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Item 1. Business

2025-03-20 compared with 2024-03-18 · 446 added, 434 removed, 875 unchanged (50% of the section changed)

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or the “Company”), is a clinical-stage biopharmaceutical company developing cell and gene therapies for life-threatening

Our lead clinical program is for prademagene zamikeracel (“pz-cel”), our investigational autologous, COL7A1 gene-corrected

epidermal sheets currently in development for recessive dystrophic epidermolysis bullosa (“RDEB”).

Pz-cel has been granted

Orphan Drug and Rare Pediatric Disease (“RPD”) designations by the U.S.

Food and Drug Administration (“FDA”)

and Orphan Drug Designation by the European Medicines Agency (“EMA”).

Our lead clinical program is for prademagene zamikeracel (“pz-cel”), an autologous, cell-based gene therapy currently

in development for recessive dystrophic epidermolysis bullosa (“RDEB”).

Pz-cel has been granted Orphan Drug and Rare Pediatric

Disease (“RPD”) designations by the U.S.

Food and Drug Administration (“FDA”) and Orphan Drug Designation by

the European Medicines Agency (“EMA”).

plan to continue development of adeno-associated virus (“AAV”) based gene therapies designed to treat ophthalmic diseases

with high unmet medical need using the novel AIM™ capsid platform that we have exclusively licensed from the University of North

Carolina at Chapel Hill (“UNC”), and internal AAV vector research programs.

Abeona’s novel, next-generation AAV capsids

are being evaluated to improve tropism profiles for a variety of devastating diseases.

with high unmet need using the novel AIM™ capsids exclusively licensed from the University of North Carolina at Chapel Hill (“UNC”)

and developed internally through our AAV vector research programs.

Abeona’s novel, next-generation AAV capsids are being evaluated

to improve tropism profiles for a variety of devastating diseases.

Mission and Strategy

is a fully-integrated cell and gene therapy company featuring research and clinical development programs, in-house manufacturing facilities,

and scientific and clinical leadership.

Our mission is to create, develop, manufacture, and deliver cell and gene therapies to transform

the lives of people impacted by life-threatening diseases.

In 2023, we continued to make progress toward fulfilling our goal of harnessing

the promise of genetic medicine and redefining the standard of care through cell and gene therapies.

In September 2023, we submitted

a Biologics License Application (“BLA”) for pz-cel to the FDA.

In November 2023, the FDA accepted and granted priority review

for our BLA for pz-cel.

Under the Prescription Drug User Fee Act (“PDUFA”), the FDA has set a target action date of May 25,

is a clinical-stage biopharmaceutical company developing cell and gene therapies for life-threatening diseases.

Our lead clinical

program is pz-cel, autologous, COL7A1 gene-corrected epidermal sheets, an investigational product currently in development for RDEB.

In November 2022, we announced positive top-line data from the VIITAL™ study evaluating the efficacy, safety and tolerability

The VIITAL™ study met both its co-primary efficacy endpoints demonstrating statistically significant,

clinically meaningful improvements in wound healing and pain reduction in large chronic RDEB wounds.

In September 2023, we

submitted a Biologics License Application (“BLA”) for pz-cel to the FDA.

In November 2023, the FDA accepted and granted

priority review for our BLA for pz-cel, and subsequently, under the Prescription Drug User Fee Act (“PDUFA”), the FDA

set a target action date of May 25, 2024.

In April 2024, the FDA issued a Complete Response Letter (“CRL”) in response

The CRL noted that certain additional information needed to satisfy the Chemistry Manufacturing and Controls

(“CMC”) requirements of the pz-cel BLA must be satisfactorily resolved before the application can be approved.

did not identify any deficiencies related to the clinical efficacy or clinical safety data in the BLA, and the FDA did not request

any new clinical trials or clinical data to support the approval of pz-cel.

In August 2024, we completed a Type A Meeting with

the FDA to discuss the forthcoming resubmission of our BLA and in October 2024, we resubmitted our BLA.

The FDA notified the

Company in November 2024 that the BLA was accepted for review, with an assigned PDUFA target action date of April 29,

partner with leading academic researchers, patient advocacy organizations, caregivers and other biotechnology companies to develop therapies

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Novel In-Vivo Gene Therapies Using AIM™ Capsid Technology.

are researching and developing AAV-based gene therapy using our novel capsids developed from the AIM™ Capsid Technology Platform

and additional Company-invented AAV capsids.

We plan to continue to develop our chimeric AAV capsids capable of improved tissue targeting

for various indications and potentially evading immunity to wild-type AAV vectors.

are researching and developing AAV-based gene therapies using novel AAV capsids both derived from the licensed AIM™ Capsid Technology

Platform and invented by the Company.

We plan to continue to develop chimeric AAV capsids capable of improved tissue targeting for various

indications and that can potentially evade immunity to wild-type AAV vectors.

our Leadership Position in Commercial-Scale Cell and Gene Therapy Manufacturing.

established current Good Manufacturing Practice (“cGMP”), clinical-scale manufacturing capabilities for engineered cell therapy

established current Good Manufacturing Practice (“cGMP”), clinical-scale manufacturing capabilities for engineered cell therapies

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

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.

We believe that our manufacturing 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 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.

Additional Cell and Gene Therapy Franchises and Adjacencies through In-Licensing and Strategic Partnerships.

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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

all features of our clinical products including compositions of matter and methods of manufacture, administration, and delivery.

to continue to expand our intellectual property portfolio by aggressively seeking patent rights for promising aspects of our product

engine and product candidates.

Next-Generation Cell and Gene Therapy

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and epidermal layers to one another.

a result of the genetic defect, 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), corneal

abrasions, 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.

a result of the genetic defect, 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), corneal abrasions, 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.

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.;

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,

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 pz-cel.

patients have an active disease with the majority of the wounds typically > 20 cm 2 (Stanford University;

Solis, D., et

In 2020, a survey of RDEB patients reported that approximately 60% have active wounds covering greater than 30% of their

bodies (Bruckner et al.;

Using genetic modeling of COL7A1 variants, 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 pz-cel.

Based on claims analysis, we estimate that approximately 750 moderate to severe RDEB patients in the U.S.

pz-cel eligible patients at the time of a potential pz-cel launch (Clearview Claims Analysis, 2024).

patients have active disease, with the majority of their wounds typically greater than 20 cm 2 in size (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.;

Wounds covering up to approximately 80% of body surface

area have been recorded in some EB patients (Hirsch et al.;

Nature Research, 2017).

our VIITAL TM phase 3 and phase 1/2a clinical trials, pz-cel was applied as a one-time surgical procedure onto RDEB wounds

and has shown up to 8 years of durable wound healing and associated pain reduction even in the toughest-to-treat in RDEB wounds.

evaluated in the VIITAL TM phase 3 trial had large wounds (> 20cm 2 ) and, on average, had wounds remained open

for 6.2 years, and in some cases up to 21 years, prior to pz-cel treatment.

Most RDEB patients have large and chronic wounds that carry

the highest burden, including the need for frequent dressing changes, pain, pruritus, risk of infection, and developing skin cancer.

and has shown up to 8 years of durable wound healing and associated pain reduction even in the tough large, chronic RDEB wounds.

Patients evaluated in the VIITAL TM phase 3 trial had large wounds (> 20cm 2 ) and, on average, had wounds

that remained open for 6.2 years, and in some cases up to 21 years, prior to pz-cel treatment.

Most RDEB patients have large and

chronic wounds that carry the highest burden, including the need for frequent lengthy dressing changes, pain, pruritus (itch), risk of

infection, and developing skin cancer.

Management of RDEB

of care in RDEB wound management currently consists of time and labor-intensive 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.

In a cost analysis conducted by Debra of America, based on 3,274 patient’s health insurance

claims from private insurance the annual cost of dystrophic epidermolysis bullosa (DEB) was identified to be 465% greater than the

annual cost to the healthcare system from all people.

The cost of wound care supplies could be as high as

$996,000 per year.

of care in RDEB wound management currently consists of lengthy and labor-intensive 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 non-adherent material, covered with padding for stability and protection, and secured with an elastic

wrap for integrity.

In a cost analysis conducted by Debra of America, based on 3,274 patient health insurance claims from private

insurance, the annual cost of care for dystrophic epidermolysis bullosa (DEB) was found to be 465% greater than the annual cost to the

healthcare system from all people.

The cost of wound care supplies could be as high as $996,000 per year.

patients also have periodic surgeries to relieve disease related issues such as narrowing of their esophagus, fusing of fingers, and

corneal abrasions.

2023, Vyjuvek ® and Filsuvez ® were approved by the FDA for treatment of wounds associated with DEB and

wounds associated with Junctional (JEB) and DEB, respectively.

The introduction of these drugs may further increase the total cost of care.

is our investigational autologous epidermal sheets in which a functioning COL7A1 gene is inserted into a patient’s own skin cells

(keratinocytes) using a retrovirus.

The keratinocytes are then grown into credit card sized sheets and surgically applied to the patient to restore Type VII collagen expression

and skin function.

2023, Vyjuvek ® and Filsuvez ® were approved by the FDA for treatment of wounds associated with DEB and wounds

associated with Junctional (JEB) and DEB, respectively.

RDEB patients continue to seek durable treatments for addressing their

wounds in the current treatment landscape.

is an investigational product comprised of autologous epidermal sheets in which a functioning COL7A1 gene is inserted into a patient’s

own skin cells (keratinocytes) using a retrovirus.

The keratinocytes are then grown into credit card-sized sheets and surgically applied

to the patient to restore Type VII collagen expression and skin function.

from a completed Phase 1/2a study that enrolled seven patients with large and chronic RDEB wounds at Stanford University showed that

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November 2022, we announced positive topline data from our VIITAL™ study.

The pivotal phase 3 VIITAL™ study evaluated the

efficacy, safety, and tolerability of pz-cel in 43 large chronic wound pairs in 11 subjects with RDEB.

The large chronic wounds randomized

and treated in VIITAL™ measured greater than 20 cm 2 of surface area and had remained open for a minimum of six months

and a maximum of 21 years (mean 6.2 years).

The co-primary endpoints of the study were:

(1) the proportion of RDEB wound sites with greater

than or equal to 50% healing from baseline, comparing randomized treated with matched untreated (control) wound sites at the six-month

timepoint, as determined by direct investigator assessment;

and (2) pain reduction associated with wound dressing change assessed by

the mean differences in scores of the Wong-Baker FACES ® Pain Rating Scale between randomized treated and matched untreated

(control) wounds at the six-month timepoint.

VIITAL™ study met its two co-primary efficacy endpoints demonstrating statistically significant, clinically meaningful improvements

in wound healing and pain reduction in large chronic RDEB wounds.

Pz-cel was shown to be well-tolerated with no serious treatment-related

adverse events observed, consistent with past clinical experience.

There were no deaths or instances of positive replication-competent

retrovirus results, and no systemic immunologic responses were reported during the study, as well as no squamous cell carcinoma at treatment

sites after application of pz-cel.

Two subjects reported at least one serious adverse event unrelated to pz-cel.

Four subjects reported

related treatment emergent adverse events, including procedural pain, muscle spasms and pruritis.

Infections unrelated to pz-cel were

observed in eight patients.

The pivotal phase 3 VIITAL™ study evaluated

the efficacy, safety, and tolerability of pz-cel in 43 large chronic wound pairs in 11 subjects with RDEB.

The large chronic wounds

randomized and treated in VIITAL™ measured greater than 20 cm 2 of surface area and had remained open for a minimum

of six months and a maximum of 21 years (mean 6.2 years).

The co-primary endpoints of the study were assessed at the six-month timepoint for:

(1) the proportion of RDEB

wound sites with greater than or equal to 50% healing from baseline, comparing randomized treated with matched untreated (control)

wound sites, as determined by direct investigator assessment;

and (2) pain reduction associated with

wound dressing change assessed by the mean differences in scores of the Wong-Baker FACES ® Pain Rating Scale between

randomized treated and matched untreated (control) wounds.

VIITAL™ study met both co-primary efficacy endpoints demonstrating statistically significant, clinically meaningful

improvements in wound healing and pain reduction in large chronic RDEB wounds.

Pz-cel was shown to be well-tolerated with no serious

treatment-related adverse events observed, consistent with past clinical experience.

There were no deaths or instances of positive

replication-competent retrovirus results, and no systemic immunologic responses were reported during the study, as well as no

squamous cell carcinoma at treatment sites after application of pz-cel.

Two subjects reported at least one serious adverse event

unrelated to pz-cel.

Four subjects reported related treatment emergent adverse events, including procedural pain, muscle spasms and

Infections unrelated to pz-cel were observed in eight patients.

September 2023, we submitted a BLA for pz-cel to the FDA.

In November 2023, the FDA accepted for filing and granted priority review

for our BLA for pz-cel.

Under the PDUFA, the FDA has set a target action date of May 25, 2024.

Pz-cel has been granted Regenerative

Medicine Advanced Therapy (“RMAT”), Breakthrough Therapy, Orphan Drug and RPD designations by the by the FDA as well as

Orphan Drug designation by the EMA.

In November 2023, the FDA accepted and granted priority review for our BLA

for pz-cel, and subsequently, under the Prescription Drug User Fee Act (“PDUFA”), the FDA set a target action date of May

In April 2024, the FDA issued a Complete Response Letter (“CRL”) in response to the BLA.

The CRL noted that certain

additional information needed to satisfy the Chemistry Manufacturing and Controls (“CMC”) requirements of the pz-cel BLA

must be satisfactorily resolved before the application can be approved.

The CRL did not identify any deficiencies related to the clinical

efficacy or clinical safety data in the BLA, and the FDA did not request any new clinical trials or clinical data to support the approval

In August 2024, we completed a Type A Meeting with the FDA to discuss our forthcoming resubmission of our BLA and in October 2024, we resubmitted our BLA.

The FDA notified the Company in November 2024 that the BLA was accepted for review, with an assigned

PDUFA target action date of April 29, 2025.

Pz-cel has been granted Regenerative Medicine Advanced Therapy (“RMAT”), Breakthrough

Therapy, Orphan Drug and RPD designations by the by the FDA as well as Orphan Drug designation by the EMA.

the potential benefits of Orphan Drug designation are a potential seven years of market exclusivity following FDA approval, potentially

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an approval for a BLA with RPD designation may qualify for a Priority Review Voucher (“PRV”), subject to final determination

A PRV may be used to receive expedited review of a subsequent marketing application for a different product or sold to another

have continued to prepare our cGMP commercial facility in Cleveland for manufacturing pz-cel to support our planned BLA filing.

study drug product for all our VIITAL™ study participants has been manufactured at our Cleveland facility.

A PRV may be used to receive an expedited review of a subsequent marketing application for a different product or sold to another

have continued to prepare our current Good Manufacturing Practices (“cGMP”) facility in Cleveland, Ohio for

manufacturing commercial grade pz-cel drug product to support our planned commercial launch of pz-cel, if approved.

drug product for all our VIITAL™ study participants has been manufactured at our Cleveland facility.

As part of our commercial

planning, we continue to engage with stakeholders across the healthcare system, including private payors that cover the majority of

RDEB lives, and healthcare providers to better understand market access and potential pricing for pz-cel.

We are also in discussions

with 5 to 7 epidermolysis bullosa centers of excellence to onboard them as pz-cel Qualified Treatment Centers (“QTC”)

following potential FDA approval.

for the treatment of X-linked Retinoschisis (“XLRS”)

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to the retina in a mouse model of XLRS.

Preclinical studies have demonstrated robust RS1 expression in the retina, improved cone photoreceptor

density and overall photoreceptor cell survival, as well as a restoration of outer retina architecture.

Results of these studies were

presented at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting in May 2023.

A pre-IND meeting for ABO-503 was conducted

with the FDA in April 2023 and provided Abeona with comprehensive feedback to support a future IND submission.

Preclinical studies have demonstrated robust RS1 expression in the retina, improved cone

photoreceptor density and overall photoreceptor cell survival, as well as a restoration of outer retina architecture.

these studies were presented at the American Society of Gene and Cell Therapy (“ASGCT”) Annual Meeting in May 2023.

pre-IND meeting for ABO-503 was conducted with the FDA in April 2023 and provided Abeona with comprehensive feedback to support a

future IND submission.

IND-enabling efficacy and toxicology animal studies are scheduled to be completed by the end of 2025.

Additionally,

cGMP manufacturing of clinical grade material has been initiated at a third-party vendor in anticipation of first in human trials being

initiated in 2026.

for the Treatment of Stargardt Disease

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There are currently no FDA approved treatments available, and to date, development of investigational gene modifying therapies has remained

challenging in part due to the large size of the ABCA4 gene, which exceeds the encapsidation capacity of a single AAV vector.

challenging in part due to the large size of the ABCA4 gene, which exceeds the encapsidation capacity of a single AAV capsid.

internal research and development team developed ABO-504, which is designed to efficiently reconstitute the full-length ABCA4 gene by

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In partnership

with academic institutions, our own scientific research teams have identified vectors within the AIM™ capsid library showing strong

potential to successfully target and reach the central nervous system as well as ocular, lung, muscle, liver, and other tissues.

on continuing research by Abeona and our research partners, we have observed improvements in gene delivery to specific tissues compared

to currently available AAV technology.

We believe AIM™ 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.

with academic institutions, our own scientific research teams have identified capsids within the AIM™ capsid library showing strong

potential to successfully target and reach the central nervous system (including the retina) as well, lung, muscle, liver, and other

Based on continuing research by Abeona and our research partners, we have observed improvements in gene delivery to specific

tissues compared to currently available AAV technology.

We believe AIM™ 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.

In July 2024, we entered into a non-exclusive agreement

with Beacon Therapeutics (“Beacon”) under which Beacon will evaluate Abeona’s patented AAV204 capsid for the development

and commercialization of potential gene therapies for select ophthalmology indications.

Following a 12-month evaluation period, Beacon

will have the option to take a worldwide, non-exclusive license to use AAV204 in connection with up to five gene or disease targets.

will also have the right to use AAV204 for up to four additional nominated gene or disease targets subject to certain conditions.

receive an upfront payment upon Beacon’s exercise of its option to license AAV204, with additional payments upon the achievement

of certain development, regulatory, and sales milestones, along with tiered royalties on worldwide net sales for licensed products incorporating

Licensing Agreements

have out-licensed certain clinical and research programs, including for the treatment of Sanfilippo syndrome type A (MPS IIIA) to Ultragenyx

Pharmaceutical Inc.

(“Ultragenyx”), and for CLN1 disease (infantile Batten disease) and Rett syndrome to Taysha Gene Therapies,

Under the terms of our agreement with Ultragenyx, we are eligible to receive payments based on the achievement

of certain sales milestones and royalties on net sales.

Under our agreements with Taysha, we are eligible to receive payments based on

certain clinical, regulatory, and sales milestones and royalties on net sales.

have out-licensed certain clinical and research programs, including for the treatment of Sanfilippo syndrome type A (MPS IIIA) to

Ultragenyx Pharmaceutical Inc.

(“Ultragenyx”), and for CLN1 disease (infantile Batten disease) and Rett syndrome to

Taysha Gene Therapies, Inc.

Under the terms of our agreement with Ultragenyx, we are eligible to receive

payments based on the achievement of certain sales milestones and royalties on net sales.

On February 18, 2025, Ultragenyx reported

that its BLA for its MPS IIIA product, UX111 (ABO-102), had been accepted for review by the FDA, with a PDUFA date of August 18, 2025.

our agreements with Taysha, we are eligible to receive payments based on certain clinical, regulatory, and sales milestones and

royalties on net sales.

Leadership Position in Commercial-Scale Cell and Gene-Therapy Manufacturing

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

Our facility is led by a team of highly skilled production, process/assay development and quality control scientists with expertise

in cell and gene therapy, particularly in cell culture, upstream manufacturing, downstream purification, assay development and wet lab

have completed our 16,000+ square foot manufacturing build-out 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 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.

have established a cGMP manufacturing facility, the Elisa Linton Center located in Cleveland, Ohio at 6555 Carnegie Avenue, 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 quality

control scientists with expertise in cell and gene therapy, particularly in cell culture, upstream manufacturing, downstream purification,

assay development and wet lab techniques.

have over 16,000+ square foot manufacturing space 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 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.

October 18, 2024, we signed a lease for 16,566 square feet of office space at 6700 Euclid Avenue, Cleveland, Ohio.

The lease commenced

on January 1, 2025 and the lease term matches the term for our existing 6555 Carnegie Avenue facility.

The additional space at the 6700

Euclid Avenue facility will allow us to convert office space at the 6555 Carnegie Avenue facility into additional manufacturing space

to increase pz-cel manufacturing capacity.

have advanced our in-house manufacturing capabilities for pz-cel.

The product is manufactured as a multilayer cellular sheet containing

corrected keratinocytes that is fastened to a petrolatum gauze backing with surgical titanium ligating clips.

Engineered sheets are applied

over wound areas, where they provide keratinocytes with functional Type VII collagen, providing immediate wound coverage and allowing

for long-term wound healing.

A key component to the pz-cel 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 facility

and have demonstrated analytical comparability between IUVPF and Abeona-produced retroviral vector.

In order to support licensure, we

have produced three cGMP process validation lots and have also created and characterized a cGMP master cell bank and a working cell bank

to support the cGMP production of the retroviral vector.

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, filtered, and purified in a multi-step process.

The product is manufactured as multilayer cellular sheets containing

gene-corrected keratinocytes that is fastened to a petrolatum gauze backing with surgical titanium ligating clips.

Engineered keratinocyte

sheets expressing functional Type VII collagen are applied over wound areas, providing immediate wound coverage and allowing for long-term

wound healing.

A key component to the pz-cel drug product manufacturing process is the retroviral vector, which delivers the functional

copy of the Collagen VII Alpha 1 cDNA to the patient’s own cells.

We manufacture the LZRSE-Col7A1 retroviral vector at our Cleveland

AAV vector manufacturing process uses the triple plasmid transient transfection method.

We insert (“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, filtered, and purified in a multi-step process.

have established and maintained strong and collaborative relationships with third-party companies specializing in the testing of cell

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to date provide a comprehensive manufacturing process for pz-cel and AAV-based vector therapies, including:

sufficient scale to support

commercial manufacturing requirements for pz-cel

processes related to biopsy,

cell collection, storage and transportation as part of manufacturing for pz-cel

processes related to product

release testing for pz-cel

processes related to the

manufacture and release testing of retroviral vector

establishing transportation

and packaging processes and materials for finished pz-cel product

proprietary AAV vector

manufacturing processes and techniques that produce a highly purified product candidate

AAV serum-free suspension

technology that is readily scalable

multiple assays to accurately

characterize our process and the AAV vectors we produce

a series of purification

processes, which may be adapted and customized for multiple different AAV capsids, with a goal of higher concentrations of active

vectors, and that are essentially free of empty capsids.

believe that these improvements will enable us to develop best-in-class, next-generation cell and gene therapy products.

scale to support commercial manufacturing requirements for pz-cel

related to biopsy, cell collection, storage and transportation as part of manufacturing for pz-cel

related to product release testing for pz-cel

related to the manufacture and release testing of retroviral vector

transportation and packaging processes and materials for finished pz-cel product

AAV vector manufacturing processes and techniques that produce a highly purified product candidate

serum-free suspension technology that is readily scalable

assays to accurately characterize our process and the AAV vectors we produce

series of purification processes, which may be adapted and customized for multiple different AAV capsids, with a goal of higher concentrations

of active vectors, and that are essentially free of empty capsids.

believe that these investments will enable us to develop best-in-class, next-generation cell and gene therapy products.

As we look to

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and international patent protection, together with our licensors, for a variety of technologies, including

AAV capsids, AAV-based biological products, methods of designing novel AAV constructs, methods for treating diseases of interest, including

RDEB, 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.

AAV capsids, AAV-based biological products, methods of designing novel AAV constructs, compositions and methods for treating diseases

of interest, including RDEB, 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.

Technologies and Intellectual Property

Recessive Dystrophic

Epidermolysis Bullosa

support our EB franchise, we have licensed a patent family from Stanford University covering pz-cel and its use in the treatment of RDEB.

Patents covering our investigational pz-cel product have been granted by the European Patent Office (EP3400287B1) and in other geographical

regions, and are expected to expire in early 2037.

Patent applications remain pending in the United States which, if granted, would be

expected to expire in 2037.

We have also filed United States and Canadian patent applications directed to the packaging and transport

of pz-cel, which, if granted, are not expected to expire before 2040.

Dystrophic Epidermolysis Bullosa

support our EB franchise, we licensed a patent family from Stanford University covering pz-cel and its use in the treatment of RDEB.

Patents covering our investigational pz-cel product have been granted in the United States (U.S.

12,110,504 and 12,173,314),

by the European Patent Office (EP3400287B1) and in other geographical regions and are expected to expire in early 2037.

Patent applications

remain pending in the United States which, if granted, would be expected to expire in 2037.

A patent covering the packaging and transport

system for pz-cel has been granted in the United States (U.S.

12,144,340) and is expected to expire in mid-2040.

may also rely on the additional protection afforded by data exclusivity (currently 12 years for biologics like pz-cel), other market

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and other geographical regions.

Patents issuing from these applications are not expected to expire before 2039.

CLN1 Disease (Infantile

Batten Disease)

Patents issuing from these applications would not be expected to expire before 2039.

Disease (Infantile Batten Disease)

have also licensed from UNC rights to two patent families directed to treating CLN1 disease (also known as infantile Batten disease).

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The second patent family is directed to treating CLN1 disease

using a combination of intrathecal and intravenous administrations, which has applications pending in the United States, Europe and other

using a combination of intrathecal and intravenous administrations, and has applications pending in the United States, Europe and other

geographical regions.

Patents issuing from applications in the second patent family will have a 20-year expiration date of no earlier

Patents issuing from applications in the second patent family would have a 20-year expiration date of no earlier

We have entered into agreements exclusively sublicensing these two CLN1 patent families to Taysha Gene Therapies, Inc.

Rett Syndrome

have licensed rights to one patent family from UNC and two patent families from The University Court of the University of Edinburgh (“U.

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of Rett Syndrome.

The patent family licensed from UNC at Chapel Hill are directed to viral genomes designed to regulate expression of

The patent family licensed from UNC at Chapel Hill is directed to viral genomes designed to regulate expression of

the MeCP2 gene, which is mutated in patients with Rett Syndrome.

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and other geographical regions.

Patents issuing from these applications will have a 20-year expiration date of no earlier than 2039.

Patents issuing from these applications would have a 20-year expiration date of no earlier than 2039.

The patent families licensed from U.

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and other geographical regions.

Patents issuing from applications in the Edinburgh patent families will have a 20-year expiration date

Patents issuing from applications in the Edinburgh patent families would have a 20-year expiration date

of no earlier than 2038.

In October 2020, we entered into an agreement exclusively sublicensing these UNC and University of Edinburgh

patent rights to Taysha Gene Therapies.

Multipartite AAV

Delivery of Large Transgenes

patent rights to Taysha Gene Therapies, Inc.

AAV Delivery of Large Transgenes

own a patent family directed to multipartite delivery of large transgenes using AAV vectors and have filed national stage applications

in the United States, Europe and other geographical regions.

Patents issuing from these applications are not expected to expire before

Patents issuing from these applications would not be expected to expire

also own a pending U.S.

provisional application directed to multipartite AAV delivery and its use for treating Stargardt disease.

New AAV Capsids and

Ophthalmic Disease Treatment via Para-retinal AAV Administration

application (U.S.

2022/0090129 A1) directed to multipartite AAV delivery and its use for treating

Stargardt disease.

AAV Capsids and Ophthalmic Disease Treatment via Para-retinal AAV Administration

own a patent family directed to (i) novel AAV capsid proteins and (ii) treating ophthalmic diseases via para-retinal administration of

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Patents issuing

from these applications are not expected to expire before 2042.

Treatment of Dominant

Optic Atrophy and X-linked Retinoschisis

from these applications would not be expected to expire before 2042.

of Dominant Optic Atrophy and X-linked Retinoschisis

own a pending PCT application (PCT/US2023/065877) directed to compositions and methods for treating dominant optic atrophy and X-linked

retinoschisis.

Patents issuing from future national stage applications of this PCT application are not expected to expire before 2043.

Patents issuing from future national stage applications of this PCT application would not be expected to expire before

expect to explore in due course strategies to support patent term extensions for all of our patent portfolios.

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process required by the FDA before a biologic product candidate may be marketed in the United States generally involves the following:

completion of preclinical

laboratory tests and in vivo studies in accordance with the FDA’s current Good Laboratory Practice (“GLP”) regulations

and applicable requirements for the humane use of laboratory animals or other applicable regulations;

submission to the FDA of

an application for an IND, which allows human clinical trials to begin unless the FDA objects within 30 days;

approval by an independent

institutional review board (“IRB”), reviewing each clinical site before each clinical trial may be initiated;

performance of adequate

and well-controlled human clinical trials according to the FDA’s Good Clinical Practice (“GCP”) regulations, and

any additional requirements for the protection of human research subjects and their health information, to establish the safety and

efficacy of the proposed biologic product candidate for its intended use;

development of manufacturing

processes to ensure the product candidate’s identity, strength, quality, purity, and potency;

preparation and submission

to the FDA of a BLA for marketing approval that includes substantial evidence of safety, purity and potency from results of nonclinical

testing and clinical trials;

satisfactory completion

of an FDA pre-approval inspection of the manufacturing facility or facilities where the biologic product candidate is produced to

assess compliance with cGMP and to assure that the facilities, methods and controls are adequate to preserve the biologic product

candidate’s identity, safety, strength, quality, potency and purity;

potential FDA audit of

the nonclinical and clinical trial sites that generated the data in support of the BLA;

payment of user fees and

the FDA review and approval, or licensure, of the BLA.

BLA application fees for products designated as orphan drugs by the FDA are

of preclinical laboratory tests and in vivo studies in accordance with the FDA’s current Good Laboratory Practice (“GLP”)

regulations and applicable requirements for the humane use of laboratory animals or other applicable regulations;

to the FDA of an application for an IND, which allows human clinical trials to begin unless the FDA objects within 30 days;

by an independent institutional review board (“IRB”), reviewing each clinical site before each clinical trial may be

of adequate and well-controlled human clinical trials according to the FDA’s Good Clinical Practice (“GCP”) regulations,

and any additional requirements for the protection of human research subjects and their health information, to establish the safety

and efficacy of the proposed biologic product candidate for its intended use;

of manufacturing processes to ensure the product candidate’s identity, strength, quality, purity, and potency;

and submission to the FDA of a BLA for marketing approval that includes substantial evidence of safety, purity and potency from results

of nonclinical testing and clinical trials;

completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the biologic product candidate is

produced to assess compliance with cGMP and to assure that the facilities, methods and controls are adequate to preserve the biologic

product candidate’s identity, safety, strength, quality, potency and purity;

FDA audit of the nonclinical and clinical trial sites that generated the data in support of the BLA;

of user fees and the FDA review and approval, or licensure, of the BLA.

BLA application fees for products designated as orphan drugs

by the FDA are waived.

testing any biologic product candidate on humans, including a gene therapy product candidate, the product candidate must undergo preclinical

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clinical trials typically are conducted in three sequential phases that may overlap or be combined:

The biologic product

candidate initially is introduced into healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution,

excretion and, if possible, to gain an early understanding of its effectiveness.

In the case of some product candidates for severe

or life-threatening diseases, especially when the product candidate may be too inherently toxic to ethically administer to healthy

volunteers, the initial human testing is often conducted in patients.

The biologic product

candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate

the efficacy of the product candidate for specific targeted diseases and to determine dosage tolerance, optimal dosage and dosing

The biologic product

candidate is administered to an expanded patient population at geographically dispersed clinical trial sites in adequate and well-controlled

clinical trials to generate sufficient data to statistically confirm the efficacy and safety of the product for approval.

These clinical

trials are intended to establish the overall risk/benefit ratio of the product candidate and provide an adequate basis for product

The biologic product candidate initially is introduced into healthy human subjects and tested for safety, dosage tolerance, absorption,

metabolism, distribution, excretion and, if possible, to gain an early understanding of its effectiveness.

In the case of some product

candidates for severe or life-threatening diseases, especially when the product candidate may be too inherently toxic to ethically

administer to healthy volunteers, the initial human testing is often conducted in patients.

The biologic product candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks,

to preliminarily evaluate the efficacy of the product candidate for specific targeted diseases and to determine dosage tolerance,

optimal dosage and dosing schedule.

The biologic product candidate is administered to an expanded patient population at geographically dispersed clinical trial sites

in adequate and well-controlled clinical trials to generate sufficient data to statistically confirm the efficacy and safety of the

product for approval.

These clinical trials are intended to establish the overall risk/benefit ratio of the product candidate and

provide an adequate basis for product labeling.

Typically, two phase 3 trials are required by the FDA for product approval.

Under some limited circumstances, however,

the FDA may approve a BLA based upon a single phase 3 clinical study plus confirmatory evidence or a single large multicenter trial

without confirmatory evidence.

some limited circumstances, however, the FDA may approve a BLA based upon a single phase 3 clinical study plus confirmatory evidence

or a single large multicenter trial without confirmatory evidence.

kinds of data may also help to support a BLA, such as patient experience data.

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labeling, among other things, are submitted to the FDA as part of a BLA requesting approval to market the product for one or more indications.

gene therapies, selecting patients with applicable genetic defects is a necessary condition to effective treatment.

gene therapies, selecting patients with applicable genetic defects is a necessary condition for effective treatment.

For the therapies

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specific prescribing information for specific indications.

A complete response letter (“CRL”) generally outlines the deficiencies

in the submission and may require substantial additional testing or information for the FDA to reconsider the application.

issued, the applicant may either:

A CRL generally outlines the deficiencies in the submission and may require

substantial additional testing or information for the FDA to reconsider the application.

If a CRL is issued, the applicant may either:

resubmit the marketing application, addressing all of the deficiencies identified in the letter;

the application;

or request an opportunity for a hearing.

If those deficiencies have been addressed to the FDA’s satisfaction in

a resubmission of the BLA, the FDA will issue an approval letter.

withdraw the application;

an opportunity for a hearing.

If those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the BLA,

the FDA will issue an approval letter.

a product candidate receives regulatory approval, the approval may be significantly limited to specific diseases, patient populations,

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to expedite development and review, such as breakthrough therapy designation, priority review and accelerated approval.

Breakthrough therapy

To qualify for the breakthrough therapy program, product candidates must be intended to treat a serious or life-threatening

disease or condition and preliminary clinical evidence must indicate that such product candidates may demonstrate substantial improvement

on one or more clinically significant endpoints over existing therapies.

The FDA will seek to ensure the sponsor of a breakthrough

therapy product candidate receives the following:

therapy designation:

To qualify for the breakthrough therapy program, product candidates must be intended to treat a serious

or life-threatening disease or condition, and preliminary clinical evidence must indicate that such product candidates may demonstrate

substantial improvement on one or more clinically significant endpoints over existing therapies.

The FDA will seek to ensure the

sponsor of a breakthrough therapy product candidate receives the following:

intensive guidance on an efficient drug development program;

intensive involvement

of senior managers and experienced staff on a proactive, collaborative, and cross-disciplinary review;

and rolling review.

Priority review:

A product candidate is eligible for priority review if it treats a serious condition and, if approved, it would be a significant

improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious condition compared to marketed

The FDA aims to complete its review of priority review applications within six months as opposed to 10 months for standard

Accelerated approval:

Drug or biologic products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that

provide meaningful therapeutic benefit over existing treatments may receive accelerated approval.

Accelerated approval means that

a product candidate may be approved on the basis of adequate and well-controlled clinical trials establishing that the product candidate

has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a

clinical endpoint other than survival or irreversible morbidity or mortality or other clinical benefit, taking into account the severity,

rarity and prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA

may require that a sponsor of a drug or biologic product candidate receiving accelerated approval perform adequate and well-controlled

intensive involvement of senior managers and experienced staff on a proactive, collaborative, and cross-disciplinary review;

rolling review.

A product candidate is eligible for priority review if it treats a serious condition and, if approved, it would be a

significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious condition compared

to marketed products.

The FDA aims to complete its review of priority review applications within six months as opposed to 10 months

for standard review.

Drug or biologic products studied for their safety and effectiveness in treating serious or life-threatening illnesses

and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval.

Accelerated approval means

that a product candidate may be approved on the basis of adequate and well-controlled clinical trials establishing that the product

candidate has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect

on a clinical endpoint other than survival or irreversible morbidity or mortality or other clinical benefit, taking into account

the severity, rarity and prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval,

the FDA may require that a sponsor of a drug or biologic product candidate receiving accelerated approval perform adequate and well-controlled

post-marketing clinical trials.

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under corporate integrity agreements, suspension and debarment from government contracts, and refusal of orders under existing government

addition, the distribution of prescription biopharmaceutical samples is subject to the Prescription Drug Marketing Act, or PDMA, which

regulates the distribution of samples at the federal level.

Both the PDMA and state laws limit the distribution of prescription biopharmaceutical

addition, the distribution of prescription biopharmaceutical samples is subject to the Prescription Drug Marketing Act (“PDMA”),

which regulates the distribution of samples at the federal level.

Both the PDMA and state laws limit the distribution of prescription

biopharmaceutical product.

Certain reporting related to samples is also required.

Free trial or starter prescriptions provided through pharmacies are also

subject to regulations under the Medicaid Drug Rebate Program and potential liability under anti-kickback and false claims laws.

the enacted Drug Quality and Security Act, or DQSA, imposed obligations on sponsors of biopharmaceutical products related to product

tracking and tracing.

Among the requirements of this legislation, sponsors are required to provide certain information regarding the

products to individuals and entities to which product ownership is transferred, are required to label products with a product identifier,

Free trial or starter prescriptions provided through

pharmacies are also subject to regulations under the Medicaid Drug Rebate Program and potential liability under anti-kickback and false

the enacted Drug Quality and Security Act (“DQSA”), imposed obligations on sponsors of biopharmaceutical products related

to product tracking and tracing.

Among the requirements of this legislation, sponsors are required to provide certain information regarding

the products to individuals and entities to which product ownership is transferred, are required to label products with a product identifier,

and are required to keep certain records regarding the product.

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to shared and separate REMS programs for reference and generic drug products.

Pediatric Disease Voucher Program

the Rare Pediatric Disease Voucher Program, the FDA can award priority review vouchers to sponsors of rare pediatric disease products

where the product is intended to treat serious or life-threatening diseases that primarily affect individuals up to age 18.

the product must contain no active ingredient (including any ester or salt of the active ingredient) that has been previously approved

Pediatric Disease Priority Review Voucher Program

the Rare Pediatric Disease Priority Review Voucher Program, the FDA can award priority review vouchers to sponsors of rare pediatric

disease products where the product is intended to treat serious or life-threatening diseases that primarily affect individuals up to

To qualify, the product must contain no active ingredient (including any ester or salt of the active ingredient) that has been

previously approved by the FDA.

The application must also meet other qualifying criteria, including eligibility for FDA priority review.

If the necessary

qualifying criteria are met, upon a sponsor’s request and product approval, the FDA may award a priority review voucher.

may be transferred and may be redeemed to receive priority review of a subsequent marketing application for a different product.

of a priority review voucher is subject to an FDA user fee.

As these vouchers are transferable, sponsors may sell these vouchers for

substantial sums of money.

Vouchers may, however, be revoked by the FDA under certain circumstances and sponsors of approved rare pediatric

disease products must submit certain reports to the FDA.

To take advantage of the benefits of this program, the product must be designated

by the FDA for a rare pediatric disease no later than September 30, 2024, and approved no later than September 30, 2026, unless the law

is reauthorized by Congress.

If the necessary qualifying criteria are met, upon a sponsor’s request and product approval, the FDA may award a priority review

This voucher may be transferred and may be redeemed to receive priority review of a subsequent marketing application for a different

Use of a priority review voucher is subject to an FDA user fee.

As these vouchers are transferable, sponsors may sell these

vouchers for substantial sums of money.

Vouchers may, however, be revoked by the FDA under certain circumstances and sponsors of approved

rare pediatric disease products must submit certain reports to the FDA.

To take advantage of the benefits of this program, the product

must be designated by the FDA for a rare pediatric disease no later than December 20, 2024 (extended from September 30, 2024 under the

Continuing Appropriations and Extensions Act, 2025, signed into law by President Biden on September 26, 2024), and approved no later

than September 30, 2026, unless the law is reauthorized by Congress.

regulation outside of the United States

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Manufacturers of advanced therapy medicinal products must demonstrate

the quality, safety and efficacy of their products to the European Medicines Agency (“EMA”) which provides an opinion regarding

the application for marketing authorization.

The European Commission grants or refuses marketing authorization in light of the opinion

delivered by EMA.

the quality, safety and efficacy of their products to the EMA which provides an opinion regarding the application for marketing authorization.

The European Commission grants or refuses marketing authorization in light of the opinion delivered by EMA.

medicinal products are authorized in the European Union based on a full marketing authorization application (as opposed to an application

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authorization may be granted to a similar medicinal product for the same orphan indication if:

The second applicant can

establish in its application that its medicinal product, although similar to the orphan medicinal product already authorized, is

safer, more effective or otherwise clinically superior;

The holder of the marketing

authorization for the original orphan medicinal product consents to a second orphan medicinal product application;

The holder of the marketing

authorization for the original orphan medicinal product cannot supply sufficient quantities of orphan medicinal product.

second applicant can establish in its application that its medicinal product, although similar to the orphan medicinal product already

authorized, is safer, more effective or otherwise clinically superior;

holder of the marketing authorization for the original orphan medicinal product consents to a second orphan medicinal product application;

holder of the marketing authorization for the original orphan medicinal product cannot supply sufficient quantities of orphan medicinal

orphan product can also obtain an additional two years of market exclusivity in the European Union for the conduct of pediatric trials.

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Such restrictions under applicable federal and state healthcare laws and regulations include the following:

the federal Anti-Kickback

Statute, which prohibits, among other things, persons, and entities from knowingly and willfully soliciting, receiving, offering

or paying remuneration, directly or indirectly, in cash or kind, in exchange for, or to induce, either the referral of an individual

for, or the purchase, order or recommendation of, any good or service for which payment may be made under federal healthcare programs

such as the Medicare and Medicaid programs.

This statute has been interpreted to apply to arrangements between pharmaceutical manufacturers,

on the one hand, and prescribers, purchasers, and formulary managers on the other.

Although a number of statutory exemptions and

regulatory safe harbors exist to protect certain common activities from falling under the Anti-Kickback Statute, these are narrow,

and practices may not fall under the applicable safe harbors and exemptions.

For example, the United States Department of Health

and Human Services recently promulgated a regulation that is effective in two phases.

First, the regulation excludes from the definition

of “remuneration” limited categories of (a) PBM rebates or other reductions in price to a plan sponsor under Medicare

Part D or a Medicaid Managed Care Organization plan reflected in point-of sale reductions in price and (b) PBM service fees.

effective January 1, 2023, the regulation expressly provides that rebates to plan sponsors under Medicare Part D either directly

to the plan sponsor under Medicare Part D, or indirectly through a pharmacy benefit manager will not be protected under the anti-kickback

discount safe harbor.

The PPACA amended the intent requirement of the federal Anti-Kickback Statute.

A person or entity no longer

needs to have actual knowledge of this statute or specific intent to violate it in order to commit a violation;

the federal false claims

and civil monetary penalties laws, including the civil False Claims Act (the “FCA”), which prohibit, among other things,

individuals, or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid or other

third-party payors that are false or fraudulent, or making a false statement to avoid, decrease, or conceal an obligation to pay

money to the federal government.

Certain marketing practices, including off-label promotion, also may implicate the FCA.

may be pursued by whistleblowers through qui tam actions, even if the government declines to intervene and civil liability may be

predicated on reckless disregard for the truth.

The PPACA also codified case law that a claim including items or services resulting

from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the FCA.

the criminal federal False Claims Act imposes criminal fines or imprisonment against individuals or entities who make or present

a claim to the government knowing such claim to be false, fictitious, or fraudulent;

the federal Physician Payments

Sunshine Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available

under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers

for Medicare & Medicaid Services (“CMS”), information related to payments and other transfers of value made to or

at the request of covered recipients, such as, but not limited to, physicians, physician assistants, nurse practitioners, clinical

nurse specialists, certified registered nurse anesthetists and teaching hospitals, as well as ownership and investment interests

held by physicians and their immediate family.

Payments made to physicians and certain research institutions for clinical trials

are included within the ambit of this law.

Reported information is made publicly available in searchable formats by CMS;

additional federal false

statements and fraud and abuse statutes prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud

or to obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under

the custody or control of, a healthcare benefit program, regardless of whether the payor is public or private, in connection with

the delivery or payment for health care benefits, knowingly and willfully embezzling or stealing from a health care benefit program,

willfully obstructing a criminal investigation of a health care offense and knowingly and willfully falsifying, concealing, or covering

up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment

for, healthcare benefits, items, or services relating to healthcare matters.

PPACA amended the intent requirement of certain of these

criminal statutes under the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”) so that a person or

entity no longer needs to have actual knowledge of the statute, or the specific intent to violate it, to have committed a violation;

state and foreign law equivalents

of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by

any third-party payor, including commercial insurers;

state laws that require pharmaceutical companies to comply with the pharmaceutical

industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government or otherwise

restrict payments that may be made to healthcare providers and other potential referral sources;

state laws that require drug manufacturers

to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing

expenditures;

and European Union and state laws governing the privacy and security of health information in certain circumstances,

many of which differ from each other in significant ways, may be stricter than those applicable in the US and may not have the same

effect, thus complicating compliance efforts.

federal Anti-Kickback Statute, which prohibits, among other things, persons, and entities from knowingly and willfully soliciting,

receiving, offering or paying remuneration, directly or indirectly, in cash or kind, in exchange for, or to induce, either the referral

of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made under federal

healthcare programs such as the Medicare and Medicaid programs.

This statute has been interpreted to apply to arrangements between

pharmaceutical manufacturers, on the one hand, and prescribers, purchasers, and formulary managers on the other.

Although a number

of statutory exemptions and regulatory safe harbors exist to protect certain common activities from falling under the Anti-Kickback

Statute, these are narrow, and practices may not fall under the applicable safe harbors and exemptions.

For example, the United States

Department of Health and Human Services recently promulgated a regulation that is effective in two phases.

First, the regulation

excludes from the definition of “remuneration” limited categories of (a) PBM rebates or other reductions in price to

a plan sponsor under Medicare Part D or a Medicaid Managed Care Organization plan reflected in point-of sale reductions in price

and (b) PBM service fees.

Second, effective January 1, 2023, the regulation expressly provides that rebates to plan sponsors under

Medicare Part D either directly to the plan sponsor under Medicare Part D, or indirectly through a pharmacy benefit manager will

not be protected under the anti-kickback discount safe harbor.

The PPACA amended the intent requirement of the federal Anti-Kickback

A person or entity no longer needs to have actual knowledge of this statute or specific intent to violate it in order to

commit a violation;

federal false claims and civil monetary penalties laws, including the civil False Claims Act (the “FCA”), which prohibit,

among other things, individuals, or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare,

Medicaid or other third-party payors that are false or fraudulent, or making a false statement to avoid, decrease, or conceal an

obligation to pay money to the federal government.

Certain marketing practices, including off-label promotion, also may implicate

FCA claims may be pursued by whistleblowers through qui tam actions, even if the government declines to intervene and civil

liability may be predicated on reckless disregard for the truth.

The PPACA also codified case law that a claim including items or

services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of

Separately, the criminal federal False Claims Act imposes criminal fines or imprisonment against individuals or entities

who make or present a claim to the government knowing such claim to be false, fictitious, or fraudulent;

federal Physician Payments Sunshine Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies for

which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions,

to report annually to the Centers for Medicare & Medicaid Services (“CMS”), information related to payments and other

transfers of value made to or at the request of covered recipients, such as, but not limited to, physicians, physician assistants,

nurse practitioners, clinical nurse specialists, certified registered nurse anesthetists and teaching hospitals, as well as ownership

and investment interests held by physicians and their immediate family.

Payments made to physicians and certain research institutions

for clinical trials are included within the ambit of this law.

Reported information is made publicly available in searchable formats

federal false statements and fraud and abuse statutes prohibit knowingly and willfully executing, or attempting to execute, a scheme

to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned

by, or under the custody or control of, a healthcare benefit program, regardless of whether the payor is public or private, in connection

with the delivery or payment for health care benefits, knowingly and willfully embezzling or stealing from a health care benefit

program, willfully obstructing a criminal investigation of a health care offense and knowingly and willfully falsifying, concealing,

or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of,

or payment for, healthcare benefits, items, or services relating to healthcare matters.

PPACA amended the intent requirement of certain

of these criminal statutes under the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”) so that a

person or entity no longer needs to have actual knowledge of the statute, or the specific intent to violate it, to have committed

and foreign law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items

or services reimbursed by any third-party payor, including commercial insurers;

state laws that require pharmaceutical companies

to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated

by the federal government or otherwise restrict payments that may be made to healthcare providers and other potential referral sources;

state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and

other healthcare providers or marketing expenditures;

and European Union and state laws governing the privacy and security of health

information in certain circumstances, many of which differ from each other in significant ways, may be stricter than those applicable

in the US and may not have the same effect, thus complicating compliance efforts.

of the laws described above or any other governmental laws and regulations may result in penalties, including civil and criminal penalties,

5 unchanged sentences

Privacy and Security

HIPAA, as amended by the

Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH Act, and similar state laws impose obligations

on certain entities with respect to safeguarding the privacy, security and transmission of protected health information.

security and certain privacy standards are directly applicable to persons or organizations of covered entities, other than members

of the covered entity’s workforce, that create, receive, maintain or transmit protected health information on behalf of a covered

entity for a function or activity regulated by HIPAA.

The HITECH Act strengthened the civil and criminal penalties that may be imposed

against covered entities, business associates and individuals, and gave state attorneys general new authority to file civil actions

for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated

with pursuing federal civil actions.

In addition, other federal and state laws, such as the California Consumer Privacy Act, may

regulate the privacy and security of information that we maintain, many of which may differ from each other in significant ways and

may not be preempted by HIPAA;

the General European Data

Protection Regulation (“GDPR”), which became applicable May 25, 2018, harmonizes data privacy laws across Europe.

GDPR sets forth rules relating to the protection with regard to the processing and transfer of personal data as well as an individual’s

right to the protection of personal data, including medical information and clinical trial related data.

In addition, there are rules

relating to the export of personal data outside the European Union and in particular there are certain challenges in relation to

export to the United States.

as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, “HITECH Act”), and similar

state laws impose obligations on certain entities with respect to safeguarding the privacy, security and transmission of protected

health information.

HIPAA’s security and certain privacy standards are directly applicable to persons or organizations of covered

entities, other than members of the covered entity’s workforce, that create, receive, maintain or transmit protected health

information on behalf of a covered entity for a function or activity regulated by HIPAA.

The HITECH Act strengthened the civil and

criminal penalties that may be imposed against covered entities, business associates and individuals, and gave state attorneys general

new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’

fees and costs associated with pursuing federal civil actions.

In addition, other federal and state laws, such as the California

Consumer Privacy Act, may regulate the privacy and security of information that we maintain, many of which may differ from each other

in significant ways and may not be preempted by HIPAA;

General European Data Protection Regulation (“GDPR”), which became applicable May 25, 2018, harmonizes data privacy laws

across Europe.

The GDPR sets forth rules relating to the protection with regard to the processing and transfer of personal data as

well as an individual’s right to the protection of personal data, including medical information and clinical trial related

In addition, there are rules relating to the export of personal data outside the European Union and in particular there are

certain challenges in relation to export to the United States.

and Reimbursement

uncertainty exists as to the coverage and reimbursement status of any products for which we may obtain regulatory approval.

In the United

States, sales of any product candidates for which regulatory approval for commercial sale is obtained will depend in part on the availability

of coverage and adequate reimbursement from third-party payors.

Third-party payors include government authorities and health programs

in the United States such as Medicare and Medicaid, managed care providers, private health insurers and other organizations.

These third-party

payors are increasingly reducing reimbursements for medical products and services.

The process for determining whether a payor will provide

coverage for a drug product may be separate from the process for setting the reimbursement rate that the payor will pay for the drug

Third-party payors may limit coverage to specific drug products on an approved list, or formulary, which might not include all

FDA-approved drugs for a particular indication.

Additionally, the containment of healthcare costs has become a priority of federal and

state governments, and the prices of drugs have been a focus in this effort.

government, state legislatures and foreign governments

have shown significant interest in implementing cost-containment programs, including price controls, required disclosures of pricing

and sensitive cost data, requirement for payment of manufacturer rebates and negotiation of supplemental rebates, restrictions on reimbursement

and requirements for substitution of generic products.

United States, sales of any product candidates for which regulatory approval for commercial sale is obtained will depend in part on

the availability of coverage and adequate reimbursement from third-party payors.

Third-party payors include government authorities

and health programs in the United States such as Medicare and Medicaid, managed care providers, private health insurers and other

organizations.

These third-party payors are increasingly reducing reimbursements for medical products and services.

The process for

determining whether a payor will provide coverage for a drug product may be separate from the process for setting the reimbursement

rate that the payor will pay for the drug product and/or application procedure.

Third-party payors may limit coverage to specific drug products on an approved

list, or formulary, which might not include all FDA-approved drugs for a particular indication.

Additionally, the containment of

healthcare costs has become a priority of federal and state governments, and the prices of drugs have been a focus in this effort.

government, state legislatures and foreign governments have shown significant interest in implementing cost-containment

programs, including price controls, required disclosures of pricing and sensitive cost data, requirement for payment of manufacturer

rebates and negotiation of supplemental rebates, restrictions on reimbursement and requirements for substitution of generic

Coverage policies and third-party reimbursement rates may change at any time.

Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less

favorable coverage policies and reimbursement rates may be implemented in the future.

Even if favorable coverage and reimbursement

status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and

reimbursement rates may be implemented in the future.

the EU, pricing and reimbursement schemes vary widely from country to country.

111 unchanged sentences

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What changed 10-K

Item 1. Business