Item 1A. Risk Factors 27
Item 1B. Unresolved Staff Comments 61
Item 1C Cybersecurity 61
Item 2. Properties 61
Item 3. Legal Proceedings 61
Item 4. Mine Safety Disclosures 61
Part II
Item 6. Reserved 62
Item 7A. Quantitative and Qualitative Disclosures about Market Risk 69
Item 8. Financial Statements and Supplementary Data 70
Item 9A. Controls and Procedures 105
Item 9B. Other Information 106
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 106
Part III
Item 10. Directors, Executive Officers, and Corporate Governance 107
Item 11. Executive Compensation 111
Item 14. Principal Accounting Fees and Services 124
Part IV
Item 15. Exhibits and Financial Statement Schedules 125
IMPORTANT
PRELIMINARY NOTE
Planned
Merger with Serina Therapeutics, Inc. and Related Transactions
On
August 29, 2023, AgeX entered into an Agreement and Plan of Merger and Reorganization (the “Merger Agreement”) with Serina
Therapeutics, Inc. (“Serina”), and Canaria Transaction Corporation, a wholly owned subsidiary of AgeX (“Merger Sub”).
Upon the terms and subject to the satisfaction of the conditions described in the Merger Agreement, Merger Sub will be merged with and
into Serina, with Serina surviving as a wholly owned subsidiary of AgeX (the “Merger”). At a special meeting of AgeX stockholders
on March 14, 2024 (the “Special Meeting”), AgeX stockholders approved certain proposals required for consummation of the
Merger pursuant to the terms of the Merger Agreement. Serina stockholders have also approved the Merger. There is no assurance that all conditions to the Merger will be met or waiver and that the Merger will be consummated.
AgeX stockholders will face a number of risks related to the terms of the Merger Agreement and the Merger, some of which risks are described
in this Annual Report on Form 10-K (“Report”). References to the “Combined Company” in this Report mean AgeX
after the Merger through which AgeX will have acquired Serina.
On
March 14, 2024 AgeX effected a 1 for 35.17 reverse stock split of its common stock (the “Reverse Stock Split”) by filing
an amendment to its certificate of incorporation, as approved by AgeX stockholders at the Special Meeting. The Reverse Stock Split resulted
in approximately 2,500,000 shares of AgeX common stock being outstanding immediately upon the filing of the amendment to the certificate
of incorporation. Except for references to authorized but unissued shares of AgeX common stock, and except as may be otherwise stated
in the notes to financial statements, numbers of shares of AgeX common stock issued and outstanding, or issuable upon the exercise of
options or warrants or upon conversion of convertible indebtedness, and AgeX common stock prices, referenced in this Report reflect the
effect of the Reverse Stock Split, and such amounts shown in the case of historical information, including amounts shown in the consolidated
financial statements and notes thereto, have been retroactively adjusted to reflect the effect of the Reverse Stock Split.
On
March 19, 2024, AgeX issued to each holder of AgeX common stock as of the dividend record date, March 18, 2024, three warrants
(“Post-Merger Warrants”) for each five shares of AgeX common stock held by such stockholder. Each Post-Merger Warrant will
be exercisable for one unit of AgeX (“AgeX Unit”) at a price equal to $13.20 per unit and will expire on July 31, 2025. Each
AgeX Unit will consist of (i) one share of AgeX common stock and (ii) one warrant (“Incentive Warrant”). Each Incentive Warrant
will be exercisable for one share of AgeX common stock at a price equal to $18.00 per warrant and will expire on the four-year anniversary
of the closing date of the Merger.
Immediately
following the Merger, equity holders of Serina immediately prior to the closing of the Merger are expected to own approximately 75% of
the outstanding shares of common stock of the Combined Company, and stockholders of AgeX immediately prior to the closing of the Merger
are expected to own approximately 25% of the outstanding shares of common stock of the Combined Company, in each case, on a pro forma
fully diluted basis, subject to certain assumptions and exclusions, including the Actual Closing Price (as defined in the Merger Agreement)
of AgeX common stock being equal to or greater than $12.00 per share, giving effect to the Reverse Stock Split and excluding the impact
of any Post-Merger Warrant, Incentive Warrant or the issuance of any share of AgeX common stock upon exercise of any Post-Merger Warrant
or Incentive Warrant.
Concurrently
with the execution of the Merger Agreement, AgeX, Serina, and AgeX’s controlling stockholder Juvenescence Limited (“Juvenescence”)
entered into a Side Letter, which will become effective immediately prior to the closing of the Merger. The Side Letter provides, among
other things, that (i) effective immediately before the consummation of the Merger, Juvenescence will cancel all out of the money AgeX
warrants held by Juvenescence; (ii) Juvenescence will exercise all Post-Merger Warrants it holds to provide the Combined Company an additional
$15 million in capital according to the following schedule: (x) at least one-third on or before May 31, 2024, (y) at least one-third
on or before November 30, 2024, and (z) at least one-third on or before June 30, 2025; (iii) Juvenescence will not sell any shares of
AgeX Series A Preferred Stock or AgeX Series B Preferred Stock and will take all actions necessary to convert all of such Preferred Stock
into AgeX common stock before a Reverse Stock Split that will occur before the Merger; (iv) Juvenescence will release all security interests,
guarantees, pledges, assignments and other forms of collateral that it may have in AgeX’s assets pursuant to the terms of Juvenescence
loans to AgeX; and (v) Juvenescence will consent to a newly formed subsidiary of AgeX assuming AgeX’s obligations with respect
to loan agreements and promissory notes governing loans payable to Juvenescence, including obligations for amounts currently owed and
future advances of loan funds, and Juvenescence shall release AgeX from those loan obligations. Juvenescence’s covenant regarding
retaining ownership of and converting the Preferred Stock into AgeX common stock has been satisfied through the conversion of the Preferred
Stock into AgeX common stock on February 1, 2024.
Prior
to the closing of the Merger, all assets of AgeX other than certain “Legacy Assets” will be transferred into a recently
formed subsidiary of AgeX “UniverXome Bioengineering, Inc. (“UniverXome”). In consideration of the transfer of
such assets, UniverXome will assume (i) all indebtedness of AgeX issued to Juvenescence that has not been previously
converted into AgeX Series A Preferred Stock or AgeX Series B Preferred Stock, which will be secured by the Legacy Assets and (ii)
all other liabilities of AgeX in existence as of the effective time of the Merger (other than certain transaction expenses related
to the Merger).
Serina
currently has a pipeline of small molecule candidates targeting central nervous system (“CNS”) indications, enabled by the
company’s proprietary POZ PlatformTM delivery technology. In addition to advancing Serina’s wholly owned pipeline
assets, Serina is working with pharma partners currently advancing pre-clinical studies exploring POZ polymer lipid-nanoparticles (“LNPs”)
in next generation LNP delivered RNA vaccines. In addition, Serina is advancing a lead drug candidate, SER-252 (POZ-apomorphine) for
the treatment of advanced Parkinson’s Disease through pre-clinical studies towards the goal of an investigational new drug submission
or “IND” to the Food and Drug Administration for the initiation of a Phase I clinical trial during the fourth quarter of
2024. Serina has two other pipeline assets that are positioned to enter IND enabling studies, SER-227 (POZ-buprenorphine) for certain
post-operative pain indications, and SER-228 (POZ-cannabidiol) for treatment refractory epilepsy indications. Serina is also focused
on expanding its LNP and anti-body drug conjugate partnering collaborations.
If
the Merger is completed, the Combined Company will primarily focus on developing Serina’s product candidates and it is anticipated
that the Combined Company will not continue to develop AgeX product candidates, other than potentially the development program of NeuroAirmid
Therapeutics, Inc. described elsewhere in this Report. If the Merger is not completed, we expect AgeX to continue to execute on its current
business strategies described under the section titled “Pre-Merger Business Strategy” below while seeking out and
evaluating potential strategic alternatives with respect to our assets and development programs, which may include a merger, business
combination, investment into AgeX, sale or other disposition of assets or other strategic transaction. In such case, we may not be successful
in executing such strategies or identifying or implementing any such strategic alternatives, and there is a risk that Juvenescence may
decide to stop funding our operations, which would likely result in our delisting and dissolution.
Summary
of Risk Factors
Below
is a summary of the material factors that make an investment in our common shares speculative or risky. This summary does not address
all of the risks that we face. Additional discussion of the risks summarized in this risk factor summary, and other risks that we face,
can be found below under the heading “Risk Factors” in Item 1A of Part I of this Report and should be carefully considered,
together with other information in this Report and our other filings with the Securities and Exchange Commission (the “SEC”)
before making investment decisions regarding our common shares.
Risks
Related to Our Financial Condition and Capital Resources
Risks
Related to Our Relationship with Juvenescence
Risks
Related to the Merger
Risks
Related to the Reverse Stock Split
Risks
Related to Our Business Operations
Risks
Related to Our Industry
Risks
Related to our Dependence on Third Parties
Risks
Related to Intellectual Property
● The process of applying for and obtaining patents can be expensive and slow.
● Our patents may not protect our technologies or products from competition.
Risks
Pertaining to Our Common Stock
Risks
Related to the Combined Company
Special
Note Regarding Forward-Looking Statements
Certain
statements contained herein are forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995.
Any statements that are not historical fact (including, but not limited to statements that contain words such as “anticipates,”
“believes,” “could,” “seeks,” “estimates,” “expects,” “intends,”
“may,” “plans,” “potential,” “predicts,” “projects,” “pro forma,”
“should,” “would” should also be considered to be forward-looking statements. Forward-looking statements involve
risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products,
uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, and maintenance of
intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements and
as such should be evaluated together with the many uncertainties that affect the businesses of AgeX, particularly those mentioned in
the cautionary statements found in AgeX’s filings with the SEC. AgeX disclaims any intent or obligation to update these forward-looking
statements.
The
forward-looking statements in this Report include, among other things, statements about:
● statements regarding future economic conditions or performance;
● statements concerning proposed products or product candidates;
For
a discussion of the factors that may cause AgeX, Serina or the Combined Company’s actual results, performance or achievements following
closing of the Merger to differ materially from any future results, performance or achievements expressed or implied in such forward-looking
statements, and for a discussion of risk associated with the ability of AgeX and Serina to complete the Merger and the effect of the
Merger on the business of AgeX, Serina and the Combined Company following the completion of the Merger, see “Risk Factors.”
Additional factors that could cause actual results to differ materially from those expressed in the forward-looking statements are
discussed in reports filed with the SEC by AgeX.
If
any of these risks or uncertainties materializes or any of these assumptions proves incorrect, the results of AgeX, or the Combined Company
following completion of the Merger, could differ materially from the forward-looking statements. All forward-looking statements in this
Report are current only as of the date on which the statements were made. AgeX does not undertake any obligation (and expressly disclaim
any such obligation) to publicly update any forward-looking statement to reflect events or circumstances after the date on which any
statement is made or to reflect the occurrence of unanticipated events, except as required by applicable law.
In
addition, statements that “AgeX believes” believes” and similar statements reflect AgeX’s beliefs and opinions
on the relevant subject. These statements are based upon information available to AgeX as of the date of this Report, and while AgeX
believes such information forms a reasonable basis for such statements, such information may be limited or incomplete, and such statements
should not be read to indicate that AgeX has conducted an exhaustive inquiry into, or review of, all potentially available relevant information.
These statements are inherently uncertain and investors are cautioned not to unduly rely upon these statements.
Industry
and Market Data
This
Report contains market data and industry forecasts that were obtained from industry publications, third-party market research and publicly
available information. These publications generally state that the information contained therein has been obtained from sources believed
to be reliable. While we believe that the information from these publications is reliable, we have not independently verified such information.
This
Report also contains estimates and other statistical data made by independent parties and by us relating to market size and growth and
other data about our industry. We obtained the industry and market data in this Report from our own research as well as from industry
and general publications, surveys and studies conducted by third parties, some of which may not be publicly available. Such data involves
a number of assumptions and limitations and contains projections and estimates of the future performance of the industries in which we
operate that are subject to a high degree of uncertainty. We caution you not to give undue weight to such projections, assumptions and
estimates.
PART
I
References
to “ AgeX,” “our” or “us” mean AgeX Therapeutics, Inc.
In
this Annual Report on Form 10-K, the description or discussion of any contract or agreement is a summary only and is qualified in all
respects by reference to the full text of the applicable contract or agreement.
Item
1. Business
Development
of Our Business
During
the twelve months ended December 31, 2023, the following significant developments related to our business have occurred:
On
August 29, 2023, we entered into the Merger Agreement with Serina, and a wholly owned subsidiary of AgeX (“Merger Sub”).
Upon the terms and subject to the satisfaction of the conditions described in the Merger Agreement, the Merger will be consummated through
the merger of Merger Sub with and into Serina, with Serina surviving as a wholly owned subsidiary of AgeX. There is no assurance the
conditions to the Merger will be met and that the Merger will be consummated. See “IMPORANT PRELIMINARY NOTE — Planned Merger
with Serina Therapeutics, Inc. and Related Transactions,” “Risk Factors,” and “Directors, Executive Officers,
and Corporate Governance” in this Report for additional information about the Merger.
Serina
currently has a pipeline of small molecule candidates targeting central nervous system (“CNS”) indications, enabled by the
company’s proprietary POZ PlatformTM delivery technology. In addition to advancing Serina’s wholly owned pipeline
assets, Serina is working with pharma partners currently advancing pre-clinical studies exploring POZ polymer lipid-nanoparticles (“LNPs”)
in next generation LNP delivered RNA vaccines. In addition, Serina is advancing a lead drug candidate, SER-252 (POZ-apomorphine) for
the treatment of advanced Parkinson’s Disease through pre-clinical studies towards the goal of an investigational new drug submission
or “IND” to the Food and Drug Administration for the initiation of a Phase I clinical trial during the fourth quarter of
2024. Serina has two other pipeline assets that are positioned to enter IND enabling studies, SER-227 (POZ-buprenorphine) for certain
post-operative pain indications, and SER-228 (POZ-cannabidiol) for treatment refractory epilepsy indications. Serina is also focused
on expanding its LNP and anti-body drug conjugate partnering collaborations.
If
the Merger is completed, the Combined Company consisting of AgeX and Serina as a subsidiary after the Meger will primarily focus on developing
Serina’s product candidates and it is anticipated that the Combined Company will not continue to develop the AgeX product candidates
and technologies, and will not pursue the business strategy, discussed below in this Report, other than potentially the neural stem cell
development program of NeuroAirmid Therapeutics, Inc. (“NeuroAirmid”).
In
connection with our sponsored Huntington’s Disease research program at the University of California at Irvine (“UCI”),
we and certain researchers who contributed to the Huntington’s Disease research work formed NeuroAirmid to pursue clinical studies
of the use of derived neural stem cell to treat that disease. The new subsidiary is still in the organizational stage and commencement
of clinical study work will depend NeuroAirmid obtaining a license from UCI to use a UCI patent and on NeuroAirmid’s ability to
obtain financing through grants or third-party investment. We presently own 50% of the issued and outstanding shares of NeuroAirmid,
Overview
of AgeX’s Current, Pre-Merger Business
We
are a biotechnology company focused on the development and commercialization of novel therapeutics targeting human aging and degenerative
diseases. Our mission is to apply our comprehensive experience in fundamental biological processes of human aging to a broad range of
age-associated medical conditions. We believe that demand for therapeutics addressing such conditions is on the rise, commensurate with
the demographic shift of aging in the United States and many other industrialized countries.
Our
proprietary technology, based on telomerase-mediated cellular immortality and regenerative biology, allows us to utilize telomerase-expressing
regenerative pluripotent stem cells (“hES cells” or “PSCs”) for the manufacture of cell-based therapies to regenerate
tissues afflicted with age-related chronic degenerative disease. We own or have licenses to a number of patents and patent applications
used in the generation of these product candidates, including intellectual property related to PureStem® technology. Our technology
platform also includes UniverCyteTM which uses the HLA-G gene to potentially confer low immune observability to cells, so as to
suppress rejection of transplanted cells and tissues. AgeX plans to use or license the use of this patented technology to produce genetically-modified
master cell banks of pluripotent stem cells that can then be differentiated into any young cell type of the human body that now express
the immune tolerogenic molecule.
Our
product candidates in the discovery stage include two cell-based therapies derived from telomerase-positive PSCs and two product candidates
derived from our proprietary tissue regeneration (iTRTM) technology. We have also sponsored a research program to derive neural
stem cells from PSCs to treat degenerative diseases such as Huntington’s Disease. We will need to conduct or sponsor research and
development work, or license our technology to other biotechnology or pharma companies interested in furthering research and development
in order to develop these cell- and drug-based therapies, each targeting large unmet needs in age-related medicine.
Overview
of Our Product Candidates
Our
product pipeline includes two cell-based and two iTR-based product candidates in development.
Our
lead cell-based therapeutic candidates in development are AGEX-BAT1 and AGEX-VASC1:
Our
lead small molecule drug-based therapeutic candidate for iTRTM in discovery is AGEX-iTR1547 and our lead biologic candidate for iTR is
AGEX-iTR1550:
Our
research related to the reprogramming of aging has also led to novel insights into cancer. We have filed patent applications on inventions
that relate to these discoveries. These technologies may provide novel targets for cancer therapy and diagnosis. One such cancer therapeutic
in the early stages of development is designated “EPROTM” (embryonic promoter-regulated oncolysis). EPRO is an
oncolytic gene therapy strategy that may provide a novel means of selectively destroying an array of different types of cancer cells.
Successful development of EPRO will be dependent, in part, on the availability of financing and licensing or joint development opportunities.
Our
currently marketed research products include human embryonic stem or hES cells produced under Good Manufacturing Practice (“cGMP”
and hES-derived cells for research:
Overview
of Our Technology Platforms
The
technology underlying our product development programs is based on telomerase-mediated cellular immortality and regenerative biology.
By “telomerase-mediated cellular immortality” we refer to the fact that cells that express sufficient levels of a protein
called telomerase are capable of replicating without limit. By “regenerative biology,” we refer to novel methods to regenerate
tissues afflicted with age-related chronic degenerative disease such as peripheral vascular disease and ischemic heart disease as well
as age-related metabolic disorders such as those associated with Type II diabetes and obesity, as well as others. We utilize telomerase-expressing
regenerative pluripotent stem cells, or PSCs, for the manufacture of cell-based therapies. We own or have licensed numerous patents and
patent applications covering methods and compositions relating to this technology platform.
We
believe our core technology platforms provide us with a strong foundation for successfully addressing many of the diseases of ageing
by focusing on broad therapeutic applicability and commercially scalable technologies:
1.
PureStem®: AgeX’s allogeneic cell derivation and manufacturing platform, based on human embryonic progenitors, which
are cells in state of development between embryonic stem cells and adult cells. We believe PureStem has the potential to solve several
major challenges faced by the cell therapy industry by generating cellular therapeutics which would:
● be commercialized as “off-the-shelf” products;
● be pure and industrially scalable;
● have lower cost of goods per unit;
● be amenable to traditional pharmaceutical supply chain logistics;
In
addition, we believe PureStem cells may have advantages over mesenchymal stem cells (MSCs), which may only survive transiently in the
body and exert any short-term benefit by releasing paracrine factors, which may limit their potential of MSCx.
MSCs
neither engraft nor become specialized cells. On the other hand, cells derived from PureStem progenitors will be engineered to be young,
not prone to the disadvantages associated with older cells, and are expected to become permanently engrafted in the body to deliver a
true regenerative outcome. To date, AgeX has isolated more than 200 cell types from PureStem.
2.
UniverCyteTM: AgeX’s pioneering technology designed to genetically modify allogeneic donor cells to potentially become
hypoimmunogenic/universal, so they can potentially be transplanted into all patients in an off-the- shelf manner, without the normal
need for human leukocyte antigen (HLA) matching between donor and receipt or immunosuppression. UniverCyte utilizes a potent molecule
called HLA-G. HLA is a group of related proteins that helps the immune system distinguish the body’s own proteins from proteins
made by foreign invaders such as viruses and bacteria. HLA-G’s only known physiological role in nature is to prevent destruction
of a semi-allogeneic fetus by the maternal immune system. We believe that UniverCyte could potentially avoid immune rejection of transplanted
cells, solving a major challenge facing the allogeneic cell therapy industry. In addition to utilizing UniverCyteTM for its own
future cell therapy products, AgeX may make UniverCyteTM available to other cell therapy companies through licensing arrangements.
3.
Induced Tissue Regeneration (iTRTM): The aim of iTR is to return aged cells back to a youthful state, thereby inducing
a capacity for scarless regeneration characteristic of early developing tissues, without reverting cells to pluripotency. This technology
is sometimes referred to as “partial reprogramming” or “epigenetic reprogramming of aging.” We believe this novel
approach may trigger complete regeneration of cells, and potentially even complex tissues, damaged as a result of age-related degenerative
processes or trauma. The premise behind iTR is that aging, and in turn degenerative diseases of old age, are a result of the loss of
two characteristics of cells; namely, replicative immortality and regenerative capacity. These two characteristics are present in embryonic
cells but are lost at the embryonic to fetal transition (EFT). With this loss, humans can no longer generate new cells or repair damaged
cells scarlessly and in sufficient numbers to maintain health. We discovered that cells begin expressing the gene COX7A1 at the
EFT when regeneration is commonly lost. Therefore, we believe the gene may be a key inhibitor of cellular regeneration. For example,
we have discovered that restoring a regenerative pattern of COX7A1 gene expression may facilitate hair regeneration in mouse models.
In addition, we have invented multiple platforms for delivering iTR using small molecules as well as biologic strategies such as those
using gene therapy to transiently express reprogramming factors. We have filed patent applications on the use of iTR in a wide array
of degenerative conditions including cancer.
4.
ESI Cell Lines: AgeX has six clinical-grade human embryonic stem cell lines, they are distinguished as the first clinical-grade
human pluripotent stem cell lines created under current Good Manufacturing Practice as described in Cell Stem Cell (2007;1:490-4). They
are listed on the NIH Stem Cell Registry in the USA and are among the best characterized and documented stem cell lines in the world.
ESI-053 is among only a few pluripotent stem cell lines from which a derived cell therapy product candidate has been granted FDA IND
clearance for human studies. The FDA cleared an IND application from ImStem Biotechnology, one of our sublicensees, for a MSC product
derived from ESI-053 for multiple sclerosis. This was believed to be the first MSC product derived from a pluripotent stem line to be
accepted for a human trial by the FDA. The ESI cell lines are available as research or clinical grade product, and have been offered
since 2006.
Pre-Merger
Business Strategy
We
believe our four proprietary platform technologies, PureStem® for cell derivation and manufacturing, UniverCyteTM
for generation of hypoimmunogenic cells and iTRTM for reversing the age of cells already in the body present AgeX with a multiplicity
of attractive opportunities which we may pursue. Given these platform technologies may be highly desirable to multiple academic and biopharma
companies due to their broad applicability and potentially important clinical and commercial benefits, AgeX plans to pursue different
business models for these platforms:
Each
of these models may provide particular benefits to AgeX in terms of financing and efficiency of operations. However, each alternative
has potential disadvantages as well. If AgeX out-licenses its technology it will avoid the costs and risks of research and development,
clinical trials, regulatory approval, manufacturing, and commercialization of product candidates, but the revenues AgeX would receive
from commercialization of products developed under those arrangements would likely be limited to royalties on product sales and potentially
licensing fees and milestone payments representing a relatively small portion of total product revenues. Similarly, co-development and
marketing or similar arrangements would permit AgeX to share costs and risks but would also require AgeX to share revenues from the product
candidates that may be successfully developed and commercialized. See elsewhere in this Report for information about certain risks associated
with reliance on arrangements with third parties for research, product development, clinical trials, manufacturing, and commercializing
product candidates.
We
plan to finance our iTRTM and AGEX-BAT1 research and development through Reverse Bio. To the extent that such financing is
obtained through the sale of capital stock or other equity securities to investors or other biopharma companies by Reverse Bio, or the
sale of Reverse Bio shares held by AgeX, our equity interest in Reverse Bio and our iTRTM and AGEX-BAT1 business would be
diluted.
However,
if the Merger is completed, the Combined Company will primarily focus on developing Serina’s product candidates and it is
anticipated that the Combined Company will not continue to develop our product candidates, other than potentially the development
program of NeuroAirmid, which is described below under “Other AgeX Products and Product Candidates — Neural Stem
Cells.”
AgeX
Technology Platforms
PureStem®
Technology
Regulatory
approval of cell- and tissue-based products require high standards of quality control. In the case of stem cell-derived products, there
is a high standard for ensuring the known identity, purity, and reproducibility of the cells to be administered. PSCs provide certain
advantages over adult stem cell products when used in the manufacture of cell-based therapeutics for the treatment of age-related disease.
These advantages include:
PureStem®
technology is based on the observation that embryonic anlagen of many tissues in the human body are naturally comprised of highly
proliferative cells with relatively long telomere length. Therefore, it is possible to generate clonal lineages of these cells in
vitro. Cells derived from adult tissues commonly permanently cease to divide after a certain number of doublings, a condition known
as senescence. In addition, adult and even fetal tissues largely contain differentiated cells often with limited or no capacity of replication
in vitro. As a result, the clonal expansion of human embryonic progenitor cell types allows not only a novel and more facile point of
scalability but also generates populations of cells that are multipotent instead of pluripotent, and therefore markedly easier to define
identity, purity, and potency.
We
have studied the fate of over 200 diverse PureStem cell lines in thousands of differentiation conditions. This was accomplished by thawing
individual cryopreserved PureStem cell lines, culturing them in the laboratory, and then exposing the cells to factors that differentiate
cells such as protein growth and differentiation factors, hormones, and small molecules implicated in causing cells to change from one
type of cell into another (differentiation). Using individual cells from the over 200 diverse PureStem cell lines previously isolated
and cryopreserved, we treated the diverse cells with thousands of differentiation conditions, prepared RNA, and determined the gene expression
pattern of the cells using gene expression microarrays. These experiments have shown that the PureStem cell lines display site-specific
markers that identify not only the type of cells, but also where in the body the cells would normally reside. Therefore, in the example
of cartilage cells, it was possible to produce diverse types of cartilage in this manner. We have licensed from our former parent company
Lineage PureStem applications outside of orthopedics, medical aesthetics, and certain ophthalmological applications.
We
have chosen two PureStem applications for our initial product development based on unmet medical need along with other factors. The first
product candidates are AGEX-BAT1, brown adipose tissue or BAT cells for the treatment of metabolic disorders such as obesity or Type
II diabetes, and AGEX-VASC1, vascular endothelial progenitors for the treatment of age-related ischemic disease such as that leading
to peripheral vascular disease and ischemic heart disease.
UniverCyteTM
Our
UniverCyteTM technology uses a proprietary, novel, modified form of HLA-G and is intended to permit donor cells to be transplanted
into patients without donor-patient tissue matching and without administering immunosuppressant medication. Immunosuppressive drugs can
reduce patient resistance to infectious diseases and cancers as well as cause organ and other toxicities. Reducing or eliminating the
need for immunosuppressants after cell transplantation by use of hypoimmunogenic cells may make therapies universally available. We plan
to use or license the use of this patented technology to produce genetically-modified master cell banks of pluripotent stem cells that
can then be differentiated into any young cell type of the human body that now express the immune tolerogenic molecule.
AgeX
Products and Product Candidates
AgeX
Therapeutic Product Candidates
AGEX-BAT1
- Brown Adipose Tissue (BAT) Progenitors
Brown
adipose tissue (BAT) is abundant early in life but lost precipitously with age. This tissue is believed to generate heat through expression
of a gene called UCP1. In addition, the high levels of glucose and lipid uptake by the tissue is believed to balance metabolism
in young people. In contrast, central obesity and Type II diabetes has been correlated with low levels of BAT.
Figure
6. Human tissue-derived BAT cells (left) stained red for the presence of UCP1 show a minority of cells being true BAT cells. PureStem-derived
AGEX-BAT1 cells are uniformly UCP1 positive.
The
demonstration in published literature in the public domain that the transplantation of BAT from young mice to obese diabetic mice resulted
in weight loss and increased insulin sensitivity has led to a search for a source of industrially-scalable clinical grade BAT cells as
well as an appropriate matrix for lipotransfer. There currently is no FDA-approved matrix for cell transplantation. As shown in Figure
6, the AGEX-BAT1 progenitors strongly express the BAT marker UCP1 when induced to differentiate and show a relatively high degree
of purity compared to human tissue-derived BAT.
We
entered into a Sponsored Research Agreement with Ohio State University using AGEX-BAT1 in mice to determine whether transplantation of
AgeX-BAT1 cells may lead to improvements in diet-induced obesity, metabolic health including glucose metabolism, and cardiac function.
For purposes of this proof of concept work, two different cell transplant matrices were tested, HyStem® and a 3-D
silk scaffold. We consider this work to be an early stage study and expect to conduct or sponsor additional research on the potential
therapeutic benefits of AGEX-BAT1.
A
number of new GLP-1 receptor agonist drugs, including Mounjaro, Ozempic, Rybelsus, and Trulicity for treating type 2 diabetes, and Wegovy
and Zepbound for weight management, have entered the market. Ozempic is also being used off label for weight loss. The attention and
acceptance that these new drugs have attained in the medical field for the treatment of type 2 diabetes and chronic weight management
may substantially limit or eliminate the prospects for developing and commercializing any product based on AGEX-BAT1, brown adipose tissue,
for those uses. Although the GLP-1 receptor agonist drugs may in certain patients be contraindicated, carry unacceptable medical risks,
lead to intolerable side effects, or may not be satisfactorily effective, it is not clear whether those patients would constitute a large
enough market for an alternative therapy to warrant the time and expense of developing AGEX-BAT1 for the uses addressed by the products
currently on the market. Further, it is likely that the administration of a AGEX-BAT1 cell therapy product would entail a surgical implant
procedure which would be expensive and would pose risks to the patient related to the surgical procedure that are not faced by users
of the injectable or pill GLP-1 receptor agonist drugs currently on the market.
AGEX-VASC1
- Vascular Progenitors
PureStem®
technology can also yield highly purified embryonic vascular components. As shown below, select clonal lines express markers such
as VE-Cadherin (CDH5) and PECAM1, as well as VWF and other markers of venous, arterial, and lymphatic endothelium. Flow cytometry shows
purity indistinguishable from 100%.
In
addition to vascular endothelial cells, we have characterized vascular smooth muscle cell progenitors. This makes it possible for us
to construct two of the key cellular components of arterial vessels, such as those compromised in coronary artery disease.
Figure
7. PureStem-derived vascular endothelial cell lines are capable of regenerating young vasculature (bottom left) and appear to have essentially
100% purity by fluorescence activated cell sorting analysis.
Leveraging
our assets in pluripotency and bioinformatics, we have performed research manipulating cellular immortality and regenerative biology
in human cells. In 2010, our scientists while at Lineage demonstrated the reversal of the developmental aging of human cells using transcriptional
reprogramming technology. In 2017, we published certain markers of the Weismann barrier, and the high prevalence of a reversion back
before the Weismann barrier in diverse cancer cell types cultured in vitro.
We
extended this research to determine whether reprogramming can be modified to only reverse the aging of cells back before the Weismann
Barrier, not back to pluripotency. We have utilized for example the gene COX7A1 as a marker of cells that have lost regenerative
potential (crossed the Weismann Barrier). As shown in Figure 8, our proprietary formulation AGEX-iTR1547 has demonstrated initial capability
of reducing the expression of the marker gene COX7A1 back to before the Weismann Barrier without reverting the cells to pluripotency.
When implemented in vivo, this partial reprogramming, or iTR, would be expected to induce tissue regeneration, and when combined
with telomerase, may be able to modulate both cellular immortality and regenerative biology for therapeutic effect. In addition to the
small molecule product candidate designated iTR1547, we have invented biological interventions based, for example, on gene therapy. Our
inventions relating to iTR biologics disclose both DNA and RNA-based strategies. Our gene delivery iTR product candidate is designated
iTR1550. We are performing research to optimize AGEX-iTR1547 and in parallel a gene delivery formulation designated AGEX-iTR1550 in order
to initiate preclinical studies of one or both of the agents on the scarless regeneration of the skin.
Figure
8. PSCs such as ES Cells and PureStem EP Cells display a regenerative capacity like cells that have not crossed the Weismann Barrier.
During pre- and post-natal development, skin cells become increasingly incapable of scarless regeneration as reflected in increasing
COX7A1 expression. iPS cell reprograming reverts cells back to pluripotency, while AgeX-iTR1547 reverts cells back only to a point
prior to the Weismann Barrier (regenerative state).
Status
and Development Plan
The
product candidates we have chosen are in the discovery stage of development. Prior to filing an investigational new drug application
(IND) for the initiation of clinical trials of our initial product candidates, AGEX-BAT1, AGEX-VASC1, and AGEX-ITR1547/AGEX-iTR1550,
a number of important research and development goals will need to be achieved, including discovery-level research for the qualification
of reagents used in the manufacture of the product, completion of the standard operating procedures (SOPs) to be used, completion of
the methods and documentation for characterization of the product; and producing and testing the genetic modifications in the master
cell banks of the pluripotent stem cells under cGMP in order to produce product that will not illicit immune rejection following transplantation.
In addition, we will be required to expand the numbers of the pluripotent stem cell master cell banks for future use; produce working
cell banks from which the product will be manufactured for clinical trials; produce the relevant product under cGMP conditions; and expand
the number of relevant cells and cryopreserve them under cGMP conditions. In addition, we will be required to design the pre-clinical
studies including the study endpoints, perform biosafety testing and release the first clinical batch based on preliminary characterization
results, and complete full product characterization. Biosafety testing will necessarily include pilot testing in animals such as (NOD/SCID)
mice, dosing spiking studies at early and later endpoints, tumorgenicity and biodistribution studies to determine whether the cells form
undesired tumors or migrate to inappropriate sites respectively in the animal. Lastly, we will need to define the clinical trial and
regulatory strategy and hold various meetings with the U.S. Food and Drug Administration (FDA), as well as successfully submit an IND
to the FDA and receive clearance to begin trials. Thereafter, we will need to demonstrate safety and efficacy of the product in human
clinical trials in Phase I and II trials, and continued safety and efficacy for achieving the desired endpoint in Phase III trials, potentially
then leading to product registration. See “Risk Factors—Risks Related to Our Business Operations” for discussion
of risks relating to product development and clinical trials. These include, but are not limited to, failure to successfully complete
the aforementioned studies due to the failure of the product, processes, or skills of our employees, unforeseen delays in the development
process, failure to raise requisite financing, or failure to receive permission from the FDA to advance product development. To the extent
we license development of one or more product candidates to third parties or enter into collaboration arrangements for product development,
our licensees or collaborators would need to undertake and achieve the foregoing goals.
Because
our product candidates are still in the discovery stage, our choice of product candidates and development plans are subject to change
based on a variety of factors. We may determine to abandon the development of one or more of our product candidates, or we may prioritize
the development of one or more product candidates, or we may select or acquire and prioritize the development of new product candidates.
Our choice and prioritization of product candidates for development will be influenced by a variety of factors, including but not limited
to:
Other
AgeX Products and Product Candidates
Neural
Stem Cells
AgeX
has sponsored a research and development program at UCI for the manufacture of neural stem cells for use in the treatment of Huntington’s
Disease and potentially other neurological diseases and disorders. AgeX has also collaborated with a research group at UCI studying the
potential use of exosomes and other extracellular vesicles for the treatment of adverse neurocognitive effects of cancer chemotherapy
and radiation therapy on brain function. The neural stem cell sponsored research and development program led to the creation of NeuroAirmid,
which is a subsidiary of AgeX co-owned with certain of the UCI researchers and in which UCI will also receive an equity interest as partial
consideration for granting to NeuroAirmid a license to use a UCI patent and certain specified technical information, materials, or data
(“Associated Technology”) created in the laboratory of the inventors of the licensed patent.
UCI
has made an IND submission to the FDA for the use of neural stem cells in a clinical trial for the treatment of Huntington’s Disease.
The FDA has removed a clinical hold on the IND permitting a clinical trial to proceed. UCI and NeuroAirmid will apply to the California
Institute for Regenerative Medicine (CIRM) for a $12,000,000 CLIN2 grant to fund the proposed clinical trial.
There
can be no assurance that: (i) NeuroAirmid and UCI will successfully conclude negotiations and enter into a license agreement providing
NeuroAirmid with a license to use a UCI patent needed for NeuroAirmid’s development and production of its planned therapeutic neural
stem cell product, (ii) CIRM will provide a grant to finance a clinical trial or that the amount of any grant that may be awarded will
ultimately be sufficient to complete the initial phase of the clinical trial; (iii) NeuroAirmid will be able to raise capital needed
to finance its operations that will not be funded by a CIRM clinical trial grant or to finance any further clinical trials after any
initial CIMR grant funding is exhausted; and (iv) if a clinical trial is commenced, it will lead to the successful clinical development
and subsequent FDA marketing approval of a therapeutic cellular product for the treatment of Huntington’s Disease or any other
neurological disease or disorder.
ESI
BIO Research Products
We,
through our ESI BIO research product division, market a number of products related to pluripotent stem cells including research-grade
as well as cGMP-grade human PSC lines. We plan to contract with third parties where the third parties to allow them to utilize cGMP PSC
lines in defined fields of application in exchange for certain compensation including the payment of royalties to us if they are successful
in developing and commercializing a product.
Subsidiaries
AgeX
has five subsidiaries, Reverse Bio, ReCyte Therapeutics, Inc. (“ReCyte”), NeuroAirmid, UniverXome Bioengineering, Inc. (“UniverXome”),
and Merger Sub. Reverse Bio, ReCyte and NeuroAirmid are early stage pre-clinical research and development companies. UniverXome was organized
to hold AgeX assets related to our current core technologies and research and development programs other than NeuroAirmid if the Meger
is consummated.
AgeX
intends to develop its iTRTM platform and AGEX-BAT1 through Reverse Bio. Reverse Bio will allow for a dedicated focus on iTRTM
in terms of equity financing and advancing the iTRTM technology to proof-of-concept in an animal model. AgeX’s
patent portfolio for iTR and AGEX-BAT1 development have been assigned to Reverse Bio, but the future operations of Reverse Bio will depend
in large measure on its ability to raise its own capital. ReCyte is involved in stem cell-derived endothelial and cardiovascular related
progenitor cells for the treatment of vascular disorders and ischemic conditions. AgeX owns 100%, 94.8%, and 50% of the outstanding capital
stock of Reverse Bio, ReCyte, and NeuroAirmid, respectively. We expect that our ownership interests in Reverse Bio and NeuroAirmid will
be diluted if those subsidiaries are successful in obtaining financing from investors or product development collaborators. All material
intercompany accounts and transactions have been eliminated in consolidation.
Manufacturing
We
presently do not have any manufacturing facilities and we will need to rely on third party contract manufacturers for the production
of our cell lines and product candidates and to comply with quality manufacturing processes and controls.
Facilities
Our
principal place of business is located at 1101 Marina Village Parkway, Suite 201, Alameda, California, which we use for office purposes
only. We do not have our own research laboratory facilities.
Commercialization
Plan
With
the exception of our research product sales which generate a trivial amount of revenues, we currently have no commercialized or marketed
products such as FDA-approved drugs in our portfolio. As a result, we have not yet assembled an infrastructure for sales and marketing.
At the point in time, if ever, that our product candidates approach clearance or approval, we plan to develop a commercial plan that
may initially include strategic marketing partnerships.
Intellectual
Property
Patents
and Trade Secrets
We
rely primarily on patents and contractual obligations with employees and third parties to protect our proprietary rights. We have sought,
and intend to continue to seek, appropriate patent protection for important and strategic components of our proprietary technologies
by filing patent applications in the U.S. and certain foreign countries. There are no assurances that any of our intellectual property
rights will guarantee protection or market exclusivity for our products and product candidates. We also use license agreements both to
access technologies developed by other companies and universities and to convey certain intellectual property rights to others. Our financial
success will be dependent, in part, on our ability to obtain commercially valuable patent claims, to protect and enforce our intellectual
property rights, and to operate without infringing upon the proprietary rights of others if we are unable to obtain enabling licenses.
The
patents for our core programs are summarized below.
AGEX-BAT1
Brown
Adipose Tissue (BAT) Progenitor Cells: The pending patent applications related to BAT progenitor cells, which are owned by AgeX,
include U.S. and international patent applications. The applications are directed to the differentiation of pluripotent stem cells (including
hES cells) into progenitor cell types capable of making the cellular components of brown fat. The patents also describe culture and purification
methods. The approximate expiration dates of the BAT patents, if issued, will range from 2034 to 2036.
AGEX-VASC1
Vascular
Progenitors: The pending patent application pertaining to purified vascular progenitor cells and embryonic vascular components are
owned by AgeX or an AgeX subsidiary or licensed from Lineage. The patents include U.S. patent applications and are directed to methods
to enhance vascular tube networks, compositions of pericyte progenitor cells, compositions of exosomes containing angiogenic molecules,
compositions of vascular and lymphatic cells, and methods to culture and purify the cells or components thereof. The approximate expiration
dates of the vascular progenitor patents, if issued, range from 2032 to 2038. We plan to file an international patent application claiming
priority from a pending US provisional application by the filing deadline, which could lead to a patent that if issued would expire in
2039.
AGEX-iTR1547
and AGEX-iTR1550
Induced
Tissue Regeneration (iTRTM): The pending patent applications related to the iTR programs, which are owned by AgeX, include
applications pending, for example, in the United States, Australia, Canada, China, Europe, Japan and a pending international patent application.
These patents and patent applications are directed to compositions and methods for healing damaged tissue using the iTR treatment methods.
The patent applications are also directed to treatment methods by regenerating aging tissue by modulating genes involved in tissue regeneration,
including reprogramming cells and tissues back to a regenerative state. The approximate expiration dates of the iTR patents, if issued,
will range from 2034 to 2041.
Other
AGEX Licensed and Sublicensed Patents
PureStem®
Progenitor Cells: The patents and pending applications related to our PureStem® technology include patents and
applications in the United States, Canada, Europe and Australia. These patents are directed to methods for generating diverse isolated
progenitor cell lines which generally do not express COX7A1 and combinations of other methods for employing pluripotent stem cell
lines suitable for clinical use. The pending applications are directed to clonally purified human embryonic progenitor cell lines and
methods for reproducible, large scale production of clonally purified human embryonic progenitor cells, compositions and methods for
generating diverse cell types, and assays useful in identifying hES cell lines and pluripotent cells resulting from the transcriptional
reprogramming of somatic cells that have embryonic telomere length. The approximate expiration date of the PureStem® issued
patents is 2031 and the approximate date of expiration of the pending patents, if issued, will range from 2029 to 2032.
The
PureStem® patent portfolio includes patents and pending applications licensed from Advanced Cell Technology, Inc., which