Theravance Biopharma, Inc. · NASDAQ:TBPH
Theravance Biopharma — 33rd International Symposium on the Autonomic Nervous System (November 2022)
44 slides from Theravance Biopharma's conference presentation, Nov 3, 2022
Slide 1: Ampreloxetine Data in Neurogenic Orthostatic Hypotension
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Slide 2: Blood pressure and pharmacodynamic response of ampreloxetine in symptomatic nOH
Blood pressure and pharmacodynamic response of ampreloxetine, a norepinephrine reuptake inhibitor, in patients with symptomatic neurogenic orthostatic hypotension Horacio Kaufmann 1 , Roy Freeman 2 , David L. Bourdet 3 , Ross Vickery 4 , Lucy Norcliffe - Kaufmann 1 , Tadhg Guerin 3 , Pietro Guaraldi
Slide 3: Presenting Author Disclosure
Presenting Author Disclosure Dr. Horacio Kaufmann reports the following conflicts of interest: Related to this presentation: ‣ Theravance Biopharma: Consultant Unrelated to this presentation: ‣ Editor - In - Chief, Clinical Autonomic Research ‣ Research Support: Biogen ‣ Royalties: UpToDate ‣ Scient
Slide 4: Ampreloxetine
Ampreloxetine ‣ Why ampreloxetine ‣ Clinical trials with ampreloxetine ‣ Phenotype with best ampreloxetine response 4
Slide 5: Neurogenic Orthostatic Hypotension (nOH)
Neurogenic Orthostatic Hypotension ( nOH ) BP, blood pressure. 5 ‣ nOH is a sustained fall in BP upon standing due to lack of activation of the sympathetic postganglionic neurons innervating the vasculature and controlled by the baroreflex
Slide 6: Pure autonomic failure, MSA, Parkinson's disease
α α α α α α α α α α α α α α α α Pure autonomic failure α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α Multiple system atrophy Parkinson’s disease
Slide 7: Control of Sympathetic Activity to the Peripheral Vasculature
Central (MSA) RVLM IML Sympathetic ganglia Ach NE 2 main phenotypes Peripheral PD/DLB/PAF mixed Increase vascular resistance Insufficient leads to nOH Sympathetic activity Pre - ganglionic Post - ganglionic Agonists midodrine NE precursor droxidopa Control of Sympathetic Activity to the Peripheral V
Slide 8: Still an Unmet Need
Still an Unmet Need MSA, multiple system atrophy; nOH , neurogenic orthostatic hypotension; OHSA, Orthostatic Hypotension Symptom Assessment. Clinical trials showed that ~30% of patients taking droxidopa had no increase in blood pressure. nOH symptoms did not significantly improve after taking droxi
Slide 9: Control of Sympathetic Activity to the Peripheral Vasculature
Central (MSA) RVLM IML Sympathetic ganglia Ach NE 2 main phenotypes Peripheral PD/DLB/PAF mixed Increase vascular resistance Insufficient Sympathetic activity Pre - ganglionic Post - ganglionic Agonists midodrine NE precursor droxidopa Reuptake inhibitor ampreloxetine Control of Sympathetic Activity
Slide 10: Ampreloxetine: A Novel Pharmacological Strategy in nOH
Blood vessel Ampreloxetine: A Novel Pharmacological Strategy in nOH BP, blood pressure; NE, norepinephrine; NET, NE transporter; nOH , neurogenic orthostatic hypotension. sympathetic nerve terminals 1 Action potential 1 NE NET Ampreloxetine NE reuptake inhibition in nOH Increase standing BP Lessen o
Slide 11: Sequential Ampreloxetine Phase 3 Studies
Sequential Ampreloxetine Phase 3 Studies a Week 4 of Study 0169 double - blind treatment used as baseline reading for Study 0170. b Defined as a sustained reduction ≥20 mmHg systolic BP or ≥10 mmHg diastolic BP within 3 min of being tilted up to ≥60 ° from a supine position as determined by a tilt -
Slide 12: Ampreloxetine Elevates Plasma NE Levels in Patients With nOH
Ampreloxetine Elevates Plasma NE Levels in Patients With nOH Amp, ampreloxetine; DHPG, 3,4 - dihydroxyphenylglycol; OL, open label; NE, norepinephrine; nOH , neurogenic orthostatic hypotension; PBO, placebo; SE, standard error. 12 * P <0.05. DHPG Norepinephrine 4 Weeks (after 4 weeks randomized trea
Slide 13: Greatest Improvements in Plasma NE Were Seen in Patients With MSA
Greatest Improvements in Plasma NE Were Seen in Patients With MSA DHPG, 3,4 - dihydroxyphenylglycol; MSA, multiple system atrophy; NE, norepinephrine; PAF, pure autonomic failure; PD, Parkinson’s disease; SE, standard error. 13 * P <0.05. Measurements assessed after 4 weeks of randomized treatment i
Slide 14: Patients Randomized to Placebo Had Worsening 3-Minute Standing SBP
Patients Randomized to Placebo During the Withdrawal Period Had Worsening 3 - Minute Standing SBP LS, least - squares; SBP, systolic blood pressure; SE, standard error. 14 Baseline Withdrawal 0 10 80 90 100 110 120 130 140 3 - m i n s t a n d i n g S B P , m e a n ± S D ( m m H g ) Placebo Ampreloxe
Slide 15: Effect on Standing SBP Most Pronounced in Patients with MSA
The Effect of Ampreloxetine Treatment on 3 - Minute Standing SBP Was Most Pronounced in Patients with MSA Randomized Withdrawal Period LS, least - squares; MSA, multiple system atrophy; PAF, pure autonomic failure; PD, Parkinson’s disease; SBP, systolic blood press ure; SE, standard error. 15 Placeb
Slide 16: Conclusions
Conclusions ‣ Ampreloxetine showed biologically driven target engagement ‣ Ampreloxetine raised circulating NE levels and reduced biomarker of intraneuronal NE metabolism (DHPG) ‣ Increases in standing BP after randomized withdrawal were most pronounced in patients with MSA ‣ Increasing bioavailabil
Slide 17: Phase 3 randomized withdrawal study of ampreloxetine in symptomatic nOH
A phase 3, 22 - week, multi - center, randomized withdrawal study of ampreloxetine in treating symptomatic neurogenic orthostatic hypotension Italo Biaggioni 1 , Horacio Kaufmann 2 , Ross Vickery 3 , Beiyao Zheng 4 , Iryna Hovbakh 5 , Valeria Iodice 6 , Monika Rudzińska - Bar 7 , Meredith Bryarly 8
Slide 18: Presenting Author Disclosure
Presenting Author Disclosure Dr. Italo Biaggioni reports the following conflicts of interest: Related to this presentation: ‣ Theravance Biopharma: Consultant and institutional clinical trial support Unrelated to this presentation: ‣ Patent holder: Automated abdominal binder for the treatment of ort
Slide 19: Sequential Ampreloxetine Phase 3 Trials
Sequential Ampreloxetine Phase 3 Trials Study 0170 was terminated early because of negative results from the prior Phase 3 study (Study 0169; NCT03750552). MSA, multiple system atrophy; NE, norepinephrine; nOH, neurogenic orthostatic hypotension; OHDAS, Orthostatic Hypotension Dai ly Activity Scale;
Slide 20: Study 0170 Design
Study 0170 Design Study 0170 was terminated early because of negative results from the prior Phase 3 study (Study 0169; NCT03750552). MSA, multiple system atrophy; NE, norepinephrine; nOH , neurogenic orthostatic hypotension; OHDAS, Orthostatic Hypotension Daily Activity Scale; OHSA #1, Orthostatic
Slide 21: Study 0170 Design
Study 0170 Design Study 0170 was terminated early because of negative results from the prior Phase 3 study (Study 0169; NCT03750552). QD, once daily; RW, randomized withdrawal. 21 Enrichment failure: n = 20 (10%) Adverse event: n = 18 (9%) Physician decision: n = 1 (0.5%) Early study termination: n
Slide 22: Baseline Demographics
Baseline for randomized withdrawal period is Week 16 of open - label period. BMI, body mass index; MSA, multiple system atrophy; OHDAS, Orthostatic Hypotension Daily Activity Scale; OHSA, Orthostatic Hy pot ension Symptom Assessment; OHSA #1, OHSA item 1; PAF, pure autonomic failure; PD, Parkinson’s
Slide 23: Study Disposition
Study Disposition Randomized Withdrawal Period 23 Placebo ( n = 64) Ampreloxetine (n = 64) Total (N = 128) Completed treatment 61 (95.3) 58 (90.6) 119 (93.0) Discontinued treatment 3 (4.7) 6 (9.4) 9 (7.0) Adverse event 1 (1.6) 1 (1.6) 2 (1.6) Study terminated by sponsor 2 (3.1) 3 (4.7) 5 (3.9) Withd
Slide 24: Primary Endpoint: Treatment Failure
Primary Endpoint: Treatment Failure (worsening of symptoms after withdrawal) Randomized Withdrawal Period ‣ Primary endpoint of reduction in treatment failure was not met ‣ …but, we had a pre - specified subgroup analysis planned based on diagnosis The logistic regression model for treatment failure
Slide 25: Rationale for a Pre-Specified Analysis Based on Diagnosis
Rationale for a Pre - Specified Analysis Based on Diagnosis ‣ NET inhibition with ampreloxetine potentiates endogenously - released norepinephrine ‣ MSA Central synucleinopathy ‣ PAF/PD ‣ Ampreloxetine will be more effective in central synucleinopathies (MSA) NEpi , norepinephrine; NET, norepinephri
Slide 26: Primary Endpoint: Treatment Failure, MSA Subpopulation
Primary Endpoint: Treatment Failure (worsening of symptoms after withdrawal) Randomized Withdrawal Period ‣ Trend for benefit was observed in the MSA subpopulation based on prespecified subgroup analyses The logistic regression model for treatment failure included terms for treatment, baseline OHSA
Slide 27: Key Secondary Endpoints: Trend for Benefit in MSA Subgroup
Key Secondary Endpoints: Trend for Benefit in MSA Subgroup Randomized Withdrawal Period ‣ OHSA composite score demonstrated nominal statistical significance in prespecified subgroup analyses CI, confidence interval; LS, least - squares; MSA, multiple system atrophy; OHDAS, Orthostatic Hypotension Da
Slide 28: Safety Summary
Safety Summary Randomized Withdrawal Period ‣ TEAEs were similar between placebo and ampreloxetine groups – No adverse events of supine hypertension were observed ‣ No clinically significant differences for laboratory parameters, ECG changes, ambulatory BP monitoring, and vital signs ‣ Two deaths: 1
Slide 29: Conclusions
Conclusions ‣ Ampreloxetine demonstrated trend for benefit in the primary and key secondary endpoints in the prespecified MSA subgroup ‣ Ampreloxetine was generally well tolerated ‣ These results encouraged us to perform a longitudinal analysis in the subset of patients with MSA MSA, multiple system
Slide 30: Longitudinal analysis of ampreloxetine in patients with MSA
Longitudinal analysis of ampreloxetine for the treatment of symptomatic neurogenic orthostatic hypotension in subset of patients with multiple system atrophy Roy Freeman 1 , Italo Biaggioni 2 , Ross Vickery 3 , Lucy Norcliffe - Kaufmann 4 , Tadhg Guerin 5 , Rajeev Saggar 5 , Lydia Lopez Manzanares 6
Slide 31: Presenting Author Disclosure
Presenting Author Disclosure ‣ Dr. Roy Freeman has received personal compensation and/or stock options for serving on scientific advisory boards of AlgoRx , Applied Therapeutics, Clexio , Cutaneous NeuroDiagnostics , Glenmark, GW Pharma, Glaxo - Smith Kline, Inhibikase , Eli Lilly, Maxona , Novartis
Slide 32: Ampreloxetine Phase 3 Program Results
Ampreloxetine Phase 3 Program Results ‣ Ampreloxetine failed to meet its primary endpoint in two pivotal trials for the treatment of nOH in patients with MSA, PD, and PAF ‣ However, a prespecified subgroup analysis by primary disease type suggested a consistent benefit for ampreloxetine over placebo
Slide 33: Neurogenic Orthostatic Hypotension in MSA and Ampreloxetine
Neurogenic Orthostatic Hypotension in MSA and Ampreloxetine ‣ nOH is a chronic, debilitating condition caused by autonomic dysfunction 1,2 ‣ nOH is present in ~80% of patients with MSA 1 ‣ Central autonomic lesions are predominant in MSA, while peripheral postganglionic fibers may remain intact 2 –
Slide 34: Phase 3 Program
Phase 3 Program a 34 a After Study 0169 did not meet its primary endpoint, the ongoing clinical program was closed; Study 0170 was >80% enrolled at this p oi nt. b Sustained reduction of ≥20 mmHg in SBP or ≥10 mmHg in DBP within 3 min of being tilted - up to ≥60 ° from a supine position as determine
Slide 35: Study Disposition MSA Subgroup
AE, adverse event; MSA, multiple system atrophy; QD, once daily; RW, randomized withdrawal. 35 Randomized N = 71 Placebo n = 36 Ampreloxetine 10 mg QD n = 35 1 did not complete 0169 • 1 withdrawal by patient 35 completed study • 33 enrolled in 0170 2 did not complete 0169 • 1 withdrawal by patient •
Slide 36: Study Disposition MSA Subgroup
AE, adverse event; MSA, multiple system atrophy; QD, once daily; RW, randomized withdrawal. 36 Randomized N = 71 Placebo n = 36 1 did not complete 0169 • 1 withdrawal by patient 35 completed study • 33 enrolled in 0170 2 did not complete 0169 • 1 withdrawal by patient • 1 AE 33 completed study • 31
Slide 37: Baseline Demographics and Clinical Characteristics MSA Subgroup
Baseline Demographics and Clinical Characteristics MSA Subgroup a All 40 randomized patients in Study 0170 originated from Study 0169. MSA, multiple system atrophy; OHDAS, Orthostatic Hypotension Daily Activity Scale; OHQ, Orthostatic Hypotension Questionnaire ; O HSA, Orthostatic Hypotension Sympto
Slide 38: Ampreloxetine Improved OHSA Composite Score Over Time in MSA
Ampreloxetine Improved OHSA Composite Score Over Time and Maintained Effect During RW in Patients With MSA BL, baseline; CI, confidence interval; MSA, multiple system atrophy; OHSA, Orthostatic Hypotension Symptom Assessment; OL, op en label; RW, randomized withdrawal. 38 Placebo, n = Ampreloxetine
Slide 39: Ampreloxetine Improved OHDAS #1 Score Over Time in MSA
Ampreloxetine Improved OHDAS #1 Score Over Time and Maintained Effect During RW in Patients With MSA BL, baseline; CI, confidence interval; MSA, multiple system atrophy; OHDAS #1, Orthostatic Hypotension Daily Activity Scale i tem 1; OL, open label; RW, randomized withdrawal. 39 OHDAS #1: Standing s
Slide 40: Individual Components of OHQ Demonstrate Benefits in MSA Subgroup
CI, confidence interval; LS, least - squares; MSA, multiple system atrophy; OHDAS, Orthostatic Hypotension Daily Activity Scale; O HQ, Orthostatic Hypotension Questionnaire; OHSA, Orthostatic Hypotension Symptom Assessment. 40 ‣ Benefits observed in OHSA composite score and ability to stand for a sh
Slide 41: Worsening in 3-Minute Standing SBP After Withdrawal in MSA
Worsening in 3 - Minute Standing SBP Was Observed Following Ampreloxetine Withdrawal in Patients With MSA BL, baseline; CI, confidence interval; BP, blood pressure; MSA, multiple system atrophy; OL, open label; RW, randomized withd raw al; SBP, systolic blood pressure. 41 Placebo, n = Ampreloxetine
Slide 42: Adverse Events During Randomized Controlled Phases
Adverse Events During Randomized Controlled Phases MSA Subgroup AE, adverse event; MSA, multiple system atrophy; RW, randomized withdrawal; SAE, serious AE; TEAE, treatment - emergent AE. 42 Study 0169 Study 0170 RW period Placebo (n = 33) Ampreloxetine (n = 35) Placebo (n = 20) Ampreloxetine (n = 2
Slide 43: Conclusions
Conclusions ‣ Benefits of ampreloxetine were observed in patients with MSA, with consistent improvement in nOH symptoms over time ‣ Worsening of nOH symptoms and SBP was observed in patients with MSA upon randomized withdrawal of ampreloxetine to placebo – Broad symptomatic impact across each OHSA c
Slide 44: New Ampreloxetine Study in Patients With MSA
44 New Ampreloxetine Study in Patients With MSA Study 0197: 20 weeks 12 - week, open - label; 8 - week, randomized, double - blind, placebo - controlled, withdrawal Phase 3 r egistrational study Long - term extension Study 0197: 2 years Long - term, open - label ‣ CYPRESS study initiation planned fo