Theravance Biopharma Stock

Theravance Biopharma, Inc. operates as a biopharmaceutical company primarily focused on the discovery, development, and commercialization of medicines.

Core Program Updates

YUPELRI (revefenacin) Inhalation Solution

UPELRI (revefenacin) inhalation solution is a once-daily, nebulized long-acting muscarinic antagonist (LAMA) approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in the U.S. Long-Acting Muscarinic Antagonist (LAMAs) are recognized by international COPD treatment guidelines as a cornerstone of maintenance therapy for COPD, regardless of severity of disease.

The company’s market research indicates there is an enduring population of COPD patients in the U.S. that either need or prefer nebulized delivery for maintenance therapy. The stability of revefenacin in both metered dose inhaler and dry powder inhaler (MDI/DPI) formulations suggests that revefenacin could also serve as a foundation for novel handheld combination products.

The company co-developed YUPELRI with its collaboration partner, Viatris Inc. Under the terms of the Viatris Development and Commercialization Agreement (the Viatris Agreement), it led the U.S. Phase 3 development program for YUPELRI in COPD, and Viatris was responsible for reimbursement of its costs related to the registrational program up until the approval of the first new drug application, after which costs were shared. YUPELRI was approved by the United States (U.S.) Food and Drug Administration (the FDA) for the maintenance treatment of patients with COPD in November 2018.

In the U.S., Viatris is leading the commercialization of YUPELRI, and the company co-promotes the product under a profit and loss sharing arrangement (65% to Viatris; 35% to it). Outside the U.S. (excluding China and adjacent territories), Viatris is responsible for development and commercialization and will pay the company a tiered royalty on net sales at percentage royalty rates ranging from low double-digits to mid-teens. The company retains worldwide rights to revefenacin delivered through other dosage forms, such as a metered dose inhaler and dry powder inhaler (MDI/DPI).

In June 2019, the company announced the expansion of the Viatris Agreement to grant Viatris exclusive development and commercialization rights to nebulized revefenacin in China and adjacent territories, which include Hong Kong SAR, the Macau SAR, and Taiwan.

In August 2021, the company announced that in collaboration with its partner Viatris, the company is 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 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. In the future, this study could also be used to support promotional efforts for YUPELRI, which could aid in the capture of more of YUPELRI’s addressable market. The company has agreed to pay 35% of the Phase 4 study costs, and Viatris has agreed to pay 65% of the Phase 4 study costs. In January 2022, the company announced the enrollment of the first patient in the Phase 4 study.

Since March 2020, YUPELRI’s growth trajectory has been impacted by the COVID-19 respiratory pandemic. However, in late 2021, the company began to observe more sustained growth in YUPELRI sales. The company continues to monitor external factors that are associated with the current healthcare market which may be impacting demand for YUPELRI due to the ongoing COVID-19 pandemic, including the return of customer orders to pre-pandemic utilization levels and the duration of use.

Ampreloxetine (TD-9855)

Ampreloxetine is an investigational, once-daily norepinephrine reuptake inhibitor (NRI) that the company is developing for the treatment of patients with Multiple System Atrophy (MSA) and symptomatic neurogenic orthostatic hypotension (nOH). nOH is caused by primary autonomic failure conditions and the majority of patients with MSA experience symptoms of nOH. Ampreloxetine has high affinity for binding to the norepinephrine (NE) transporter. By blocking the action of the NE transporter, ampreloxetine causes an increase in extracellular concentrations of norepinephrine. Ampreloxetine is wholly owned by the company.

Based on positive results from a small exploratory Phase 2 study in nOH and discussions with the FDA, the company advanced ampreloxetine into a Phase 3 program. The company announced the initiation of patient dosing in study in early 2019. The Phase 3 program consisted of two pivotal studies and one non-pivotal study. The first pivotal study (SEQUOIA), a four-week, randomized double-blind, placebo-controlled study, was designed to evaluate the efficacy and safety of ampreloxetine in Parkinson’s disease (PD), pure autonomic failure (PAF) and MSA patients with symptomatic nOH. The second pivotal study (REDWOOD), a four-month open label study followed by a six-week randomized withdrawal phase was designed to evaluate the durability of the same patient groups response to ampreloxetine. The protocol for the pivotal studies stipulated an enrollment threshold of 40% MSA patients based on the hypothesis ampreloxetine would work the best in patients with MSA because they have more intact nerves on which ampreloxetine can exert its effect, relative to the other patient types in the study. The third, non-pivotal study (OAK), was designed to allow patients who completed REDWOOD to have continued access to ampreloxetine for up to three and half years.

In September 2021, the company reported that the SEQUOIA Phase 3 clinical study did not meet its primary endpoint. Most treatment-related adverse events were mild or moderate in severity. Serious adverse events occurred in two patients on placebo and four on ampreloxetine and none of which were considered related to the study drug. No deaths were reported, and there was no signal for supine hypertension.

In April 2022, the company reported that the REDWOOD Phase 3 clinical study did not meet its primary endpoint as the results were not statistically significant for the overall population of patients which included patients with PD, PAF, and MSA. The pre-specified subgroup analysis by disease type suggested that the average benefit seen in patients receiving ampreloxetine was largely driven by a benefit to MSA patients. The benefit to MSA patients in the study was observed in multiple endpoints, including Orthostatic Hypotension Symptom Assessment Scale (OHSA) composite, Orthostatic Hypotension Daily Activities Scale (OHDAS) composite, Orthostatic Hypotension Questionnaire (OHQ) composite and OHSA #1. Throughout the study, there was no indication of worsening of supine hypertension among any of the patient sub-groups. Data suggest that ampreloxetine was well-tolerated and no new safety signals were identified among any of the patient sub-groups.

In June 2022, the company held a Type C meeting with the FDA. From this meeting, it aligned on a path to an NDA filing with one additional Phase 3 clinical study in MSA patients with symptomatic nOH, using the OHSA composite score as the primary endpoint. The company expects this additional Phase 3 study to begin enrolling in first quarter of 2023.

Licensed Programs

Skin-selective Pan-JAK inhibitor Program

In December 2019, the company entered into a global license agreement with Pfizer Inc. (Pfizer) for its preclinical skin-selective, locally acting pan-JAK inhibitor program (the Pfizer Agreement). The compounds in this program are designed to target validated pro-inflammatory pathways and are specifically designed to possess skin-selective activity with minimal systemic exposure.

Under the Pfizer Agreement, Pfizer has an exclusive license to develop, manufacture and commercialize certain compounds for all uses other than gastrointestinal, ophthalmic, and respiratory applications.

Selective 5-HT4 Agonist (TD-8954)

TD-8954 is a selective 5-HT4 receptor agonist that was being developed for potential use in the treatment of gastrointestinal motility disorders. Pursuant to a License and Collaboration Agreement that the company executed in June 2016 with Millennium Pharmaceuticals, Inc., an indirect wholly-owned subsidiary of Takeda Pharmaceutical Company Limited (Takeda), Takeda conducted a Phase 2 study of TD-8954 as a potential treatment for post-operative gastrointestinal dysfunction. The Phase 2 study did not meet its endpoints, and the company mutually agreed with Takeda to discontinue further development of this program and the Collaboration Agreement in February 2023.

Economic Interests and Other Assets

Mid- and Long-Term Economic Interest in GSK-Partnered Respiratory Programs

On July 20, 2022, the company completed the sale of all of its equity interests in TRC representing its 85% economic interest in the sales-based royalty rights on worldwide net sales of GSK's TRELEGY to Royalty Pharma.

TRELEGY (the combination of fluticasone furoate/umeclidinium bromide/vilanterol)

TRELEGY provides the activity of an inhaled corticosteroid (FF) plus two bronchodilators (Umeclidinium, a LAMA, and VI, a long-acting beta2 agonist, or LABA) in a single delivery device administered once-daily. TRELEGY is approved for use in the U.S., European Union (EU), and other countries for the long-term, once-daily, maintenance treatment of patients with COPD. Additionally, the FDA approved an sNDA for the use of TRELEGY to treat asthma in adults in September 2020 making TRELEGY the first once-daily single inhaler triple therapy for the treatment of both asthma and COPD in the U.S. GSK has obtained approval for the asthma indication in ten additional markets. TRELEGY is expected to generate global peak sales of $3.5 billion annually according to consensus estimates.

Velusetrag (TD-5108)

Velusetrag is an oral, investigational medicine developed for gastrointestinal motility disorders. It is a highly selective agonist with high intrinsic activity at the human 5-HT4 receptor.

On June 30, 2022, the company entered into an Asset Purchase Agreement (APA) to sell all of its velusetrag assets to Alfasigma S.p.A. (Alfasigma).

Development Projects

The company’s development projects are prioritized by those with the highest expected potential value. The company’s enhanced focus remains on near-term value opportunities which include driving YUPELRI growth and conducting a new FDA-aligned ampreloxetine Phase 3 study. On February 27, 2023, the company announced the decision to discontinue research activities, including its inhaled JAK program. This includes nezulcitinib, a nebulized, lung-selective JAK inhibitor positioned for the treatment of acute and chronic lung diseases.

Strategy

The company’s focus is to deliver medicines that make a difference in people's lives. In pursuit of its purpose, the company leverages decades of expertise, which has led to the development of FDA-approved YUPELRI (revefenacin) inhalation solution indicated for the maintenance treatment of patients with COPD. Ampreloxetine, the company’s late-stage investigational norepinephrine reuptake inhibitor in development for symptomatic nOH, has the potential to be a first in class therapy effective in treating a constellation of cardinal symptoms in MSA patients.

The key elements of the company’s strategy are to focus on insight and innovation; outsource non-core activities; create and foster an integrated environment; and aggressively manage uncertainty.

Patents and Proprietary Rights

As of December 31, 2022, the company owned a total of 235 issued US patents and 1,491 granted foreign patents, as well as additional pending US patent applications and foreign patent applications. The claims in these various patents and patent applications are typically directed to compositions of matter, including claims covering product candidates, crystalline forms, lead compounds and key intermediates, pharmaceutical compositions, methods of use and/or processes for making its compounds. The company’s patents and patent applications are also directed to other inventions made during the research and development process. In particular, its wholly-owned subsidiary Theravance Biopharma R&D IP, LLC owns the following US patents that are listed in the FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) for YUPELRI (revefenacin) inhalation solution: US Patent No. 7,288,657, expiring on December 23, 2025; US Patent No. 7,491,736, expiring March 10, 2025; US Patent No. 7,521,041, expiring March 10, 2025; US Patent No. 7,550,595, expiring March 10, 2025; US Patent No. 7,585,879, expiring March 10, 2025; US Patent No. 7,910,608, expiring March 10, 2025; US Patent No. 8,034,946, expiring March 10, 2025; US Patent No. 8,053,448, expiring March 10, 2025; US Patent No. 8,273,894, expiring March 10, 2025; US Patent No. 8,541,451, expiring August 25, 2031; US Patent No. 9,765,028, expiring July 14, 2030; US Patent No. 10,106,503, expiring March 10, 2025; US Patent No. 10,343,995, expiring March 10, 2025; US Patent No. 10,550,081, expiring July 14, 2030; US Patent No. 11,008,289, expiring July 14, 2030; US Patent No. 11,247,969, expiring March 10, 2025; and US Patent 11,484,531, expiring October 23, 2039 (each of the aforementioned expiration dates not including any patent term extensions that may be available under the Drug Price Competition and Patent Term Restoration Act of 1984). Thus, the last to expire patent listed in the Orange Book for YUPELRI (revefenacin) inhalation solution expires on October 23, 2039. On December 19, 2018, the company filed patent term extension (PTE) applications in the US Patent and Trademark Office (USPTO) for US Patent Nos. 7,288,657 and 7,585,879. These PTE applications are pending and, if granted, the company will be permitted to extend the term of one of these patents for the period determined by the USPTO.

Issued US and foreign patents generally expire 20 years after their filing date. The patent rights relating to YUPELRI (revefenacin) inhalation solution consist of issued US patents, pending US patent applications and counterpart patents and patent applications in a number of jurisdictions, including Europe.

Additionally, some of the company’s patents and patent applications directed to products in development. The company’s patent rights relating to ampreloxetine include an issued US composition of matter patent that expires in 2030 and an issued US method of treatment patent that expires in 2037 (in each case, not including any patent term extensions that may be available under the Drug Price Competition and Patent Term Restoration Act of 1984). The company’s patent rights relating to nezulcitinib include an issued US composition of matter patent that expires in 2039 (not including any patent term extensions that may be available under the Drug Price Competition and Patent Term Restoration Act of 1984). The patent portfolios for these development products include additional pending patent applications and granted patents in a number of jurisdictions. Nevertheless, issued patents can be challenged, narrowed, invalidated, or circumvented, which could limit its ability to stop competitors from marketing similar products and threaten its ability to commercialize its product candidates. The company’s patent position, similar to other companies in its industry, is generally uncertain and involves complex legal and factual questions.

During January 2023, the company received notice from Accord Healthcare, Inc.; Cipla USA, Inc. and Cipla Limited; Eugia Pharma Specialties Ltd.; Lupin Inc.; Mankind Pharma Ltd.; Orbicular Pharmaceutical Technologies Private Limited; and Teva Pharmaceuticals, Inc. (collectively, the generic companies), that they have each filed with FDA an ANDA, for a generic version of YUPELRI. The notices from the generic companies each included a Paragraph IV certification with respect to five of its patents listed in FDA’s Orange Book for YUPELRI. The asserted patents relate generally to polymorphic forms of and a method of treatment using YUPELRI. In February 2023, the company filed patent infringement suits against the generic companies in federal district courts, including the United States District Court for the District of New Jersey, the U.S. District Court for the District of Delaware, and the U.S. District Court for the Middle District of North Carolina. The complaint alleges that by filing the ANDAs, the generic companies have infringed five of its Orange Book listed patents. The company is seeking a permanent injunction to prevent the generic companies from introducing a generic version of YUPELRI that would infringe its patents. As a result of this lawsuit, a stay of approval through May 2026 will be imposed by FDA on the generic companies’ ANDAs pending any adverse court decision.

Competition

For the treatment of COPD, Trelegy competes in all major markets with AstraZeneca’s Breztri Aerosphere (budesonide/glycopyrronium/formoterol fumarate, dosed twice per day). Trimbow (beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide, dosed twice per day) from Chiesi Farmaceutici is an additional COPD competitor in Europe.

For the treatment of asthma, TRELEGY is the only triple therapy approved in the U.S. and competes in Japan with Novartis’s Enerzair Breezhaler (indacaterol acetate, glycopyrronium bromide and mometasone furoate, dosed once daily).

In both COPD and asthma, TRELEGY also competes with open triple therapy, which can be accomplished by the concurrent use of two or three products. An example of such use includes a LABA/ICS combination such as AstraZeneca’s Symbicort and a LAMA, such as Boehringer Ingelheim’s Spiriva.

Sale of Theravance Respiratory Company, LLC

In July 2022, the company completed the sale of all of its equity interests in Theravance Respiratory Company, LLC (TRC) representing its 85% economic interest in the sales-based royalty rights on worldwide net sales of GSK's TRELEGY ELLIPTA (TRELEGY) to Royalty Pharma Investments 2019 ICAV (Royalty Pharma).

Government Regulation

Before commencing clinical studies in humans in the U.S., the company must submit to the FDA an investigational new drug application (IND) that includes among other things, the general investigational plan and protocols for specific human studies and the results of preclinical studies. The Patient Protection and Affordable Care Act, as amended (the Healthcare Reform Act), substantially changed the way healthcare is financed by both governmental and private insurers; and impacts pricing and reimbursement of YUPELRI and the marketed drugs with respect to which the company is entitled to royalty or similar payments, and related commercial operations.

History

Theravance Biopharma, Inc. was incorporated in the Cayman Islands in 2013.