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| Item 7.01. | Regulation FD Disclosure. |
On November 2, 2022, Theravance Biopharma issued a press release and presented additional data from its Phase 3 clinical trial of ampreloxetine in patients with neurogenic orthostatic hypotension (nOH) at the 33rd International Symposium on the Autonomic Nervous System, a meeting of the American Autonomic Society. The press release is furnished as Exhibit 99.1 and data are furnished in Exhibit 99.2 to this Current Report on Form 8-K and are incorporated by reference herein.
The information in this Item 7.01 and in Item 9.01 of this Current Report on Form 8-K, including Exhibits 99.1 and 99.2, is being furnished and shall not be deemed “filed” for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Securities Exchange Act of 1934”), or otherwise subject to the liabilities of that Section, nor shall it be incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Securities Exchange Act of 1934, except as expressly set forth by specific reference in such a filing.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits
| 99.1 | Press Release dated November 2, 2022 |
| 99.2 | Presentation entitled Ampreloxetine Data in Neurogenic Orthostatic Hypotension Presented at the 33rd International Symposium on the Autonomic Nervous System | |
| 104 | Cover Page Interactive Data File (cover page XBRL tags embedded within the Inline XBRL document) |
SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| THERAVANCE BIOPHARMA, INC. | |
| Date: November 2, 2022 | By: /s/ Brett Grimaud |
| Brett Grimaud | |
| Senior Vice President, General Counsel and Secretary |
Exhibit 99.1
Ampreloxetine Data
in Neurogenic Orthostatic Hypotension to be Presented at the
33rd International Symposium on the Autonomic Nervous System
| · | Totality of Evidence from the Phase 3 Clinical Program Demonstrates Ampreloxetine was Effective in Treating Symptoms and Improving Activities of Daily Living in MSA Patients with Neurogenic Orthostatic Hypotension |
| · | Safety Profile of Ampreloxetine was Similar to that of Placebo |
DUBLIN, November 2, 2022 -- Theravance Biopharma, Inc. ("Theravance Biopharma" or the "Company") (NASDAQ: TBPH) today will present new ampreloxetine data in neurogenic orthostatic hypotension (nOH) from the Company’s Phase 3 program at the 33rd International Symposium on the Autonomic Nervous System, a meeting of the American Autonomic Society (AAS). Ampreloxetine is an investigational, once-daily norepinephrine reuptake inhibitor in development for the treatment of symptomatic nOH in patients with multiple system atrophy (MSA).
“These ampreloxetine data are encouraging for patients with MSA suffering with neurogenic orthostatic hypotension. There is an urgency to treat MSA patients with nOH due to the impact on quality of life and the extreme caregiver burden. Ampreloxetine appears to broadly impact a critical group of symptoms related to blood pressure control and may represent a potential therapy for MSA patients,” said Roy Freeman, MBChB, Professor of Neurology, Director, Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, who assisted in the design and interpretation of the ampreloxetine Phase 3 program and is an author on all three abstracts presented at the AAS meeting.
Disclosure: Dr. Freeman is a consultant serving as an advisor for drug development and clinical trial design for Theravance Biopharma.
Study results presented at the 2022 AAS meeting, session 1 include:
Clinical Effectiveness of Ampreloxetine
| · | Clinically meaningful and nominal statistically significant (p < 0.05) differences relative to placebo in MSA patients on the following endpoints in Study 0170: |
| o | Orthostatic Hypotension Symptom Assessment Scale (OHSA) composite score (LS mean difference: -1.6 [95% CI: -2.7, -0.5]) |
| o | Orthostatic Hypotension Questionnaire (OHQ) composite score (LS mean difference: -1.2 [95% CI: -2.3, -0.2]) |
| o | Orthostatic Daily Activities Scale (OHDAS) Item 1 – Standing a short time (LS mean difference: -2.0 [95% CI: -3.6, -0.4]) |
| · | Symptomatic improvement in patients with MSA was broadly demonstrated on the individual components of the OHSA composite in Study 0170 including: |
| o | dizziness (LS mean difference: -1.5 [95% CI: -3.2, 0.2]) |
| o | vision (LS mean difference: -1.7 [95% CI: -3.2, -0.3]) |
| o | weakness (LS mean difference: -0.7 [95% CI: -2,3, 0.9]) |
| o | fatigue (LS mean difference: -1.5 [95% CI: -3.1, 0.1]) |
| o | trouble concentrating (LS mean difference -1.8 [95% CI: -3.3, -0.4]) |
| o | head/neck discomfort (LS mean difference: -2.2 [95% CI: -3.7, -0.7]) |
| · | Durability of clinical effect was demonstrated by ampreloxetine in MSA patients as reflected in the reduction of the OHSA composite score and OHDAS item 1 over the course of 20 weeks (5 months) across the Phase 3 program (studies 0169 and 0170 open-label period). |
Blood Pressure and Pharmacodynamics
| · | Standing systolic blood pressure across all studied patients (including MSA, Parkinson’s disease and Pure Autonomic Failure) with nOH was maintained by ampreloxetine and worsened after withdrawal to placebo [treatment difference: 8.6 mm Hg; p<0.05] during the randomized withdrawal phase of study 0170. The benefit was most pronounced in patients with MSA [treatment difference: 15.7 mm Hg; p < 0.05]. |
| · | Ampreloxetine increased levels of plasma norepinephrine (NE) [47%; p< 0.05] and decreased levels of dihydroxyphenyl glycol (DHPG) [-22%; p < 0.05] over the course of 4 weeks in patients with nOH, consistent with its mechanism of action. The increase in NE [57%; p< 0.05] was especially notable in the sub-group of patients with MSA. |
Safety and Tolerability
| · | Ampreloxetine was generally well-tolerated in patients with nOH, including in the sub-group of MSA patients. Treatment-emergent adverse events were similar between the placebo and ampreloxetine groups with no clinically significant differences in laboratory parameters, ECG changes, ambulatory BP monitoring, and vital signs. |
| · | No adverse events of supine hypertension were observed in the Phase 3 randomized withdrawal period (Study 0170). |
Theravance Biopharma is focused on beginning the registrational Phase 3 Study in MSA patients with nOH: Study 0197, CYPRESS, a 12-week open-label, 8-week double-blind, placebo-controlled, randomized withdrawal study with a primary endpoint of change in OHSA composite score. Theravance Biopharma aims to start Study 0197 in the first quarter of 2023, moving the trial forward as expeditiously as possible building on the insights, experience and relationships gained from the ampreloxetine clinical trials already completed.
About Ampreloxetine
Ampreloxetine (TD-9855) is an investigational, once-daily norepinephrine reuptake inhibitor in development for the treatment of symptomatic nOH in patients with multiple system atrophy (MSA). Phase 3 results (Study 0170) showed a benefit to MSA patients in the study that was observed in multiple endpoints including Orthostatic Hypotension Symptom Assessment (OHSA) composite, Orthostatic Hypotension Daily Activities Scale (OHDAS) composite, Orthostatic Hypotension Questionnaire (OHQ) composite and OHSA #1. The Company held a Type C meeting with the FDA in June 2022 and agreed on a path to NDA filing with one new Phase 3 clinical study in MSA patients with symptomatic nOH. The Company plans to start the new Phase 3 study in early 2023, with a primary endpoint of Change in OHSA Composite Score.
Patients with MSA may benefit from ampreloxetine treatment due to the presence of central autonomic pathway degeneration and intact peripheral postganglionic fibers that is specific to MSA. As a NET re-uptake inhibitor, ampreloxetine may enhance the function of the residual sympathetic nerves resulting in increases in norepinephrine levels, standing BP, and reduction in symptoms of nOH in patients with MSA.
About Study 0170, a Phase 3 Study
Study 0170 (NCT03829657) was a 22-week Phase 3 study comprised of a 16-week open-label period and a 6-week double-blind, placebo-controlled, randomized withdrawal period. The primary endpoint of treatment failure at week 6 was defined as a worsening of both Orthostatic Hypotension Symptom Assessment Scale (OHSA) question #1 and Patient Global Impression of Severity (PGI-S) scores by 1.0 point. After Study 0169 did not meet its primary endpoint, the Company took actions to close out the ongoing clinical program including Study 0170. The study was more than 80% enrolled (n=128/154 planned) despite stopping early. The primary endpoint was not statistically significant for the overall population of patients, which included patients with Parkinson's disease, pure autonomic failure and MSA (odds ratio=0.6; p-value=0.196). The pre-specified subgroup analysis by disease type suggests the benefit seen in patients receiving ampreloxetine was largely driven by MSA patients (n=40). An odds ratio of 0.28 (95% CI: 0.05, 1.22) was observed in MSA patients indicating a 72% reduction in the odds of treatment failure with ampreloxetine compared to placebo (read more about the data here).
About Multiple System Atrophy (MSA) and Symptomatic Neurogenic Orthostatic Hypotension (nOH)
MSA is a progressive brain disorder that affects movement and balance and disrupts the function of the autonomic nervous system. The autonomic nervous system controls body functions that are mostly involuntary. One of the most frequent autonomic symptoms associated with MSA is a sudden drop in blood pressure upon standing (nOH).1 There are approximately 50,000 MSA patients in the US2 and 70-90% of MSA patients experience nOH symptoms.3 Despite available therapies, many MSA patients remain symptomatic with nOH.
Neurogenic orthostatic hypotension (nOH) is a rare disorder defined as a fall in systolic blood pressure of >20 mm Hg or diastolic blood pressure of >10 mm Hg, within 3 minutes of standing. Severely affected patients are unable to stand for more than a few seconds because of their decrease in blood pressure, leading to cerebral hypoperfusion and syncope. A debilitating condition, nOH results in a range of symptoms including dizziness, lightheadedness, fainting, fatigue, blurry vision, weakness, trouble concentrating, and head and neck pain.
1 https://medlineplus.gov/genetics/condition/multiple-system-atrophy/
2 2019 IQVIA Claims Analysis; NIH, UC San Diego Health Movement Disorder Center Multiple System Atrophy | UC San Diego Health (ucsd.edu)
3 Mathias CJ, et al. J Neurol 1999 Oct;246(10):893-8
About Theravance Biopharma
Theravance Biopharma, Inc.'s overarching purpose and goal as a biopharmaceutical company is focused on delivering Medicines that Make a Difference® in people's lives. In pursuit of its purpose, Theravance Biopharma leverages decades of expertise, which has led to the development of FDA-approved YUPELRI® (revefenacin) inhalation solution indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Its pipeline of internally discovered programs is targeted to address significant unmet patient needs.
For more information, please visit www.theravance.com.
THERAVANCE BIOPHARMA®, THERAVANCE®, and the Cross/Star logo are registered trademarks of the Theravance Biopharma group of companies (in the U.S. and certain other countries).
YUPELRI® is a registered trademark of Mylan Specialty L.P., a Viatris Company. Trademarks, trade names or service marks of other companies appearing on this press release are the property of their respective owners.
Forward-Looking Statements
This press release contains certain "forward-looking" statements as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding, among other things, statements relating to goals, plans, objectives, expectations and future events. Theravance Biopharma intends such forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995. Examples of such statements include statements relating to: the Company’s goals, designs, strategies, plans and objectives, the ability to provide value to shareholders, the Company’s regulatory strategies and timing of clinical studies (including the data therefrom), the potential characteristics, benefits and mechanisms of action of the Company's product and product candidates, the market for products being commercialized, potential regulatory actions and commercialization (including differentiation from other products or potential products and addressable market), and product sales or profit share revenue. These statements are based on the current estimates and assumptions of the management of Theravance Biopharma as of the date of this press release and are subject to risks, uncertainties, changes in circumstances, assumptions and other factors that may cause the actual results of Theravance Biopharma to be materially different from those reflected in the forward-looking statements. Important factors that could cause actual results to differ materially from those indicated by such forward-looking statements include, among others, risks related to the satisfaction of the conditions to the Offer, volatility and fluctuations in the trading price and volume of the Shares, and general economic and market conditions. Other risks affecting Theravance Biopharma are in the Company’s Form 10-Q filed with the SEC on August 8, 2022, and other periodic reports filed with the SEC. In addition to the risks described above and in Theravance Biopharma’s filings with the SEC, other unknown or unpredictable factors also could affect Theravance Biopharma’s results. No forward-looking statements can be guaranteed, and actual results may differ materially from such statements. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Theravance Biopharma assumes no obligation to update its forward-looking statements on account of new information, future events or otherwise, except as required by law.
Contact: Andrew Hindman
Chief Financial Officer
investor.relations@theravance.com
650-808-4145
Exhibit 99.2
THERAVANCE BIOPHARMA ® , THERAVANCE ® , the Cross/Star logo and MEDICINES THAT MAKE A DIFFERENCE ® are registered trademarks of the Theravance Biopharma group of companies (in the U.S. and certain other countries). All third party trademarks used herein are the property of their respective owners. Ampreloxetine Data in Neurogenic Orthostatic Hypotension Presented at the 33 rd International Symposium on the Autonomic Nervous System November 2, 2022 © 2022 Theravance Biopharma. All rights reserved.
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 5 , Alexandru Barboi 6 , Valeria Iodice 7 , Italo Biaggioni 8 1 NYU Langone Health, New York University School of Medicine, New York, NY, USA; 2 Beth Israel Deaconess Medical Center, Boston, MA, USA; 3 Theravance Biopharma US, Inc., South San Francisco, CA, USA; 4 Theravance Biopharma Ireland Limited, Dublin, Ireland; 5 University of Bologna, Bologna, Italy; 6 NorthShore University Health System, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA; 7 National Hospital for Neurology and Neurosurgery, Queen Square, Institute of Neurology, University College London, London, UK; 8 Vanderbilt University Medical Center, Nashville, TN, USA Poster #117
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 ‣ Scientific Advisory Board: Lilly USA, Ono Pharma UK Ltd, Vaxxinity , Takeda Pharmaceuticals, 3
Ampreloxetine ‣ Why ampreloxetine ‣ Clinical trials with ampreloxetine ‣ Phenotype with best ampreloxetine response 4
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
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
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 Vasculature Ach, acetylcholine; DLB, dementia with Lewy bodies; IML, intermediolateral cell column; MSA, multiple system atrophy; NE, nor epi nephrine; nOH , neurogenic orthostatic hypotension; PAF, pure autonomic failure; PD, Parkinson’s disease; RVLM, rostral ventrolateral medulla.
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 droxidopa in patients with MSA Subgroup analysis What determines the response to treatment? 40% of patients with nOH taking pressor agents are still symptomatic
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 to the Peripheral Vasculature Ach, acetylcholine; DLB, dementia with Lewy bodies; IML, intermediolateral cell column; MSA, multiple system atrophy; NE, nor epi nephrine; PAF, pure autonomic failure; PD, Parkinson’s disease; RVLM, rostral ventrolateral medulla.
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 organ hypoperfusion Reduce symptoms of nOH Potentiate the effect of NE when released at neurovascular junction Harness the activity of the residual sympathetic nerves
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 - table test. BP, blood pressure; DHPG, 3,4 - dihydroxyphenylglycol; MSA, multiple system atrophy; NE, norepinephrine; nOH , neurogenic orthostatic hypotension; OHSA #1, Orthostatic Hypotension Symptom Assessment item #1; PAF, pure autonomic failure; PD, Parkinson’s disease; QD, once daily; RW, randomized withdrawal. 11 BP Plasma NE, DHPG Eligibility Study 0169 • nOH diagnosis b • Score of ≥4 on OHSA #1 at Visit 1 • Diagnosis of MSA, PD, or PAF • Plasma NE ≥100 pg /mL Study 0170 • Compliant with Study 0169 or • De novo per same criteria as Study 0169 Ampreloxetine 10 mg QD Placebo QD
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 treatment) +47% −22% * * PBO randomizedAmp randomized 0.0 0.5 1.0 1.5 2.0 G e o m e t r i c m e a n r a t i o ± S E PBO randomized → Amp OL Amp randomized → Amp OL 0.0 0.5 1.0 1.5 2.0 G e o m e t r i c m e a n r a t i o ± S E 8 Weeks (after 4 weeks randomized treatment + 4 weeks open - label ampreloxetine) +69% −30% +10% −13% * * *
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 in Study 0169. DHPG Norepinephrine Placebo Ampreloxetine 0.0 0.5 1.0 1.5 2.0 G e o m e t r i c m e a n r a t i o ± S E MSA +57% −18% * * * +22% −26% Placebo Ampreloxetine 0.0 0.5 1.0 1.5 2.0 G e o m e t r i c m e a n r a t i o ± S E PD * +45% −24% *
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 Ampreloxetine 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 Ampreloxetine Treatment difference: 8.6 mmHg ( P <0.05) Placebo Ampreloxetine -15 -10 -5 0 5 L S m e a n c h a n g e ± S E ( m m H g ) worsening −7.9 0.7
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 Placebo Ampreloxetine Placebo Ampreloxetine -20 -10 0 10 20 L S m e a n c h a n g e ± S E ( m m H g ) MSA PAF Placebo Ampreloxetine -20 -10 0 10 20 L S m e a n c h a n g e ± S E ( m m H g ) PD Placebo Ampreloxetine -20 -10 0 10 20 L S m e a n c h a n g e ± S E ( m m H g ) worsening −10.0 5.6 −8.3 −1.8 −2.3 0.2 Treatment difference: 15.7 mmHg ( P <0.05) Treatment difference: 6.5 mmHg Treatment difference: 2.5 mmHg
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 bioavailability of NE with ampreloxetine may be particularly beneficial in patients with MSA BP, blood pressure; DHPG, 3,4 - dihydroxyphenylglycol; MSA, multiple system atrophy; NE, norepinephrine; nOH , neurogenic orthostatic hypotension. 16
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 , Sergii Moskovko 9 , Cyndya A Shibao 1 , Roy Freeman 10 1 Vanderbilt University Medical Center, Nashville, TN, USA; 2 NYU Langone Health, New York University School of Medicine, New York, NY, USA; 3 Theravance Biopharma Ireland Limited, Dublin, Ireland; 4 Theravance Biopharma US, Inc., South San Francisco, CA, USA; 5 Clinical Hospital No. 9, Kharkiv, Ukraine; 6 National Hospital for Neurology and Neurosurgery, Queen Square, Institute of Neurology, University College London, London, UK; 7 Andrzej Frycz Modrzewski Krakow University , Krakow, Poland; 8 UT Southwestern Medical Center, Dallas, TX, USA; 9 Vinnytsia National Medical University, Vinnytsia Oblast, Ukraine; 10 Beth Israel Deaconess Medical Center, Boston, MA, USA Poster #106
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 orthostatic hypotension ‣ Consultant: Amneal , Regeneron, Takeda Funding for this study: ‣ The study was funded by Theravance Biopharma Ireland Limited 18
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; OHSA #1, Orthostatic Hypotension Symptom Assessment item 1; PAF, pure autonomic failure; PD, Parkinson’s disease; PGI - S, Patient Global Impression of Severity; QD, once daily; RW, randomized withdrawal. 19 Study 0169 did not meet the primary endpoint based on reduction in OHSA#1 Eligibility • Age ≥30 years • nOH diagnosis • Score of ≥4 on OHSA #1 at Visit 1 • Diagnosis of MSA, PD, or PAF • Plasma NE ≥100 pg /mL • Study 0170 – compliant in Study 0169 or de novo (same criteria as above) • Study 0171 – completed Study 0170
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 Hypotension S ymp tom Assessment item 1; PAF, pure autonomic failure; PD, Parkinson’s disease; PGI - S, Patient Global Impression of Severity; QD, once daily; RW, randomized withdrawal. 20 Endpoints Primary Treatment failure: Worsening from baseline of both OHSA #1 (≥1 point) and PGI - S (≥1 point) Key Secondary Change from baseline in: • OHSA #1 • OHSA composite score • OHDAS composite score • PGI - S Study 0170 eligibility 0169 Rollovers • Completion of Study 0169 with ≥80% study medication compliance De novo • nOH • OHSA #1 ≥4 at Visit 1 • MSA, PD, or PAF • Plasma NE levels ≥100 pg /mL Enrichment Criteria • Reduction of OHSA #1 ≥2 at Week 4 • OHSA #1 ≤7 at Week 16
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 = 13 (6%) Withdrawal by subject: n = 18 (9%) Other: n = 5 (2%) N = 203 128 randomized
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 disease; PGI - S, Patient Global Impression of Severity; SD, standard deviation. 22 Placebo (n = 64) Ampreloxetine (n = 64) Total (N = 128) Male, n (%) 49 (76.6) 42 (65.6) 91 (71.1) Age, mean ± SD, years 68.2 ± 8.1 67.5 ± 8.6 67.9 ± 8.3 White, n (%) 63 (98.4) 61 (95.3) 124 (96.9) BMI, mean ± SD, kg/m 2 25.9 ± 4.7 25.4 ± 4.3 25.7 ± 4.5 Primary neurological diagnosis, n (%) MSA 20 (31.3) 20 (31.3) 40 (31.3) PD 34 (53.1) 34 (53.1) 68 (53.1) PAF 10 (15.6) 10 (15.6) 20 (15.6) OHSA #1, mean ± SD 2.5 ± 1.8 3.1 ± 2.0 2.8 ± 1.9 OHSA #1 <4, n (%) 43 (67.2) 35 (54.7) 78 (60.9) OHSA composite score, mean ± SD 2.2 ± 1.5 2.7 ± 1.7 2.4 ± 1.7 OHDAS composite score, mean ± SD 3.4 ± 2.3 3.3 ± 2.4 3.3 ± 2.4 PGI - S score, mean ± SD 2.4 ± 0.9 2.4 ± 0.8 2.4 ± 0.8 Baseline Demographics and Clinical Characteristics Randomized Withdrawal Period
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) Withdrawal by patient 0 1 (1.6) 1 (0.8) Other 0 1 (1.6) 1 (0.8) All data are presented as n (%).
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 included terms for treatment, baseline OHSA #1, baseline PGI - S, and disease type (MSA, PAF, or PD). Profile - likelihood CI is shown. CI, confidence interval; MSA, multiple system atrophy; OHSA #1, Orthostatic Hypotension Symptom Assessment item 1; PAF, pure au tonomic failure; Parkinson’s disease; PGI - S, Patient Global Impression of Severity. 24
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, norepinephrine transporter; MSA, multiple systems atrophy; PAF, pure autonomic failure; PD, Parkinson’ s d isease. 25 Intact noradrenergic nerves ՝ NEpi release NEpi Potentiation by NET Inhibition Neurodegeneration of noradrenergic nerves ՝ ↓ ↓ NEpi release NEpi ✓ X Cyndya Shibao
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 #1, baseline PGI - S, and disease type (MSA, PAF, or PD). Profile - likelihood CI is shown. CI, confidence interval; MSA, multiple system atrophy; OHSA #1, Orthostatic Hypotension Symptom Assessment item 1; PAF, pure au tonomic failure; PD, Parkinson’s disease; PGI - S, Patient Global Impression of Severity. 26
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 Daily Activity Scale; O HSA, Orthostatic Hypotension Symptom Assessment; OHSA #1, OHSA item 1; PAF, pure autonomic failure; PD, Parkinson’s disease; PGI - S, Patient Global Impression of Severity. 27
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 respiratory tract infection (unrelated) and 1 unknown cause a a Death of unknown cause was imputed as related to treatment. BP, blood pressure; ECG, electrocardiogram; SAE, serious adverse event; TEAE, treatment - emergent adverse event. 28 All data are presented as n (%). Ampreloxetine was administered at 10 mg once daily. Placebo (n = 64) Ampreloxetine (n = 64) Any TEAEs 16 (25.0) 17 (26.6) TEAEs related to study drug 2 (3.1) 5 (7.8) SAEs 2 (3.1) 4 (6.3) SAEs related to study drug 1 (1.6) 2 (3.1) TEAEs leading to permanent study drug discontinuation 1 (1.6) 1 (1.6) Deaths during study 0 2 (3.1)
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 atrophy. 29 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 , Valeria Iodice 7 , Monika Rudzińska - Bar 8 , Maria Teresa Pellecchia 9 , Horacio Kaufmann 4
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 , Valeria Iodice 7 , Monika Rudzińska - Bar 8 , Maria Teresa Pellecchia 9 , Horacio Kaufmann 4 1 Beth Israel Deaconess Medical Center, Boston, MA, USA; 2 Vanderbilt University Medical Center, Nashville, TN, USA; 3 Theravance Biopharma Ireland Limited, Dublin, Ireland; 4 NYU Langone Health, New York University School of Medicine, New York, NY, USA; 5 Theravance Biopharma US, Inc., South San Francisco, CA, USA; 6 Hospital Universitario de La Princesa , Madrid, Spain; 7 National Hospital for Neurology and Neurosurgery, Queen Square, Institute of Neurology, University College London, London, UK; 8 Andrzej Frycz Modrzewski Krakow University , Krakow, Poland; 9 Università di Salerno, Salerno, Italy Poster #4
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, NeuroBo , Regenacy , Theravance Biopharma, and Vertex; has received personal compensation for editorial activities (Editor) with Autonomic Neuroscience – Basic and Clinical; has received research support from the National Institutes of Health (1R01NS10584401A1, R01HL111465 - 01A1); is a member of the Multiple System Atrophy Coalition Clinical Advisory Board, and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks; and is a Board member of the International Diabetic Neuropathy Consortium of the Peripheral Nerve Society and the Neuropathic Pain Consortium of the Peripheral Nerve Society ‣ The study was funded by Theravance Biopharma Ireland Limited 31
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 in patients with MSA across multiple endpoints in a randomized withdrawal period ‣ These results prompted an in - depth analysis across Phase 3 clinical studies of all patients with MSA, and assessment for a potential future confirmatory trial ‣ We report the longitudinal results of a Phase 3 ampreloxetine program evaluating efficacy, durability of treatment effect, and safety for nOH treatment in the prespecified subgroup of patients with MSA MSA, multiple system atrophy; nOH , neurogenic orthostatic hypotension; PAF, pure autonomic failure; PD, Parkinson’s disease. 32
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 – Due to integrity of peripheral postganglionic fibers, patients with MSA may therefore be particularly well suited for NE reuptake inhibition treatment compared to patients with PD or PAF ‣ Ampreloxetine is an oral, once - daily inhibitor of NE reuptake being developed for the treatment of nOH 2 1. Kalra DK, et al. Clin Med Insights: Cardiol . 2020;14: 1179546820953415. 2. Kaufmann H, et al. Clin Auton Res . 2021;31(6):699 – 711. MSA, multiple system atrophy; NE, norepinephrine; NET, norepinephrine transporter; nOH , neurogenic orthostatic hypotension; PAF, pure autonomic failure; PD, Parkinson’s disease. 33
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 determined by a tilt - table test. DBP, diastolic blood pressure; MSA, multiple system atrophy; NE, norepinephrine; nOH , neurogenic orthostatic hypotension; OHQ, Orthostatic Hypotension Questionnaire; OHSA #1, Orthostatic Hypotension Symptom As ses sment item 1; OL, open - label; PAF, pure autonomic failure; PD, Parkinson’s disease; QD, once daily; RW, randomized withdrawal; SBP, systolic b lood pressure. Endpoints Efficacy • OHQ – Composite scores – Individual items • Orthostatic standing test – 3 - minute standing SBP Safety • Adverse events Longitudinal analysis (prespecified MSA subgroup) Eligibility • Study 0169 – Age ≥30 years – nOH diagnosis b – Score of ≥4 on OHSA #1 at Visit 1 – Diagnosis of MSA , PD, or PAF – Plasma NE ≥100 pg /mL • Study 0170 – OL period: Compliant in Study 0169 or de novo (same criteria as Study 0169) – RW period: OHSA #1 reduction ≥2 points at Week 4 of OL period and OHSA #1 score ≤7 at Week 16 of OL period • Study 0171 : Completed Study 0170
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 • 1 AE 33 completed study • 31 enrolled in 0170 Ampreloxetine 10 mg QD open label N = 66 2 de novo 26 did not complete 0170 open label • 7 AEs • 1 physician decision • 2 sponsor decision • 6 withdrawal by patient • 8 failed to meet continuation criteria • 2 other Ampreloxetine 10 mg QD n = 20 Placebo n = 20 1 did not complete 0170 RW • 1 sponsor decision 1 did not complete 0170 RW • 1 sponsor decision 19 completed study • 17 enrolled in 0171 19 completed study • 17 enrolled in 0171 Ampreloxetine 10 mg QD open label N = 34 34 did not complete 0171 open label • 1 AE • 33 sponsor decision Study 0169 Study 0170 Study 0171 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 enrolled in 0170 Ampreloxetine 10 mg QD open label N = 66 2 de novo 26 did not complete 0170 open label • 7 AEs • 1 physician decision • 2 sponsor decision • 6 withdrawal by patient • 8 failed to meet continuation criteria • 2 other Placebo n = 20 1 did not complete 0170 RW • 1 sponsor decision 1 did not complete 0170 RW • 1 sponsor decision 19 completed study • 17 enrolled in 0171 19 completed study • 17 enrolled in 0171 Ampreloxetine 10 mg QD open label N = 34 34 did not complete 0171 open label • 1 AE • 33 sponsor decision Study 0169 Study 0170 Study 0171 Study Disposition MSA Subgroup Ampreloxetine 10 mg QD n = 35 Ampreloxetine 10 mg QD n = 20
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 Symptom Assessment; OHSA #1, OHSA item 1; RW, randomized withdrawal; SBP, systolic blood pressure; SD, standard deviation. 37 Data are presented as mean (SD) unless otherwise indicated. ‣ Demographic and clinical characteristics were generally well balanced across treatment groups Study 0169 Study 0170 RW period Placebo (n = 33) Ampreloxetine (n = 34) Total (N = 67) Placebo (n = 20) Ampreloxetine (n = 20) Total a (N = 40) Male , n (%) 20 (60.6) 15 (44.1) 35 (52.2) 13 (65.0) 8 (40.0) 21 (52.5) White , n (%) 31 (93.9) 32 (94.1) 63 (94.0) 19 (95.0) 17 (85.0) 36 (90.0) Age , years 63.7 (9.6) 63.3 (8.5) 63.5 (9.0) 62.6 (6.7) 63.6 (9.0) 63.1 (7.8) OHSA #1 score 6.6 (1.5) 6.7 (1.6) 6.6 (1.6) 3.2 (2.1) 2.8 (2.2) 3.0 (2.1) OHSA composite score 5.3 (1.6) 5.4 (1.8) 5.3 (1.7) 2.8 (1.8) 2.6 (1.9) 2.7 (1.9) OHDAS composite score 6.4 (2.0) 6.4 (2.5) 6.4 (2.2) 4.8 (2.3) 3.9 (2.4) 4.3 (2.4) OHQ composite score 5.8 (1.6) 5.8 (2.0) 5.8 (1.8) 3.8 (1.7) 3.3 (2.0) 3.5 (1.9) 10 - min supine SBP , mmHg 142.9 (22.8) 141.2 (20.1) 142.1 (21.3) 136.0 (19.5) 141.4 (23.4) 138.7 (21.4) 3 - min standing SBP , mmHg 102.0 (27.0) 96.8 (23.0) 99.4 (25.0) 106.6 (18.1) 102.7 (21.6) 104.5 (19.8)
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 , n = 33 34 31 32 64 42 20 20 18 20 OHSA composite score
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 short time Placebo, n = Ampreloxetine , n = 32 32 30 29 60 41 19 20 16 20
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 short time Individual Components of OHQ Demonstrate Benefits of Ampreloxetine in MSA Subgroup Randomized withdrawal period
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 , n = 30 31 29 29 58 38 18 20 15 18 3 - minute standing SBP
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 = 20) Any TEAEs 19 (57.6) 19 (54.3) 7 (35.0) 4 (20.0) TEAEs related to study drug 5 (15.2) 5 (14.3) 1 (5.0) 1 (5.0) SAEs 2 (6.1) 4 (11.4) 1 (5.0) 2 (10.0) SAEs related to study drug 0 0 1 (5.0) 1 (5.0) TEAEs leading to permanent study drug discontinuation 0 1 (2.9) 0 0 Deaths during study 0 0 0 0 All data are from the safety population and presented as n (%). Ampreloxetine was administered at 10 mg once daily. Patients are only counted once in each row. ‣ Overall, the AE profile was similar between placebo and ampreloxetine groups during the randomized controlled phases
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 component: dizziness, vision, weakness, fatigue, trouble concentrating, head/neck discomfort ‣ The safety profile of ampreloxetine was similar to that of placebo during randomized controlled phases ‣ Patients with MSA may benefit from ampreloxetine treatment due to the presence of central autonomic pathway degeneration and intact peripheral postganglionic fibers MSA, multiple system atrophy; nOH , neurogenic orthostatic hypotension; OHSA, Orthostatic Hypotension Symptom Assessment; SBP, systolic blood pressure. 43
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 for first quarter of 2023 MSA, multiple system atrophy; nOH , neurogenic orthostatic hypotension.