Item 1. Business
ITEM 1. BUSINESS.
DESCRIPTION OF BUSINESS
Research and Development
We are a pharmaceutical company
currently engaged in the research and development of innovative pharmaceutical solutions, including an oral insulin capsule to be used
for the treatment of individuals with diabetes, and the use of orally ingestible capsules or pills for delivery of other polypeptides.
We utilize Clinical Research Organizations, or CROs, to conduct our clinical studies.
Through our research and development
efforts, we have successfully developed an oral dosage form intended to withstand the harsh environment of the stomach and intestines
and effectively deliver active insulin or other proteins, such as Glucagon-like peptide-1, or GLP-1, leptin, and others. The excipients
in the formulation are not intended to modify the proteins chemically or biologically, and the dosage form is designed to be safe to ingest.
We plan to continue to conduct clinical trials to show the effectiveness of our technology.
Oral insulin :
Our proprietary flagship product, an orally ingestible insulin capsule, or ORMD-0801, allows insulin to travel from the gastrointestinal
tract via the portal vein to the bloodstream, revolutionizing the manner in which insulin is delivered. It enables the passage in a more
physiological manner than current delivery methods of insulin.
FDA Guidance: In August
2017, the U.S. Food and Drug Administration, or FDA, instructed us that the regulatory pathway for the submission of ORMD-0801 would be
a BLA. If approved the BLA pathway would grant us 12 years of marketing exclusivity for ORMD-0801, from the approval date, and an additional
six months of exclusivity may be granted to us if the product also receives approval for use in pediatric patients.
Phase IIb Study: In
May 2018, we initiated a three-month dose-ranging Phase IIb clinical trial of ORMD-0801 (Cohort A). This placebo controlled, randomized,
90-day treatment clinical trial was conducted on 269 type 2 diabetic, or T2D, patients in multiple centers throughout the United States
pursuant to an Investigational New Drug application, or IND, with the FDA. The primary endpoints of the trial were to assess the safety
and evaluate the effect of ORMD-0801 on HbA1c levels over a 90-day treatment period. Secondary endpoints of the trial included measurements
of fasting plasma glucose, or FPG, post-prandial glucose, or PPG levels, during a mixed-meal tolerance test, or MMTT, and weight. In
May 2019, we initiated an extension of this protocol for approximately 75 T2D patients, who were dosed using a lower dosage of insulin
(Cohort B).
Cohort A :
In November 2019, we announced positive results from the initial cohort of the Phase IIb trial. Patients randomized in the trial to once-daily
ORMD-0801 achieved a statistically significant (p-value 0.036) reduction from baseline in HbA1c of 0.60% (0.54% with placebo adjustment).
This 0.54% reduction in HbA1c is clinically meaningful. Treatment with ORMD-0801 demonstrated an excellent safety profile, with no serious
drug-related adverse events and with no increased frequency of hypoglycemic episodes when compared to placebo. In addition, during this
90-day trial, no weight gain was observed. In the initial cohort, 269 U.S.-based patients were enrolled and treated with a dose-increasing
approach: 16 mg initial dose, titrated to 24 mg per dose, and then titrated to 32 mg per dose. Patients were randomized into three groups
to assess dosing frequency: once-daily (32 mg per day), twice-daily (64 mg per day), thrice daily (96 mg per day). There was a corresponding
placebo for each treatment arm. Two hundred nine (209) patients completed treatment to the 12-week endpoint and were included in the data
analysis (24 subjects did not complete the full 12 weeks of treatment). The twice-daily arms achieved statistically significant (p-value
0.042) reductions from baseline in HbA1c of 0.59% (0.53% with placebo adjustment). The thrice-daily arm did not meet statistical significance
(p-value 0.093). In addition, due to evidence of treatment-by-center interaction, two sites (36 patients (13.4% of enrolled subjects))
were excluded from the statistical analysis as they showed results opposite from the rest of the statistically significant results. Our
internal investigation as well as an independent investigation did not find a cause for such discrepancy.
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Cohort B :
In February 2020, we announced positive topline data from the second and final cohort of the Phase IIb trial with a different regimen
across three daily dose ranges (8 mg, 16 mg, 32 mg). Patients randomized in the trial treated with 8 mg of ORMD-0801 once-daily achieved
a statistically significant (p-value 0.028) observed mean reduction of 1.29% from baseline and a least square mean reduction of 0.95%
from baseline, or 0.81% adjusted for placebo. Patients who had HbA1c readings above 9% at baseline and received 8 mg of oral insulin once-daily
experienced a 1.26% reduction in HbA1c by week 12. Treatment with ORMD-0801 at all doses demonstrated an excellent safety profile, with
no serious drug-related adverse events and with no increased frequency of hypoglycemic episodes or weight gain compared to placebo. The
primary efficacy endpoint was a reduction in HbA1c at week 12.
Phase III Study :
Based on guidance received from the FDA as part of the end-of-phase II meeting process for our oral insulin candidate, ORMD-0801, we have
submitted to the FDA the protocols for our upcoming pivotal Phase III studies. In line with the FDA’s expectations and recommendations,
we intend to conduct two Phase III studies concurrently in patients with T2D. These studies involve about 1,125 patients to provide evidence
of ORMD-0801’s safety and efficacy in T2D patients over a treatment period of 6 to 12 months. A geographically diverse patient population
will be recruited from multiple sites throughout the United States, Europe, and Israel. Our Phase III study will be composed from 2 protocols:
ORA-D-013-1 :
This study will treat T2D patients with inadequate glycaemic control who are currently on 2 or 3 oral glucose-lowering agents. This U.S.
study will recruit 675 patients from at least 75 clinical sites located throughout the U.S. Patients will be randomized 1:1:1 in this
double-dummy study into cohorts of: 8 mg ORMD-0801 once-daily at night and placebo 45 minutes before breakfast; 8 mg ORMD-0801 twice-daily,
at night and 45 minutes before breakfast; and placebo twice-daily, at night and 45 minutes before breakfast. The primary endpoint of the
study is to evaluate the efficacy of ORMD-0801 compared to placebo in improving glycaemic control as assessed by HbA1c, with a secondary
efficacy endpoint of assessing the change from baseline in fasting plasma glucose at 26 weeks. We initiated this trial in December 2020.
In November 2021, we announced that 75% of the 675 patients were enrolled and randomized.
ORA-D-013-2 :
This study will include T2D patients with inadequate glycaemic control who are managing their condition with either diet alone or with
diet and metformin monotherapy. A total of 450 patients will be recruited through 36 sites in the U.S. and 25 sites in Western Europe
and Israel. Patients will be randomized 1:1 into two cohorts dosed with: 8 mg ORMD-0801 at night; and placebo at night. The primary endpoint
is to evaluate the efficacy of ORMD-0801 compared to placebo in improving glycaemic control as assessed by HbA1c over a 26-week treatment
period, with a secondary efficacy endpoint of assessing the change from baseline in fasting plasma glucose at 26 weeks. We initiated this
trial in the U.S. in March 2021. In August 2021, we announced that over 25% of the 450 patients were enrolled and randomized.
We expect to receive the efficacy
data from the trials after patients have completed the first 6 months of treatment. Safety will be further monitored as patients will
be exposed to the drug over an additional 6 months (total 12 months). The trial’s topline results are expected in 2022 and we anticipate
filing a BLA with the FDA in 2023. A BLA would grant us 12 years of marketing exclusivity from the date of approval in the U.S.
NASH trial: In June
2020, we presented topline data of 8 patients from an open-label trial that assessed the safety, tolerability, and early effects of 16
mg ORMD-0801 (2x8 mg capsules) on liver fat in T2D, patients with nonalcoholic steatohepatitis, or NASH. The 12-week dosing had no serious
adverse events and it induced an observed mean 6.9±6.8% reduction in liver fat content (p-value: 0.035), and the relative reduction
of 30%, as measured by MRI-derived proton density fat fraction, or MRI-PDFF. In parallel, concentrations of gamma-glutamyltransferase
(GGT), a key marker of chronic hepatitis, were significantly lower after 12 weeks of treatment as compared to baseline (-14.6±13.1
U/L; p value: 0.008).
In September 2020, we initiated an open label clinical
trial of our oral insulin capsule, ORMD-0801, for the treatment of NASH. This 10 patient multi-center trial is comprised of three clinical
sites in Belgium. The trial will measure change and percent change in MRI-PDFF from baseline to week 12.
In December 2020, we initiated a double blind,
placebo controlled clinical trial of our oral insulin capsule, ORMD-0801, for the treatment of NASH. This 30 patient multi-center trial
is comprised of five clinical sites: three in the U.S. and two in Israel. The trial will measure change and percent change in MRI-PDFF
from baseline to week 12. In September 2021, we announced that over 50% of the patients were enrolled and randomized.
Oral Glucagon-Like Peptide-1: Oral
Glucagon-Like Peptide-1, or GLP-1, is an incretin hormone, which stimulates the secretion of insulin from the pancreas. In addition to
our flagship product, the ORMD-0801 insulin capsule, we use our technology for an orally ingestible GLP-1 capsule, or ORMD-0901.
In February 2019, we completed a Phase I pharmacokinetic
trial to evaluate the safety and pharmacokinetics of ORMD-0901 compared to placebo in healthy volunteers. We initiated a follow-on trial
in T2D patients, in June 2021 in the U.S. under an IND submitted to the FDA.
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The following table gives
an overview of the above described primary R&D pipeline:
Our clinical trials are planned
in order to substantiate our results as well as for purposes of making future filings for drug approval. We also plan to conduct further
research and development by deploying our proprietary drug delivery technology for the delivery of other polypeptides in addition to insulin,
and to develop other innovative pharmaceutical products.
Oral Vaccine
On March 18, 2021, we entered into a license agreement,
or the Oravax License Agreement, with Oravax. For more information about the Oravax License Agreement, please see below under “Out-Licensed
Technology”.
Oravax, Oramed’s 63% owned joint venture
combines our proprietary POD™ oral delivery technology and the novel vaccine technology of Premas Biotech Pvt. Ltd., or Premas.
We are considering ways in which our shareholders could benefit more directly from Oravax, including potentially issuing some of our shares
in Oravax to our shareholders as a dividend, which would make Oravax a publicly held company that may in turn apply for listing on a stock
exchange.
A single dose of Oravax’s oral vaccine produced
a significant antibody response in a preclinical in-vivo study. Oravax’s novel vaccine technology may be a candidate for
protection against COVID-19 and its variants due to triple antigen targeting, easier distribution and ease of administration.
On October 29, 2021, we announced Oravax’s
oral COVID-19 vaccine has received clearance from the South African Health Products Regulatory Authority to initiate Phase I trial and
subsequently to commence patient enrollment in a first in human, Phase 1 clinical trial, for its oral COVID-19 vaccine.
Other Products
We are developing a new drug
candidate, a weight loss treatment in the form of an oral leptin capsule. During the third quarter of the 2020 calendar year, we finalized
a proof of concept single-dose trial for this candidate to evaluate its pharmacokinetics and pharmacodynamics (glucagon reduction) in
10 type 1 adult diabetic patients without any safety issues. Patients who received leptin on average had a decrease in glucose as compared
to the placebo group during the first 30-180 minutes following dosing. At different time periods, the leptin treated patients on average
had glucagon values that were either lower than or similar to, those in the placebo group. We are currently in the middle of a second
study of 15 type 1 adult diabetic patients who serve as both the active and placebo arms in this study, with anticipated results in the
fourth quarter of the 2021 calendar year.
Raw Materials
Our oral insulin capsule is
currently manufactured by Fidelio Healthcare, a diversified European Contract Development and Manufacturing Organization (CDMO) in the
pharmaceutical and healthcare industries.
In July 2010, Oramed Ltd.
entered into the Manufacturing and Supply Agreement, or MSA, with Sanofi-Aventis Deutschland GMBH, or Sanofi-Aventis. According to the
MSA, Sanofi-Aventis will supply Oramed Ltd. with specified quantities of recombinant human insulin to be used for clinical trials.
We purchase, pursuant to separate
agreements with third parties, the raw materials required for the manufacturing of our oral capsule. We generally depend upon a limited
number of suppliers for the raw materials. Although alternative sources of supply for these materials are generally available, we could
incur significant costs and disruptions if we need to change suppliers. The termination of our relationships with our suppliers or the
failure of these suppliers to meet our requirements for raw materials on a timely and cost-effective basis could have a material adverse
effect on our business, prospects, financial condition and results of operations.
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Market Overview
Diabetes is a disease in which
the body does not produce or properly use insulin. Insulin is a hormone that causes sugar to be absorbed into cells, where the sugar is
converted into energy needed for daily life. The cause of diabetes is attributed both to genetics (type 1 diabetes, or T1D) and, most
often, to environmental factors such as obesity and lack of exercise (T2D). According to the International Diabetes Federation, or IDF,
an estimated 463 million adults (20-79 years) worldwide suffered from diabetes in 2019 and the IDF projects this number will increase
to 700 million by 2045. Also, according to the IDF, in 2019, an estimated 4.2 million people died from diabetes. According to the American
Diabetes Association, or ADA, in the United States there were approximately 34.2 million people with diabetes, or 10.5% of the United
States population in 2018. Diabetes is a leading cause of blindness, kidney failure, heart attack, stroke and amputation. The latest report
of the ADA that analyzed the economic costs of diabetes in the U.S in 2017 indicates that the total cost of diagnosed diabetes in the
United States in 2017 was $327 billion.
Intellectual Property
We own a portfolio of patents
and patent applications covering our technologies, and we are aggressively protecting these technology developments on a worldwide basis.
Leadership
Management :
We are led by an experienced management team knowledgeable in the treatment of diabetes. Our Chief Scientific Officer, Miriam Kidron,
PhD, is a recognized pharmacologist and a biochemist and the innovator primarily responsible for our oral insulin technology development
and know-how.
Scientific Advisory
Board : Our management team has access to our internationally recognized Scientific Advisory Board whose members are thought-leaders
in their respective areas. The Scientific Advisory Board is comprised of Dr. Roy Eldor, Dr. Ele Ferrannini, Dr. Alexander Fleming, Dr.
Avram Hershko, Dr. Harold Jacob, Dr. Julio Rosenstock and Dr. Jay Skyler.
Strategy
We plan to ultimately seek
a strategic commercial partner, or partners, with extensive experience in the development, commercialization, and marketing of insulin
applications and/or other orally digestible drugs. We anticipate such partner or partners would be responsible for, or substantially support,
late-stage clinical trials (Phase III) to increase the likelihood of obtaining regulatory approvals and registrations in the appropriate
markets in a timely manner. We further anticipate that such partner, or partners, would also be responsible for sales, marketing and support
of our products in these markets. Such planned strategic partnership, or partnerships, may provide a marketing and sales infrastructure
for our products as well as financial and operational support for global clinical trials, post marketing studies, label expansions and
other regulatory requirements concerning future clinical development. In 2015, we successfully executed this strategy when we, Oramed
Ltd. and HTIT entered into a Technology License Agreement pursuant to which we granted HTIT an exclusive commercialization license in
the territory of the People’s Republic of China, Macau and Hong Kong, or the Territory, related to our oral insulin capsule, ORMD-0801.
Any future strategic partner, or partners, may also provide capital and expertise that would enable the partnership to develop new oral
dosage forms for other polypeptides. While our strategy is to partner with an appropriate party, no assurance can be given that we will
in fact be able to reach an agreeable partnership with any third party. Under certain circumstances, we may determine to develop one or
more of our oral dosage forms on our own, either world-wide or in select territories.
In line with our strategy,
we have entered into a joint venture focused on the development of novel oral COVID-19 vaccines, based on our proprietary oral delivery
technology and our partners’ novel vaccine technology.
In addition to developing
our own oral dosage form drug portfolio, we are, on an on-going basis, considering in-licensing and other means of obtaining additional
technologies to complement and/or expand our current product portfolio. Our goal is to create a well-balanced product portfolio that will
enhance and complement our existing drug portfolio.
Potential Material Impact of COVID-19
The COVID-19 pandemic has
negatively impacted the global economy, disrupted consumer spending and global supply chains and created significant volatility and disruption
of financial markets. Although to date the COVID-19 pandemic has not had a material adverse effect on us, the COVID-19 pandemic may have
a material adverse effect on our business and financial performance in the future. The extent of the impact of the COVID-19 pandemic,
including our ability to execute our business strategies as planned, will depend on future developments, including the duration and severity
of the pandemic, which are highly uncertain and cannot be predicted.
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Although, as of the date of
this Annual Report on Form 10-K, we do not expect any material impact on our long-term activity, the extent to which COVID-19 impacts
our business will depend on future developments, which are highly uncertain and cannot be predicted, including new information which may
emerge concerning the severity of COVID-19 and the actions to contain COVID-19 or treat its impact, among others.
Patents and Licenses
We maintain a proactive intellectual
property strategy, which includes patent filings in multiple jurisdictions, including the United States and other commercially significant
markets. We hold 36 patent applications currently pending, with respect to various compositions, methods of production and oral administration
of proteins and exenatide. Expiration dates for pending patents, if granted, will fall between 2026 and 2039.
We hold 87 patents, one of
which was issued during the fiscal year ended August 31, 2021, or fiscal 2021, including patents issued by the United States, Swiss, German,
French, U.K., Italian, Netherlands, Swedish, Spanish, Australian, Israeli, Japanese, New Zealand, South African, Russian, Canadian, Hong
Kong, Chinese, European and Indian patent offices that cover a part of our technology, which allows for the oral delivery of proteins;
patents issued by the Australian, Canadian, European, Austrian, Belgian, French, German, Irish, Italian, Luxembourg, Monaco, Netherlands,
Norwegian, Spanish, Swedish, Swiss, U.K., Israeli, New Zealand, South African, Russian and Japanese patent offices that cover part of
our technology for the oral delivery of exenatide; and patents issued by the European, Austrian, Belgian, Denmark, French, German, Irish,
Italian, Luxembourg, Monaco, Netherlands, Norway, Spanish, Swedish, Swiss, U.K. and Japanese patent offices for treating diabetes.
Consistent with our strategy
to seek protection in key markets worldwide, we have been and will continue to pursue the patent applications and corresponding foreign
counterparts of such applications. We believe that our success will depend on our ability to obtain patent protection for our intellectual
property.
Our patent strategy is as
follows:
●
Aggressively protect all current and future technological developments to assure strong and broad protection by filing patents and/or continuations in part as appropriate,
●
Protect technological developments at various levels, in a complementary manner, including the base technology, as well as specific applications of the technology, and
●
Establish comprehensive coverage in the United States and in all relevant foreign markets in anticipation of future commercialization opportunities.
We also rely on trade secrets
and unpatentable know-how that we seek to protect, in part, by confidentiality agreements. Our policy is to require our employees, consultants,
contractors, manufacturers, outside scientific collaborators and sponsored researchers, our board of directors, or our Board, technical
review board and other advisors, to execute confidentiality agreements upon the commencement of employment or consulting relationships
with us. These agreements provide that all confidential information developed or made known to the individual during the course of the
individual’s relationship with us is to be kept confidential and not disclosed to third parties except in specific limited circumstances.
We also require signed confidentiality or material transfer agreements from any company that is to receive our confidential information.
In the case of employees, consultants and contractors, the agreements provide that all inventions conceived by the individual while rendering
services to us shall be assigned to us as the exclusive property of the Company. There can be no assurance, however, that all persons
who we desire to sign such agreements will sign, or if they do, that these agreements will not be breached, that we would have adequate
remedies for any breach, or that our trade secrets or unpatentable know-how will not otherwise become known or be independently developed
by competitors.
Out-Licensed Technology
ENTERA BIO
In June 2010, Oramed Ltd.
entered into a joint venture agreement with D.N.A Biomedical Solutions Ltd., or D.N.A, for the establishment of Entera Bio Ltd., or Entera.
Under the terms of a license
agreement, as amended, that was entered into between Oramed Ltd. and Entera in August 2010, we out-licensed technology to Entera, on an
exclusive basis, for the development of oral delivery drugs for certain indications to be agreed upon between the parties. The out-licensed
technology differs from our main delivery technology that is used for oral insulin and GLP-1 analog and is subject to different patent
applications. Entera’s initial development effort is for an oral formulation for the treatment of osteoporosis. In March 2011, we
entered into a patent transfer agreement, or the Patent Transfer Agreement, to replace the original license agreement pursuant to which
Oramed Ltd. assigned to Entera all of its right, title and interest in and to the patent application that it had licensed to Entera in
August 2010. Under this agreement, Oramed Ltd. is entitled to receive from Entera royalties of 3% of Entera’s net revenues and a
license back of that patent application for use in respect of diabetes and influenza.
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In March 2011, we also consummated
a transaction with D.N.A, whereby we sold to D.N.A 47% of Entera’s outstanding share capital on an undiluted basis, retaining a
3% interest as of March 2011. In consideration for the shares sold to D.N.A, we received, among other payments, ordinary shares of D.N.A.
The D.N.A ordinary shares are traded on the Tel Aviv Stock Exchange and its quoted price is subject to market fluctuations, and may, at
times, have a price below the value on the date we acquired such shares. In addition, the ordinary shares of D.N.A have historically experienced
low trading volume; as a result, there is no guarantee that we will be able to resell the ordinary shares of D.N.A at the prevailing market
prices. During the years ended August 31, 2021, 2020 and 2019, we did not sell any of the D.N.A ordinary shares. As of August 31, 2021,
we held approximately 1.7% of D.N.A’s outstanding ordinary shares.
On December 11, 2018, Entera
announced that it had entered into a research collaboration and license agreement, or the Amgen License, with Amgen Inc. related to research
of inflammatory disease and other serious illnesses. As reported by Entera, under the terms of the Amgen License, Entera will receive
a modest initial technology access fee from Amgen and will be responsible for preclinical development at Amgen’s expense. Entera
will be eligible to receive up to $270,000,000 in aggregate payments, as well as tiered royalties up to mid-single digits, upon achievement
of various clinical and commercial milestones if Amgen decides to move all of these programs forward. To the extent the Amgen License
results in net revenues as defined in the Patent Transfer Agreement, Oramed Ltd. will be entitled to the aforementioned royalties.
HTIT
On November 30, 2015, we,
Oramed Ltd. and HTIT entered into a Technology License Agreement, or TLA, and on December 21, 2015, these parties entered into an Amended
and Restated Technology License Agreement that was further amended by the parties on June 3, 2016 and July 24, 2016, or the License Agreement.
According to the License Agreement, we granted HTIT an exclusive commercialization license in the Territory, related to our oral insulin
capsule, ORMD-0801, or the Product. Pursuant to the License Agreement, HTIT will conduct, at its own expense, certain pre-commercialization
and regulatory activities with respect to our subsidiary’s technology and ORMD-0801 capsule, and will pay (i) royalties of 10% on
net sales of the related commercialized products to be sold by HTIT in the Territory, or Royalties, and (ii) an aggregate of $37.5 million,
of which $3 million was payable immediately, $8 million will be paid subject to our entry into certain agreements with certain third parties,
and $26.5 million will be payable upon achievement of certain milestones and conditions. In the event that we will not meet certain conditions,
the Royalties rate may be reduced to a minimum of 8%. Following the final expiration of our patents covering the technology in the Territory
in 2033, the Royalties rate may be reduced, under certain circumstances, to 5%. The royalty payment obligation shall apply during the
period of time beginning upon the first commercial sale of the Product in the Territory, and ending upon the later of (i) the expiration
of the last-to-expire licensed patents in the Territory; and (ii) 15 years after the first commercial sale of the Product in the Territory,
or the Royalty Term. The License Agreement shall remain in effect until the expiration of the Royalty Term. The License Agreement contains
customary termination provisions. Through August 31, 2021, we received aggregate milestone payments of $20.5 million out of the aggregate
amount of $37.5 million.
On August 21, 2020, we received
a letter from HTIT, disputing certain pending payment obligations of HTIT under the TLA. We wholly dispute said claims and we are in discussions
with HTIT in an attempt to reach a mutually agreeable solution.
Oravax License
On March 18, 2021, we entered into the Oravax License
Agreement with Oravax, pursuant to which we will grant to Oravax an exclusive, worldwide license , or the License, under our rights in
certain patents and related intellectual property in which Oravax will receive certain rights relating to our proprietary oral delivery
technology to further develop, manufacture and commercialize oral vaccines for COVID-19 and other novel coronaviruses based on Premas’s
proprietary vaccine technology involving a triple antigen virus like particle, or the Oravax Product, which was previously owned by Cystron
Biotech LLC, or Cystron, and later acquired by Akers Biosciences Inc., or Akers.
In consideration for the grant
of the License, the Oravax License Agreement provides that we will receive (i) royalties equal to 7.5% on net sales, as defined in the
Oravax License Agreement, of each product commercialized by Oravax, its affiliates and permitted sublicensees related to the License during
the term specified in the Oravax License Agreement, (ii) sublicensing fees equal to 15% of any non-sales-based consideration received
by Oravax from a permitted sublicensee and (iii) other payments ranging between $25 million to $100 million, based on certain sales milestones
being achieved by Oravax. The parties further agreed to establish a development and steering committee, which will consist of three members,
of which two members will be appointed by us, that will oversee the ongoing research, development, clinical and regulatory activity with
respect to the Oravax Product. In addition, we agreed to buy and Oravax agreed to issue to us 1,890,000 shares of common stock of Oravax,
representing 63% of the common stock of Oravax for the aggregate amount of $1.5 million. Akers agreed to contribute to Oravax $1.5 million
in cash and substantially all of the assets of Cystron, including a license agreement to Premas’s novel vaccine technology. Nadav
Kidron, the Company’s President and Chief Executive Officer, was one of the former members of Cystron. See note 12 to the financial
statements.
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Government Regulation
The Drug Development
Process
Regulatory requirements for
the approval of new drugs vary from one country to another. In order to obtain approval to market our drug portfolio, we need to go through
a different regulatory process in each country in which we apply for such approval. In some cases, information gathered during the approval
process in one country can be used as supporting information for the approval process in another country. As a strategic decision, we
decided to first explore the FDA regulatory pathway. The following is a summary of the FDA’s requirements.
The FDA requires that pharmaceutical
and certain other therapeutic products undergo significant clinical experimentation and clinical testing prior to their marketing or introduction
to the general public. Clinical testing, known as clinical trials or clinical studies, is either conducted internally by life science,
pharmaceutical or biotechnology companies or is conducted on behalf of these companies by CROs.
The process of conducting
clinical studies is highly regulated by the FDA, as well as by other governmental and professional bodies. Below we describe the principal
framework in which clinical studies are conducted, as well as describe a number of the parties involved in these studies.
Protocols. Before commencing
human clinical studies, the sponsor of a new drug or therapeutic product must submit an IND application to the FDA. The application contains,
among other documents, what is known in the industry as a protocol. A protocol is the blueprint for each drug study. The protocol sets
forth, among other things, the following:
●
Who must be recruited as qualified participants,
●
How often to administer the drug or product,
●
What tests to perform on the participants, and
●
What dosage of the drug or amount of the product to give to the participants.
Institutional Review Board.
An institutional review board is an independent committee of professionals and lay persons which reviews clinical research studies involving
human beings and is required to adhere to guidelines issued by the FDA. The institutional review board does not report to the FDA, but
its records are audited by the FDA. Its members are not appointed by the FDA. All clinical studies must be approved by an institutional
review board. The institutional review board’s role is to protect the rights of the participants in the clinical studies. It approves
the protocols to be used, the advertisements which the company or CRO conducting the study proposes to use to recruit participants, and
the form of consent which the participants will be required to sign prior to their participation in the clinical studies.
Clinical Trials. Human clinical
studies or testing of a potential product are generally done in three stages known as Phase I through Phase III testing. The names of
the phases are derived from the regulations of the FDA. Generally, there are multiple studies conducted in each phase.
Phase I. Phase I studies involve
testing a drug or product on a limited number of healthy or patient participants, typically 24 to 100 people at a time. Phase I studies
determine a product’s basic safety and how the product is absorbed by, and eliminated from, the body. This phase lasts an average
of six months to a year.
Phase II. Phase II
trials involve testing of no more than 300 participants at a time who may suffer from the targeted disease or condition. Phase II
testing typically lasts an average of one to two years. In Phase II, the drug is tested to determine its safety and effectiveness
for treating a specific illness or condition. Phase II testing also involves determining acceptable dosage levels of the drug. Phase
II studies may be split into Phase IIa and Phase IIb sub-studies. Phase IIa studies may be conducted with patient volunteers and are
exploratory (non-pivotal) studies, typically designed to evaluate clinical efficacy or biological activity. Phase IIb studies are
conducted with patients defined to evaluate definite dose range and evaluate efficacy. If Phase II studies show that a new drug has
an acceptable range of safety risks and probable effectiveness, a company will generally continue to review the substance in Phase
III studies.
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Phase III. Phase III studies
involve testing large numbers of participants, typically several hundred to several thousand persons. The purpose is to verify effectiveness
and long-term safety on a large scale. These studies generally last two to three years. Phase III studies are conducted at multiple locations
or sites. Like the other phases, Phase III requires the site to keep detailed records of data collected and procedures performed.
Biological License Application.
The results of the clinical trials for a biological product are submitted to the FDA as part of a BLA. Following the completion of Phase
III studies, assuming the sponsor of a potential product in the United States believes it has sufficient information to support the safety
and effectiveness of its product, the sponsor will generally submit a BLA to the FDA requesting that the product be approved for marketing.
The application is a comprehensive, multi-volume filing that includes the results of all clinical studies, information about the drug’s
composition, and the sponsor’s plans for producing, packaging and labeling the product. The FDA’s review of an application
can take a few months to many years, with the average review lasting 18 months. Once approved, drugs and other products may be marketed
in the United States, subject to any conditions imposed by the FDA. Approval of a BLA provides 12 years of exclusivity in the U.S. market.
Phase IV. The FDA may require
that the sponsor conduct additional clinical trials following new drug approval. The purpose of these trials, known as Phase IV studies,
is to monitor long-term risks and benefits, study different dosage levels or evaluate safety and effectiveness. In recent years, the FDA
has increased its reliance on these trials. Phase IV studies usually involve thousands of participants. Phase IV studies also may be initiated
by the company sponsoring the new drug to gain broader market value for an approved drug.
Similar to the U.S., a European
sponsor of a biological product may submit a Marketing Approval Application to the EMA for the registration of the product. The approval
process in Europe consists of several stages, which together are summed up to 210 days from the time of submission of the application
(net, without periods in which the sponsor provides answers to questions raised by the agency) following which, a Marketing Approval may
be granted. During the approval process, the sponsor’s manufacturing facilities will be audited in order to assess Good Manufacturing
Practice compliance.
The drug approval process
is time-consuming, involves substantial expenditures of resources, and depends upon a number of factors, including the severity of the
illness in question, the availability of alternative treatments, and the risks and benefits demonstrated in the clinical trials.
Other Regulations
Various federal, state and
local laws, regulations, and recommendations relating to safe working conditions, laboratory practices, the experimental use of animals,
the environment and the purchase, storage, movement, import, export, use, and disposal of hazardous or potentially hazardous substances,
including radioactive compounds and infectious disease agents, used in connection with our research are applicable to our activities.
They include, among others, the U.S. Atomic Energy Act, the Clean Air Act, the Clean Water Act, the Occupational Safety and Health Act,
the National Environmental Policy Act, the Toxic Substances Control Act, and Resources Conservation and Recovery Act, national restrictions
on technology transfer, import, export, and customs regulations, and other present and possible future local, state, or federal regulation.
The compliance with these and other laws, regulations and recommendations can be time-consuming and involve substantial costs. In addition,
the extent of governmental regulation which might result from future legislation or administrative action cannot be accurately predicted
and may have a material adverse effect on our business, financial condition, results of operations and prospects.
Competition
Competition in General
Competition in the area of
biomedical and pharmaceutical research and development is intense and significantly depends on scientific and technological factors. These
factors include the availability of patent and other protection for technology and products, the ability to commercialize technological
developments and the ability to obtain regulatory approval for testing, manufacturing and marketing. Our competitors include major pharmaceutical,
medical products, chemical and specialized biotechnology companies, many of which have financial, technical and marketing resources significantly
greater than ours. In addition, many biotechnology companies have formed collaborations with large, established companies to support research,
development and commercialization of products that may be competitive with ours. Academic institutions, governmental agencies and other
public and private research organizations are also conducting research activities and seeking patent protection and may commercialize
products on their own or through joint ventures. We are aware of certain other products manufactured or under development by competitors
that are used for the treatment of the diseases and health conditions that we have targeted for product development. We can provide no
assurance that developments by others will not render our technology obsolete or noncompetitive, that we will be able to keep pace with
new technological developments or that our technology will be able to supplant established products and methodologies in the therapeutic
areas that are targeted by us. The foregoing factors could have a material adverse effect on our business, prospects, financial condition
and results of operations. These companies, as well as academic institutions, governmental agencies and private research organizations,
also compete with us in recruiting and retaining highly qualified scientific personnel and consultants.
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Competition within our sector
is increasing, so we will encounter competition from existing firms that offer competitive solutions in diabetes treatment solutions.
These competitive companies could develop products that are superior to, or have greater market acceptance, than the products being developed
by us. We will have to compete against other biotechnology and pharmaceutical companies with greater market recognition and greater financial,
marketing and other resources.
Our competition will be determined
in part by the potential indications for which our technology is developed and ultimately approved by regulatory authorities. In addition,
the first product to reach the market in a therapeutic or preventive area is often at a significant competitive advantage relative to
later entrants to the market. Accordingly, the relative speed with which we, or our potential corporate partners, can develop products,
complete the clinical trials and approval processes and supply commercial quantities of the products to the market are expected to be
important competitive factors. Our competitive position will also depend on our ability to attract and retain qualified scientific and
other personnel, develop effective proprietary products, develop and implement production and marketing plans, obtain and maintain patent
protection and secure adequate capital resources. We expect our technology, if approved for sale, to compete primarily on the basis of
product efficacy, safety, patient convenience, reliability, value and patent position.
Competition for Our
Oral Insulin Capsule
We anticipate the oral insulin
capsule to be a competitive diabetes drug because of its anticipated efficacy and safety profile. The following are some of the treatment
options for T1D and T2D patients:
●
Insulin injections,
●
Insulin pumps, or
●
A combination of diet, exercise and oral medication which improve the body’s response to insulin or cause the body to produce more insulin.
Scientific Advisory Board
We maintain a Scientific Advisory
Board consisting of internationally recognized scientists who advise us on scientific and technical aspects of our business. The Scientific
Advisory Board meets periodically to review specific projects and to assess the value of new technologies and developments to us. In addition,
individual members of the Scientific Advisory Board meet with us periodically to provide advice in their particular areas of expertise.
The Scientific Advisory Board consists of the following members, information with respect to whom is set forth below: Dr. Roy Eldor, Professor
Ele Ferrannini, Dr. Alexander Fleming, Professor Avram Hershko, Dr. Harold Jacob, Dr. Julio Rosenstock and Dr. Jay Skyler.
Dr. Roy Eldor , MD,
PhD, joined the Oramed Scientific Advisory Board in July 2016. He is an endocrinologist, internist and researcher with over twenty
years of clinical and scientific experience. He is currently Director of the Diabetes Unit at the Institute of Endocrinology, Metabolism& Hypertension, Tel-Aviv Sourasky Medical Center. Prior to that, Dr. Eldor served as Principal Scientist at Merck Research Laboratories,
Clinical Research–- Diabetes & Endocrinology, Rahway, New Jersey. He has previously served as a senior physician in internal
medicine at the Diabetes Unit in Hadassah Hebrew University Hospital, Jerusalem, Israel; and the Diabetes Division at the University of
Texas Health Science Center in San Antonio, Texas (under the guidance of Dr. R.A. DeFronzo). Dr. Eldor is a recognized expert, with over
50 peer reviewed papers and book chapters, and has been a guest speaker at numerous international forums.
Professor Ele Ferrannini ,
MD, joined the Oramed Scientific Advisory Board in February 2007. He is a past President to the European Association for the
Study of Diabetes, which supports scientists, physicians and students from all over the world who are interested in diabetes and related
subjects in Europe, and performs functions similar to that of the ADA in the United States. Professor Ferrannini has worked with various
institutions including the Department of Clinical & Experimental Medicine, University of Pisa School of Medicine, and CNR (National
Research Council) Institute of Clinical Physiology, Pisa, Italy; and the Diabetes Division, Department of Medicine, University of Texas
Health Science Center at San Antonio, Texas. He has also had extensive training in internal medicine and endocrinology, and has specialized
in diabetes studies. Professor Ferrannini has received a Certificate of the Educational Council for Foreign Medical Graduates from the
University of Bologna, and with cum laude honors completed a subspecialty in Diabetes and Metabolic Diseases at the University of Torino.
He has published over 500 original papers and 50 book chapters and he is a “highly cited researcher,” according to the Institute
for Scientific Information.
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Dr. Alexander Fleming,
MD an endocrinologist, is Founder and Executive Chairman of Kinexum, a strategic advisory firm. At the FDA from 1986 to 1998,
he served as a supervisory medical officer in the Division of Metabolism and Endocrine Drug Products and was responsible for landmark
approvals of the first statin, metformin, and other endocrine and metabolic therapies. He also represented the FDA at the World Health
Organization and on multiple expert working groups of the International Conference on Harmonization (ICH). Dr. Fleming coined the term,
Metabesity, which refers to the constellation of major chronic diseases and the aging process itself, all which share common metabolic
root causes and potential preventive therapies. He organized the first Congress on Metabesity in London in October 2017, followed by annual
conferences. Dr. Fleming founded in 2020 the not-for-profit Kitalys Institute as a means of producing Metabesity conferences and advancing
interventions of any kind that can improve health and healthspan.
Professor Avram Hershko,
MD, PhD , joined the Oramed Scientific Advisory Board in July 2008. He earned his MD degree (1965) and PhD degree (1969) from the
Hebrew University-Hadassah Medical School of Jerusalem. Professor Hershko served as a physician in the Israel Defense Forces from 1965
to 1967. After a post-doctoral fellowship with Gordon Tomkins at the University of San Francisco (1969 - 72), he joined the faculty
of the Haifa Technion becoming a professor in 1980. He is now Distinguished Professor in the Unit of Biochemistry in the B. Rappaport
Faculty of Medicine of the Technion. Professor Hershko’s main research interests concern the mechanisms by which cellular proteins
are degraded, a formerly neglected field of study. Professor Hershko and his colleagues showed that cellular proteins are degraded by
a highly selective proteolytic system. This system tags proteins for destruction by linkage to a protein called ubiquitin, which had previously
been identified in many tissues, but whose function was previously unknown. Subsequent work by Professor Hershko and many other laboratories
has shown that the ubiquitin system has a vital role in controlling a wide range of cellular processes, such as the regulation of cell
division, signal transduction and DNA repair. Professor Hershko was awarded the Nobel Prize in Chemistry (2004) jointly with his former
PhD student Aaron Ciechanover and their colleague Irwin Rose. His many honors include the Israel Prize for Biochemistry (1994), the Gairdner
Award (1999), the Lasker Prize for Basic Medical Research (2000), the Wolf Prize for Medicine (2001) and the Louisa Gross Horwitz Award
(2001). Professor Hershko is a member of the Israel Academy of Sciences (2000) and a Foreign Associate of the U.S. Academy of Sciences
(2003).
Dr. Harold Jacob, MD ,
joined the Oramed Scientific Advisory Board in November 2016. Since 1998, Dr. Jacob has served as the president of Medical Instrument
Development Inc., a company which provides a range of support and consulting services to start-up and early stage companies as well as
patenting its own proprietary medical devices. Since 2011, Dr. Jacob has also served as an attending physician at Hadassah University
Medical Center, where he has served as the director of the gastrointestinal endoscopy unit since September 2013. Dr. Jacob has advised
a spectrum of companies in the past and he served as a consultant and then as the Director of Medical Affairs at Given Imaging Ltd., from
1997 to 2003, a company that developed the first swallowable wireless pill camera for inspection of the intestine. He has licensed patents
to a number of companies including Kimberly-Clark Corporation. Since 2014, Dr. Jacob has served as the Chief Medical Officer and a director
of NanoVibronix, Inc., a medical device company using surface acoustics to prevent catheter acquired infection as well as other applications,
where he served as Chief Executive Officer from 2004 to 2014. He practiced clinical gastroenterology in New York and served as Chief of
Gastroenterology at St. John’s Episcopal Hospital and South Nassau Communities Hospital from 1986 to 1995, and was a Clinical Assistant
Professor of Medicine at SUNY from 1983 to 1990. Dr. Jacob founded and served as Editor in Chief of Endoscopy Review and has authored
numerous publications in the field of gastroenterology.
Dr. Julio Rosenstock,
MD , joined the Oramed Scientific Advisory Board in January 2020. Dr. Rosenstock is Director of the Dallas Diabetes Research Center
at Medical City, and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center, Dallas. He is board certified
in Internal Medicine, and Endocrinology and Metabolism. His clinical and research activities have focused on exploring novel agents and
therapeutic strategies to improve glycemic control. Over the last 30 years, he has participated in hundreds of clinical trials and has
had an active role in the development of new diabetes oral agents, incretin-related therapies and insulin formulations, acting often as
a lead clinical investigator and scientific advisor. Dr. Rosenstock has been the author or co-author of 338 peer-reviewed manuscripts
(H-index 105) and several hundred scientific abstracts. He has also contributed to 13 book chapters on various topics in the field of
diabetes. He is currently an Associate Editor of Diabetes Care.
Dr. Jay Skyler, MD,
MCAP , joined the Oramed Scientific Advisory Board in January 2020. Dr. Skyler is Professor of Medicine, Pediatrics, & Psychology
in the Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Miami Leonard M. Miller School of Medicine.
He previously held the position of Director of the Division of Endocrinology, Diabetes& Metabolism. In addition, Dr. Skyler is Deputy
Director of Clinical Research and Academic Programs at the Diabetes Research Institute, and an Adjunct Professor of Pediatrics at the
Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver. Dr. Skyler’s research focuses on the clinical aspects
of diabetes, specifically the conduct of randomized controlled clinical trials. From 1993 until 2015, he was Chairman of the NIH (NIDDK)-sponsored
Diabetes Prevention Trial–- Type 1 (DPT-1) and its successor Type 1 Diabetes TrialNet, a nationwide (and global) network conducting
clinical trials to prevent T1D.
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Employees
We have been successful in
retaining experienced personnel involved in our research and development program. In addition, we believe we have successfully recruited
the clinical/regulatory, quality assurance and other personnel needed to advance through clinical studies or have engaged the services
of experts in the field for these requirements. As of August 31, 2021, we have contracted with thirteen individuals for employment or
consulting arrangements. Of our staff, five are senior management, four are engaged in research and development work, and the remaining
four are involved in administration work.
Additional Information
Additional information about
us is contained on our Internet website at www.oramed.com. Information on our website is not incorporated by reference into this report.
On our website, under “Investors”, “SEC Filings”, we make available free of charge our Annual Reports on Form
10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and amendments to those reports filed or furnished pursuant to Section
13(a) of the Securities Exchange Act of 1934, as amended, or the Exchange Act, as soon as reasonably practicable after we electronically
file such material with, or furnish it to, the U.S. Securities and Exchange Commission, or the SEC. Reports filed with the SEC are made
available on its website at www.sec.gov. The following Corporate Governance documents are also posted on our website: Code of Ethics,
Whistleblowing Policy and the Charters for each of the Audit Committee, Compensation Committee and Nominating Committee of our Board.