10-K
1
pharmacyte_10k-043021.htm
FORM 10-K
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 10-K
(Mark One)
☒ ANNUAL REPORT PURSUANT TO SECTION 13
OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended April 30, 2021
or
☐ TRANSITION REPORT PURSUANT TO SECTION
13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the transition period from __________ to __________
Commission File Number 001-40699
PHARMACYTE BIOTECH, INC.
(Exact name of registrant as specified in its charter)
Securities registered pursuant to Section 12(b)
of the Act:
Title of each class Trading symbol(s) Name of each exchange on which registered
Indicate by check mark if the registrant is a
well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate by check mark if the registrant is not
required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
Indicate by check mark whether the registrant
(1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months
(or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements
for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the registrant
has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 232.405)
during the precedent 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐
Indicate by check mark whether the registrant
is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company or an emerging growth company.
See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company and emerging
growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☐
If an emerging growth company, indicate by check
mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting
standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant
is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒
State the aggregate market value of the voting
and non-voting common equity held by non-affiliates computed by reference to the price at which the common equity was last sold, or the
average bid and asked price of such common equity, as of October 31, 2020: $20,214,663.
As of August 9, 2021, the registrant had 1,611,671
outstanding shares of common stock.
DOCUMENTS INCORPORATED BY REFERENCE
None.
Cautionary Note Regarding Forward-Looking Statements
This Report on Form 10-K
(“Report”) includes “forward-looking statements” within the meaning of the federal securities laws. All
statements other than statements of historical fact are “forward-looking statements” for purposes of this Report,
including any projections of earnings, revenue or other financial items, any statements regarding the plans and objectives of
management for future operations, any statements concerning proposed new products or services, any statements regarding future
economic conditions or performance, any statements regarding expected benefits from any transactions and any statements of
assumptions underlying any of the foregoing. In some cases, forward-looking statements can be identified by use of terminology such
as “may,” “will,” “should,” “believes,” “intends,”
“expects,” “plans,” “anticipates,” “estimates,” “goal,”
“aim,” “potential” or “continue,” or the negative thereof or other comparable terminology.
Although we believe that the expectations reflected in the forward-looking statements contained in this Report are reasonable, there
can be no assurance that such expectations or any of the forward-looking statements will prove to be correct, and actual results
could differ materially from those projected or assumed in the forward-looking statements. Thus, investors should refer to and
carefully review information in future documents we file with the United States Securities and Exchange Commission
(“Commission”). Our future financial condition and results of operations, as well as any forward-looking statements, are
subject to inherent risk and uncertainties, including, but not limited to, the risk factors set forth in “Part I, Item 1A
– Risk Factors” set forth in this Report and for the reasons described elsewhere in this Report. Among others, these
include our estimates regarding expenses, future revenues, capital requirements and needs for additional financing; whether the
United States Food and Drug Administration (“FDA”) approves our Investigational New Drug Application (“IND”)
after we submit a response to the FDA’s clinical hold, so that we can commence our planned clinical trial involving locally
advanced, inoperable, non-metastatic pancreatic cancer (“LAPC”); the success and timing of our preclinical studies and
clinical trials; the potential that results of preclinical studies and clinical trials may indicate that any of our technologies and
product candidates are unsafe or ineffective; our dependence on third parties in the conduct of our preclinical studies and clinical
trials; the difficulties and expenses associated with obtaining and maintaining regulatory approval of our product candidates; the
material adverse impact that the coronavirus pandemic may have on our business, including our planned clinical trial involving LAPC,
which could materially affect our operations as well as the business or operations of third parties with whom we conduct business;
and whether the FDA will approve our product candidates after our clinical trials are completed, assuming the FDA allows our
clinical trials to proceed after submission and review of our response to the FDA’s clinical hold. All forward-
looking statements and reasons why results may differ included in this Report are made as of the date hereof, and we do not intend
to update any forward-looking statements except as required by law or applicable regulations. Except where the context otherwise
requires, in this Report, the “Company,” “we,” “us” and “our” refer to PharmaCyte
Biotech, Inc., a Nevada corporation, and, where appropriate, its subsidiaries.
PART I
ITEM 1. BUSINESS.
Overview
We are a biotechnology
company focused on developing cellular therapies for cancer and diabetes based upon a proprietary cellulose-based live cell
encapsulation technology known as “Cell-in-a-Box®.”. The Cell-in-a-Box® technology is
intended to be used as a platform upon which therapies for several types of cancer, including locally advanced, inoperable,
non-metastatic pancreatic cancer (“LAPC”) will be developed. The current generation of our product candidate is referred
to as “CypCapsTM”. On September 1, 2020, we submitted an Investigational New Drug Application (“IND”) to the U.S. Food
and Drug Administration (“FDA”) for a planned Phase 2b clinical trial in LAPC. On October 1, 2020, the Company received
notice from the FDA that it had placed the IND on clinical hold. On October 30, 2020, the FDA sent a letter to us setting forth the
reasons for the clinical hold and specific guidance on what we must do to have the clinical hold lifted. To lift the clinical hold,
the FDA has informed us that we need to conduct several additional preclinical studies and assays. The FDA also requested additional
information regarding several topics, including DNA sequencing data, manufacturing information and product release specifications.
We are in the process of conducting these studies and assays and gathering additional information to submit to the FDA. See
“Our Investigational New Drug Application and the Clinical Hold” below.
The Cell-in-a-Box® encapsulation
technology potentially enables genetically engineered live human cells to be used as a means to produce various biologically active molecules.
The technology is intended to result in the formation of pinhead sized cellulose-based porous capsules in which genetically modified
live human cells can be encapsulated and maintained. In a laboratory setting, this proprietary live cell encapsulation technology has
been shown to create a micro-environment in which encapsulated cells survive and flourish. They are protected from environmental challenges,
such as the sheer forces associated with bioreactors and passage through catheters and needles, etc., which we believe enables greater
growth and production. The capsules are largely composed of cellulose (cotton) and are bio inert.
We are developing therapies
for pancreatic and other solid cancerous tumors by using genetically engineered live human cells that we believe are capable of converting
a cancer prodrug into its cancer-killing form. We encapsulate those cells using the Cell-in-a-Box® technology and place
those capsules in the body as close as possible to the tumor. In this way, we believe that when a cancer prodrug is administered to a
patient with a particular type of cancer that may be affected by the prodrug, the killing of the patient’s cancerous tumor may be
optimized.
We have also been considering
ways to exploit the benefits of the Cell-in-a-Box® technology to develop therapies for cancer that involve prodrugs
based upon certain constituents of the Cannabis plant; these constituents are of the class of compounds known as “cannabinoids”.
Until: (i) the FDA allows us to commence a clinical
trial in LAPC described in our IND for which the FDA has placed a clinical hold, (ii) we validate our Cell-in-a-Box® encapsulation
technology in our planned Phase 2b clinical trial in LAPC and (iii) the availability of sufficient additional funding, we are not spending
any further resources developing this cannabinoid program.
In addition, we have been exploring
ways to delay the production and accumulation of malignant ascites fluid that results from many types of abdominal cancerous tumors. Malignant
ascites fluid is secreted by abdominal cancerous tumors into the abdomen after the tumors have reached a certain stage of growth. This
fluid contains cancer cells that can seed and form new tumors throughout the abdomen. This fluid accumulates in the abdominal cavity,
causing swelling of the abdomen, severe breathing difficulties and extreme pain.
In our pancreatic cancer development
program, our plan is to determine whether our product candidate can prevent or delay the production and accumulation of malignant
ascites fluid. For the same reasons as those given above until: (i) the FDA allows us to commence a clinical trial in LAPC described
in our IND for which the FDA has placed a clinical hold, (ii) we validate our Cell-in-a-Box® encapsulation technology
in our planned Phase 2b clinical trial in LAPC and (iii) the availability of sufficient additional funding, we are not spending any
further resources developing this malignant ascites fluid program.
We have also been developing
a potential therapy for Type 1 diabetes and insulin-dependent Type 2 diabetes. Our product candidate for the treatment of diabetes consists
of encapsulated genetically modified insulin-producing cells. The encapsulation will be done using the Cell-in-a-Box® technology.
Implanting these cells in the body is designed to function as a bio-artificial pancreas for purposes of insulin production.
The Cell-in-a-Box®
encapsulation technology potentially enables genetically engineered live human cells to be used as miniature factories for the production
of various biologically active molecules. The technology is intended to result in the formation of pinhead sized cellulose-based porous
capsules in which genetically modified live human cells can be encapsulated and maintained. In a laboratory setting, this proprietary
live cell encapsulation technology has been shown to create a micro-environment in which encapsulated cells survive and flourish. They
are protected from environmental challenges, such as the sheer forces associated with bioreactors, passage through catheters and needles,
etc., which we believe enables greater growth and production. The capsules are largely composed of cellulose (cotton) and are bio inert.
As with the two previous programs, until: (i)
the FDA allows us to commence a clinical trial in LAPC described in our IND upon which the FDA has placed a clinical hold, (ii) we validate
our Cell-in-a-Box® encapsulation technology in our planned Phase 2b clinical trial in LAPC and (iii) the availability of
sufficient additional funding, we are not spending any further resources developing the diabetes program.
Cancer Therapy
Targeted Chemotherapy
Our live-cell encapsulation technology-based
potential therapies consist of encapsulated genetically modified living cells, with the type of encapsulated cell dependent on the
disease being treated. For our lead product candidate, a therapy for pancreatic cancer, we propose that approximately 15,000-20,000
genetically modified live cells that produce an enzyme (an isoform of cytochrome P450), which we believe will convert the
chemotherapy prodrug ifosfamide into its cancer-killing form, will be encapsulated using the Cell-in-a-Box® technology.
In the clinical trial, if the FDA allows us to proceed, approximately 300 of these capsules will be placed in the patients’
blood supply and guided into place using interventional radiography so that they finally reside as close to the tumor in the
pancreas as possible. Low doses (one gram per square meter of body surface area of the patient) of the chemotherapy prodrug
ifosfamide will then be given to the patient intravenously.
The prodrug ifosfamide is normally activated in
the patient’s liver. By activating the prodrug near the tumor using the Cell-in-a-Box® capsules, we believe our cellular
therapy will act as a type of “bio-artificial liver.” Using this type of “targeted chemotherapy,” we are seeking
to create an environment that enables optimal concentrations of the “cancer-killing” form of ifosfamide at the site of the
tumor. Because the cancer-killing form of ifosfamide has a short biological half-life, we believe that this approach will result in little
to no collateral damage to other organs in the body. We also believe this treatment will significantly reduce tumor size with no treatment-related
side effects.
Figure 1: Proposed treatment for pancreatic
cancer by targeted deployment and activation of chemotherapy using Cell-in-a-Box® encapsulated cells.
Figure 2: Hypothesized mechanism of
action of treatment for pancreatic cancer by targeted deployment of the encapsulated live cells and activation of the chemotherapy
prodrug drug ifosfamide. The immune system cells are too large to enter the capsule.
Pancreatic Cancer Therapy
We believe an unmet medical need exists for patients
with LAPC whose pancreas tumor no longer responds after 4-6 months of treatment with either Abraxane® plus gemcitabine
or the 4-drug combination known as FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin). Both combinations are the current
standards of care for pancreatic cancer. We believe that these refractory patients have no effective treatment alternative once their
tumors no longer respond to these therapies. Two of the most commonly used treatments for these patients are 5-fluorouiracil (“5-FU”)
or capecitabine (a prodrug of 5-FU) plus radiation (chemoradiation therapy). We believe that both treatments are only marginally effective
in treating the tumor and both result in serious side effects. More recently, radiation treatment alone is being used at some cancer centers
in the United States (“U.S.”).
Other treatments are being tried at various
cancer centers in the U.S. in an attempt to address this lack of an effective treatment for many LAPC patients, but their success is
far from certain. We are developing a therapy comprised of Cell-in-a-Box® encapsulated live cells implanted near the
pancreas tumor followed by the infusion of low doses of the cancer prodrug ifosfamide. We believe that our therapy, if approved, can
serve as a “consolidation therapy” that can be used with the current standards of care for LAPC and thus address this
critical unmet medical need. Two previous human clinical trials of an encapsulated live cell and ifosfamide combination for LAPC
were conducted in Germany by Bavarian Nordic during 1998 – 2000, and such trials were referenced in our IND for LAPC,
submitted on September 1, 2020.
Subject to the FDA allowing us to move forward,
we plan to commence a clinical trial involving patients with LAPC whose tumors have ceased to respond to either Abraxane®
plus gemcitabine or FOLFIRINOX after 4-6 months of either therapy. We had a Pre-Investigational New Drug Application meeting (“Pre-IND
meeting”) with the Center for Biologics Evaluation and Research of the FDA (“CBER”) in January 2017. At that Pre-IND
meeting, the FDA communicated its agreement with certain aspects of our clinical development plan, charged us with completing numerous
tasks and provided us with the guidance on the tasks we believed we needed to complete for a successful IND submission for LAPC, although
no assurance was given that we would be allowed to commence a Phase 2b clinical trial. Data developed from two earlier trials conducted
by Bavarian Nordic, a fully integrated biotechnology company in Denmark, using the same technology and same cell line were included in
our IND. The results of those trials are discussed below.
Our Investigational New Drug Application and
the Clinical Hold
On September 1, 2020, we submitted an IND to the
FDA for a planned Phase 2b clinical trial in LAPC. Shortly thereafter, we received Information Requests from the FDA related to the IND.
We timely responded to all Information Requests.
On October 1, 2020, we received notice that the
FDA had placed our IND on clinical hold.
On October 30, 2020, the FDA sent a letter to
us setting forth the reasons for the clinical hold and providing specific guidance on what we must do to have the clinical hold lifted.
In order to address the clinical hold, the FDA has requested that we:
· Provide additional sequencing data and genetic stability studies;
· Provide additional detailed description of the manufacturing process;
· Provide additional product release specifications for our encapsulated cells;
The FDA also requested that we address the following
issues as an amendment to the IND:
We have assembled a scientific and regulatory
team of experts to address the FDA requests. That team is working to complete the items requested by the FDA. We are in varying stages
of addressing the studies and acquiring the information requested by the FDA.
The following provides a summary of the activities
in which we are engaged to have the clinical hold lifted:
Summary of the Company’s Activities During
the Period of this Report
During the first half of the fiscal year 2021,
we focused our R&D efforts on completing the IND and submitting it to the FDA. The balance of the fiscal year 2021 was spent on our
R&D efforts focused on taking the necessary steps to have the clinical hold lifted. These include: (i) assembling a team of scientific
and regulatory experts to handle the tasks we must undertake to have the clinical hold lifted; (ii) going through a selection process
of consultants and laboratories that will conduct the studies and assays required by the FDA; (iii) designing and documenting most of
the studies and assays required by the FDA; and (iv) conducting the studies and assays we have designed and documented. The fruit of those
efforts are summarized above in section entitled, “Our Investigational New Drug Application and the Clinical Hold.”
The major activities accomplished during the fiscal
year 2021 include the following:
Reconfirmed that Dr. Manuel Hidalgo Will
Be the Principal Investigator for our Clinical Trial in LAPC
Dr. Manuel Hidalgo reconfirmed that he will
be the Principal Investigator for our planned clinical trial in LAPC, should the FDA lift the clinical hold. Dr. Hidalgo is a leading
physician-scientist who specializes in pancreatic cancer and drug development. He currently serves as Chief of the Division of
Hematology and Medical Oncology at Weill Cornell Medicine and New York-Presbyterian/Weill Cornell Medical Center. Previously, Dr.
Hidalgo was a Professor of Medicine at the Harvard Medical School and the Chief of the Division of Hematology Oncology and Director
of the Rosenberg Clinical Cancer Center at the Beth Israel Deaconess Medical Center.
Completed a Medical Manual that is Pivotal
to Our IND Submission
We completed a medical manual that was included
in our IND submission. The manual entitled, “Angiography Manual – Transarterial Chemoinfusion of the Pancreas” (“Angiography
Manual”), will be used to guide Interventional Radiologists on the placement of a catheter that begins at the femoral artery in
the leg and ends as close to the pancreatic tumor as possible in patients participating in our planned clinical trial in LAPC should the
FDA lift the clinical hold. By following the directions in this manual, Interventional Radiologists will be able to place the CypCapsTM
inside patients in a precise location.
The Angiography Manual was prepared by a team
of medical professionals. The initial version was prepared by Dr. David H. O’Leary, an Interventional Radiologist and Senior Vice
President of the Medical Department at Medpace (PharmaCyte’s Contract Research Organization (“CRO”)). Dr. O’Leary’s
version was then reviewed by Dr. Manuel Hidalgo (“Dr. Hidalgo”), the Principal Investigator (“PI”) for our planned
clinical trial in LAPC, and later by Dr. Matthias Löhr (“Dr. Löhr”), who was the PI for the first two clinical trials
using our treatment for LAPC.
Dr. Jens-Christian Kröeger (“Dr. Kröeger”),
who was the Interventional Radiologist during the two earlier clinical trials using our technology, provided valuable assistance in the
preparation of the Angiography Manual. A final review of the Angiography Manual was performed by Dr. Bradley Pua, an Interventional Radiologist
with Weill Cornell Medicine and a colleague of Dr. Hidalgo.
A Paper Audit of the Austrianova Manufacturing Facility was Conducted
after Batch Records Deemed cGMP Compliant
We had cGMP Validation, our cGMP regulatory consultant,
conduct a paper audit of the manufacturing facility in Thailand where CypCapsTM are produced by Austrianova.
In addition, Austrianova and cGMP Validation completed
their work together to achieve what has been deemed cGMP compliant batch records for the two manufacturing runs produced by Austrianova.
Both worked closely together to revise the batch records that were generated during the two manufacturing runs that produced our clinical
trial product for our planned clinical trial in LAPC.
A
batch record is a detailed written document of a manufactured batch of product prepared during a
pharmaceutical manufacturing process. A batch record contains data and the step-by-step process for manufacturing
each batch of our CypCapsTM. The completed
manufacturing batch records indicate that the two batches were properly made and checked by quality control
personnel at Austrianova according to cGMP standards. This was necessary so that the batches comply with the standards
required by the FDA for a batch record for each manufacturing run.
Began the FDA Required Two-Year Stability
Study on Our Clinical Trial Product
We began the FDA required Stability Study of our
clinical trial product. This is a rolling two-year study to demonstrate how the frozen clinical trial product performs over time after
being frozen for certain periods of time and then thawed and tested for functionality. While the study will continue for 2 years, the
FDA required at least 3 months of stability data to be included in the IND for its submission.
The tests for the Stability Study started approximately
3 months (the first time point in the 2-year study) from the issuance of the Certificate of Analysis for the second manufacturing
run and will continue for 24 months. Data from the balance of the Stability Study will be provided to the FDA as the data becomes available.
The Stability Study consists of many of the same
tests that were performed as “release testing” that enabled Austrianova to issue to us a Certificate of Analysis for the second
manufacturing run of the two back-to-back manufacturing runs.
Various tests are taken at one or more of the
following time points: months 0, 3, 6, 9, 12, 18 and 24. Month 0 represents the “release testing” for the Certificate of Analysis
for the second manufacturing run that we previously announced earlier last year.
The parameters for testing are: (i) Identity (Assay:
label integrity, polymerase chain reaction and sequencing for a transgene marker); (ii) Purity (Assay: appearance post thaw, pH,
capsule integrity post-thaw and cultured 3 days); (iii) Viable Cell Number (Assay: determined by cell size); (iv) Potency (Assay:
resorufin enzymatic activity); and (v) Integrity (Assay: container-closure integrity).
A Change History of the Manufacturing Process
Was Developed for Inclusion in the IND
With our support, Austrianova completed the “change
history” information and data for CypCapsTM (2nd generation product) compared to CapCellsTM (1st
generation product). The history of the changes to the manufacturing of the two generations of product was a critical component of our
IND submission.
The first generation of product was referred to
as “CapCellsTM”, and the current generation of product is referred to as “CypCapsTM.” Although the cellulose
material is basically the same, a material of improved quality is used in the 2nd generation product. The differences relate to control
of impurities with heavy metal content and microbial and endotoxin levels being below the limits in the relevant literature for powdered
cellulose. In addition, the production process for the cellulose is more closely controlled in the 2nd generation product.
The original cell line used is also now better characterized at the genetic level. Lastly, the encapsulated cells undergo a maturation
process in the 2nd generation product and are stored frozen for a longer shelf life.
The FDA requires that all relevant information
and data from different generations of the same manufactured medicinal product be compared to each other to ensure that the original manufactured
product is essentially the same as the current one. There can be improvements to the product, but to use the data from the two clinical
trials in the 1990s to support our clinical trial in LAPC, it was imperative to develop information and data to support that the two generations
of the products are essentially the same – the only difference being improvement to the overall product using the same manufacturing
process.
Austrianova also had to gather the data for the
release specifications for each generation of encapsulated cells and explain why changes were made and how the changes made for an improved
product using the same manufacturing process. Information and data about the capsule maturation and storage were also developed.
In addition, the quality control release assay
information and supporting data had to be assembled. This involved capsule diameter; viability of encapsulated cells; sterility; pyrogenicity;
potency; cell identity; endotoxins; enzymatic activity; capsule count; label check; and pH.
Accelerated the Development of the FDA Required
Container Closure Integrity Test
We accelerated the development of our Container
Closure Integrity (“CCI”) test, which is an essential component of the Stability Test mentioned above. The company we selected
to develop our CCI test was able to complete the development phase of the test much sooner than we anticipated given the test had to be
developed anew because it is specific to our clinical trial product.
The FDA specifically requires a CCI test be run
on pre-filled syringes containing 300 cellulose sulphate microcapsules in 2mls of freezing medium, and then the data from the CCI test
is included in our IND submission.
The first developmental phase of the CCI test
was to develop a High Voltage Leak Detection (“HVLD”) program setup and feasibility study. The objective was to develop a
preliminary leak test method with the capability of differentiation of our syringe system with 5μm defects
and those without 5μm defects. These parameters were utilized for performance qualification and functioned to verify the use of our
system with a HVLD instrument.
The second developmental phase of the CCI was
to develop the method for such a HVLD system. The method development included using a PTI E-Scan HVLD leak test instrument with a sample
set of laser-drilled defects (small manually created holes on the sides of several syringes) and use of syringes with no known defects
at all. Certain parameters were used for optimization. The method was developed using our filled syringes. A representative placebo was
also utilized. The final product was verified in development prior to the validation with the optimized parameters.
The third developmental phase was to validate
a leak test method using HVLD technology. All work was completed using a PTI E-Scan HVLD leak test instrument. Validation included three
test series across multiple days and operators.
Completed the Three-Month Product Stability
Testing Required by the FDA
We completed the three-month product
stability testing that is required by the FDA for our CypCapsTM. Our Cell-in-a-Box®
encapsulated cell product CypCapsTM passed all the FDA-required tests for the first three-months of the 24-month stability
study.
As based in the “International
Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use” (“ICH”) guidelines,
regulatory agencies around the world, including the FDA, require a shelf-life determination for all medical products. Living products,
like cell therapies such as CypCapsTM, as well as live vaccines etc., are particularly sensitive and more prone to inactivation over
time, so it is especially important to determine the shelf-life for these products.
A battery of tests was performed on the CypCapTM
that had been frozen post-production for three months of storage at -80 degrees C. Samples were thawed to show that the cells inside the
CypCapsTM were still alive and functional as well as free of infectious agents. Some of these tests were performed by Austrianova
(cell count, biological activity of the cells, capsule integrity, label integrity), whereas others (sterility, pH measurement) were performed
by contract laboratories.
Completed the Container
Closure Integrity Testing Required by the FDA
We completed the Container
Closure Integrity testing the FDA requires be conducted on our CypCapsTM.
This CCI test is a component of the 24-month stability
study. The CCI test is part of the ongoing study to determine the shelf life of the CypCapsTM final product that the FDA requires
for all medical products. The data from the CCI test was included in our IND. All future longer-term shelf-life analyses, such as the
next CCI test at the one-year post-production time period, will be reported to the FDA but was not required for our IND submission. As
explained above, regulatory agencies around the world, including the FDA, require a shelf-life determination for all medical products.
Living products, like cell therapies such as CypCapsTM, as well as live vaccines, are particularly sensitive and more prone to inactivation
over time, so it is particularly important to determine the shelf-life for our clinical trial product.
Submitted Drug Master File to the FDA
With the support of the Company, Austrianova submitted
a Drug Master File (“DMF”) to the FDA in connection with of our IND submission. The DMF provides all confidential and detailed
information covering the production of the CypCapsTM final product, which was produced by Austrianova and will be used in our planned
clinical trial in LAPC.
A DMF is submitted to the FDA to provide detailed
information about facilities, processes and materials used in the manufacturing, processing and packaging of human drugs and biologics.
It is a prerequisite to securing approval and commercialization and ensures confidentiality of proprietary information related to the
Active Pharmaceutical Ingredient (“API”) used in the manufacture of CypCapsTM.
The DMF requirements are complex and specific,
encompassing every detail involved with the manufacture of the API – from raw materials to analytical methods, process development
and optimization. The scrutiny goes all the way back to the starting materials used in the API.
Appointed Dr. José Iglesias as Consulting Chief Medical
Officer for the Clinical Trial in Pancreatic Cancer
We appointed Dr. José L. Iglesias as
consulting Chief Medical Officer for our planned clinical trial in LAPC, should the FDA lift the clinical hold. Dr. Iglesias brings a
wealth of experience to PharmaCyte in developing and testing a variety of cancer chemotherapeutic agents, including key positions
with many prominent biotechnology companies such as Eli Lilly, Amgen, Abraxis, and Celgene. We believe Dr. Iglesias’s body of
work is ideally suited to guide us through our planned clinical trial in LAPC. As the global Vice-President of Clinical Development
at Celgene, Dr. Iglesias led the team that obtained FDA approval for Abraxane®
(the nab-paclitaxel/gemcitabine combination), which is a first-line therapy in pancreatic cancer.
Dr. Iglesias is familiar with the treatment of
various abdominal cancers and is experienced with the use of gemcitabine in patients. He designed the Phase 2 clinical trial for the development
of nab-paclitaxel for use against metastatic breast cancer while at Celgene. Dr. Iglesias has also been awarded numerous prestigious fellowships
and he is the co-author of 68 publications in scientific journals.
Submitted IND to the FDA for Clinical Trial in Locally Advanced
Inoperable Pancreatic Cancer
We submitted our IND to the FDA for a planned
Phase 2b clinical trial in locally advanced inoperable pancreatic cancer. As noted above, on October 1, 2020, the FDA placed the IND on
clinical hold. See “Our Investigational New Drug Application and the Clinical Hold”.
Should the FDA lift the clinical hold, the
proposed multicenter, randomized, open-label Phase 2b clinical trial is intended to evaluate the efficacy and safety of
CypCapsTM (genetically engineered human cells encapsulated using the Cell-in-a-Box® technology) in combination
with low doses of the chemotherapy prodrug, ifosfamide, as compared to chemoradiation therapy with capecitabine plus external beam
radiation therapy (“EBRT”) or stereotactic body radiation therapy (“SBRT”) alone. The study population will
consist of approximately 100 patients. Patients will be randomized in a 1:1 ratio to either treatment with the study therapy or a
comparator. The randomization will be stratified by previous treatment (Abraxane® plus gemcitabine or FOLFIRINOX) and
the control arm choice (capecitabine/EBRT or SBRT alone).
The primary objective will be determined by progression
free survival. The secondary objectives for this study are to determine if CypCapsTM plus low dose ifosfamide will: (i)
increase overall survival; (ii) increase the objective response rate; (iii) increase the rate of conversion of the pancreatic tumor from
inoperable to operable; (iv) decrease the pancreatic cancer tumor marker CA 19-9; and (v) improve a patient’s quality of life. In
addition, this clinical trial will assess the safety and tolerability of CypCapsTM plus low dose ifosfamide.
Completed Second Container
Closure Integrity Test
We completed the second Container
Closure Integrity test that the FDA required for our CypCapsTM product. This test is a component of the 24-month stability study
of our CypCapsTM. As explained above, the CCI test is part of the ongoing study to determine the shelf life of the CypCapsTM
final product. The data from the second CCI test was submitted to the FDA as part of our IND submission.
Completed Six-Month Stability Study
We completed the six-month product stability
testing that is required by the FDA for our CypCapsTM. We intend for this product to be used, if not previously consumed in
pre-clinical testing and not expired, in the Company’s planned clinical trial in LAPC for which we submitted our IND to the
FDA and the FDA placed the IND on clinical hold.
Independent of
the IND, we are working on our ongoing storage stability study to determine the shelf life of the Cell-in-a-Box®
encapsulated cell product. The product will be kept stored frozen at -180oC throughout the
entire duration of the 24-month stability study. The six-month time point of the study was reached, and CypCapsTM have
passed all the FDA-required tests. With each time point reached, we believe this means our final product has proven that
it can remain functional when frozen and stored up to that time point.
This six-month stability study is a continuation
of the ongoing 24-month stability study to demonstrate the shelf life of our final clinical trial product that the FDA requires for all
medicinal products. These six-month data, as well as all future longer-term shelf-life analyses, such as the next twelve months post-production
shelf-life evaluation, was reported to the FDA and became part of our IND submission.
ICH guidelines, as well as regulatory agencies
around the world, including the FDA, require that shelf-life data needs to be determined and provided for any new medicinal product. The
functionality of cell-based therapies such as CypCapsTM, as well as live vaccines, are particularly prone to loss of viability and
thus activity during storage. This necessitates detailed shelf-life determination studies for such products.
A whole range of predefined and agreed tests have
been performed on our CypCapsTM that were unfrozen after six months of storage at -80oC. These studies include determinations
of the number of cells, cell viability, biological activity of the cells, integrity of the capsules, sterility and pH. It also includes
verifying that the labels are still securely adhering to the frozen syringes and are still legible. These tests were performed either
by Austrianova (cell count, biological activity of the cells, capsule integrity, label integrity) or by its affiliated subcontractor (sterility,
pH measurement).
We believe the recently reported Container Closure
Integrity test demonstrates the syringes are properly sealed and that the contents of the syringes have not been contaminated is
also formally part of the product stability testing. Thus, the CypCapsTM product passed all of the required tests at this six-month
time point.
Completed 9-Month Stability
Study
We completed the nine-months product
stability testing that is required by the FDA for our CypCapsTM final product, which will be used in the Company’s planned
clinical trial in LAPC should the FDA lift its clinical hold.
The ongoing stability
study is designed to determine the shelf life of the Cell-in-a-Box® encapsulated cell product, CypCapsTM, frozen
at -180oC. Once the nine-month time point was reached, the CypCapsTM passed all of the necessary tests, including
cell viability, enzyme activity and cell potency, pH, label check, capsule appearance and integrity. This nine-month data, as well as
all future longer-term time points of the shelf life analyses, such as the next milestone, the 12-month time point, will be reported to
the FDA as an update to our submitted IND.
Began Physical Testing of the CypCapsTM
We commenced additional physical parameter testing
of our CypCapsTM product for pancreatic cancer, in line with the recommendations provided by the FDA following our IND
submission. The FDA asked that two additional methods be developed to determine the strength of the encapsulated cells we plan to use
in our planned clinical trial in LAPC should the FDA lift its clinical hold.
The first method involves pressing down on the
capsule and measuring either the pressure required for it to burst, or for it to deform. Since the CypCapsTM are very
small, special machinery that can measure such tiny changes has to be used to demonstrate this.
The second method involves letting water flow
into the CypCapsTM, effectively “blowing them up.” The point at which the capsules explode will be used as
a quality control parameter.
Previous work has shown the pressures and water
conditions used in these tests to be well outside of the normal conditions encountered by the capsules inside the human body, so these
tests are designed to simulate hypothetical conditions.
Earlier studies have also shown that the capsules
do not burst even when placed under very high pressure. Further, even in the very unlikely event that the capsule could break open, the
cells inside will be recognized as foreign bodies by the immune system. Also, the encapsulated cells are primed for their suicide since
they express the cytochrome P450 gene and thus would be killed by the low dose ifosfamide given as part of the treatment for LAPC.
Began DNA Sequence Encoding and Stability Testing of the DNA
Sequence
We commenced additional studies to determine the
exact sequence of the DNA encoding of the enzyme in the cells of our CypCapsTM product for pancreatic cancer and the stability
of the sequences, in accordance with the requests provided by the FDA following our IND submission.
The cell clone used to produce the CypCapsTM
product has been augmented to produce the cytochrome P450 enzyme. This enzyme converts ifosfamide from its inactive form to its cancer-killing
form and is the basis for how CypCapsTM works. We have already shown that the enzyme is produced, that the expression
of the enzyme is stable over time, and that the enzyme is functional. The FDA has now asked PharmaCyte to provide the exact DNA sequence
and configuration of the genetic augmentation responsible for the production of cytochrome P450 in the cells. This requires additional
studies that necessitates a multi-pronged approach, including the employment of a new, state of the art, technique.
The information provided by these analyses will
also strengthen and extend the already existing data that we have already presented to the FDA on: (i) the site of integration of the
DNA encoding of the cytochrome P450 enzyme; and (ii) the data on the stability of the cells, even before they are encapsulated using the
Cell-in-a-Box® technology to produce the CypCapsTM product. These new studies will add to the data that
we already have on the long-term stability and shelf life of the final CypCapsTM product. Thus, while the data generated
will not change the fact that the CypCapsTM product is functional, biologically active and effective, it will generate
further data on the exact configuration of the DNA that gives rise to the therapeutic effects of CypCapsTM.
Completed 12-Month Stability Study
We completed the twelve-months product
stability testing required by the FDA for our CypCapsTM final clinical trial product. Our CypCapsTM product passed
all the required stability tests. The product has now shown itself to be stable and active after being stored for 12 months at -180oC.
The study will continue to determine the maximum shelf life of the CypCapsTM product.
As explained above,
the ongoing stability study is designed to determine the shelf life of the Cell-in-a-Box® encapsulated cell product,
CypCapsTM, stored frozen at -180oC. Upon analysis after 12 months in storage at -180oC,
the unfrozen CypCapsTM product passed all of the specified tests, including cell viability, enzyme activity and cell potency
as well as pH, label check, capsule appearance, and integrity. This twelve-month data, as well as all future longer-term time points of
the shelf life analyses, such as the next time point to be evaluated after 18-months of storage at -80oC,
will be reported to the FDA. This ongoing stability study was initiated prior to the submission of our IND
submission to the FDA.
Cannabinoids to Treat Cancer
Numerous studies have demonstrated the
therapeutic potential of certain cannabinoids (constituents of Cannabis) in patients with cancer. Two of the most widely
studied cannabinoids in this regard are tetrahydrocannabinol (“THC”) and cannabidiol (“CBD”). Cannabinoids
are potentially: (i) anti-proliferative (slow tumor growth); (ii) anti-metastatic (slow tumor spread); (iii) anti-angiogenic
(slowing blood vessel development); and (iv) pro-apoptotic initiate programed cell death). In in vitro and in vivo
models, the therapeutic potential of cannabinoids is broad. Results support the therapeutic potential in lung, brain, thyroid,
lymphoma, liver, skin, pancreas, uterus breast and prostate cancers. In a review of 51 scientific studies, among other properties,
it was observed that cannabinoids can regulate cellular signaling pathways critical for cell growth and survival. These properties
indicate that cannabinoids could be useful in the treatment of cancer.
We have many competitors that are developing Cannabis-based
treatments for cancer. Jazz Pharmaceuticals has acquired GW Pharmaceuticals, PLC who had an approved cannabinoid product for the treatment
of multiple sclerosis spasticity and was developing a product portfolio to treat a variety of illnesses, including glioblastoma (brain
cancer). Cannabis Science, Inc. has been developing topical cannabinoid treatments for basal and squamous cell skin cancers and Kaposi’s
sarcoma, and is exploring pre-clinical development of cannabinoid-based anti-cancer drugs in a collaborative agreement with other entities.
OWC Pharmaceutical Research Corp. is developing Cannabis-based products targeting a variety of indications and has a collaborative
agreement with an academic medical center in Israel to study the effects of cannabinoids on multiple myeloma (a cancer of plasma cells).
Cannabis Pharmaceuticals, Inc. is developing personalized anti-cancer and palliative Cannabis-based treatments aimed mainly at
improving the cachexia, anorexia syndrome and quality-of-life issues that are often characteristic of patients with devastating diseases
like cancer.
In contrast to the work being done by these
companies, we plan to focus on developing specific therapies based on chosen molecules rather than using complex Cannabis
extracts. We intend to use the Cell-in-a-Box® technology in combination with genetically modified cell lines designed
to activate cannabinoid molecules for the treatment of diseases and their related symptoms. Our initial target will be glioblastoma
– a very difficult-to treat form of brain cancer.
In May 2014, we entered into a research
agreement with the University of Northern Colorado (“UNC”). The goal of the original research was to develop methods for
the identification, separation and quantification of constituents of Cannabis, some of which are prodrugs, which could potentially be
used in combination with the Cell-in-a-Box® technology to treat cancer.
In January 2017, we entered into a second research
agreement with UNC. The goal of this research is to assess the synthesis of the patG gene and its incorporation into a vector, transfection
of human embryonic kidney cells using this vector and assessment of cannabinoic acid decarboxylase activity.
During 2017, UNC identified an organism
whose genome contains the genetic code for production of an enzyme capable of activating a cannabinoid prodrug into its active
cancer-killing form. Our Cannabis program now has two primary areas of focus. The first is evaluating the therapeutic
potential of cannabinoids, such as THC and CBD, particularly in our main “target” tumor – glioblastoma.
UNC’s laboratory research has confirmed that a purified cannabinoid showed a potent dose-dependent decrease in cell viability
for various cancers, suggesting that this cannabinoid exhibits significant anti-proliferative effects (stops the growth and
multiplication of cancer cells). This activity has been demonstrated in brain (glioblastoma), pancreas, breast, lung, colon and
melanoma cancer cells. The second area of focus is in finding an enzyme capable of converting an inactive, side-effect-free,
cannabinoid prodrug into its active cancer-killing form.
Clinically, targeted cannabinoid-based
chemotherapy would be accomplished by implanting the encapsulated bio-engineered cells near the site of a tumor, along with
administration of a cannabinoid prodrug which would become activated at the site of the tumor by an enzyme produced by the
encapsulated cells. We believe this could lead to better efficacy than existing therapies with minimal
treatment related adverse events.
Until: (i) the FDA allows us to commence a clinical
trial in LAPC described in our IND for which the FDA has placed a clinical hold; (ii) we validate our Cell-in-a-Box® encapsulation
technology in our planned Phase 2b clinical trial in LAPC and (iii) the availability of sufficient additional funding occurs, we are not
spending any further resources developing this program.
Malignant Ascites Fluid Therapy
We have been exploring ways to delay the
production and accumulation of malignant ascites fluid that results from many types of abdominal tumors. Malignant ascites fluid is
secreted by an abdominal tumor into the abdomen after the tumor reaches a certain stage of growth. This fluid contains cancer cells
that can seed and form new tumors throughout the abdomen. As this ascites fluid accumulates in the abdominal cavity, it can cause
gross swelling of the abdomen, severe breathing difficulties and extreme pain.
Once an abdominal tumor reaches a certain
stage of development, the tumor secretes malignant ascites fluid into the abdominal cavity. When that occurs, malignant ascites
fluid must be removed by paracentesis on a periodic basis. This procedure is painful and costly. We know of no available therapy
that prevents or delays the production and accumulation of malignant ascites fluid. Preclinical studies were conducted by
Translational Drug Development (“TD2”), an early-stage Clinical Research Organization (“CRO”) specializing
in oncology, to examine whether the combination of Cell-in-a-Box® encapsulated cells plus low doses of
ifosfamide can delay the production and accumulation of malignant ascites fluid. We believe the data from these studies support our
plans to further explore whether the treatment might play a role in malignant ascites fluid production and accumulation. However,
the conclusions were difficult to interpret with certainty. As a result, we plan to conduct another preclinical study in Germany to
determine if our conclusions from the TD2 studies are valid. If this is successful, and subject to discussions with the FDA, we plan
to submit an IND to seek approval from the FDA to conduct a Phase 1 clinical trial in the U.S. to determine if our drug
product candidate can delay the production and accumulation of malignant ascites fluid.
Until: (i) the FDA allows us to commence a clinical
trial in LAPC described in our IND for which the FDA has placed a clinical hold, (ii) we validate our Cell-in-a-Box® encapsulation
technology in our planned Phase 2b clinical trial in LAPC and (iii) the availability of sufficient additional funding occurs, we are not
spending any further resources developing this program.
Diabetes Therapy
A Bio-Artificial Pancreas to Treat Diabetes
We are developing a therapy for Type 1 diabetes
and insulin-dependent Type 2 diabetes based upon the encapsulation of a human liver cell line genetically engineered to produce, store
and secrete insulin at levels in proportion to the levels of blood sugar in the human body. We are also considering an alternative route
to bringing a biological treatment for diabetes into the clinic. We are exploring the possibility of encapsulating human insulin-producing
stem cells and then transplanting them into a diabetic patient. Our plans are subject to discussions with the FDA.
The cell line we select will be encapsulated
using the Cell-in-a-Box® encapsulation technology. If appropriate animal testing is completed successfully, and
subject to discussions with the FDA, we intend to submit an IND to seek the FDA’s approval to transplant encapsulated
insulin-producing cells into diabetic patients. The goal for these approaches is to develop a bio-artificial pancreas for purposes
of insulin production for diabetics who are insulin-dependent.
Our diabetes program began with two of the
most critical components of a biological diabetes therapy - a line of human cells which release insulin in response to the blood
glucose level in their environment and a technology to protect the cells from an attack by the immune system once they are
transplanted into a patient’s body to replace his or her own destroyed insulin-producing cells. This technology is the
Cell-in-a-Box® encapsulation technology. The cells used are called Melligen cells. They are patent-protected and have
been licensed to us by University of Technology Sydney (“UTS”).
Regulations for the use of living cells as a
medical product require that the potential of the cells to grow and form a tumor in a patient be assessed. This so-called
“tumorigenicity study” has been completed by the University of Veterinary Medicine Vienna (“VetMed”).
Melligen cells showed very low tumorigenicity – at a level we believe would expect to pass regulatory scrutiny, although this
is subject to discussions with the FDA.
Putting Melligen cells and the Cell-in-a-Box®
technology together, we conducted the first functional study in diabetic mice. The results did not meet our expectations. We discovered
that, contrary to what we had expected and what we had read in published scientific papers on the Melligen cells published by UTS, the
cells are not stable. With extensive testing and experiments, we discovered that the Melligen cells lose some of their specific beneficial
properties over time.
We entered into a new research agreement