Innoviva Profile
Innoviva, Inc. (Innoviva), together with its subsidiaries, has a portfolio of royalties and innovative healthcare assets. The company has three primary sets of assets: a royalty portfolio, operating assets in critical care and infectious disease, and other strategic healthcare assets.
The company's royalty portfolio contains respiratory assets partnered with Glaxo Group Limited ('GSK'), including RELVAR/BREO ELLIPTA (fluticasone furoate/vilanterol, 'FF/VI') and ANORO ELLIPTA (umeclidinium bromide/vilanterol, 'UMEC/VI').
The company expanded its portfolio through the acquisition of Entasis Therapeutics Holdings Inc. ('Entasis') on July 11, 2022 and the acquisition of La Jolla Pharmaceutical Company ('La Jolla') on August 22, 2022. The company's commercial and marketed products include GIAPREZA (angiotensin II), approved in the United States ('U.S.') to increase blood pressure in adults with septic or other distributive shock, and XERAVA (eravacycline) approved in the U.S. for the treatment of complicated intra-abdominal infections in adults. On May 23, 2023, XACDURO (formerly known as sulbactam-durlobactam or SUL-DUR), was approved by the United States Food and Drug Administration ('FDA') and the company commenced commercial sales of XACDURO in the third quarter of 2023. The company's development pipeline includes zoliflodacin, an investigational treatment for uncomplicated gonorrhea that reported positive data in a pivotal Phase 3 clinical trial on November 1, 2023. As such, the company has a wholly owned robust critical care and infectious disease operating platform with a hospital focus anchored by three differentiated products with significant growth potential and a promising drug candidate.
In addition, the company owns other strategic healthcare assets, such as a large equity stake in Armata Pharmaceuticals, Inc., a leader in the development of bacteriophages with potential use across a range of infectious and other serious diseases. The company also has economic interests in other healthcare companies.
Strategy
The company's strategy is focused on increasing stockholder value by, among other things, maximizing the potential value of the company's respiratory assets partnered with GSK, creating value through the company's critical care and infectious disease platform, and optimizing the company's operations. The company continues to diversify its royalty management business through actively pursuing opportunistic acquisitions of promising companies and assets in the healthcare industry and enhancing the returns on the company's capital.
Royalty Product Portfolio
Relationship with GSK
LABA Collaboration
In November 2002, the company entered into its LABA Collaboration Agreement with GSK to develop and commercialize once-daily products for the treatment of chronic obstructive pulmonary disease ('COPD') and asthma. The collaboration has developed three combination products, two of which the company still retain rights in. Those two are as follows:
RELVAR/BREO ELLIPTA ('FF/VI') (BREO ELLIPTA is the proprietary name in the U.S. and Canada and RELVAR ELLIPTA is the proprietary name outside the U.S. and Canada), a once-daily combination medicine consisting of a LABA, vilanterol ('VI'), and an inhaled corticosteroid ('ICS'), fluticasone furoate ('FF'); and
ANORO ELLIPTA ('UMEC/VI'), a once-daily medicine combining a long-acting muscarinic antagonist ('LAMA'), umeclidinium bromide ('UMEC'), with a LABA, VI.
Integrated Critical Care / Infectious Disease Assets
Commercial and Marketed Products
The company's critical care and infectious disease portfolio was formed through the 2022 acquisitions of Entasis and La Jolla. It comprises three differentiated commercial stage products and a pipeline.
GIAPREZA (angiotensin II)
GIAPREZA (angiotensin II) injection is approved by the U.S. FDA as a vasoconstrictor indicated to increase blood pressure in adults with septic or other distributive shock. GIAPREZA is approved by the European Commission ('EC') and by the Great Britain Medicines and Health Care Products Regulatory Agency ('MHRA') for the treatment of refractory hypotension in adults with septic or other distributive shock who remain hypotensive despite adequate volume restitution and application of catecholamines and other available vasopressor therapies. GIAPREZA mimics the body's endogenous angiotensin II peptide, which is central to the renin-angiotensin-aldosterone system ('RAAS'), which in turn regulates blood pressure. GIAPREZA is marketed in the U.S. by La Jolla and is marketed in Europe and Great Britain by PAION Deutschland GmbH on behalf of La Jolla. PAION AG and PAION Deutschland GmbH (together and individually 'PAION') filed for insolvency in Germany on October 27, 2023 and the insolvency proceedings were opened on January 1, 2024. PAION announced on December 22, 2023 that it concluded negotiations with Humanwell Healthcare Group and entered into an agreement on the sale of the essential business operations of PAION AG and PAION Deutschland GmbH with the approval of the insolvency administrator in both procedures. La Jolla did not oppose the sale and is in discussions with the acquirer regarding the continued business relationship.
Angiotensin II for the Treatment of High-Output Shock ('ATHOS-3')
GIAPREZA was approved by the U.S. FDA, EC and MHRA based on the results of ATHOS-3, which were published in the New England Journal of Medicine in August 2017. ATHOS-3 was a multinational, randomized, double-blind, placebo-controlled study in which 321 adults with septic or other distributive shock who remained hypotensive despite fluid and vasopressor therapy received either GIAPREZA or placebo, both in addition to background vasopressor therapy. The primary endpoint was mean arterial pressure ('MAP') response, defined as a MAP of 75 mm Hg or higher or an increase in MAP from baseline of at least 10 mm Hg without an increase in the dose of background vasopressors at Hour 3 (Khanna et al, New England Journal of Medicine 2017; 377:419-430).
GIAPREZA provides the ability to rapidly achieve and adjust therapeutic response. GIAPREZA rapidly increased MAP with a median time to MAP response of approximately 5 minutes. The plasma half-life of GIAPREZA is less than 1 minute.
XERAVA (eravacycline)
XERAVA (eravacycline) for injection is approved by the U.S. FDA and Singapore Health Sciences Authority ('HSA') as a tetracycline class antibacterial indicated for the treatment of cIAI due to susceptible microorganisms in patients 18 years of age and older. XERAVA is approved by the EC, MHRA, and the Hong Kong Department of Health ('DoH') for the treatment of cIAI in adults. XERAVA is marketed in the U.S. by the company's wholly owned subsidiary, Tetraphase Pharmaceuticals, Inc. ('Tetraphase'), and is marketed in Europe and Great Britain by PAION on behalf of Tetraphase and is marketed in mainland China, Taiwan, Hong Kong, Macau, South Korea, Singapore, the Malaysian Federation, the Kingdom of Thailand, the Republic of Indonesia, the Socialist Republic of Vietnam and the Republic of the Philippines by Everest Medicines Limited ('Everest').
cIAIs are the second most common source of severe sepsis in the ICU cIAIs are defined as consequences of perforations of the gastrointestinal tract that result in contamination of the peritoneal space.
Investigating Gram-negative Infections Treated with Eravacycline ('IGNITE')
XERAVA was approved by the U.S. FDA, HSA, EC, MHRA, and DoH based on the results of IGNITE1 and IGNITE4, which were published in JAMA Surgery in March 2017 and Clinical Infectious Diseases in December 2018, respectively.
IGNITE1 was a multinational, randomized, double-blind, active-controlled study in 538 patients with clinical evidence of cIAIs requiring urgent surgical or percutaneous intervention who received either XERAVA or ertapenem. The primary endpoint was clinical cure, defined as complete resolution or significant improvement of signs or symptoms of the index infection, at the test of cure ('TOC') visit. The TOC visit was conducted 25 to 31 calendar days after the first dose of the study drug was administered.
IGNITE4 was a multinational, randomized, double-blind, active controlled study in 499 patients with clinical evidence of cIAIs requiring urgent surgical or percutaneous intervention who received either XERAVA or meropenem. The primary endpoint was clinical cure, defined as complete resolution or significant improvement of signs or symptoms of the index infection, at the TOC visit. The TOC visit was conducted 25 to 31 calendar days after the first dose of the study drug was administered.
XERAVA demonstrated statistical noninferiority in clinical cure rate in the micro-ITT population, which included all randomized subjects who had baseline bacterial pathogens that caused cIAIs and against at least one of which the investigational drug has in vitro (in a test tube) antibacterial activity (N=846).
XACDURO
XACDURO (sulbactam for injection; durlobactam for injection), co-packaged for intravenous use (formerly known as sulbactam-durlobactam or SUL-DUR), was approved by the United States Food and Drug Administration ('FDA') on May 23, 2023, and the company commenced commercial sales of XACDURO in the third quarter of 2023. XACDURO is a novel IV antibiotic. The product is a combination of sulbactam, a beta-lactam antibiotic, and durlobactam, a novel beta-lactamase inhibitor ('BLI') with broad spectrum beta-lactamase coverage, including Classes A, C and D, that was specifically developed for the treatment of a variety of serious infections caused by carbapenem-resistant Acinetobacter. XACDURO is addressing a large unmet medical need in treating patients with serious Acinetobacter infections who prior to this launch have had few options for effective treatment.
Acinetobacter Treatment Trial Against Colistin ('ATTACK')
The company completed ATTACK, a Phase 3 registration trial of XACDURO for the treatment of patients with carbapenem-resistant Acinetobacter infections, with positive top-line data announced in October 2021 and published in The Lancet Infectious Diseases in May 2023. ATTACK enrolled 207 patients at 95 clinical sites in 16 countries. This was a two-part trial with Part A being the randomized, comparative portion (XACDURO vs colistin) in patients with documented Acinetobacter hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VAPB), ventilated pneumonia (VP), or bacteremia, and Part B being an open-labeled portion, including Acinetobacter infections resistant to, or having previously failed colistin or polymyxin B treatment. Baseline Acinetobacter isolates tested were greater than 95% carbapenem resistant.
XACDURO met the primary efficacy endpoint of 28-day all-cause mortality compared to colistin in the CRABC m-MITT population of Part A. XACDURO mortality was 19.0% (12/63) compared to 32.3% (20/62) in the colistin arm (treatment difference of -13.2%; 95% CI: -30.0, 3.5). Similar trends were demonstrated in 28-day and 14-day all-cause mortality favoring XACDURO across all study populations evaluated to date. A statistically significant difference in clinical cure at Test of Cure (TOC) was observed with 61.9% in the XACDURO arm compared to 40.3% in the colistin arm (95% CI 2.9-40.3). In Part B, the 28-day all-cause mortality was 17.9% (5/28) and consistent with that observed in Part A.
Safety analyses from a total of 177 patients treated with XACDURO suggested that XACDURO was generally well-tolerated with a favorable safety profile compared to colistin. XACDURO met the primary safety objective with a statistically significant lower incidence of nephrotoxicity as measured by the RIFLE classification for acute kidney injury. XACDURO nephrotoxicity was 13.2% (12/91) versus 37.6% (32/85) in the colistin arm (p = 0. 0002). Overall adverse events (AEs) in the safety population were comparable between treatment groups with 87.9% (80/91) in the XACDURO arm vs. 94.2% (81/86) in the colistin arm in Part A, 89.3% (25/28) in Part B. Drug related AEs were 12.1% (10.7% in Part B) with XACDURO compared to 30.2% with colistin. The most common non-infectious AEs (greater than or equal to 10%) in the XACDURO arm were diarrhea (16.5%), allergic and hypersensitivity reactions (16.5%), anemia (13.2%) and hypokalemia (12.1%) in Part A. These AEs were also >10% in the colistin arm as was acute kidney injury.
Competition
GIAPREZA competes with catecholamines (primarily norepinephrine), which are available as generics and inexpensive and typically used first line to treat distributive shock, and vasopressin, including Vasostrict (Endo International plc) and vasopressin generic drugs, which are typically used second line.
Regulatory Exclusivity
GIAPREZA, XERAVA and XACDURO are New Chemical Entities ('NCEs') approved by the U.S. FDA.
On February 15, 2022, La Jolla received a paragraph IV notice of certification (the 'Notice Letter') from Gland Pharma Limited ('Gland') advising that Gland had submitted an Abbreviated New Drug Application ('ANDA') to the FDA seeking approval to manufacture, use or sell a generic version of GIAPREZA in the U.S. prior to the expiration of U.S. Patent Nos.: 9,220,745; 9,572,856; 9,867,863; 10,028,995; 10,335,451; 10,493,124; 10,500,247; 10,548,943; 11,096,983; and 11,219,662 (the 'GIAPREZA Patents'), which are listed in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (the 'Orange Book'). The Notice Letter alleges that the GIAPREZA Patents are invalid, unenforceable and/or will not be infringed by the commercial manufacture, use or sale of the generic product described in Gland's ANDA.
On March 29, 2022, La Jolla filed a complaint for patent infringement of the GIAPREZA Patents against Gland and certain related entities in the United States District Court for the District of New Jersey in response to Gland's ANDA filing. In accordance with the Hatch-Waxman Act, because GIAPREZA is a new chemical entity and La Jolla filed a complaint for patent infringement within 45 days of receipt of the Notice Letter, the FDA cannot approve Gland's ANDA any earlier than 7.5 years from the approval of the GIAPREZA NDA unless the District Court finds that all of the asserted claims of the patents-in-suit are invalid, unenforceable and/or not infringed.
On February 22, 2023, La Jolla received a paragraph IV notice of certification (the 'Second Notice Letter') from Gland advising that Gland had amended its ANDA filing to include a paragraph IV certification alleging that all claims of the newly-issued and Orange Book-listed U.S. Patent No. 11,559,559 ('the '559 Patent'), which covers GIAPREZA, are invalid, unenforceable and/or not infringed.
On March 22, 2023, La Jolla filed a First Amended Complaint in this litigation adding Gland's marketing and distribution partners for its ANDA angiotensin II product, Fresenius Kabi USA LLC and Fresenius Kabi SwissBiosim GmbH (collectively, the 'Fresenius Kabi Defendants'), as co-defendants. On April 7, 2023, La Jolla filed a Second Amended Complaint in response to the Second Notice Letter, adding claims that the manufacture, use, sale, offer for sale, or import of Gland's ANDA angiotensin II product will infringe the '559 Patent. On November 14, 2023, La Jolla filed a Third Amended Complaint adding additional infringement claims against the Fresenius Kabi Defendants. The company intends to vigorously enforce its intellectual property rights relating to GIAPREZA.
Zoliflodacin
Zoliflodacin is a late-stage product candidate, a potential single oral dose cure for the treatment of uncomplicated gonorrhea caused by the bacterial pathogen N. gonorrhoeae. Gonorrhea is an area of significant medical need and zoliflodacin is the only novel single dose treatment in development that provides a potential monotherapy oral alternative to intramuscular injections of ceftriaxone for the treatment of gonorrhea, including infections caused by drug-resistant strains. Zoliflodacin targets the validated mechanism of action of the fluoroquinolone class of antibiotics but does so in a novel manner to avoid existing fluoroquinolone resistance. In November 2023, the company reported positive top-line data results of a pivotal Phase 3 trial. The study demonstrated statistical non-inferiority of microbiological cure at the urogenital site when compared to treatment with intramuscular infection of ceftriaxone and oral azithromycin, a current global standard of care regimen. This trial was initiated in 2019 in collaboration with GARDP, who funded all the Phase 3 clinical trial and pharmaceutical development costs and in return received commercial rights for zoliflodacin in WHO-defined low-income and select middle-income countries. The company retained commercial rights in all other countries, including the major markets in North America, Europe and the Asia-Pacific.
Completed Clinical Trials
Phase 3 registrational trial: The company completed a global, multi-center Phase 3 registrational trial in collaboration with GARDP who conducted and funded all Phase 3 clinical trial and pharmaceutical development costs. The Phase 3 trial enrolled a total of 930 patients with uncomplicated gonorrhea, including women, adolescents, and people living with HIV, making it the largest clinical trial ever conducted for a new treatment against gonorrhea infection, with 16 trial sites in regions with a high prevalence of gonorrhea across five countries, including Belgium, the Netherlands, South Africa, Thailand, and the U.S. The trial compared a single, oral, 3g dose of zoliflodacin to a globally recognized standard of care regimen (500mg ceftriaxone IM plus 1g oral azithromycin) for the treatment of uncomplicated gonorrhea.
Phase 2 clinical proof-of-concept trial: The company has completed a multi-center, randomized, open-label Phase 2 clinical trial comparing a single oral dose of 2.0g or 3.0g of zoliflodacin to 500mg intramuscular ceftriaxone for the treatment of uncomplicated gonorrhea. In this trial, 179 randomized patients received treatment and zoliflodacin was generally well tolerated, with efficacy outcomes comparable to ceftriaxone. Microbiological eradication and clinical cure in urogenital infections with a single dose of zoliflodacin, the primary endpoint of the trial, was comparable to ceftriaxone, with 100% cure rate in both the 3.0g zoliflodacin and ceftriaxone groups in the per-protocol population. The results of this clinical trial were published in The New England Journal of Medicine in 2018.
Phase 1 clinical trial: The company evaluated zoliflodacin in two Phase 1 clinical trials studying 72 healthy volunteers in total. In one trial, the company evaluated PKs and tolerability in 48 subjects and food effects in 18 subjects, and in the second trial, the company evaluated absorption, distribution, metabolism and excretion in six subjects. Zoliflodacin was generally well tolerated in these trials at doses the company would expect to be clinically active for treating uncomplicated gonorrhea. Administration of a high-fat meal was associated with an increase in zoliflodacin plasma concentration, suggesting that zoliflodacin could be administered with or without food.
Preclinical Data
The company has generated biochemical, microbiological and in vivo data on zoliflodacin. The data suggest that zoliflodacin retains potent activity against contemporary clinical isolates in the U.S., Europe, China, Thailand and South Africa that are resistant to other antibiotic classes, including fluroquinolones, which was expected given its novel mechanism of action. In addition, the data show significant resistance against two of the four standard antibiotics indicated for gonorrhea, ciprofloxacin, a fluoroquinolone, and azithromycin, a macrolide.
Manufacturing
Manufacturing of RELVAR/BREO ELLIPTA (FF/VI) and ANORO ELLIPTA (UMEC/VI) is performed by GSK. In all of the company's manufacturing agreements, the company requires that contract manufacturers produce active pharmaceutical ingredients ('APIs') and drug products in accordance with the FDA's current Good Manufacturing Practices ('cGMPs') and all other applicable laws and regulations.
Government Regulation
XERAVA and XACDURO have been designated by the United States Food and Drug Administration (FDA) as a QIDP. Zoliflodacin has also been designated as a QIDP by the FDA for the treatment of uncomplicated gonorrhea.
The company has applied for restoration of patent term for one U.S. Patent covering XERAVA.
In addition to FDA restrictions on marketing of pharmaceutical products, several other types of state and federal laws restrict the company's business activities, including certain marketing practices. These laws include, without limitation, anti-kickback laws, false claims laws, data privacy and security laws, as well as transparency laws regarding payments or other items of value provided to healthcare providers.
The company is subject to a variety of financial disclosure and securities trading regulations as a public company in the U.S., including laws relating to the oversight activities of the SEC and the regulations of the Nasdaq Capital Market, on which the company's shares of common stock are traded. The company is also subject to various laws and regulations relating to safe working conditions, laboratory practices and the experimental use of animals.
Intellectual Property
GIAPREZA
As of February 15, 2023, the licensed intellectual property portfolio relating to GIAPREZA included 12 issued U.S. patents, 2 pending U.S. patent applications, 9 issued foreign patents and 12 pending foreign patent applications. The issued U.S. patents, and patents that may issue from the pending U.S. patent applications, will expire between 2029 and 2034, absent any disclaimers, extensions, or adjustments of patent term. The foreign patents, and patents that may issue from the pending foreign patent applications, will expire in 2034, absent any disclaimers, extensions, or adjustments of patent term.
As of February 15, 2023, the intellectual property portfolio relating to GIAPREZA also included 4 issued U.S. patents, 6 pending U.S. patent applications, 8 issued foreign patents and 10 pending foreign patent applications. The issued U.S. patents, and patents that may issue from the pending U.S. patent applications, will expire between 2034 and 2040, absent any disclaimers, extensions, or adjustments of patent term. The foreign patents, and patents that may issue from the pending foreign patent applications, will expire between 2034 and 2037, absent any disclaimers, extensions, or adjustments of patent term.
XERAVA
As of February 15, 2023, the company owned 2 issued U.S. patents, 1 pending U.S. patent application, 17 issued foreign patents and 4 pending foreign patent applications relating to XERAVA. The issued U.S. patents, and the patent that may issue from the pending U.S. patent application, will have an expiration date of August 7, 2029, absent any disclaimers, extensions, or adjustments of patent term. The term of 1 of the U.S. patents has received 508 days of patent term adjustment. The foreign patents, and patents that may issue from the pending foreign applications, will likewise have an expiration date of August 7, 2029, absent any disclaimers, extensions, or adjustments of patent term.
As of February 15, 2023, the company also filed applications for Supplementary Protection Certificates based on European Patent No. 2323972 covering the composition of matter and use of XERAVA. Some applications have been granted and others are pending.
In addition, as of February 15, 2023, the company also owned 2 issued U.S. patent, 1 pending U.S. patent application, 2 granted foreign patents and 9 pending foreign patent applications that relate to crystalline forms of eravacycline, any U.S. patent that may issue from the pending patent application will expire in 2037 absent any disclaimers, extensions, or adjustments of patent term. Likewise, any foreign patents that may issue from the pending foreign patent applications will expire in 2037. The company also owned 7 issued U.S. patents, 1 pending U.S. patent application, 39 issued foreign patents and 12 pending foreign patent applications relating to other tetracycline-related intellectual property.
XACDURO
As of February 15, 2023, the company owned 4 issued U.S. patents, 115 issued foreign patents and 5 pending foreign patent applications (of which 1 is allowed) relating to XACDURO. The issued U.S. patents have an expiration date of April 2, 2033 and November 17, 2035, absent any disclaimers, extensions, or adjustments of patent term. The foreign patents, and patents that may issue from the pending foreign applications, will likewise have an expiration date of April 2, 2033 and November 17, 2035, absent any disclaimers, extensions, or adjustments of patent term.
Zoliflodacin
The company's intellectual property portfolio for zoliflodacin contains patent applications directed to compositions of matter for zoliflodacin and other chemical analogs, as well as synthetic methods and methods of use and modes of treatment. As of February 15, 2023, the company owned seven issued U.S. patents, 74 issued foreign patents, as well as two pending foreign patent applications. The issued foreign patents are in several jurisdictions, including Australia, Brazil, Canada, China, Eurasia, the European Union, Hong Kong, India, Israel, Japan, Mexico, New Zealand, the Philippines, Singapore, South Africa, South Korea, Taiwan, and the United Kingdom. Issued U.S. and foreign patents and patents issuing from pending U.S. and foreign applications have expiration dates of October 2029, January 2034 and May 2035.
Trademarks
The company's trademark portfolio consists of various registered trademark and service mark rights in several jurisdictions, including the United States, the European Union, Japan, Argentina, Australia, Brazil, Canada, India, Mexico, Norway, Russia, South Korea, Switzerland, Taiwan, Turkey and the United Kingdom; and pending applications in other jurisdictions.
Strategic Partnership with Sarissa Capital
Strategic Advisory Agreement
On December 11, 2020, the company entered into a Strategic Advisory Agreement (the 'Services Agreement') with Sarissa Capital Management LP ('Sarissa Capital'), pursuant to which Sarissa Capital provides a variety of strategic services to the company in order to assist the company in the development and execution of the company's acquisition strategy intended to diversify its assets and the potential sources of revenue.
Partnership Agreement
On December 11, 2020, Innoviva Strategic Partners LLC, the company's wholly owned subsidiary, ('Strategic Partners'), entered into a subscription agreement and an Amended and Restated Limited Partnership Agreement (the 'Partnership Agreement') pursuant to which Strategic Partners became a limited partner of ISP Fund LP (the 'Partnership'). The general partner of the Partnership is an affiliate of Sarissa Capital, and pursuant to an investment management agreement, Sarissa Capital acts as the investment adviser to the Partnership. The Partnership was formed for the purposes of investing in equity securities in the healthcare, pharmaceutical and biotechnology industries.
History
The company was incorporated in Delaware in 1996 under the name Advanced Medicine, Inc. and began operations in 1997. The company changed its name to Theravance, Inc. in 2002. Further, the company changed its name to Innoviva, Inc. in 2016.
