SECURITIES AND EXCHANGE COMMISSION
Washington, DC 20549
Current Report Pursuant
to Section 13 or 15(d) of the
Securities Exchange Act of 1934
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Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ¨
Item 2.02. Results of Operations and Financial Condition.
On August 3, 2021, Theravance Biopharma, Inc. issued a press release and is holding a conference call regarding its financial results for the quarter ended June 30, 2021 and a business update. A copy of the press release is furnished as Exhibit 99.1 to this Current Report and a copy of materials that will accompany the call is furnished as Exhibit 99.2 to this Current Report. Additionally, a copy of an Appendix of additional materials is furnished as Exhibit 99.3 to this Current Report.
The information in Item 2.02 and in Item 9.01 of this Current Report
on Form 8-K, including Exhibits 99.1, 99.2 and 99.3, 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.
|99.1||Press Release dated August 3, 2021|
|99.2||Slide deck entitled Second Quarter 2021 Financial Results and Business Update|
|99.3||Slide deck entitled Appendix August 3, 2021|
|104||Cover Page Interactive Data File (cover page XBRL tags embedded within the Inline XBRL document)|
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|THERAVANCE BIOPHARMA, INC.|
|Date: August 3, 2021||By:||
/s/ Andrew Hindman
|Senior Vice President and Chief Financial Officer|
Theravance Biopharma, Inc. Reports Second Quarter 2021 Financial Results and Provides Business Update
|Ø||Company reiterates Q3 2021 top-line results timing for ampreloxetine Phase 3 and izencitinib Phase 2b in ulcerative colitis|
|Ø||Company’s implied 35% share of YUPELRI® (revefenacin) US net sales1: $14.6 million, up 38% from Q2 2020|
|Ø||TRELEGY® Q2 2021 global net sales hit $405 million, up 68% from Q2 20202|
DUBLIN, IRELAND – AUGUST 3, 2021 – Theravance Biopharma, Inc. (“Theravance Biopharma” or the “Company”) (NASDAQ: TBPH) today reported financial results for the second quarter of 2021.
“We made strong progress in the second quarter. Our field team is energized and has recently been able to increase its face-to-face engagements with customers, driving continued sales volume and market share growth. As we look to the future for YUPELRI, we and our partner Viatris are initiating a controlled clinical study intended to provide data for a possible label update,” said Rick E Winningham, Chief Executive Officer. “We continued to execute across our clinical trials and eagerly anticipate study results this quarter and later this year/early next. 2021 is a pivotal year for Theravance Biopharma, and we are looking forward to the second half of the year furthering our mission of medicines that make a difference.”
Upcoming Clinical Milestones
|·||Q3 2021: Izencitinib (gut-selective oral pan-Janus kinase (JAK) inhibitor for inflammatory intestinal diseases) Phase 2b in ulcerative colitis (study 0157) – top-line results expected in Q3 2021.|
|·||Q3 2021: Ampreloxetine (norepinephrine reuptake inhibitor) Phase 3 for symptomatic neurogenic orthostatic hypotension (study 0169) – enrollment complete and top-line results expected in Q3 2021.|
|·||Q4 2021/Q1 2022: Izencitinib (gut-selective oral pan-JAK inhibitor for inflammatory intestinal diseases) Phase 2 in Crohn’s disease (study 0173) – top-line results expected in late Q4 2021/early Q1 2022.|
|Ø||YUPELRI® (revefenacin) inhalation solution, the first and only once-daily, nebulized bronchodilator approved in the U.S. for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD), continued to increase its share of the long-acting nebulized COPD market, increasing to 21% in April 2021, up from 19% in January 2021, and net sales increased by 38% year-over-year (Q2 2020 vs. Q2 2021).|
|o||The Company, in collaboration with our partner Viatris, is also initiating a Phase 4 study comparing improvements in lung function in adults with severe to very severe COPD and suboptimal inspiratory flow rate following once-daily treatment with either YUPELRI® (revefenacin) delivered via standard jet nebulizer or tiotropium delivered via a dry powder inhaler (Spiriva® HandiHaler®). This study is aimed at helping to better inform decisions when physicians are designing a personalized COPD treatment plan with patients.|
1 While Viatris Inc. (“Viatris”) records the total YUPELRI net sales, the Company is entitled to a 35% share of the profits and losses pursuant to a co-promotion agreement with Viatris.
2 As reported by Glaxo Group Limited or one of its affiliates (GSK); reported sales converted to USD; economic interest related to TRELEGY (the combination of fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI), jointly developed by GSK and Innoviva, Inc.) entitles the Company to upward tiering payments equal to approximately 5.5% to 8.5% on worldwide net sales of the product (net of Theravance Respiratory Company, LLC (TRC) expenses paid and the amount of cash, if any, expected to be used in TRC over the next four fiscal quarters). 75% of the income from the Company’s investment in TRC is pledged to service outstanding notes and 25% of income from the Company’s investment in TRC is retained by the Company.
|Ø||Nezulcitinib, an investigational, inhaled, lung-selective, pan-JAK inhibitor in development for hospitalized patients with COVID-19, reported Phase 2 top-line results (read more about the data here).|
|Ø||On June 29, 2021, the Company closed a public offering of ordinary shares at a price to the public of $15.00 per share, with gross proceeds of $115.6 million, before deducting underwriting discounts and commissions and offering expenses.|
|·||TRELEGY (first once-daily single inhaler triple therapy for COPD and asthma), in which the Company holds an economic interest, posted second quarter 2021 global net sales of $405 million (up from $241 million, 68%, in the second quarter of 2020); Theravance Biopharma is entitled to tiered payments equal to approximately 5.5% to 8.5% of TRELEGY global net sales.3|
Second Quarter Financial Results
|·||Revenue: Total revenue for the second quarter of 2021 was $12.9 million, comprised of non-cash collaboration revenue of $2.0 million primarily attributed to our global collaboration with Janssen and $10.9 million in Viatris collaboration revenue. Total revenue for the second quarter represents a $2.1 million decrease over the same period in 2020.|
|·||YUPELRI: The Viatris collaboration revenue of $10.9 million for the second quarter of 2021 represents amounts receivable from Viatris and is comprised of the Company’s 35% share of net sales of YUPELRI as well as its proportionate amount of the total shared costs incurred by the two companies. The non-shared YUPELRI costs incurred by Theravance Biopharma are recorded within operating expenses. While Viatris records the total net sales of YUPELRI within its financial statements, our implied 35% share of net sales of YUPELRI for the second quarter of 2021 was $14.6 million.|
|·||Research and Development (R&D) Expenses: R&D expenses for the second quarter of 2021 were $51.1 million, compared to $62.4 million in the same period in 2020. Second quarter R&D expenses included total non-cash share-based compensation of $7.3 million.|
|·||Selling, General and Administrative (SG&A) Expenses: SG&A expenses for the second quarter of 2021 were $25.9 million, compared to $24.8 million in the same period in 2020. Second quarter SG&A expenses included total non-cash share-based compensation of $7.6 million.|
|·||Operating Loss: Operating loss for the second quarter of 2021 was $64.1 million compared to $72.2 million in the same period of 2020.|
3 As reported by Glaxo Group Limited or one of its affiliates (GSK); reported sales converted to USD; economic interest related to TRELEGY (the combination of fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI), jointly developed by GSK and Innoviva, Inc.) entitles the Company to upward tiering payments equal to approximately 5.5% to 8.5% on worldwide net sales of the product (net of Theravance Respiratory Company, LLC (TRC) expenses paid and the amount of cash, if any, expected to be used in TRC over the next four fiscal quarters). 75% of the income from the Company’s investment in TRC is pledged to service outstanding notes and 25% of income from the Company’s investment in TRC is retained by the Company.
|·||Cash Position: Cash, cash equivalents and marketable securities totaled $265.0 million as of June 30, 2021.|
2021 Financial Guidance
|·||Operating Expenses (excluding share-based compensation): The Company reiterates that it expects full year 2021 R&D expense of $195 million to $225 million, and SG&A expense of $80 million to $90 million.|
Conference Call and Live Webcast Today at 5 pm ET
Theravance Biopharma will hold a conference call and live webcast accompanied by slides today at 5 pm ET / 2 pm PT / 10 pm IST. To participate, please dial (855) 296-9648 from the U.S. or (920) 663-6266 for international callers, using the confirmation code 2615108. Those interested in listening to the conference call live via the internet may do so by visiting www.theravance.com, under the Investors section, Presentations and Events.
A replay will be available on www.theravance.com for 30 days through September 2, 2021. An audio replay will also be available through 8:00 p.m. ET on August 10, 2021, by dialing (855) 859-2056 from the U.S., or (404) 537-2406 for international callers, and then entering confirmation code 2615108.
About Theravance Biopharma
Theravance Biopharma, Inc. is a diversified biopharmaceutical company primarily focused on the discovery, development and commercialization of organ-selective medicines. Its purpose is to pioneer a new generation of small molecule drugs designed to better meet patient needs. Its research is focused in the areas of inflammation and immunology.
In pursuit of its purpose, Theravance Biopharma applies insights and innovation at each stage of its business and utilizes its internal capabilities and those of partners around the world. The Company applies organ-selective expertise to target disease biologically, to discover and develop medicines that may expand the therapeutic index with the goal of maximizing efficacy and limiting systemic side effects. These efforts leverage years of experience in developing lung-selective medicines to treat respiratory disease, including 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 patient needs.
Theravance Biopharma has an economic interest in potential future payments from Glaxo Group Limited or one of its affiliates (GSK) pursuant to its agreements with Innoviva, Inc. relating to certain programs, including TRELEGY.
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.
This press release contains and the conference call will contain 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 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 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 potential that the Company's research programs will progress product candidates into the clinic, the Company's expectations for product candidates through development, the Company's expectations regarding its allocation of resources, potential regulatory approval and commercialization (including their differentiation from other products or potential products), product sales or profit share revenue and the Company's expectations for its expenses, excluding share-based compensation and other financial results. These statements are based on the current estimates and assumptions of the management of Theravance Biopharma as of the date of the press release and the conference call 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: disagreements with Innoviva, Inc. and TRC LLC, the uncertainty of arbitration and litigation and the possibility that the results of these proceedings could be adverse to the Company, additional future analysis of the data resulting from our clinical trial(s), delays or difficulties in commencing, enrolling or completing clinical studies, the potential that results from clinical or non-clinical studies indicate the Company's compounds or product candidates are unsafe, ineffective or not differentiated, risks that product candidates do not obtain approval from regulatory authorities, the feasibility of undertaking future clinical trials for our product candidates based on policies and feedback from regulatory authorities, dependence on third parties to conduct clinical studies, delays or failure to achieve and maintain regulatory approvals for product candidates, risks of collaborating with or relying on third parties to discover, develop, manufacture and commercialize products, and risks associated with establishing and maintaining sales, marketing and distribution capabilities with appropriate technical expertise and supporting infrastructure. In addition, while we expect the effects of COVID-19 to continue to adversely impact our business operations and financial results, the extent of the impact on our ability to generate revenue from YUPELRI® (revefenacin), our clinical development programs (including but not limited to our later stage clinical programs for izencitinib and ampreloxetine), and the value of and market for our ordinary shares, will depend on future developments that are highly uncertain and cannot be predicted with confidence at this time. These potential future developments include, but are not limited to, the ultimate duration of the COVID-19 pandemic, travel restrictions, quarantines, social distancing and business closure requirements in the United States and in other countries, other measures taken by us and those we work with to help protect individuals from contracting COVID-19, and the effectiveness of actions taken globally to contain and treat the disease, including vaccine availability, distribution, acceptance and effectiveness. Other risks affecting Theravance Biopharma are in the Company's Form 10-Q filed with the SEC on May 6, 2021 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: Gail B. Cohen
THERAVANCE BIOPHARMA, INC.
CONDENSED CONSOLIDATED BALANCE SHEETS
|June 30,||December 31,|
|Cash and cash equivalents and short-term marketable securities||$||264,953||$||292,941|
|Receivables from collaborative arrangements||12,220||15,868|
|Amounts due from TRC, LLC||27,741||53,799|
|Prepaid clinical and development services||15,913||20,374|
|Other prepaid and current assets||12,353||10,359|
|Total current assets||333,180||393,341|
|Property and equipment, net||16,583||16,422|
|Operating lease assets||41,508||43,260|
|Equity in net assets of TRC, LLC||35,822||12,750|
|Liabilities and Shareholders' Deficit|
|Convertible senior notes due 2023, net||227,499||226,963|
|Non-recourse notes due 2035, net||375,069||372,873|
|Long-term operating lease liabilities||57,768||47,220|
|Other long-term liabilities||2,162||2,181|
|Total liabilities and shareholders’ deficit||$||429,251||$||469,057|
|(1)||The condensed consolidated balance sheet as of December 31, 2020 has been derived from the audited consolidated financial statements included in the Company's Annual Report on Form 10-K for the year ended December 31, 2020.|
THERAVANCE BIOPHARMA, INC.
CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS
(In thousands, except per share data)
|Three Months Ended June 30,||Six Months Ended June 30,|
|Viatris collaboration agreement||10,934||9,520||21,319||21,250|
|Costs and expenses:|
|Research and development (1)||51,093||62,404||118,692||128,417|
|Selling, general and administrative (1)||25,931||24,780||56,481||51,105|
|Total costs and expenses||77,024||87,184||175,173||179,522|
|Loss from operations||(64,110||)||(72,176||)||(148,002||)||(144,652||)|
|Income from investment in TRC, LLC||21,926||21,381||38,473||34,896|
|Loss on extinguishment of debt||-||-||-||(15,464||)|
|Interest and other income (expense), net||1,171||(662||)||937||798|
|Loss before income taxes||(52,625||)||(62,848||)||(132,077||)||(145,754||)|
|Provision for income tax benefit (expense)||220||(39||)||(7||)||(186||)|
|Net loss per share:|
|Basic and diluted net loss per share||$||(0.80||)||$||(1.00||)||$||(2.03||)||$||(2.39||)|
|Shares used to compute basic and diluted net loss per share||65,669||62,861||65,085||61,162|
|(1)||Amounts include share-based compensation expense as follows:|
|Three Months Ended June 30,||Six Months Ended June 30,|
|Research and development||$||7,315||$||8,098||$||15,236||$||15,963|
|Selling, general and administrative||7,626||8,487||15,537||15,898|
|Total share-based compensation expense||$||14,941||$||16,585||$||30,773||$||31,861|
Second Quarter 2021 Financial Results and Business Update August 3, 2021 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. © 2021 Theravance Biopharma. All rights reserved.
Forward - looking statements 2 Under the safe harbor provisions of the U . S . Private Securities Litigation Reform Act of 1995 , the company cautions investors that any forward - looking statements or projections made by the company are subject to risks and uncertainties that may cause actual results to differ materially from the forward - looking statements or projections . Examples of forward - looking statements in this presentation may include the Company’s goals, designs, strategies, plans and objectives, 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 potential that the Company’s research programs will progress product candidates into the clinic, the Company’s expectations for product candidates through development, the Company's expectations regarding its allocation of resources, potential regulatory approval and commercialization (including their differentiation from other products or potential products), product sales or profit share revenue and the Company’s expectations for its expenses, excluding share - based compensation and other financial results . The company’s forward - looking statements are based on the estimates and assumptions of management as of the date of this presentation and are subject to risks and uncertainties that may cause the actual results to be materially different than those projected, such as risks related to the impacts on the COVID - 19 global pandemic on our business, delays or difficulties in commencing, enrolling or completing clinical studies, the potential that results from clinical or non - clinical studies indicate the Company’s compounds or product candidates are unsafe, ineffective or not differentiated, risks that product candidates do not obtain approval from regulatory authorities, the feasibility of undertaking future clinical trials for our product candidates based on policies and feedback from regulatory authorities, dependence on third parties to conduct clinical studies, delays or failure to achieve and maintain regulatory approvals for product candidates, risks of collaborating with or relying on third parties to discover, develop, manufacture and commercialize products, and risks associated with establishing and maintaining sales, marketing and distribution capabilities with appropriate technical expertise and supporting infrastructure, disagreements with Innoviva, Inc . and TRC LLC, the uncertainty of arbitration and litigation and the possibility that an arbitration award or litigation result could be adverse to the Company . Other risks affecting Theravance Biopharma are in the company's Form 10 - Q filed with the SEC on May 6 , 2021 , and other periodic reports filed with the SEC .
Agenda 3 Introduction Gail B. Cohen Vice President, Corporate Communications Overview Rick E Winningham Chief Executive Officer Development and Commercial Update Richard A. Graham Senior Vice President, Development Frank Pasqualone Senior Vice President, Chief Business Officer Financial Update Andrew A. Hindman Senior Vice President, Chief Financial Officer Closing Remarks Rick E Winningham Chief Executive Officer
Theravance Biopharma difference: Targeting disease with organ selective medicines TI, therapeutic index. 4 Target disease biology Optimize effect in the organ where the disease is active Expand TI with the goal of maximizing efficacy and limiting systemic side effects TI TI Disease Therapeutic Index Pathway Pioneering a new generation of small molecule drugs designed to better meet patient needs
TBPH holds 85% economic interest in upward - tiering royalty stream of 6.5% – 10% payable by GSK (net of TRC expenses paid and the amount of cash, if any, expected to be used by TRC pursuant to the TRC Agreement over the next four fiscal quarters). 75% of TRC income received is pledged to service outstanding notes, 25% of royalties retained by TBPH. Our non - recourse Triple II 9.5% Fixed Rate Term Notes are due on or before 2035. All statements concerning TRELEGY based on publicly available information. TRELEGY is FF/UMEC/VI or flutic aso ne furoate/ umeclidinium /vilanterol; comprised of inhaled corticosteroid, long - acting muscarinic receptor antagonist, and long - acting β2 agonists, active components of Anoro (UMEC/VI). nOH , neurogenic orthostatic hypotension. 5 Nezulcitinib (TD - 0903) Phase 2 (0188) COVID - 19 REPORTED 6.21.21 Izencitinib DIONE (0173) Phase 2 Crohn’s disease Izencitinib RHEA (0157) Phase 2b ulcerative colitis Ampreloxetine SEQUOIA (0169) Phase 3 symptomatic nOH Commercial progress of YUPELRI ® & GSK’s TRELEGY TOPLINE RESULTS Q1'22 Q2 Q3 Q1 Q4 2021 Multiple potential milestones & value - driving catalysts
Respiratory market t rends across n ebulized and handheld YUPELRI and TRELEGY with strong YoY growth while respective markets declined or remained flat 6 1. IQVIA XPO Excl. LTC (Retail) and SolutionsRx (DME / Med B FFS) through 4/30/2021 2. COPD Handheld Market Excludes BREZTRI (newly launched product) - 7% - 31% - 11% - 9% 0% 50% Neb Sub Total LONHALA MAGNAIR BROVAVA ALBUTEROL/IPRATROPIUM PERFOROMIST YUPELRI 1% - 13% - 7% - 7% - 6% - 5% 4% 4% 7% 40% COPD HH Sub Total SPIRIVA HH BREO ATROVENT INCRUSE BEVESPI ANORO SPIRIVA RESPIMAT STIOLTO TRELEGY COPD Handheld Product Growth YoY TRx Growth 1 12 Months Ending Apr’21 vs. Same Time Last Year 0% 0% Nebulized Product Growth YoY TRx Growth 1 12 Months Ending Apr’21 vs. Same Time Last Year 2
Izencitinib (TD - 1473/JNJ - 8398) Oral gut - selective pan - JAK inhibitor to treat inflammatory bowel diseases
Izencitinib : Phase 2b Induction study in ulcerative colitis *3 izencitinib doses. NCT03758443 aMS , adapted Mayo Score; tMS , total Mayo Score; UC, ulcerative colitis. 8 Program Status ‣ Ph 3 Maintenance ongoing Randomization Q3’21 Ph 2b Induction Study data readout Placebo Izencitinib * Ph 2b dose - finding induction: once - daily oral dose for 8 weeks Ph 3 maintenance: once - daily oral dose for 44 weeks Responders from Ph 2b and Ph 3 Induction Placebo Izencitinib N=240 Ph 3 Induction Study starts after dose selection Key inclusion criteria: Age ≥18 y with moderately - to - severely active UC with corticosteroid dependence or failure of conventional or biologic therapy Geographies: South Africa, Asia, Australia, Europe, Middle East, North America Study 0157 Endpoints ‣ Primary: – Change from baseline in tMS at Week 8 ‣ Secondary: – Clinical response and remission by aMS components – Standard disease surrogate biomarkers – Safety
Ampreloxetine (TD - 9855) Once - daily norepinephrine reuptake inhibitor to treat symptomatic neurogenic orthostatic hypotension ( nOH )
Ampreloxetine : Phase 3 Randomized, double - blind, placebo - controlled study Note: Ampreloxetine Phase 3 registrational program is comprised of Studies 0169, 0170 and safety data from 0171 will be included *Orthostatic Hypotension Symptom Assessment Question 1: negative change indicates improvement in symptoms; improvement of 1 p oin t is defined as the MCID (minimal clinically important difference). Discontinuation rates for the Phase 3 trials as of June 2021: 0169 – 5%. nOH , neurogenic orthostatic hypotension; OHDAS, orthostatic hypotension daily activities scale; OHSA, Orthostatic hypotension sy mpt om assessment; PGI - C, patient global impression of change. NCT03750552 10 Key inclusion criteria: Age >30 y with symptomatic nOH with OHSA #1 score ≥4 Geographies: North America, Australia/New Zealand, Europe, Russia, UK Randomization Q3’21 Efficacy Data Ampreloxetine Placebo Once - daily 10 mg oral dose: 4 weeks Program Status ‣ Phase 3 registrational program ongoing ‣ All participants who complete Study 0169 are eligible for Study 0170 N=188 Study 0169 Objectives ‣ Primary: Change from baseline in OHSA #1 score at Week 4* ‣ Secondary: – Change from baseline in OHSA composite score over 4 wk – Change from baseline in OHDAS composite score over 4 wk – PGI - C at Week 4 – Incidence of falls – Safety
FDA - approved for the maintenance treatment of COPD First and only once - daily, nebulized maintenance medicine for COPD
YUPELRI ® (revefenacin) inhalation solution 1. Global Strategy for Diagnosis, Management, and Prevention of COPD, 2018. 2. TBPH market research (N = 160 physicians); refers to US COPD patients. COPD, chronic obstructive pulmonary disease; LAMA, long - acting muscarinic antagonist. 12 Once - daily LAMAs are first - line therapy for moderate - to - very severe COPD 1 9% of COPD patients (~800,000) use nebulizers for ongoing maintenance therapy; 41% use nebulizers at least occasionally for bronchodilator therapy 2 Companies co - promote under US profit/loss share TBPH and VTRS worldwide strategic collaboration to develop and commercialize nebulized YUPELRI ® (revefenacin) 65% 35% TBPH VTRS FDA - approved for the maintenance treatment of COPD First and only once - daily, nebulized maintenance medicine for COPD
TBPH implied 35% of YUPELRI ® US net sales by quarter See TBPH 10K filed February 26, 2021 for greater detail re TBPH implied 35%. 13 TBPH implied 35% of YUPELRI US net sales represents TBPH’s portion of the combined TBPH and VIATRIS net revenue TBPH Implied 35% of Total Net Sales ($M) $3.2 $5.8 $10.4 $12.9 $10.6 $13.0 $13.5 $12.9 $14.6 0 2 4 6 8 10 12 14 16 Q2'19 Q3'19 Q4'19 Q1'20 Q2'20 Q3'20 Q4'20 Q1'21 Q2'21
YUPELRI ® hospital sales and community TRx trends Continued market share growth across both the hospital and retail channels 0.3% 1.1% 2.2% 3.4% 5.4% 6.5% 6.3% 7.4% 7.8% 8.8% 0% 2% 4% 6% 8% 10% 12% 14% 16% 18% 20% Q1'19 Q2'19 Q3'19 Q4'19 Q1'20 Q2'20 Q3'20 Q4'20 Q1'21 Q2'21 Hospital LA - NEB Market Share* Hospital Market Share YUPELRI LA-NEB Market Share 1. Joint VTRS/TBPH Market Research. * Hospital LA - NEB Market Share - IQVIA DDD through 06/30/2021. ** Community LA - NEB Market Share - IQVIA XPO Excl. LTC (Retail) and SolutionsRx (DME / Med B FFS) through 4/30/2021 (Q2’21 Comm unity LA - NEB Market Share Incomplete). *** Retail TRx Volume - Symphony Health METYS Prescription Dashboard through 6/30/2021. 14 TRx volume represents retail only which is typically 33% of Retail + DME 1.5% 6.1% 9.8% 13.1% 15.3% 16.3% 17.4% 18.7% 19.7% 21.0% 0K 2K 4K 6K 8K 10K 12K 14K 16K 18K 20K 0% 5% 10% 15% 20% 25% Q1'19 Q2'19 Q3'19 Q4'19 Q1'20 Q2'20 Q3'20 Q4'20 Q1'21 Q2'21 Retail TRx Volume*** Community LA - NEB Market Share** Community Market Share with TRx Retail TRx YUPELRI LA-NEB Market Share Most patients who receive YUPELRI ® in the hospital are discharged with an Rx 1 **Community LA - NEB Market Share includes Retail + DME / Med B FFS through April ’21 LA - NEB Market: YUPELRI, BROVANA, LONHALA, PERFOROMIST
15 15 YUPELRI 815 hospital accounts have ordered 2 ‣ 69% have ordered more than once 91% formulary win rate 3 Highest number of formulary support presentations in Q2’21 since launch 75% commercial coverage 4 Positive growth trends for YUPELRI ® continuing into 2H2021 1. Symphony Health, Metys , 01/01/2021 – 07/23/2021, Weekly New to Product (N2P) Rx Volume. 2. IQVIA DDD launch through March 2021. 3. TBPH Commercial Data Warehouse. 4. Decision Resources Group (DRG) as of May 2021. 0 50 100 150 200 250 300 350 2021-01-01 2021-01-15 2021-01-29 2021-02-12 2021-02-26 2021-03-12 2021-03-26 2021-04-09 2021-04-23 2021-05-07 2021-05-21 2021-06-04 2021-06-18 2021-07-02 2021-07-16 N2PRx Count YUPELRI Weekly New to Product Rx 1 YUPELRI N2PRx Linear (YUPELRI N2PRx)
Economic interest GSK’s TRELEGY ELLIPTA (FF/UMEC/VI): First and only once - daily single inhaler triple therapy
0 50 100 150 200 250 300 350 400 450 500 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 TRx Volume (Thousands) Month Post Launch Strongest US ELLIPTA Launch ANORO ELLIPTA ARNUITY ELLIPTA BREO ELLIPTA INCRUSE ELLIPTA TRELEGY Launched in US in November 2017 Source: GSK, Symphony Health Metys monthly TRx data for the time period Sept'13 to Jun'21. TRELEGY Mortality Ad Comm BREO Asthma Approval TRELEGY Asthma Approval Economic interest in GSK’s TRELEGY 1. TBPH holds 85% economic interest in upward - tiering royalty stream of 6.5% – 10% payable by GSK (net of TRC expenses paid and the amount of cash, if any, expected to be used by TRC pursuant to the TRC Agreement over the next four fiscal quarters). 75% of TRC income received is pledged to service outstanding notes, 25% of royalties retained by TBPH. Our non - recourse Triple II 9.5% Fixed Rate Term Notes are due on or before 2035. All statements concerning TRELEGY based on publicly available information. TRELEGY is FF/UMEC/VI or flutic aso ne furoate/umeclidinium/vilanterol; comprised of inhaled corticosteroid, long - acting muscarinic receptor antagonist, and long - acting β2 agonists, active components of Anoro (UMEC/VI). 17 TRELEGY Upward - tiering royalties of ~5.5 – 8.5% of global net sales 1 Q2 global net sales of $405M Year - over - year sales growth of 68% from the same period in 2020 1H’21 sales were up 49% to $746M driven by growth in all regions ‣ US sales grew 51% to $522M ‣ Europe sales grew 21% to $130M ‣ Internationally, where TRELEGY asthma was approved in Japan in Q4’20, sales grew more than 100% to $94M YB17 YB18
Second quarter 2021 financial highlights 1. Cash, cash equivalents and marketable securities. 2. Amounts include share - based compensation. 18 $ 265.0 million cash 1 as of June 30, 2021 Research and development operating expense excluding share - based compensation 43,778 54,306 103,456 112,454 Selling, general and administrative operating expense excluding share - based compensation 18,305 16,293 40,944 35,207 ($, in thousands) Revenue: Collaboration revenue Licensing revenue Viatris collaboration agreement Total revenue Costs and expenses: Research and development 2 Selling, general and administrative 2 Total costs and expenses Loss from operations Share - based compensation expense: Research and development Selling, general and administrative Total share - based compensation expense Operating expense excluding share - based compensation: (64,110) (72,176) (148,002) (144,652) 7,315 8,098 15,236 15,963 7,626 8,487 15,537 15,898 14,941 16,585 30,773 31,861 51,093 62,404 118,692 128,417 25,931 24,780 56,481 51,105 77,024 87,184 175,173 179,522 12,914 15,008 27,171 34,870 $ 1,980 $ 5,488 $ 5,852 $ 12,120 — — — 1,500 10,934 9,520 21,319 21,250 Three Months Ended June 30, 2021 2020 (Unaudited) Six Months Ended June 30, 2021 2020 (Unaudited)
Differentiated, Wholly - Owned Pipeline Viatris Partnership Janssen Collaboration Economic Interest • TRELEGY: Triple combo for COPD and Asthma 1 • 5.5% to 8.5% of global net sales 2 • Global Partnership for YUPELRI ® : nebulized bronchodilator for COPD • US profit share (35% TBPH / 65% VIATRIS) • Ex - US royalties • Up to $258mm in remaining milestones, including milestones related to the expanded China partnership • Global partnership for izencitinib : Phase 2b/3 for UC and Phase 2 for Crohn’s disease • Up to $900mm in remaining milestone payments, including $200mm upon Phase 2 subject to Janssen opt - in • TD - 5202: Phase 1 for Celiac disease • Ampreloxetine: Phase 3 for symptomatic nOH • Nezulcitinib: Phase 2 for ALI due to COVID - 19 and lung transplant rejection • TD - 8236: Phase 2 for asthma • Inhaled ALK5i: Phase 1 for IPF • Ocular JAKi: Pre - clinical DME 19 1. Asthma approved in the US and Japan only. 2. TBPH holds 85% economic interest in upward - tiering royalty stream of 6.5% – 10 % payable by GSK (net of TRC expenses paid and the amount of cash, if any, expected to be used by TRC pursuant to the TRC Agreement over the next four fiscal quarters). 75% of TRC income received is pledged to servi ce outstanding notes, 25% of royalties retained by TBPH. ALI, acute lung inflammation; ALK5i, transforming growth factor β receptor I kinase inhibitor; COPD, chronic obstructive pulm ona ry disease; DME, diabetic macular edema ; IPF, Idiopathic pulmonary fibrosis; JAKi , Janus kinase inhibitor; nOH , neurogenic orthostatic hypotension; UC, ulcerative colitis. 19 Confidential
TBPH holds 85% economic interest in upward - tiering royalty stream of 6.5% – 10% payable by GSK (net of TRC expenses paid and the amount of cash, if any, expected to be used by TRC pursuant to the TRC Agreement over the next four fiscal quarters). 75% of TRC income received is pledged to service outstanding notes, 25% of royalties retained by TBPH. Our non - recourse Triple II 9.5% Fixed Rate Term Notes due on or before 2035. All statements concerning TRELEGY based on publicly available information. TRELEGY is FF/UMEC/VI or fluticasone fur oate/umeclidinium/vilanterol; comprised of inhaled corticosteroid, long - acting muscarinic receptor antagonist, and long - acting β2 agonists, active components of Anoro (UMEC/VI). nOH, neurogenic orthostatic hypotension. 20 Nezulcitinib (TD - 0903) Phase 2 (0188) COVID - 19 REPORTED 6.21.21 Izencitinib DIONE (0173) Phase 2 Crohn’s disease Izencitinib RHEA (0157) Phase 2b ulcerative colitis Ampreloxetine SEQUOIA (0169) Phase 3 symptomatic nOH Commercial progress of YUPELRI ® & GSK’s TRELEGY TOPLINE RESULTS Q1'22 Q2 Q3 Q1 Q4 2021 Multiple potential milestones & value - driving catalysts
Q&A Session Rick E Winningham Chairman and Chief Executive Officer Andrew A. Hindman Senior Vice President, Chief Financial Officer Frank Pasqualone Senior Vice President, Chief Business Officer Richard A. Graham Senior Vice President, Development
About YUPELRI ® (revefenacin) inhalation solution YUPELRI ® (revefenacin) inhalation solution is a once - daily nebulized LAMA approved for the maintenance treatment of COPD in the US . Market research by Theravance Biopharma indicates approximately 9 % of the treated COPD patients in the US use nebulizers for ongoing maintenance therapy . 1 LAMAs are a cornerstone of maintenance therapy for COPD and YUPELRI ® is positioned as the first once - daily single - agent bronchodilator product for COPD patients who require, or prefer, nebulized therapy . YUPELRI ® ’s stability in both metered dose inhaler and dry powder device formulations suggest that this LAMA could also serve as a foundation for novel handheld combination products . 1. TBPH market research (N=160 physicians); refers to US COPD patients. COPD, chronic obstructive pulmonary disease; LAMA, long - acting muscarinic antagonist. 23
YUPELRI ® (revefenacin) inhalation solution YUPELRI ® inhalation solution is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD) . Important Safety Information (US) YUPELRI is contraindicated in patients with hypersensitivity to revefenacin or any component of this product . YUPELRI should not be initiated in patients during acutely deteriorating or potentially life - threatening episodes of COPD, or for the relief of acute symptoms, i . e . , as rescue therapy for the treatment of acute episodes of bronchospasm . Acute symptoms should be treated with an inhaled short - acting beta 2 - agonist . As with other inhaled medicines, YUPELRI can produce paradoxical bronchospasm that may be life - threatening . If paradoxical bronchospasm occurs following dosing with YUPELRI, it should be treated immediately with an inhaled, short - acting bronchodilator . YUPELRI should be discontinued immediately and alternative therapy should be instituted . YUPELRI should be used with caution in patients with narrow - angle glaucoma . Patients should be instructed to immediately consult their healthcare provider if they develop any signs and symptoms of acute narrow - angle glaucoma, including eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema . Worsening of urinary retention may occur . Use with caution in patients with prostatic hyperplasia or bladder - neck obstruction and instruct patients to contact a healthcare provider immediately if symptoms occur . Immediate hypersensitivity reactions may occur after administration of YUPELRI . If a reaction occurs, YUPELRI should be stopped at once and alternative treatments considered . The most common adverse reactions occurring in clinical trials at an incidence greater than or equal to 2 % in the YUPELRI group, and higher than placebo, included cough, nasopharyngitis, upper respiratory infection, headache and back pain . Coadministration of anticholinergic medicines or OATP 1 B 1 and OATP 1 B 3 inhibitors with YUPELRI is not recommended . YUPELRI is not recommended in patients with any degree of hepatic impairment . OATP, organic anion transporting polypeptide. 24
Appendix August 3, 2021 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. © 2021 Theravance Biopharma. All rights reserved.
Decades - long track record of driving innovative products to market for diseases of high unmet need Investment highlights 2 Innovative, commercial - stage biopharma with strong development track record Diversified pipeline of organ - selective medicines for rare disease, respiratory, GI and ocular indications Wholly - owned and partnered pipeline of differentiated assets Three major clinical readouts expected by early - 2022 Organ - selective approach serves as an engine for new opportunities Applying organ - selective expertise to biologically compelling pathways aiming to better serve patients Multiple near - term catalysts provide opportunity for value Underlying stream of derisked, long - tailed cash flow Strong base of cash flow, anchored by Yupelri and our economic interest in TRELEGY Multiple commercial and near - commercial products create growing revenue profile Topline growth poised for potential acceleration
Program Indication US Patients 1 Research Phase 1 Phase 2 Phase 3 Filed Marketed Collaborator Ampreloxetine (TD - 9855) NRI S ymptomatic nOH ~350k Wholly - owned Organ - Selective Izencitinib (TD - 1473) GI JAKi UC ~900k CD ~800k Janssen Biotech, Inc . TD - 5202 Irreversible JAK3i Celiac Disease UC CD ~5mm YUPELRI ® (revefenacin) LAMA COPD >8mm Nezulcitinib (TD - 0903) Inhaled JAKi Acute and chronic lung inflammation >32mm Wholly - owned TD - 8236 Inhaled JAKi Asthma ~25mm Inhaled ALK5i Idiopathic pulmonary fibrosis ~140k Program Indication Research Phase 1 Phase 2 Phase 3 Filed Marketed Rights Economic Interests TRELEGY 2 FF/UMEC/VI COPD >8mm GSK & Innoviva, Inc. Asthma ~25mm Skin - selective JAKi Dermatological diseases >8mm Key programs for large patient populations supported by proven development and commercial expertise 3 Phase 2 Phase 2 Phase 2b/3 Phase 1 Phase 3 Marketed Marketed Research Marketed Phase 1 Phase 2 1. TBPH estimate derived from integrating multiple data sources 2. TBPH holds 85% economic interest in upward - tiering royalty st ream of 6.5% – 10% payable by GSK (net of TRC expenses paid and the amount of cash, if any, expected to be used by TRC pursuant to the TRC Agreement over the next four fiscal quarters). 75% of TRC income received is p led ged to service outstanding notes, 25% of royalties received retained by TBPH. All statements concerning TRELEGY ELLIPTA based on publicly available information. ALK5i, transforming growth factor β receptor I kinase inhibitor; CD, Crohn’s di sease; COPD, chronic obstructive pulmonary disease; FF/UMEC/VI, fluticasone furoate/umeclidinium/ vilanterol; JAKi, Janus kinase inhibitor; LAMA, long - acting muscarinic receptor antagonist; nO H, neurogenic orthostatic hypotension; NRI, norepinephrine reuptake inhibitor; UC, ulcerative colitis.
Research and development portfolio of designed molecules: brain, lung, GI and eye 4 Molecular Design Biology Medicinal Chemistry DMPK Development and Commercial Symptomatic nOH (Neurogenic orthostatic hypotension) Asthma Lung Transplant Rejection IPF (idiopathic pulmonary fibrosis) COPD (chronic obstructive pulmonary disorder) — APPROVED COVID - 19 CD (Crohn’s disease) UC (ulcerative colitis) Celiac Disease DME (diabetic macular edema) DMPK, drug metabolism and pharmacokinetics; GI, gastrointestinal.
Early stage pipeline, value creation opportunities *Asthma that requires high - dosage ICS + LABAs to prevent the disease from being uncontrolled, or asthma that remains uncontrolle d despite treatment. 1. https://www.aafa.org/asthma - facts/ . 2. 1% prevalence in US, BeyondCeliac.org. 3. 2018 US population 327M Census.gov. 4. Raghu G, et al. Lancet Resp. 2014: 2(7) :56 6 - 572; 5. Raghu G, et al. Eur Respir J. 2016: 48(1):179 - 186. 6. © 2016 DR/Decision Resources, LLC. ALK5i, transforming growth factor β receptor I kinase inhibitor; IPF, idiopathic pulmonary fibrosis; JAKi , Janus kinase inhibitor.. 5 Program Patient Population Status Indication Uncontrolled Asthma TD - 8236 TD - 5202 Inhaled ALK5i Ocular JAKi Celiac Disease Ulcerative Colitis Crohn’s Disease ~25mm Moderate and Severe* US Asthmatics 1 Phase 2; evaluating back - up compounds ~5mm US Patients 2,3 Phase 1 Complete IPF ~140k US Prevalence; currently orphan disease 4,5 Phase 1 Diabetic Macular Edema ~2.7mm US Prevalence 6 Preclinical
Izencitinib (TD - 1473/JNJ - 8398) Oral gut - selective pan - JAK inhibitor to treat inflammatory bowel diseases
IBD represents an area of high unmet need Favorable Phase 1b data led to late - stage IBD studies Izencitinib: a novel approach to JAK inhibition for IBD 7 Izencitinib Preclinical and clinical data package represents a potential breakthrough approach for the treatment of IBD Oral, gut - selective agent Potent inhibition of Tyk2 Anti - inflammatory activity in disease model Low systemic exposure with high colonic concentrations Favorable Phase 1b data Phase 1b data 6 ‣ Demonstrated gut selectivity – High colonic concentration with low systemic drug exposures, consistent with pre - clinical data – For the goal of maximized therapeutic index ‣ Demonstrated numerically higher rates of clinical outcomes with reductions in biomarkers after only 4 weeks of treatment – Numerical improvements in rectal bleeding and mucosal healing IBD MARKET DYNAMICS 6.8mm global cases in 2017 1 1.6mm current US patients 2 ~780k current US Crohn’s patients 3 ~907k US Ulcerative Colitis patients 4 $16bn global IBD treatment market in 2018 5 $31bn US disease burden 2 Biologics have become mainstay of treatment in moderate - to - severe patients 1. GBD 2017 Inflammatory Bowel Disease Collaborators. Lancet 2020;5:17 - 30. 2. https://www.crohnscolitisfoundation.org/sites/default/files/2019 - 02/Updated%20IBD%20Factbook.pdf . 3. https://www.healthline.com/health/crohns - disease/facts - statistics - infographic 4. https://med.stanford.edu/news/all - news/2020/02/stanford - scientists - link - ulcerative - colitis - to - missing - gut - micro.html 5. https://www.transparencymarketresearch.com/inflammatory - bowel - disease.html 6. Sandborn et al. J Crohns Colitis;2020: 14:1202 - 13. IBD, inflammatory bowel disease; JAK, Janus kinase; Tyk, tyrosine kinase.
STAT - induced Inflammation α N UCLEUS STAT P STAT P STAT P STAT P STAT JAK β γ JAK JAK inhibitor JAK - STAT pathway: orchestrating signaling of multiple pro - inflammatory cytokines Clark JD, et al. J Med Chem 2014; 57:5023 - 5038. EPO, erythropoietin; GM - CSF, granulocyte - macrophage colony - stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kina se; STAT, signal transducer and activator of transcription; TPO, thrombopoietin; Tyk, tyrosine kinase. 8 γ c cytokines (IL - 2, IL - 4, IL - 7, IL - 9, IL - 15, IL - 21) Type 1 IFNs, IL - 10 family IL - 6, IL - 11, IL - 13, IL - 27, IL - 31, IL - 35 IFN γ IL - 12, IL - 23 EPO, TPO GM - CSF, IL - 3, IL - 5 α JAK1 β γ JAK3 α JAK1 β γ Tyk2 α JAK1 β γ JAK2 Tyk2 α JAK1 β γ JAK2 α JAK2 β γ Tyk2 α JAK2 β γ JAK2
0 5 10 15 120 140 S y s t e m i c S a f e t y M a r g i n ( P l a s m a A U C ) Non-rodentRodent High margins of systemic safety in nonclinical studies Gut selectivity confers low systemic exposure and offers the potential for reduced adverse effects Low systemic plasma concentrations in UC patients Izencitinib’s oral, gut - selective, pan - JAK approach is designed to reduce systemic side effects *Simulated tofacitinib concentrations extracted from Dowty ME, et al. J Pharmacol Exp Ther 2014;348:165 - 73. Margins of safety reflect the ratio of nonclinical to clinical plasma exposures at the highest studied clinical dose (izencit ini b) or approved dose (tofacitinib). Rodent species was rat for izencitinib and tofacitinib; non - rodent species was dog for izencitinib and monkey for tofacitinib. AUC, area under curve; BID, twice daily; hr , hour; JAK, Janus kinase; UC, ulcerative colitis. 9 Tofacitinib 10 mg BID (simulated)* Izencitinib 20 mg Izencitinib 80 mg Izencitinib 270 mg 0 1 2 3 4 0 100 200 300 Plasma Concentration (nM) Time (hr) Oral bioavailability Tofacitinib: 74% Izencitinib: 2% Izencitinib Tofacitinib Izencitinib: 12 – 136 - fold over dose range 20 – 200 mg Tofacitinib: <1X Safety margin range
Izencitinib’s oral, gut - selective, pan - JAK approach is designed to maximize efficacy in IBD GI, gastrointestinal; IBD, inflammatory bowel disease; JAK, Janus kinase; UC, ulcerative colitis. 10 Vehicle treated control Izencitinib treatment CD3+ pan - T cells Blocks inflammation and penetrates deep within mouse colon The gut - selective approach is intended to maximize concentration where it matters, at the site of action in the GI tract Demonstrates improvement in UC patients in Phase 1b 0 44 20 30 30 70 18 73 0 20 40 60 80 100 Endoscopy Rectal Bleeding % of Patients Placebo (n=9) 20 mg (n=10) 80 mg (n=10) 270 mg (n=11) Izencitinib
Favorable data from this innovative exploratory Phase 1b study 1 ‣ Confirmed gut selectivity – High colonic concentration with low systemic drug exposures, consistent with pre - clinical data – For the goal of maximized therapeutic index ‣ Demonstrated numerically higher rates of clinical outcomes with reductions in biomarkers after only 4 weeks of treatment – Numerical improvements in rectal bleeding and mucosal healing ‣ Led to decision to proceed with development of izencitinib Global collaboration with Janssen Biotech, Inc. leverages joint development expertise with the potential for up to a total of $1B in milestone payments to TBPH plus profit - share in US (33% TBPH, 67% Janssen) and double - digit royalties to TBPH ex - US 2 1. Sandborn et al. J Crohns Colitis;2020: 14:1202 - 13. 2. Deal value up to $1B in payments to TBPH, including $100M upfront previously received; subject to Janssen opt - in. 3. Maintenance study will have induction responder patients re - randomized to active doses compared to placebo at 44 weeks. 4. Patients may enter the Long - Term safety study by completing or terminating Maintenance study due to loss of response. 11 Phase 2: 12 weeks (N=160) Dose - finding induction Active treatment extension: 48 weeks Crohn’s disease (0173) Phase 2b/3: 8 weeks (N=240) Dose - finding induction Maintenance phase 3 : 44 weeks Phase 3: 8 weeks (N=640) Dose - confirming induction Responders Ulcerative colitis (0157) Long - Term Safety Study 4 : 3 years (0164) Ongoing; Phase 2b data expected Q3 2021 Pre - clinical and Phase 1b results led to late stage IBD studies with izencitinib Ongoing; data expected late Q4 2021 / early Q1 2022 11
Izencitinib: Phase 2 study in Crohn’s disease Endpoints ‣ Primary: Improvement in CDAI score at week 12 in patients with moderately to severely active CD ‣ Exploratory: – Clinical response measured by CDAI at 12 weeks – CDAI clinical remission at 12 weeks – SES - CD change from baseline to Week 12 – Endoscopic response [Time Frame: 12 weeks] – SFAP clinical remission [Time Frame: 12 weeks] *2 izencitinib doses. NCT03635112 CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; SES - CD, Simple Endoscopic Score for Crohn's Disease; SFAP, Stool Freq uency and Abdominal Pain. 12 Key inclusion criteria: Age ≥18 y with moderately - to - severely active CD (CDAI 220 – 450) with corticosteroid dependence or failure of conventional or biologic therapy Geographies: South Africa, Asia, Australia, Europe, Middle East, New Zealand, UK, USA Study 0173 Program Status ‣ Ongoing Randomization Late Q4’21 Early Q1’22 Topline results Placebo Izencitinib* Ph 2 dose - finding induction: once - daily oral dose for 12 weeks Active treatment extension: once - daily oral dose for 48 weeks N=160 Izencitinib
Izencitinib: Phase 3 studies in ulcerative colitis Endpoints ‣ Primary: – Induction & Maintenance: clinical remission by aMS components at Week 8 and Week 44 ‣ Secondary: – Induction & Maintenance: endoscopic healing, symptomatic remission, clinical response by aMS, mucosal healing, maintenance of clinical response, corticosteroid - free remission, maintenance of clinical remission NCT03758443 aMS, adapted Mayo Score; UC, ulcerative colitis. 13 Program Status ‣ Phase 3 Induction study to begin post Phase 2b completion ‣ Phase 3 Maintenance study ongoing Study 0157 Randomization Placebo Izencitinib Ph 3 dose - confirming induction: once - daily oral dose for 8 weeks Responders from Ph 2b and Ph 3 Induction Placebo Izencitinib N=640 Ph 3 Induction Study starts after dose selection from Ph 2b Induction Ph 3 maintenance: once - daily oral dose for 44 weeks Key inclusion criteria: Age ≥18 y with moderately - to - severely active UC with corticosteroid dependence or failure of conventional or biologic therapy Geographies: South Africa, Asia, Australia, Europe , Middle East, North America, Japan
Izencitinib: Phase 3 study in ulcerative colitis Assessments ‣ Safety and tolerability of izencitinib administered for up to 3 years in patients with moderate - to - severe UC after participation in the Protocol 0157 Maintenance Study NCT03758443 UC, ulcerative colitis. 14 Key inclusion criteria: Eligible patients from Ph 3 Maintenance Study of Protocol 0157 Geographies: South Africa, Asia, Australia, Europe, Middle East, North America, Japan Long - term treatment 156 weeks (3 years) Izencitinib Study 0164
Month 6 0 5 10 15 20 F i r s t B P A R R a t e ( % ) Pan - JAK inhibitors can prevent transplant rejections ‣ JAK inhibition was superior to cyclosporine in prevention of acute and chronic rejections ‣ Serious infections increased with systemic JAK inhibitors including CMV 1. Vincenti F, et al. Am J Transplant 2015;15:1644 - 53. *p<0.001 vs CsA . BPAR, biopsy - proven acute rejection; CMV, cytomegalovirus; IF/TA, interstitial fibrosis/tabular atrophy; JAK, Janus kinase; SE, standard error. 15 Chronic Rejection Tofacitinib is superior to CsA in efficacy measures Acute Rejection Increased infection risk with tofacitinib over CsA CsA Tofacitinib 50 40 30 20 10 0 Month 12 * IF/TA (%) 24 5 53 25 0 20 40 60 Tofacitinib CsA CMV disease Serious infection 12 - month Kaplan - Meier estimates, % (SE) Noninferiority trial of tofacitinib vs cyclosporine (CsA) in kidney transplant recipients 1
Ampreloxetine (TD - 9855) Once - daily norepinephrine reuptake inhibitor to treat symptomatic neurogenic orthostatic hypotension
nOH profoundly impacts QoL Study 0169 primary endpoint: Change from baseline in OHSA Question 1 OHSA measures core nOH symptom: Dizziness / lightheadedness due to brain hypoperfusion Clinically significant endpoint: 1 - point OHSA improvement 1. https://www.parkinson.org/Understanding - Parkinsons/Statistics ; https://www.ninds.nih.gov/Disorders/Patient - Caregiver - Education/Fact - Sheets/Multiple - System - Atrophy . 2. Claassen DO, et al. BMC Neurol 2018;18:125 https://doi.org/10.1186/s12883 - 018 - 1129 - x . 3. Low PA. AMJC 2015;21:13,October 30 https://www.ajmc.com/view/ace0034_oct15_noh_low . 4. Not all patients are treated with prescription medication. MSA, multiple system atrophy; nOH, neurogenic orthostatic hypotension; OHSA, orthostatic hypotension symptom assessment; PD, Par kinson’s disease; QoL, quality of Life; Tx, treatment. Ampreloxetine: new approach in nOH 17 MARKET DYNAMICS ~350K US patients 1 : 70 – 80% of MSA patients 2 30 – 50% of PD patients 3 have nOH 4 Specialist network in place : concentrated group of neurologists/ cardiologists treat patients; ‘at risk’ patients already identified and managed by specialty institutions Physicians report urgency to treat due to high impact on patients’ QoL, high risk of injury from falls and caregiver burden Established nOH Tx paradigm: nOH included in medical treatment guidelines for PD/MSA patients; once diagnosed with nOH, patients prescribed drug SYMPTOMS IMPACT Depression Social isolation Poor QoL Falls (fractures/head trauma) Morbidity ‣ Dizziness or lightheadedness ‣ Fatigue ‣ Difficulty walking ‣ Weakness ‣ Impaired cognition ‣ Pain (back of head/neck/shoulders) ‣ Blurred vision ‣ Tremulousness ‣ Vertigo
Ampreloxetine: a once - daily, potent and selective norepinephrine reuptake inhibitor with a differentiated MOA for treating nOH Current nOH treatment options: ‣ No durable effect ‣ Multiple daily dosing ‣ Black box warning for SH 1. Kaufmann H, et al. Mov Disord. 2019;34(suppl 2). Poster presented at the 2019 International Congress of Parkinson’s and Mo vem ent Disorder Society. Note: a 1 - point change in the OHSA#1 score is considered clinically meaningful. MOA, mechanism of action; NE, norepinephrine; NET, norepinephrine transporters; nOH neurogenic orthostatic hypotension; OHSA #1, orthostatic hypotension symptom assessment question #1; SH, supine hypertension. 18 Ampreloxetine is designed to target and correct the norepinephrine imbalance… …and demonstrated a clinically meaningful and durable impact 1 Our goal: ampreloxetine to be the first treatment to demonstrate a sustained impact for patients managing the chronic and debilitating symptoms of nOH Change in OHSA #1 Efficacy Durability Withdrawal Study Week 0 - 1 - 4 - 7 4 20 24 Improvement Worsens back to baseline Vasoconstriction Blood pressure NE Release at Neurovascular Junction Ampreloxetine A XON TERMINAL D ENDRITE NE ~ 2 - fold increase Plasma NE Pre - dose Post - dose Reduction in syncope Normal …with potential for market differentiation…
Ampreloxetine: potential to provide meaningful and durable symptom improvement to underserved patients All subjects who complete Study 169 may enroll into 170; all subjects who complete 170 may enroll into extension study/171. Baseline OHSA #1 (Orthostatic Hypotension Symptom Assessment Question 1) >4 points. Negative change indicates improvement in sym ptoms; improvement of 1 point is defined as the MCID (minimal clinically important difference). Discontinuation rates for the Phase 3 trials as of Jan. 2020: 0169 – 5.3 percent; 0170 – 33.3 percent 19 Phase 3 registrational program ongoing; 4 - week efficacy data expected Q3 2021 Study 169: 4 weeks (N=188) Randomized, double - blind, placebo - controlled, parallel group Study 170: 22 weeks (N=254) Randomized 6 - week withdrawal phase Phase 3 Registrational Program Extension study: 3 years Completers
Ampreloxetine: Phase 3 registrational program Placebo - controlled, randomized withdrawal study *Negative change indicates improvement in symptoms; improvement of 1 point is defined as the MCID (minimal clinically importa nt difference). Discontinuation rates for the Phase 3 trials as of Jan. 2020: 0170 – 33.3%. NCT03829657 nOH, neurogenic orthostatic hypotension; OHDAS, orthostatic hypotension daily activities scale; OHSA, orthostatic hypotension sy mptom assessment; PGI - S, patient global impression of disease severity. 20 Key inclusion criteria: Age >30 y with symptomatic nOH with OHSA #1 score ≥4 Geographies: Argentina, Australia, Canada, Europe, New Zealand, Russia, UK, US Program Status ‣ Phase 3 registrational program ongoing ‣ All participants who complete Study 0170 are eligible for Extension Study 0171 Ampreloxetine Randomization Q3’22 Top - line results Ampreloxetine Placebo Open - label once - daily 10 mg oral dose: 16 weeks Once - daily 10 mg oral dose: 6 week withdrawal phase – PGI - S – % Time spent standing – Average no. of steps taken Study 0170 N=258 Objectives ‣ Primary: 1 - pt worsening from baseline in both OHSA #1 score* and PGI - S during withdrawal phase ‣ Secondary: Changes from baseline at Week 6 post - randomization – OHSA #1 – OHSA composite score – OHDAS composite score
Ampreloxetine: Phase 3 program 6 - month safety study + 3 - year optional extension Assessments ‣ Through Week 26: – Physical and neurological exams – Vital signs – ECGs – Clinical laboratory tests – Concomitant medications *Through week 26; for FDA filing NCT04095793 AE, adverse event; C - SSRS, Columbia Suicide Severity Rating Scale; ECG, electrocardiogram. 21 Program Status ‣ Includes patients who completed Study 0170 – AEs – Treatment compliance – Incidence of falls – Changes from baseline in C - SSRS Key inclusion criteria: patients who completed Study 0170 and, in investigator’s opinion, would benefit from long - term treatment with ampreloxetine Geographies: Argentina, Australia, Canada, Europe, New Zealand, Russia, UK, US Study 0171 Ampreloxetine Once - daily oral dose: 182 weeks Q3’22 Top - line results*
Decentralized trials move activities from the clinic to home ‣ Site - centric operating model ‣ Burden on site resources ‣ Patient burden Source: Theravance Biopharma Clinical Operations. 22 Global clinical trials are being decentralized along a continuum Traditional Trial Operations Decentralized Trial ‣ Patient - centric model ‣ Leverage technology for remote visits, monitoring and data collection ‣ Established home health and distribution channels
nOH is included in medical treatment guidelines for PD and MSA patients; once diagnosed, patients get on drug treatment quickly A concentrated group of neurologists and cardiologists treat patients with nOH; ‘at risk’ patients already identified and managed by specialty institutions TBPH’s infrastructure capable of commercializing ampreloxetine in the US with limited and targeted additions to current resources Physicians report high urgency to treat snOH due to the high impact on patients’ QoL, high risk of injury from falls and caregiver burden Meaningful value proposition will drive patient access; Ampreloxetine has the potential to improve the durability of treatment effect and thereby reduce costly events associated with nOH Strong message from PD and MSA advocacy groups that patients need new therapies to better manage nOH Ampreloxetine: has the potential to transform Theravance Biopharma into an independent commercial biopharma MSA, multiple system atrophy; nOH , neurogenic orthostatic hypotension; PD, Parkinson’s disease; QoL, quality of life; snOH, symptomatic neurogenic orthostatic hy potension. 23 Established disease, targeted market Established nOH treatment paradigm Specialist networks in place Manageable opportunity A strong value proposition An urgency to treat Understanding of current access barriers Established patient advocacy
Nezulcitinib (TD - 0903) Program Nebulized lung - selective pan - JAK inhibitor to treat: ► Acute hyperinflammation of the lung in COVID - 19 ► Chronic inflammation for the treatment and prevention of lung transplant rejection
Nezulcitinib (TD - 0903): breaking new ground with inhaled JAKi 1. https://www.kff.org/coronavirus - covid - 19/fact - sheet/coronavirus - tracker/ as of 4.29.21 2. https://coronavirus.jhu.edu/map.html as of 4.25.21 3. https://covid.cdc.gov/covid - data - tracker/#vaccinations as of 5.3.21 4. https://www.cdc.gov/coronavirus/2019 - ncov/transmission/variant.html as of 4.2.21 25 COVID - 19 MARKET DYNAMICS >149M COVID - 19 patients globally 1 ; >32M patients in US 2 56% of US population ≥1 vaccine dose; 40% fully vaccinated 3 Virus still surging in communities / parts of the world 1 5 variants of concern in US 4 Declining but substantial proportion of population refusing vaccination 5 Disproportionate burden on people of color 6 BUILDING A PIPELINE IN A PRODUCT Potential areas for exploration: ALI in COVID - 19 in hospitalized patients Preventing progression of lung hyperinflammation that leads to hospitalization Accelerated recovery of long - haul COVID - 19 patients Future applications for coronavirus and influenza inflammation Prevention of lung transplant rejection 5. https://www.aamc.org/news - insights/herd - immunity - closer - we - think as of 4.25.21 6. https://www.kff.org/coronavirus - covid - 19/issue - brief/latest - data - on - covid - 19 - vaccinations - race - ethnicity/ as of 4.25.21 7. https://www.medrxiv.org/content/10.1101/2021.03.09.21252944v1 , n=25 Focused execution in acute lung injury (ALI) driven by patient need Only therapeutic in development with nebulized lung - targeted approach Treatments needed for hospitalized COVID - 19 patients with acute lung injury TD - 0903 Dose finding placebo controlled data 7 ‣ Generally well - tolerated ‣ Low systemic exposure ‣ Positive trend in clinical status, reduced hospital stay ‣ No deaths in 3, 10 mg cohorts ‣ Improved oxygenation from baseline to Day 7 ‣ Improved inflammatory biomarkers
Nezulcitinib: Randomized, double - blind, placebo - controlled Ph 2 study in hospitalized patients with COVID - 19 requiring oxygen support Objectives ‣ Primary: Number of respiratory - free days from randomization through Day 28 ‣ Secondary: Tolerability, PK ‣ Exploratory : Clinical status, duration of hospitalization, repeat - dose safety *Loading dose (double the standard dose) administered on Day 1. NCT04402866 IMV, invasive mechanical ventilation; PK, pharmacokinetics; SARS - CoV - 2, Severe acute respiratory syndrome coronavirus 2; SOC, st andard of care, includes remdesivir, dexamethasone, anticoagulation. 26 Part 2 Study 0188 Key inclusion criteria: Hospitalized patients aged 18 – 80 y requiring supplemental oxygen to maintain >90% saturation (not requiring IMV) with positive SARS - CoV - 2 test <72 h prior to randomization and symptom onset >2 – 10 d prior to hospitalization Countries: South Africa, Europe, UK, USA Randomization Q2’21 Top - line results Nezulcitinib 3 mg* + SOC (n=99) Placebo + SOC (n=99) Double - blind once - daily nebulized treatment: 7 days Total observation: 28 days
Asymptomatic or pre - symptomatic Mild illness Moderate illness Severe illness Critical illness COVID recovery Features Positive SARS - CoV - 2 test; no symptoms Mild symptoms (e.g., fever, cough, or change in taste or smell); no dyspnea Clinical or radiographic evidence of LRT disease; oxygen saturation ≥94% Oxygen saturation <94%; respiratory rate ≥30 breaths/min; lung infiltrates >50% Respiratory failure, shock, and multiorgan dysfunction or failure Testing Screening test; if patient has known exposure, diagnostic test Diagnostic test Diagnostic test Diagnostic test Diagnostic test Isolation Yes Yes Yes Yes Yes Proposed disease pathogenesis Potential treatment Potential for nezulcitinib to improve lung immune system balance across disease progression LRT, lower respiratory tract; SARS - CoV - 2, Severe acute respiratory syndrome coronavirus 2. 27 Viral replication Inflammation Antiviral therapy Antibody therapy Systemic anti - inflammatory Nezulcitinib ongoing program Aid lung recovery Prevent progression
Nezulcitinib showed a trend of improvement in 28 - day all - cause mortality rate and time to mortality (ITT) 1. Hazard ratio (nezulcitinib vs placebo) and 95% CI calculated from Cox proportional hazards model adjusting for baseline ag e s trata (≤60 vs >60 years). 2. Unstratified log - rank p - value comparing distribution of nezulcitinib vs placebo. CI, confidence interval; HR, hazard ratio; ITT, intent - to - treat. 28 Nezulcitinib Placebo Deaths, n (%) 6 (5.7) 13 (12.5) HR (95% CI) 1 0.42 (0.16, 1.12) p - value 2 0.08 Cumulative Proportion Died Placebo (n=104) Nezulcitinib (n=106) Time from Randomization (days) 0 7 14 21 28 0.1 0.0 0.2 0.3
Executive summary of safety results Safety data based on 205 treated patients. 29 Nezulcitinib n=103 Placebo n=102 Adverse events 34.0% 41.2% Serious adverse events 9.7% 15.7% Liver abnormalities or disease 9.7% 7.8% Serious infections 1.0% 2.0% Venous thromboembolism 0 4.9% ‣ Nezulcitinib was well tolerated when administered once - daily for up to seven days
Nezulcitinib Phase 2 COVID - 19 trial summary ‣ Efficacy outcomes, n=210 (ITT) – Primary: No statistically significant difference between nezulcitinib and placebo for RFDs from randomization through Day 28 – Secondary: No difference in change from baseline at Day 7 in SaO 2 /FiO 2 ratio, proportion of patients in each category of the 8 - point Clinical Status scale, and proportion of patients alive and respiratory failure - free at Day 28 – A favorable trend in improvement for nezulcitinib when compared to placebo for 28 - day all - cause mortality and time to recovery ‣ Post - hoc analyses for baseline CRP, n=201 – CRP <150 mg/L (n=171): Nezulcitinib showed improvement in time to recovery and 28 - day all - cause mortality – CRP ≥150 mg/L (n=30): No differences between groups ‣ Nezulcitinib was well - tolerated when administered once - daily for up to seven days ‣ Plasma exposure was low, consistent with expectations for a lung - selective medicine CRP, C - Reactive protein; ITT, intent - to - treat; RFDs, Respiratory Failure - Free Days; SaO 2 /FiO 2 , percent oxygen saturation in arterial blood/fractional percentage of inspired oxygen. 30
TD - 8236 Potential first inhaled JAKi for asthma
High medical and economic burden in uncontrolled asthma *Asthma that requires high - dosage ICS + LABAs to prevent the disease from being uncontrolled) or asthma that remains uncontrolle d despite treatment. 1. World Health Organization; 2. https://www.aafa.org/asthma - facts/; 3. Sadatsafavi, M., et al. Can Respir J 2010;17:74 - 80. 4. N urmagambetov T, et al. Ann Am Thorac Soc 2018;15:348 - 56; 5. TBPH estimate based on multiple data sources. ICS, inhaled corticosteroids; IFN, interferon; IL, interleukin; JAK, Janus kinase; LABA, long - acting β2 agonists; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; STAT, signal transducer and activator of transcription; T2, type 2; TSLP, thymic stromal lymphopoietin. 32 16 14 Severe* Moderate US asthma market (October 2020) 5 61 25 US cases 8% of adults 8% of children 2 Healthcare utilization 3 25M ~$15B P ATIENT P OPULATION C URRENT T REATMENT L ANDSCAPE S TRATEGIC O PPORTUNITY TD - 8236 Potential to transform the treatment of respiratory inflammation by treating moderate - to - severe asthma regardless of T2 phenotype, including patients who remain symptomatic despite compliance on high - dose ICS ICS + LABA (often fail to control disease) Approved biologics (affect subsets of patients) US medical costs 4 ~$58B T2 - high T2 - low IL - 4 IL - 23 /IL - 12 IL - 13 IL - 6 IL - 5 IL - 27 TSLP IFN - γ Bold: biologics in development or approved. JAK/STAT cytokines implicated in moderate - to - severe asthma • XOLAIR (omalizumab) • NUCALA (mepolizumab) • CINQAIR (reslizumab) • FASENRA (benralizumab) • DUPIXENT (dupilumab) Step - up for severe asthma: LTRAs, tiotropium, OCS, biologics cases worldwide 1 339M
TD - 8236: Phase 1 clinical trial design CXCL, chemokine (C - X - C motif) ligand; FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroids; IFN, interferon; IgE, immunoglobulin E; IL, interleukin; ILC2, type 2 innate lymphoid cells; MAD, multiple - ascending dose; MoA, Mechanism of Action; PK, pharmacokinetic; PD, pharmacodynamic; pSTAT, phosphorylated signal transducer a nd activator of transcription; SAD, single - ascending dose; T2, type 2; Th2, T helper type 2; TSLP, thymic stromal lymphopoietin. 33 Parts A & B completed September 2019; Part C enrollment completed — data reported in Q4 2020 Part B: MAD (Mild asthmatics) Part A: SAD (Healthy volunteers) Safety, PK Safety, PK, PD (FeNO) All cohorts: N=6 active/2 Placebo 4500 µg 500 µg 1500 µg 150 µg 50 µg 4000 µg 1 2 3 4 5 6 7 D 150 µg 500 µg 1500 µg 1 2 3 4 5 6 7 D 1 2 3 4 5 6 7 D 1 2 3 4 5 6 7 D Part C: MoA Biomarkers (Moderate - to - severe asthmatics + ICS) N=16 active/8 placebo 1 2 3 4 5 6 7 D 1500 µg ‣ Goal: build confidence in compound, MoA and dose in early - development ‣ Endpoints: FeNO; pSTAT1 and pSTAT6 in bronchoalveolar lavage fluid; cytokines; epithelial gene expression T2 - dominant, n=8 Non - T2 - dominant, n=8 x x
TD - 8236: Positive Phase 1 trial in healthy subjects and patients with mild and moderate - to - severe asthma ‣ Biomarkers of JAK target engagement (pSTAT1 and pSTAT6) significantly reduced in lungs of T2 high and T2 low moderate/severe asthmatics on top of ICS ‣ Ongoing analysis of effect of TD - 8236 on additional biomarkers including cytokines and gene expression FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroids; JAK, Janus kinase; PD, pharmacodynamic; PK, pharmacokine tic ; pSTAT , phosphorylated signal transducer and activator of transcription; T2, type 2. 34 Phase 1 Profile Healthy Volunteer Single Dose (Part A) Mild Asthma Multiple Dose (Part B) Moderate - to - Severe Asthma [+ ICS] Multiple Dose (Part C) Generally well tolerated x x x Minimal systemic exposure x x x PK and PD profile consistent with once - daily dosing x x x Biologic activity in lungs of patients with asthma x ↓ FeNO x ↓ FeNO, pSTAT1, pSTAT6
-50 -40 -30 -20 -10 0 10 20 30 40 -0.4 -0.2 0.0 0.2 0.4 Favors Placebo Favors TD - 8236 Favors TD - 8236 Favors Placebo No impact of TD - 8236 on the Late Asthmatic Response (LAR) ‣ TD - 8236 was generally well tolerated as a single - daily dose administered for 14 consecutive days 35 Primary Endpoint: Weighted Mean Area Under the Curve, 3 – 8 h. CI, confidence interval; FeNO, fractional exhaled nitric oxide; LS, least - squares. % Change in FeNO Late Asthmatic Response Difference from Placebo, Liters (LS Means ± 95% CI) Difference from Placebo, % (LS Means ± 95% CI) 1500 µg 150 µg Day 14 Day 14 Day 7 - 0.01 n=22 - 0.04 n=20 4.28 n=22 - 20.16 n=24 - 3.72 n=22 - 26.87 n=23 Significant reductions in inflammation marker (FeNO) and favorable safety and tolerability
-50 -40 -30 -20 -10 0 10 20 30 40 TD - 8236 FeNO reductions consistent across Phase 1 and 2 ‣ FeNO reductions observed in moderate - to - severe asthmatics taking inhaled corticosteroids CI, confidence interval; FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroids; LAC, lung allergen challenge; LS, least - squares. 36 Phase 1 (Part B) Mild Asthmatics Phase 2 (LAC) Mild Asthmatics Phase 1 (Part C) Moderate – Severe Asthmatics + ICS Difference from Placebo (%) (LS Means ± 95% CI) 1500 µg 150 µg Day 7 Day 7 Day 14 Day 7 - 7.65 n=6 - 24.90 n=6 4.28 n=22 - 20.16 n=24 - 3.72 n=22 - 26.87 n=23 - 22.80 n=8 Favors Placebo Favors TD - 8236
TD - 5202 Organ - gut selective irreversible JAK3 inhibitor to treat inflammatory intestinal diseases
Celiac disease has no current treatments and serious health consequences 38 1. http://www.drschaer - institute.com/us/celiac - disease/epidemiology - 1033.html ; 2. 1% prevalence in US, BeyondCeliac.org; 3. 2018 US population 327M Census.gov. 4. Reunala T, et al. Nutrients 2018;10;pii: E602; 5. Guandalini et al. Digestive Diseases Sciences 2016;61:2823 - 30; 6. Theravan ce Market Research. JAK, Janus kinase. S TRATEGIC O PPORTUNITY P ATIENT P OPULATION US patients 2,3 3.3M No approved treatment Only available intervention is strict life - long gluten - free diet 30% of diagnosed patients are poorly controlled despite best dietary efforts 6 TD - 5202 Organ - gut selective irreversible JAK3 inhibitor: potential to deliver significant value for both patients and payers increase in US over past 50 y 4 4 – 4.5x Global prevalence 1 1% higher healthcare costs than controls 5 >2x C URRENT T REATMENT L ANDSCAPE Celiac Normal
JAK3 - dependent cytokines play central role in pathogenesis of celiac disease ‣ Proof - of - relevance from recent positive Phase 2 data with systemic JAK3 inhibitor in alopecia areata, another T - cell mediated disease ‣ Localized JAK3 inhibition has the potential to avoid systemic immunosuppression (genetic JAK3 deficiency leads to severe immunodeficiency) Figure adapted from Jabri B and Sollid L. J Immunol 2017;198:3005 - 14. CD, Crohn’s disease; IE - CTL, intraepithelial cytotoxic lymphocyte; IEL, intraepithelial lymphocyte; IFN, interferon; IL, interle ukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; Th1, T helper 1 cells. 39 IL - 2, IL - 4, IL - 7, IL - 9, IL - 15, IL - 21 I MMUNE C ELL CD Pathogenesis α N UCLEUS STAT P STAT P STAT P STAT P STAT JAK1 β γ JAK3 P P P Gluten peptides G LUTEN - S PECIFIC T H 1 CELLS I NTESTINAL E PITHELIUM L AMINA P ROPIA I NTESTINAL L UMEN IFNγ IL - 2 IL - 21 IEL IE - CTL IL - 15
TD - 5202 First - in - human overall results summary ‣ No serious or severe AEs were reported ‣ All treatment - emergent AEs in TD - 5202 - treated subjects were mild in severity AE, adverse event; BID, twice daily; C max,ss , maximal steady - state concentration; ECG, electrocardiogram; IC 50 , inhibitory concentration at which 50% of JAK signaling is blocked; JAK, Janus kinase; IC 50 , NK, natural killer. 40 TD - 5202: generally well - tolerated (single dose ≤2000 mg, multiple doses ≤1000 mg BID) for 10 consecutive days in healthy subjects ‣ Systemic exposures were dose proportional from 100 to 1000 mg BID ‣ Low steady - state systemic exposures: mean C max,ss ~11 - fold below the protein - adjusted JAK IC 50 at the highest tested dose (1000 mg BID), consistent with a gut - selective approach ‣ No clinically significant changes from baseline in vital signs and ECG assessments ‣ No clinically significant changes in chemistry or hematology parameters – No changes in NK cell count
Inhaled ALK5i Potential best - in - disease therapy for the treatment of idiopathic pulmonary fibrosis (IPF)
Limited treatment options 2 currently approved therapies, with modest efficacy and poor tolerability S TRATEGIC O PPORTUNITY P ATIENT P OPULATION Inhaled ALK5i Potential first - in - class inhaled ALK5 inhibitor anti - fibrotic agent for IPF Despite treatment with the current SoC, IPF patients continue to experience disease progression and exacerbation C URRENT T REATMENT L ANDSCAPE Idiopathic pulmonary fibrosis (IPF) remains a fatal chronic lung disease with limited treatment options 1. Raghu G, et al. Lancet Resp. 2014: 2(7):566 - 572; 2. Raghu G, et al. Eur Respir J. 2016: 48(1):179 - 186; 3. National Heart Lung and Blood Institute (NIH), Public Domain, https://commons.wikimedia.org/w/index.php?curid=29590103. ALK5i, transforming growth factor β receptor I kinase inhibitor; Soc, Standard of Care. 42 US prevalence; currently orphan disease 1,2 140,000 Lungs with IPF 3 Profound dyspnea, unrelenting cough, impairment of activities of daily living Mortality with IPF remains high
Significant opportunity remains for effective IPF treatments ‣ Mortality with IPF remains high – <50% alive 3 years after diagnosis 1 1. King TE, et al. Am J Respir Crit Care Med 2001;164:1171 - 81. IPF, idiopathic pulmonary fibrosis. 43 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 Years Probability of Survival Male Female To arrest disease progression with improved tolerability Goal
TGFβ, transforming growth factor β. 44 S CARRING TISSUES Collagen deposition Stimuli Genetic susceptibility Repetitive injury AEC damage TGF β A LVEOLAR E PITHELIAL C ELLS (AEC) T YPE 2 T YPE 1 Normal M YOFIBROBLASTS Fibrogenesis, proliferation Targeting the TGFβ pathway A core signaling pathway that drives fibrosis
Selectively targeting the TGFβ pathway through ALK5 inhibition Adapted from: Neuzillet C, et al. Oncotarget 2013;5:78 – 94. α SMA, α - smooth muscle actin; ERK, extracellular signal - regulated kinase; IPF, idiopathic pulmonary fibrosis; JNK, c - Jun N - terminal kina se; PI3K, phosphatidylinositol - 4,5 - bisphosphate 3 - kinase; Smad2/3, mothers against decapentaplegic homolog 2/3; TGFR (ALK5), transforming growth factor receptor. 45 F IBROBLASTS M YOFIBROBLASTS Fibroblast to Myofibroblast Transition (FMT) Increased extracellular matrix Increased a SMA Increased migration ERK Smad2/3 PI3K p38 JNK Rho IPF progression P P ALK5i Activation: Multiple an integrins Proteases Thrombospondin Free Radicals TGFR2 Latent TGFβ TGFR1 (ALK5) Inhibiting a core signaling pathway that drives fibrosis regardless of activation mechanism
ALK5 inhibition directly interrupts FMT in IPF ALK5i, transforming growth factor β receptor I kinase inhibitor; α SMA, α - smooth muscle actin; FMT, fibroblast to myofibroblast transition. 46 Reference Standard ALK5i Log [M] % inhibition of α SMA - 9 - 8 - 7 - 6 - 5 0 50 100 150 FMT a SMA expressed a SMA reduced Negative control ALK5i treated
Current treatment options have no effect on FMT at clinically relevant concentrations 1. https://www.tga.gov.au/sites/default/files/auspar - nintedanib - esilate - 160208.pdf . 2. Ogura T, et al. Eur Respir J. 2015;45:1382 - 92. C max , maximal concentration; FMT, fibroblast to myofibroblast transition; IC 50 , half maximal inhibitory concentration. 47 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 Pirfenidone Nintedanib Log [M] Nintedanib IC 50 Pirfenidone IC 50 Clinical C max Unbound 1,2
Wound repair Bone healing Cardiovascular homeostasis Tumor suppression Endocrine function Lung selectivity avoids unwanted systemic side effects Modified from: Akhurst RJ, Hata A. Nat Rev Drug Discov 2012;11:790 - 811. ALK5i, TGFβ receptor I kinase inhibitor; TGFβ, transforming growth factor β. 48 Maintaining key systemic regulatory roles of TGFβ Inhaled ALK5i Minimizing systemic inhibition of a cytokine essential for homeostasis
Ocular JAKi Potential best - in - disease, pan - JAK inhibitor with long - acting ocular anti - inflammatory activity
Diabetic macular edema causes blindness in diabetics 1. © 2016 DR/Decision Resources, LLC. All rights reserved. Reproduction, distribution, transmission or publication is prohibit ed. Reprinted with permission. 2. Romero - Aroca, World J Diabetes 2011;2(6): 98 - 104. 3. Lee et al Curr Med Res Opin 2008;24:1549 - 59. Images from Angiogenesis Foundation, www.scienceofdme.org . DME, Diabetic macular edema; JAKi, Janus kinase inhibitor; VEGFi, vascular endothelial growth factor inhibitor. 50 Vision with DME Normal vision US prevalence 1 2.7 million #1 Anti - VEGF treatments Most patients have suboptimal response S TRATEGIC O PPORTUNITY P ATIENT P OPULATION Ocular JAKi C URRENT T REATMENT L ANDSCAPE Potential to offer an alternative treatment for DME patients who are not optimally responding to treatment with VEGFi 140% higher direct and indirect healthcare costs in patients with DME vs diabetics without ocular disease 3 cause of blindness in diabetes 2 1st Intraocular steroids Side effects limit utility 2nd Nonpharmacological treatments (e.g. laser coagulation) limited efficacy and significant adverse events
Inflammation, not just VEGF, is a key driver of DME 51 1. Gonzalez VH, et al. Am J Ophthalmol 2016;172:72 - 79. DME, diabetic macular edema; VEGF, vascular endothelial growth factor. Current Pharmacological Treatments Intraocular steroids Hyperglycemia Disruption of blood - retinal barrier Vascular leakage DME VEGF Retinal capillary damage Inflammatory cytokines Need for broad, sustained release, anti - inflammatory with a safer side - effect profile ‣ High frequency of formation of cataracts and glaucoma ‣ One third do not respond to anti - VEGF while another third have a suboptimal response 1 ‣ Require frequent intravitreal injections Intraocular anti - VEGF agents
0.00 0.25 0.50 0.75 1.00 1.25 VEGF IL-6 IP-10 MCP-1 Unmet need for an anti - inflammatory drug: opportunity for eye - selective JAK inhibition Adapted from Sohn HJ, et. al. Am J Ophthalmol 2011; 152:686 - 694. IL - 6, interleukin - 6; IP - 10, interferon γ - induced protein 10; JAK, Janus kinase; MCP - 1, monocyte chemoattractant protein - 1; VEGF, vascular endothelial growth factor. 52 Effect of anti - VEGF Effect of Steroids 0.00 0.25 0.50 0.75 1.00 1.25 VEGF IL-6 IP-10 MCP-1 Untreated Treated Normalized Protein Level
Ocular pan - JAK inhibition has the potential to address key disease pathways in DME 53 DME, diabetic macular edema; IL - 6, interleukin - 6; IP - 10, interferon γ - induced protein 10; JAK, Janus kinase; MCP - 1, monocyte chemoattractant protein - 1; pSTAT, phosphorylated signal transducer and a ctivator of transcription; Tyk, tyrosine kinase; VEGF, vascular endothelial growth factor. TD - EyeJAKi inhibits key DME inflammatory pathways: JAK2 JAK1 IL - 6 Tyk2 JAK1 Interferons MCP - 1 IP - 10 TD - Eye JAKi ‣ IL - 6 and interferon signaling pathways in human primary cells ‣ IL - 6 induced pSTAT3 and interferon - induced IP - 10 in the back of the eye in vivo
0 1 2 3 0.000001 0.00001 0.0001 0.001 0.01 0.1 1 10 100 1000 Time (months) C o m p o u n d c o n c e n t r a t i o n ( g / m L o r g / g ) A pan - JAK inhibitor designed for eye selectivity with projected dosing interval of at least three months 54 JAK, Janus kinase. Single intravitreal injection of TD - Eye JAKi in Rabbits Vitreous humor (depot) Retina Plasma α STAT P STAT P STAT JAK β γ JAK N UCLEUS P STAT P STAT JAKi