Slide 1: A phase 1/2 trial of FOG-001, a first-in-class direct β-catenin:TCF inhibitor
A phase 1/2 trial of FOG-001, a first-in-class direct β-catenin:TCF inhibitor Preliminary safety and efficacy in patients with solid tumors bearing Wnt pathway-activating mutations (WPAM+) Samuel J. Klempner1, Michael Cecchini2 , Moh’d Khushman3, Shivaani Kummar4, Meredith Pelster5, Jordi Rodon6, Su
Slide 2: Disclosure Information: Samuel J. Klempner
Disclosure Information: Samuel J. Klempner I have the following relevant financial relationships to disclose: § Consulting/Advisory: Bristol-Myers Squibb, Merck, Astellas, Daiichi-Sankyo, Natera, Novartis, AstraZeneca, Mersana, I-Mab, Sanofi-Aventis, Amgen, Boehringer-Ingelheim, Taiho Oncology, Eisa
Slide 3: FOG-001: A Novel β-catenin:TCF Inhibitor
FOG-001: A Novel β-catenin:TCF Inhibitor § FOG-001 is a first-in-class and only direct inhibitor of β-catenin that competitively inhibits the interaction between β-catenin and the T-cell factor (TCF) family of transcription factors, the most downstream node in the Wnt pathway § By directly targeting
Slide 4: FOG-001-101 First in Human Trial of FOG-001: Phase 1/2 in MSS CRC and WPAM+ Solid Tumors
FOG-001-101 First in Human Trial of FOG-001: Phase 1/2 in MSS CRC and WPAM+ Solid Tumors Part 1a (MSS CRC and WPAM+ Solid Tumors) Dose 6 Part 1b (MSS CRC only – PD cohort) Dose 5.5 480 mg/m2 Dose 5 420 mg/m2 Dose 4 360 mg/m2 Dose 6 Dose 3 240 mg/m2 Dose 5.5 480 mg/m2 Dose 2 144 mg/m2 Dose 5 420 mg/m
Slide 5: FOG-001 Pharmacokinetic Characteristics
FOG-001 Pharmacokinetic Characteristics FOG-001 has favorable pharmacokinetic characteristics: • Extensive distribution, dose-proportional exposure, low inter-patient variability • Exposures at DL4 and above meet or exceed the efficacious exposures observed in sensitive mouse CRC PDX models ©Parabil
Slide 6: Favorable Safety Profile for All Doses Tested
Favorable Safety Profile for All Doses Tested Treatment-related Adverse Events (TRAEs) in Part 1 in ≥10% Patients DL1 36 mg/m2 DL2 72 mg/m2 DL3 144 mg/m2 DL4 240 mg/m2 DL5 360 mg/m2 DL5.5 420 mg/m2 DL6 480 mg/m2 All participants (N=3) (N=8) (N=11) (N=18) (N=20) (N=13) (N=21) (N=94) Any Any Any Any A
Slide 7: FOG-001 Efficacy in non-CRC WPAM+ Solid Tumors
FOG-001 Efficacy in non-CRC WPAM+ Solid Tumors Investigator-determined RECIST response Time on treatment by WPAM+ tumor type Efficacy-evaluable population defined as patients who had at least 1 dose and 1 post-baseline scan at Week 8+ • Responses observed across multiple Wnt/β-catenin driven solid t
Slide 8: Baseline Demographics and Patient Characteristics in CRC
Baseline Demographics and Patient Characteristics in CRC Patients with CRC (n=67) • N = 67 MSS CRC patients enrolled Median age (range), years 54.0 (30–77) across Part 1a and Part 1b Sex, n (%) Male / female 45 (67.2) / 22 (32.8) • Patients were heavily pre-treated with Race, n (%) majority having r
Slide 9: Baseline Demographics and Patient Characteristics in CRC
Baseline Demographics and Patient Characteristics in CRC Patients with CRC (n=67) • N = 67 MSS CRC patients enrolled Median age (range), years 54.0 (30–77) across Part 1a and Part 1b Sex, n (%) Male / female 45 (67.2) / 22 (32.8) • Patients were heavily pre-treated with Race, n (%) majority having r
Slide 10: FOG-001 Efficacy in MSS CRC
FOG-001 Efficacy in MSS CRC Investigator-determined RECIST 1.1 response of target lesions Doselevels Dose Levels1–3 Dose Dose Levels levels 4–6 1-3 4-6 Best % change from baseline 100 80 60 RECIST 1.1 40 20 0 SD -20 -40 Disease control rate in MSS CRC participants with at least one on-study scan at
Slide 11: ctDNA Response in CRC to FOG-001 Treatment by Dose Level
ctDNA Response in CRC to FOG-001 Treatment by Dose Level Increased rate of molecular responses (MR) observed at efficacious dose levels 4–6 Dose levels 1–3 Dose levels 4–6 Best % change from baseline 200 600 Best % change from baseline 400 200 100 100 50 0 0 MR MR -100 -100 ^ ^ # * * * ctDNA test pe
Slide 12: ctDNA Molecular Responses Correlate with Clinical Activity in MSS CRC
ctDNA Molecular Responses Correlate with Clinical Activity in MSS CRC Percent of participants with stable disease per RECIST 1.1 on at least one post-baseline scan (8 weeks or later) Days on treatment (average ±SEM) Mean Time on Treatment (days) 80 % Participants with 150 Stable Disease 60 100 40 50
Slide 13: FOG-001 Demonstrates Exposure-Related Inhibition of WNT Signaling
FOG-001 Demonstrates Exposure-Related Inhibition of WNT Signaling Part 1b MSS CRC paired tumor biopsies RNAseq (screening vs on-treatment (3–5 weeks post 1st dose)) On-target PD WNT Pathway Genes 4 WNT Gene Average WNT-4 Gene On-treatement vs BL WPAM - 1 P=0.012 0 (Log2FC) -1 -2 -3 0 1000 2000 3000
Slide 14: FOG-001 Inhibition of WNT Signaling Provides Rationale for Combination Development
FOG-001 Inhibition of WNT Signaling Provides Rationale for Combination Development Part 1b MSS CRC paired tumor biopsies RNAseq (screening vs on-treatment (3–5 weeks post 1st dose)) WNT Pathway Suppression of Induction of Inhibition of DNA Damage Induction of Angiogenesis and Induction of Tumor Inhi
Slide 15: Combination Cohorts in Ongoing FOG-001-101 Study (NCT05919264)
Combination Cohorts in Ongoing FOG-001-101 Study (NCT05919264) Key inclusion and exclusion criteria Monotherapy cohorts Key inclusion criteria FOG-001 monotherapy dose escalation; standard 3+3 design (solid tumor with WNT- pathway activating mutations (WPAMs) including • Aged 18 years or older Desmo
Slide 16: Conclusions
Conclusions § FOG-001 monotherapy is well tolerated with a manageable safety profile • No Grade 4 or Grade 5 TRAEs; Grade 3 TRAEs were manageable with supportive treatment and dose holds • No patients discontinued treatment due to TRAEs § FOG-001 is the first and only true Wnt/β-catenin inhibitor as
Slide 17: Acknowledgements
Acknowledgements § I would like to thank the patients and their caregivers, and all site investigators and study staff involved in the study as well as Parabilis Medicines as study sponsor § Medical writing and editorial assistance were provided by Miller Medical Communications, funded by Parabilis