + olaparib MOMA-313 (3 mg/kg BID) + olaparib MOMA-313 (10 mg/kg BID) + olaparibMOMA-313 (10 mg/kg BID) 0 10 20 30 0 500 1000 1500 2000 2500 Time (d) Tumor Volume (mm3) 0 4 8 12 0.01 0.1 1 10 100 Time (h) [MOMA-313] (rel. to unbound IC90) IC90,u IC50,u • DLD1 tumor xenografts engineered to generate a doxycycline-inducible DSB in established tumors • MOMA-313 displays dose-dependent inhibition of a TMEJ DNA repair product • The maximal effect of MOMA-313 on TMEJ is comparable to genetic ablation of Polθ, indicating complete target coverage 0.0001 0.001 0.01 0.1 1 10 0 50 100 [MOMA-313], µM Cellular Polθ Activity [% of 13-bp deletion product] IC50 = 4 nM 0.0001 0.001 0.01 0.1 1 10 0 50 100 [MOMA-313], µM Cell viability [% of DMSO] DLD1-BRCA2-/- DLD1 (parental) DoTc24510 MDA-MB-231 BRCA2-deficient: HR-proficient: IC50 = 2-3 nM IC50 >10 μM MOMA-313 inhibits cellular Polθ DNA repair activity and selectively kills HR-deficient cancer cells 0.0001 0.001 0.01 0.1 1 0 50 100 [olaparib], μM Normalized cell viability [% of DMSO] 1000 nM 250 nM 62.5 nM 15.6 nM 3.9 nM 1.0 nM 0.2 nM 0.06 nM 0.02 nM 0 nM [MOMA-313] 48 72 96 120 0 10 20 30 40 Apoptosis Time (h) CC3-positive cells [percentage of total cells] DMSO MOMA-313 (30 nM) olaparib (300 nM) saruparib (5 nM) MOMA-313 + olaparib MOMA-313 + saruparib * all compounds dosed at cell viability IC90 levels 48 72 96 120 0 10 20 30 DNA Damage Time (h) gH2AX-positive cells [percentage of total cells] 2025 AACR Annual Meeting MOMA-313 enhances olaparib in vivo efficacy across a range of models and settings 0 10 20 30 0 500 1000 1500 2000 2500 Time (d) Tumor Volume (mm3) Vehicle olaparib (100 mg/kg QD) olaparib (100 mg/kg QD) olaparib (30 mg/kg QD) olaparib (30 mg/kg QD) olaparib (10 mg/kg QD) olaparib (10 mg/kg QD) MOMA-313 (10 mpk BID) MOMA-313 (10 mg/kg BID) plus Single-agent olaparib MOMA-313 provides robust combination benefit across a wide range of olaparib doses in DLD1-BRCA2-/- xenograft model 0 10 20 30 40 0 500 1000 1500 2000 2500 Time (d) Tumor Volume (mm3) Vehicle olaparib (100 mg/kg QD) Continuous dosing MOMA-313 interruption olaparib interruption MOMA-313 + olaparib dose-interruption MOMA-313 (10 mg/kg BID) MOMA-313 + olaparib Strong combination efficacy maintained with dose interruptions of MOMA-313, olaparib, or both agents (1 cycle of 5-on 2-off → 3 cycles of 5-on 4-off) Robust combination efficacy at reduced olaparib dose or with treatment interruptions (DLD1-BRCA2-/- CDX) • Potential for clinical activity of combination therapy even when full-dose olaparib is not tolerated MOMA-313 displays dose-dependent efficacy in combination with olaparib (DLD1-BRCA2-/- CDX) • Tumor efficacy is directly linked to in vivo target inhibition: >90% Polθ inhibition drives tumor regressions Cellular TMEJ assay: MOMA-313 inhibits repair of DNA double-strand breaks Cell viability: MOMA-313 shows HRD-selective activity 0 7 14 21 28 35 42 49 56 63 0 500 1000 1500 Time (d) Tumor Volume (mm3) Vehicle olaparib (30 mg/kg QD) olaparib + MOMA-313 MOMA-313 (10 mg/kg BID) 0 7 14 21 28 35 42 49 56 0 200 400 600 Time (d) Tumor Volume (mm3) Vehicle olaparib (10 mg/kg QD) olaparib + MOMA-313 MOMA-313 (10 mg/kg BID) 0 10 20 30 40 50 0 1000 2000 3000 Time (d) Tumor Volume (mm3) Vehicle olaparib (100 mg/kg QD) olaparib + MOMA-313 (3 mg/kg BID) olaparib + MOMA-313 (30 mg/kg BID) MOMA-313 (30 mg/kg BID) MOMA-313 is efficacious against PDX models spanning multiple HRD genotypes and tissues BRCA2mut pancreatic PDX BRCA1mut ovarian PDX BRCA2mut breast PDX Enhanced induction of DNA damage and apoptosis with combination treatmentClass-wide PARPi synergy (olaparib shown) Robust and complete in vivo target inhibition drives tumor regressionsMOMA-313 is a potent Polθ inhibitor with cellular efficacy in HR-deficient models Background: Loss of homologous recombination (HR), a core DNA damage repair pathway, is common in many types of cancer that harbor inactivating mutations in BRCA1, BRCA2 and functionally related proteins.1 HR-deficient tumors are widely treated with PARP inhibitors, but the duration of response and survival benefit is often limited.2,3 HR-deficient cells rely heavily on DNA polymerase theta (Polθ) to repair DNA breaks via a process called theta-mediated end-joining (TMEJ).4 Inhibition of Polθ may provide deeper and more durable anti-tumor responses due mechanistic synergy with a PARP inhibitor.5 Polθ inhibition may also prevent the emergence of clinical PARP inhibitor resistance caused by BRCA reversion mutations which have been linked to Polθ DNA repair activity.6 MOMA-313 is a novel, potent and selective small molecule inhibitor of the Polθ DNA helicase domain in clinical development with a PARP inhibitor to drive deeper and more durable responses in HR-deficient tumors. MOMA- 313 has been optimized to achieve high target coverage at a low human dose, a strong safety profile, and broad combinability. Clinical evaluation of MOMA-313 is ongoing (NCT06545942), with monotherapy and PARP inhibitor combination arms currently enrolling. BACKGROUND • Polθ inhibition is synthetic lethal with HR-deficiency • MOMA-313 enhances the response to PARP inhibition X X Polθ PARPi DNA double-strand break PARP Microhomology Homologous Recombination (HR) Theta-mediated end-joining (TMEJ) DNA single-strand break HR Mutation MOMA-313 Strand-invasion • MOMA-313 is a potent and selective inhibitor of the Polθ helicase domain that inhibits Polθ-dependent TMEJ in vitro and in vivo • MOMA-313 selectively inhibits the proliferation of HR-deficient cancer cells and displays class-wide synergy with PARP inhibitors • In combination with a PARP inhibitor, MOMA-313 drives the regression of HR- deficient CDX and PDX models with a robust PK-PD-Efficacy relationship • Phase I clinical trial is currently enrolling monotherapy and combination therapy cohorts (NCT06545942) MOMA-313 SUMMARY MOMA-313 clinical development strategy Metastatic pancreatic, prostate, and breast cancer with HRD alterations NCT06545942 – Poster CT192 Phase I enrolling pan-PARP inhibitor mono + olaparib combo MOMA-313 chemo, RLT & ADC proprietary sPARP1i Future development MOMA-313 inhibits Polθ DNA threading and microhomology alignment for DSB repair MOMA-313 binds in the Polθ helicase DNA channel to prevent DNA threading, alignment, and annealing DIMER TETRAMER Apo Protein MOMA-313 DNA substrate MOMA-313-bound POLθ is an inactive tetramer with a distinct D5 sub-domain conformation that prevents DNA threading DNA binding drives a conformational change in the D5 sub-domain enabling the formation of an active protein dimer that aligns and anneals DNA microhomologies • MOMA-313 binds to the Polθ helicase domain in a channel that threads DNA to align opposing microhomologies for DNA double-strand break repair • DNA threading and annealing are incompatible with the orientation of the D5 sub- domain in the MOMA-313-bound structure • The MOMA-313 series does not display DNA-competitive behavior in biochemical Polθ ATPase assays (right), suggesting that MOMA-313 inhibits a multistep DNA binding mechanism DNA-bound Polθ helicase is a dimer MOMA-313 stabilizes a DNA-free Polθ tetramer MOMA-313 displays robust synergy with PARP inhibitors in cellular efficacy and PD assays (BRCA2mut DoTc24510 cells) Zerio, C. J., et al. Nat. Struct. Mol. Biol. (2025) 1 Hoppe, M. M. et al., J. Natl. Cancer Inst. 110, 704–713 (2018). 2 Golan, T. et al., New Engl. J. Med. 381, 317–327 (2019). 3 De Bono, J. et al., New Engl J. Med. 382, 2091–2102 (2020). 4 Ceccaldi, R. et al., Nature 518, 258–262 (2015). 5 Ramsden, D. A. et al., Nat. Rev. Mol. Cell Biol. 23, 125–140 (2022). 6 Pettitt, S. J. et al., Cancer Discov. 10, 1475–1488 (2020). D5 sub-domain D5 sub-domain 1749 10-9 10-8 10-7 10-6 10-9 10-8 10-7 10-6 Compound IC50 (M) @ 100 nM DNA Compound IC50 (M) 100 nM DNA 1000 nM DNA Expected potency shift for DNA-competitive mechanism Polθ in vitro ATPase assay DNA competition assay MOMA-313 series DNA #1 DNA #2 MOMA-313 olaparib IC50 shift

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