Fulcrum Therapeutics, Inc. · NASDAQ:FULC
Fulcrum Therapeutics — Technical Presentation (October 2019)
20 slides from Fulcrum Therapeutics's technical presentation, Oct 4, 2019
Slide 1: Phase 1 clinical trial of losmapimod in FSHD: safety, tolerability and target engagement
Phase 1 clinical trial of losmapimod in FSHD: safety, tolerability and target engagement EudraCT number: 2018-004754-19 Michelle L. Mellion1, Lucienne Ronco1, Drew Thompson1, Michelle Hage1, Sander Brooks2, Emilie van Brummelen2, Lisa Pagan2, Umesh Badrising3, William Tracewell1, Shane Raines1, Bazi
Slide 2: Disclosures
Disclosures Stock/Stock Options in Biogen, Vertex Pharmaceuticals, and Fulcrum Full-time employee as Medical Director at Fulcrum Therapeutics
Slide 3: Aberrant expression of DUX4 causes FSHD
Aberrant expression of DUX4 causes FSHD Healthy FSHD DUX4 FSHD1 <10 repeats FSHD2 >8-20 repeats + SMCHD1/DNMT3B mutations DUX4 is a homeodomain transcription factor
Slide 4: Losmapimod reduced DUX4 expression in FSHD myotubes
Losmapimod, a selective p38α/β MAPK inhibitor, reduced DUX4 expression in FSHD myotubes n=8 n=3 HSP27 is a substrate of p38 MAP kinase pathway MBD3L2 is a DUX4-target gene
Slide 5: Objectives
Objectives Primary Objective: Initial Safety and Tolerability in FSHD Note: Safety and tolerability previously demonstrated in 25 studies in over 3,500 healthy adult volunteers and patients across other multiple indications (see poster P.44, Cadavid D et al). Secondary Objective: PK and Target Engag
Slide 6: Study design
Study design Part A: N=10 Healthy Volunteers; Single Ascending Dose; 4:1 randomization Single dose 2 placebo: 8 losmapimod 7.5mg Single dose 2 placebo: 8 losmapimod 15 mg Wash-out Note: Lower extremity muscle biopsies were performed in normal appearing muscles identified by MRI Part B: N=15 FSHD1 Pa
Slide 7: Demographics
Demographics Part A Healthy Volunteers Part B FSHD1 Gender (M:F) 6M:4F 6M:9F Age Mean SD Min/Max 31.4 17.2 22/64 41.6 11.6 26/64 BMI Mean SD Min/Max 22.7 2.4 19.6/27.2 24.8 3.0 20.7/31.4 Ricci (FSHD Disability Score) Mean SD Min/Max N/A 2.6 0.7 1.5/4
Slide 8: Safety and tolerability
Safety and tolerability No Serious Adverse Events (SAE) No clinically significant changes in vital signs, laboratory analyses, ECG or urinalysis Muscle needle biopsies were well tolerated Adverse Effects (AE) (n) Part A Somnolence (5) Headache (4) Dizziness (2) Part B Headache (4) Backpain (3) Fatig
Slide 9: Assessment of Pharmacokinetics (PK)
Assessment of Pharmacokinetics (PK)
Slide 10: Similar PK profile in HV and FSHD1 subjects
Similar PK profile in HV and FSHD1 subjects
Slide 11: Accumulation observed with repeated dosing
Accumulation observed with repeated dosing Cmax (ng/ml) AUC0-12 (ng*hr/ml) Tmax (hr) mean (SD) CV % mean (SD) CV % median Part B (Day 1) 7.5 mg 40.8 (21.1) 51.7 201.5 (74.6) 37.0 4.5 15 mg 85.0 (16.7) 19.7 410.2 (50.3) 12.0 4.6 Part B (Day 14) 7.5 mg 56.3 (14.2) 25.3 394.6 (92.8) 23.5 4.5 15 mg 100.
Slide 12: Robust in vitro inhibition of p38 activity at ≥30 ng/mL
Robust In Vitro inhibition of p38 activity at ≥30 ng/mL ~30 ng/mL (~78 nM)
Slide 13: Losmapimod BID sustained concentrations for robust target engagement
Losmapimod 15 mg BID sustained concentrations for robust target engagement Pre-treatment muscle biopsy On-treatment muscle biopsy
Slide 14: Losmapimod showed dose dependent concentrations in muscle
Losmapimod showed dose dependent concentrations in muscle Muscle Plasma N Mean ng/g (SD) CV(%) Mean ng/ml (SD) CV(%) 7.5 mg 6 42.1 (10.5) 24.9 52.6 (15.7) 30.2 15 mg 6 63.6 (34.0) 53.5 75.0 (42.5) 56.7 Ratio to Plasma approximately 1:1
Slide 15: Assessment of Pharmacodynamics (PD)
Assessment of Pharmacodynamics (PD)
Slide 16: Losmapimod: in vivo PK/PD in rodents
Losmapimod: in vivo PK/PD in rodents Muscle:plasma exposure ratio is approximately 1 in rodents Losmapimod inhibits p38 in muscle rapidly following acute dosing.
Slide 17: Sustained and dose dependent target engagement in blood
Sustained and dose dependent target engagement in blood 15 mg PO BID dose resulted in greater inhibition of p38 activity Note: measurement of TE in on-treatment muscle biopsy is ongoing
Slide 18: In vitro p38 MAPK inhibition reduced DUX4 activity and muscle cell death
In Vitro inhibition of p38 MAPK resulted in a reduction of DUX4 activity and muscle cell death ~30 ng/mL (~78 nM)
Slide 19: Conclusions
Conclusions Achieved clinically relevant, dose-dependent concentrations in muscle Similar exposures in plasma and muscle as shown in pre-clinical models Data supports the design of the ongoing Phase 2 clinical trials currently enrolling Open label 64-week study (NCT 04004000) Placebo-controlled 24-w
Slide 20: Acknowledgements
Acknowledgements Healthy volunteers and FSHD patients who participated in the study Fulcrum’s phase 1 study FIS 001-2018 management team Centre for Human Drug Research (CHDR) Fulcrum’s FSHD Clinical Advisory Board Centre for Human Drug Research (CHDR) Leiden University Medical Center Radboud Univers
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