Fulcrum Therapeutics, Inc. · NASDAQ:FULC
Fulcrum Therapeutics — Technical Presentation (July 2021)
53 slides from Fulcrum Therapeutics's technical presentation, Jul 14, 2021
Slide 1: Emerging Therapeutic Approaches in Facioscapulohumeral Muscular Dystrophy
Emerging Therapeutic Approaches in Facioscapulohumeral Muscular Dystrophy July 14, 2021 10AM EST FULCRUM THERAPEUTICS 1
Slide 2: Today's Agenda and Objective
Today’s Agenda and Objective Agenda Topic Lead Time (ET) Welcome, Objective, and Overview of Meeting Jennifer McNary 10:00-10:05am Background on FSHD Chris Morabito, MD 10:05-10:15am Overview of Pre-Clinical Data Chris Moxham, PhD 10:15-10:20am ReDUX4 Study Results Michelle Mellion, MD 10:20-10:40am
Slide 3: Fulcrum Overview
Fulcrum Overview Clinical stage biopharmaceutical company using systematic approach to identify small molecules able to rebalance gene expression ▪ ~7,000 genetically defined diseases today ▪ We are building on decades of research highlighting gene expression role in disease ▪ High-throughput produc
Slide 4: Background on FSHD – Chris Morabito, MD
Background on FSHD – Chris Morabito, MD FULCRUM THERAPEUTICS 4
Slide 5: No Treatment Options for People Living With FSHD That Address Disease Progression
Currently, There Are No Treatment Options for People Living With FSHD That Address Disease Progression FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY (FSHD) is caused by the aberrant expression of DUX4 in skeletal muscle STOCHASTIC DUX4 EXPRESSION contributes to disease heterogeneity, asymmetry, and variabi
Slide 6: Losmapimod is a Selective p38 α/β MAP kinase inhibitor
Losmapimod is a Selective p38 α/β MAP kinase inhibitor • Four different p38 MAP Kinase proteins have been identified: alpha, beta, delta, and gamma (α, β, δ, γ) • Losmapimod inhibits the activity of p38 MAP Kinase α a d β and reduces phosphorylation of substrates, including HSP27 and other proteins
Slide 7: Losmapimod is a Selective p38 α/β MAP kinase inhibitor
Losmapimod is a Selective p38 α/β MAP kinase inhibitor • Four different p38 MAP Kinase proteins have been identified: alpha, beta, delta, and gamma (α, β, δ, γ) • Losmapimod inhibits the activity of p38 MAP Kinase α a d β and reduces phosphorylation of a d substrates, including HSP27 and other prote
Slide 8: ReDUX4 Hypothesis: Losmapimod Modifies the Course of FSHD
ReDUX4 Hypothesis: Losmapimod Modifies the Course of FSHD Hypothesis: Losmapimod will reduce FSHD-related muscle degeneration through reduction of myotoxic DUX4, leading to decreased muscle fat replacement and, ultimately, slowing of functional loss Muscle Health Function Quality of Life Decrease of
Slide 9: FSHD is a Progressive, Lifelong Disease
FSHD is a Progressive, Lifelong Disease How can losmapimod slow or halt progressive change in a 48-week study? ▪ Can an 80 participant, 48-week trial show patient benefit safely? ▪ Can trends across multiple analyses converging on benefit provide support for efficacy? ▪ Is losmapimod well tolerated
Slide 10: Losmapimod Clinical Development Program
Losmapimod Clinical Development Program ▪ Refined clinical endpoints: DUX4, MRI, Muscle Fulcrum Preparatory Studies Function, PROs ▪ Safe and tolerable in FSHD subjects Phase 1 ▪ Target engagement demonstrated Complete ▪ Losmapimod penetrates FSHD muscle ▪ Molecular endpoint in muscle biopsy Ongoing
Slide 11: ReDUX4 Trial Was Designed To Capture a Wide Range of FSHD Disease Progression
ReDUX4 Trial Was Designed To Capture a Wide Range of FSHD Disease Progression Phase 2b, randomized, double-blind, placebo-controlled, multi-site international study* SAFETY AND TOLERABILITY MOLECULAR PHARMACOKINETICS AND DUX4-Driven Gene Expression PHARMACODYNAMICS FUNCTION-PATIENT STRUCTURAL REPORT
Slide 12: ReDUX4 Trial Design
ReDUX4 Trial Design* Baseline Assessment 7-Day Safety & Randomization Follow-Up 48-Week Placebo-Controlled Treatment Period 28-day Placebo tablet twice per day (N=40) Open Label Screening Extension (OLE) Period Losmapimod tablet 15 mg twice per day (N=40) Study (N=76) MRI Visit 1 Visit 2 Visit 3 Vis
Slide 13: Evaluating Biomarkers in ReDUX4
Evaluating Biomarkers in ReDUX4 DUX4-Driven Gene Whole-Body Expression in Muscle Musculoskeletal MRI Biopsies by RT-qPCR *Analyses at 16 or 36 weeks. *Analyses at 48 weeks. FULCRUM THERAPEUTICS 13
Slide 14: Evaluating Clinical Outcome Assessments (COAs)
Evaluating Clinical Outcome Assessments (COAs)* Timed Up and Go (TUG) FSHD-TUG Dynamometry Reachable Workspace Motor Function (RWS) Measurement Domain 1 FULCRUM THERAPEUTICS 14 *Analyses at 48 weeks.
Slide 15: Evaluating Patient Reported Outcomes (PROs)
Evaluating Patient Reported Outcomes (PROs)* Patients’ Global Impression FSHD-Health Index of Change (PGIC) (FSHD-HI) “Since the start of the study, my overall status is”: FULCRUM THERAPEUTICS 15 *Analyses at 48 weeks.
Slide 16: Overview of Pre-Clinical Data – Chris Moxham, PhD
Overview of Pre-Clinical Data – Chris Moxham, PhD FULCRUM THERAPEUTICS 16
Slide 17: Measuring DUX4-Driven Gene Expression
Measuring DUX4-Driven Gene Expression DUX4 is the root cause of FSHD • Present in very low amounts in the FSHD muscle • Activates expression of DUX4 targets genes during embryogenesis • DUX4 target genes should not be expressed in skeletal muscle • Measuring DUX4 target gene expression can tell us a
Slide 18: Losmapimod Reduced DUX4 Expression in Preclinical FSHD Studies
Losmapimod Reduced DUX4 Expression in Preclinical FSHD Studies Losmapimod reduced p38 activity, DUX4 expression, DUX4 Preclinical study demonstrated a reduction of DUX4 activity activity, and cell death in patient-derived FSHD myotubes across multiple patient-derived FSHD1/2 myotubes 125 125 n=8 % o
Slide 19: Heterogeneity of muscle composition in FSHD
Heterogeneity of muscle composition in FSHD Stochastic DUX4 expression and FSHD pathology in the FSHD muscle DUX4 expression happens in Different muscles in an STIR signal in MRI helps to Biopsy procedure was a subset of myonuclei and individual with FSHD have identify muscles most likely designed t
Slide 20: ReDUX4 Study Results – Michelle Mellion, MD
ReDUX4 Study Results – Michelle Mellion, MD FULCRUM THERAPEUTICS 20
Slide 21: ReDUX4 Study Participant Randomization Was Well Balanced
ReDUX4 Study Participant Randomization Was Well Balanced Placebo Losmapimod BID (N=40) 15 mg BID (N=40) Completed 38 (95%) 39 (97.5%) Discontinued* 2 (5.0%) 1 (2.5%) DEMOGRAPHICS N 40 40 Age (years) Mean (SD) 45.7 (+/- 12.69) 45.7 (+/- 12.44) White 39 (97.5) 31 (77.5) Asian 0 5 (12.5) Race n (%) Oth
Slide 22: Evaluating Biomarkers in ReDUX4
Evaluating Biomarkers in ReDUX4 DUX4-Driven Gene Expression in Muscle Biopsies by RT-qPCR *Analyses at 16 or 36 weeks. FULCRUM THERAPEUTICS 22
Slide 23: DUX4-Driven Gene Expression Selected as the Primary Endpoint
A Novel Biomarker, DUX4-Driven Gene Expression, Was Selected as the Primary Endpoint STIR signal in MRI helps to Biopsy procedure was ▪ DUX4-driven gene expression levels identify muscles more likely designed to sample proximal represent DUX4 activity to express DUX4 regions in repeated biopsies ▪ R
Slide 24: Primary Endpoint: Reduction of DUX4-Driven Gene Expression in Muscle Biopsies
Primary Endpoint: Reduction of DUX4-Driven Gene Expression in Muscle Biopsies Changes in either group were not observed in the treatment period*, and the primary endpoint was not met ▪ Subgroup analysis by quartile of DUX4-driven gene expression showed no differences ▪ DUX4-driven gene expression wa
Slide 25: Challenges of DUX4 Experimental Biomarker
Challenges of DUX4 Experimental Biomarker ▪ Losmapimod reduced DUX4-driven gene expression preclinically in vitro and in vivo ▪ Translation to clinic was limited despite having validated qPCR assay ▪ Stochastic expression - dynamic range varies by ~1000-fold ▪ Scarce expression - ~1/1000 myonuclei s
Slide 26: Evaluating Biomarkers in ReDUX4
Evaluating Biomarkers in ReDUX4 Whole-Body Musculoskeletal MRI *Analyses at 48 weeks. FULCRUM THERAPEUTICS 26
Slide 27: New Paradigm of Image Analysis in NMD
New Paradigm of Image Analysis in NMD FULCRUM THERAPEUTICS 27
Slide 28: Muscle Categorization Captures FSHD Disease Heterogeneity
Muscle Categorization Captures FSHD Disease Heterogeneity Normal-Appearing “A” Intermediate “B” End-Stage “C” FULCRUM THERAPEUTICS 28
Slide 29: Less Muscle Fat Infiltration vs Placebo in Intermediate Muscles
Losmapimod Treated Participants Showed Significantly Less Muscle Fat Infiltration (MFI) vs Placebo in Intermediate Muscles* Muscle Fat Infiltration (MFI) Muscle Fat Fraction (MFF) Lean Muscle Volume (LMV) Intermediate Muscles Intermediate Muscles Intermediate Muscles 0 Worsening ✱ p=0.38 Change from
Slide 30: Normal-Appearing Muscles Appear Preserved With Losmapimod vs Placebo
Normal-Appearing Muscles Appear Preserved With Losmapimod vs Placebo* Muscle Fat Infiltration (MFI) Muscle Fat Fraction (MFF) Lean Muscle Volume (LMV) Normal-Appearing Muscles Normal-Appearing Muscles Normal-Appearing Muscles 0.3 0.6 0.0 Worsening p=0.18 Change from BL (p.p.) Change from BL (p.p.) C
Slide 31: Evaluating Clinical Outcome Assessments (COAs) and Patient Reported Outcomes (PROs)
Evaluating Clinical Outcome Assessments (COAs) and Patient Reported Outcomes (PROs)* Timed Up and Go (TUG) FSHD-TUG Dynamometry Reachable Workspace Motor Function (RWS) Measurement Domain 1 Patients’ Global Impression of FSHD-Health Index Change (PGIC) (FSHD-HI) “Since the start of the study, my ove
Slide 32: Reachable Work Space (RWS)
Reachable Work Space (RWS) Evaluating Upper Arm and Shoulder Function in FSHD subjects ▪ Centrally read evaluation of individual global upper extremity function, including shoulder and proximal arm ▪ Tracks 3D upper limb trajectory ▪ Divided into 5 regions; shoulder as origin ▪ Calculation of total
Slide 33: Significant Improvement in Total Surface Area by Reachable Workspace
Losmapimod Showed Significant Improvement in Total Surface Area by Reachable Workspace* ▪ Placebo group lost about 2% to No Weight at 48 weeks 4% of Total Surface Area (with and Total Surface Area without weight) • Placebo (n=29) Non-Dominant • Losmapimod (n=26) ▪ Losmapimod group showed trends of s
Slide 34: Hand-Held Dynamometry
Hand-Held Dynamometry Evaluating Upper and Lower Extremity Strength in FSHD subjects ▪ Quantitative isometric dynamometry used to assess muscle strength of upper and lower limbs bilaterally Shoulder Abduction ▪ Evaluation performed by trained Physical Therapists ▪ Muscle groups to be assessed includ
Slide 35: Losmapimod Showed Improved Muscle Strength vs Placebo
Losmapimod Showed Improved Muscle Strength vs Placebo* ▪ Placebo group lost about 15% of • Placebo shoulder and ankle dorsiflexors Dynamometry (Max) • Losmapimod strength after 48 weeks PBO LOS Right Ankle (n=12) (n=15) ▪ Losmapimod group Dorsiflexors p=0.05 Left Ankle ▪ Showed trends of slower prog
Slide 36: Trend in Decreasing Timed Up and Go Completion Time vs Placebo
Losmapimod-Treated Participants Showed a Trend in Decreasing Timed Up and Go (TUG) Completion Time vs Placebo* Average Completion Time p=0.30 1.25 Change from baseline at week 48 (sec) 1.00 0.75 > 0.5 second change from Placebo (p=NS) 0.50 Worsening 0.25 0.00 Placebo Losmapimod (n=29) (n=25) FULCRUM
Slide 37: Participants Reported Significant Improvement vs Placebo
Trial Participants Who Received Losmapimod Reported Significant Improvement vs Placebo* Pat t ’ l bal I r f Cha g PGIC (PGIC) evaluates the impression of change in study participants by asking 7 “Since the start of the study, my overall ✱ LS means at week 48 status is”: 6 p=0.02 5 Worsening (±SE) 4
Slide 38: Fewer participants reported worsening on Losmapimod vs Placebo
Fewer participants reported worsening on Losmapimod vs Placebo* n= 39 34 35 33 30 31 39 36 35 35 27 29 100 ▪ Losmapimod r v th Pat t ’ l bal I r f Cha g (P IC) c ar d t lac b ▲ More study participants 80 ▼ Fewer study participants reported improvement reported worsening Improved Worsened Percentage
Slide 39: Losmapimod Was Generally Well Tolerated With No Severe, Drug-Related Adverse Events
Losmapimod Was Generally Well Tolerated With No Severe, Drug-Related Adverse Events ▪ Treatment-emergent adverse events (TEAEs) occurred in 29 (72.5%) losmapimod and 23 (57.5%) placebo participants ▪ For both losmapimod and placebo: ▪ The majority of TEAEs were assessed by the principal investigator
Slide 40: Putting it all together – Chris Morabito, MD
Putting it all together – Chris Morabito, MD FULCRUM THERAPEUTICS 40
Slide 41: From the Voice of the Patient
From the Voice of the Patient*… ▪ “Having a significant treatment for FSHD would really be life changing. I would like to see something that would stop progression of the disease. If I were to stop progression right now, I would still be able to walk in 10 years. I would still be able to smile, to g
Slide 42: Improved Muscle Health, Strength, and Upper Body Function: Reachable Workspace
Treatment with Losmapimod Resulted in Improved Muscle Health, Strength, and Upper Body Function: Clinical Outcome of Reachable Workspace Decreased Muscle Improved Muscle Strength in Improved Function in Upper Fat Infiltration Upper Extremities Extremities Observed absolute differences of up >30% bet
Slide 43: Improved Muscle Health, Strength, and Function: Timed Up and Go
Treatment with Losmapimod Resulted in Improved Muscle Health, Strength, and Function: Timed Up and Go Decreased Muscle Improved Muscle Strength in Improved Function in Lower Fat Infiltration Lower Extremities Extremities Observed absolute differences of up to 40% between placebo and losmapimod treat
Slide 44: Totality of Evidence Supports Losmapimod as Potential Disease-Modifying Treatment for FSHD
The Totality of Evidence Supports Losmapimod as a Potential, Transformative Disease-Modifying Treatment for FSHD SAFETY AND TOLERABILITY DATASET PHARMACOKINETICS AND MOLECULAR >3600 subjects treated PHARMACODYNAMICS In vitro and in vivo data Extensive evaluations in patients Losmapimod for FSHD FUNC
Slide 45: Acknowledgements
Acknowledgements People Living With FSHD Participating in This Study Collaborating Organizations ReDUX4 Study Sites Principal Investigator Rabi Tawil, MD. URMC ReDUX4 Physical Therapists Site Investigators ▪ Alan Pestronk, MD. WUSTL ReDUX4 Study Coordinators ▪ Angela Genge, MD. Montreal Neurological
Slide 46: Q&A / Discussion
Q&A / Discussion FULCRUM THERAPEUTICS 46
Slide 47: Thank you!
Thank you! Fulcrum Therapeutics, Inc. 26 Landsdowne Street Cambridge, MA 02139 Email: info@fulcrumtx.com FULCRUM THERAPEUTICS 47
Slide 48: Back-up
Back-up FULCRUM THERAPEUTICS 48
Slide 49: Imaging Protocol for Whole Body MRI
Imaging Protocol for Whole Body MRI Neck Torso Right Arm Left Arm Legs Patient reposition Patient reposition Total examination time ~30 min FULCRUM THERAPEUTICS 49
Slide 50: Evaluating Skeletal Muscle Health by Whole Body Musculoskeletal MRI
Evaluating Skeletal Muscle Health by Whole Body Musculoskeletal MRI* Dystrophic Skeletal Muscle Holistic and Quantitative Picture of Muscle Health Tissue in FSHD 18 muscles were analyzed bilaterally (36 total) Fatty and fibrotic tissue infiltration contribute to the loss of function by 50% altering
Slide 51: FSHD-TUG, Motor Function Measurement, and FSHD-HI Did Not Demonstrate Differences
FSHD-TUG, Motor Function Measurement, and FSHD-HI Did Not Demonstrate Differences Between Losmapimod and Placebo* The placebo results suggest that these measures did not detect progression FSHD-TUG Motor Function Measure FSHD Health Index (FSHD-HI) Average Completion Time MFM Domain 1 Score Total FS
Slide 52: Reachable Work Space (RWS)
Reachable Work Space (RWS) Evaluating Upper Arm and Shoulder Function in FSHD subjects FULCRUM THERAPEUTICS 1Han et al., 2015 “Reachable workspace reflects dynamometer-measured upper extremity strength in facioscapulohumeral muscular dystrophy” 52
Slide 53: Improvement in Total Surface Area and Multiple RWS Metrics
Improvement in Total Surface Area Was Seen in Trends of Slowed Disease Progression and Improvement on Multiple RWS Metrics* No Weight 500 g Weight Q1 Non-Dominant Q1 Non-Dominant p=0.02 Q1 Dominant Q1 Dominant Q2 Non-Dominant Q2 Non-Dominant Q2 Dominant Q2 Dominant p<0.1 Q3 Non-Dominant Q3 Non-Domin
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