Slide 1: Results From a Global Phase 3 Trial Evaluating an Oral, Fixed-Dose Combination in ALS
Results From a Global Phase 3 Trial Evaluating an Oral, Fixed-Dose Combination of Sodium Phenylbutyrate and Taurursodiol in Amyotrophic Lateral Sclerosis Leonard H van den Berg, MD, PhD Professor of Neurology UMC Utrecht Brain Center Director Netherlands ALS Centre Chair of TRICALS
Slide 2: Disclosures
Disclosures • The institution of Dr. van den Berg has received compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for: – Amylyx, Ferrer, Sanofi, Biogen, Takeda, Novartis, BMS, ArgenX, Projenx • The institution of Dr. van den Berg has receive
Slide 3: Please Note
Please Note • This presentation is intended to provide scientific information about sodium phenylbutyrate and taurursodiol (PB&TURSO) • Some of the statements and content shared in this presentation have not been evaluated by any health authority 3
Slide 4: About PB&TURSO
About PB&TURSO • Fixed-dose combination of 2 small molecules, sodium phenylbutyrate and taurursodiol (PB&TURSO)1 • Hypothesized to simultaneously mitigate endoplasmic reticulum stress and mitochondrial dysfunction, 2 pathways leading to neuronal degeneration and death in ALS and other neurodegenerat
Slide 5: Background: The CENTAUR Trial of PB&TURSO in ALS Met Primary Endpoint
Background: The CENTAUR Trial of PB&TURSO in ALS Met Primary Endpoint1 25% Slower Decline in Function (ALSFRS-R)1 4.8 Months Longer Median Survival2 1 37.5 HR = 0.64 0.8 Survival probability 35.0 PB&TURSO PB&TURSO 0.6 ALSFRS-R 32.5 23.5 Placebo 30.5 0.4 18.7 27.5 0.2 p = 0.034 Placebo p = 0.048 25.0
Slide 6: PHOENIX Was a Global Collaboration
PHOENIX Was a Global Collaboration Steering Committee Co-Chairs Leonard van den Berg, MD, PhD | Sabrina Paganoni, MD, PhD 6
Slide 7: PHOENIX Was 48 Weeks Long with an Ongoing Open-Label Extension
PHOENIX Was 48 Weeks Long with an Ongoing Open-Label Extension Inclusion Criteria • Clinically definite or PB&TURSO clinically probable ALS N = 397 (2+ body regions) Randomized 3:2 PB&TURSO • <24 months from N = 664 symptom onset Placebo Open-Label Extension Phase • Slow vital capacity >55% N = 267
Slide 8: PHOENIX Methods
PHOENIX Methods Stratification Factors • CENTAUR-Like Population: Clinically Definite ALS (3+ body regions), SVC >60%, <18 mo from symptom onset • Edaravone use (at time of screening) CENTAUR-Like Current Edaravone Region Subgroup Use (U.S. and Europe) Pre-Specified Subgroups 8
Slide 9: Pre-Specified Primary and Secondary Endpoints
Pre-Specified Primary and Secondary Endpoints Primary Endpoint ALSFRS-R Total Score Independence Performing Daily Activities Change from Baseline at Week 48 (walking, talking, eating, dressing, etc.) Secondary Endpoints ALSAQ-40 Total Score ALS-specific Quality of Life Decreasing Change from Baselin
Slide 10: Majority of Participants in PHOENIX Were Enrolled in Europe
Majority of Participants in PHOENIX Were Enrolled in Europe United States Europe n=112 n=552 17% 83% U.S. Participants Rolled Off PHOENIX in 2022 When FDA Approval Occurred 10
Slide 11: Participant Disposition
Participant 664 Randomized Disposition 397 (60%) Randomized 267 (40%) Randomized to PB&TURSO (ITT) to Placebo (ITT) 42% Discontinued Follow-Up 43% Discontinued Follow-Up • 14% Adverse Event • 13% Adverse Event • 3% Disease Progression • 2% Disease Progression • 1% Lack of Efficacy • <1% Lack of Effi
Slide 12: Demographics and Baseline Characteristics Were Well Balanced
Demographics and Baseline Characteristics Were Well Balanced Characteristic PB&TURSO Placebo N = 397 N = 267 Age (years), mean (SD) 60.0 (11.0) 58.8 (10.5) Male 63% 60% Sex Female 37% 40% Europe 83% 83% Region U.S. 17% 17% Time Since Symptom Onset (months), mean (SD) 14.8 (5.3) 13.8 (5.2) Bulbar Ons
Slide 13: Primary Endpoint: ALSFRS-R
Primary Endpoint Change from Baseline in ALSFRS-R Total Score at Week 48 (ITT; mortality adjusted progression model) PB&TURSO Placebo PB&TURSO Placebo N = 397 N = 267 Mean Change from Baseline in -14.98 -15.32 ALSFRS-R ALSFRS-R Total Score (-15.98, -13.98) (-16.54, -14.11) (95% CI) Difference 0.343
Slide 14: Pre-Specified ALSFRS-R Subgroup Analyses
Pre-Specified ALSFRS-R Subgroup Analyses Change from Baseline in ALSFRS-R Total Score at Week 48 (ITT; mortality adjusted progression model) PB&TURSO Placebo N N Subgroup Difference in Mean Change from Baseline (95% CI) 0.343 Primary Endpoint (ITT Population) 397 267 (-1.22, 1.91) 2.01 CENTAUR-Like
Slide 15: Secondary Endpoints
Secondary Endpoints Change from Baseline in ALSAQ-40 and SVC at Week 48 (ITT; Mixed Model Repeated Measures) Difference in Mean Change from PB&TURSO Placebo Baseline Week 48 N = 397 N = 267 (95% CI) Mean Change from Baseline in ALSAQ-40 39.8 38.4 1.41 (95% CI) (36.9, 42.8) (34.8, 42.1) (-3.3, 6.2) M
Slide 16: Longer Follow-Up Needed for Overall Survival Analysis to Reach Maturity
Longer Follow-Up Past Week 48 Needed for Overall Survival Analysis to Reach Maturity Endpoint ALSFRS-R Total Score Change from Baseline at Week 48 Overall Survival Maturity Definition: Minimum of 70% of the participants have ALSAQ-40 Total Score died or 3 years have passed since the last Change from
Slide 17: PB&TURSO Was Generally Well-Tolerated in PHOENIX
PB&TURSO Was Generally Well-Tolerated in PHOENIX Safety Results Concordant with CENTAUR Trial Adverse Event PB&TURSO Placebo N = 396 N = 267 Any 89% 88% Drug-Related 53% 28% Serious 26% 28% Fatal 10% 15% Treatment Emergent Adverse Events ≥10% In Either Treatment Arm Any TEAE (≥10%) 64% 55% Fall 27%
Slide 18: Current Status of PB&TURSO in ALS
Current Status of PB&TURSO in ALS • Amylyx has announced that it has started a process with the FDA and Health Canada to voluntarily discontinue the marketing authorizations for PB&TURSO • This will remove the product from the market in the U.S. and Canada based on topline results from the Phase 3 P
Slide 19: Summary and Next Steps for PHOENIX
Summary and Next Steps for PHOENIX • Demographics and baseline disease characteristics were well-balanced • No differences between groups for primary endpoint, ALSFRS-R, or secondary endpoints, ALSAQ-40 and SVC – Complete secondary endpoint survival data will not be available until 2025/2026 • PB&TU
Slide 20: We Extend our Sincere Gratitude to the PHOENIX Participants, Investigators, and Sites
We Extend our Sincere Gratitude to the PHOENIX Participants, Investigators, and Sites Belgium Italy Spain United States (cont’d) • University Hospitals Leuven • Azienda Ospedaliero – Universitaria Di • Biodonostia Health Research Institute; • Augusta University Neuroscience Center Modena Hospital Un