PharmaCyte Biotech, Inc. (OTCQB:PMCB), a clinical stage
biotechnology company focused on developing targeted therapies for
cancer and diabetes using its signature live-cell encapsulation
technology, Cell-in-a-Box®, today released an educational,
interview-style Q&A article with Sarah DeMare, the Product
Development Champion with Facet Life Sciences and U.S. Agent for
PharmaCyte, who discusses the IND submission process for
PharmaCyte’s upcoming clinical trial in locally advanced pancreatic
cancer (LAPC).
Since coming to an understanding with
the FDA on a path forward after PharmaCyte’s pre-IND meeting in
January, is there a list of items that you can share with us that
when completed will allow PharmaCyte to file its Investigational
New Drug application (IND)?
Sarah DeMare: “The single most
important item PharmaCyte needed to learn from the FDA at the
pre-IND meeting was the acceptability of PharmaCyte’s proposed cell
line. Without that understanding, PharmaCyte was unable to move
forward with the manufacture of its product candidate for the LAPC
clinical trial.”
“An IND encompasses many things, dealing with
the manufacture and characterization of the product candidate, the
clinical study design and nonclinical studies. PharmaCyte’s therapy
for pancreas cancer has undergone or been part of several studies,
so incorporation of that information into the IND is not ‘rate
limiting’ or ‘slowing down the progress towards submitting an IND.’
The clinical study design that PharmaCyte agreed to undertake after
meeting with the FDA is currently being drafted. This is also not
rate limiting. To conduct the clinical trial, PharmaCyte will need
to manufacture, test and release a Master Cell Bank, a Working Cell
Bank and the encapsulated live cells. This information is also
required to be described and documented in detail in the IND.
The manufacture of these items is the rate limiting factor involved
in submitting the IND.”
“Before the IND is filed, the following items must be available
for inclusion:
(a) Documentation of preclinical work done on the
cells.(b) Toxicology studies.(c) Documentation of
preclinical work done on the capsules themselves. (d) A wide
array of CMC (Chemistry, Manufacturing and Controls) documentation
that verifies that the final biologic product (the encapsulated
cells) has been produced under current Good Manufacturing Practices
(cGMP)-compliant conditions.(e) Labeling for the final
investigational biologic product.(f) Previous evidence of
human experience with the pancreas cancer therapy (low-dose
ifosfamide plus Cell-in-a-Box® encapsulated genetically modified
human cells).(h) The Investigator’s Brochure.(i) The Informed
Consent Form(j) The Case Report Form”
Can you talk about the items on the list
in relation to PharmaCyte’s progress and what further rate limiting
steps are on the path to filing the
IND?
Sarah DeMare: “Documentation of
work done on items (a), (b) and (c) and a significant amount of
material concerning item (d) have been accumulated to date. As for
item (f), publications of Phase 1/2 and Phase 2 trials that were
published in scientific journals are “in-house,” as are original
clinical reports of those clinical trials. The clinical trial
protocol is nearing the “final” stage. Items (h), (i) and (j) will
be written by Translational Drug Development (TD2), the Contract
Research Organization (CRO) PharmaCyte has retained to conduct the
clinical trial in the U.S. and oversee its conduct in Europe by
Clinical Network Services (CNS).”
“The rate limiting step to being able to file
the IND and, ultimately, begin the clinical trial is the
manufacture of the combination drug product. For live cell-based
products, a Master Cell Bank or ‘MCB’ first needs to be
manufactured, characterized, tested and released. The speed at
which the MCB can be produced is dependent on several different
things. First, is the availability of starting materials. Some
starting materials can have a significant lead-time when ordering,
and you cannot begin manufacture until you have all your starting
materials. Second, is the growth rate of the live cells. Cells grow
at different rates. There isn’t much that can be done to speed up
that process. Unfortunately, it is not a 1 to 2-day event.
“
“Also, when working with a Contract Manufacturer
Organization (CMO) to make your cell bank, some things are out of
your control. For example, scheduling. CMOs typically schedule
their manufacturing rooms out months in advance for their clients,
so sometimes you need to wait in the queue for your turn. In
addition, and perhaps most importantly, the MCB needs to be tested
to ensure its quality, which is of utmost importance. These tests
are also not tests that can always be done quickly. Sterility is a
good example. This test is mandatory to ensure the sterility of
your MCB and takes approximately 6 weeks to obtain results.”
“The purpose of creating a MCB is to provide a
repository of live cells that are essentially identical to the
material tested in clinical trials and throughout the development
process. After creating a MCB, a Working Cell Bank or ‘WCB’ must be
manufactured. Creation of a WCB is an important step, as it allows
your Master Cell Bank to have a longer useful life.”
“This is an important point, and it’s worth
illustrating. Let’s say you can make 300 vials in your MCB. Let’s
also say that each vial of cells can produce enough drug product to
treat 100 patients. That would mean you could potentially treat
30,000 patients with the entire MCB. Sounds like a lot,
right? Maybe, but this MCB will need to provide cells to
patients for years to come. At some point in the future, the MCB
will be depleted. This would require another MCB to be produced,
and in such a complex system there would be no guarantee that the
original cells could be duplicated exactly. In the best case, this
means extensive testing would be needed to prove that the new MCB
is equivalent to the old MCB.”
“If those tests reveal differences that could
affect efficacy, a new clinical study may be needed to demonstrate
that the new MCB is equivalent to the old MCB. There is always the
potential that it will not be equivalent. That is the situation the
FDA would like to avoid, which is why a Working Cell Bank is
needed. To make a WCB, you take one vial of your Master Cell
Bank and grow it into more vials to become your Working Cell Bank.
So, theoretically, you could get 200 vials of your Working Cell
Bank from 1 vial of your Master Cell Bank. Assuming one vial of
your WCB still treats 100 patients, you could treat 20,000 patients
from only 1 vial of Master Cell Bank. Using this example, a
200-vial Master Cell Bank could treat up to 4 million patients.
Compare that to the 30,000 patients you could treat with the entire
Master Cell Bank, and you can see that having a WCB allows your MCB
to go much further and last much longer.”
“Producing a Working Cell Bank is similar to the
Master Cell Bank in that it takes time for the live cells to grow,
and you need to test and release the live cells. Sterility
testing is still required, and it still takes 6 weeks to
perform.”
“Finally, with the Working Cell Bank ready, the
drug product can be manufactured, tested and released. The FDA will
want to see the test results that demonstrate the quality of the
drug product in the IND. So, the IND cannot be filed until the
testing of the drug product is completed.”
In your experience with the FDA, discuss
the importance of following the FDA's guidance to the
letter?
Sarah DeMare: “The FDA is most
concerned with patient safety. So, while there may be opportunity
to state that certain pieces of information will be available at a
later date, those issues that directly impact patient safety are
important to include in your IND. From a manufacturing perspective,
for a product that is being injected into the body, sterility is of
utmost importance to the FDA. Not only sterility of the live cells
in the vials, but understanding the manufacturing process, the
environment in which the cells were manufactured and where the
starting materials came from are critically important. There is a
lot of information about this to be described in detail in the
IND.”
“Following the guidance that the FDA has provided at the pre-IND
meeting gives the company the best chance of success at having the
IND accepted after the 30-day period.”
What are the potential downsides to
submitting an IND that doesn't follow the FDA's guidance to the
letter?
Sarah DeMare: “The obvious
answer is that if the FDA feels like there are concerns with
patient safety, the FDA will place PharmaCyte on clinical hold
until those concerns can be resolved. Depending on what the issues
are, they may be resolved with some additional testing or
characterization, perhaps describing something with a bit more
clarity or providing site processes and procedures. The worst-case
scenario would be if the FDA found an issue with the Master Cell
Bank that could not be resolved and resulted in needing to
manufacture the Master Cell Bank, Working Cell Bank and drug
product again to the FDA’s satisfaction. This is why it is so
important to make sure it is done right the first time.”
“Another less obvious answer is the impression
it would leave on the FDA. A sponsor of an IND, like PharmaCyte, is
going to have many opportunities to interact with the FDA on its
path to a Biologics License Application (BLA) approval. An initial
IND is that ‘first impression’ so to speak. Having a well thought
out, well put together and well written IND with all of the
required information can demonstrate to the FDA that the sponsor
understands what needs to be done and is serious about the intent
to bring an important and novel therapy to patients.”
If PharmaCyte, or any company for that
matter, follows the FDA's guidance step by step on the path to
filing an IND and the final submission is closely married to that
which was discussed in the pre-IND meeting, is it your experience
that the company can get through the 30-day period without comment
from the FDA?
Sarah DeMare: “In my personal
experience, there are always comments from the FDA during the
30-day wait. However, under the scenario you have described, the
comments should be minor and the sponsor should be able to quickly
respond to them without issue. For example, the FDA may ask for
slight changes in wording to the protocol. However, those issues
will be communicated and will need to be responded to within 30
days. The issues that arise during the 30-day window are almost
always related to patient safety. It is very common for the FDA to
send the ‘safe to proceed’ letter to the sponsor with a list of
items for the sponsor to consider or complete over the course of
development, but that doesn’t impede the sponsor from beginning its
clinical trial.”
PharmaCyte will follow up this interview-style
Q&A article with an additional interview with TD2 that will be
more focused on the clinical trial, clinical sites, training, etc.
and will discuss what work is being done in parallel with the work
that is ongoing to complete the IND discussed by Ms. DeMare. It is
this clinical-focused work that will allow PharmaCyte to begin its
clinical trial almost immediately upon receiving the “safe to
proceed” letter from the FDA—30 days after filing the company’s
IND.
About PharmaCyte Biotech
PharmaCyte Biotech is a clinical stage
biotechnology company developing therapies for cancer and diabetes
based upon a proprietary cellulose-based live cell encapsulation
technology known as “Cell-in-a-Box®.” This technology will be used
as a platform upon which therapies for several types of cancer and
diabetes are being developed. PharmaCyte’s therapy for cancer
involves encapsulating genetically engineered human cells that
convert an inactive chemotherapy drug into its active or
“cancer-killing” form. These encapsulated cells are implanted as
close to the patient’s cancerous tumor as possible. Once implanted,
a chemotherapy drug that is normally activated in the liver
(ifosfamide) is given intravenously at one-third the normal dose.
The ifosfamide is carried by the circulatory system to where the
encapsulated cells have been implanted. When the ifosfamide flows
through the encapsulated cells, they act as a “bio-artificial
liver” and activate the chemotherapy drug at the site of the
cancer. This “targeted chemotherapy” has proven effective and safe
to use in past clinical trials and results in no treatment related
side effects.
In addition to developing a novel therapy for
cancer, PharmaCyte is developing a therapy for Type 1 diabetes and
insulin-dependent Type 2 diabetes. PharmaCyte plans to encapsulate
a human cell line that has been genetically engineered to produce,
store and release insulin in response to the levels of blood sugar
in the human body. The encapsulation will be done using the
Cell-in-a-Box® technology. Once the encapsulated cells are
implanted in a diabetic patient they will function as a
“bio-artificial pancreas” for purposes of insulin production.
Safe Harbor
This press release contains forward-looking
statements, which are generally statements that are not historical
facts. Forward-looking statements can be identified by the words
"expects," "anticipates," "believes," "intends," "estimates,"
"plans," "will," "outlook" and similar expressions. Forward-looking
statements are based on management's current plans, estimates,
assumptions and projections, and speak only as of the date they are
made. We undertake no obligation to update any forward-looking
statement because of new information or future events, except as
otherwise required by law. Forward-looking statements involve
inherent risks and uncertainties, most of which are difficult to
predict and are generally beyond our control. Actual results or
outcomes may differ materially from those implied by the
forward-looking statements due to the impact of numerous risk
factors, many of which are discussed in more detail in our Annual
Report on Form 10-K and our other reports filed with the Securities
and Exchange Commission.
More information about PharmaCyte Biotech can be
found at www.PharmaCyte.com. Information may also be obtained by
contacting PharmaCyte’s Investor Relations Department.
Contact:
Investor Relations:
PharmaCyte Biotech, Inc.
Investor Relations Department
Telephone: 917.595.2856
Email: Info@PharmaCyte.com