We have designed, launched, and fully enrolled an open-label clinical trial to assess long term

safety, tolerability, changes in biomarkers and clinical outcome assessments of losmapimod in

patients with FSHD1.

6. Conclusion

3. Study Objectives

1. Safety and tolerable of long-term dosing with Losmapimod in patients with FSHD1

Open-Label Pilot Study of Losmapimod in FSHD1 (NCT04004000)Design of an Open-Label Pilot Study of Losmapimod to Evaluate the Safety, Tolerability, and Changes in Biomarker

and Clinical Outcome Assessments in Subjects with Facioscapulohumeral Muscular Dystrophy 1 (FSHD1)

Joost Kools1, Nicol Voermans1, Karlien Mul1, Lucienne Ronco², Adefowope Odueyungbo², Venkateswarlu Kondragunta², Kelly Marshall², Mary Bylo2, Michelle Mellion², Baziel van Engelen1, Diego Cadavid²1 Department of Neurology, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.

2Fulcrum Therapeutics. Cambridge, Massachusetts, USA.

4. Study Design1. Background - Facioscapulohumeral Dystrophy (FSHD)

▪ FSHD is a serious, rare, progressive and disabling disease, with no approved disease modifying therapies.

▪ Second most common muscular dystrophy

▪ Autosomal Dominant

▪ Onset usually around 15-30 years old

▪ Clinical Presentation

▪ Slowly progressive

▪ Asymmetric muscle weakness

▪ Affects face, arms, legs and trunk

Front Side Back

Skeletal Muscle Replacement by Fat in FSHD

as Reported in the LiteratureSee poster Cadavid et al., “Development and Evaluation of a whole-body MRI imaging protocol and analysis

algorithms to measure skeletal muscle in FSHD”

Green= not affected

Yellow= small increases reported in some studies

Orange=high fat replacement in almost all studies

2. Study Rationale

D4Z4 DUX4 FSHD

P38α/β Losmapimod

▪ Aberrant expression of DUX4 activates a downstream transcriptional program causing skeletal muscle loss and replacement by fat.

▪ Losmapimod is a small molecule inhibitor of p38α/β.

▪ Treatment with losmapimod resulted in dose-dependent reduction of DUX4 protein, DUX4 transcriptional program and skeletal muscle cell death in FSHD myotubes.

▪ Over 3,500 humans have been exposed with acceptable safety and tolerability for up to one year of treatment.

▪ A treatment that reduces or prevents aberrant DUX4 activity in skeletal muscles may stop or prevent loss of function and further accumulation of disability and could potentially enable improved repair of partially damaged muscles.

▪ Chemistry & Hematology lab

▪ Vital Signs

▪ Physical Examination

▪ ECG

2. Pharmacokinetics and Target Engagement in

blood and skeletal muscle

▪ Pharmacokinetics (PK) in blood

▪ Drug concentrations in muscle

▪ HSP27, a downstream target of P38,

in blood and muscle

Exploratory: Change from baseline in 14 biomarkers and clinical outcome measures

▪ A Phase 2 Open-Label pilot study with 8 weeks baseline, 52 weeks treatment and 4 weeks follow-up periods.

▪ Treatment consists of losmapimod 15 mg twice daily.

▪ Fourteen Dutch patients were enrolled.

5. Main Inclusion and Exclusion Criteria

Inclusion Criteria

1. 18 and 65 years old

2. Genetically proven FSHD1 (1 to 9 D4Z4 repeats)

3. Ricci score of 2 to 4 inclusive (on 0-5 scale)

4. STIR+ lesion eligible for muscle biopsy

Exclusion Criteria

1. Drugs or supplements that may affect muscle function

2. Acute or chronic history of liver disease

3. Known severe renal impairment

4. Contraindication to MRI or muscle biopsy

6. Baseline Characteristics

Participant Sex Age (y) Ricci-score

(0-5)

Age of onset

(y)

Repeat units

1 Male 23 2.5 13 8

2 Female 51 4 24 6

3 Male 52 4 6 4

4 Male 53 3 20 5

5 Male 57 3.5 30 7

6 Male 58 4 32 4

7 Male 49 3 12 5

8 Female 55 4 19 4

9 Male 33 3 16 3

10 Male 54 3.5 16 6

11 Male 34 4 16 3

12 Male 35 4 10 3

13 Male 36 3 18 4

14 Female 50 3 8 5

Total mean

(SD) Male (78.5%) 45.7 (11.1) 3.5 (0.5) 17.1 (7.6) 4.8 (1.5)

7. Baseline Clinical Outcome Assessments (Continued)

Assessment N Mean (SD) Range

Upper Extremity Strength Dynamometry – Hand-Held

Left Dorsiflexion (kg) 9 13.07(4.14) (6.97, 18.97)

Right Dorsiflexion (kg) 8 13.27(4.7) (6.73, 18.77)

Left Elbow Extension (kg) 10 8.67(2.35) (5.56, 12.67)

Right Elbow Extension (kg) 10 9.5(3.36) (3.93, 13.97)

Left Elbow Flexion (kg) 11 16.46(5.14) (6.5, 24.6)

Right Elbow Flexion (kg) 11 13.78(4.93) (5, 22)

Left Shoulder Abduction (kg) 14 6.74(3.92) (2.4, 15.87)

Right Shoulder Abduction (kg) 14 4.8(2.94) (1.67, 10.6)

Composite Upper Extremity Strength Dynamometry – Hand-Held

Left average (kg) 14 10.51(3.7) (3, 17.23)

Right average (kg) 14 9.38(3.57) (1.97, 15.44)

Dynamometry – Bed Frame

Left Dorsiflexion (kg) 12 10.27(4.68) (1.85, 15.87)

Right Dorsiflexion (kg) 13 8.46(5.45) (1.94, 18.43)

Left Elbow Extension (kg) 10 10.56(3.17) (6.82, 16.58)

Right Elbow Extension (kg) 10 10.17(4.23) (5.3, 17.87)

Left Elbow Flexion (kg) 11 16.23(5.16) (8.2, 24.46)

Right Elbow Flexion (kg) 11 15.29(4.42) (6.9, 22.47)

Left Shoulder Abduction (kg) 14 8.03(3.6) (3.84, 13.56)

Right Shoulder Abduction (kg) 14 6.19(2.93) (2.98, 14.21)

Left Hand Grip (kg) 14 34.73(11) (21.33, 57.17)

Right Hand Grip (kg) 14 31.34(12) (15.96, 55.23)

Left Shoulder External Rotation

(kg)

14 7.69(4.78) (2.38, 19.22)

Right Shoulder External Rotation

(kg)

14 6.48(3.28) (1.7, 13.27)

Left Knee Flexion (kg) 14 14.65(15.17) (1.75, 59.94)

Right Knee Flexion (kg) 14 13.63(10.42) (2.49, 32.37)

Left Knee Extension (kg) 14 22.09(11.89) (3.6, 39.34)

Right Knee Extension (kg) 14 23.89(12.82) (7.36, 56.95)

MFM Domain 1

Total Score 14 73.81(21.97) (25.64, 97.44)

6-Minute Walk Test

Total distance (m) 14 454.78(104.6) (172, 587)

Spirometry

Forced Vital Capacity (L) 14 96.93(10.58) (78, 117)

7. Baseline Clinical Outcome Assessments

Assessment N Mean (SD) Range

Classic TUG

Trial 1 (seconds) 14 11.28(4.47) (7.38, 21.7)

Trial 2 (seconds) 14 11.23(5.14) (7.2, 24.2)

FSHD TUG

Trial 1 (seconds) 14 17.55(8.08) (10.86, 37.26)

Trial 2 (seconds) 14 16.51(7.53) (10.01, 35.83)

P.296