Nabriva Therapeutics plc, a biopharmaceutical company, engages in the commercialization and research and development of novel anti-infective agents to treat serious infections.
The company has the commercial rights to two approved products, SIVEXTRO and XENLETA, as well as one development product candidate, CONTEPO.
SIVEXTRO
SIVEXTRO is a novel oxazolidinone class antibiotic to treat susceptible Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), one of the...
Nabriva Therapeutics plc, a biopharmaceutical company, engages in the commercialization and research and development of novel anti-infective agents to treat serious infections.
The company has the commercial rights to two approved products, SIVEXTRO and XENLETA, as well as one development product candidate, CONTEPO.
SIVEXTRO
SIVEXTRO is a novel oxazolidinone class antibiotic to treat susceptible Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), one of the serious public health threats identified by the U.S. Centers for Disease Control and Prevention (CDC). Available in both IV and oral formulations, SIVEXTRO was approved by the FDA for the treatment of adults with acute bacterial skin and skin structure infection (ABSSSI), such as cellulitis, wound infections, and Erysipelas and in 2020 the label was expanded to include adolescents 12 years of age and older.
XENLETA
XENLETA is a semi-synthetic pleuromutilin antibiotic that is the first in its class for intraveneous (IV) and oral administration in humans. XENLETA is designed to inhibit the synthesis of a specific protein on the bacterial ribosome, which is required for bacteria to grow, by binding with high affinity and specificity at molecular targets.
In September 2019, the company announced that the oral and IV formulations of XENLETA were available in the United States for the treatment of community-acquired bacterial pneumonia (CABP) in adults through major specialty distributors. This followed the approval by the FDA of its New Drug Application (NDA) for XENLETA in August 2019 for the treatment of adults with CABP. XENLETA is the first oral and IV treatment in the pleuromutilin class of antibiotics available for the systematic administration in humans.
The company markets XENLETA to primary care physicians in the community near its target hospitals using its own targeted hospital sales force and marketing organization. The company entered into a license and commercialization agreement in 2019 with Sunovion Pharmaceuticals Canada Inc. (Sunovian) for the commercial rights to XENLETA in Canada. In 2020, the company announced that Sunovian received approval from Health Canada to market oral and IV formulations of XENLETA (lefamulin) for the treatment of community-acquired pneumonia (CAP) in adults, with the related Notice of Compliance from Health Canada.
In 2020, the company announced that the European Commission (EC) issued a legally binding decision for approval of the marketing authorization application for XENLETA for the treatment of CAP, in adults when it is considered inappropriate to use antibacterial agents that are commonly recommended for initial treatment or when these agents have failed following a review by the European Medicines Agency (EMA). The EC approved XENLETA for countries of the European Economic Area (EEA) and the United Kingdom (U.K.).
In 2021, Sumitomo Pharmaceuticals (Suzhou) and the company announced Sumitomo Pharmaceuticals (Suzhou) received approval to market oral and IV formulations of XENLETA for the treatment of community-acquired pneumonia in adults in Taiwan.
In 2021, the company announced that Sumitomo Pharmaceuticals´ (Suzhou) NDA to market oral and IV formulations of lefamulin for the treatment of community-acquired pneumonia (CAP) in adults in mainland China was accepted for review by the Chinese Center for Drug Evaluation (CDE) China's regulatory authority, on November 23, 2021. The expected time for the application review is up to 24 months.
CONTEPO
In 2018, the company completed the acquisition of Zavante Therapeutics, Inc. (Zavante) together with its lead product candidate CONTEPO (fosfomycin for injection), or the Acquisition. With the Acquisition, Zavante became the company's wholly owned subsidiary.
CONTEPO is a novel, potentially first-in-class investigational IV antibiotic in the United States with a broad spectrum of Gram-negative and Gram-positive activity, including activity against most multi-drug resistant (MDR) strains, such as extended-spectrum ß-lactamase- (ESBL)-producing Enterobacteriaceae. CONTEPO utilizes a new dosing regimen that optimizes its pharmacokinetics and pharmacodynamics.
The company submitted an NDA for marketing approval of CONTEPO for the treatment of complicated urinary tract infection (cUTI), including acute pyelonephritis (AP) in adults in the United States, to the FDA in October 2018. The NDA submission is utilizing the 505(b)(2) regulatory pathway and is supported by a robust data package, including a pivotal Phase 2/3 clinical trial (known as ZEUS), which met its primary endpoint of statistical non-inferiority to high dose piperacillin/tazobactam in patients with cUTI, including AP. In April 2019, the FDA issued a complete response letter (CRL) in connection with the company's NDA for CONTEPO for the treatment of cUTIs, including AP, stating that it was unable to approve the application in its current form. The CRL requested that issues related to facility inspections and manufacturing deficiencies at the company's active pharmaceutical ingredient contract manufacturer be addressed prior to the FDA approving the NDA. The company requested a 'Type A' meeting with the FDA to discuss its findings and this meeting occurred in July 2019.
The company resubmitted its NDA in December 2019 and the FDA acknowledged the resubmission in January 2020. In 2020, the company received a second CRL from the FDA. Although its European contract manufacturing partners were prepared for regulatory authority inspections, the CRL cites observations at its manufacturing partners that could not be resolved due to FDA's inability to conduct onsite inspections because of travel restrictions. In 2020, the company participated in a 'Type A' meeting with the FDA to obtain any new information related to the FDA´s pending conduct of inspections of foreign manufacturers during the COVID-19 pandemic that has negatively impacted a number of FDA product reviews, including its NDA for CONTEPO.
The company requested an extension of the timeline for a potential CONTEPO NDA resubmission until June 2023, which the FDA granted on March 21, 2022.
License Agreements
China Region License Agreement
In 2018, the company entered into the China Region License Agreement, with Sinovant Sciences, Ltd. (Sinovant), an affiliate of Roivant Sciences, Ltd., to develop and commercialize lefamulin in the greater China region. As part of the China Region License Agreement, Nabriva Therapeutics Ireland DAC and Nabriva Therapeutics GmbH, the company's wholly owned subsidiaries, granted Sinovant an exclusive license to develop and commercialize, and a non-exclusive license to manufacture, certain products containing lefamulin, or the China Region Licensed Products, in the People's Republic of China, Hong Kong, Macau, and Taiwan, together the Extended China Territory. In 2021, the company enters into an assignment, assumption and novation agreement, or the Assignment Agreement, pursuant to which the company consented to the assignment by Sinovant, an affiliate of Roivant Sciences, Ltd., of the China Region License Agreement to develop and commercialize lefamulin in the greater China region to Sumitomo Pharmaceuticals (Suzhou), a wholly-owned subsidiary of Sumitomo Dainippon Pharma Co., Ltd. (Sumitomo). Pursuant to the Assignment Agreement, the company agreed to release Sinovant and its affiliates from their obligations under the China Region License Agreement and consented to Sumitomo Pharmaceuticals (Suzhou)'s assumption of such obligations. In addition, Sumitomo has agreed to guarantee all of the obligations of Sumitomo Pharmaceuticals (Suzhou) under the China Region License Agreement.
Sunovion License Agreement
In 2019, the company enters into the Sunovion License Agreement with Sunovion Pharmaceuticals Canada Inc. (Sunovion). As part of the Sunovion License Agreement, Nabriva Therapeutics Ireland DAC, the company's wholly owned subsidiary, granted Sunovion an exclusive license under certain patent rights, trademark rights and know-how to commercialize certain products, including XENLETA in the forms clinically developed by the company or any of its affiliates, or the Sunovion Licensed Products in Canada in all uses in humans in CABP and in any other indication for which the Sunovion Licensed Products have received regulatory approval in Canada. Under the Sunovion License Agreement, Sunovion and Nabriva Therapeutics Ireland DAC established a joint development committee, or the Sunovion JDC, to review and oversee regulatory approval and commercialization plans in Canada. Sunovion will be solely responsible for all costs related to obtaining regulatory approval of and commercializing Sunovion Licensed Products in the Canada and is obligated to use commercially reasonable efforts to develop, obtain regulatory approval for, and commercialize Licensed Product in Canada.
In 2019, the company, through Sunovion, submitted a New Drug Submission (NDS) to market oral and intravenous formulations of XENLETA for the treatment of CAP in adults. Sunovion received approval from Health Canada to market oral and intravenous formulations of XENLETA for the treatment of community-acquired pneumonia in adults, with the Notice of Compliance from Health Canada dated July 10, 2020.
Named Patient Program Agreement with WE Pharma Ltd.
In 2020, the company announced that WE Pharma Ltd., or WEP Clinical, a specialist pharmaceutical services company, had signed an exclusive agreement with the company to supply XENLETA on a named patient or expanded access basis in certain countries outside of the U.S., China and Canada. The Named Patient Program (NPP) is designed to ensure that physicians, contingent on meeting the necessary eligibility criteria and receiving approval, can request IV or oral XENLETA on behalf of patients who live in certain countries where it is not yet available and have an unmet medical need.
Manufacturing
The company continues to rely on third parties for the manufacture of XENLETA and CONTEPO. It has in-house knowledge and experience in the relevant chemistry associated with XENLETA and CONTEPO; and the relevant manufacturing and supply chain processes associated with the commercial supply of XENLETA and CONTEPO. The company engages third-party consultants, to assist in the management of its third-party manufacturers. The company procures its supply of SIVEXTRO from Merck & Co., Inc.
XENLETA
The company has a long-term commercial supply agreement with SEL Biochem Xinjiang Co., Ltd (SEL) and Fountain International Development Holding Limited for the supply of pleuromutilin, which is the key intermediate for XENLETA API production. Under this agreement, SEL is required to manufacture and supply and the company is required to purchase from SEL a specified percentage of its commercial requirements of pleuromutilin. The term of the agreement expires on August 28, 2025, subject to automatic renewal for successive three-year periods.
In 2018, the company enters into a long-term commercial supply agreement with Arran Chemical Company Limited, or Arran, for the supply of the chiral acid starting material required in the synthesis of XENLETA API. Under this agreement, Arran is required to manufacture and supply, and it is required to purchase from Arran the amount forecast for the first six months of a twelve-month rolling forecast provided monthly by the company. The agreement term expires on November 12, 2023, and continues thereafter unless terminated by either party with not less than twelve months written notice.
In addition, pursuant to the First Amendment, Hovione agreed to extend the duration of the Hovione Supply Agreement from November 22, 2025, to November 22, 2030.
The company has also entered into a long-term commercial supply agreement with Patheon UK Limited, or Patheon, for the supply of IV vials of XENLETA. Under this agreement, Patheon is required to supply and it is required to purchase a specified percentage of its commercial requirements of IV vials of XENLETA. The initial term of the agreement expires on December 31, 2023, but it remains in force until it is terminated by either party upon 24-months prior written notice, expiring on or at any time after the expiry of the initial term.
In 2021, the company entered into a side agreement to the long-term commercial supply agreement, reducing the annual binding volume requirements for IV vials of XENLETA for the years 2022 to 2025.
In addition, the company enters into a long-term commercial supply agreement with Almac Pharma Services Limited, or Almac, for the commercial supply of XENLETA tablets. Under this agreement, Almac is required to supply and it is required to purchase services relating to the manufactured tablets equaling a specified minimum annual spend. The initial term of the agreement expired on August 7, 2022, but it remains in force until it is terminated by either party with 24-months prior written notice, expiring on or at any time after the expiry of the initial term.
In 2018, the company entered into a commercial packaging and supply agreement, or the Packaging Agreement with Sharp Corporation, or Sharp, for the commercial packaging of XENLETA acetate for oral and intravenous administration. Under the Packaging Agreement, Sharp has agreed to provide certain packaging services to the company, including labeling, serialization and final packaging of the packaged products. The Packaging Agreement has an initial five-year term ending December 31, 2023, and would automatically renew after the initial term for additional one-year terms unless either party gives notice of its intention to terminate the Packaging Agreement at least 90 days prior to the end of the then-current term.
In 2019, the company entered into long-term commercial supply agreement with Fresenius Kabi Norge AS, or Fresenius, for the supply of sodium citrate buffer infusion bags for use with IV vials of XENLETA. The initial term of the agreement expires on December 31, 2023, but it remains in force until it is terminated by either party with 24-months prior written notice, expiring on or at any time after the expiry of the initial term.
CONTEPO
In 2016, Zavante, Laboratorios ERN, S.A. (ERN) and Ercros, S.A. (Ercros) entered into an amended and restated three-way agreement (the 'Three-Way Agreement'), which established the basis for related supply agreements with ERN and Ercros in anticipation of FDA approval of fosfomycin disodium and succinic acid injection for IV use filled, finished and packaged into containers for use by end users ('Product') in the United States. Pursuant to the Three-Way Agreement, Zavante has the direct responsibility for the manufacture and supply of the commercial Product in the United States.
Under the Three-Way Agreement, ERN has agreed to provide Zavante with certain technical documentation (Technical Documentation) and data required for submission of an NDA or Abbreviated NDA (ANDA), as applicable, for the Product, and other assistance in connection with the submission of an NDA or ANDA, pursuant to the ERN Supply Agreement; Ercros has agreed to provide Zavante with certain Technical Documentation and the manufacture and supply of a blend of fosfomycin disodium and succinic acid (the 'API Mixture') for the manufacture of the Product, pursuant to the terms of the Ercros Supply Agreement; and Zavante has agreed to obtain the commercial supply of the Product, under one or more separate agreements with third party manufacturers. The rights and obligations of each of the parties are set forth in each of the ERN Supply Agreement and the Ercros Supply Agreement.
In 2016, Zavante and Ercros entered into a manufacturing and supply agreement (the 'Ercros Supply Agreement') pursuant to the Three-Way Agreement. Under the Ercros Supply Agreement, Ercros has agreed, pursuant to purchase orders entered into under the Ercros Supply Agreement, to manufacture the exclusive supply of the API Mixture for Zavante in support of filing an NDA or an ANDA, as applicable, and the commercial supply of fosfomycin disodium and succinic acid injection for IV use in the United States. In addition, Ercros has agreed to provide access to certain technical documentation as may be requested by Zavante in connection with the filing of an NDA.
The Ercros Supply Agreement has an initial ten-year term ending July 28, 2026, and would automatically renew after the initial term for additional two-year terms unless either party gives notice of its intention to terminate the Ercros Supply Agreement approximately 18 months prior to the end of the then-current term.
In 2016, Zavante and ERN entered into an amended and restated pharmaceutical manufacturing and exclusive supply agreement, as amended on December 1, 2016, March 1, 2017, May 1, 2017, and December 20, 2017, pursuant to the Three-Way Agreement, or the ERN Supply Agreement. Under the ERN Supply Agreement, each party is required to use commercially reasonable efforts to complete certain development activities required for submission of an NDA or an ANDA for fosfomycin sodium and succinic acid. In addition, ERN has agreed to provide to Zavante include certain technical documentation and data as required by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use's guidelines and the FDA for submission of an NDA or an ANDA for the bulk formulation of CONTEPO, and certain regulatory support in connection with the bulk formulation of CONTEPO sold or intended for commercial sale and human use.
The ERN Supply Agreement has an initial ten-year term ending July 28, 2026 and automatically renew after the initial term for additional two-year terms unless either party gives notice of its intention to terminate the ERN Supply Agreement at least 18 months prior to the end of the then-current term.
In 2017, Zavante and Fisiopharma, S.r.l. (Fisiopharma) entered into a manufacturing and supply agreement, as amended on May 8, 2017 (the 'Fisiopharma Supply Agreement'). Under the Fisiopharma Supply Agreement, Fisiopharma has agreed, pursuant to purchase orders entered into under the Fisiopharma Supply Agreement, to manufacture and supply fosfomycin disodium for IV injection in bulk drug vials (the 'Bulk Drug Vials') to Zavante in support of filing an NDA or an ANDA, as applicable, and a specified percentage of Zavante's commercial requirements of Bulk Drug Vials for the United States.
The Fisiopharma Supply Agreement has an initial ten-year term ending April 25, 2027, and would automatically renew after the initial term for additional one-year terms unless Zavante gives notice of its intention to terminate the Fisiopharma Supply Agreement approximately six months prior to the end of the then-current term.
Intellectual Property
As of January 31, 2023, the company owned 26 different families of patents and patent applications, including 24 families directed to the various pleuromutilin derivatives as the compositions of matter, processes for their manufacture, and their use in pharmaceutical compositions and methods of treating disease. The remaining two families are directed to ß lactamase inhibitors and siderophore cephalosporin conjugates. Its patent portfolio includes 18 issued U.S. patents, 23 granted European patents 11 granted Chinese patents, 11 granted patents in Taiwan, 6 granted patents in Canada, 14 granted patents in Hong Kong and 16 granted Japanese patents, as well as patents in other jurisdictions. The company also has pending patent applications in the United States, Europe, China, Taiwan, Canada, Hong Kong, Japan and other countries and regions, including Asia, Australia, Eastern Europe, and South America, including notably Brazil, Israel, and India among others.
All of these patents and patent applications are assigned solely to the company and were either originally filed by it or originally filed by Sandoz and subsequently assigned to it.
As of January 31, 2023, XENLETA, was protected by the following six patent families:
The first patent family includes patents and applications with claims that specifically recite XENLETA and/or its use in the treatment of microbial infections. This family includes two issued patents in each of the United States, Europe, China, Hong Kong and Japan and one issued patent in Taiwan and Canada, as well as issued patents in 16 other jurisdictions and 4 pending patent applications in other jurisdictions, including one divisional application in the United States. The standard term for patents in this family expires in 2028. A patent term adjustment of 303 days has already been obtained in the United States for one patent. A patent term extension for this patent has been granted extending the term to 2033. Supplementary Patent Certificates, or SPCs, have been filed for the first granted European patent extending the patent term to 2033. Similarly, a Certificate of Supplementary Protection was filed for the granted patent in Canada extending the patent term to 2030 and a patent term extension application was filed for the granted patent in Taiwan extending the term to 2033.
The second patent family includes patents and applications with claims directed to the processes for the manufacture of XENLETA, crystalline intermediates useful in the processes, and the resulting crystalline salts. This family includes 26 granted patents, including issued patents in the United States, Europe, China, Taiwan, Canada, Hong Kong, and Japan and 5 pending patent applications in other jurisdictions. The standard term for patents in this family expires in 2031.
The third patent family includes patents and applications with claims directed to processes for the synthetic manufacture of crystalline intermediates useful in the manufacture of XENLETA. This family includes granted patents in the United States, Europe, China, Taiwan, Hong Kong, and Japan and 2 granted patents in other jurisdictions. The standard term for patents in this family expires in 2031.
The fourth patent family includes patents and applications with claims directed to pharmaceuticals and treatments for Helicobacter infection, including pleuromutilins, such as XENLETA. This family includes issued patents in the United States, Europe, and Hong Kong. The standard term for patents in this family expires in 2023. A patent term adjustment of 921 days has already been obtained for the U.S. patent.
The fifth patent family is directed to pharmaceutical compositions of XENLETA and covers 11 granted patents including issued patent in Europe, China, Taiwan, Hong Kong, and Japan and 6 pending patent applications in various other jurisdictions, including the United States and Canada. The standard term for patents in this family expires 2036.
The sixth patent family is directed to methods for purification of pleuromutilin, key intermediate in the XENLETA drug substance synthesis, and covers 9 granted patents, including issued patents in the United States, Europe, China, Taiwan, Hong Kong, and Japan and 2 pending patent applications in Canada and the Republic of Korea. The standard term for patents in this family expires in 2038.
The remaining 17 pleuromutilin patent families are directed to either molecules in the intellectual property landscape surrounding the company's approved product and product candidates in development including specific medical use or molecules, which can be potentially further developed by it but have not yet been pursued. All patent applications in these families have been filed at least in the United States and/or Europe, and most have been filed in other countries. Many of these patent applications have already resulted in granted patents.
Finally, the company owns one patent family directed to ß lactamase inhibitor compounds and one patent family directed to siderophore cephalosporin conjugates. The patent application in the ß-lactamase inhibitors family has been granted in Europe. The standard term for patent in this family expires in 2030. The siderophore cephalosporin conjgates patent family has been filed in the United States, Europe, Japan and eight other jurisdictions.
Zavante holds an issued United States patent (U.S. 11,541,064 expiring in 2038) directed to the dosing regimens of Fosfomycin in renally impaired patients. Zavante holds two issued United States patents (U.S. 9,345,717 and U.S. 10,086,006) directed to methods for identifying dosing regimens that decrease the potential for on-therapy drug resistance. Additionally, Zavante has filed a patent application based on results from the ZEUS Study that relates to methods for treating patients with resistant bacterial infections and, specifically, Gram-negative bacterial infections. The company also plans to rely on regulatory protection afforded to CONTEPO through QIDP designation, data exclusivity, and market exclusivity where available.
Research and Development
For the year ended December 31, 2022, the company's research and development expenses included $14.3 million.
History
The company was incorporated in 2005. It was formerly known as Nabriva Therapeutics Forschungs GmbH and changed its name to Nabriva Therapeutics plc in 2007.
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