UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
WASHINGTON,
DC 20549
FORM
10-K
(Mark One)
For the fiscal year ended December 31, 2021
Or
For the transition period from _______ to _______
Commission
file number 001-15771
ABEONA
THERAPEUTICS INC.
(Exact
name of registrant as specified in its charter)
1330
Avenue of the Americas, 33rd Floor, New
York, NY10019
(Address
of principal executive offices, zip code)
(646)813-4701
(Registrant’s
telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Securities Exchange Act of 1934:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common Stock, $0.01 par value ABEO Nasdaq Capital Markets
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 of this chapter) during the preceding 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 definitions of “large accelerated filer,” “accelerated filer,” “smaller
reporting company” and “emerging growth company” in Rule 12b-2 of the 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 has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered
public accounting firm that prepared or issued its audit report. Yes ☐ No ☒
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒
The
aggregate market value of the voting and non-voting common equity held by non-affiliates computed by reference to the average bid and
asked price of such common equity, as of June 30, 2021, was approximately $137,200,000.
The
number of shares outstanding of the registrant’s common stock as of March 21, 2022 was 147,378,022 shares.
TABLE
OF CONTENTS
Page
Part I
Item 1. Business 3
Item 1A. Risk Factors 30
Item 1B. Unresolved Staff Comments 62
Item 2. Properties 62
Item 3. Legal Proceedings 63
Item 4. Mine Safety Disclosures 63
Part II
Item 6. [Reserved] 65
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 75
Item 8. Financial Statements and Supplementary Data 75
Item 9A. Controls and Procedures 76
Item 9B. Other Information 77
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 77
Part III
Item 10. Directors, Executive Officers and Corporate Governance 78
Item 11. Executive Compensation 84
Item 14. Principal Accounting Fees and Services 93
Item 15. Exhibits, Financial Statement Schedules 94
Signatures 95
FORWARD-LOOKING
STATEMENTS
This
Form 10-K (including information incorporated by reference) contains statements that express management’s opinions, expectations,
beliefs, plans, objectives, assumptions or projections regarding future events or future results and therefore are, or may be deemed
to be, “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section
21E of the Securities Exchange Act of 1934, as amended. Words such as “expects,” “anticipates,” “intends,”
“plans,” “believes,” “could,” “would,” “seeks,” “estimates,”
and variations of such words and similar expressions, and the negatives thereof, are intended to identify such forward-looking statements.
We caution readers not to place undue reliance on any such “forward-looking statements,” which speak only as of the date
made, and advise readers that these forward-looking statements are not guarantees of future performance and involve certain risks, uncertainties,
estimates, and assumptions by management that are difficult to predict. Various factors, some of which are beyond the Company’s
control, could cause actual results to differ materially from those expressed in, or implied by, such forward-looking statements. All
such forward-looking statements, whether written or oral, and whether made by us or on our behalf, are expressly qualified by these cautionary
statements and any other cautionary statements that may accompany the forward-looking statements. In addition, we disclaim any obligation
to update any forward-looking statements to reflect events or circumstances after the date of this report, except as may otherwise be
required by the federal securities laws.
Forward-looking statements necessarily involve
risks and uncertainties, and our actual results could differ materially from those anticipated in forward-looking statements due to a
number of factors. These statements include statements about: our Phase 3 clinical trial (VIITALTM) for patients with recessive
dystrophic epidermolysis bullosa (“RDEB”) and our beliefs relating thereto; our ability to follow patients in the Phase 3
clinical trial; our plans to continue development of AAV-based gene therapies designed to treat ophthalmic and other diseases and next-generation
AAV-based gene therapies; the discontinuation of development activities for our ABO-101 and ABO-102 programs; the potential impacts of
the COVID-19 pandemic on our business, operations, and financial condition; the achievement of or expected timing, progress and results
of clinical development, clinical trials and potential regulatory approvals;; our pipeline of product candidates; our belief that we
have sufficient resources on hand, access to additional financial resources and/or financial flexibility to fund operations for at least
the next 12 months from the date of filing of this report; our belief that EB-101 could potentially benefit patients with RDEB; our ability
to develop our novel AAV-based gene therapy platform technology; our belief in the adequacy of the clinical trial data from our VIITALTM,
together with the data generated in the program to date, to support regulatory approvals; our dependence upon our third-party and related-party
customers and vendors and their compliance with regulatory bodies; our estimates regarding expenses, future revenues, capital requirements,
and needs for additional financing; our intellectual property position and our ability to obtain, maintain and enforce intellectual property
protection and exclusivity for our proprietary assets; our estimates regarding the size of the potential markets for our product candidates,
the strength of our commercialization strategies and our ability to serve and supply those markets; and future economic conditions or
performance.
Important factors that could affect performance
and cause results to differ materially from management’s expectations are described in the sections entitled “Risk Factors”
and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in this Form 10-K. These
factors include: the impact of the COVID-19 pandemic on our business, operations (including our clinical trials), and financial condition,
and on our ability to access the capital markets; our ability to regain and maintain compliance with the listing standards of the Nasdaq
Capital Market; the successful discontinuation development activities for our ABO-101 and ABO-102 programs; our ability to increase our
authorized capital; our ability to access our existing at-the-market sale agreement and any dilution that may result from accessing such
sales agreement; our ability to fund our operating expenses and capital expenditure requirements for at least the next 12 months given
our existing cash, cash equivalents and short-term investments; our ability to access additional financial resources and/or our financial
flexibility to reduce operating expenses if required; our ability to obtain additional equity funding from current or new stockholders,
out-licensing technology and/or other assets, deferring and/or eliminating planned expenditures, restructuring operations and/or reducing
headcount, and sales of assets; the dilutive effect that raising additional funds by selling additional equity securities would have
on the relative equity ownership of our existing investors, including under our existing at-the-market sale agreement; development of
our novel AAV-based gene therapy platform technology; the outcome of any interactions with the U.S. Food and Drug Administration (“FDA”)
or other regulatory agencies relating to any of our products or product candidates; our ability to complete enrollment of patients into
clinical trials to secure sufficient data to assess efficacy and safety; our ability to continue to secure and maintain regulatory designations
for our product candidates; our ability to develop manufacturing capabilities compliant with current good manufacturing practices for
our product candidates; our ability to manufacture cell and gene therapy products and produce an adequate product supply to support clinical
trials and potentially future commercialization; the rate and degree of market acceptance of our product candidates for any indication
once approved; and our ability to meet our obligations contained in license agreements to which we are party.
PART
I
ITEM 1. BUSINESS
Business
Abeona
Therapeutics Inc., a Delaware corporation (together with our subsidiaries, “we,” “our,” “Abeona”
or the “Company”), is a clinical-stage biopharmaceutical company developing cell and gene therapies for
life-threatening rare genetic diseases. Our lead clinical program is EB-101, an autologous, gene-corrected cell therapy for
recessive dystrophic epidermolysis bullosa (“RDEB”), which is currently in the pivotal Phase 3 VIITALTM clinical
trial. Following a comprehensive portfolio review in early 2022, we have decided to focus our research and development resources on
the VIITALTM readout while actively pursuing a potential commercialization partner for EB-101 with the objective of reducing
operating expenses and extending our cash runway. As part of this portfolio prioritization, we have intensified our pursuit of a
strategic partnership to take over development activities for our adeno-associated virus (“AAV”)-based gene
therapy ABO-102 for Sanfilippo syndrome type A (“MPS IIIA”) and we have discontinued development of our AAV-based gene
therapy ABO-101 for Sanfilippo syndrome type B (“MPS IIIB”).
We
plan to continue development of AAV-based gene therapies designed to treat ophthalmic and other diseases and next-generation
AAV-based gene therapies using the novel AIMTM capsid platform that we have exclusively licensed from the University of North Carolina
at Chapel Hill (“UNC”), and internal AAV vector research programs.
We
believe that our current product candidates are eligible for orphan drug designation, breakthrough therapy designation, or other
expedited review processes in the U.S., Europe, Japan, or other world markets. Our pipeline includes programs for which we hold several
U.S. and European Union (“EU”) regulatory designations, and a pipeline of additional earlier stage programs:
Our pipeline features early- and late-stage candidates with the potential to transform the treatment of devastating genetic diseases,
and we are conducting clinical trials in the U.S. and abroad.
Our
Mission and Strategy
Abeona
is at the forefront of cell and gene therapy research and development. We are a fully-integrated company featuring therapies in
clinical development, in-house manufacturing facilities, a robust pipeline, and scientific and clinical leadership. We see our mission
as working to create, develop, manufacture, and deliver cell and gene therapies for people impacted by serious diseases. We partner
with leading academic researchers, patient advocacy organizations, caregivers and other biotechnology companies to develop
therapies that address the underlying cause of a broad spectrum of rare genetic diseases for which no effective treatment options exist
today.
In
2021, we continued to make progress toward fulfilling our goal of harnessing the promise of genetic medicine to transform the lives of
people impacted by serious diseases and redefining the standard of care through cell and gene therapies. Our strategy to achieve
this goal consists of:
Advancing
our Clinical Cell and Gene Therapy Programs and Research and Development with a Focus on Rare and Orphan Diseases.
Through
our cell and gene therapy expertise in research and development, we believe we are positioned to introduce efficacious and safe
therapeutics to transform the standard of care in devastating diseases and establish our leadership position in the field.
Applying
Novel Next-Generation AIMTM Capsid Technology to Develop New In-Vivo Gene Therapies.
We
are researching and developing next-generation AAV-based gene therapy using our novel capsids developed from the AIMTM Capsid Technology
Platform and additional Company-invented AAV capsids. We plan to continue to develop chimeric AAV capsids capable of improved tissue
targeting for various indications and potentially evading immunity to wildtype AAV vectors.
Establishing
Leadership Position in Commercial-Scale Cell and Gene Therapy Manufacturing.
We
established current Good Manufacturing Practice (“cGMP”), clinical-scale manufacturing capabilities for gene-corrected cell
therapy and AAV-based gene therapies in our state-of-the-art Cleveland, Ohio facility. We believe that our platform provides us with
distinct advantages, including flexibility, scale, reliability, and the potential for reduced development risk, reduced cost, and faster
times to market. We have focused on establishing internal Chemistry, Manufacturing and Controls (“CMC”) capabilities that
drive value for our organization through process development, assay development and manufacturing. We have also deployed robust quality
systems governing all aspects of product lifecycle from preclinical through commercial stage.
Establishing
Additional Cell and Gene Therapy Franchises and Adjacencies through In-Licensing and Strategic Partnerships.
We
seek to be the partner of choice in gene therapy treatment and have closely collaborated with leading academic institutions, key opinion
leaders, patient foundations, and industry partners to generate novel intellectual property, accelerate research and development, and
understand the needs of patients and their families.
Maintaining
and Growing IP Portfolio.
We
strive to have a leading intellectual property portfolio. To that end, we seek patent rights for various aspects of our programs, including
vector engineering and construct design, our production process, and all features of our clinical products including composition of matter
and method of administration and delivery. We expect to continue to expand our intellectual property portfolio by aggressively seeking
patent rights for promising aspects of our product engine and product candidates.
Our
Pipeline
Our pipeline features early- and late-stage candidates with the potential to transform the treatment of devastating genetic diseases.
Our
lead clinical program is EB-101, an autologous, gene-corrected cell therapy for RDEB, which is currently in a Phase 3 clinical
trial. Following a comprehensive portfolio review in early 2022, we have decided to focus our research and development resources on the EB-101
program with the objective of reducing operating expenses and extending our cash runway. As part of this portfolio prioritization, we have intensified our pursuit
of a strategic partnership to take over development activities for our AAV-based gene therapy ABO-102 for MPS IIIA and we
have discontinued development of our AAV-based gene therapy ABO-101 for MPS IIIB. We continue to develop
additional AAV-based gene therapies designed to treat ophthalmic and other diseases and next-generation AAV-based gene therapies
using the novel AIMTM capsid platform that we have exclusively licensed from UNC, and internal AAV vector research
programs.
Developing
Next Generation Cell and Gene Therapy
EB-101
for the Treatment of Recessive Dystrophic Epidermolysis Bullosa (“RDEB”)
Disease
Overview
RDEB
belongs to a group of genetic skin disorders known more broadly as epidermolysis bullosa. Patients with RDEB have a defect in the COL7A1
gene, resulting in the inability to produce Type VII collagen, which plays a vital role in anchoring the skin’s dermal and epidermal
layers.
RDEB
patients have fragile skin, which can easily damage to produce open and blistering wounds, disfiguring scars throughout the body, fused
fingers and toes, limits in range of motion at joints (e.g., arms and legs), and an abnormal narrowing of the esophagus. Long-term RDEB
patients can suffer from anemia, are at high risk of developing aggressive squamous cell carcinomas, infections, and premature death.
The most severe patients are approximately 20 times more likely to die by 30 years of age than the general population.
Similar
to other rare diseases, the incidence and prevalence of RDEB are not well defined. Incidence of 0.2 to 3.05 per million
births and prevalence of 0.14 to 1.35 per million people have been observed across different geographies, primarily estimated by limited
population analyses of clinical databases or registries (Eichstadt et al.; Clinical, Cosmetic and Investigational Dermatology, 2019).
Using genetic modeling of COL7A1 variants, which is believed to cause RDEB, Stanford University estimated the incidence of RDEB to be
approximately 63 per million births, and prevalence could be up to 3,850 patients in the U.S., whose wounds may benefit from COL7A1-mediated
treatments such as EB-101.
RDEB
patients have, on average, 11 active wounds on their bodies, with the majority > 20 cm2 (Stanford University; Solis, D.,
et al., 2017). In 2020, a survey of RDEB patients reported that approximately 60% have active wounds covering greater than 30% of their
bodies (Bruckner et al.; Orphanet Journal of Rare Diseases, 2020). Wounds covering up to approximately 80% of body surface area have
been recorded in some EB patients (Hirsch et al.; Nature Research, 2017).
We
expect EB-101 could be a treatment option for large and chronic RDEB wounds for which EB-101 has shown durable healing
and associated pain reduction in a phase 1/2 clinical trial. The data from the phase 1/2 clinical trial supports the VIITALTM phase
3 trial. These larger and/or chronic wounds carry the highest burden, including the need for frequent dressing changes, pain, pruritus,
risk of infection, and developing skin cancer.
Current
Management of RDEB
At
present, there are no approved treatments for RDEB in the U.S. or Europe.
Wound
management currently consists of supportive care to limit contamination and infection, and reduction in mechanical forces that produce
new blisters. Care usually includes treatment of new blisters by lancing and draining. Wounds are then dressed with a non-adherent material,
covered with padding for stability and protection, and secured with an elastic wrap for integrity. The estimated annual cost of wound
dressings alone for an RDEB patient can range from $245,000 per year to significantly higher in more severe cases.
RDEB
patients also have periodic surgeries to relieve disease related issues such as narrowing of their esophagus, fusing of fingers, and
corneal abrasions.
Program
Status
EB-101
is an autologous, gene-corrected cell therapy in which a functioning COL7A1 gene is inserted into a patient’s own skin cells (keratinocytes)
using a retrovirus. The keratinocytes are then transplanted back to the patient to restore Type VII collagen expression and skin function.
EB-101
has been granted Regenerative Medicine Advanced Therapy (“RMAT”), Breakthrough Therapy, Rare Pediatric Disease, and Orphan
Drug designations by the U.S. Food and Drug Administration (“FDA”); as well as Orphan Drug designation by the European Medicines
Agency (“EMA”).
Results
from a completed Phase 1/2 study that enrolled 7 patients with large and chronic RDEB wounds at Stanford University showed that EB-101
was well-tolerated and resulted in significant and durable wound healing (Siprashvili, Z., et al., 2016), with up to seven years of follow-up
(Eichstadt, S., et al. JCI Insight 2019). To date, there have been no reported serious adverse events.
Over
the past two years, we have been conducting a pivotal Phase 3 clinical trial, referred to as VIITALTM, evaluating the potential
of EB-101 for the treatment of RDEB. VIITALTM is an ongoing randomized, control-matched Phase 3 clinical trial assessing treatment
with EB-101 in 10 to 15 patients, comprising approximately 36 large chronic wound sites treated in total. The co-primary endpoints
of VIITALTM are a) proportion of EB-101 treated wounds with >50% healing from baseline at 24 weeks and b) improvement in pain
at 24 weeks assessed by the Wong-Baker pain scale at time of dressing change versus an untreated control wound. The FDA has agreed on
the endpoints and other characteristics of the study.
We achieved target enrollment for the VIITALTM study in the first
quarter of 2022. Given that the co-primary endpoints are measured at 24 weeks following treatment, we anticipate topline results in the
third quarter of 2022. We are focusing our research and development resources on the VIITALTM readout while actively pursuing a potential
commercialization partner.
In
2021, we continued to prepare our cGMP commercial facility in Cleveland, Ohio for manufacturing EB-101 drug product to support our planned
Biologics License Application (“BLA”) filing. EB-101 study drug product for all our VIITALTM study participants has
been manufactured at our Cleveland facility and we have now completed the update to Module 3 of the Investigational New Drug
Application describing the in-house production of both retroviral vector and the final drug product. Based on feedback from the FDA, we believe that we have alignment with the FDA on the CMC requirements for EB-101, including
characterization and validation plans to support the BLA submission.
ABO-102
and ABO-101 for the treatment of Mucopolysaccharidosis (MPS) III (Sanfilippo syndrome)
Disease
Overview
MPS
III (Sanfilippo syndrome) is a group of four inherited lysosomal storage diseases, described as type A, B, C or D, which result from
enzyme deficiencies responsible for abnormal accumulation of glycosaminoglycans (“GAGs”), which are long, linear polysaccharides
also known as mucopolysaccharides, in body tissues that lead to progressive cell damage, and neurodevelopmental and physical decline.
The incidence of MPS III (all four types combined) is estimated to be 1 in 70,000 births.
Lysosomes
are intra-cellular sacs that harbor enzymes for replacing used materials and
breaking them down for disposal. Children with MPS III are missing a lysosomal enzyme that is essential in breaking down mucopolysaccharides,
specifically heparan sulfate. The partially broken down heparan sulfate remains stored in cells in the body causing progressive lysosomal
and cell damage and eventually cell death. Babies may show little sign of the disease early in life, but as neurodevelopment is impaired
and more cells become damaged, symptoms start to appear within the first few years of life.
In
MPS III, the predominant symptoms are speech/language delay, cognitive decline, behavioral abnormalities, motor dysfunction, and seizures,
eventually leading to premature death. Most patients with the rapidly progressing form of MPS III do not reach a level of cognitive function
above that of an unaffected three-year-old child. Accumulation of heparan sulfate and related cell dysfunction also affects other organs,
leading to liver enlargement and soft tissue coarsening. To date, there is no cure for MPS III and care is only supportive and palliative.
Program
Status
In
2021, we continued developing AAV-based gene therapies ABO-102 and ABO-101 for MPS IIIA and MPS IIIB (Sanfilippo syndrome Type A and
Sanfilippo syndrome Type B, respectively). These gene therapies are administered once through intravenous infusion. ABO-102 and ABO-101
deliver a functioning copy of the defective gene to cells of the central nervous system (“CNS”) and peripheral organs with
the aim of halting the deleterious effects caused by the malfunctioning enzyme and impairment of lysosomal functioning. Both viral vector
constructs rely on the neurotropism of the AAV9 serotype and its ability to cross the blood brain barrier (“BBB”) and deliver
the functional copy of the gene to the CNS.
ABO-102
for MPS IIIA
Preclinical
in vivo efficacy studies in animals with MPS IIIA showed that a single dose of ABO-102 significantly restored cell and organ function,
corrected neurological deficits, increased motor control, and increased the lifespan by more than 100% one year after treatment compared
with untreated control animals. In addition, safety studies conducted in animal models of MPS IIIA demonstrated that delivery of ABO-102
was well-tolerated with minimal side effects. ABO-102 received Fast Track and RMAT designations by the FDA, PRIME designation in the
EU, Orphan Drug designations in the U.S. and EU, and FDA Rare Pediatric Disease designation.
MPS
IIIA is caused by the absence of functional SGSH gene. In the pivotal gene transfer clinical trial of ABO-102 (scAAV9.U1a.hSGSH) for
patients with MPS IIIA (study ABT-001; NCT02716246), subjects receive a single intravenous injection of ABO-102 to facilitate systemic
delivery, including to the CNS, of a functional SGSH gene.
Subjects are evaluated at multiple time points post-treatment for safety and signals of biopotency and clinical efficacy. The results
to-date from the high dose cohort 3 showed evidence of preservation of neurocognitive development with continuous cognitive gains within
normal range of a non-afflicted child, especially for children treated with ABO-102 with DQ higher than 60 around or before 30 months
of age, as well as dose-related and sustained reduction in cerebrospinal fluid (“CSF”) levels of heparan sulfate, denoting
transgene expression in the CNS, and a durable reduction of liver volume. No treatment related serious adverse events (“SAEs”)
have been reported to date, with follow-up longer than two years post treatment in the majority of patients.
Summary
of MPS IIIA ABO-102 Phase 1/2/3 Study Data as of March 2022:
● 24 patients treated over three cohorts (including 18 patients in Cohort 3)
● Clear dose-response and sustained reduction of heparan sulfate levels in CSF
● Sustained reduction in liver volume
○ ABO-102 has been well tolerated to date
○ No deaths
○ No infusion-related adverse events
○ No serious drug-related adverse events
○ ELISpot negative for the SGSH enzyme
In 2021, we continued recruitment in a second Phase 1/2 clinical trial
with ABO-102 (study ABT-003; NCT04088734) to treat certain patients who did not qualify for participation in study ABT-001 for MPS IIIA.
A total of 5 patients were treated. The ABT-003 study was terminated in March 2022 based on a lack of improved neurocognitive ability
in older children with more advanced disease.
As
part of our portfolio prioritization in early 2022, we have intensified our pursuit of a strategic partnership to take over development
activities for ABO-102. As part of the FDA’s feedback on the Statistical Analysis Plan in January 2022, the FDA recommended that
all participants be followed to an age of at least 60 months, which would shift timing of the neurocognitive outcomes data readout to
late-2024/early-2025, as compared to our prior projection of the second quarter of 2023.
ABO-101
for MPSIIIB
Preclinical
in vivo efficacy studies in mice with MPS IIIB showed that a single dose of ABO-101 significantly restored cell and organ function,
corrected neurological deficits, increased neuromuscular control, and normalized lifespan compared with untreated control animals. In
addition, safety studies conducted in MPS IIIB mice and wildtype mice, and in non-human primates, demonstrated that systemic delivery
of ABO-101 was well tolerated with minimal side effects.
In
the ABO-101 (rAAV9.CMV.hNAGLU) program for patients with MPS IIIB, subjects in our ongoing Phase 1/2 gene transfer clinical study (study
ABT-002; NCT03315182) receive a single, intravenous infusion of ABO-101, which uses an AAV9 vector to introduce a functional NAGLU gene
to treat patients with MPS IIIB disease. Subjects are evaluated at multiple time points post-injection for safety assessments and efficacy
parameters.
In
2021, we reported updated data from the ABT-002
trial showing dose dependent increases in plasma NAGLU activity, with normalization up to 6 months in cohort 3, accompanied by dose-dependent
reductions of plasma and urinary heparan sulfate and urinary GAGs and decreased CSF levels of heparan sulfate levels sustained up to
24 months. Preliminary neurocognitive assessments, brain and liver MRI analyses demonstrate changes in the direction of improvement.
Longer follow-up with patients treated in cohorts 2 and 3 is needed to confirm preliminary cognitive and brain volumetric changes. There
was one serious drug-related adverse event of prolonged hospitalization reported in cohort 3 where the patient experienced a grade 2
episode of diarrhea and vomiting after treatment with ABO-101 and was required to stay in the hospital for two additional days for observation.
Summary
of MPS IIIB ABO-101 Phase 1/2 Study Data as of March 2022:
● 14 patients treated
○ ABO-101 has been well tolerated to date
○ No deaths
○ No infusion-related adverse events
○ ELISpot negative for the NAGLU enzyme
In 2021, we discontinued enrollment in our ABO-101 study and in March 2022, we decided to discontinue all further ABO-101 development
activities.
Next-Generation
Gene Therapy Treatments anchored in AIMTM Vector Platform
In
2016, we licensed a library of first-generation novel AAV capsids from UNC. In partnership with academic institutions, our own scientific
research teams have identified vectors within the AIMTM capsid library showing strong potential to successfully target and reach
the central nervous system as well as ocular, lung, muscle, liver, and other tissues. Based on continuing research being conducted by
Abeona and our research partners, we observed improvements in gene delivery to specific tissues compared to currently available AAV technology.
We believe AIMTM vectors also have the potential for redosing subjects who previously received certain AAV gene therapy or subjects
who have pre-existing antibodies to naturally occurring AAV serotypes.
ABO-50X
for the treatment of genetic eye disorders
Program
Overview
This
research program comprises several vectors being tested for different monogenic retinal disorders. Eighty percent of genetic eye disorders
affect the photoreceptor or RPE cells, and correction of mutations in the retina has been accomplished by several groups using AAV gene
therapy delivered through subretinal or intravitreal injection. We are exploring various routes of administration to deliver AAV to the
retina, including subretinal, intravitreal and para-retinal delivery. We believe intravitreal delivery of small volume gene therapies
is an attractive alternative to deliver gene therapy to the retina in an out-patient setting. We anticipate para-retinal injection to
be safer as compared to subretinal and may serve programs that currently require subretinal dosing.
Program
Status
ABO-50X
AAV-based vectors are currently undergoing lead candidate identification. Preclinical animal studies are ongoing in indication-specific
disease mouse models with readouts expected in the later part of 2022.
Early
preclinical findings from mouse models identified the novel AIMTM capsid AAV204 as one of three lead candidate capsids that demonstrate
robust transduction of retinal cells. The data in mice demonstrated that intravitreal administration of AAV204 resulted in broad retinal
expression that penetrated to the photoreceptor and retinal pigmented epithelium layers.
Mouse
findings were confirmed in non-human primates where we noted that intravitreal administration of AAV204, expressing green fluorescent
protein (GFP), resulted in broad transgene expression in the peripheral retina as well as intense expression in the fovea 25 days post-administration.
Para-retinal administration of AAV204, expressing GFP, also showed transduction of photoreceptor cells in the fovea as well as strong
expression in retinal ganglion cells throughout the retina.
ABO-201
for the treatment of CLN3 disease, also known as juvenile Batten disease (or Juvenile Neuronal Ceroid Lipofuscinosis) (“CLN3 Disease”)
Disease
Overview and Program Overview
CLN3
disease is a rare, fatal, autosomal recessive (inherited) disorder of the nervous system that typically begins between 4 and 8 years
of age. Often the first noticeable sign of CLN3 disease is vision impairment, which tends to progress rapidly and eventually result in
blindness. As the disease progresses, children experience loss of previously acquired skills (developmental regression). This regression
usually begins with the loss of the ability to speak in complete sentences. Children then lose motor skills, such as the ability to walk
or sit. They also develop movement abnormalities that include rigidity or stiffness, slow or diminished movements (hypokinesia), and
stooped posture. Beginning in mid-to-late-childhood, affected children may have recurrent seizures (epilepsy), heart problems, behavioral
problems, and difficulty sleeping. Normal life expectancy is greatly reduced with most people with juvenile Batten disease only living
into their twenties or thirties. As of December 31, 2021, no specific treatment is known that can halt or reverse the symptoms of CLN3
disease.
ABO-201
(scAAV9.CLN3) is an AAV-based gene therapy that has shown preclinical efficacy following delivery of a functioning copy of the CLN3 gene
in a mouse model of CLN3 disease. Preclinical studies have previously demonstrated reduced lysosomal storage and decreased astrocyte/microglia
activation in the CNS as well as improved motor function.
ABO-401
for the Treatment of Cystic Fibrosis
Disease
Overview and Program Overview
Cystic
Fibrosis (“CF”) is a progressive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator
(“CFTR”) gene. Malfunction of this gene affects cells that produce mucus, sweat and digestive fluids. In unaffected individuals,
these secreted fluids are normally thin and slippery, but in cystic fibrosis, a defective CFTR gene causes the secretions to become thick
and sticky. Instead of acting as a lubricant, the secretions plug up tubes, ducts, and passageways, especially in the lungs and pancreas,
and cause repeated lung infections and difficulty breathing, impaired pancreatic function and digestive abnormalities.
The
preclinical ABO-401 program employs the AAV204 AIMTM capsid. ABO-401 has shown the ability to deliver the CFTR transgene to
the lungs of gut-corrected delta-F508 mice. Another study also demonstrated correction of the underlying chloride current deficit in
human CF donor-derived nasal and bronchial epithelium cells treated with ABO-401. Correction of chloride channel current following ABO-401
administration occurred regardless of underlying mutations of the CFTR gene, including the most common CF mutation, delta-F508.
Establishing
Leadership Position in Commercial-Scale Cell and Gene-Therapy Manufacturing
We
have established a cGMP manufacturing facility, the Elisa Linton Center located in Cleveland, Ohio, which enables us to enhance supply
chain control, establish tighter quality control testing, increase supply capacity, reduce production costs and gain manufacturing efficiency
for clinical trials related to our product candidates and ensure commercial demand is met in the event our therapies receive marketing
approval. Our facility is led by a team of highly-skilled production, process/assay development and QC scientists with expertise in cell
and gene therapy, particularly in cell culture, upstream manufacturing, downstream purification, assay development and wet lab techniques.
We
have completed the first two phases of our 26,000+ square foot manufacturing build-out plans in Cleveland, Ohio. The first phase, completed
in 2018, was a 6,000 square foot state-of-the-art cGMP production facility for the manufacturing of cell and gene therapies. The
facility is designed to initially manufacture clinical drug products with later intent of manufacturing commercial grade cGMP drug product.
The second phase, completed in 2019, was the completion of an additional 8,000 square feet of state-of-the-art laboratory space to support
our expanding quality control, process development, and assay development teams. The second phase also included nearly 2,000 square feet
of cGMP Inventory Control space. In connection with our shift in strategic priorities in 2022, we have ceased the planned build-out
of additional AAV manufacturing space intended for ABO-102.
We
have advanced our in-house manufacturing capabilities for our autologous cell replacement therapy (EB-101) for the treatment of RDEB.
The product is manufactured as a multilayer cellular sheet containing corrected keratinocytes that is fastened to a petrolatum gauze
backing with surgical hemoclips. Gene-corrected sheets are applied over wound areas, where they are expected to produce keratinocytes
with functioning Type VII collagen, providing wound coverage and allowing for long-term wound healing. A key component to the EB-101
drug product manufacturing process is the retroviral vector which delivers the functional copy of the Collagen VII Alpha 1 cDNA to the
autologous patient cells. Initially developed at the Indiana University Vector Production Facility, we have transferred the cGMP manufacturing
process for the LZRSE-Col7A1 retroviral vector to our Cleveland, Ohio facility and have produced three cGMP lots for analytical
and clinical comparability. We have also created and characterized a cGMP master cell bank and a working cell bank to support the cGMP
production of the retroviral vector.
We
have established AAV vector manufacturing capabilities that use the triple plasmid transient transfection method. We insert, or transfect,
many copies of three DNA plasmids encoding the specific therapeutic gene sequence, or transgene, the capsid coding sequence, and helper
sequences into AAV-293 cells using a serum-free, suspension-based bioreactor vector production technology. During an incubation period
following transfection, each cell produces AAV vectors through biosynthesis using the cells’ natural machinery. At the end of the
incubation period, the newly generated AAV vectors are harvested, purified and filtered in a multi-step process. We continue to maintain
focus on cGMP compliance and ensuring adequate supply to support our future clinical activity.
We
have established and maintained strong and collaborative relationships with third-party companies specializing in the testing of cell
and gene therapy material to complement our process and assay development needs.
We
have made significant investments in developing optimized manufacturing processes and believe that our processes and methods developed
to date provide a comprehensive manufacturing process for EB-101 and AAV-based vector therapies, including:
● sufficient scale to support commercial manufacturing requirements for EB-101
● processes related to product release testing for EB-101
● AAV serum-free suspension technology that is readily scalable
We
believe that these improvements will enable us to develop best-in-class, next-generation cell and gene therapy products. As we look to
potentially commercialize EB-101, if approved, we are working towards filing a potential BLA to support commercial manufacturing of EB-101
from our Cleveland facility. Based on feedback from the FDA, we believe that we have alignment with the FDA on the CMC requirements for
EB-101, including characterization and validation plans.
Maintain
a Strong Intellectual Property Portfolio
We
strive to protect our commercially important proprietary technology, inventions, and know-how, including by seeking, maintaining, and
defending patent rights, both for inventions developed internally and for inventions licensed from third parties. We also rely on trade
secrets and know-how relating to our proprietary technology platforms, continuing technological innovation, and in-licensing opportunities
to develop, strengthen and maintain our position in the field of cell and gene therapy. We may also rely on regulatory protection
afforded through data exclusivity, market exclusivity, and patent term extensions where available.
Our
success may depend in part on our ability to obtain and maintain patent and other protections for commercially important technology,
inventions and know-how related to our business; defend and enforce our patents; preserve the confidentiality of our trade secrets; and
operate without infringing the valid enforceable patents and intellectual property rights of third parties. Our ability to stop third
parties from making, having made, using, selling, offering to sell, or importing our products may depend on the extent to which we have
rights under valid and enforceable licenses, patents or trade secrets that cover these activities. In some cases, these rights may need
to be enforced by third-party licensors. With respect to both licensed and company-owned intellectual property, we may not be granted
patents with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future,
nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful
in protecting our commercial products and methods of manufacturing the same.
We
are actively seeking U.S. and international patent protection for a variety of technologies, including the following: research tools
and methods, methods for transferring genetic material into cells, AAV-based biological products, methods of designing novel AAV constructs,
methods for treating diseases of interest and methods for manufacturing, packaging, and transporting our product candidates. We also
intend to seek patent protection or rely upon trade secret rights to protect other technologies that may be used to discover and validate
targets and that may be used to identify and develop novel biological products. We seek protection, in part, through confidentiality
and proprietary information agreements. We are a party to various license agreements that give us rights to use specific technologies
in our research and development, and future commercialization.
Licensed
Technologies and Intellectual Property
1. Mucopolysaccharidosis (“MPS”) IIIA and IIIB
We
have secured an exclusive license through Nationwide Children’s Hospital to patent applications for AAV-based treatments for patients
with MPS IIIA and IIIB, including four pending applications in the United States. United States patent(s) that may be granted from this
family would be expected to expire between approximately late 2029 and mid-2032.
2. CLN3 Disease (Juvenile Batten Disease)
We
have licensed exclusive rights to an international patent family from the University of Nebraska Medical Center and the Ohio State Innovation
Foundation, directed to AAV gene therapy for the treatment of CLN3 disease (also known as juvenile Batten disease). The licensed patent
family includes pending national stage applications in the United States, Canada, Europe, China, Japan, New Zealand, and Australia, as
well as U.S. Patent No. 10,876,134 (“the ‘134 Patent”), entitled “Gene therapy for juvenile batten disease,”
which was issued on December 29, 2020 and contains claims directed to CLN3-related vectors, methods, and formulations. The ‘134
Patent is expected to expire in approximately December 2035 absent any future grant of patent term extension.
3. Recessive Dystrophic Epidermolysis Bullosa
To
support our EB franchise, we have licensed a patent family from Stanford University covering technology for the treatment of RDEB. Patents
covering our investigational EB-101 product have been granted by the European Patent Office (EP3400287B1), in Australia (AU2017205925A),
and in Hong Kong (HK40000104), and are expected to expire in early 2037. National stage patent applications remain pending in the United
States, Canada, Israel, Japan, South Korea, China, New Zealand, Russia, Mexico, South Africa, and Brazil. United States patent(s) that
may be granted from this portfolio would be expected to expire in approximately 2037. We have also filed a United States patent application
directed to packaging and transport of the EB product, which has been published as WO2021011821A1.
4. AIMTM Capsids
We
have an exclusive license to an international patent family from UNC covering novel adeno-associated virus (“AAV”) capsids
(“AIMTM capsids”) that may potentially be used to deliver a wide variety of therapeutic transgenes to human cells to
treat genetic diseases. National stage applications directed to the AIMTM capsids have been filed in the United States, Australia,
Brazil, China, Hong Kong, Europe, Canada, Israel, India, Japan, South Korea, Mexico, New Zealand, Russia, and South Africa. The first
patent in this patent family, U.S. Patent No. 10,532,110 (the “‘110 Patent”), was issued to UNC on January 14, 2020.
The ‘110 Patent is entitled to 352 days of patent term adjustment, making its projected expiration date November 6, 2036. The second
patent in this patent family, U.S. Patent No. 10,561,743 (the “‘743 Patent”), was issued to UNC on February 18, 2020.
The ‘743 Patent is expected to expire on November 20, 2035. We have exclusive rights to both the ‘110 Patent and the ‘743
Patent under our license with UNC.
5. CLN1 Disease (Infantile Batten Disease)
We
have also licensed from UNC rights to a patent portfolio directed to optimized CLN1 genes and expression cassettes for use in treating
CLN1 disease (also known as infantile Batten disease). Patent applications are pending in the United States, Canada, Europe, Israel,
India, China, Japan, South Korea, Australia, New Zealand, Mexico, Brazil, Russia, and South Africa. United States patent(s) that may
be granted from this portfolio would be expected to expire in approximately 2037. In August 2020, we entered into an agreement exclusively
sublicensing the CLN1 patent portfolio to Taysha Gene Therapies.
6. Rett Syndrome
We
have licensed rights to patent applications from both UNC and the University of Edinburgh relating to gene therapy for the treatment
of Rett Syndrome. The patent applications licensed from UNC at Chapel Hill are directed to viral genomes designed to regulate expression
of the MeCP2 gene, which is mutated in patients with Rett Syndrome. The patent applications licensed from the University of Edinburgh
are directed to expression cassettes for MeCP2 polypeptides and to synthetic MeCP2 polypeptides. National stage applications for the
patent application directed to MeCP2 expression cassettes are now pending in the United States, Canada, Brazil, China, Japan, Australia,
Europe, India, South Korea, and Russia, and national stage applications for the international application directed to synthetic polypeptides
are currently pending in the United States, Canada, Brazil, China, and Japan. In October 2020, we entered into an agreement exclusively
sublicensing these UNC and University of Edinburgh patent rights to Taysha Gene Therapies. United States patents that may be granted
based on the UNC patent applications or the University of Edinburgh patent applications would be expected to expire in approximately
2039.
We
will explore in due course strategies to support patent term extensions for all of our licensed portfolios.
U.S.
Biologic Products Development Process
In
the United States, the FDA regulates biologic products including gene therapy products under the Federal Food, Drug, and Cosmetic Act
(“FDCA”), the Public Health Service Act (“PHSA”), and regulations implementing these laws. The FDCA, PHSA and
their corresponding regulations govern, among other things, the testing, manufacturing, safety, efficacy, labeling, packaging, storage,
record keeping, distribution, advertising, and promotion of biologic products. Applications to the FDA are required before conducting
human clinical testing of biologic products. FDA approval also must be obtained before marketing of biologic products. Gene therapy studies
may also need to comply with the National Institutes of Health (“NIH”) Guidelines for Research Involving Recombinant or Synthetic
Nucleic Acid Molecules (“NIH Guidelines”), which includes additional requirements, such as the review and approval of the
study by an Institutional Biosafety Committee.