Tetraphase Pharmaceuticals: Tackling Antimicrobial Resistance with Fully Synthetic Tetracyclines and 180% Net Sales Growth

Antibiotics are effective medications for treating bacterial infections and have saved countless lives. However, excessive use can lead to adverse consequences; the widespread application of antibiotics in human medicine and agricultural production has given rise to extensive bacterial resistance, with the combined use of multiple antibiotics further promoting the emergence of multidrug resistance.

Bacterial resistance enables bacteria to withstand antibiotics at clinical therapeutic concentrations, rendering these drugs ineffective for treatment. According to statistics from the Centers for Disease Control and Prevention (CDC), nearly 23,000 people die annually in the United States due to antibiotic resistance. It is projected that by 2050, the number of human deaths caused by multidrug-resistant organisms will rise to 10 million, surpassing cancer-related mortality and becoming one of the leading causes of death worldwide. The issue of antibiotic resistance has been recognized as an urgent threat by the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA).

Addressing the issue of antibiotic resistance is an urgent priority. In light of this societal reality, biopharmaceutical company Tetraphase Pharmaceuticals (NASDAQ: TTPH, hereinafter referred to as “Tetraphase”) has made combating antibiotic resistance its core mission.Aiming to leverage its synthetic chemistry platform to develop drugs that overcome antibiotic resistance. Currently, Tetraphase has one marketed product—the antibacterial injection XERAVA™ (eravacycline)—and three investigational compounds in clinical or preclinical testing.

What strategies has Tetraphase Pharmaceuticals devised to overcome antibiotic resistance? Have its marketed products gained market acceptance? Can it sustain its momentum in the future?

There is a wide variety of antibiotics. Tetracycline, as a broad-spectrum antibiotic, has garnered significant attention due to its effective bacteriostatic and bactericidal properties. Previously available tetracyclines were primarily natural and semi-synthetic variants. Natural tetracyclines have unstable chemical structures and are prone to inducing drug resistance. Compared with natural tetracyclines, semi-synthetic tetracyclines exhibit stronger antibacterial efficacy, better absorption, and broader clinical application; however, their “semi-synthetic” nature limits potential chemical modifications, resulting in a narrower scope of applicability.

Distinct from natural and semi-synthetic tetracyclines, Dr. Andrew Myers and his research team pioneered a fully synthetic chemical technology that achieved total synthesis from basic building blocks for the first time, enabling the synthesis and testing of more than 3,000 tetracycline compounds and overcoming key obstacles in the development of novel tetracyclines.

Dr. Andrew Myers is an internationally renowned synthetic chemist and currently serves as the Amory Houghton Professor of Chemistry and Chemical Biology at Harvard University. Building on the aforementioned research achievements, Dr. Myers co-founded Tetraphase Pharmaceuticals in 2006.

Leveraging Dr. Andrew Myers’ technological achievements and an extensive tetracycline library, the novel antibiotics developed by Tetraphase Pharmaceuticals not only help address bacterial resistance but also hold potential applications in non-antibiotic therapeutic areas, including oncology and inflammatory diseases.

After a 16-year journey in new drug development, Tetraphase has successfully leveraged its proprietary technology platform to advance a fully synthetic tetracycline product into the commercialization stage, while also maintaining a pipeline of several fully synthetic tetracycline candidates.

Pipeline Products Available for Out-Licensing (Image source: Tetraphase official website)

XERAVA®(eravacycline)It is a novel, fully synthetic fluorinated tetracycline antibiotic that received approval from the FDA and the European Commission in August and September 2018, respectively, for the treatment of complicated intra-abdominal infections (cIAI) in patients aged 18 years and older; Tetraphase Pharmaceuticals submitted its New Drug Application (NDA) in China in 2021.

XERAVA features chemical modifications to the core tetracycline structure, with substitutions at the C7 and C9 positions distinguishing it from any natural or semi-synthetic tetracyclines. Studies have demonstrated that XERAVA is 2 to 4 times more potent than tigecycline against Gram-positive and Gram-negative bacteria in vitro, and 2 to 8 times more potent against most anaerobic bacteria. Furthermore, two pivotal clinical trial reports indicate that XERAVA is associated with a lower incidence of gastrointestinal adverse reactions.

Structure of the Tetracycline XERAVA

In addition to XERAVA, Tetraphase has three fully synthetic tetracycline antibiotic candidates.

TP-271It is a fully synthetic tetracycline antibiotic that demonstrates in vitro efficacy against Gram-negative and Gram-positive pathogens associated with respiratory tract infections. It has received FDA Qualified Infectious Disease Product (QIDP) designation and Fast Track designation for both intravenous and oral formulations, and is currently in Phase I clinical trials.

TP-6076It is a fully synthetic tetracycline antibiotic with in vitro activity against multidrug-resistant Gram-negative pathogens and is currently in Phase I clinical trials.

TP- 2846is a novel tetracycline-derived anti-leukemic agent. Preclinical data indicate that TP-2846 has the potential to inhibit mitochondrial translation and induce growth arrest in leukemia cells.

Tetraphase’s strength in new drug development has garnered significant favor from investors. Since its inception, Tetraphase has completed eight rounds of financing, raising a total of over $200 million.

However, this does not mean that Tetraphase has never faced financial pressure. After the launch of XERAVA, its sales performance was dismal, and coupled with the need for substantial R&D investment in its pipeline candidates, Tetraphase found it increasingly difficult to sustain operations.

In June 2020, Tetraphase entered into a definitive merger agreement with the biopharmaceutical company La Jolla Pharmaceutical Company (NASDAQ: LJPC, hereinafter referred to as “La Jolla”), under which La Jolla acquired Tetraphase for $43 million in upfront cash and up to $16 million in potential future cash payments contingent on contingent value rights.

Previously, publicly listed biopharmaceutical companies AcelRx and Melinta both participated in the open bidding for the acquisition of Tetraphase Pharmaceuticals and signed merger agreements, but ultimately lost to La Jolla Pharmaceutical, resulting in their failure. The competitive bidding among these three biopharmaceutical companies demonstrates the potential value of Tetraphase Pharmaceuticals.

For Tetraphase, the decision to join La Jolla significantly boosted the net sales of its marketed product, XERAVA, thereby generating new momentum for development.In 2019, XERAVA’s annual net sales amounted to only $3.6 million. Following La Jolla’s acquisition of Tetraphase Pharmaceuticals, XERAVA’s U.S. net product sales rose to $10.1 million in 2021, representing a year-over-year growth rate of 23% and an 180% increase compared with 2019.

From La Jolla’s perspective, this acquisition has expanded its product portfolio and strengthened its competitive advantage in the marketplace. Larry Edwards, President and Chief Executive Officer of La Jolla, stated that the integration with Tetraphase Pharmaceuticals has increased La Jolla’s net sales while reducing operating costs. Although La Jolla remains unprofitable, its net losses have been decreasing year over year, demonstrating significant profit potential.

La Jolla Financial Report (Data Source: La Jolla Official Website)

Overall, this merger has achieved a “1+1>2” effect.

In addition to Tetraphase Pharmaceuticals’ tetracycline-class antibiotic XERAVA, La Jolla has another marketed product—the vasoconstrictor GIAPREZA™ (angiotensin II)—which received FDA approval in December 2017 and EC approval in August 2019 for the treatment of hypotension in adults with septic or other distributive shock.

Biopharmaceutical companies prioritize specialized biomedical expertise for product development in the early stages, while placing greater emphasis on organizational management and marketing capabilities in later stages. As a company with two marketed products, La Jolla has demonstrated team strengths commensurate with these requirements.

As the CEO of Tetraphase, Larry Edwards brings extensive experience in marketing and management. Academically, he holds a Bachelor’s degree in Business and Healthcare Administration from Ohio University. Professionally, during his tenure at Tetraphase, he has served as Vice President of Marketing, Vice President of Commercial Operations, Chief Commercial Officer, and Chief Operating Officer. Prior to joining Tetraphase, he was Senior Marketing Manager for the Gram-Negative Franchise at the biopharmaceutical company Cubist Pharmaceuticals, and Global Marketing Director for Clostridium difficile and emerging infectious disease products at Merck & Co.

Following the acquisition of Tetraphase by La Jolla, Larry Edwards became President, Chief Executive Officer, and a member of the Board of Directors of La Jolla. Kevin Tang serves as Chairman of the Board of La Jolla.

Kevin Tang has served as Chairman of La Jolla since 2014, bringing extensive experience in managing multiple biopharmaceutical companies. In 2002, he founded and served as President of Tang Capital Management, an investment firm focused on life sciences. He previously served as Chairman and Chief Executive Officer of Odonate Therapeutics, Chairman of Heron Therapeutics, and Director of Penwest Pharmaceuticals (acquired by Endo Pharmaceuticals in 2010), Ardea Biosciences (a biotechnology company acquired by AstraZeneca PLC in 2012), and Trimeris (a biopharmaceutical company).

Tetraphase leverages total synthesis chemistry to overcome antibiotic resistance. With strong sales of marketed products, a robust R&D platform, ample growth momentum for new products, and a leadership team with extensive marketing and management experience, multiple factors are helping Tetraphase maintain a steady and positive development trend.