Entera Bio(ENTX) - 2022 Q4 - Annual Report

Product Development - Entera has two clinical stage product candidates: EB613 for osteoporosis and EB612 for hypoparathyroidism, both designed as first-in-class daily mini tablets of human parathyroid hormone (hPTH (1-34)) [35] - EB613 has completed Phase 2 trials with 118 patients, meeting both primary and secondary endpoints, and is expected to initiate Phase 3 registrational study in H2 2023 [43] - EB612 has received orphan drug designation from the FDA and EMA for hypoparathyroidism, with a Phase 1 PK study for a new formulation expected to begin in H1 2023 [43] - Entera's proprietary technology aims to deliver orally administered proteins with sufficient bioavailability, addressing the treatment gap in chronic diseases requiring persistent management [35] - Entera's strategy includes establishing global partnerships to diversify and shorten the development timeline of its product candidates [43] - The company is exploring additional products based on FDA-approved injectable protein therapeutics to leverage its technology platform [44] - Entera aims to shift the treatment paradigm for chronic conditions by developing first-in-class orally delivered therapies, potentially allowing patients to manage their conditions without injections [42] - The Phase 1 studies involved 72 healthy subjects, with no serious adverse events reported, and doses of oral PTH tablets up to 3 mg were well tolerated [60] - The Phase 2 study's results supported the selection of the 2.5 mg dose with a titration regimen for the proposed pivotal Phase 3 study of EB613 [71] - The pivotal Phase 3 study protocol aims to compare the effects of oral hPTH(1-34) daily tablets versus placebo on BMD in postmenopausal women with osteoporosis [78] - EB612 is the first oral formulation of PTH (1-34, teriparatide) hormone replacement treatment developed in a mini tablet form, with orphan drug designation granted by the FDA and EMA for hypoparathyroidism [84] - In a Phase 2a clinical trial, EB612 demonstrated a 42% reduction in median calcium supplement use and a 21% decrease in 24-hour urine calcium excretion [87] - The Phase 2 PK/PD trial showed an average increase of approximately 0.3 mg/dL in serum calcium and a 30% decrease in 24-hour urinary calcium on the day of treatment compared to baseline [87] Market Opportunity - The U.S. has an estimated 10.2 million individuals with osteoporosis, with over 2 million related fractures occurring annually, leading to costs of approximately $25.3 billion by 2025 [50] - Current anabolic therapies for osteoporosis require injections, with less than 10% of patients using these due to inconvenience and pain associated with injections [59] - The global market for osteoporosis treatments is significant, with the peak annual sales of Forteo (teriparatide) reaching $1.7 billion prior to patent expiration [47] - Approximately 200,000 people are affected by hypoparathyroidism in the US, EU, and Japan, with a significant unmet need for effective treatments [81] - The current standard of care for hypoparathyroidism involves high doses of calcium and vitamin D, which can lead to severe long-term morbidities [82] - Natpara®, an injectable PTH treatment, was recalled in 2019 and will be permanently phased out by the end of 2024, creating a market opportunity for new therapies [83] Clinical Trial Results - In the Phase 2 study, a dose of 2.5 mg EB613 daily tablets showed statistically significant increases in bone formation markers P1NP and Osteocalcin at Month 3 (p<0.05 and P<0.01, respectively) [66] - The placebo-adjusted increase in total hip BMD was 1.84% and femoral neck BMD was 2.76% for the 2.5 mg EB613 group, both statistically significant (P<0.02 and P<0.002, respectively) [69] - The FDA agreed that total hip BMD could serve as the primary endpoint for the registrational study of EB613 in post-menopausal women with osteoporosis [76] Regulatory Environment - The FDA regulates the company's product candidates under the Federal Food, Drug, and Cosmetic Act, requiring substantial time and financial resources for compliance [115] - The process for obtaining FDA approval involves multiple steps, including preclinical studies, IND application, and clinical trials [118] - Clinical trials are conducted in three phases, with annual progress reports required to be submitted to the FDA [124] - The FDA requires compliance with Current Good Manufacturing Practice (cGMP) before approving a New Drug Application (NDA) or Biologics License Application (BLA) to ensure consistent production within required specifications [127] - The FDA has 60 days to conduct an initial review of an NDA or BLA submission to determine if it is sufficient for filing, followed by a ten-month review period for standard applications and six months for priority reviews [131] - The FDA may designate a product for fast track review if it addresses an unmet medical need for a serious condition, allowing for greater interactions with the FDA during the review process [139] - The FDA may issue an Emergency Use Authorization (EUA) for unapproved drugs during a designated emergency, which is product-specific and subject to specific conditions [142] - The FDA may require post-approval studies, including Phase 4 clinical trials, to further assess a product's safety after approval [136] - The FDA can withdraw approval if compliance with regulatory requirements is not maintained or if new problems are discovered post-market [151] Financial Overview - The company incurred net losses of $13.1 million in 2022 and $12.2 million in 2021, with an accumulated deficit of $95.5 million as of December 31, 2022 [216] - The company expects to continue incurring substantial losses for the next several years, particularly as it develops EB613 and EB612, and anticipates significant net losses and accumulated deficits during this period [216] - Existing cash and cash equivalents are projected to fund operations into the third quarter of 2024, assuming no delays in securing additional capital or entering strategic collaborations [216] - The company has raised substantial doubt about its ability to continue as a going concern, depending on its ability to obtain additional financing [217] - The company anticipates needing substantial additional funding to support the execution of its long-term growth strategy, including a potential Phase 3 trial of EB613 and further development of EB612 [221] Collaboration and Partnerships - The company has a collaboration with Amgen, receiving an initial technology access fee of $725,000 and is eligible for up to $270 million in milestone payments [94] - The company aims to maximize the value of its product candidates by either independently commercializing them or seeking collaborations with third parties [103] Compliance and Legal Risks - The company is subject to significant legal, accounting, and compliance costs as a public company listed on Nasdaq, which may strain resources and distract management [232] - The company is subject to ongoing government regulation, and failure to comply could delay or prevent the marketing of its products [215] - Legislative changes, including increased rebates and mandatory discounts under the ACA, may reduce the profitability of drug products [201] - The U.S. government and third-party payers are increasingly scrutinizing drug pricing, which could adversely affect the marketability of the company's products [200] - The company faces significant barriers to entry for new products due to intense downward pressure on healthcare costs and pricing controls in various countries [199]