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Item 1. Business

2025-03-28 compared with 2024-03-08 · 173 added, 145 removed, 540 unchanged (37% of the section changed)

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We focus on underserved, chronic medical conditions for which oral administration of a protein therapy has the potential to significantly shift a treatment paradigm.

Our pipeline includes five differentiated, first-in-class oral peptide programs targeting PTH(1-34), GLP-1 and GLP-2:

Currently, most protein therapies are administered via frequent intravenous, subcutaneous or intramuscular injections.

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From a technical standpoint, oral delivery of therapeutic proteins is challenging due to the enzymatic degradation within the gastrointestinal tract and poor absorption into the blood stream due to the protein’s polarity and molecular weight.

We leverage our N-Tab™ oral delivery technology, which is designed to simultaneously stabilize the peptide in the gastrointestinal tract and promote its absorption into the bloodstream.

The following chart summarizes the current stage of development for each of our oral peptide candidates.

Oral PTH(1-34) Programs

Our most advanced product candidate, EB613, oral PTH (1-34), is being developed as the first oral, osteoanabolic (bone building) once-daily tablet treatment for post-menopausal women with low bone mineral density (“BMD”) and high-risk osteoporosis with no prior fracture.

We leverage our N-Tab™ platform, which is designed to simultaneously stabilize the peptide in the gastrointestinal tract and promote its absorption into the bloodstream.

EB613 Program

Our most advanced product candidate, EB613, oral PTH(1-34), is being developed as the first oral, osteoanabolic (bone building) once-daily tablet treatment for post-menopausal women with low bone mineral density (“BMD”) and high-risk osteoporosis.

Anabolic drugs are indicated for the treatment of very high-risk osteoporosis patients as first line therapy and as second line treatment in osteoporosis patients who cannot tolerate or progress on other osteoporosis drugs.

Despite the superior efficacy of anabolic drugs, existing treatments require daily or monthly subcutaneous injections and are used in a minority of very high-risk patients.

EB613 is intended to provide an oral anabolic treatment earlier in an osteoporosis patient’s journey to increase skeletal mass, reduce the risk of fracture and consequently limit the progression of the disease, and its associated disability and mortality.

A placebo controlled, dose ranging Phase 2 study of EB613 tablets (n= 161) met primary (pharmacodynamic/bone turnover biomarker) and secondary endpoints (BMD).

Following the completion of a Type C and a Type D meeting with the U.S.

Food and Drug Administration’s (FDA), we announced the FDA’s concurrence that a 2-year, placebo-controlled phase 3 (registrational) study with Total Hip BMD as primary endpoint could support a new drug application (“NDA”) for EB613.

In November 2023, we reported that the American Society for Bone and Mineral Research (ASBMR) announced that the SABRE (Strategy to Advance BMD as a Regulatory Endpoint) project team had submitted its full qualification plan to the FDA for the use of BMD as a surrogate endpoint for fractures in future trials of new anti-osteoporosis drugs.

The highest EB613 oral PTH tablet dose (2.5 mg), produced an increase in markers of bone formation while simultaneously decreasing the markers of bone breakdown.

Significant gains in bone mineral density of the spine and hip were observed at the end of the 6-month study and there were no significant safety concerns.

In April 2024, the phase 2 data was published in the Journal of Bone and Mineral Research (JBMR).

Regulatory Background

Initial approvals of drugs for the treatment of osteoporosis have required a placebo-controlled trial demonstrating reduction in the risk of fractures as the primary outcome measure in women with postmenopausal osteoporosis.

The regulatory requirement for using fracture as the primary efficacy endpoint is challenging due to the patient types who would need to be studied:

(1) very high risk patients may be randomized to placebo in a clinical trial, which poses an ethical concern;

and (2) evaluation of moderate risk patients would require a very large sample size to evaluate treatment effectiveness.

The last drug approval for osteoporosis occurred in 2019.

In the United States, the Foundation for the National Institute of Health-American Society for Bone and Mineral Research-Study to Advance BMD as a Regulatory Endpoint (FNIH-ASBMR-SABRE, previously known as the FNIH-Bone Quality Project [FNIH-BQP], hereinafter SABRE) was launched in 2013.

This initiative was established as a public-private partnership with the Federal Drug Administration (FDA) to study whether change in BMD at the lumbar spine, total hip or femoral neck in a placebo-controlled trial of an osteoporosis drug was predictive of vertebral, nonvertebral, hip and all clinical fracture risk reduction.

SABRE aims to change the framework for how clinical trials of new anti-osteoporosis drugs are conducted and to promote innovation in the field of osteoporosis.

The FNIH-ASBMR-SABRE working group obtained treatment group-level and patient-level BMD and fracture incidence data from the sponsors of most of the approved osteoporosis drug treatments including individual patient data from 53 clinical trials covering 176,750 individuals across seven osteoporosis drug classes (Black et al., 2020;

Eastell et al., 2022;

Vilaca & Eastell, 2024).

Based on a meta-regression analysis to assess the relationship between change in total hip BMD (active-placebo) and the anti-fracture effect in randomized clinical trials for each fracture type, the SABRE group demonstrated that treatment-related change in total hip BMD is best associated with fracture reduction.

Following Type C and Type D meetings with the FDA in March 2023, we announced the FDA’s concurrence that a 2-year, placebo-controlled phase 3 (registrational) study with Total Hip BMD as primary endpoint could support a new drug application (“NDA”) for EB613;

however the SABRE BMD endpoint remained unqualified as a surrogate endpoint by FDA at that time.

In November 2023, the ASBMR announced that the SABRE project team had submitted its full qualification plan to the FDA for the use of BMD as a surrogate endpoint for fractures in future trials of new anti-osteoporosis drugs.

In March 2024, the ASBMR announced that the FDA had communicated to the SABRE project team that a ruling to qualify the treatment-related change in bone mineral density (BMD) as a surrogate endpoint for fractures in future trials of new anti-osteoporosis drugs would be provided within 10 months.

The EB613 osteoporosis clinical program has been developed under the auspices of this new approach to osteoporosis drug development.

We believe EB613 stands as the first program to potentially avail itself of the ASBMR-SABRE BMD endpoint.

The EB612 program is being developed as the first oral PTH(1-34) tablet peptide replacement tablet therapy for hypoparathyroidism.

SABRE is expected to provide an update on its FDA interactions and the qualification of the BMD endpoint in 2025.

EB612 Program

Our product candidate, EB612, is being developed as the first oral PTH(1-34) tablet peptide replacement therapy for patients with hypoparathyroidism.

With respect to our EB612 program, we are currently testing new generations of our N-Tab™ Technology with the naked PTH(1-34) peptide to assess the effectiveness of once or twice a day dosing regimens, as well as collaborating with a third party on another peptide in this field.

In June 2024, Phase 1 clinical data for EB612 was presented at the Endocrine Society ENDO 2024 Annual Meeting.

The data reported from this Phase 1 clinical study include pharmacokinetic (PK), pharmacodynamic (PD) and safety results from the application of a new generation of Entera’s N-Tab™ technology platform and EB612, the active peptide fragment 1-34 of the N-terminal region of human parathyroid hormone (teriparatide) dosed twice a day (BID).

Significant systemic exposure was reported following both administrations of EB612 tablets.

Aside from positive PK measures, sustainable PD effects were reported, including serum levels of calcium (albumin corrected), phosphate, and 1,25(OH)2-Vitamin D (reaching +3.9%, -20.8%, and +73.2% change on average from baseline, respectively) and decreased endogenous serum PTH(1-84) (reaching -43.0% change on average from baseline).

There were no treatment-emergent Adverse Events of hypercalcemia reported.

There were no treatment-emergent Serious AEs.

The only Study Drug-Related AE was mild headache, reported in two out of fifteen subjects.

No significant findings were observed in blood and urine lab tests.

All vital signs were within the normal range.

To date, Entera’s proprietary PTH tablets have been safely administered to a total of 102 healthy subjects in Phase 1 studies and 153 patients in Phase 2 studies in osteoporosis and hypoparathyroidism, two diseases that remain underserved with the current standard of care and which disproportionately affect women.

We believe these product candidates, if approved, hold the potential to become standards of care for patients with osteoporosis and hypoparathyroidism.

Our ability to deliver our oral PTH(1-34) peptide in a simple mini tablet format with reproduceable, dose dependent pharmacokinetics and rapid biological responses across gender, age, and health status was highlighted as part of two poster sessions at the ASBMR 2023 Annual Meeting.

Our ability to deliver our oral PTH(1-34) peptide in a simple tablet format with reproduceable, dose dependent pharmacokinetics and rapid biological responses across gender, age, and health status was highlighted as part of two poster sessions at the ASBMR 2023 Annual Meeting.

We believe our work to date has built the foundation for our oral PTH(1-34) tablets to potentially treat diverse patient populations, including younger men and women athletes at risk of stress fractures.

We are exploring the use of our PTH(1-34) tablets for the treatment of stress fractures in athletes and expect to collaborate with an investigator sponsored study in this area.

More details on this study are expected in the second half of 2024.

Oral GLP-2 and Oral GLP-1/Glucagon Programs in Collaboration with OPKO Biologics

In May 2023, the results from our oral GLP-2 program were published in the International Journal of Peptide Research and Therapeutics, “Oral Delivery Technology Enabling Gastro-Mucosal Absorption of Glucagon-Like-Peptide-2 Analog (Teduglutide) - A Novel Approach for Injection-Free Treatment of Short Bowel Syndrome.” We believe GLP-2 represents a strong candidate for our N-Tab™ Technology and warrants further development as an injection-free alternative to patients suffering from short bowel syndrome and other gastrointestinal disorders where GLP-2 plays a role.

In September 2023, we entered into a research collaboration agreement with OPKO Biologics, Inc., a subsidiary of OPKO Health, Inc.

Under the terms of this agreement, OPKO has agreed to supply its proprietary long-acting GLP-2 peptide and certain Oxyntomodulin analogs for the development of oral tablet formulations using our proprietary N-Tab™ technology.

Oxyntomodulin (OXM) is a naturally occurring peptide hormone found in the colon, with glucagon-like-peptide 1 (GLP-1) and glucagon dual agonist activity which suppresses appetite and induces weight loss.

OPKO has developed several proprietary, modified OXM analogs as potential candidates for treating obesity, including an injectable pegylated peptide which demonstrated significant reductions in weight loss and decreased plasma triglyceride levels in over 430 patients in phase 2/2B studies.

We expect in vivo PK/PD data from both the oral GLP-2 tablet program and the oral OXM tablet program in 2024.

We and OPKO have each agreed to be responsible for specific phases of development of the two oral peptides to the point of demonstrated in vivo feasibility.

Our goal is to develop first-in-class orally delivered therapies for underserved, chronic medical conditions for which a tablet peptide or peptide replacement therapy has the potential to significantly shift a treatment paradigm.

We are developing our product candidates to potentially become the first oral, daily tablet peptide or peptide replacement therapies designed for patients to live injection-free as they actively manage their chronic diseases.

Oral GLP-2 and Oral GLP-1/Glucagon Programs in Collaboration with OPKO Health

In May 2023, the results from our oral glucagon-like-peptide 2 (GLP-2) program were published in the International Journal of Peptide Research and Therapeutics, “Oral Delivery Technology Enabling Gastro-Mucosal Absorption of Glucagon-Like-Peptide-2 Analog (Teduglutide, Gattex®) - A Novel Approach for Injection-Free Treatment of Short Bowel Syndrome.” We believe GLP-2 represents a strong candidate for our N-Tab™ technology and warrants further development as an injection-free alternative to patients suffering from short bowel syndrome and other gastrointestinal disorders where GLP-2 plays a role.

In September 2023, we entered into a research collaboration agreement (the “2023 Collaboration Agreement”) with OPKO Biologics, Inc., a subsidiary of OPKO Health, Inc.

Under the terms of this agreement, OPKO has agreed to supply its proprietary long-acting GLP-2 peptide and certain Oxyntomodulin (OXM) analogs for the development of oral tablet candidates using our proprietary N-Tab™ technology.

In March 2024, we announced positive in vivo pharmacokinetic (PK) results from our collaborative research, combining a proprietary long acting GLP-2 agonist developed by OPKO with Entera’s proprietary N-Tab™ technology.

The program is focused on developing the first GLP-2 peptide tablet alternative for patients suffering from short bowel syndrome and additional disorders involving mucosal inflammation and nutrient malabsorption.

Currently, the only approved GLP-2 agonist, which is marketed under the name Gattex® (teduglutide), requires daily sub-cutaneous injections.

Zealand Pharma and Ironwood are developing long acting GLP-2 therapies requiring once and twice weekly injections.

Entera and OPKO completed a proof of concept (PoC) single dose pharmacokinetic study in rodents.

Oral GLP-2 tablets exhibited significant systemic exposure.

Furthermore, plasma levels achieved with the oral tablet form of the GLP-2 analogue were about 10-fold higher than therapeutic plasma concentrations reported for subcutaneously administered teduglutide (Gattex® label).

The pharmacokinetic analysis of the data obtained following the IV injections of the GLP-2 peptide showed the plasma half-life in rats to be about six times longer than the half-life reported for teduglutide in the same animal model.

This data is consistent with previously reported PK data relating to OPKO’s GLP-2 peptide’s long-acting profile, which had initially been developed as a weekly subcutaneous injection.

Given the challenging compliance rates attributed to injectable GLP-2 therapy and heterogeneity of SBS patients, we believe a daily tablet format may address a significant unmet need in treating and titrating SBS patients more effectively than injectable alternatives.

Oral GLP-1/Glucagon

OXM is a naturally occurring GLP-1/Glucagon dual agonist peptide hormone found in the small intestine that acts to suppress appetite, induce weight loss and has additional cardioprotective and anti-fibrotic attributes.

The program is focused on developing the first oral dual agonist GLP-1/Glucagon peptide as a potential once-daily tablet treatment for patients with obesity and metabolic disorders using the N-Tab™ platform.

Currently, there are no approved dual GLP-1/Glucagon agonists available.

OPKO previously reported that weekly injections of pegylated OXM demonstrated significant weight loss and reduction in HbA1, triglyceride and cholesterol levels in 113 obese and diabetic patients in a Phase 2B study.

The OXM agonist peptide (OPK-88006) is a GLP-1/Glucagon dual agonist peptide that has been modified to maintain its long-acting profile while increasing its potential potency.

The program combines OPKO’s (OPK-88006) and Entera’s proprietary N-Tab™ technology.

In September 2024, we jointly announced with OPKO topline pharmacokinetic/pharmacodynamic (PK/PD) results for the OXM program.

Oral OXM exhibited significant systemic exposure across two in vivo models, a favorable PK profile and bioavailability.

The high plasma concentrations with prolonged systemic exposure were consistent with the reported half-life for semaglutide (Rybelsus®), the only approved oral GLP-1 analog.

Oral OXM showed a statistically significant reduction in plasma glucose levels compared with placebo.

Additionally, in March 2025, we entered into a collaboration and license agreement with OPKO (the “2025 Collaboration Agreement”) with respect to the preclinical and clinical development and decision making related to the Oral OXM program for the treatment of obesity, metabolic and fibrotic disorders in humans.

For additional information, see Item 7.

Management’s Discussion and Analysis of Financial Condition and Results of Operations—Recent Developments—License and Collaboration Agreement with OPKO, contained in this Annual Report.

Given the scarcity of oral peptide treatments and potential safety challenges attributed to small molecule approaches, we believe Oral OXM may address a significant number of patients suffering from chronic metabolic diseases.

We plan to file an Investigational New Drug application with the FDA later this year.

Our goal is to develop first-in-class oral peptides and protein replacement therapies for underserved, chronic medical conditions for which a tablet treatment has the potential to significantly shift a treatment paradigm.

We are developing our product candidates to potentially become the first oral, daily tablet peptide or protein replacement therapies designed for patients to live injection-free as they actively manage their chronic diseases.

We aspire to continue to validate our platform across a variety of additional high value therapeutic proteins.

Our strategy to achieve these goals includes:

• Advancing EB613, Potentially the First Daily Anabolic PTH(1-34) Tablet into Phase 3 for the Treatment of Post-Menopausal Women with Low Bone Mass and Osteoporosis :

Our six-month placebo-controlled Phase 2 double-blind, dose-ranging trial of EB613 in 161 patients with low bone mass and osteoporosis met both primary and secondary endpoints and was selected for oral presentation at the American Society of Bone Mineral Research (ASBMR) annual conference in 2021.

Based on the outcome of our October 2022 Type C meeting with the FDA, we believe that EB613 may be the first osteoporosis program to be permitted by FDA to pursue a placebo controlled, BMD endpoint registrational Phase 3 study to support a NDA.

We view this outcome as testament to the treatment gap and unmet need for a viable alternative to treat the millions of osteoporosis patients who, despite current guidelines and availability of highly efficacious anabolic agents, are unwilling to take daily or monthly injections.

We are preparing to initiate a Phase 3 registrational study for EB613 pursuant to the FDA’s qualification of a quantitative BMD endpoint which is expected to occur in 2024.

• Advancing EB613, Potentially the First Daily Anabolic PTH(1-34) Tablet Treatment into Phase 3 for the Treatment of Post-Menopausal Women with Low Bone Mass and Osteoporosis :

Our six-month placebo-controlled Phase 2 double-blind, dose-ranging trial of EB613 in 161 patients with low bone mass and osteoporosis met both primary and secondary endpoints was selected for oral presentation at the ASBMR annual conference in 2021 and published at JBMR in March 2024.

Based on the outcomes of our FDA meetings, we believe that EB613 may be the first osteoporosis program to be permitted by FDA to pursue a placebo controlled, BMD endpoint registrational Phase 3 study to support an NDA.

We view this potential outcome as testament to the treatment gap and unmet need for a viable alternative to treat the millions of osteoporosis patients who, despite current guidelines and availability of highly efficacious injectable anabolic agents, remain undertreated.

We are preparing to initiate a Phase 3 registrational study for EB613 pursuant to the FDA’s qualification of a quantitative BMD endpoint, which we currently expect to occur in 2025.

• Advancing the First Daily PTH(1-34) Peptide Replacement Tablet Therapy for the Treatment of Hypoparathyroidism:

In 2015, we successfully completed a Phase 2a four-month trial in 19 patients with hypoparathyroidism which demonstrated clinical benefit, including a statistically significant reduction in calcium supplementation, maintenance of calcium levels above the lower target level for Hypoparathyroidism patients (>7.5 mg/dL) throughout the study and statistically significant rapid decline in median serum phosphate levels two hours following the first dose, which was maintained for the duration of the study.

The FDA and the European Medicines Agency, or EMA, have granted EB612 orphan drug designation for the treatment of hypoparathyroidism.

With respect to our EB612 program, we are currently testing new generations of our N-Tab™ Technology with the naked PTH(1-34) peptide to assess the effectiveness of once or twice a day dosing regimens as well as collaborating with a third party on another peptide in this field.

The FDA and the European Medicines Agency (“EMA”) have granted EB612 orphan drug designation for the treatment of hypoparathyroidism.

In addition, we continue to collaborate productively with a third party on the oral tablet development of another PTH replacement treatment for hypoparathyroidism.

• Identifying and Developing Potentially High Value Oral Peptides in Collaboration with Strategic Partners such as our Oral GLP-2 and Oxyntomodulin (Oral GLP-1/Glucagon ) Programs with OPKO:

We intend to leverage our N-Tab™ platform by applying it to the development of additional, currently approved injectable peptides and therapeutic proteins with known mechanisms of action and established safety profiles.

We believe this will allow us to advance our product candidates more efficiently and predictably through the research and clinical development cycle.

For example, in collaboration with OPKO, we are focusing on the development of the first oral OXM, a dual targeted GLP1/glucagon peptide, in tablet form for the treatment of metabolic disorders and the first oral GLP-2 peptide tablet as an injection-free alternative for patients suffering from rare malabsorption conditions, such as short bowel syndrome.

Both these peptides have well characterized pre-clinical PK/PD and toxicology.

• Establishing Select Global and Regional Development and Commercial Partnerships :

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We intend to explore opportunities to diversify and shorten the preclinical and clinical development of these candidates in a capital-efficient manner, including selectively pursuing research and clinical development partnerships with biopharmaceutical companies with specific domain expertise as well as with biopharmaceutical companies with proven commercial footprints to de-risk our late-stage programs.

• Identifying and Developing Potentially High Value Oral Peptides in Collaboration with Strategic Partners such as our GLP-2 and Oxyntomodulin Programs:

We intend to leverage our N-Tab™ Technology platform by applying it to the development of additional, currently approved injectable peptides and therapeutic proteins with known mechanisms of action and established safety profiles.

We believe this will allow us to advance our product candidates more efficiently and predictably through the research and clinical development cycle.

For example, in collaboration with OPKO, we are focusing on the development of the first oral OXM, a dual targeted GLP1/glucagon peptide, in tablet form for the treatment of obesity and the first oral GLP-2 peptide tablet as an injection-free alternative for patients suffering from rare malabsorption conditions, such as short bowel syndrome.

Both these peptides have well characterized pre-clinical PK/PD and toxicology.

Parathyroid hormone (PTH) is an 84-amino acid hormone that regulates calcium and phosphate homeostasis and bone metabolism in the body.

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Forteo® requires a daily subcutaneous injection.

First Daily Osteoanabolic Mini Tablets for the Treatment of Osteoporosis

EB613 is the first once daily tablet formulation of hPTH (1-34), (teriparatide) and has the same amino acid sequence as Forteo ® (teriparatide daily subcutaneous injection), a leading anabolic agent which achieved peak annual sales of $1.7 billion prior to patent expiration.

First Daily Osteoanabolic Tablet Treatment for the Treatment of Osteoporosis

EB613 is the first once daily PTH (1-34, teriparatide) tablet treatment, and has the same amino acid sequence as Forteo ® (teriparatide daily subcutaneous injection), a leading anabolic agent which has been marketed for 23 years, and achieved peak annual sales of $1.7 billion prior to patent expiration in 2018.

Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, which leads to greater fragility of bones and an increase in fracture risk.

Osteoporosis is a serious condition that can result in pain, permanent disability, loss of independence and often death.

One in three women over age 50 will develop osteoporosis, and one in two women aged 50 and older will develop an osteoporosis-related fracture.

Osteoporosis is most frequently associated with menopause in women, aging in both women and men and glucocorticoid steroid use (greater than three months).

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Furthermore, it estimated that the number of fractures in the United States due to osteoporosis will rise to three million by 2025, resulting in an estimated $25.3 billion in costs each year.

Worldwide, osteoporosis affects an estimated 200 million women, according to the International Osteoporosis Foundation, or IOF, and causes more than 8.9 million fractures annually, which is equivalent to an osteoporotic fracture occurring approximately every three seconds.

Worldwide, osteoporosis affects an estimated 200 million women, according to the International Osteoporosis Foundation (the “IOF”) and causes more than 8.9 million fractures annually, which is equivalent to an osteoporotic fracture occurring approximately every three seconds.

The IOF has estimated that 1.6 million hip fractures occur worldwide each year, and by 2050 this number could reach between 4 to 6 million.

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The three currently approved osteoanabolic drugs that stimulate bone formation all require daily or monthly subcutaneous injections:

teriparatide (hPTH[1-34]);

abaloparatide (a PTH-related protein analog);

and romosozumab (an antibody that inhibits sclerostin and also inhibits bone resorption).

teriparatide (PTH(1-34) ), Forteo®);

abaloparatide (a PTH-related protein analog, Tymlos®));

and romosozumab (an antibody that inhibits sclerostin and also inhibits bone resorption, Evenity®).

It is estimated that less than 10% of currently treated osteoporosis patients agree to injectable osteoanabolic treatment despite guideline recommendations, their efficacy versus the anti-resorptives and the approval of lower cost generics.

There are currently no FDA-approved oral anabolic treatments for osteoporosis.

EB613 is positioned to potentially be the first, once daily osteoanabolic mini tablet treatment for women with high-risk post-menopausal osteoporosis and no prior fractures.

EB613 is positioned to potentially be the first, once daily osteoanabolic tablet treatment for women with high-risk post-menopausal osteoporosis.

Phase 1 Safety, PK and PD Data for Oral PTH(1-34) Tablet Programs

Our Oral PTH (1-34) formulations, including EB613 and EB612, have been administered collectively to a total of 102 healthy subjects in three Phase 1 studies.

In an ongoing phase 1 study evaluating the current EB613 formulation, Forteo and new formulations for EB613 and EB612, 30 healthy subjects have been administered various doses (PTH (1-34) 1.5 mg – 2.5 mg) tablets and regimens (QD or BID) of oral PTH in the first two cohorts completed in 2023.

Our Oral PTH(1-34) tablet candidates, including EB613 and EB612, have been administered collectively to a total of 102 healthy subjects in three Phase 1 studies.

In the first two cohorts of a 2023 phase 1 study evaluating the current EB613 formulation, Forteo and new formulations for EB613 and EB612, 30 healthy subjects were administered various doses (PTH(1-34) 1.5 mg – 2.5 mg) and regimens (QD or BID) of oral PTH.

No drug-related severe adverse events (SAEs) were reported, and four subjects reported four mild adverse events (AEs) of nausea (N=1), palpitation (N=1), and headache (N=2).

These AEs are consistent with those reported with injectable PTH analogs.

In the Phase 1 studies, the PK profile of EB613 daily tablets was characterized by a rapid increase in plasma hPTH(1-34) levels, with peak concentrations of the drug observed within 30 minutes after dose, and a rapid decline thereafter.

The blood half-life of hPTH(1-34) in humans is less than five minutes (see Forteo® USPI).

Due to this very short elimination time and a short absorption phase, hPTH(1-34) levels decrease below limit of quantitation within two hours after drug administration.

Across Phase 1 studies, the PK profile of EB613 daily tablets was characterized by a rapid increase in plasma PTH(1-34) levels, with peak concentrations of the drug observed within 30 minutes after dose, and a rapid decline thereafter.

The blood half-life of PTH(1-34) in humans is less than five minutes (see Forteo® USPI).

Due to this very short elimination time and a short absorption phase, PTH(1-34) levels decrease below limit of quantitation within two hours after drug administration.

As a result, no drug accumulation is expected with once daily tablet dosing.

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The most common drug-related AEs reported were headache, nausea, dizziness and presyncope.

There were no treatment emergent hypercalcemia adverse events, and serial serum chemistry evaluations found no increase in group mean calcium or changes in calcium exceeding predefined limits in patients treated with EB613 2.5 mg daily tablets.

There were no treatment emergent hypercalcemia adverse events, and serial serum chemistry evaluations found no increase in mean calcium or changes in calcium exceeding predefined limits in patients treated with EB613 2.5 mg daily tablets.

There were no reported drug-related SAEs.

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The decrease in bone resorption (CTX) resulting from EB613 daily tablets was unanticipated based on historical results from subcutaneously daily injectable PTH, Forteo®;

and indicates a potential dual mechanism of action for the EB613 PTH (1-34) tablets which seems to induce bone formation and decrease bone resorption, with a lower rate of bone turnover.

and indicates a potential dual mechanism of action for EB613 which seems to induce bone formation and decrease bone resorption, with a lower rate of bone turnover.

Bone Mineral Density

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The FDA also provided guidance regarding the proposed process scale-up, process qualification approach and stability plan for EB613.

Early in the first quarter of 2022, Entera received additional 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 given EB613’s different PK profile, PD (biomarker) profile and BMD outcomes from the phase 2.

The FDA also commented on a possible exploration of a placebo controlled phase 3 study and a potential Total Hip (TH) BMD endpoint given recently published 24-month Surrogate Threshold Effects (STEs) that are considered associated with fracture risk reduction.

About ASBMR-FNIH SABRE

Initiated in 2013, the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium Bone Quality Project assembled data from more than 150,000 participants across more than 50 clinical trials of anti-osteoporosis drugs.

The project team re-evaluated these existing data to understand which measurements could predict the ability of the treatment to reduce fractures.

The study findings identified an increase in BMD, as measured by a low-dose X-ray imaging technique, as a strong predictor of the extent to which treatments reduce fracture risk.

A change in BMD could therefore be used in future clinical trials to determine the effectiveness of osteoporosis drugs.

Through a partnership with ASBMR, the FNIH extended and continues to support the original study, renamed SABRE, to seek FDA approval for the surrogate biomarker as a replacement to fracture outcomes.

Early in the first quarter of 2022, Entera received additional 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 program and potential approvability of EB613 given EB613’s PK profile, PD (biomarker) profile and BMD outcomes from the phase 2.

The FDA also commented on a possible exploration of a placebo-controlled phase 3 study and a potential Total Hip (TH) BMD endpoint given recently published 24-month Surrogate Threshold Effects (STEs) by the SABRE project team that are considered associated with fracture risk reduction and the SABRE ongoing qualification process with FDA of the BMD endpoint as a surrogate for fracture.

FDA Type C Meeting

In October 2022, we announced the successful conclusion of our Type C meeting with the FDA and the FDA’s agreement that a single Phase 3 placebo-controlled study with a BMD endpoint could support a NDA submission of EB613 oral PTH tablets.

In October 2022, we announced the successful conclusion of our Type C meeting with the FDA and the FDA’s concurrence that a single Phase 3 placebo-controlled study with a BMD endpoint could support a NDA submission of EB613.

The FDA also agreed (i) that TH BMD could serve as the primary endpoint for the registrational study of EB613 in post-menopausal women patients diagnosed with osteoporosis, (ii) with the proposed 2:1 randomization (EB613 vs.

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In February 2023, we announced that a Type D meeting protocol review had been accepted by the FDA to provide responses by March 30th, 2023.

The pivotal, Phase 3 study protocol is entitled “A 24-Month Phase 3, Randomized, Double-Blind, Global Multicenter Study Comparing the Effects of Oral hPTH(1-34) (EBP05[EB613]) Daily Tablets vs.

The pivotal, Phase 3 study protocol is entitled “A 24-Month Phase 3, Randomized, Double-Blind, Global Multicenter Study Comparing the Effects of Oral PTH(1-34) (EBP05[EB613]) Daily Tablets vs.

Placebo on Bone Mineral Density (BMD) in Postmenopausal Women with Osteoporosis.” The objective of the Type D meeting review was to confirm that the protocol met the FDA’s expectations, including the analysis of the primary endpoint and the population PK evaluations, ahead of potential initiation of the Phase 3 study.

In April 2023, we reported that the FDA would not be opposed to Entera initiating the Phase 3 study under the proposed FNIH BQP pathway and that the Company’s proposed PK sampling scheme seemed reasonable.

On the same day, we announced that we plan to continue our dialogue with the FDA and await the final qualification of the ASBMR-FNIH SABRE BQP criteria and their guidance on the statistical evaluation of our BMD endpoint before initiating a Phase 3 study for EB613.

In April 2023, we reported that the FDA would not be opposed to Entera initiating the Phase 3 study under the proposed SABRE endpoint and that the Company’s proposed PK sampling scheme seemed reasonable.

On the same day, we announced that we plan to continue our dialogue with the FDA and await the final qualification of the SABRE criteria and their guidance on the statistical evaluation of our BMD endpoint before initiating a Phase 3 study for EB613.

In November 2023, we announced that the SABRE project team has submitted to the FDA its full qualification plan to use the treatment-related change in BMD as a surrogate endpoint for fractures in future trials of new anti-osteoporosis drugs.

BMD is the first surrogate endpoint undergoing qualification by the FDA under the 21st Century Cures Act which was signed into law on December 13, 2016, to help accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently.

An update on the qualification of this endpoint is expected in 2024.

In March 2024, ASBMR announced that the FDA had communicated to the SABRE project team that a ruling to qualify the treatment-related change in bone mineral density (BMD) as a surrogate endpoint for fractures in future trails of new anti-osteoporosis drugs would be provided within 10 months.

In September 2024, we presented new comparative pharmacological data for EB613 at the ASBMR 2024 Annual Meeting in Toronto.

An update on FDA’s potential the qualification of BMD as a surrogate endpoint for fractures in future trials of new anti-osteoporosis drugs by SABRE is expected in 2025.

First Daily PTH Replacement Therapy Tablets for the Treatment of Hypoparathyroidism

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An injectable form of full length human PTH (1-84) marketed under the name Natpara®, was approved for the treatment of hypoparathyroidism in 2015.

However, it was recalled in 2019 due to a plastic particulate and will be permanently phased out globally by the end of 2024.

There are two injectable PTH candidates for hypoparathyroidism undergoing late-stage clinical development:

TransCon™ PTH, developed by Ascendis Pharma and Eneboparatide, a parathyroid hormone receptor 1 (PTHR1) agonist, developed by Amolyt Pharma.

Both TransCon™ PTH and eneboparatide require a daily subcutaneous injection.

Our product candidate for hypoparathyroidism, EB612, is the first oral formulation of PTH (1-34, teriparatide) hormone replacement treatment developed in a tablet form.

However, it was recalled in 2019 due to a plastic particulate and was permanently phased out globally at the end of 2024.

TransCon PTH, once-daily injectable, long-acting prodrug of parathyroid hormone (PTH(1-34)) developed by Ascendis Pharma A/S was FDA Approved in August 2023 and EU Approved in November 2023.

Eneboparatide, once-daily injectable long-acting parathyroid hormone 1 (PTH1) receptor agonist, developed by Amolyt Pharma (acquired by AstraZeneca 2024) reported topline data that the primary endpoint for its Phase 3 study was met in March 2025.

A long acting once weekly injectable PTH peptide prodrug (MBX2109) developed by MBX Biosciences, Inc.

is in Phase 2 clinical testing with topline data expected in Q3 2025.

Finally, oral small molecule PTHR1 (SEP786) developed by Septerna Inc, discontinued a Phase I trial in February 2025 due to safety.

Our product candidate for hypoparathyroidism, EB612, is the first oral PTH (1-34) hormone replacement treatment developed in a tablet form.

The FDA and the EMA have granted EB612 orphan drug designation for the treatment of hypoparathyroidism.

We believe that EB612 may have inherent advantages compared to injectable forms because this is a protein replacement therapy requiring long term use, and we believe that patients have a preference for oral medication, and our tablets may enable more flexibility for titration and more individualized treatment.

Phase 2a Clinical Trial

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We initiated a two-part Phase 2 PK/PD trial in 2014.

This trial was designed to provide a bridge from our completed Phase 2a trials, which was conducted prior to the marketing approval of Natpara, and our planned future clinical trials, and to also allow us to better understand the relative strength and dose of our product as compared to the then marketed product, Natpara.

This trial was designed to provide a bridge from our completed Phase 2 study, which was conducted prior to the marketing approval of Natpara, and to allow us to better understand the relative strength and dose of EB612 as compared to the then marketed product, Natpara.

The relevant endpoints for the PK/PD trial included an examination of levels of PTH(1-34), PTH(1-84) (Natpara), serum calcium, serum phosphate, urinary calcium and urinary phosphate.

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and (iv) a decrease in average levels of 24-hour urinary calcium of approximately 30% on the day of treatment as compared to baseline.

The concentration of PTH (1-34) in blood after administration of Oral PTH (1-34) in the trial was sufficient to produce the observed pharmacodynamic effects and did not induce hypercalcemia.

The concentration of PTH(1-34) in blood after administration of EB612 in the trial was sufficient to produce the observed pharmacodynamic effects and did not induce hypercalcemia.

No serious adverse events were reported.

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Planned Additional Clinical Development and Regulatory Pathway

We have since developed an improved formulation of EB612 based on new intellectual property of our N-Tab™ Technology, which we have designed to optimize its PK profile and the potential for reduced daily dosing.

We initiated a PK study in May 2023, which is testing various potential drug candidates based on our new platform, including several which could be developed for the treatment of hypoparathyroidism.

We have since developed a new generation of EB612 based on new intellectual property of our N-Tab™ Technology, which we have designed to optimize its PK profile and the potential for reduced daily dosing.

We initiated a PK study in May 2023, which tested various potential drug candidates based on our new platform, including several which could be developed for the treatment of hypoparathyroidism.

In April 2024, we submitted pharmacokinetic (PK) and early PD Data from a Phase 1 study evaluating an unmodified PTH (1-34) peptide and a new generation of Entera's N-Tab™ platform to the Endocrine Society Annual Meeting (ENDO 2024).

In June 2024, we presented Phase 1 clinical data at the ENDO 2024 Annual Meeting, that supports potentially moving the BID (twice-daily) tablet dose to Phase 2 development in patients with hypoparathyroidism.

Additionally, we are also collaborating with a third party to combine our N-Tab™ Technology with another peptide for hypoparathyroidism.

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Patent Rights

As of March 1, 2024, our 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, 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, Netherlands, Spain, Sweden, and Switzerland.

Related patent applications are pending before the European Patent Office (EPO) and in the United States, Hong Kong, Brazil and India.

Patents specifically covering PTH have already been granted in the United States, Hong Kong, Israel, Australia, Russia and Japan, and have been granted by the EPO and validated in Belgium, France, Germany, Great Britain, Ireland, Italy, Liechtenstein, Luxembourg, Netherlands, Spain, Sweden, and Switzerland.

In addition, patent applications which specifically cover PTH are currently pending in Hong Kong, Brazil and India.

This issued patent and any patent that may issue from the pending patent applications are currently 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 us pursuant to the Patent Transfer Agreement with Oramed.

Three patent families filed in various jurisdictions, which we believe, if issued as patents containing substantially the same claims as those in the applications, would cover certain oral administration technologies.

The mentioned technologies include compositions which utilize an absorption enhancer to enable the absorption of a therapeutically active agent in a controlled manner.

We believe that certain of the pending claims contained in these patent applications, if issued in substantially the same form, would cover the formulations of EB612 and EB613.

Patent applications covering certain formulations with a controlled absorption profile were filed with the EPO and in the United States, Canada, Hong Kong, Israel and Mexico (the application filed in Israel has matured into a patent and a divisional application has been filed therein).

Other patent applications covering certain formulations for co-administration and/or co-formulation with an antacid and/or protease inhibitor were filed with the EPO and in the United States, Canada and Hong Kong (the application in the United States has matured into a patent, and a divisional application has been filed therein).

Any patents that issue from these patent applications are expected to expire in February 2036, assuming all annuity and maintenance payments are paid thereon.

Patent applications covering certain formulations and regimens were 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 (the applications filed in New Zealand and India have matured into a patent;

the application filed in Israel has recently been allowed).

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 families were filed in various jurisdictions, which we believe, 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;

the applications in Japan, Canada, China and Israel have matured into patents, and divisional applications have been filed in Japan, Israel and China), hypoparathyroidism (filed with the EPO and in the United States, Brazil, Canada, Hong Kong, Israel and Japan;

the applications in Japan, Brazil and Israel have matured into patents 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 were filed in February 2023, which we believe, 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.

provisional patent applications have been filed in August 2023, which, if issued as patents containing substantially the same claims as those in the applications, we believe would cover additional new discoveries for the oral delivery of large molecules.

Any patents that issue from these patent applications are expected to expire in August 2043, assuming all annuity and maintenance payments are paid thereon and while not considering patent term extension when applicable.

provisional patent applications have been filed in November 2023, which, if issued as patents containing substantially the same claims as those in the applications, we believe would cover features uncovered during the clinical studies conducted with EB613.

Any patents that issue from these patent applications are expected to expire in November 2043, assuming all annuity and maintenance payments are paid thereon and while not considering patent term extension when applicable.

As of March 2025, our global patent portfolio included issued patents and patent applications.

We believe that the granted patents as well as certain of the pending claims contained in our patent applications, if issued in substantially the same form, would cover our proprietary technology platform (N-Tab™) and the candidates used in various pipeline programs as indicated in the following table:

Subject Mater

# Pending Applications

# Issued Patents

Geographical Scope

Nominal Patent Term

United States, Europe, Japan, China, Canada, Singapore, United Arab Emirates, Israel, Brazil, Mexico, South Africa, India, Australia, New Zealand, Russia, South Korea and Hong Kong

GLP1/Glucagon

United States, Europe, Japan, China, Canada, Singapore, United Arab Emirates, Israel, Brazil, Mexico, South Africa, India, Australia, New Zealand, Russia, South Korea and Hong Kong

Issued patents and any patent that may issue from the pending patent applications are currently expected to expire by the Nominal Patent Term as noted in the above table, assuming national phase filings are timely effected.

The nominal patent term does not include potential patent extension and/or patent term addition when applicable.

The term of individual patents depends upon the legal term for patents in the countries in which they are granted.

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Commercialization Strategy

We hold global rights to all of our internally developed product candidates (including EB613 and EB612), which provide us the optionality to grow our internal pipeline independently or license selected rights to our product candidates in different geographies or throughout the world.

We aim to maximize the value of our product candidates by either independently commercializing our products in one or more major geographies by building an internal sales and marketing organization, or by seeking collaborations with third parties with commercialization infrastructure, in either case subject to applicable regulatory approval.

We hold global rights to our internally developed product candidates (including EB613 and EB612), and intend to maximize the value of these candidates commercially with strong partners that have the requisite commercial infrastructure within a specific therapeutic indication, target or geography.

In relation to Oral GLP-1/Glucagon , under the terms of the 2025 Collaboration Agreement, OPKO and Entera hold 60% and 40% pro-rata ownership interests, respectively, in the program and be responsible for 60% and 40% of the program’s development costs, respectively.

Following the completion of the Phase 1 stage, we have the option to continue to fund our 40% share to maintain our pro-rata ownership interest in the program.

Should we opt-out, we will retain a 15% ownership interest in the Oral OXM program, while OPKO will retain 85% and be responsible for ongoing development activities and funding of the program.

Our Oral GLP-2 program is governed by a 2023 MTA and Collaboration Agreement which we have shared responsibilities.

The medical and pharmaceutical industries in which we operate are highly competitive and subject to rapid and significant technological change and changes in practice.

While we believe that our technology, knowledge, experience and scientific resources provide us with competitive advantages, we face competition from many different sources, including large pharmaceutical, specialty pharmaceutical, biotechnology, and generic drug companies and academic and government institutions.

We believe that the key competitive factors that will affect the development and commercial success of our oral PTH product candidates for osteoporosis, hypoparathyroidism and any other product candidates that we develop, are the efficacy, safety and tolerability profile, convenience in dosing, product labeling, price and availability of reimbursement from the government and other third-parties.

We believe that the key competitive factors that will affect the development and commercial success of our product candidates for osteoporosis, hypoparathyroidism and any other product candidates that we develop, are the efficacy, safety and tolerability profile, convenience in dosing, product labeling, price and availability of reimbursement from the government and other third-parties.

Our commercial opportunity could be reduced or eliminated if our competitors have products that are better in one or more of these categories.

We expect that, if approved, our oral PTH product candidates for osteoporosis, hypoparathyroidism and other product candidates that we develop, would compete with a number of existing products.

We expect that, if approved, our oral PTH product candidates for osteoporosis, hypoparathyroidism and other product candidates that we are developing for metabolic disorders and short bowel syndrome, would compete with a number of existing products.

Furthermore, we believe that we face competition in relation to our oral drug delivery platform, N-Tab™, as we believe that other non-invasive medical drug delivery technologies, including alternative oral delivery systems as well as transdermal patches, are being developed by other parties.

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The Israeli Innovation Authority (IIA) Grants

We have received grants of approximately $0.5 million from the IIA to partially fund our research and development.

We have received grants of approximately $0.5 million from the IIA to partially fund our PTH research and development for Osteoporosis.

The grants are subject to certain requirements and restrictions under Encouragement of Industrial Research, Development and Technological Innovation in Industry Law 5744-1984 and the IIA regulations, which we refer to collectively as the “Research Law”.

In general, until the grants are repaid with interest, royalties are payable to the Israeli government in the amount of 3% on revenues derived from sales of products or services developed in whole or in part using the IIA grants, including EB613, EB612 and any other oral PTH product candidates we may develop.

The royalty rate may increase to 5%, with respect to approved applications filed following any year in which we achieve sales of over $70 million.

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As of December 31, 2024, the total royalty amount that would be payable by the Company to the IIA, before interest and payments as described above, is approximately $460 thousand.

As of December 31, 2023, we had paid royalties to the IIA in the amount of $83,000 related to a collaboration agreement and other material transfer agreements (“MTAs”).

As of December 31, 2023, we owed $13,000 to the IIA, which was paid in February 2024.

As of December 31, 2024, we had paid royalties to the IIA in the amount of $96 thousand.

In addition to paying any royalties due, we must abide by other restrictions associated with receiving such grants under the Research Law that continue to apply even following repayment to the IIA.

These restrictions may impair our ability to outsource manufacturing, engage in change of control transactions or otherwise transfer our “know-how” (in its meaning under the Research Law) in or outside of Israel, and may require us to obtain the approval of the IIA for certain actions and transactions and pay additional royalties and other amounts to the IIA.

These restrictions may impair our ability to outsource manufacturing, engage in change of control transactions or otherwise transfer our IIA-related “know-how” (in its meaning under the Research Law) in or outside of Israel, and may require us to obtain the approval of the IIA for certain actions and transactions and pay additional royalties and other amounts to the IIA.

We may not receive the required approvals for any proposed transfer and, even if received, we may be required to pay the IIA a portion of the consideration that we receive upon any transfer of such technology to a non-Israeli entity up to 600% of the grant amounts and the interest.

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Such a non-Israeli interested party is required to sign an undertaking towards the IIA in which it undertakes to comply with the Research Law.

Notice or undertaking to the IIA may not be required in respect of purchase of Ordinary Shares in standard acquisition or trading in the stock exchange following to an IPO that was approved by the IIA.

If we fail to comply with the Research Law, we may be forced to return the grants and/or be subject to other payments to the IIA, monetary fines and/or criminal charges.

Oramed Patent Transfer Agreement

In 2010, in connection with our establishment as a joint venture between D.N.A Biomedical Solutions Ltd.

(“D.N.A Biomedical”) and Oramed Ltd.

(“Oramed”), a subsidiary of Oramed Pharmaceuticals, Inc., we entered into a patent license agreement with Oramed pursuant to which Oramed granted us a worldwide, royalty-bearing, exclusive, irrevocable, perpetual and sub-licensable license under certain Oramed patent rights, to develop, manufacture and commercialize products for certain indications to be specified by us and Oramed, other than diabetes, obesity and influenza.

In February 2011, D.N.A Biomedical and Oramed entered into a share purchase agreement for the sale by Oramed to D.N.A Biomedical of 47% of our Ordinary Shares at the time of the transaction in February 2011.

In connection with this transaction, in February 2011 we entered into a Patent Transfer Agreement with Oramed to replace the original 2010 license agreement.

Pursuant to the terms of the Patent Transfer Agreement, Oramed assigned to us all of its right, title and interest in the previously licensed patent rights, and, in return, we granted to Oramed a worldwide, royalty-free, exclusive, irrevocable, perpetual and sublicensable license under the assigned patent rights to develop, manufacture and commercialize products or otherwise exploit such patent rights in the fields of diabetes and influenza.

Additionally, we agreed not to engage, directly or indirectly, in any activities in the fields of diabetes and influenza.

In consideration for such assignment, we agreed to pay Oramed royalties equal to 3% of our net revenues generated, directly or indirectly, from exploitation of the assigned patent rights, including the sale, lease or transfer of the assigned patent rights or sales of products or services covered by the assigned patent rights.

Either party may terminate the Patent Transfer Agreement for the other party’s uncured material breach upon 45 days’ written notice (and immediately upon written notice in the event of an incurable breach), or if the other party undergoes certain insolvency-related events.

The royalty obligations imposed on us will survive termination of the Patent Transfer Agreement.

In 2011, we entered into a patent transfer agreement with Oramed Ltd.

(“Oramed”), which we refer to as the Patent Transfer Agreement, pursuant to which Oramed assigned to us all of its rights, title and interest in the patent rights Oramed licensed to us when we were originally organized, subject to a worldwide, royalty-free, exclusive, irrevocable, perpetual and sub-licensable license granted to Oramed under the assigned patent rights to develop, manufacture and commercialize products or otherwise exploit such patent rights in the fields of diabetes and influenza.

Additionally, we agreed not to engage, directly or indirectly, in any activities in the fields of diabetes and influenza that involve the use of, or utilize, the patents underlying the Patent Transfer Agreement.

Under the terms of the Patent Transfer Agreement, we agreed to pay Oramed royalties equal to 3% of our net revenues generated, directly or indirectly, from our exploitation of the assigned patent rights, including the sale, lease or transfer of the assigned patent rights or sales of products or services covered by the assigned patent rights.

Manufacturing

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Government Regulation and Product Approval

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research, development, testing, manufacture, pricing, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products.

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research, development, testing, manufacture, pricing, quality control, approval, packaging, storage, recordkeeping, labelling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products.

The processes for obtaining regulatory approvals in the United States and in other countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

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The failure to comply with the applicable requirements at any time during the product development process, including preclinical testing, clinical testing, the approval process or post-approval process, may subject an applicant to delays in the conduct of clinical trials, regulatory review and approval, and/or administrative or judicial sanctions.

These sanctions may include, but are not limited to, the FDA’s refusal to allow an applicant to proceed with clinical testing, refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, warning letters, adverse publicity, customer notifications, product recalls, product seizures, refusal to grant export or import approval total or partial suspension of production or distribution, consent decrees, injunctions, fines, and civil or criminal investigations and penalties brought by the FDA or Department of Justice, or other governmental entities.

These sanctions may include, but are not limited to, the FDA’s refusal to allow an applicant to proceed with clinical testing, refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, warning letters, adverse publicity, customer notifications, product recalls, product seizures, refusal to grant export or import approval, total or partial suspension of production or distribution, consent decrees, injunctions, fines, and civil or criminal investigations and penalties brought by the FDA, Department of Justice, or other governmental entities.

The process required by the FDA before a new drug or biologic may be marketed in the United States generally involves satisfactorily completing each of the following steps:

• preclinical laboratory tests, animal studies and formulation studies all performed in accordance with the FDA’s Good Laboratory Practice regulations;

• preclinical laboratory tests, animal studies and formulation studies all performed in accordance with the FDA’s Good Laboratory Practice regulations, or GLP;

• submission to the FDA of an initial new drug, or IND, application for human clinical testing, which must become effective before human clinical trials may begin;

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Preclinical tests include laboratory evaluations of product chemistry, formulation, and stability, as well as animal studies to evaluate the potential for efficacy and toxicity.

The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements.

The results of the preclinical tests, together with manufacturing information and analytical data, are submitted to the FDA as part of an Investigational New Drug (“IND”) application.

The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements, including GLP.

The results of the preclinical tests, together with manufacturing information and analytical data, are submitted to the FDA as part of an IND application.

Some preclinical tests may continue even after submission of the IND application.

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A sponsor who wishes to conduct a clinical trial outside the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND.

If a clinical trial outside the United States is not conducted under an IND, the sponsor may submit data from the clinical trial to the FDA in support of a NDA so long as the clinical trial is conducted in consistent with GCP and in compliance with an international guideline for the ethical conduct of clinical research known as the Declaration of Helsinki and/or the laws and regulations of the country or countries in which the clinical trial is performed, whichever provides the greater protection to the participants in the clinical trial.

If a clinical trial outside the United States is not conducted under an IND, the sponsor may submit data from the clinical trial to the FDA in support of a NDA so long as the clinical trial is conducted in accordance with GCP and in compliance with an international guideline for the ethical conduct of clinical research known as the Declaration of Helsinki and/or the laws and regulations of the country or countries in which the clinical trial is performed, whichever provides the greater protection to the participants in the clinical trial.

Further, each clinical trial must be reviewed and approved by an IRB either centrally or individually at each institution at which the clinical trial will be conducted.

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such Phase 3 studies are referred to as “pivotal.”

In some cases, the FDA may approve an NDA or a BLA for a product candidate but require the sponsor to conduct additional clinical trials to further assess the drug’s safety and effectiveness after NDA or BLA approval.

In some cases, the FDA may approve an NDA or a BLA for a product candidate but require the sponsor to conduct additional clinical trials to further assess the product candidate’s safety and effectiveness after NDA or BLA approval.

Such post-approval trials are typically referred to as Phase 4 clinical trials.

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Clinical Trial Approval

Requirements for the conduct of clinical trials in the EU including cGCP, are implemented in the current Clinical Trials Directive 2001/20/EC and the GCP Directive 2005/28/EC.

Pursuant to Directive 2001/20/EC and Directive 2005/28/EC, as amended, a system for the approval of clinical trials in the EU has been implemented through national legislation of the EU member states.

Under this system, approval must be obtained from the competent national authority in which a trial is planned to be conducted, or in multiple member states if the clinical trial is to be conducted in a number of member states.

To this end, a CTA is submitted, which must be supported by an investigational medicinal product dossier, or IMPD, and further supporting information prescribed by Directive 2001/20/EC and Directive 2005/28/EC and other applicable guidance documents.

Furthermore, a clinical trial may only be started after a competent ethics committee has issued a favorable opinion on the clinical trial application in that country.

On January 31, 2022, the Clinical Trials Regulation (EU) No.

536/2014 replaced the current Clinical Trials Directive 2001/20/EC.

To ensure that the rules for clinical trials are identical throughout the EU, the Clinical Trials Regulation (EU) No.

536/2014 was passed as a regulation which is directly applicable in all EU member states.

The Clinical Trials Directive 2001/20/EC will, however, still apply three years from the date of entry into application of the Clinical Trials Regulation to (i) clinical trials applications submitted before the entry into application and (ii) clinical trials applications submitted within one year after the entry into application if the sponsor opts for the old system.

Requirements for the conduct of clinical trials in the EU including cGCP, are implemented in the current Clinical Trials Regulation (EU) No.

536/2014 to ensure that the rules for clinical trials are identical throughout the EU.

Regulation (EU) No 536/2014 aims to simplify and streamline the approval of clinical trial in the EU.

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In addition, the sponsor must establish that there is no other satisfactory method approved in the EU of diagnosing, preventing or treating the condition, or if such a method exists, the proposed orphan drug will be of significant benefit to patients.

Orphan drug designation provides a number of benefits, including fee reductions, regulatory assistance, and the possibility to apply for a centralized EU marketing authorization (see “Government Regulation and Product Approval-Regulation Outside the United States-Centralized Authorization Procedure”), as well as 10 years of market exclusivity following a marketing authorization.

During this market exclusivity period, neither the EMA, nor the European Commission nor the Member States can accept an application or grant a marketing authorization for a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

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Even if a compound is considered to be a new chemical entity and the innovator is able to gain the period of data exclusivity, another company nevertheless could also market another version of the drug if such company obtained marketing authorization based on an MAA with a complete independent data package of pharmaceutical test, pre-clinical tests and clinical trials.

However, products designated as orphan medicinal products enjoy, upon receiving marketing authorization, a period of 10 years of orphan market exclusivity (see also “Government Regulation and Product Approval-Regulation and Marketing Authorization in the European Union-Orphan Drug Designation and Exclusivity”).

However, products designated as orphan medicinal products enjoy, upon receiving marketing authorization, a period of 10 years of orphan market exclusivity.

Depending upon the timing and duration of the EU marketing authorization process, products may be eligible for up to five-year supplementary protection certificates, or SPCs.

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In order to conduct clinical trials on humans in Israel, prior authorization must be obtained from the medical director of the institution (i.e., the Director of Hospital) in which the clinical trials are scheduled to be conducted.

All clinical trials must first be approved by the Institutional Review Board / Independent Ethics Committee which may request additional prior approval from the Israeli Ministry of Health (IMOH), as required under the Guidelines for Clinical Trials in Human Subjects implemented pursuant to the Israeli Public Health Regulations (Clinical Trials in Human Subjects), 5740-1980, as amended from time to time.

All clinical trials must first be approved by the Institutional Review Board / Independent Ethics Committee which may request additional prior approval from the Israeli Ministry of Health ("IMOH"), as required under the Guidelines for Clinical Trials in Human Subjects implemented pursuant to the Israeli Public Health Regulations (Clinical Trials in Human Subjects), 5740-1980, as amended from time to time (referred to as "The Israeli Public Health Regulations").

Pursuant to the Israeli Public Health Regulations, such authorization generally cannot be granted unless, among other things, the relevant institutions' ethics committee has provided its prior approval of the testing and that the trial complies with the standards set forth by the Declaration of Helsinki.

The Institutional Review Board / Independent Ethics Committee and IMOH prioritizes the safety, rights and the wellbeing of the participants are addressed, as well as among other things, evaluating the anticipated benefits that are likely to be derived from the project to determine if it justifies the risks and inconvenience to be inflicted on the participating human subjects.

The institution may also conduct audits to insure that all international GCP and IMOH guidelines are being adhered to in order to maintain the proper conduct and accuracy of the information gathered in the course of the clinical testing.

The institution may also conduct audits to ensure that all international GCP and IMOH guidelines are being adhered to in order to maintain the proper conduct and accuracy of the information gathered in the course of the clinical testing.

Other Healthcare Laws

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The Affordable Care Act was enacted in the United States in March 2010 and contains provisions that may reduce the profitability of drug products, including, for example, increased rebates for drugs subject to the Medicaid Drug Rebate Program, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies’ share of sales to federal health care programs.

In addition, other legislative changes have been proposed and adopted since the Affordable Care Act was enacted.

These changes included aggregate reductions to Medicare payments to providers of 2% per fiscal year, effective April 1, 2013 and, due to subsequent legislative amendments to the statute, will stay in effect through 2027, unless additional Congressional action is taken;

however, pursuant to the CARES Act, and subsequent legislation, these reductions were suspended from May 1, 2020 through March 31, 2022 due to the COVID-19 pandemic.

In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, reduced Medicare payments to several providers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

These laws may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse effect on customers for our drugs, if approved, and, accordingly, our financial operations.

Moreover, recently there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their commercial products.

Moreover, recently there has been heightened governmental scrutiny over the way manufacturers set prices for their commercial products.

There have been several recent U.S.

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The FDA released a final rule on September 24, 2020, effective November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada.

Further, on November 20, 2020, the U.S.

Department of Health and Human Services, or HHS, finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.

Further, on August 16, 2022, Congress enacted the Inflation Reduction Act allowing CMS to negotiate directly with drug manufacturers to lower the price of some of the costliest drugs under the Medicare program, as well as requiring drug manufacturers to provide Medicare with a rebate if the price of drugs increases faster than the rate of inflation.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

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We expect that additional state and federal healthcare reform measures, as well as legal changes by foreign governments, will be adopted in the future, any of which could limit the amounts that governments will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.

As of December 31, 2023, we had a total of 19 employees, of whom 17 are full-time employees all based in Israel (including our Chief Executive Officer and Chief Operating Officer), and one part-time consultant based in Israel who serves as our Chief Financial Officer.

In addition, we employ a number of specialized outside advisors and expert consultants based in the United States, the United Kingdom and Europe, including our Chief Medical Officer, key clinical advisors and our regulatory team.

As of December 31, 2024, we had a total of 20 employees, of whom 18 are full-time employees all based in Israel.

In addition, we employ a number of specialized clinical, non-clinical, statistical, regulatory and development advisors based in the United States, the United Kingdom and Europe.

The distribution of our full-time employees according to main areas of activity is set forth in the following table:

16 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business