UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): August 1, 2022
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Securities registered pursuant to Section 12(b) of the Act:
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933
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Item 7.01 Regulation FD Disclosure.
On August 1, 2022, Entera Bio Ltd., a company organized under the laws of the State of Israel (the "Company", "we", "us", or "our")
made available an updated corporate presentation. A copy of the presentation is attached hereto as Exhibit 99.1 and incorporated by reference in this Item 7.01. A copy of the presentation is also available on our website at
https://investors.enterabio.com.
Use of our Website and Social Media to Distribute Material Company Information
We use our website as a channel of distribution for important Company information. We routinely post on our website important
information, including press releases, investor presentations and financial information, which may be accessed by clicking on the “Investors” section of www.enterabio.com. We also use our website to expedite public access to time-critical
information regarding our Company in advance of or in lieu of distributing a press release or a filing with the SEC disclosing the same information. Therefore, investors should look to the “Investors” section of our website for important and
time-critical information.
The information contained in this Item 7.01, including in Exhibit 99.1 attached hereto, is “furnished” and not “filed” for purposes of
Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section. Such information shall not be incorporated by reference in another filing under the Exchange Act or the
Securities Act of 1933, as amended, except to the extent such other filing specifically incorporates such information by reference.
Item 9.01 Exhibits
(d) Exhibits.
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Exhibit
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Exhibit
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104
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Cover Page Interactive Data File.
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SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its
behalf by the undersigned thereunto duly authorized.
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ENTERA BIO LTD.
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Date: August 1, 2022
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By:
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/s/ Miranda J. Toledano
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Name: Miranda J. Toledano
Title: Chief Executive Officer
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Exhibit 99.1
Entera Bio Corporate PresentationAugust 2022
Disclaimer Various statements in this presentation are “forward-looking statements” within the meaning
of the Private Securities Litigation Reform Act of 1995. All statements (other than statements of historical facts) in this presentation regarding our prospects, plans, financial position, business strategy and expected financial and
operational results may constitute forward-looking statements. Words such as, but not limited to, “anticipate,” “believe,” “can,” “could,” “expect,” “estimate,” “design,” “goal,” “intend,” “may,” “might,” “objective,” “plan,” “predict,”
“project,” “target,” “likely,” “should,” “will,” and “would,” or the negative of these terms and similar expressions or words, identify forward-looking statements. Forward-looking statements are based upon current expectations that involve
risks, changes in circumstances, assumptions and uncertainties. Forward-looking statements should not be read as a guarantee of future performance or results and may not be accurate indications of when such performance or results will be
achieved. Important factors that could cause actual results to differ materially from those reflected in Entera’s forward-looking statements include, among others: changes in the interpretation of clinical data; results of our clinical
trials; the FDA’s interpretation and review of our results from and analysis of our clinical trials; unexpected changes in our ongoing and planned preclinical development and clinical trials, the timing of and our ability to make regulatory
filings and obtain and maintain regulatory approvals for our product candidates; the potential disruption and delay of manufacturing supply chains; loss of available workforce resources, either by Entera or its collaboration and laboratory
partners; impacts to research and development or clinical activities that Entera is contractually obligated to provide, such as those pursuant to Entera’s agreement with Amgen; overall regulatory timelines; the size and growth of the
potential markets for our product candidates; the scope, progress and costs of developing Entera’s product candidates; Entera’s reliance on third parties to conduct its clinical trials; Entera’s expectations regarding licensing, business
transactions and strategic collaborations; Entera’s operation as a development stage company with limited operating history; Entera’s ability to continue as a going concern absent access to sources of liquidity; Entera’s ability to obtain and
maintain regulatory approval for any of its product candidates; Entera’s ability to comply with Nasdaq’s minimum listing standards and other matters related to compliance with the requirements of being a public company in the United States;
Entera’s intellectual property position and its ability to protect its intellectual property; and other factors that are described in the “Cautionary Statements Regarding Forward-Looking Statements,” “Risk Factors” and “Management’s
Discussion and Analysis of Financial Condition and Results of Operations” sections of Entera’s most recent Annual Report on Form 10-K filed with the SEC, as well as the company’s subsequently filed Quarterly Reports on Form 10-Q and Current
Reports on Form 8-K. There can be no assurance that the actual results or developments anticipated by Entera will be realized or, even if substantially realized, that they will have the expected consequences to, or effects on, Entera.
Therefore, no assurance can be given that the outcomes stated or implied in such forward-looking statements and estimates will be achieved. Entera cautions investors not to rely on the forward-looking statements Entera makes in this
presentation. The information in this presentation is provided only as of the date of this presentation, and Entera undertakes no obligation, to update or revise publicly any forward-looking statements, whether as a result of new information,
future events or otherwise, except to the extent required by law.
Entera Bio: Leader in Oral Delivery of Therapeutic Proteins Founded in 2009 (Jerusalem, Israel); IPO
in 2018 (Nasdaq: ENTX) Proprietary 1st in Class Oral PTH Candidates with Demonstrated Clinical Efficacy in Phase 2 Studies External Strategic Partnerships to Diversify Pipeline and Revenue Streams (e.g. Amgen) EB613 (oral PTH (1-34),
teriparatide) First Oral Bone Forming / Anabolic Drug for Osteoporosis Phase 2 study met biomarker and 6-month BMD endpoints (ASBMR late-breaker oral presentation, 2021) 6-month lumbar spine BMD data in line with SC Forteo injection; total
hip and femoral neck BMD changes were greater than previously reported data with SC Forteo® injection FDA Type C Meeting based on revised Phase 3 protocol submitted (response expected in H2’2022) EB612 First Oral PTH for Hypoparathyroidism
- Granted Orphan Designation (US, EU) Pilot 4-month Phase 2 results presented (ASBMR 2015) and published in peer-reviewed journal (JBMR 2021) Phase 2 PK-PD study versus Natpara presented (ASBMR 2019) Rapid decline in median serum
phosphate levels and maintenance of target calcium levels throughout the study Novel formulation leverages Entera’s 2nd generation peptide delivery platform (PK study expected in H1’2023) We Focus on High Unmet Clinical Needs where Oral
Delivery of a Protein Therapy Can Significantly Improve the Standard of Care
Miranda Toledano, MBA, Chief Executive Officer 23 years of C-level leadership, principal investment
and wall street/ transactional experience in the biotech sector Art Santora, MD, PhD, Chief Medical Officer 35 years of special care, academic research, FDA in endocrinology focusing on osteoporosis and other diseases of bone and calcium
metabolism; lead clinical physician for Fosamax® Dana Yaacov, CPA, MBA, Chief Financial Officer 15 years of finance management and accounting experience Hillel Galitzer, PhD, MBA , Chief Operating Officer 21 years of biotech
experience in clinical trial and supply chain operations support and early-stage R&D Anke Hoppe, BSc, VP of Clinical Operations 30 years of experience overseeing clinical operations across big pharma, small biotech, and CROs Gregory
Burshtein, PhD, VP of R&D 18 years experience in oral drug delivery research, formulation and pre-clinical development Execution Oriented Leadership Team
Professor John P. Bilezikian Vice-Chair, Department of Medicine for International Research and
Education; Chief, Emeritus, of the Division of Endocrinology; Director, Emeritus, of the Metabolic Bone Diseases Program at Columbia University Medical Center Professor Maria Luisa Brandi Professor of Endocrinology, FIRMO Foundation,
Italy Professor Bart Clarke Professor of Medicine and Consultant, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic Professor Felicia Cosman Professor of Medicine, Emerita, Columbia University College of
Physicians and Surgeons, Division of Endocrinology; Co-Editor in Chief of the journal Osteoporosis International Professor William Fraser Professor of Medicine at Norwich Medical School at the University of East Anglia and Consultant in
Metabolic Medicine at the Norfolk and Norwich University Hospital, UK Dr. Roger Garceau Former Chief Medical Officer and EVP at NPS Pharmaceuticals and Shire plc (Natpara®); Sanofi/Pharmacia Professor Sophia Ish-Shalom Vice President of
the Israeli Foundation for Osteoporosis and Bone Diseases (IFOB) , Endocrine Clinic Elisha Hospital prior Head of Bone and Mineral Metabolism Unit, Rambam Health Care Campus , Israel Professor Socrates Papapoulos Emeritus Professor in
Diseases of Bone & Mineral Metabolism, Advisor Center for Bone Quality, Leiden University Medical Center, The Netherlands Global Clinical & Scientific Advisory Board
Entera Proprietary Oral Delivery Platform Synergistic Activity of Proteolysis Inhibition and
Permeability Enhancement Oral delivery of most therapeutic proteins is challenging due to poor absorption into the blood stream, enzymatic degradation within the gastrointestinal tract, and variable drug exposure Note: SNAC (Salcaprozate
sodium) increases gastric epithelial membrane fluidity without affecting tight junctions, thereby allowing transcellular passage into systemic circulation of the protein API. SNAC is a component of Novo Nordisk’s Rybelsus® which has been
approved by the FDA and EMA. Absorption Enhancer Dramatically Increases Systemic Plasma Levels of Protein Stability of Peptide in Solution in presence of Trypsin Entera’s Proprietary Technology - Synergistically Protects & Transports
Large Molecules 1. Prevents the degradation of the therapeutic protein in the GI tract; maintains the integrity of the protein (stability) 2. Enhances peptide absorption by increasing transcellular transport (bioavailability)
Program Target Preclinical Phase 1 Phase 2 Phase 3 Partner Next
Milestone EB613 Osteoporosis Phase 3 EB612 Hypoparathyroidism (Orphan Disease) Human PK EB613 Non-Union Fractures Internal Review GLP-2 Short Bowel Syndrome Undisclosed hGH GH
deficiency Undisclosed Undisclosed Anti- inflammatory Undisclosed Undisclosed Various Undisclosed Internal Pipeline Focuses On Approved Injectable Proteins Partnership Agreements Include Novel Undisclosed Targets EB612 PTH 1-34
BLA EB613 PTH 1-34 505b2 Evaluating additional high value therapeutic proteins which could be developed as oral formulations to offer significant benefit to patients PTH 1-34 PTH 1-34 (2nd generation) PTH 1-34 Multiple
EB613 (oral PTH (1-34), teriparatide) Oral Bone Forming / Anabolic for the Treatment of Osteoporosis
EB613: First Oral PTH Drug Candidate for Osteoporosis *P1NP: amino pro-peptide of type 1
collagen Osteoporosis: Skeletal disease characterized by low bone mass, micro-architectural deterioration of bone tissue and increased bone fragility leading to an increased susceptibility to fractures. Currently the vast majority of
patients have a preference and are treated with oral therapy (bisphosphonates) Parathyroid hormone (PTH) is an 84-amino acid hormone and the primary regulator of calcium and phosphate metabolism in bone and kidney. EB613 is an oral
formulation of synthetic hPTH (1-34), (teriparatide), a peptide consisting of the first 34 amino acids of PTH (the functional region), developed with Entera’s proprietary drug delivery technology which stabilizes the teriparatide and promotes
absorption in the gastrointestinal tract. Subcutaneous Forteo® (teriparatide injection) has been the leading anabolic treatment of osteoporosis since 2002 (with U.S. peak sales of $960m) Favorable phase 3 safety profile similar to Forteo
and differentiated from oral bisphosphonates The most common adverse events included mild nausea, moderate back pain, moderate headache, and moderate upper abdominal pain End of Phase 2 Minutes: FDA suggested Entera explore a
placebo-controlled study with BMD ASBMR-FNIH STEs as primary endpoint. Type C meeting expected H2’2022 Phase 2 study met primary endpoint showing a statistically significant increase of P1NP*, a marker of bone formation, at 3 months; at 6
months of treatment with EB613, the increase in spine bone mineral density (BMD) was similar in magnitude to that previously reported with SC Forteo ® injections; Increases in total hip and femoral neck BMD with EB613 were greater than those
previously reported with SC Forteo ® injections Indication Molecule/ Drug Product Key Efficacy Profile Key Safety Profile
Osteoporosis Results From An Imbalance In The Bone Remodeling Cycle That Occurs When Bone Resorption
Outpaces Bone Formation The Bone Remodeling Cycle can be separated into two distinct processes: Resorption (osteoclasts) and Formation (osteoblasts) Sources: International Osteoporosis foundation accessed March 2022; Salamanna, F. et
al. Osteoporosis and the Bone Remodeling Cycle Bone Density Healthy vs. Osteoporotic Osteoporosis is a disease associated with low bone mass and enhanced skeletal fragility and is most commonly caused by: Menopause in women Aging in
both women and men Glucocorticoid steroid use (greater than 3 months)
Notes: * Estrogen products are indicated for prevention of osteoporosis as a secondary benefit when
used to control menopausal symptoms. Not a 1st line treatment due to adverse reactions, **SERMs – Selective estrogen receptor modulators Sources: Osteoporosis, accessed March 2022, retrieved from: hopkinsmedicine.org; DerSarkissian, C.
Osteoporosis: Diagnosis and Treatment. 2021, Retrieved from: webmd.com; Frost & Sullivan, EnteraBio Initiation of Coverage, 2019;. Osteoporosis Diagnosis Anabolic Bone forming Antiresorptive Stop or slow bone
loss Bisphosphonates Estrogen*/HRT SERMs** Monoclonal Antibodies Fosamax® Alendronate PTH receptor activation Boniva® Ibandronate Acid Atelvia® & Actonel®Risedronic Acid Reclast® Zoledronic Acid Forteo® Teriparatide Estrogen
only Evenity®Romosozumab-apqg Prolia®Denosumab Tymlos®Abaloparatide Estrogen + Progestin Evista® Raloxifene Calcitonin RANK-Ligand Inhibitor Current Osteoporosis Pharmacologic Treatment Is Segmented Into: Anti-Resorptive &
Anabolic Options EB613Oral PTH (1-34) Current anabolic (bone forming) approved drugs require daily (Forteo®, Tymlos®) or monthly injections. There are no oral anabolic agents currently available to patients
Healthcare Providers Typically Use T-score BMD Classifications, Patient Fracture History and Preference
To Drive Therapy Selection Injections deter many patients from using PTH, contributing to a treatment gap in high-risk patients. An oral formulation of PTH with adequate bioavailability, similar safety and effects on BMD may address this
unmet clinical need Low BMD Category Percent of Patients with low BMD Initial Typical Treatment Recommendation Internists Endocrinologists Osteopenia 55% 27% Vitamin D and Calcium Supplements High Risk Osteoporosis(T-scores between
-2.5 and -3.0 without a history of fractures) 35% 43% Bisphosphonates; limited Anabolic penetration Very High Risk Osteoporosis(T-scores ≤ -3.0 or ≤ -2.5 with prior fragility fractures) 10% 23% Bisphosphonates / Anabolic
therapies T-Score Scale Bone Mineral Density Results T-score Normal Bone Density +1.0 0 -1.0 Low Bone Density (Osteopenia) -1.5 -2.0 -2.5 Osteoporosis* -3.0 Source: Triangle Insights Primary Research Apr. 2022;, Low BMD
Category based on AACE guidelines (Camacho 2020, Endo Practice) HCPs indicated most of their osteoporosis patients are: Post-menopausal women (~70%) Or older men (~15%)
Source: IQVIA prescription data (note the capture rate of IQVIA may be low due to injectable
administration of anabolic drugs on the market); TIG Primary Research Apr. 2022 IQVIA-Based HCP Primary-Based Total Osteoporosis Treated Population ~3.16M ~3.23M Bisphosphonate Patients ~1.74M (~55%) ~1.74M (~54%) SERMs
Patients ~206K (~7%) ~206K (~6%) Rank-Ligand Inhibitor Patients ~1.14M (~36%) ~1.02M (~32%) Anabolic Patients ~65K (~2%) ~260K (~8%) Bisphosphonates include Fosamax®, Boniva®, Atelvia®, Reclast®, and generic versions of listed
products; SERMs include Evista® and generic raloxifene; Rank-Ligand Inhibitors include Prolia®; Anabolics include Evenity®, Forteo®, generic teriparatide, and Tymlos® Share of Osteoporosis Treated Population by Medication Class
IQVIA-Based HCP-Based Estimated Treated Population by Class of Osteoporosis Medication Anabolic Treated Patients Comprise Less Than 10% of Currently Treated Osteoporosis Patients Population Treated by Class of Osteoporosis
Medication (2021)
EB613 Poised To Create A Paradigm Shift In The Treatment of Osteoporosis As The First Oral Anabolic
Therapy Key Product Needs Forteo® (Lilly) Tymlos® (Radius) Evenity® (Amgen) Prolia® (Amgen) Bisphosphonates(generics) Entera EB613 Treats Osteoporosis Rebuilds Bone Oral Dosing No Refrigeration Self-Administered * Source:
Triangle Insights Primary Research Apr. 2022 *Zoledronic acid is administered by intravenous administration Current Anabolic drugs, including PTH (1-34) (teriparatide) injections - Forteo® or Generics, Tymlos® and Evenity® increase the rate
of bone formation but require daily or monthly injections EB613 is positioned as the first potential oral anabolic PTH treatment for osteoporosis Bisphosphonates (oral daily pills) are the most common treatment of post-menopausal
osteoporosis – orally administered and inexpensive, but many patients progress and have low tolerance There have been no new oral drugs in >10 years
EB613 Phase 2 ResultsA Six-Month Study of Oral PTH in Postmenopausal Women with Low Bone Mass – 6 Month
Bone Mineral Density (BMD) Results
EB613 Phase 2 Clinical Trial Design Arm 1: Placebo tablets QD Arm 2: 0.5 mg * Arm 3: 1.0 mg * Arm
4: 1.5 mg QD Arm 5: 2.5 mg QD * ** Arm 6: 2.5mg titrated QD ** Key inclusion criteria 50+ years old and 3+ years post menopause Low bone mass Key exclusion criteria Osteoporosis treatment within last 2 years Known medical
predisposition Severe osteoporosis that precludes placebo Randomization N=160 (target) Endpoints Data 3 M Partial** & Final interim analysis of primary endpoint 6 M Final analysis / Topline data – All endpoints Primary – at 3
months Serum P1NP change from baseline at 3 months Secondary – at 6 months BMD change from baseline at 6 months P1NP, Osteocalcin, Bone Alkaline Phosphatase Serum CTX, Urine NTX/Creatinine Plasma hPTH (1-34) at T15 min 6-Month,
Randomized Dose-Ranging Placebo-Controlled Study Conducted at 4 sites in Israel between June 2019 and May 2021; Final enrollment =161 * Following an interim analysis, a 2.5mg arm was added and recruitment to the 0.5mg & 1.0 mg arms was
stopped ** Following AEs typical of orthostasis additional subjects in the 2.5mg group received 1.5mg for 1 month, 2.0mg for the next month and 2.5mg during months 3 to 6 (Titrated). Screening Treatment*
EB613 Predictive Profile Of Bone Biomarkers and Significant Dose-Dependent Increases in BMD 2.5mg
selected as Phase 3 dose – sustained “anabolic window” from Month 3 to Month 6 in patients treated with EB613. A significant dose response of 0.5, 1.0, 1.5 and 2.5 mg doses on Month 1 P1NP and Osteocalcin (P<0.0001). Serum CTX decreased
21% from baseline at Month 6 (p<0.01) while P1NP was unchanged Oral PTH produced a statistically significant Dose Response in Lumbar Spine BMD (p<0.0001) Presented at Late Breaker LB-1116 and Poster FRI-237– ASBMR 2021
Notes: 1. Cosman, et al. Current Osteoporosis Reports (2021) 19:189–205; 2. Leder BZ et.al. JCEM (2015)
(historical data from Abaloparatide vs. Forteo) * P< 0.05. ** P< 0.01 * ** ** ** 0.8% Placebo vs 1.1% Teriparatide Difference = 0.3% at Femoral Neck2 0.4% Placebo vs 0.5% Teriparatide Difference = 0.1% at Total
Hip2 3.78 2.73 2.76 1.84 EB613 Positively Impacts Lumbar Spine, Femoral Neck and Total Hip BMD at 6 Months, With Excellent Statistical Significance EB613 produced a statistically significant dose response in lumbar spine BMD
(p<0.0001), a statistically significant dose response in femoral neck BMD (p<0.002) and total hip BMD (p<0.008) EB613 appears to have a greater impact on femoral neck and total hip BMD than previously reported studies involving SC
injection Forteo®1,2 Placebo Adjusted BMD by Site of Measurement Pooled (Titrated + Non-Titrated) 2.5mg Non-Titrated 2.5mg
EB613: 6 Month Placebo Adjusted BMD by Site at 2.5mg Dose Presented at Late Breaker LB-1116 and Poster
FRI-237– ASBMR 2021 At 6 months of treatment with 2.5mg EB613: The increase in spine BMD was similar in magnitude to that previously reported with SC injection Forteo Increases in total hip and femoral neck BMD were greater than those
previously reported with SC injection Forteo 1.6% Placebo vs 5.5% Teriparatide Difference = 3.9% Placebo adjusted Lumbar Spine BMD Placebo adjusted Femoral Neck BMD 0.8% Placebo vs 1.1% Teriparatide Difference = 0.3% Placebo
Adjusted Total Hip BMD 0.4% Placebo vs 0.5% Teriparatide Difference = 0.1% Historical data (Leder BZ et.al. JCEM 2015)
EB613 Phase 2 Adverse Event Profile Adverse event profile similar to that observed with Forteo, and
typical of orthostatic hypotension EB613 not associated with serum calcium increases or hypercalcemia adverse events Greater than 90% of subjects tolerated the 2.5 mg dose well, after titration (1.5mg for 1 month, 2.0mg for the next month
and 2.5mg during months 3 to 6) AEs commonly attributed to vasodilatation with subcutaneous injectable PTH were observed - headache, nausea, presyncope and dizziness There were no serious drug-related AEs Subject disposition Placebo
(N=43) EBP05 0.5 mg orally QD (N=25) EBP05 1 mg orally QD (N=29) EBP05 1.5 mg orally QD (N=28) EBP05 2.5 mg orally QD (N=19) EBP05 2.5 mg titrated orally QD
(N=17) N % N % N % N % N % N % Randomized 43 100 25 100 29 100 28 100 19 100 17 100 Discontinued Before Month 3 3 7 3 12 2 6.9 4 14.3 7 36.8 1 5.9 Discontinued from Study Before Month
6 5 11.6 3 12 3 10.3 6 21.4 9 47.4 1 5.9
18 M Treatment Screening EB613 Proposed Phase 3 Clinical Trial Design Arm 1: EBP05 2.5mg
(N=400) 2:1 Randomization N=600 (target) A Global Phase 3, 18-Month, Placebo-Controlled Study (2:1), with a 6-Month Alendronate Extension Designed to address FDA suggestion - Placebo-Controlled study, BMD endpoint (ASBMR-FNIH
Criteria) Open label Alendronate (N=600) Titration to 2.5mg Dose Key inclusion criteria 50+ yrs old and 5+ yrs post menopause BMD: T-score -2.5 to -3.0 Key exclusion criteria Osteoporosis treatment w/in last 2 yrs Known medical
predisposition Severe osteoporosis that precludes placebo 6M Extension Endpoints Arm 2: Placebo tablets (N=200) Primary –Fracture risk reduction based on total hip BMD STEs FNIH, fracture specific surrogate thresholds using Total Hip
BMD at 18 months Secondary – BMD changes from baseline Bone turnover Biomarkers Exploratory - 24 month BMD changes Bone turnover Biomarkers Data 18 M Final analysis / Topline data – Primary & Secondary endpoints 24 M Final
analysis / Topline data – Exploratory Post Extension period endpoints
ASBMR-FNIH BMD Regulatory Endpoint Backgrounder Message from the president of the ASBMR on June 23rd
2022: The FDA Biomarkers Qualification Program accepted the ASBMR-Foundation for the National Institutes of Health (FNIH) Strategy to Advance BMD as a Regulatory Endpoint (SABRE) project team’s Qualification Plan to use the treatment-related
change in bone mineral density (BMD) as a surrogate endpoint for fractures in future trials of new anti-osteoporosis drugs The FNIH collected data from over 50 randomized trials and individual data from over 170,000 patients The FNIH
conducted a meta-regression of 38 placebo-controlled trials of 19 therapeutic agents1 and a meta-regression analyses of 91,779 individual patient data from 23 randomized placebo-controlled trials2 The FNIH concluded that total hip (TH) BMD,
as opposed to lumbar spine and femoral neck BMD, was found to be the best predictor of fracture risk reduction, at all sites (vertebral, non-vertebral and hip) FNIH’s submission of the Full Qualification Package, for final approval by the
FDA, is expected by the end of the year3 Bouxsein et. al. Journal of Bone and Mineral Research, Vol. 33, 2018, pp 1–11 Black et. al. Lancet Diabetes Endocrinol 2020; 8: 672–82 FNIH, June 1, 2022 press release
https://fnih.org/news/announcements/fda-approves-biomarkers-qualification-plan-first-surrogate-endpoint-anti
EB613 Phase 3 Clinical Trial Design Background – ASBMR-FNIH STEs The primary endpoint proposed for
EB613 Phase 3 is based on the ASBMR- FNIH’s Surrogate Threshold Effect (STE) using Total Hip (TH) BMD as the predictor of significant fracture reduction for all different fracture types. Placebo adjusted TH BMD STEs: 1.42% - vertebral
fractures 1.83% - all fractures 2.13% - nonvertebral fractures 3.18% - hip fractures Entera’s proposed Phase 3 study will evaluate the % change in BMD of EB613 measured at the hip vs. placebo This change will be tested to see which STEs
are surpassed. Beginning with vertebral followed by all fractures and nonvertebral fractures. Eastell et. al. Journal of Bone and Mineral Research, 2021, pp 1–7
EB613 Positioning EB613, as a first in class oral PTH treatment, may potentially offer a viable
anabolic (bone formation) therapeutic option to lower the risk of fracture for high risk (based on low BMD score or prior fracture history) osteoporotic patients PTH receptor activation is a mechanistically validated and key target in the
treatment of osteoporosis (Forteo® and Tymlos®) Based on third party research, many high-risk patients (approximately 35-40% of the estimated 3.2 million treated patients in the US) are reluctant to take daily injections and only turn to
currently injectable anabolic drugs when their disease becomes very severe (with multiple fractures) EB613 Phase 3 design is in accordance with End of Phase 2 suggestion by FDA to explore a placebo-controlled study using the ASBMR-FNIH BMD
Biomarker Tool 18 month double blind placebo-controlled treatment phase followed by 6-month transition to alendronate adheres to a real-world treatment paradigm and ensures all patients will receive active treatment Based on recent
third-party market research, healthcare providers would support the use of anabolics earlier in the treatment paradigm - yet hampered to date due to difficulty of administration (injectables) and price
EB612 Oral PTH (1-34) For the Treatment of Hypoparathyroidism
Hypoparathyroism: PTH Orphan Indication with Sub-Par Clinical Care References:
https://rarediseases.org/rare-diseases/hypoparathyroidism
https://www.takeda.com/en-us/newsroom/news-releases/2019/takeda-issues-us-recall-of-natpara-parathyroid-hormone-for-injection-due-to-the-potential-for-rubber-particulate/ TransCon™ PTH Top-Line Phase 3 Data from PaTHway
(ascendispharma.com) How many people are affected by HypoPT? Approximately 200K afflicted with hypoparathyroidism in the US, EU and Japan What is the market opportunity in HypoPT? Current standard of care creates long term
co-morbidities Natpara® (parathyroid hormone) injection was approved in 2015 and was withdrawn from US market in September 2019; Natpara® had sales of $230m in 2018, its 3rd full year of sales, before it was recalled. The recall was not
connected to the safety or efficacy of parathyroid hormone TransCon PTH, an investigational once-daily long-acting prodrug of parathyroid hormone (PTH(1-34)) U.S. FDA regulatory submission on track for Q3 and EU MAA for Q4 2022, according to
Ascendis Hypoparathyroidism (HypoPT) is a rare condition in which the parathyroid glands fail to produce sufficient levels of Parathyroid hormone (PTH) PTH (along with vitamin D and calcitonin) plays a role in regulating the levels of
calcium and phosphorus in the blood and in determining bone growth and bone cell activity HypoPT is characterized by hypocalcemia and hyperphosphatemia Clinical management includes frequent high doses of calcium and activated Vitamin D
which are associated with severe long-term morbidities: Unmet Need and Market Opportunity Hypoparathyroidism Overview Cardiovascular Heart failure, blood vessel calcification Neurologic Cognitive impairment, basal ganglia
calcification Skeletal Reduced bone turnover Renal Kidney stones, renal failure
EB612: First Oral PTH (1-34) Tablets for Hypoparathyroidism, Summary of PK and Pilot Phase 2 Data
Efficacy: 42% reduction (p=0.001) from baseline in median calcium supplement use Maintenance of median Ca levels above the lower target level for Hypoparathyroidism patients (>7.5 mg/dL) throughout the study Rapid decline of 23%
(p=0.0003) in median serum phosphate levels 2 hours following the first dose that was maintained for the duration of the study Safety: One subject experienced 4 AEs and left the study after the first day (withdrew consent), another subject
experienced an SAE prior to the administration of the first dose and, hence, unrelated to the study Phase 2, open-label, 2-period partial crossover study to evaluate the PK and PD (NCT03516773) Population: N=16 with hypoPT ≥1 year, taking
supplemental Ca and either alfacalcidol or calcitriol Treatment: two doses (0.75 and 2.25) and three regimens of Oral hPTH (1-34) and Natpara® [hPTH(1-84)] 100 μg SC injection QD Efficacy: Oral hPTH (1-34) 2.25 mg QID for one day is
associated with an increase in serum albumin-corrected calcium and 1,25(OH)2D and a decrease in serum phosphate The magnitude of these changes are comparable to Natpara® 100 μg QD Two, thee and four doses/day regimens showed a
dose-dependent increase in 1,25(OH)2D, indicating that the long-term treatment even with the less frequent regimens may be an effective treatment option Safety: There were no treatment emergent adverse events of hypercalcemia reported and no
treatment-emergent Serious Adverse Events Oral Calcium Intake Per Protocol Analysis (N=15) Improved/ Decreased Urinary Ca Excretion Over a 24-Hour Period Study Design Phase 2a, open-label, multicenter pilot study to evaluate the safety,
tolerability and PK (NCT02152228) Population: N=19 with hypoPT≥1 year, taking ≥1gr/day Ca and 25(OH)D 20ng/ml Treatment: first 3 doses of PTH (1-34) 0.75 mg/dose administered at research center; subjects then self administered 4
times/day Results
EB612 Positioning EB613 is potentially the first oral PTH (1-34) treatment of
hypoparathyroidism Hypoparathyroidism (HypoPT) is a rare condition in which the parathyroid glands fail to produce sufficient levels of Parathyroid hormone (PTH) Pilot Phase 2 oral presentation (ASBMR 2015) and peer-reviewed publication in
JBMR (March 2021) 42% reduction (p=0.001) from baseline in median calcium supplement use Maintenance of median Ca levels above the lower target level for Hypoparathyroidism patients (>7.5 mg/dL) throughout the study Rapid decline of 23%
(p=0.0003) in median serum phosphate levels 2 hours following the first dose that was maintained for the duration of the study 80% of the subjects had a decrease in urinary calcium levels by the end of the study Phase 2 PK-PD study versus
Natpara presented (ASBMR 2019) Novel formulation leverages Entera’s 2nd generation peptide delivery platform (PK study expected in H1’2023)
Key Short-Term Catalysts EB613 FDA Type C Meeting on Phase 3 Protocol (H2’2022E) ASBMR
Additional Data from Phase 2 6-Month BMD Study (September 11, 2022E) EB613 EB612 PK Data from 2nd Generation Formulation for Hypoparathyroidism (H1’2023E) EB613 Phase 3 Pivotal Study Initiation for Osteoporosis (H1’ 2023E) Phase 2/3
(pending FDA discussion) Initiation for Hypoparathyroidism (H2’2023E) EB612
Thank YouContact:Entera Bio:Ms. Miranda ToledanoChief Executive OfficerEmail: miranda@enterabio.com
Appendix
EB613 Phase 3 Clinical Trial Design - FNIH June 23rd, 2022 message from the president of the ASBMR
(American Society for Bone and Mineral research) Dr. Ebeling reported on the FNIH progress and support from the ASBMR1. https://www.asbmr.org/about/council/presidents-corner-detail/message-from-asbmr-president-peter-ebeling-ao-frac-7 “Dear
Colleagues:I am very happy to announce that the US Food and Drug Administration (FDA) Biomarkers Qualification Program recently accepted the ASBMR-Foundation for the National Institutes of Health (FNIH) Strategy to Advance BMD as a Regulatory
Endpoint (SABRE) project team’s Qualification Plan to use the treatment-related change in bone mineral density (BMD) as a surrogate endpoint for fractures in future trials of new anti-osteoporosis drugs.Indeed, this is the first qualification
plan accepted by the FDA for a surrogate endpoint under the 21st Century Cures Act, a remarkable achievement for the Project Team. This team, including ASBMR members Dennis Black, Mary Bouxsein and Richard Eastell, now plans to submit a Full
Qualification Package based on this approved plan for final approval by the FDA before the end of this year.The ASBMR is proud to financially support this critical initiative. Achieving FDA approval to utilize BMD as a surrogate endpoint in
future osteoporosis drug development trials could provide patients with more options to fight a disease that leads to debilitating fractures that cause disability, loss of independence and even death. It is also likely to attract more
researchers to the musculoskeletal field, enabling a new horizon of discoveries to help our patients.”
EB613 Phase 3 Clinical Trial Design Background - FNIH The Foundation for National Institutes of Health
(FNIH) – Bone Quality Project (BQP), supported by the FDA and other public, private and academic partners has been evaluating the potential use of existing biomarkers such as BMD to enable the development of anti osteoporosis drugs since
2013.1 The FNIH-BQP has been working closely with the FDA to ensure alignment with the FDA’s requirements and expectations as evident from extensive correspondence between the FNIH and
FDA.2 https://fnih.org/our-programs/biomarkers-consortium/programs/bone-quality-project 2. https://fda.force.com/ddt/s/ddt-project?ddtprojectid=97 3.
file:///C:/Users/HILLEL-THINK/Downloads/265-FNIH-Legacy-project-transition-to-507-process_1.pdf FDA responded to the proposed use of percentage change in BMD in our original Letter of Intent in 2016, stating that “Percentage change in DXA
BMD should be the most appropriate measure as this metric would not be affected by the DXA machine type or normative database used. However, there may be a threshold of percent change in BMD, above which we are comfortable with stating
fracture risk reduction has been demonstrated.” Aug. 2018 FNIH Status update to the FDA3
Entera Proprietary Oral Delivery Platform: Key Advantages and Validation Significantly Increased
Bioavailability of Macromolecules Reduced Pharmacokinetic Variability Versality Across Molecular Weight and Target Profile Advantageous Stability versus Injectables Controlled Onset of Action, Minutes to Hours Simple Production Process
Preserving API activity IP Protection across existing and next generation of our platform