UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, DC 20549
FORM
Current Report Pursuant
to Section 13 or 15(d) of the
Securities Exchange Act of 1934
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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).
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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 May 4, 2021, Theravance Biopharma, Inc. issued a press release and is holding a conference call regarding its financial results for the quarter ended March 31, 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.
(d) Exhibits.
| 99.1 | Press Release dated May 4, 2021 | |
| 99.2 | Slide deck entitled First Quarter 2021 Financial Results and Business Update | |
| 99.3 | Slide deck entitled Appendix May 4, 2021 | |
| 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, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| THERAVANCE BIOPHARMA, INC. | ||
| Date: May 4, 2021 | By: | /s/ Andrew Hindman |
| Andrew Hindman | ||
| Senior Vice President and Chief Financial Officer | ||
Exhibit 99.1
Theravance Biopharma, Inc. Reports First Quarter 2021 Financial Results and Provides Business Update
| Ø | Company completed enrollment for Phase 2 nezulcitinib (TD-0903, COVID lung hyperinflammation) and Phase 2b izencitinib (ulcerative colitis) studies, is near completion of enrollment for ampreloxetine Phase 3, and reaffirms readout timing for these trials |
| Ø | Company updates timing for izencitinib (Crohn’s disease) readout to late Q4/early Q1 2022 |
| Ø | Company’s implied 35% share of YUPELRI® (revefenacin) net sales1: $12.9 million |
| Ø | TRELEGY® Q1 2021 global net sales hit a record $341 million, up 37% from Q1 2020. Company is entitled to tiered royalties of 5.5% to 8.5% on TRELEGY net sales2 |
DUBLIN, IRELAND – may 4, 2021 – Theravance Biopharma, Inc. (“Theravance Biopharma” or the “Company”) (NASDAQ: TBPH) today reported financial results for the first quarter of 2021.
“2021 is on track to be a transformational year as we make significant progress towards our business goals,” said Rick E Winningham, Chief Executive Officer. “Our commercial assets provide cash flow to invest in our diversified clinical pipeline. GSK’s TRELEGY continues an exceptional, unabated growth trajectory. Our YUPELRI team, with our partner Viatris, continues to drive performance despite pandemic-associated headwinds. While we experienced slightly down sequential quarter-over-quarter net sales results, our January 2021 market share was 19%—its highest level since launch—and we ended the quarter on a strong note with March volume demand demonstrating 28% growth over February.”
“Additionally, we are focused on advancing development of our innovative and differentiated pipeline. We continue to progress nezulcitinib, our wholly-owned nebulized lung-selective pan-JAK inhibitor, our potentially best-in-class ampreloxetine for symptomatic neurogenic orthostatic hypotension and izencitinib, our oral gut-selective pan-JAK inhibitor for inflammatory bowel disease that is partnered with Janssen Pharmaceuticals. Our team is looking forward to four significant clinical readouts between now and Q1 2022: our Phase 2 nezulcitinib trial in Q2, our Phase 3 ampreloxetine and Phase 2b izencitinib Ulcerative Colitis trials each in Q3, and the Phase 2 izencitinib Crohn’s disease trial in Q4/Q1 2022. We remain committed to delivering each of these clinical data sets with the highest quality as expeditiously as possible.”
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.
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Upcoming Clinical Milestones
| · | Q2 2021: Nezulcitinib (nebulized lung-selective pan-Janus kinase (JAK) inhibitor) Phase 2 for acute hyperinflammation of the lung in COVID-19 (study 0188) – enrollment complete and topline results expected in Q2. |
| · | Q3 2021: Ampreloxetine (norepinephrine reuptake inhibitor) Phase 3 for symptomatic neurogenic orthostatic hypotension (study 0169) – enrollment near complete and topline results expected in Q3. |
| · | Q3 2021: Izencitinib (gut-selective oral pan-JAK inhibitor for inflammatory intestinal diseases) Phase 2b in ulcerative colitis (study 0157) – enrollment complete and topline results expected in Q3. |
| · | Q4 2021/Q1 2022: Izencitinib (gut-selective oral pan-JAK inhibitor for inflammatory intestinal diseases) due to enrollment challenges, Phase 2 in Crohn’s disease (study 0173) – enrollment ongoing and topline results now expected in late Q4 2021/early Q1 2022. |
Quarterly Highlight
| 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 19.0% in January 2021, up from 18.6% in December 2020. |
Economic Interest
| · | TRELEGY (first once-daily single inhaler triple therapy for COPD and asthma), in which the Company holds an economic interest, posted first quarter 2021 global net sales of $341 million (up from $249 million, 36.9%, in the first quarter of 2020); Theravance Biopharma is entitled to tiered royalties of 5.5% to 8.5% of TRELEGY global net sales.3 |
First Quarter Financial Results
| · | Revenue: Total revenue for the first quarter of 2021 was $14.3 million, comprised of non-cash collaboration revenue of $3.9 million primarily attributed to our global collaboration with Janssen and $10.4 million in Viatris collaboration revenue. Total revenue for the first quarter represents a $5.6 million decrease over the same period in 2020. |
| · | YUPELRI: The Viatris collaboration revenue of $10.4 million for the first 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 first quarter of 2021 was $12.9 million. |
| · | Research and Development (R&D) Expenses: R&D expenses for the first quarter of 2021 were $67.6 million, compared to $66.0 million in the same period in 2020. First quarter R&D expenses included total non-cash share-based compensation of $7.9 million. |
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.
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| · | Selling, General and Administrative (SG&A) Expenses: SG&A expenses for the first quarter of 2021 were $30.6 million, compared to $26.3 million in the same period in 2020. First quarter SG&A expenses included total non-cash share-based compensation of $7.9 million. |
| · | Operating Loss: Operating loss for the first quarter of 2021 was $83.9 million compared to $72.5 million in the same period of 2020. |
| · | Cash Position: Cash, cash equivalents and marketable securities totaled $210.0 million as of March 31, 2021. |
2021 Financial Guidance
| · | Operating Expenses (excluding share-based compensation): The Company 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 1092615. Those interested in listening to the conference call live via the internet may do so by visiting Theravance.com, under the Investors section, Presentations and Events.
A replay will be available on Theravance.com for 30 days through June 3, 2021. An audio replay will also be available through 8:00 pm ET on May 11, 2021, by dialing (855) 859-2056 from the U.S., or (404) 537-3406 for international callers, and then entering confirmation code 1092615.
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.
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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. Trade names or service marks of other companies appearing on this press release are the property of their respective owners
Page 4 of 7
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, 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 or ineffective, 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-K filed with the SEC on February 26, 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
Corporate Communications
917-214-6603
Page 5 of 7
THERAVANCE BIOPHARMA, INC.
CONDENSED CONSOLIDATED BALANCE SHEETS
(In thousands)
| March 31, | December 31, | |||||||
| 2021 | 2020 | |||||||
| (Unaudited) | (1) | |||||||
| Assets | ||||||||
| Current assets: | ||||||||
| Cash and cash equivalents and short-term marketable securities | $ | 209,968 | $ | 292,941 | ||||
| Receivables from collaborative arrangements | 11,915 | 15,868 | ||||||
| Receivables from licensing arrangements | - | - | ||||||
| Amounts due from TRC, LLC | 42,359 | 53,799 | ||||||
| Prepaid clinical and development services | 18,792 | 20,374 | ||||||
| Other prepaid and current assets | 10,037 | 10,359 | ||||||
| Total current assets | 293,071 | 393,341 | ||||||
| Property and equipment, net | 16,944 | 16,422 | ||||||
| Operating lease assets | 42,517 | 43,260 | ||||||
| Equity in net assets of TRC, LLC | 19,439 | 12,750 | ||||||
| Restricted cash | 833 | 833 | ||||||
| Other assets | 2,304 | 2,451 | ||||||
| Total assets | $ | 375,108 | $ | 469,057 | ||||
| Liabilities and Shareholders' Deficit | ||||||||
| Current liabilities | $ | 86,492 | $ | 123,571 | ||||
| Convertible senior notes due 2023, net | 227,230 | 226,963 | ||||||
| Non-recourse notes due 2035, net | 375,181 | 372,873 | ||||||
| Long-term operating lease liabilities | 57,026 | 47,220 | ||||||
| Other long-term liabilities | 2,397 | 2,181 | ||||||
| Shareholders' deficit | (373,218 | ) | (303,751 | ) | ||||
| Total liabilities and shareholders’ deficit | $ | 375,108 | $ | 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.
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THERAVANCE BIOPHARMA, INC.
CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS
(In thousands, except per share data)
| Three Months Ended March 31, | ||||||||
| 2021 | 2020 | |||||||
| (Unaudited) | ||||||||
| Revenue: | ||||||||
| Collaboration revenue | $ | 3,872 | $ | 6,632 | ||||
| Licensing revenue | - | 1,500 | ||||||
| Viatris collaboration agreement | 10,385 | 11,730 | ||||||
| Total revenue | 14,257 | 19,862 | ||||||
| Costs and expenses: | ||||||||
| Research and development (1) | 67,599 | 66,013 | ||||||
| Selling, general and administrative (1) | 30,550 | 26,325 | ||||||
| Total costs and expenses | 98,149 | 92,338 | ||||||
| Loss from operations | (83,892 | ) | (72,476 | ) | ||||
| Income from investment in TRC, LLC | 16,547 | 13,515 | ||||||
| Interest expense | (11,873 | ) | (9,941 | ) | ||||
| Loss on extinguishment of debt | - | (15,464 | ) | |||||
| Interest and other income, net | (234 | ) | 1,460 | |||||
| Loss before income taxes | (79,452 | ) | (82,906 | ) | ||||
| Provision for income tax expense | (227 | ) | (147 | ) | ||||
| Net loss | $ | (79,679 | ) | $ | (83,053 | ) | ||
| Net loss per share: | ||||||||
| Basic and diluted net loss per share | $ | (1.24 | ) | $ | (1.40 | ) | ||
| Shares used to compute basic and diluted net loss per share | 64,493 | 59,463 | ||||||
(1) Amounts include share-based compensation expense as follows:
| Three Months Ended March 31, | ||||||||
| (In thousands) | 2021 | 2020 | ||||||
| Research and development | $ | 7,921 | $ | 7,865 | ||||
| Selling, general and administrative | 7,911 | 7,411 | ||||||
| Total share-based compensation expense | $ | 15,832 | $ | 15,276 | ||||
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Exhibit 99.2
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First Quarter 2021 Financial Results and Business Update May 4, 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. |
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Forward-looking statements 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 or ineffective, 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-K filed with the SEC on February 26, 2021, and other periodic reports filed with the SEC. |
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Agenda |
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Key programs supported by proven development and commercial expertise ProgramIndicationResearchPhase 1Phase 2Phase 3FiledMarketedCollaborator Ampreloxetine (TD-9855) NRISymptomatic nOH Phase 3 Wholly-owned UC Izencitinib (TD-1473) GI JAKi CD Phase 2b/3 Phase 2 Janssen Biotech, Inc. Organ-Selective Irreversible JAK3iInflammatory intestinal diseases YUPELRI® (revefenacin) LAMACOPD Nezulcitinib (TD-0903) Inhaled JAKiCOVID-19 Phase 1 Phase 2 Marketed TD-8236 Inhaled JAKi Asthma Phase 2 Wholly-owned Inhaled ALK5iIdiopathic pulmonary fibrosis Phase 1 ProgramIndicationResearchPhase 1Phase 2Phase 3FiledMarketedRights Economic Interests FF/UMEC/VI COPD Asthma Marketed Marketed GSK & Innoviva, Inc. Skin-selective JAKiDermatological diseases Research 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 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 disease; COPD, chronic obstructive pulmonary disease; FF/UMEC/VI, fluticasone furoate/umeclidinium/ vilanterol; JAKi, Janus kinase inhibitor; LAMA, long-acting muscarinic receptor antagonist; nOH, neurogenic orthostatic hypotension; NRI, norepinephrine reuptake inhibitor; UC, ulcerative colitis. 4 |
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Commercial progress of YUPELRI® & GSK’s TRELEGY Q1 TOPLINE 2021 Multiple potential milestones & value-driving catalysts Q2RESULTS Q3 Q4 Nezulcitinib (TD-0903) Phase 2 (0188) COVID-19 Ampreloxetine SEQUOIA (0169) Phase 3 symptomatic nOH Izencitinib RHEA (0157) Phase 2b ulcerative colitis Q1'22 Izencitinib DIONE (0173) Phase 2 Crohn’s disease 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 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 |
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Theravance Biopharma difference: Targeting disease with organ selective medicines Pathway DiseaseTherapeutic Index TITI Target disease biologyOptimize effect in the organ where the disease is active Expand TI with the goal of maximizing efficacy and limiting systemic side effects TI, therapeutic index. 6 Pioneering a new generation of small molecule drugs designed to better meet patient needs |
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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 |
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Nezulcitinib (TD-0903): breaking new ground with inhaled JAKi Focused execution in acute lung injury (ALI) driven by patient need >149M COVID-19 patients globally1; >32M patients in US2 BUILDING A PIPELINE IN A PRODUCT Treatments needed for hospitalized COVID-19 patients with acute lung injury TD-0903 Dose finding placebo controlled data7 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 Only therapeutic in development with nebulized lung-targeted approach Virus still surging in communities / parts of the world1 Preventing progression of lung hyperinflammation that leads to hospitalization https://www.kff.org/coronavirus-covid-19/fact-sheet/coronavirus-tracker/ as of 4.29.21 https://coronavirus.jhu.edu/map.html as of 4.25.21 https://covid.cdc.gov/covid-data-tracker/#vaccinations as of 5.3.21 https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant.html as of 4.2.21 https://www.aamc.org/news-insights/herd-immunity-closer-we-think as of 4.25.21 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 8 56% of US population ≥1 vaccine dose; 40% fully vaccinated3 ALI in COVID-19 in hospitalized patients 5 variants of concern in US4 Accelerated recovery of long-haul COVID-19 patients Declining but substantial proportion of population refusing vaccination5 Future applications for coronavirus and influenza inflammation Disproportionate burden on people of color6 Prevention of lung transplant rejection |
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Nezulcitinib: a lung-selective inhaled immunotherapy in development Broadly inhibits the pulmonary inflammatory cascade caused by viral infection Potential therapeutic benefit via three activities: Potent pan-JAK inhibition α βγ JAKJAK P NUCLEUS P P P 100 STAT STAT STAT % Inhibition Protection against virus-induced cell death STAT Prevention of cell entry, limiting virus dissemination in lung ACE2TMPRSS2 850 Fold Change Vehicle STAT 60 40 20 0 0.11100.1110 4Vehicle 2 0 -9-8-7-6-5-4 Log(Compound(M)) Nezulcitinib 30 20 10 0 -9-8-7-6-5-4 Log(Compound(M)) MCP-1, GM-CSF) NezulcitinibDexamethasone Nezulcitinib + Dexamethasone (0.1 μM) Nezulcitinib + Dexamethasone (0.01 μM) Our goal: nezulcitinib to be the first inhaled treatment to broadly interrupt viral-induced activation and restore immune system balance in the lung ACE2, angiotensin-converting enzyme 2; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFNγ, interferon gamma; IL-6, interleukin 6; IP-10, IFNγ-induced protein 10; JAK, Janus kinase; LDH, lactate dehydrogenase; MCP-1, monocyte chemoattractant protein-1; STAT, signal transducer and activator of transcription; TMPRSS2, transmembrane protease, serine 2. 9 |
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Izencitinib (TD-1473/JNJ-8398) Oral gut-selective pan-JAK inhibitor to treat inflammatory bowel diseases |
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Izencitinib’s oral, gut-selective, pan-JAK approach is designed to reduce systemic side effects High margins of systemic safety in nonclinical studies Updated slide to Come Low systemic plasma concentrations in UC patients 140 120 Systemic Safety Margin (Plasma AUC) 10 5 IzencitinibTofacitinib Safety margin range Izencitinib: 12–136-fold over dose range 20–200 mg Plasma Concentration (nM) 200 100 Tofacitinib 10 mg BID (simulated)* Izencitinib 20 mg Izencitinib 80 mg Izencitinib 270 mg Oral bioavailability Tofacitinib: 74% Izencitinib: 2% 0 Rodent xp Ther 2014;348:165-73. highest studied clinical dose (izencitinib) or a e colitis. Tofacitinib: <1X 0 01234 Time (hr) Updated footer to Gut selectivity confers low systemic exposure and offers the potential for reduced adverse effects *Simulated tofacitinib concentrations extracted from Dowty ME, et al. J Pharmacol E Margins of safety reflect the ratio of nonclinical to clinical plasma exposures at the AUC, area under curve; BID, twice daily; hr, hour; JAK, Janus kinase; UC, ulcerativ Come pproved dose (tofacitinib). 11 |
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Izencitinib’s oral, gut-selective, pan-JAK approach is designed to maximize efficacy in IBD Blocks inflammation and penetrates deep within mouse colon Demonstrates improvement in UC patients in Phase 1b Vehicle treated control Izencitinib Placebo (n=9)20 mg (n=10)80 mg (n=10)270 mg (n=11) The gut-selective approach is intended to maximize concentration where it matters, at the site of action in the GI tract IBD, inflammatory bowel disease; JAK, Janus kinase; UC, ulcerative colitis. GI, gastrointestinal. 12 CD3+ pan-T cells 70 73 44 30 30 20 18 0 80 % of Patients Izencitinib treatment 20 0 EndoscopyRectal Bleeding |
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Ampreloxetine (TD-9855) Once-daily norepinephrine reuptake inhibitor to treat symptomatic neurogenic orthostatic hypotension |
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Ampreloxetine: new approach in nOH MARKET DYNAMICS SYMPTOMS ~350K US patients1: 70–80% of MSA patients2 30–50% of PD patients3 have nOH4 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 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 Clinical significant endpoint: 1-point OHSA improvement Dizziness or lightheadedness Fatigue Difficulty walking Weakness Impaired cognition Pain (back of head/neck/shoulders) Blurred vision Tremulousness Vertigo IMPACT Falls (fractures/head trauma) Morbidity https://www.parkinson.org/Understanding-Parkinsons/Statistics; https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Multiple-System-Atrophy. 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, Parkinson’s disease; QoL, quality of Life; Tx, treatment. 14 |
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Ampreloxetine: a once-daily, potent and selective norepinephrine reuptake inhibitor with a differentiated MOA for treating nOH Ampreloxetine is designed to target and correct the norepinephrine imbalance… …with potential for market differentiation… …and demonstrated a clinically meaningful and durable impact1 NE Release at Neurovascular Junction AXON TERMINAL Ampreloxetine NE DENDRITE Plasma NE Post-dose Pre-dose Current nOH treatment options: No durable effect Multiple daily dosing Black box warning for SH Efficacy Normal Change in OHSA #1 -1 - 4 Improvement Durability Reduction in syncope Withdrawal Worsens back to baseline VasoconstrictionBlood pressure - 7 42024 Study Week Our goal: ampreloxetine to be the first treatment to demonstrate a sustained impact for patients managing the chronic and debilitating symptoms of nOH 1. Kaufmann H, et al. Mov Disord. 2019;34(suppl 2). Poster presented at the 2019 International Congress of Parkinson’s and Movement 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. 15 |
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FDA-approved for the maintenance treatment of COPD First and only once-daily, nebulized maintenance medicine for COPD |
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YUPELRI® (revefenacin) inhalation solution FDA-approved for the maintenance treatment of COPD First and only once-daily, nebulized maintenance medicine for COPD Once-daily LAMAs are first-line therapy for moderate-to-very severe COPD1 9% of COPD patients (~800,000) use nebulizers for ongoing maintenance therapy; 41% use nebulizers at least occasionally for bronchodilator therapy2 TBPH and VTRS worldwide strategic collaboration to develop and commercialize nebulized YUPELRI® (revefenacin) TBPH 35% 65% Companies co-promote under US profit/loss share Global Strategy for Diagnosis, Management, and Prevention of COPD, 2018. TBPH market research (N = 160 physicians); refers to US COPD patients. COPD, chronic obstructive pulmonary disease; LAMA, long-acting muscarinic antagonist. 17 |
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See TBPH 10K filed February 26, 2021 for greater detail re TBPH implied 35%. 18 TBPH implied 35% of YUPELRI® US net sales by quarter TBPH Implied 35% of Total Net Sales ($M) $13.5 $12.9 $13.0 $12.9 $10.6 $10.4 $5.8 $3.2 14 12 10 8 6 4 2 0 Q2'19Q3'19Q4'19Q1'20Q2'20Q3'20Q4'20Q1'21 TBPH implied 35% of YUPELRI US net sales represents TBPH’s portion of the combined TBPH and VIATRIS net revenue |
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YUPELRI® hospital sales and community TRx trends Hospital LA-NEB Market Share* Hospital Market Share 20% 18% 16% 14% 12% 10% 8% 6% 8.0% 8.5% 7.0% 6.7% 5.8% 4% 3.5% 2.2% 2% 0% 1.1% 0.3% Q1'19 Q2'19 Q3'19 Q4'19 Q1'20 Q2'20 Q3'20 Q4'20 Q1'21 YUPELRI LA-NEB Market Share 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% Community Market Share with TRx 18.6% 17.5% 19.0% 15.3% Q1'19 Q2'19 Q3'19 Q4'19 Q1'20 Q2'20 Q3'20 Q4'20 Q1'21 Retail TRx YUPELRI LA-NEB Market Share Community LA-NEB Market Share** 1. Joint VTRS/TBPH Market Research. * Hospital LA-NEB Market Share - IQVIA DDD through 03/31/2021. ** Community LA-NEB Market Share - IQVIA XPO Excl. LTC (Retail) and SolutionsRx (DME / Med B FFS) through 1/31/2021 (Q1’21 Community LA-NEB Market Share Incomplete). *** Retail TRx Volume - Symphony Health METYS Prescription Dashboard through 3/31/2021. 19 Retail TRx Volume*** **Community LA-NEB Market Share includes Retail + DME / Med B FFS through January ’21 LA-NEB Market: YUPELRI, BROVANA, LONHALA, PERFOROMIST |
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11 YUPELRI 719 hospital accounts have ordered2 ?67% have ordered more than once 91% formulary win rate3 Highest number of formulary support presentations in Q1'21 since launch 74% commercial coverage4 Increasing New Patient Starts Continue to Drive LA-NEB Market Share Growth 1 Positive growth trends for YUPELRIcontinuing beyond March |
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Economic interest GSK’s TRELEGY ELLIPTA (FF/UMEC/VI): First and only once-daily single inhaler triple therapy |
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Economic interest in GSK’s TRELEGY Upward-tiering royalties of ~5.5–8.5% of worldwide net sales1 TRELEGY Asthma Approval TRELEGY Mortality Ad Comm BREO Asthma Approval TRELEGY TRELEGY 400 350 TRx Volume (Thousands) 250 200 150 100 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Month Post Launch Q1 net sales of $341MM Year-over-year sales growth of 37% from the same period in 2020 US sales ($238MM) benefited from new asthma indication approved and launched in Q3 2020 International and EU sales grew to $103M; asthma indication approved in Japan in Q4 2020 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 fluticasone furoate/umeclidinium/vilanterol; comprised of inhaled corticosteroid, long-acting muscarinic receptor antagonist, and long-acting β2 agonists, active components of Anoro (UMEC/VI). 22 ANORO ELLIPTAARNUITY ELLIPTABREO ELLIPTAINCRUSE ELLIPTA Launched in US in November 2017 Source: GSK, Symphony Health Metys monthly TRx data. Source: Symphony Health, Metys, September 2013 – March 2021, Monthly TRx Volume |
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First quarter 2021 financial highlights $210.0 million cash1 as of March 31, 2021 Three Months Ended March 31, Cash, cash equivalents and marketable securities. Amounts include share-based compensation. 23 |
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Commercial progress of YUPELRI® & GSK’s TRELEGY Q1 TOPLINE 2021 Multiple potential milestones & value-driving catalysts Q2RESULTS Q3 Q4 Nezulcitinib (TD-0903) Phase 2 (0188) COVID-19 Ampreloxetine SEQUOIA (0169) Phase 3 symptomatic nOH Izencitinib RHEA (0157) Phase 2b ulcerative colitis Q1‘22 Izencitinib DIONE (0173) Phase 2 Crohn’s disease 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 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. 24 |
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Rick E Winningham Chairman and Chief Executive Officer Andrew A. Hindman Senior Vice President, Chief Financial Officer Q&A Session Frank Pasqualone Senior Vice President, Chief Business Officer Richard A. Graham Senior Vice President, Development |
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Theravance Biopharm a®® Medicines That Make a Difference ® |
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1. TBPH market research (N=160 physicians); refers to US COPD patients. COPD, chronic obstructive pulmonary disease; LAMA, long-acting muscarinic antagonist. 27 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. |
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OATP, organic anion transporting polypeptide. 28 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 beta2-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 OATP1B1 and OATP1B3 inhibitors with YUPELRI is not recommended. YUPELRI is not recommended in patients with any degree of hepatic impairment. |
Exhibit 99.3
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Appendix May 4, 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. |
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Research and development portfolio of designed molecules: brain, lung, GI and eye Symptomatic nOH (Neurogenic orthostatic hypotension) COPD (chronic obstructive pulmonary disorder) — APPROVED CD (Crohn’s disease) UC DME (diabetic macular edema) Biology DMPK Asthma COVID-19 (ulcerative colitis) Celiac Disease Molecular Design Lung Transplant Rejection Medicinal Chemistry Development and Commercial DMPK, drug metabolism and pharmacokinetics; GI, gastrointestinal. 2 IPF (idiopathic pulmonary fibrosis) |
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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 |
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Leveraging respiratory expertise for potential acute treatment in response to a global pandemic PATIENT POPULATION >149M patients worldwide1 >32M US patients1 ~2.4% patients become hospitalized2 CURRENT US TREATMENT LANDSCAPE 3 vaccines available via Emergency Use Authorization3,4 1 approved treatment; 10 available via Emergency Use Authorization3,4 STRATEGIC OPPORTUNITY TD-0903 Inhaled lung-specific therapeutic: potential to be used in combination with other treatment modalities (e.g., antivirals) to provide additional therapeutic benefit with reduced risk of systemic immunosuppressive issues that may occur with systemic anti-inflammatories https://coronavirus.jhu.edu/map.html, number as of 4/29. 2. IHME. 3. https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap#dashboard 4. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#othercurrenteuas 4 |
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*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, standard of care, includes remdesivir, dexamethasone, anticoagulation. 5 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: SA, EUR, UK, USA Nezulcitinib 3 mg* + SOC (n=99) Placebo + SOC (n=99) Randomization Q2’21 Top-line results Double-blind once-daily nebulized treatment: 7 days Total observation: 28 days Objectives Primary: Number of respiratory-free days from randomization through Day 28 Secondary: tolerability, PK Exploratory: Clinical status, duration of hospitalization, repeat-dose safety |
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Potential for nezulcitinib to improve lung immune system balance across disease progression Asymptomatic or pre-symptomaticMild illnessModerate illnessSevere illnessCritical illnessCOVID 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 testDiagnostic testDiagnostic testDiagnostic test IsolationYesYesYesYesYes Proposed disease pathogenesis Viral replication Inflammation Potential treatment Antiviral therapy Antibody therapySystemic anti-inflammatory Prevent progression Nezulcitinib ongoing programAid lung recovery LRT, lower respiratory tract; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2. 6 |
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Nezulcitinib: Phase 2 study in hospitalized patients with COVID-19 requiring oxygen support Dose Finding Data 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: SA, EUR, UK, USA Nezulcitinib 10 mg + SOC Placebo + SOC Nezulcitinib 1 mg* + SOC Nezulcitinib 3 mg* + SOC Randomization Q1’21 Data Reported Double-blind once-daily nebulized treatment (n=25): 7 days Total observation: 28 days Objectives Primary: Repeat-dose safety, tolerability, PK, oxygenation and biomarkers Results Nezulcitinib was generally well-tolerated, with no drug-related SAEs Low, dose-dependent systemic exposure at all doses Positive trend vs placebo in improving clinical status, oxygenation and reducing hospital stay No deaths in nezulcitinib 3 and 10 mg cohorts vs 2 on placebo and 1 in 1 mg cohort *Loading dose (double the standard dose) administered on Day 1. NCT04402866 https://www.medrxiv.org/content/10.1101/2021.03.09.21252944v1 IMV, invasive mechanical ventilation; PK, pharmacokinetics; SAEs, serious adverse events; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; SOC, standard of care. 7 |
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https://www.medrxiv.org/content/10.1101/2021.03.09.21252944v1 CRP, C-reactive protein; IL, interleukin; PK, pharmacokinetics; RAGE, receptor for advanced glycation end-products; S/F ratio, ratio of oxygen saturation in the blood vs the flow of oxygen administered to the patient. 8 Overall conclusions from Nezulcitinib Phase 2 dose finding data Study 0188 |
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Nezulcitinib appears to stabilize clinical status within 7 days, compared to placebo Nezulcitinib showed a positive trend toward more clinical improvement 50% of placebo patients required mechanical ventilation by Day 6 100 Placebo Nezulcitinib 10 mg Nezulcitinib 1 mg Nezulcitinib 3 mg 7 6 5Hosp, requiring supplemental O2 % Patients Hosp, not requiring suppl O2, but 40(whether or not related to COVID-19) 3 2 1 0 1234567 123456712345671234567 Day Not hosp, no limitations on activities Placebo pooled from Cohorts 1–3. https://www.medrxiv.org/content/10.1101/2021.03.09.21252944v1 ECMO, extracorporeal membrane oxygenation; Hosp, hospitalized; Suppl, supplemental. 9 |
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Nezulcitinib shows numerical improvement in clinical status compared to placebo through 28 days 2 deaths on placebo and 1 death on 1 mg, but none on 3 and 10 mg groups More patients out of hospital and with no limitations by Day 28 with nezulcitinib than placebo 100 Placebo Nezulcitinib 10 mg Nezulcitinib 1 mg Nezulcitinib 3 mg 7 6 5Hosp, requiring supplemental O2 % Patients Hosp, not requiring suppl O2, but 40(whether or not related to COVID-19) 3 2 1 0 17142128 171421281714212817142128 Day Not hosp, no limitations on activities Placebo pooled from Cohorts 1–3. https://www.medrxiv.org/content/10.1101/2021.03.09.21252944v1 ECMO, extracorporeal membrane oxygenation; Hosp, hospitalized; Suppl, supplemental. 10 |
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Nezulcitinib lung-selective profile demonstrates low plasma exposure Day 7 steady-state exposures of nezulcitinib approximately dose proportional Initial loading dose on Day 1 for 1 mg and 3 mg doses in order to achieve near-steady-state exposures as quickly as possible Plasma exposures were low relative to estimated IC50 for systemic JAK inhibition Mean Nezulcitinib Plasma Concentration, ng/mL (SD) 100 10 1 0.1 0.01 0 Day 7 PK JAK protein-adjusted IC50 481224 Time (hr) 10 mg 3 mg 1 mg https://www.medrxiv.org/content/10.1101/2021.03.09.21252944v1 Hr, hour; IC50, inhibitory concentration at which 50% of JAK signaling is blocked; JAK, Janus kinase; PK, pharmacokinetics; SD, standard deviation. 11 |
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Nezulcitinib 3 mg showed positive trend in improving blood oxygenation versus placebo as measured by S/F Ratio 150 S/F Ratio Mean SaO2/FiO2 Ratio Change From Baseline (SEM) Nezulcitinib 3 mg 50 0 -50 Placebo -100 1 234567 Day Nezulcitinib 3 mg progressed to Phase 2 Part 2 with data expected Q2 2021 https://www.medrxiv.org/content/10.1101/2021.03.09.21252944v1 SEM, standard error of mean; S/F ratio, ratio of oxygen saturation in the blood vs the flow of oxygen administered to the patient. 12 |
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Nezulcitinib 3 mg reduces relevant systemic biomarkers 400 CRPIL-6 400 400 IL-10 400 Soluble RAGE % Difference in GM From BL (95% CI) 300 300 300 200 200 200 200 100 0 -100 41.0 -74.9 100 0 -100 -35.5 -80.2 100 0 -100 -24.0 -70.1 100 0 -100 -36.9 -83.0 -200 -200 -200 -200 Placebo Nezulcitinib 3 mg https://www.medrxiv.org/content/10.1101/2021.03.09.21252944v1 BL, baseline; CI, confidence interval; CRP, C-reactive protein; GM, geometric mean; IL, interleukin; RAGE, receptor for advanced glycation end-products. 13 |
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Ampreloxetine (TD-9855) Once-daily norepinephrine reuptake inhibitor to treat symptomatic neurogenic orthostatic hypotension |
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Reduced quality of life, significant caregiver burden and limited therapeutic options for symptomatic nOH patients PATIENT ~350K ~700K ~700K nOH is a symptom of MSA, PAF and PD 70–80% of MSA patients1, and POPULATIONUS patients APAC patients EU patients 30–50% of PD patients2 have nOH3 CURRENT TREATMENT Current treatments (midodrine, fludrocortisone, droxidopa) have significant limitations LANDSCAPE Subset of patients do not respond None demonstrate durable effect Safety profiles that limit use Require multiple daily dosing STRATEGIC OPPORTUNITY Ampreloxetine Designed to reduce symptoms of nOH by prolonging the effect of endogenous norepinephrine with the potential to provide a meaningful and durable symptom improvement to underserved patients Mathias C, et al. J Neurol 1999;246:893-8. Ha AD, et al. Parkinsonism Relat Disord 2011;17:625-8. Not all patients are treated with prescription medication.15 APAC, Asian and Pacific; MSA, multiple system atrophy; PAF, pure autonomic failure; PD, Parkinson's Disease; nOH, neurogenic orthostatic hypotension |
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Palma JA, Kaufmann H. Mov Disord Clin Pract 2017;4:298-308. NE, norepinephrine; NET, norepinephrine transporters; nOH, neurogenic orthostatic hypotension. 16 AXON TERMINAL NE DENDRITE Normal NE Release at Neurovascular Junction Systolic Blood Pressure Untreated nOH Vasodilation Normal Reduction in syncope Vasoconstriction Blood pressure Ampreloxetine Increased standing blood pressure Increased brain perfusion Reduce symptoms of symptomatic nOH1 + Ampreloxetine |
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Baseline OHSA #1 (Orthostatic Hypotension Symptom Assessment Question 1) >4 points. Negative change indicates improvement in symptoms; improvement of 1 point is defined as the MCID (minimal clinically important difference). nOH, neurogenic orthostatic hypotension; SD, standard deviation. 17 Ampreloxetine: Potential to provide meaningful and durable symptom improvement to underserved patients Ampreloxetine Phase 2 data in nOH; 20 weeks of treatment Efficacy Durability Withdrawal Considered clinically meaningful Mean (SD) change from baseline in OHSA #1 score 2 1 0 -1 -2 -3 -4 -5 -6 -7 04812162024 n=17n=13n=7n=6 Week |
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Ampreloxetine: Phase 3 registrational program Randomized, double-blind, placebo-controlled study Study 0169 Key inclusion criteria: Age >30 y with symptomatic nOH with OHSA #1 score ≥4 Countries: Australia, Canada, Europe, New Zealand, Russia, UK, US Ampreloxetine Placebo N=188 Randomization Q3’21 Efficacy Data Once-daily 10 mg oral dose: 4 weeks 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 Status Phase 3 registrational program ongoing All participants who complete Study 0169 are eligible for Study 0170 Note: Ampreloxetine Phase 3 registrational program is comprised of Studies 0169 and 0170; Study 171 safety data through week 26 will be included *Orthostatic Hypotension Symptom Assessment Question 1: negative change indicates improvement in symptoms; 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%. nOH, neurogenic orthostatic hypotension; OHDAS, orthostatic hypotension daily activities scale; OHSA, Orthostatic hypotension symptom assessment; PGI-C, patient global impression of change. NCT03750552 18 |
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Ampreloxetine: Phase 3 registrational program Placebo-controlled, randomized withdrawal study Study 0170 Key inclusion criteria: Age >30 y with symptomatic nOH with OHSA #1 score ≥4 Countries: Argentina, Australia, Canada, Europe, New Zealand, Russia, UK, US Ampreloxetine Ampreloxetine Placebo N=258 Randomization Q3’22 Top-line results Open-label once-daily 10 mg oral dose: 16 weeks Once-daily 10 mg oral dose: 6 week withdrawal phase 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 Status Phase 3 registrational program ongoing All participants who complete Study 0170 are eligible for Extension Study 0171 OHSA #1 OHSA composite score OHDAS composite score PGI-S % Time spent standing Average no. of steps taken *Negative change indicates improvement in symptoms; improvement of 1 point is defined as the MCID (minimal clinically important difference). Discontinuation rates for the Phase 3 trials as of Jan. 2020: 0170 – 33.3%. NCT03829657 nOH, neurogenic orthostatic hypotension; OHSA, orthostatic hypotension symptom assessment; PGI-S, patient global impression of disease severity. 19 |
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Ampreloxetine: Phase 3 registrational program 6-month safety study + 3-year optional extension Key inclusion criteria: patients who completed Study 0170 and, in investigator’s opinion, would benefit from long-term treatment with ampreloxetine Countries: Argentina, Australia, Canada, Europe, New Zealand, Russia, UK, US Ampreloxetine Study 0171 Q3’22 Top-line results* Once-daily oral dose: 182 weeks Primary endpoints Through Week 26: Physical and neurological exams Vital signs ECGs Clinical laboratory tests Concomitant medications AEs Treatment compliance Incidence of falls Changes from baseline in C-SSRS Status Includes patients who completed Study 0170 *Through week 26; for FDA filing NCT04095793 AE, adverse event; C-SSRS, Columbia Suicide Severity Rating Scale; ECG, electrocardiogram. 20 |
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Source: Theravance Biopharma Clinical Operations. 21 Global clinical trials are being decentralized along a continuum Traditional Trial Operations Decentralized Trial Site-centric operating model Burden on site resources Patient burden Patient-centric model Leverage technology for remote visits, monitoring and data collection Established home health and distribution channels |
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Ampreloxetine: has the potential to transform Theravance Biopharma into an independent commercial biopharma Established disease, targeted market A strong value proposition MSA, multiple system atrophy; PD, Parkinson’s disease; QoL, quality of life; snOH, symptomatic neurogenic orthostatic hypotension. 22 Established nOH treatment paradigm nOH is included in medical treatment guidelines for PD and MSA patients; once diagnosed, patients get on drug treatment quickly Manageable opportunity TBPH’s infrastructure capable of commercializing ampreloxetine in the US with limited and targeted additions to current resources Specialist networks in place A concentrated group of neurologists and cardiologists treat patients with nOH; ‘at risk’ patients already identified and managed by specialty institutions Understanding of current access barriers 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 An urgency to treat Physicians report high urgency to treat snOH due to the high impact on patients’ QoL, high risk of injury from falls and caregiver burden Established patient advocacy Strong message from PD and MSA advocacy groups that patients need new therapies to better manage nOH |
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Izencitinib (TD-1473/JNJ-8398) Oral gut-selective pan-JAK inhibitor to treat inflammatory bowel diseases |
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Need for new medicines to treat inflammatory bowel disease PATIENT POPULATION 6.8M $16B global cases, 20171 global IBD treatment market, 20185 1.6M $31B current US patients2 US disease burden2 Current US 780K CD cases3 patients 907K UC cases4 CURRENT TREATMENT LANDSCAPE Standard of care: Biologics have become the mainstay of treatment in moderate-to-severe patients Steroids, immunosuppressants, and TNF inhibitors associated with side effects that further decrease HRQoL STRATEGIC OPPORTUNITY Gut-selective agent: if used earlier in the course of disease, has Izencitinibpotential to be a new cost-effective therapy option that reduces associated disease management costs and improves patient HRQoL 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 CD, Crohn’s disease; HRQoL, health-related quality of life; IBD, inflammatory bowel disease; TNF, tumor necrosis factor; UC, ulcerative colitis. 24 |
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JAK-STAT pathway: orchestrating signaling of multiple pro-inflammatory cytokines αβγ JAK JAKJAK inhibitor STAT STAT STAT STAT STAT PInflammation NUCLEUS γc 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-35IFNγIL-12, IL-23 EPO, TPO GM-CSF, IL-3, IL-5 αβγ αβγ αβγ αβγ αβγ αβγ JAK1 JAK3 JAK1 Tyk2 JAK1 Tyk2 JAK2 JAK1 JAK2 JAK2 Tyk2 JAK2 JAK2 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 kinase; STAT, signal transducer and activator of transcription; TPO, thrombopoietin; Tyk, tyrosine kinase. 25 |
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Izencitinib: Phase 2 study in Crohn’s disease Izencitinib* N=160Izencitinib Late Q4’21 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 Countries: Africa, Asia, Australia, EU, Middle East, New Zealand, UK, USA Randomization Placebo results Ph 2 dose-finding induction: once-daily oral dose for 12 weeks Active treatment extension: once-daily oral dose for 48 weeks 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] Status Ongoing *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 Frequency and Abdominal Pain. 26 |
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Key inclusion criteria: Age ≥18 y with moderately-to-severely active UC with corticosteroid dependence or failure of conventional or biologic therapy Countries: Africa, Asia, Australia, EU, Middle East, North America, Japan Izencitinib* Izencitinib Placebo Placebo Study 0157 N=240 Q3’21 Ph 2b Induction Study data readout Ph 3 Induction Study starts after dose selection Responders from Ph 2b and Ph 3 Induction Ph 2b dose-finding induction: once-daily oral dose for 8 weeks Ph 3 maintenance: once-daily oral dose for 44 weeks Randomization Endpoints Primary: Change from baseline in tMS at Week 8 Secondary: Clinical remission by aMS components Status Ph 3 Maintenance ongoing *3 izencitinib doses. NCT03758443 aMS, adapted Mayo Score; tMS, total Mayo Score; UC, ulcerative colitis. 27 |
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Izencitinib: Phase 3 studies in ulcerative colitis Key inclusion criteria: Age ≥18 y with moderately-to-severely active UC with corticosteroid dependence or failure of conventional or biologic therapy Countries: Africa, Asia, Australia, EU, Middle East, North America, Japan Izencitinib Izencitinib Placebo Placebo N=640 Responders from Ph 2b and Ph 3 Induction Ph 3 Induction Study starts after dose selection from Ph 2b Induction Ph 3 dose-confirming induction: once-daily oral dose for 8 weeks Ph 3 maintenance: once-daily oral dose for 44 weeks Randomization Endpoints Primary: Induction & Maintenance: clinical remission by aMS components at Week 8 and mWeek 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 Status Phase 3 Induction study to begin post Phase 2b completion Phase 3 Maintenance study ongoing NCT03758443 aMS, adapted Mayo Score; mWeek, maintenance Week; UC, ulcerative colitis. 28 |
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NCT03758443 UC, ulcerative colitis. 29 Study 0164 Key inclusion criteria: Eligible patients from Ph 3 Maintenance Study of Protocol 0157 Countries: Africa, Asia, Australia, EU, Middle East, North America, Japan Izencitinib Long-term treatment 156 weeks (3 years) Endpoints Primary: –Assess the 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 |
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Pan-JAK inhibitors can prevent transplant rejections Noninferiority trial of tofacitinib vs cyclosporine (CsA) in kidney transplant recipients1 Tofacitinib is superior to CsA in efficacy measures Increased infection risk with tofacitinib over CsA Tofacitinib Acute Rejection First BPAR Rate (%) IF/TA (%) 10 5 0 Month 6 CsA Chronic Rejection * 40 30 20 10 0 Month 12 CMV diseaseSerious infection 53 24 25 5 12-month Kaplan-Meier estimates, % (SE) 40 20 0 TofacitinibCsA 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; TWC2, time-weighted 2-h post-dose concentrations. 30 JAK inhibition was superior to cyclosporine in prevention of acute and chronic rejections Serious infections increased with systemic JAK inhibitors including CMV |
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TD-8236 Potential first inhaled JAKi for asthma |
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High medical and economic burden in uncontrolled asthma PATIENT POPULATION 339M cases worldwide1 25M US cases 8% of adults 8% of children2 Moderate 1625 14 Severe* 61 Healthcare utilization3 ~$58B ~$15B US medical costs4 US asthma market (October 2020)5 CURRENT TREATMENT LANDSCAPE ICS + LABA (often fail to control disease) Approved biologics (affect subsets of patients) XOLAIR (omalizumab) NUCALA (mepolizumab) CINQAIR (reslizumab) FASENRA (benralizumab) DUPIXENT (dupilumab) Step-up for severe asthma: LTRAs, tiotropium, OCS, biologics JAK/STAT cytokines implicated in moderate-to-severe asthma Bold: biologics in development or approved. STRATEGIC OPPORTUNITY 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 *Asthma that requires high-dosage ICS + LABAs to prevent the disease from being uncontrolled) or asthma that remains uncontrolled 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. Nurmagambetov 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 |
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TD-8236: Phase 1 clinical trial design Parts A & B completed September 2019; Part C enrollment completed — data reported in Q4 2020 Part C: MoA Biomarkers (Moderate-to-severe asthmatics + ICS) 4500 µg All cohorts: N=6 active/2 Placebo N=16 active/8 placebo 1500 µg 1500 µg 50 µg 150 µg T2-dominant, n=8 Non-T2-dominant, n=8 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 and activator of transcription; SAD, single-ascending dose; T2, type 2; Th2, T helper type 2; TSLP, thymic stromal lymphopoietin. 33 Part B: MAD (Mild asthmatics) Safety, PK, PD (FeNO) D 1 2 3 4 5 6 7 4 0 00 µ g 1 5 00 µ g Goal: build confidence in compound, MoA and dose in early-development Endpoints: FeNO; pSTAT1 and pSTAT6 in bronchoalveolar lavage fluid; cytokines; epithelial gene expression ✓ 150 µg |
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FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroids; JAK, Janus kinase; PK, pharmacokinetic; PD, pharmacodynamic; pSTAT, phosphorylated signal transducer and activator of transcription; T2, type 2. 34 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 |
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No impact of TD-8236 on the Late Asthmatic Response (LAR) Significant reductions in inflammation marker (FeNO) and favorable safety and tolerability Late Asthmatic Response 150 µg 1500 µg Favors TD-8236 Favors Placebo Difference from Placebo, Liters (LS Means ± 95% CI) 0.2 Day 14Day 7 Favors Placebo Favors TD-8236 Difference from Placebo, % (LS Means ± 95% CI) 30 20 10 Day 14 0.0 -0.2 -0.4 -0.01 n=22 -0.04 n=20 0 -10 -20 -30 -40 -50 4.28 n=22 -20.16 n=24 -3.72 n=22 -26.87 n=23 Primary Endpoint: Weighted Mean Area Under the Curve, 3–8 h. CI, confidence interval; FeNO, fractional exhaled nitric oxide; LS, least-squares. 35 TD-8236 was generally well tolerated as a single-daily dose administered for 14 consecutive days |
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TD-8236 FeNO reductions consistent across Phase 1 and 2 150 µg 1500 µg Phase 1 (Part B) Mild Asthmatics Difference from Placebo (%) (LS Means ± 95% CI) Phase 2 (LAC) Mild Asthmatics Phase 1 (Part C) Moderate–Severe Asthmatics + ICS Day 7Day 7Day 14Day 7 30 20 10 4.28 0 -10 -20 -30 -40 -50 -7.65 n=6 -24.90 n=6 n=22 -20.16 n=24 -3.72 n=22 -26.87 n=23 Favors TD-8236 Favors Placebo n=8 CI, confidence interval; FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroids; LAC, lung allergen challenge; LS, least-squares. 36 FeNO reductions observed in moderate-to-severe asthmatics taking inhaled corticosteroids |
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TD-5202 Organ-gut selective irreversible JAK3 inhibitor to treat inflammatory intestinal diseases |
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Celiac disease has no current treatments and serious health consequences PATIENT1% 3.3M 2,3 4–4.5x >2x POPULATION Global prevalence1 US patients increase in US over past 50 y4 higher healthcare costs than controls5 CURRENT TREATMENT LANDSCAPE No approved treatment Normal Celiac STRATEGIC OPPORTUNITY TD-5202 Organ-gut selective irreversible JAK3 inhibitor: potential to deliver significant value for both patients and payers 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. Theravance Market Research. JAK, Janus kinase. 38 |
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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, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; Th1, T helper 1 cells. 39 IL-2 IL-21 CD Pathogenesis Gluten peptides IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 INTESTINAL LUMEN α β γ IE-CTL IEL INTESTINAL EPITHELIUM LAMINA PROPIA P JAK1 JAK3 IMMUNE CELL P IL-15 IFNγ P STAT NUCLEUS P P GLUTEN-SPECIFIC TH1 CELLS P P STAT STAT STAT STAT Localized JAK3 inhibition has the potential to avoid systemic immunosuppression (genetic JAK3 deficiency leads to severe immunodeficiency) |
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AE, adverse event; BID, twice daily; Cmax,ss, maximal steady-state concentration; ECG, electrocardiogram; IC50, inhibitory concentration at which 50% of JAK signaling is blocked; JAK, Janus kinase; IC50, 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 No serious or severe AEs were reported All treatment-emergent AEs in TD-5202-treated subjects were mild in severity 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 Systemic exposures were dose proportional from 100 to 1000 mg BID Low steady-state systemic exposures: mean Cmax,ss ~11-fold below the protein-adjusted JAK IC50 at the highest tested dose (1000 mg BID), consistent with a gut-selective approach |
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Inhaled ALK5i Potential best-in-disease therapy for the treatment of idiopathic pulmonary fibrosis (IPF) |
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Idiopathic pulmonary fibrosis (IPF) remains a fatal chronic lung disease with limited treatment options PATIENT POPULATION 140,000 US prevalence; currently orphan disease1,2 Profound dyspnea, unrelenting cough, impairment of activities of daily living Mortality with IPF remains high Lungs with IPF3 CURRENT TREATMENT LANDSCAPE Limited treatment options 2 currently approved therapies, with modest efficacy and poor tolerability STRATEGIC OPPORTUNITY 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 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 |
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Significant opportunity remains for effective IPF treatments Male Female Probability of Survival 0.6 0.4 0.2 0.0 051015 Goal To arrest disease progression with improved tolerability Mortality with IPF remains high –<50% alive 3 years after diagnosis1 1. King TE, et al. Am J Respir Crit Care Med 2001;164:1171-81. IPF, idiopathic pulmonary fibrosis. 43 |
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Targeting the TGFβ pathway A core signaling pathway that drives fibrosis Normal TYPE 2 TYPE 1 ALVEOLAR EPITHELIAL CELLS (AEC) AEC damage Stimuli Genetic susceptibility Repetitive injury Fibrogenesis, proliferation TGFβ Collagen deposition MYOFIBROBLASTS SCARRING TISSUES TGFβ, transforming growth factor β. 44 |
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Adapted from: Neuzillet C, et al. Oncotarget 2013;5:78–94. αSMA, α-smooth muscle actin; ERK, extracellular signal-regulated kinase; IPF, idiopathic pulmonary fibrosis; JNK, c-Jun N-terminal kinase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; Smad2/3, mothers against decapentaplegic homolog 2/3; TGFR (ALK5), transforming growth factor receptor. 45 TGFR2 TGFR1 (ALK5) Selectively targeting the TGFβ pathway through ALK5 inhibition FIBROBLASTS Latent TGFβ Activation: Multiple ; integrins Proteases Thrombospondin Free Radicals Fibroblast to Myofibroblast Transition (FMT) Increased extracellular matrix Increased SMA Increased migration IPF progression P P ALK5i MYOFIBROBLASTS ERK PI3K Smad2/3 p38 JNK Rho |
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ALK5i, transforming growth factor β receptor I kinase inhibitor; αSMA, α-smooth muscle actin; FMT, fibroblast to myofibroblast transition. 46 % inhibition of αSMA FMT Negative control SMA expressed ALK5i treated SMA reduced Reference Standard ALK5i 150 100 50 0 -9 -8 -7 Log [M] -6 -5 |
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https://www.tga.gov.au/sites/default/files/auspar-nintedanib-esilate-160208.pdf. Ogura T, et al. Eur Respir J. 2015;45:1382-92. Cmax, maximal concentration; FMT, fibroblast to myofibroblast transition; IC50, half maximal inhibitory concentration. 47 Clinical Cmax Unbound1,2 Nintedanib IC50 Pirfenidone IC50 Pirfenidone -10-9-8-7-6-5-4-3-2-10 Log [M] |
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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 Minimizing systemic inhibition of a cytokine essential for homeostasis Inhaled ALK5i Maintaining key systemic regulatory roles of TGFβ Wound repair Bone healing Cardiovascular homeostasis Tumor suppression Endocrine function |
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Ocular JAKi Potential best-in-disease, pan-JAK inhibitor with long-acting ocular anti-inflammatory activity |
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140% PATIENT million#1 cause of higher direct and indirect healthcare costs blindness in US prevalence1 diabetes2 in patients with DME vs diabetics without ocular disease3 Normal vision Vision with DME CURRENT TREATMENT 1st Anti-VEGF treatments Most patients have suboptimal response LANDSCAPE 2nd Intraocular steroids Side effects limit utility STRATEGIC OPPORTUNITY Ocular JAKi Potential to offer an alternative treatment for DME patients who are not optimally responding to treatment with VEGFi © 2016 DR/Decision Resources, LLC. All rights reserved. Reproduction, distribution, transmission or publication is prohibited. Reprinted with permission. 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 Nonpharmacological treatments (e.g. laser coagulation) limited efficacy and significant adverse events |
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1. Gonzalez VH, et al. Am J Ophthalmol 2016;172:72-79. DME, diabetic macular edema; VEGF, vascular endothelial growth factor. 51 Hyperglycemia Disruption of blood-retinal barrier Retinal capillary damage VEGF Inflammatory cytokines Intraocular anti-VEGF agents One third do not respond to anti-VEGF while another third have a suboptimal response1 Require frequent intravitreal injections Vascular leakage Need for broad, sustained release, anti-inflammatory with a safer side-effect profile DME |
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Unmet need for an anti-inflammatory drug: opportunity for eye-selective JAK inhibition 1.25 Effect of anti-VEGFEffect of Steroids VEGF IL-6 IP-10 MCP-1 Normalized Protein Level 1.00 0.75 0.75 0.50 0.50 0.25 0.25 0.00 0.00 VEGFIL-6IP-10MCP-1 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 UntreatedTreated |
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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 activator of transcription; Tyk, tyrosine kinase; VEGF, vascular endothelial growth factor. 53 IL-6 Interferons JAK1 JAK2 JAK1 Tyk2 TD-Eye JAKi MCP-1 IP-10 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 |
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JAK, Janus kinase. 54 STAT STAT STAT STAT STAT Compound concentration (g/mL or g/g ) α βγ JAK JAK JAKi P P P P NUCLEUS Single intravitreal injection of TD-Eye JAKi in Rabbits 1000 100 10 Vitreous humor (depot) 1 Retina 0.1 0.01 0.001 0.0001 Plasma 0.00001 0.000001 0123 Time (months) |