Slide 1: Ampreloxetine in MSA: A pre-specified subgroup analysis of a phase 3 trial
Ampreloxetine in MSA: A pre-specified subgroup analysis of a phase 3, double-blind, placebo- controlled, randomized withdrawal trial Authors: Lucy Norcliffe-Kaufmann, Ross Vickery, Tadhg Guerin, Horacio Kaufmann, Italo Biaggioni, Valeria Iodice, Jens Jordan and Roy Freeman – on behalf of the REDWOOD
Slide 2: Disclosures
DISCLOSURES • LNK, RV, and TG have received personal compensation as employees and shareholders of Theravance Biopharma, Inc. HK, RF, IB, JJ and VI have received consultancy fees from Theravance Biopharma. HK and VI received funding through academic grants for research support from Theravance Biopha
Slide 3: Introduction
INTRODUCTION • 70-80% of patients with MSA will develop nOH in their lifetime1 • This adds significant disability, functional decline, and risk of early death from all-cause mortality • Despite treatment with available pressor agents, 68% of MSA patients with nOH remain symptomatic2 • Ampreloxetine
Slide 4: Underlying pathology in MSA
nOH GCIs Underlying pathology in MSA GCIs in the striatonigral & olivopontocerebellar systems, and central autonomic network RVLM • This pathology is unique to MSA • No drug has been developed for nOH specifically for patients intact peripheral autonomic neurons still capable of releasing NE IMLC PR
Slide 5: Pharmacological strategies for nOH
Pharmacological strategies for nOH ⍺1 NE Norepinephrine DHPG Action adrenoreceptor transporter (NE) (NE metabolite) potential volume expansion DROXIDOPA conversion NE precursor FLUDROCORTISONE NE UNMET NEED degraded • Both FDA-approved pressor DHPG agents act on vascular ⍺1- adrenoreceptors at the n
Slide 6: Pharmacological strategies for nOH
Pharmacological strategies for nOH ⍺1 NE Norepinephrine DHPG Action adrenoreceptor transporter (NE) (NE metabolite) potential volume expansion AMPRELOXETINE DROXIDOPA conversion NE precursor FLUDROCORTISONE NE • Ampreloxetine in MSA targets the right treatment to the right degraded patient at the ri
Slide 7: Ampreloxetine nOH program
AMPRELOXETINE nOH PROGRAM PHASE PHASE PHASE Today 2 3 3 PAF MSA PD CYPRESS STUDY PRE-SPECIFIED MSA SUBGROUP ANALYSIS PAF MSA PD * objective 34 participants 228 participants ENROLLING NOW
Slide 8: Objective
OBJECTIVE • A pre-specified subgroup analysis of ampreloxetine (oral, 10 mg/once-per-day) for neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA)
Slide 9: Methods: Protocol design and procedures
METHODS: Protocol Design and procedures SEQUOIA REDWOOD 4-weeks 16-weeks 6-weeks RCT OPEN-LABEL RWD ≥20/10 BP fall at 3 min n =64 ampreloxetine ampreloxetine OHSA OH item item 11≥4 >4 MSA R 1:1 ampreloxetine R 1:1 Randomization roll Randomization Plasma NE overs ≥100 pg/ml placebo placebo Committee
Slide 10: Results: Patient flow
RESULTS 4-weeks SEQUOIA Randomized n=71 PATIENT FLOW RCT Placebo Ampreloxetine 10mng QD n=36 n=35 n=2 did not complete n=1 did not complete FAS - baseline (N=67) - 1 withdrawal by patient - 1 withdrawal by patient - 1 AE n=35 completed n=33 completed 16-weeks n=33 enrolled in 0170 n=31 enrolled in 0
Slide 11: Results: Baseline (pre-treatment) characteristics
RESULTS: Baseline (pre-treatment) Characteristics Well-balanced between groups (FAS, SEQUOIA) DEMOGRAPHICS FEATURES OF MSA NEUROGENIC OH 1.6Y 67.2% SYSTOLIC 142.0 HEART RATE 70.2 85.6 SINCE DOPAMINERGIC 47.8 DIAGNOSIS DIASTOLIC bpm MEDICATIONS mmHg 52.2 UMSARS UMSARS 4 PART 1 SYSTOLIC 99.4 83.1 HEAR
Slide 12: Measurable outcome nOH symptoms
nOH SYMPTOMS MEASURABLE ASSESSMENT OUTCOME Orthostatic Hypotension Questionnaire (OHQ) 10 item -symptom, validated scale, accepted by the FDA for drug approvals IMPACT OF trouble POSTION concentrating dizziness light-headedness visual changes Coat Orthostatic Hypotension Symptom Assessment (OHSA) ha
Slide 13: Results: Symptom burden and function
6-weeks RESULTS: Symptom burden and function REDWOOD RWD favors favors REDWOOD, FAS n=40 ampreloxetine placebo Primary Outcome Treatment Failure 0.28 [0.05, 1.22] 0.01 0.10 1.00 10.00 Odds Ratio (log10) [95% CI] OHQ Composite Scores OHSA OHSA -1.6 [-2.7, -0.5] Composite FINDINGS OHDAS -0.8 [-2.1, 0.
Slide 14: Results: Symptom burden and function
6-weeks RESULTS: Symptom burden and function REDWOOD RWD REDWOOD, FAS n=40 Open Label Placebo Ampreloxetine Standing for a short time Examples morning hygiene, brushing your teeth, COMPOSITE SCORE Item 1 STANDINGbrushing SHORT yourTIME hair Standing for a long time waiting in a line at the post offi
Slide 15: Results: Pharmacodynamics
4-weeks RESULTS: Pharmacodynamics SEQUOIA RCT Catecholamines, seated, HPLC analysis, SEQUOIA FAS n=67 NE DHPG NE:DHPG ratio release Norepinephrine (pg/ml ± SE) NE:DHPG ratio (△% ± SE) DHPG (ng/ml ± SE) breakdown reuptake FINDINGS • Profile was consistent with the activity of a highly selective perip
Slide 16: Results: BP and HR
6-weeks REDWOOD RESULTS: BP and HR BP and HR, REDWOOD FAS n=40 RWD RWD 6 week RWD 6 week OPEN-LABEL 16 weeks 3 min FINDINGS • A pressor effect was observed over 16-weeks of open-label treatment, that was lost after 6- weeks of placebo withdrawal
Slide 17: Conclusions
CONCLUSIONS • This pre-specified subgroup analysis of MSA patients entering the ampreloxetine RW trial show a durable symptomatic benefit with improvement in activities of daily living that was lost after ampreloxetine was withdrawn • The pharmacodynamic profile of ampreloxetine was consistent with
Slide 18: Future directions
FUTURE DIRECTIONS • This targeted therapy is ideally suited to patients with intact peripheral autonomic neurons and uses a highly specific NE re- uptake inhibitor to restore residual peripheral autonomic nerve function on standing • We are now nearing completion of the ampreloxetine CYPRESS study,