89bio Stock

89bio, Inc. operates as a clinical-stage biopharmaceutical company.

The company focuses on the development and commercialization of innovative therapies for the treatment of liver and cardio-metabolic diseases.

The company’s lead product candidate, pegozafermin, a specifically engineered glycoPEGylated analog of fibroblast growth factor 21 (FGF21), is being developed for the treatment of nonalcoholic steatohepatitis (NASH) and for the treatment of severe hypertriglyceridemia (SHTG). In 2020 and 2022, the company presented positive topline results from cohorts 1 through 6 and cohort 7, respectively, in the company’s Phase 1b/2a trial of pegozafermin in NASH patients, which has informed the advancement of the company’s clinical strategy in NASH. The company initiated a Phase 2b trial (ENLIVEN) evaluating pegozafermin in fibrosis stage 2 or 3 NASH patients in June 2021. In the ENLIVEN trial, patients receive weekly doses or an every two-week dose of pegozafermin or placebo for 24 weeks followed by a blinded extension phase of an additional 24 weeks for a total treatment period of 48 weeks. ENLIVEN completed enrollment in August 2022 and the company is expecting to report topline data from this trial in March 2023. In 2021, the company completed a pharmacokinetic study of pegozafermin in NASH patients with compensated cirrhosis (fibrosis stage F4) demonstrating that a 30 mg dose of pegozafermin has similar single-dose pharmacokinetics and pharmacodynamics in F4 as it does in non-cirrhotic NASH. The company is evaluating the potential opportunity for pegozafermin in these fibrosis stage F4 patients. The company is also developing pegozafermin for the treatment of SHTG. In June 2022, the company announced positive topline results from the ENTRIGUE Phase 2 trial of pegozafermin in SHTG patients. The company has received feedback from the FDA supporting the advancement of pegozafermin into Phase 3 and are planning to initiate the first of two recommended Phase 3 trials in the second quarter of 2023. In parallel, the company has developed plans to optimize its clinical development program across both indications that would leverage the safety database from the company’s SHTG Phase 3 program to support the company’s NASH program. The company expects to finalize these plans after the company has reviewed results from the ENLIVEN trial.

FGF21 is a metabolic hormone that regulates energy expenditure and glucose and lipid metabolism. FGF21 analogs represent a promising class of drugs to treat NASH, because they not only address the liver manifestations, but also have an effect on the multiple co-morbidities that worsen NASH. FGF21 is a clinically validated mechanism that has been shown in humans to reduce steatosis, improve the histological features of NASH and address cardio-metabolic dysregulation. It is thought to exert effects on liver fibrosis by improving metabolic regulation, which reduces ongoing liver injury thus giving the liver time to heal. FGF21 also generates an on-target effect to increase adiponectin, a hormone released from adipose tissue that, among other functions, can suppress development and progression of hepatic fibrosis. However, FGF21 in its native form suffers from a short half-life and a tendency to aggregate in solution, both of which impact its suitability as a viable drug. To address these challenges, the company has specifically engineered pegozafermin to extend the half-life of the molecule while maintaining potency and thereby the clinical benefits of FGF21.

Pegozafermin may be a differentiated FGF21 therapy based on its robust and durable biological effects, a favorable tolerability profile and its potential for every two-week dosing. Given its ability to address the key liver pathologies in NASH, as well as the underlying metabolic dysregulation in NASH patients, pegozafermin has the potential to become a backbone of treatment in NASH. Pegozafermin is the only FGF21 analog being developed for the treatment of SHTG and its broad metabolic effects could potentially differentiate it from competitors in this market. Pegozafermin has a long half-life which allows convenient weekly or every two-week dosing and is the only FGF21 analog being tested for every two-week dosing. The convenient dosing regimen may support adoption and compliance amongst patients living with these chronic and generally asymptomatic diseases. Pegozafermin is self-administered by patients subcutaneously in a liquid formulation. The company has developed a new pre-filled syringe using its approved liquid formulation and plan to utilize this presentation in the company’s planned SHTG Phase 3 trial in the second quarter of 2023.

Strategy

The key components of the company’s strategy are to rapidly advance pegozafermin through clinical development for the treatment of NASH; progress pegozafermin for the treatment of SHTG; scale-up and optimize the manufacturing of pegozafermin; and establish a commercial infrastructure in key geographies.

Focus on Liver and Cardio-Metabolic Disease

The company is focused on developing and commercializing therapeutic interventions that have a clinically meaningful impact on patients with liver and cardio-metabolic diseases. These diseases, including NASH and SHTG, represent leading global causes of morbidity and mortality. Despite a wave of public health campaigns to promote better diet and exercise habits and a range of treatment options available for many of these diseases, there is a significant unmet medical need for more effective therapies to improve patient outcomes and reduce the burden on global healthcare systems.

The company is developing its lead product candidate, pegozafermin, a specifically engineered glycoPEGylated analog of FGF21, for the treatment of NASH and SHTG. Pegozafermin is an ideal candidate for the treatment of NASH based on its ability to address the key liver pathologies in NASH, its ability to address the underlying metabolic dysregulation in NASH patients, its favorable tolerability profile, and its potential for a longer dosing interval. Multiple epidemiological studies have linked NAFLD to increased cardiovascular disease, concluding that the majority of deaths among NAFLD patients are attributable to cardiovascular disease. As a result, it is important that new therapeutics options for NASH address the underlying cardiovascular and metabolic dysregulations in these patients. The company is also developing pegozafermin for the treatment of SHTG given the potential of pegozafermin to meaningfully reduce triglycerides. Pegozafermin may have a competitive differentiation from approved therapies and other molecules in development based on its impact on improving liver fat and other metabolic markers in addition to triglyceride reduction.

Pegozafermin

The company is developing pegozafermin, a specifically engineered glycoPEGylated analog of FGF21, for the treatment of NASH and SHTG. Pegozafermin has been specifically engineered to retain the activity of native FGF21 while extending its half-life. Specifically, it has been engineered to: (1) protect against proteolysis and reduce renal clearance, (2) have an extended half-life, (3) minimize susceptibility to aggregate in solution and (4) optimize its potency, enabling the potential use of lower dosage/doses. Additionally, pegozafermin may enhance binding affinity for ß-Klotho, by altering the conformation of the C-terminus which could have a positive impact on efficacy.

Pegozafermin Clinical Development in NASH

Phase 1a Clinical Trial of Single-Dose of Pegozafermin in Healthy Volunteers

The company conducted a Phase 1a clinical trial to evaluate the safety, tolerability and pharmacokinetics (‘PK’) of pegozafermin in 58 healthy volunteers. In this randomized, double-blind, placebo-controlled, Phase 1a, first-in-human, SAD clinical trial the PK profile of pegozafermin was generally dose-proportional or slightly more than dose-proportional with a half-life of approximately 55 to 100 hours. At single doses of 9.1 mg and higher, significant improvements were observed in key lipid parameters measured at Day 8 and Day 15 after dosing on Day 1. The mean changes versus baseline include significant reductions in triglycerides (up to 51%) and LDL-C (up to 37%) and increase in HDL-C (up to 36%) despite the baseline values being in the normal range. Pegozafermin demonstrated rapid (starting from Day 2), sustained and durable improvements on lipid parameters for two weeks or more after single-dose administration. Pegozafermin was well tolerated across the dose range and there were no deaths, serious adverse events or discontinuations due to adverse events. The most commonly observed treatment-related adverse events, occurring in at least two subjects in the pooled pegozafermin group, were injection site reactions and headache, all of which were reported as mild. No clinically meaningful trends were observed in gastrointestinal events, laboratories or vital signs, including blood pressure or heart rate changes.

Phase 1b/2a Proof of Concept Clinical Trial in NASH Patients

In 2020 and 2022, the company presented positive topline results from cohorts 1 to 6 and cohort 7, respectively, in the company’s Phase 1b/2a trial in NASH patients which has informed the advancement of the company’s clinical strategy in NASH. The Phase 1b/2a trial for cohorts 1 to 6 was multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose-ranging and enrolled a total of 81 patients to receive weekly (3 mg/9 mg/18 mg/27 mg) or every two-week (18 mg/36 mg) dosing of pegozafermin or placebo for up to 12 weeks. Key endpoints assessed were safety, tolerability, and PK of pegozafermin as well as change in liver fat measured by MRI-PDFF and other metabolic markers. Cohort 7 was an open label cohort that enrolled 20 patients who received weekly dosing of pegozafermin at 27 mg for 20 weeks. Key endpoints assessed were changes in histology from baseline, liver fat changes from baseline and safety and tolerability. The trial design is shown in Figure 4 below.

Phase 2b (ENLIVEN) Trial in Fibrosis Stage 2 or 3 NASH Patients

ENLIVEN is a multicenter, randomized, double-blind, placebo-controlled Phase 2b trial in biopsy-confirmed NASH patients with fibrosis stage 2 or 3 and NAS = 4. The trial enrolled a total of 219 patients who receive either a weekly dose (15 mg or 30 mg) or an every two-week dose (44 mg) of pegozafermin in a liquid formulation or placebo for 24 weeks with a randomization schema of 4: 4: 2.5: 1 (placebo: 30 mg QW: 44 mg Q2W: 15 mg QW). All patients will continue treatment in a blinded extension phase for 24 weeks for a total treatment period of 48 weeks, with some of the placebo patients re-randomized to receive pegozafermin in the extension phase. The primary analysis will evaluate the effect of pegozafermin on the two FDA approvable histology endpoints 1-point fibrosis improvement with no worsening of NASH and NASH resolution with no worsening of fibrosis and will include patients who met histologic entry criteria F2/F3 patients and NAS = 4 based on the three-panel consensus read of biopsies at baseline to ensure consistency between baseline and end of treatment biopsy reading methods. This three-panel consensus read was instituted after receipt of data from the expansion cohort of the Phase 1b/2a trial (cohort 7) to address biopsy reading variability and increase the likelihood of showing the true benefit of pegozafermin while maintaining adequate study power. Prior to this change, biopsy entry criteria for ENLIVEN was based on a single reader. The company expects to report topline data in March 2023.

Agreements with Teva

Agreements Relating to FGF21 Program

In April 2018, the company entered into an Asset Transfer and License Agreement (the ‘FGF21 Agreement’) with Teva Pharmaceutical Industries Ltd (Teva), under which the company acquired certain patents, intellectual property and other assets relating to Teva’s glycoPEGylated FGF21 program. Under this agreement, Teva also granted a perpetual, non-exclusive (but exclusive as to pegozafermin), non-transferable, worldwide license to patents and know-how related to glycoPEGylation technology for use in the research, development, manufacture and commercialization of the compound pegozafermin and products containing pegozafermin. In addition, the company entered into a Sublicense Agreement with ratiopharm (the ‘ratiopharm Sublicense’), under which the company were granted a perpetual, exclusive, worldwide sublicense to patents and know-how related to glycoPEGylation technology used in the development, manufacture and commercialization of pegozafermin and products containing pegozafermin.

Under the FGF21 Agreement, the company is obligated to use commercially reasonable efforts to develop and commercialize pegozafermin in each of the United States and five major European countries. The company has the right to sublicense all rights licensed to the company by Teva under the FGF21 Agreement.

In April 2018, the company also entered into a reagent supply and technology transfer agreement, under which Teva supplied the company with certain reagents required for the glycoPEGylation process that are necessary for the company’s development and commercialization of pegozafermin, and transfer to the company certain know-how required for the production of such reagents. This agreement expired in accordance with its terms on December 31, 2022. The company transferred the manufacturing of such reagents to new suppliers prior to the end of 2022.

FASN Agreements

In April 2018, the company entered into an Asset Transfer and License Agreement with Teva under which the company acquired from Teva patents, intellectual property and other assets relating to Teva’s development program of small molecule inhibitors of FASN (the ‘FASN Agreement’). Under the FASN Agreement the company is obligated to use commercially reasonable efforts to develop and commercialize FASN in the United States and five major European countries. The company has the right to sublicense all rights licensed to the company by Teva under the FASN Agreement.

Government Regulation and Product Approval

The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of biologics, such as those the company is developing.

In addition to the foregoing, local, state and federal laws, including in the United States and Israel, regarding such matters as safe working conditions, manufacturing practices, environmental protection, fire hazard control and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act, and the Toxic Substances Control Act, affect the company’s business.

Suppliers

Northway Biotechpharma (‘BTPH’) is the company’s sole source supplier for pegozafermin.

Sales and Marketing

In order to commercialize any products that are approved for commercial sale, the company must either develop a sales and marketing infrastructure or collaborate with third parties that have sales and marketing experience.

The company may elect to establish the company’s own sales force to market and sell a product for which the company obtain regulatory approval if the company expect that the geographic market for a product the company develop on the company’s own is limited or that the prescriptions for the product will be written principally by a relatively small number of physicians. If the company decide to market and sell any products ourselves, the company do not expect to establish direct sales capability until shortly before the products are approved for commercial sale.

The company plan to seek third-party support from established pharmaceutical and biotechnology companies for those products that would benefit from the promotional support of a large sales and marketing force. In these cases, the company might seek to promote the company’s products in collaboration with marketing partners or rely on relationships with one or more companies with large established sales forces and distribution systems.

Intellectual Property

FGF21 Patents

The company’s FGF21 patent portfolio includes six families:

The first family is entitled ‘Remodeling and GlycoPEGylation of Fibroblast Growth Factor (FGF)’. This patent family provides granted patent protection in 39 countries around the globe, including the United States (U.S. Patent Number 9,200,049, expiry date: June 25, 2028; and U.S. Patent Number 10,874,714, expiry date: October 10, 2028), Canada, Europe (broadly), and Japan (latter three expire October 31, 2025) for FGF21 conjugates comprising a variety of modifying groups that can be attached at several different amino acid positions. GlycoPEGylated FGF21 is specifically claimed. The granted claims broadly protect the company’s lead drug candidate pegozafermin and pharmaceutical compositions thereof, as well as methods for making and using pegozafermin to treat FGF21 deficiency in a patient in need thereof.

The second family is entitled ‘Mutant FGF-21 Peptide Conjugate and Uses Thereof’ and is specifically directed to pegozafermin. The Patent Cooperation Treaty (‘PCT’) Patent Application for this family was filed on September 4, 2018 (PCT/IB2018/00112). A U.S. Prioritized Examination Continuation Patent Application (Application Serial No. 16/225,640) was filed on December 19, 2018 as a continuation of PCT/IB2018/0112 and from which U.S. Patent Number 10,407,479 was issued on September 10, 2019. The term of the U.S. Patent Number 10,407,479 is September 4, 2038. The issued claims are directed to pegozafermin and a defined genus specifically encompassing pegozafermin and compositions thereof (including site-specific mutations at positions 173 and 176), as well as methods for making and using pegozafermin for a variety of therapeutic indications. Such indications include methods for treating NASH or metabolic syndrome. Subjects where there is a need to reduce blood glucose or to reduce HbA1C include those afflicted with diabetes Type 2, NASH and metabolic syndrome. The claims encompass different therapeutic regimens for administering pegozafermin (e.g., once a week or once every two weeks), which regimens are based on pegozafermin’s surprisingly long half-life in vivo. This patent family provides granted patent protection of pegozafermin in 24 ex-United States jurisdictions around the globe: Australia, Canada, China, Europe (broadly), Israel, Japan, Korea and Hong Kong (expiry date: September 4, 2038). One U.S. Patent Application and one China Patent Application are pending in this family.

The third family is entitled ‘Methods Of Treatment Using Mutant FGF-21 Peptide Conjugates’. This patent family provides granted patent protection in United States (U.S. Patent Number 11,427,623). The term of the U.S. Patent Number 11,427,623 is September 4, 2038. One U.S. Patent Application is pending in this family.

The fourth family is entitled ‘Methods for promoting weight loss’. A PCT application was filed January 29, 2021 (PCT/IB2021/000044) with claims directed towards method to reduce total body weight, body fat content and/or BMI. A United States National phase application was filed July 20, 2022. This patent application has not yet been published.

The fifth family is entitled ‘Liquid Formulations Comprising Mutant FGF-21 Peptide Pegylated Conjugates’ with claims directed to on stable liquid formulation of FGF21. A PCT Patent Application for this family was filed on March 10, 2022. A U.S. Prioritized Examination Patent Application was filed on March 10, 2022. The company will continue to file patent applications to cover various formulations of FGF21.

The sixth family is entitled ‘Chemical Synthesis of Cytidine-5'-Monophospho-N-Glycyl-Sialic Acid’ with claims directed to the chemical synthesis of Cytidine-5'-Monophospho-N-Glycyl-Sialic Acid. A PCT Patent Application for this family was filed on December 20, 2022.

FASN Patents

The company’s FASN patent portfolio consists of three patent families, including patents and/or patent applications in the United States, the European Patent Convention, Canada, Mexico, Israel, China and Japan.

The first patent family, directed to TEV-48317, which the company acquired from Teva under the FASN Agreement, and other 1,4-substituted piperidine-based FASN inhibitors, is protected by three granted U.S. patents that cover these compounds, pharmaceutical compositions comprising these compounds, and/or methods of treating FASN-mediated disorders using these compounds. The non-extended term for these patents would expire on June 17, 2036. A pending U.S. application has also been filed. The first patent family also includes twelve foreign patents and two foreign patent applications. The second patent family is directed to other 1,4-substituted piperidine-based FASN inhibitors, pharmaceutical compositions, and methods of treating FASN-mediated disorders. The second patent family includes one granted U.S. patent, one U.S. patent application, nine foreign patents, and two foreign patent applications. The third patent family is directed to spiropiperidine FASN inhibitors, pharmaceutical compositions containing these compounds, and methods of treating FASN-mediated disorders using these compounds. The third patent family includes one granted U.S. patent, one U.S. patent application and five foreign patent applications.

Research and Development

The company’s research and development expenses were $80.8 million for the year ended December 31, 2022.

History

89bio, Inc. was founded in 2018. The company was incorporated in 2018 in Israel.