Entera Bio Stock

Entera Bio Ltd. (Entera) operates as a clinical-stage biopharmaceutical company. The company focuses on the development and commercialization of orally delivered large molecule therapeutics for use in areas with significant unmet medical need and where adoption of injectable therapies is limited due to cost, convenience and compliance challenges for patients.

The company's most advanced product candidates, EB613 for the treatment of osteoporosis and EB612 for the treatment of hypoparathyroidism, are based on its proprietary technology platform and are both in clinical development. Additionally, the company intends to license its oral delivery technology to biopharmaceutical companies for use with their proprietary compounds.

The company focuses on the development of orally delivered macromolecule therapeutics, including peptides and therapeutic proteins. Entera's proprietary technology is designed to deliver orally administered proteins with sufficient bioavailability to meet treatment goals, using white mini tablets of the desired protein.

The company strategically focuses on underserved, chronic medical conditions where oral administration of a mini tablet peptide or peptide replacement therapy has the potential to significantly shift a treatment paradigm.

The company has two product candidates in the clinical stage of development: EB613 and EB612. Both candidates are first-in-class daily mini tablets of human parathyroid hormone (hPTH (1-34), teriparatide). Entera's proprietary PTH tablets have been safely administered to a total of 72 healthy subjects in Phase 1 studies and 153 patients across Phase 2 studies in osteoporosis and hypoparathyroidism, two diseases that remain underserved with the standard of care and which disproportionately affect women. In addition to these product candidates, it has various internal early stage research programs in other approved peptides such as GLP-2 and hGH, as well as outside early stage collaborations to potentially diversify its revenue stream.

Pipeline

Product Candidates

The company retains global rights to both EB613 and EB612. The company's lead product candidates, EB613 for the treatment of osteoporosis and EB612 for the treatment of hypoparathyroidism are first-in-class mini tablet formulations of synthetic human PTH (1-34) (teriparatide), designed to have differing pharmacokinetic, or PK, profiles.

Additionally, given its expertise in oral PTH, the company investigates the efficacy of alternative oral PTH tablets for the treatment of delayed-union or non-union fractures independently or in collaboration with a strategic partner.

EB613: First Daily Osteoanabolic Mini Tablets for the Treatment of Osteoporosis

EB613 is the first once daily mini tablet formulation of hPTH (1-34), (teriparatide) and has the same amino acid sequence as Forteoâ (teriparatide daily subcutaneous injection), a leading anabolic agent.

In July 2022, the company engages a third-party firm to conduct primary market research with endocrinologist and general practice clinicians who treat osteoporosis patients and to analyze prescription and sales data for osteoporosis treatments.

In the first Phase 1a study of 42 healthy subjects, escalating single doses of oral PTH tablets containing up to 1.8 mg of hPTH(1-34) were well tolerated. There were no serious adverse events (SAEs) reported. In the subsequent Phase 1b study of 30 healthy subjects, single doses of five formulations of oral PTH tablets containing up to 3 mg of hPTH(1-34), administered collectively a total of 280 times were well tolerated, with no SAEs reported.

The Phase 2 clinical trial of EB613 was a dose-ranging, placebo-controlled, double-blind study in 161 postmenopausal women with osteoporosis or low BMD conducted at four leading medical centers in Israel. The trial evaluated 0.5 mg to 2.5 mg daily tablets on BMD, pharmacodynamic bone markers, including P1NP and Osteocalcin - bone formation markers, CTX - a bone resorption marker, and various safety endpoints. The initial treatment regimen included a top dose of 1.5 mg.

After successful completion of the Phase 2 dose ranging study of EB613, the company held an end-of-Phase 2 meeting at the end of 2021 with the FDA to discuss various aspects of its nonclinical and clinical development plan.

Early in the first quarter of 2022, Entera received EOP2 minutes from the FDA, suggesting that a non-inferiority head-to-head study versus Forteo Phase 3 design may not be favorable to the success of the study and potential approvability of EB613 oral PTH tablets.

The company subsequently requested an additional EOP2 to the FDA to seek agreement on the specifications and control of the drug substance, drug product and excipients to support the Phase 3 study and eventual product registration. The company received a written response from the FDA towards the end of the first quarter of 2022, confirming that the specifications for the drug substance, excipients and drug product appear reasonable and that final determination on the adequacy of the proposed excipients and drug product specification will be made during the NDA review. The FDA also provided guidance regarding the proposed process scale-up, process qualification approach and stability plan for EB613.

EB612: First Daily PTH Replacement Therapy Tablets for the Treatment of Hypoparathyroidism

The company's product candidate for hypoparathyroidism, EB612, is the first oral formulation of PTH (1-34, teriparatide) hormone replacement treatment developed in a mini tablet form. The FDA and the EMA have granted EB612 orphan drug designation for the treatment of hypoparathyroidism.

In 2015, the company successfully completed a multicenter Phase 2a clinical trial of EB612 in hypoparathyroidism patients. This study demonstrated the safety and tolerability of EB612 administered four times daily for 16 weeks to patients with hypoparathyroidism. In this study, patients were titrated up to a maximum of 12 EB612 0.75 mg tablets a day (total daily dose of 9 mg) according to each subject's albumin-adjusted serum calcium (ACa), and supplement treatment regimen. Of the 19 enrolled patients, 17 completed the trial. No drug-related serious adverse events were reported and most of the adverse events were not considered study drug-related.

The company has initiated a two-part Phase 2 PK/PD trial in 2014. This trial was designed to provide a bridge from one of its completed Phase 2a trials, which was conducted prior to the marketing approval of Natpara, and its planned future clinical trials, and to also allow it to better understand the relative strength and dose of its product as compared to the then marketed product, Natpara.

In 2018, the company announced the completion of part I of this Phase 2 PK/PD trial which showed an increase in the serum calcium by an average of approximately 0.3 mg/dL over baseline, with such increase maintained over a 24-hour period; a decrease in serum phosphate by an average of 0.5 mg/dL below baseline with such decrease maintained over a 24-hour period; an increase in average levels of serum active vitamin D of approximately 90% on the day of treatment as compared to baseline; and a decrease in average levels of 24-hour urinary calcium of approximately 30% on the day of treatment as compared to baseline.

The second part of the PK/PD trial evaluated a variety of dosing treatment regimens with a high and low dose of EB612, as well as Natpara with patients also receiving calcium supplements and either alfacalcidol or calcitriol.

The company has developed an improved formulation of EB612 based on new intellectual property, which it has designed to optimize its PK profile and the potential for reduced daily dosing. The company anticipates that the outcome of the PK study will help determine the design of a Phase 2/3 trial of EB612 in patients with hypoparathyroidism. If successful, the phase 2/3 clinical trial of EB612 in hypoparathyroidism may potentially support a submission for regulatory approval of EB612.

The company's proprietary technology is designed to address both issues by utilizing a combination of a synthetic absorption enhancer, or carrier molecule, to facilitate the enhanced absorption of large molecules, and protease inhibitors to prevent enzymatic degradation. By designing its product candidates to address both the issues of absorption and degradation, it has been able to significantly increase bioavailability and decrease the variability of the PTH dose delivered in its clinical trials. The company selects protease inhibitors and other excipients that act by specifically inhibiting several gastrointestinal enzymes designed to assist in the degradation and digestion of proteins without interfering with normal gastrointestinal activity.

Development and License Agreements

In addition to the development of the company's product candidates, it has an early-stage research collaboration and license agreement with Amgen, Inc. (Amgen) centered on combining its proprietary drug delivery platform with drugs selected by Amgen to create new products.

Strategy

The key elements of the company's strategy include advancing EB613, potentially the first daily anabolic PTH mini tablet into Phase 3 for the treatment of post-menopausal women with low bone mass and osteoporosis; advancing the new formulation of EB612 through clinical development as the first daily PTH mini tablet for the treatment of hypoparathyroidism; establishing select global and regional development and commercial partnerships; and identifying and developing additional products internally based on FDA-approved injectable protein therapeutics.

Intellectual Property

Patent Rights

As of March 27, 2023, the company's global patent portfolio included the following patents and patent applications:

Patents claiming compositions comprising a protein, an absorption enhancer and a protease inhibitor as well as methods for oral administration of a protein with an enzymatic activity, which compositions cover EB612 and EB613, have been issued in the United States, Australia, Japan, China, Hong Kong, Israel, Canada, New Zealand, and Russia and have been granted by the European Patent Office (EPO) and validated accordingly in Belgium, France, Germany, Great Britain, Ireland, Italy, Liechtenstein, Luxembourg, the Netherlands, Spain, Sweden, and Switzerland. Related patent applications are pending before the European Patent Office (EPO) and in the United States, Hong Kong, Brazil, China, and India. Patents specifically covering PTH have already been granted in the United States, Hong Kong, Israel, Russia, and Japan, and have been granted by the EPO and validated in Belgium, France, Germany, Great Britain, Ireland, Italy, Liechtenstein, Luxembourg, the Netherlands, Spain, Sweden, and Switzerland. In addition, patent applications which specifically cover PTH are pending in Hong Kong, Brazil, China, and India. The issued patent in China is limited to insulin. This issued patent and any patent that may issue from the pending patent applications are expected to expire in August 2029, assuming all annuity and maintenance payments are paid thereon. Rights to these patents and patent applications were assigned to the company pursuant to the Patent Transfer Agreement with Oramed Ltd. (Oramed).

An application covering certain formulations with a controlled absorption profile was filed with the European Patent Office (EPO) and in the United States, Canada, Hong Kong, Israel, and Mexico. Other patent applications covering certain formulations for co-administration with an antacid or protease inhibitor was filed with the EPO and in the United States, Canada, and Hong Kong. Any patents that issue from these patent applications are expected to expire in February 2036, assuming all annuity and maintenance payments are paid thereon. Another application covering certain formulations and regimens was filed with the EPO and in the United States, Australia, Brazil, Canada, China, Hong Kong, India, Israel, Japan, Mexico, New Zealand, Singapore, South Africa, and South Korea. Any patents that issue from this patent application are expected to expire in August 2037, assuming all annuity and maintenance payments are paid thereon.

Three patent applications filed in various jurisdictions, which if issued as patents containing substantially the same claims as those in the applications, would contain method of treatment claims covering the use of orally administered PTH for the treatment of osteoporosis (filed with the EPO and in the United States, Canada, China, Hong Kong, Israel and Japan; and the application in Japan has been granted, and a divisional applications has been filed therein), hypoparathyroidism (filed with the EPO and in the United States, Brazil, Canada, Hong Kong, Israel and Japan; and the application in Japan has been granted, and a divisional applications has been filed therein) and bone fractures and related conditions (filed with the EPO and in the United States, Canada and Hong Kong). Any patents that issue from these patent applications are expected to expire in February 2036, assuming all annuity and maintenance payments are paid thereon, and while not considering patent term extension when applicable.

Seven international PCT patent applications have been filed in 2023, which if issued as patents containing substantially the same claims as those in the applications, would cover new discoveries for the oral delivery of large molecules. Any patents that issue from these patent applications are expected to expire in February 2043, assuming all annuity and maintenance payments are paid thereon and while not considering patent term extension when applicable.

The company holds global rights to all of its internally developed product candidates (including EB613 and EB612), which provide it the optionality to grow its internal pipeline independently or license selected rights to its product candidates in different geographies or throughout the world.

Research and Development

For the year ended December 31, 2022, the company's research and development expenses were $5.8 million.

Government Regulation and Product Approval

In the United States, the company's product candidates are regulated by the FDA as drugs under the Federal Food, Drug, and Cosmetic Act, or the FDCA, the Public Health Service Act, or the PHSA, and regulations implemented by the FDA. The company's activities require permits from various governmental authorities, including local municipal authorities, the Ministry of Environmental Protection, and the Ministry of Health.

History

Entera Bio Ltd. was founded in 2009. The company was incorporated as a limited liability company under the laws of the state of Israel in 2009.