GTBP US Equity☆

UNITED

STATES

SECURITIES

AND EXCHANGE COMMISSION

Washington,

D.C. 20549

FORM

10-K

(Mark One)

For the fiscal year ended: December 31, 2022 or

For the transition period from _____________ to _____________

Commission

File Number: 001-40023

GT

BIOPHARMA, INC.

(Exact

name of Registrant as specified in its charter)

8000

Marina Blvd.

Suite

100

Brisbane,

CA94005

(Address

of principal executive offices) (Zip code)

(415)919-4040

(Registrant’s

telephone number including area code)

Securities

registered pursuant to Section 12(b) of the Act:

Title of Securities Exchanges on which Registered

Common Stock, $0.001 Par Value Nasdaq Capital Market

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 during the preceding 12 months (or for such shorter period that the registrant was required to submit and post

such files). Yes ☒ No ☐

Indicate

by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting

company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,”

“smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☐

If

an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying

with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate

by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒

The

aggregate market value of the registrant’s common stock, $0.001 par value per share, held by non-affiliates on June 30, 2022 was

approximately $89.8 million. As of March 30, 2023, there were 36,809,271 shares of the registrant’s common stock, $0.001 par value,

issued and outstanding.

DOCUMENTS

INCORPORATED BY REFERENCE

In

Part III, portions of the registrant’s 2023 Proxy Statement to be filed with the Securities and Exchange Commission within 120

days of the Registrant’s fiscal year end.

Table

of Contents

PART I 1

Item 1. Business 1

Item 1A. Risk Factors 9

Item 1B. Unresolved Staff Comments 30

Item 2. Properties 30

Item 3. Legal Proceedings 30

Item 4. Mine Safety Disclosures 30

Item 6. [Reserved] 31

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 38

Item 8. Financial Statements and Supplementary Data 38

Item 9A. Controls and Procedures 38

Item 9B. Other Information 39

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 39

PART III 39

Item 10. Directors, Executive Officers and Corporate Governance 39

Item 11. Executive Compensation 39

Item 14. Principal Accounting Fees and Services 39

Item 15. Exhibits and Financial Statement Schedules 40

SUMMARY

RISK FACTORS

Our

business involves significant risks. Below is a summary of the material risks that our business faces, which makes an investment in our

securities speculative and risky. This summary does not address all these risks. These risks are more fully described below under the

heading “Risk Factors” in Part I, Item 1A of this annual report on Form 10-K. Before making investment decisions regarding

our securities, you should carefully consider these risks. The occurrence of any of the events or developments described below could

have a material adverse effect on our business, results of operations, financial condition, prospects and stock price. In such event,

the market price of our securities could decline, and you could lose all or part of your investment. In addition, there are also additional

risks not described below that are either not presently known to us or that we currently deem immaterial, and these additional risks

could also materially impair our business, operations or market price of our common stock.

PART

I

CAUTIONARY

NOTICE REGARDING FORWARD-LOOKING STATEMENTS

This

Annual Report on Form 10-K, including any documents which may be incorporated by reference into this Annual Report, contains “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. All statements other than statements of historical fact are “Forward-Looking Statements” for purposes

of these provisions, including our plans of operation, any projections of revenues or other financial items, any statements of the plans

and objectives of management for future operations, any statements concerning proposed new products or services, any statements regarding

future economic conditions or performance, and any statements of assumptions underlying any of the foregoing. All Forward-Looking Statements

included in this document are made as of the date hereof and are based on information available to us as of such date. We assume no obligation

to update any Forward-Looking Statement. In some cases, Forward-Looking Statements can be identified by the use of terminology such as

“may,” “will,” “expects,” “plans,” “anticipates,” “intends,”

“believes,” “estimates,” “potential,” or “continue,” or the negative thereof or other

comparable terminology. Although we believe that the expectations reflected in the Forward-Looking Statements contained herein are reasonable,

there can be no assurance that such expectations or any of the Forward-Looking Statements will prove to be correct, and actual results

could differ materially from those projected or assumed in the Forward-Looking Statements. Future financial condition and results of

operations, as well as any Forward-Looking Statements are subject to inherent risks and uncertainties, including any other factors referred

to in our press releases and reports filed with the Securities and Exchange Commission. All subsequent Forward-Looking Statements attributable

to the company or persons acting on its behalf are expressly qualified in their entirety by these cautionary statements. Additional factors

that may have a direct bearing on our operating results are described under “Risk Factors” and elsewhere in this Annual Report

on Form 10-K.

Introductory

Comment

Throughout

this Annual Report on Form 10-K, the terms “GT Biopharma,” “GTBP,” “we,” “us,” “our,”

“the company” and “our company” refer to GT Biopharma, Inc., a Delaware corporation formerly known as DDI Pharmaceuticals,

Inc., Diagnostic Data, Inc. and Oxis International, Inc., together with our subsidiaries.

ITEM

1. BUSINESS

We

are a clinical stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology products based

on our proprietary Tri-specific Killer Engager (TriKE®) fusion protein immune cell engager technology platform. Our TriKE®

platform generates proprietary therapeutics designed to harness and enhance the cancer killing abilities of a patient’s own

natural killer cells, or NK cells. Once bound to an NK cell, our moieties are designed to enhance the NK cell, and precisely direct it

to one or more specifically targeted proteins expressed on a specific type of cancer cell or virus infected cell, resulting in the targeted

cell’s death. TriKE®s can be designed to target any number of tumor antigens on hematologic malignancies or solid

tumors and do not require patient-specific customization.

We

are using our TriKE® platform with the intent to bring to market immuno-oncology products that can treat a range of hematologic

malignancies, and solid tumors. The platform is scalable, and we are putting processes in place to be able to produce investigational

new drug (IND) ready moieties in a timely manner after a specific TriKE® conceptual design. Specific drug candidates can

then be advanced into the clinic on our own or through potential collaborations with partnering companies. We believe our TriKE®s

may have the ability, if approved for marketing, to be used as both monotherapy and in combination with other standard-of-care therapies.

We

are also using our TriKE® platform to develop therapeutics useful for the treatment of infectious disease such as for

the treatment of patients infected by the human immunodeficiency virus (HIV). While the use of anti-retroviral drugs has

substantially improved the health and increased the longevity of individuals infected with HIV, these drugs are designed to suppress

virus replication to help modulate progression to acquired immunodeficiency syndrome (AIDS) and to limit further transmission of the

virus. Despite the use of anti-retroviral drugs, infected individuals retain reservoirs of latent HIV-infected cells that, upon

cessation of anti-retroviral drug therapy, can reactivate and re-establish an active HIV infection. For a curative therapy,

destruction of these latent HIV infected cells must take place. The HIV-TriKE® contains the antigen binding fragment

(Fab) from a broadly neutralizing antibody targeting the HIV-Env protein or a protein that binds infected CD4+ T cells. The HIV-TriKE® is designed to target HIV

while redirecting NK cell killing specifically to actively replicating HIV infected cells. The HIV-TriKE® induced NK

cell proliferation and demonstrated the ability in vitro to reactivate and kill HIV-infected T-cells. These findings indicate a

potential role for the HIV-TriKE® in the reactivation and elimination of the latently infected HIV reservoir cells by

harnessing the NK cell’s ability to mediate the antibody-directed cellular cytotoxicity (ADCC).

Our

initial work has been conducted in collaboration with the Masonic Cancer Center at the University of Minnesota under a program led by

Dr. Jeffrey Miller, the Deputy Director. Dr. Miller is a recognized key opinion leader in the field of NK cell and IL-15 biology and

their therapeutic potential. We have exclusive rights to the TriKE® platform and are generating additional intellectual

property for specific moieties.

Immuno-Oncology

Platform

Tri-specific

Killer Engagers (TriKE®s)

The

generation of chimeric antigen receptor, or CAR, expressing T cells from monoclonal antibodies has represented an important step forward

in cancer therapy. These therapies involve the genetic engineering of T cells to express either CARs, or T cell receptors, or TCRs, and

are designed such that the modified T cells can recognize and destroy cancer cells. While a great deal of interest has recently been

placed upon chimeric antigen receptor T, or CAR-T, therapy, it has certain limitations for broad potential applicability because it can

require an individual approach that is expensive, time consuming, and may be difficult to apply on a large scale. NK cells represent

an important immunotherapeutic target as they are involved in tumor immune-surveillance, can mediate antibody-dependent cell-mediated

cytotoxicity (ADCC), contain pre-made granules with perforin and granzyme B and can quickly secrete inflammatory cytokines, and unlike

T cells they do not require antigen priming and can kill cells in the absence of major histocompatibility complex (MHC) presentation

of antigens. Unlike full-length antibodies, TriKE® constructs are composed of a single-chain fusion protein that binds

the CD16 receptor of NK cells directly producing a potent and lasting cytotoxic killing response, interleukin 15 (IL-15) to promote NK

cell activation, persistence and proliferation, and a cancer cell targeting moiety. An additional benefit of TriKE® may

have been its attractive biodistribution, as a consequence of their smaller size, which we expect to be important in the treatment of

solid tumors. In addition to these advantages, TriKE® is designed to be non-immunogenic, have appropriate clearance properties,

and can be engineered to target a variety of tumor antigens.

We

believe there is a continued unmet medical need for targeted immuno-oncology therapies that can have the potential to be dosed in a patient-friendly

outpatient setting, can be used on a stand-alone basis, augment the current monoclonal antibody therapeutics, or be used in conjunction

with more traditional cancer therapy. We believe our TriKE® constructs have this potential and therefore we have generated,

and intend to continue to generate, a pipeline of product candidates to be advanced into the clinic on our own or through potential collaborations

with larger companies.

GTB-3550

TriKE® and Phase 1 Acute Myeloid Leukemia/Myelodysplastic Syndrome (AML/MDS) Phase 1 Clinical Trial

GTB-3550

is the Company’s first-generation TriKE® product candidate which is a single-chain, tri-specific recombinant fusion

protein construct composed of the variable regions of the heavy and light chains of anti-CD16 and anti-CD33 antibodies and a modified

form of IL-15, all connected by small peptide linkers. The GTB-3550 Phase 1 clinical trial for treatment of patients with CD33-expressing, high risk myelodysplastic syndromes

and refractory/relapsed acute myeloid leukemia opened for patient enrollment in September 2019 and completed enrollment in September

2021. The clinical trial was conducted at the University of Minnesota’s Masonic Cancer Center in Minneapolis, Minnesota under the

direction of Dr. Erica Warlick and Dr. Mark Juckett.

Background

and Select Non-Clinical Data

In

conjunction with our research agreement with the Masonic Cancer Center at the University of Minnesota, the exploration of targeting NK

cells to a variety of tumors initially focused on novel bi-specific killer engagers, or BiKEs, composed of the variable portions of antibodies

targeting the CD16 activating receptor on NK cells and CD33 (AML and MDS; see figure below), B7H3 (solid tumors – breast, lung,

colon, prostate), Her2 (Breast, Gastric), or CD19/CD22 (B cell lymphomas) on the tumor cells.

Subsequently,

a tri-specific (TriKE®) construct that replaced the linker molecule between the CD16 scFv and the CD33 scFv with a modified

IL-15 molecule, containing flanking sequences, was generated, and tested. Data indicates that the CD16 x IL-15 x CD33 potently induce

proliferation of healthy donor NK cells, possibly greater than that induced by exogenous IL-15, which is absent in the BiKE platform.

Targeted delivery of the IL-15 through the TriKE® also resulted in specific expansion of the NK cells without inducing

T cell expansion on post-transplant patient samples.

When

compared to the CD16 x CD33 BiKE, the CD16 x IL-15 x CD33 TriKE® is also capable of potently restoring killing capacity

of post-transplant NK cells against CD33-expressing HL-60 targets and primary AML blasts. These results demonstrated the ability to functionally

incorporate an IL-15 cytokine into the BiKE platform and also demonstrated the possibility of targeting a variety of cytokines directly

to NK cells while reducing off-target effects and the amount of cytokines needed to obtain biologically relevant function.

The

figure below is a schematic of a BiKE construct (top) and a TriKE® construct (bottom), which has the modified IL-15 linker

between the CD16 scFv and the CD33 scFv components.

The CD33 -targeting TriKE® constructs was tested against

three separate human tumor cell lines to evaluate specificity: CD33+ HL-60 (promyelocitic leukemia) cells, CD33, Raji (Burkitt’s

lymphoma), and CD33- HT29 (colorectal adenocarcinoma). TriKE® (GTB-3550) activity was only seen against the CD33+ HL-60

cells containing a Luc reporter to allow for in vivo imaging of the tumors, were used to show in vivo efficacy of BiKE (1633) and TriKE®

(GTB-3550) against relevant human tumor targets (HL-60-luc) over an extended period of time. The system consisted of initial conditioning

of mice using radiation (250-275 cGy), followed by injection of the tumor cells (I.V. for HL-60-luc, a three-day growth phase, injection

of human NK cells, and repeated injection of the drugs of interest, BiKE and TriKE® (three to five times a week). Imaging

was carried out at Day 7, 14, and 21, and extended as needed. Subsequent studies were also carried out to evaluate other TriKEs expressing

targeting arms against other tumor antigens (B7H3 and HER2 for instance).

The

figure below shows the results (tumor burden and mortality) when dosing NK cells alone (top panel), the BiKE version (lacking IL-15)

of GTB-3550 (middle panel; called 1633), and the TriKE®, GTB-3550 (bottom panel; then called 161533) in the above human

tumor model, HL-60-luc. In the NK-cell-only arm, two out of the five mice were dead by Day 21 with two of the surviving mice having extensive

tumor burden as depicted by the colored images. In contrast, all five mice in each of the BiKE and TriKE® arms survived.

In addition, the tumor burden in the TriKE®-treated mice was significantly less than in the BiKE-treated mice, demonstrating

the improved efficacy from NK cells in the TriKE®-treated mice.

Based

on these results, and others, the IND for GTB-3550 was filed in June 2017 by the University of Minnesota. The FDA requested that additional

preclinical toxicology, additional information and clarifications on manufacturing, and clinical development plans. The requested additional

information and clarifications were completed and incorporated into the IND in eCTD format. We filed the IND amendment in June 2018 and

announced on November 1, 2018, that the FDA granted approval of the IND and the Company was authorized to initiate a first-in-human Phase

1 study with GTB-3550 in AML, MDS, and severe mastocytosis. The Phase 1 clinical trial was initiated in September 2019 and closed in

September 2021.

Targeting

Solid Tumors and Other Potentially Attractive Characteristics

Unlike

full-length antibodies, TriKE® is composed of a single-chain fusion protein that binds the CD16 receptor of NK cells directly

producing a potentially more potent and lasting response as demonstrated by preclinical studies. An additional benefit due to the smaller

size of TriKE® is enhanced biodistribution which we expect to be important in the treatment of solid tumors. In addition

to these potential advantages, TriKE® is designed to be non-immunogenic, have appropriate clearance properties and can

be engineered quickly to target a variety of tumor antigens. We believe these attributes make them an ideal pharmaceutical platform for

potentiated NK cell-based immunotherapies and have the potential to overcome some of the limitations of CAR-T therapy and other antibody

therapies.

Examples

of our earlier stage solid tumor targeting product candidates are focused on CD33, B7-H3, Her2, CD19, CLEC12A, CD22, and CD133

alone and in combination. We believe these constructs have the potential to target prostate, breast, colon, ovarian, liver, and head

and neck cancers. Depending on the availability of drug supply, we hope to initiate human clinical testing for certain of our solid tumor

product candidates in 2023.

Efficient

Advancement of Potential Future Product Candidates – Production and Scale Up

We

are using our TriKE® platform with the intent to bring to market multiple immuno-oncology products that can treat a range

of hematologic malignancies and solid tumors. The platforms are scalable, and we are currently working with a third-party product manufacturer

investigating the optimal GMP production expression system for TriKE® constructs.

We

believe TriKE®s will have the ability, if approved for marketing, to be used as both monotherapy and in combination with

standard-of-care therapies.

Immuno-Oncology

Product Candidates

GTB-3550

GTB-3550

was our first TriKE® product candidate. It reflected our first-generation TriKE® platform. It is a single-chain,

tri-specific scFv recombinant fusion protein conjugate composed of the variable regions of the heavy and light chains of anti-CD16 and

anti-CD33 antibodies and a modified form of IL-15. We studied this anti-CD16-IL-15-anti-CD33 TriKE® in CD33 positive leukemias,

a marker expressed on tumor cells in acute myelogenous leukemia, or AML, myelodysplastic syndrome, or MDS. CD33 is primarily a myeloid

differentiation antigen with endocytic properties broadly expressed on AML blasts and, possibly, some leukemic stem cells. CD33 or Siglec-3

(sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage.

It is usually considered myeloid-specific, but it can also be found on some lymphoid cells. The anti-CD33 antibody fragment used for

these studies was derived from the M195 humanized anti-CD33 scFV and has been used in multiple human clinical studies. It has been exploited

as target for therapeutic antibodies for many years. We believe the recent approval of the antibody-drug conjugate gemtuzumab validates

this targeted approach.

GTB-3550

is being replaced by a more potent next-generation camelid nanobody TriKE®, GTB-3650, targeting relapsed/refractory

Acute Myeloid Leukemia (AML) and high-risk Myelodysplastic Syndromes (MDS).

About

High-Risk Myelodysplastic Syndromes

Myelodysplastic

Syndromes is a rare form of bone marrow-related cancer caused by irregular blood cell production within the bone marrow. As a result

of this irregular production, MDS patients do not have sufficient normal red blood cells, white blood cells and/or platelets in circulation.

High-risk MDS is associated with poor prognosis, diminished quality of life, and a higher chance of transformation to acute myeloid leukemia.

The goals of therapy are to reduce disease associated symptoms and the risk of disease progression and death, thereby improving both

quality and quantity of life. United States incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought

to be under diagnosed. The prevalence has been estimated to be from 60,000 to 170,000 in the United States. Approximately 40% of patients

with High-Risk MDS transform to AML, another aggressive cancer with poor outcomes.

About

Acute Myeloid Leukemia

Acute

myeloid leukemia is a type of cancer in which the bone marrow makes abnormal myeloblasts (a type of white blood cell), red blood cells,

or platelets. The median age at the time of diagnosis is 65–69 years. AML is an aggressive disease and is fatal without anti-leukemic

treatment. Among patients treated with chemotherapy, 65% to 80% achieve complete remission. Despite a plethora of novel agents that have

been approved by the U.S. Food and Drug Administration since 2017 for treatment of AML, once complete remission (CR) is achieved, approximately

50% of patients age < 60 years of age and up to 90% of patients ≥ 60 years of age will relapse, despite consolidation strategies.

Furthermore, while 10–40% of younger AML patients are primarily refractory to AML induction therapy, the number is considerably

higher for patients above 60 years (40–60%). The vast majority of fit AML patients will undergo hematopoietic stem cell transplantation

(HSCT) after achieving a CR. However, 40% of these patients relapse after HSCT. Thus, refractory or relapsed (r/r) AML is a very common

scenario in AML and despite recent advances and new targeted therapies, the management of AML remains a challenge, particularly in older

adults ineligible for intensive therapies. According to the National Cancer Institute (NCI), the five-year survival rate is about 35%

in people under 60 years old, and 10% in people over 60 years old. Older people whose health is too poor for intensive chemotherapy have

a typical survival of five to ten months. AML accounts for approximately 1.8% of cancer deaths in the United States.

About

GTB-3550 TriKE® Clinical Trial

We

opened our GTB-3550 Phase 1 clinical trial in September 2019 and enrolled our first patient in January 2020. Patients with CD33+ malignancies

(primary induction failure or relapsed AML with failure of one reinduction attempt or high-risk MDS progressed on two lines of therapy)

age 18 and older were eligible (ClinicalTrials.gov Identifier NCT03214666). The primary endpoint is to identify the maximum tolerated

dose (MTD) of GTB-3550 TriKE®. Correlative objectives include the number, phenotype, activation status and function of

NK cells and T cells. From January, 2020 until September, 2021 twelve patients received escalating doses of GTB-3550 in the Phase 1 trial.

The results of this trial were presented at several conferences in 2021. To summarize, the therapy was overall well tolerated and safe.

There were no serious cases of cytokine release syndrome observed. Four of twelve patients had transient reductions in bone marrow leukemic

blast cells. Correlative studies showed activation, proliferation, and persistence of functionally active endogenous NK cells. The results

of our first generation GTB-3550 Phase 1 clinical trial support our plans to advance the next generation camelid nanobody into the clinic.

The

Next Generation of Camelid Nanobody TriKE®s

Our

goal is to be a leader in immuno-oncology therapies targeting a broad range of indications including hematological malignancies and solid

tumors. A key element of our strategy includes introducing a next-generation camelid nanobody platform. Camelid antibodies (often referred

as nanobodies) are smaller than human immunoglobulin and consist of two heavy chains. These nanobodies have the potential to have greater

affinity to target antigens, potentially resulting in greater potency. GT Biopharma is utilizing this camelid antibody structure for

all its new TriKE® product candidates.

Generation

of humanized single-domain antibody targeting CD16 for incorporation into the TriKE® platform

To

develop second generation TriKE®s, we designed a new humanized CD16 engager derived from a single-domain antibody. While

scFvs consist of a heavy and a light variable chain joined by a linker, single-domain antibodies consist of a single variable heavy chain

capable of engaging without the need of a light chain counterpart (see figure below).

These

single-domain antibodies are thought to have certain attractive features for antibody engineering, including physical stability, ability

to bind deep grooves, and increased production yields, amongst others. Pre-clinical studies demonstrated increased NK cell activation

against CD33+ targets including NK cell degranulation (% CD107a+) and IFNg with the single-domain CD16 TriKE® (cam 16-wt15-33;

GTB-3650) compared to the original TriKE® (scFv16-m 15-33; GTB-3550) (see figure below). These data were published by

Felices M et al (2020) in Cancer Immunol Res.

CD33+

HL60 Targets

GTB-3650

GTB-3650

is a CD33 targeted TriKE® which targets CD33 on the surface of myeloid leukemias. We are advancing GTB-3650 through

preclinical studies and anticipate filing an Investigational New Drug (IND) application in the first half of 2023. We further

anticipate starting a study targeting patients with relapsed/refractory AML and high grade MDS by the end of 2023.

GTB-5550

GTB-5550

is a B7-H3 targeted TriKE® which targets B7-H3 on the surface of advanced solid tumors. We are advancing GTB-5550

through preclinical studies and have initiated a GMP manufacturing campaign in anticipation of filing an IND in the late second half

of 2023 and starting a study targeting patients with B7-H3 positive solid tumors in the first half of 2024.

Oncology

Markets

Acute

Myeloid Leukemia and Myelodysplastic Syndromes

AML

is a heterogeneous hematologic stem cell malignancy in adults with incidence rate of 4.3% per 100,000 populations. The median age at

the time of diagnosis is 68 years. AML is an aggressive disease and is fatal without anti-leukemic treatment. AML is the most common

form of adult leukemia in the U.S. These patients will require frontline therapy, usually chemotherapy including cytarabine and an anthracycline,

a therapy that has not changed in over 40 years. Myelodysplastic syndromes are a heterogeneous group of myeloid neoplasms characterized

by dysplastic features of erythroid/myeloid/megakaryocytic lineages, progressive bone marrow failure, a varying percentage of blast cells,

and enhanced risk to evolve into acute myeloid leukemia. It is estimated that over 10,000 new cases of MDS are diagnosed each year and

there are minimal treatment options; other estimates have put this number higher. In addition, the incidence of MDS is rising for unknown

reasons.

B7-H3

Positive Solid Tumors

The

B7-H3 protein, which functions as a checkpoint inhibitor, has been identified in many of the most common solid tumor cancers, including

but not limited to bladder, breast, cervical, colorectal, endometrial, esophageal, gastric, glioma, kidney, liver, lung, pancreatic,

prostate, head and neck cancer, and melanoma. In recent studies, B7-H3 has been identified as a critical promoter of tumor cell proliferation,

migration, invasion, epithelial-to-mesenchymal transition, cancer stemness and drug resistance. Because this protein does not seem to

be expressed in normal cells, this makes it an attractive target for therapeutic intervention.

Manufacturing

We

do not currently own or operate manufacturing facilities for the production of clinical or commercial quantities of any of our product

candidates. We rely on a third-party contract manufacturing operation to produce and/or test our compounds and expect to continue to

do so to meet the preclinical and clinical requirements of our potential product candidates as well as for our future commercial needs.

We do not have long-term commitments with a third-party product manufacturer. We require in our manufacturing and processing agreements

that third-party product manufacturers produce intermediates, active pharmaceutical ingredients, or API, and finished products in accordance

with the FDA’s current Good Manufacturing Practices (cGMP), and all other applicable laws and regulations. We maintain confidentiality

agreements with potential and existing manufacturers to protect our proprietary rights related to our drug candidates.

Patents

and Trademarks

Immuno-oncology

platform

TriKE®

Patents

On

August 24, 2021, two patents were issued by the US Patent Office covering our pipeline of clinical and non-clinical product candidates

consisting of tri-specific killer engagers, or TriKE®s, designed to target natural killer, or NK, cells and tumor or virus

infected cells forming an immune synapse between the NK cell and the tumor cell thereby inducing NK cell activation at that site. The

patents broadly include TriKE®s that target the CD16 receptor, which includes the more potent camelid nanobody sequence,

an IL-15 activating domain, and any targeting domain.

University

of Minnesota License Agreements

2016

Exclusive Patent License Agreement

We

are party to an exclusive worldwide license agreement with the Regents of the University of Minnesota, (“UofMN”) to further

develop and commercialize cancer therapies using TriKE® technology developed by researchers at the UofMN to target NK

cells to cancer. Under the terms of the 2016 agreement, we received exclusive rights to conduct research and to develop, make, use, sell,

and import TriKE® technology worldwide for the treatment of any disease, state or condition in humans. We are responsible

for obtaining all permits, licenses, authorizations, registrations and regulatory approvals required or granted by any governmental authority

anywhere in the world that is responsible for the regulation of products such as the TriKE® technology, including without

limitation the FDA and the European Agency for the Evaluation of Medicinal Products in the European Union. Under the agreement, the University

of Minnesota received an upfront payment of $200,000, annual license maintenance fees of $100,000 beginning in 2021, 4% royalty fees

(not to exceed 6% under subsequent license agreements or amendments to this agreement), upon sale of a licensed product or a minimum

annual royalty payment ranging from $250,000 to $5.0 million. The agreement also includes certain milestone payments totaling $3.1 million,

and one-time sales milestone payments of $1.0 million upon reaching $250 million in gross sales and $5.0 million upon reaching $500 million

in cumulative gross sales of licensed products.

2021

Exclusive License Agreement

On

March 26, 2021, we entered into an agreement with the UofMN specific to the B7H3 targeted TriKE®. Under the agreement,

the UofMN received an upfront license fee of $20,000, and will receive annual license maintenance fees of $5,000 beginning in 2022, 2.5%

to 5% royalty fees or minimum annual royalty payments of $250,000 beginning in the first year after the first commercial sale of licensed

product, and $2.0 million beginning in the fifth year after the first commercial sale of licensed product. The agreement also includes

certain milestone payments totaling $3.1 million and one-time sales milestone payments of $1.0 million upon reaching $250 million in

gross sales, and $5.0 million upon reaching $500 million in cumulative gross sales of licensed products. There is no double payment intended;

if one of the milestone payments has been paid under the 2016 agreement, no further payment is due for the corresponding milestone above.

Employees and Human Capital Resources

At

the date of this Annual Report, we have 2 full-time employees and eight consultants to carry on our operations. Many of our activities are outsourced to consultants who provide

services to us on a project basis. As business activities require and capital resources permit, we will hire additional employees to

fulfill our Company’s needs.

Form

and Year of Organization

In

1965, the corporate predecessor of GT Biopharma, Diagnostic Data, Inc., was incorporated in the State of California. Diagnostic Data

changed its incorporation to the State of Delaware in 1972, and changed its name to DDI Pharmaceuticals, Inc. in 1985. In 1994, DDI Pharmaceuticals

merged with International BioClinical, Inc. and Bioxytech S.A. and changed its name to OXIS International, Inc. On July 17, 2017, we

amended our Certificate of Incorporation for the purpose of changing our name from Oxis International, Inc. to GT Biopharma, Inc.

Available Information

We post our annual report on Form 10-K, quarterly reports on Form 10-Q,

current reports on Form 8-K, and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange

Act, free of charge, on the Investors section of our public website (www.gtbiopharma.com) as soon as reasonably practicable after we electronically

file such material with, or furnish it to, the SEC . In addition, you can read our SEC filings over the Internet at the SEC’s

website at www.sec.gov. The contents of these websites are not incorporated into this annual report on Form 10-K. Further, our references

to the URLs for these websites are intended to be inactive textual references only.

ITEM

1A. RISK FACTORS

Investing

in our common stock involves a high degree of risk. You should carefully consider the risks and uncertainties described below in addition

to the other information contained in this Annual Report on Form 10-K before deciding whether to invest in shares of our common stock.

If any of the following risks actually occur, our business, financial condition or operating results could be harmed. In that case, the

trading price of our common stock could decline and you may lose part or all of your investment. In the opinion of management, the risks

discussed below represent the material risks known to the company. Additional risks and uncertainties not currently known to us or that

we currently deem immaterial may also impair our business, financial condition and operating results and adversely affect the market

price of our common stock.

Risks

Related to Our Business

Our

business is at an early stage of development and we may not develop therapeutic products that can be commercialized.

Our

business is at an early stage of development. We do not have immune-oncology products in late stage clinical trials. We are still in

the early stages of identifying and conducting research on potential therapeutic products. Our potential therapeutic products will require

significant research and development and pre-clinical and clinical testing prior to regulatory approval in the United States and other

countries. We may not be able to obtain regulatory approvals, enter clinical trials for any of our product candidates, or commercialize

any products. Our product candidates may prove to have undesirable and unintended side effects or other characteristics adversely affecting

their safety, efficacy or cost effectiveness that could prevent or limit their use. Any product using any of our technology may fail

to provide the intended therapeutic benefits or achieve therapeutic benefits equal to or better than the standard of treatment at the

time of testing or production.

We

have a history of operating losses and we expect to continue to incur losses for the foreseeable future and we may never generate revenue

or achieve profitability.

During

the year ended December 31, 2022, the Company reported a net loss of $20.9 million and as of December 31, 2022 and had an

accumulated deficit of $674.5 million. We have not generated any revenue to date and are not profitable, and have incurred losses in

each year since our inception. We do not expect to generate any product sales or royalty revenues for the foreseeable future. We

expect to incur significant additional operating losses for the foreseeable future as we expand research and development and

clinical trial efforts.

Our

ability to achieve long-term profitability is dependent upon obtaining regulatory approvals for our products and successfully commercializing

our products alone or with third parties. However, our operations may not be profitable even if any of our products under development

are successfully developed and produced and thereafter commercialized. Even if we achieve profitability in the future, we may not be

able to sustain profitability in subsequent periods.

Even

if we succeed in commercializing one or more of our product candidates, we expect to continue to incur substantial research and development

and other expenditures to develop and market additional product candidates. The size of our future net losses will depend, in part, on

the rate of future growth of our expenses and our ability to generate revenue. Our prior losses and expected future losses have had and

will continue to have an adverse effect on our stockholders’ equity and working capital.

We

will need additional capital to conduct our operations and develop our products, and our ability to obtain the necessary funding is uncertain.

We

have used a significant amount of cash since inception to finance the continued development and testing of our product candidates, and

we expect to need substantial additional capital resources to develop our product candidates going forward and launch and commercialize

any product candidates for which we receive regulatory approval.

We

may not be successful in generating and/or maintaining operating cash flow, and the timing of our capital expenditures and other expenditures

may not result in cash sufficient to sustain our operations through the commercialization of our product candidates. If financing is

not sufficient and additional financing is not available or available only on terms that are detrimental to our long-term survival, it

could have a material adverse effect on our ability to continue to function. The timing and degree of any future capital requirements

will depend on many factors, including:

● scientific and clinical progress in our research and development programs;

● our progress with pre-clinical development and clinical trials;

● the time and costs involved in obtaining regulatory approvals;

● the number and type of product candidates that we pursue.

Additional

financing through strategic collaborations, public or private equity or debt financings or other financing sources may not be available

on acceptable terms, or at all. Additional equity financing could result in significant dilution to our stockholders, and any debt financings

will likely involve covenants restricting our business activities. Further, if we obtain additional funds through arrangements with collaborative

partners, these arrangements may require us to relinquish rights to some of our technologies, product candidates or products that we

would otherwise seek to develop and commercialize on our own.

If

sufficient capital is not available, we may be required to delay, reduce the scope of or eliminate one or more of our research or product

development initiatives, any of which could have a material adverse effect on our financial condition or business prospects.

Our

research and development costs could exceed our projections requiring us to significantly modify our planned operations.

Our

currently projected expenditures for 2023 include approximately $10.2 million for research and development. The actual cost

of our programs could differ significantly from our current projections if we change our planned development process. In the event that

actual costs of our clinical program, or any of our other ongoing research activities, are significantly higher than our current estimates,

we may be required to significantly modify our planned level of operations.

The

successful development of any product candidate is highly uncertain. It is difficult to reasonably estimate or know the nature, timing

and costs of the efforts necessary to complete the development of, or the period in which material net cash inflows are expected to commence

from any product candidate, due to the numerous risks and uncertainties associated with developing drugs. Any failure to complete any

stage of the development of products in a timely manner could have a material adverse effect on our operations, financial position and

liquidity.

We

previously identified material weaknesses in our internal controls over financial reporting. While we have worked to remedy these weaknesses,

if we fail to maintain an effective system of internal control over financial reporting, we may not be able to accurately report our

financial results or prevent fraud. As a result, stockholders could lose confidence in our financial and other public reporting, which

would harm our business and the trading price of our common stock.

Effective

internal control over financial reporting is necessary for us to provide reliable financial reports and, together with adequate disclosure

controls and procedures, are designed to prevent fraud. Any failure to implement required new or improved controls, or difficulties encountered

in their implementation, could cause us to fail to meet our reporting obligations. Ineffective internal control could also cause investors

to lose confidence in our reported financial information, which could have a negative effect on the trading price of our common stock.

We

previously identified material weaknesses in our internal control over financial reporting as a company, which resulted in unauthorized

transactions involving our assets and common stock. As defined in Regulation 12b-2 under the Securities Exchange Act of 1934, or the

Exchange Act, a “material weakness” is a deficiency, or combination of deficiencies, in internal control over financial reporting,

such that there is a reasonable possibility that a material misstatement of our annual or interim consolidated financial statements will

not be prevented, or detected on a timely basis.

We

have taken measures to mitigate the issues identified and implement a functional system of internal controls over financial reporting.

However, such controls may become inadequate due to changes in conditions, or the degree of compliance with such policies or procedures

may deteriorate, which could result in the discovery of additional material weaknesses and deficiencies. In any event, the process of

determining whether our existing internal control over financial reporting is compliant with Section 404 of the Sarbanes-Oxley Act, or

Section 404, and sufficiently effective requires the investment of substantial time and resources, including by certain members of our

senior management.

We

are required, pursuant to Section 404, to furnish a report by management on, among other things, the effectiveness of our internal control

over financial reporting. However, for as long as we are a “smaller reporting company,” our independent registered public

accounting firm will not be required to attest to the effectiveness of our internal control over financial reporting pursuant to Section

404. While we could be a smaller reporting company for an indefinite amount of time, and thus relieved of the above-mentioned attestation

requirement, an independent assessment of the effectiveness of our internal control over financial reporting could detect problems that

our management’s assessment might not. Such undetected material weaknesses in our internal control over financial reporting could

lead to financial statement restatements and require us to incur the expense of remediation.

Our

intellectual property may be compromised.

Part

of our value going forward depends on the intellectual property rights that we have been and are acquiring. There may have been many

persons involved in the development of our intellectual property, and we may not be successful in obtaining the necessary rights from

all of them. It is possible that in the future, third parties may challenge our intellectual property rights. We may not be successful

in protecting our intellectual property rights. In either event, we may lose the value of our intellectual property, and if so, our business

prospects may suffer.

If

our efforts to protect the proprietary nature of the intellectual property related to our technologies are not adequate, we may not be

able to compete effectively in our market and our business would be harmed.

We

rely upon a combination of patents, trade secret protection and confidentiality agreements to protect the intellectual property related

to our technologies. Any disclosure to or misappropriation by third parties of our trade secret or other confidential information could

enable competitors to quickly duplicate or surpass our technological achievements, thus eroding any competitive advantage we may derive

from this information.

The

strength of patents in the biotechnology and pharmaceutical field involves complex legal and scientific questions and can be uncertain.

The patent applications we own or license may fail to result in issued patents in the United States or in foreign countries. Third parties

may challenge the validity, enforceability or scope of any issued patents we own or license or any applications that may be issued as

patents in the future, which may result in those patents being narrowed, invalidated or held unenforceable. Even if they are unchallenged,

our patents and patent applications may not adequately protect our intellectual property or prevent others from developing similar products

that do not fall within the scope of our patents. If the breadth or strength of protection provided by the patents we hold or pursue

is threatened, our ability to commercialize any product candidates with technology protected by those patents could be threatened. Further,

if we encounter delays in our clinical trials, the time during which we would have patent protection for any covered product candidates

that obtain regulatory approval would be reduced. Since patent applications in the United States and most other countries are confidential

for a period of time after filing, we cannot be certain at the time of filing that we are the first to file any patent application related

to our product candidates.

In

addition to the protection afforded by patents, we seek to rely on trade secret protection and confidentiality agreements to protect

proprietary know-how that is not patentable, processes for which patents are difficult to enforce and any other elements of our discovery

platform and drug development processes that involve proprietary know-how, information or technology that is not covered by patents or

not amenable to patent protection. Although we require all of our employees and certain consultants and advisors to assign inventions

to us, and all of our employees, consultants, advisors and any third parties who have access to our proprietary know-how, information

or technology to enter into confidentiality agreements, our trade secrets and other proprietary information may be disclosed or competitors

may otherwise gain access to such information or independently develop substantially equivalent information. Further, the laws of some

foreign countries do not protect proprietary rights to the same extent or in the same manner as the laws of the United States. As a result,

we may encounter significant difficulty in protecting and defending our intellectual property both in the United States and abroad. If

we are unable to prevent material disclosure of the trade secret intellectual property related to our technologies to third parties,

we may not be able to establish or maintain the competitive advantage that we believe is provided by such intellectual property, which

could materially adversely affect our market position and business and operational results.

Claims

that we infringe the intellectual property rights of others may prevent or delay our drug discovery and development efforts.

Our

research, development and commercialization activities, as well as any product candidates or products resulting from those activities,

may infringe or be accused of infringing a patent or other form of intellectual property under which we do not hold a license or other

rights. Third parties may assert that we are employing their proprietary technology without authorization. There may be third-party patents

of which we are currently unaware, with claims that cover the use or manufacture of our product candidates or the practice of our related

methods. Because patent applications can take many years to issue, there may be currently pending patent applications that may later

result in issued patents that our product candidates may infringe. In addition, third parties may obtain patents in the future and claim

that use of our technologies infringes one or more claims of these patents. If our activities or product candidates infringe the patents

or other intellectual property rights of third parties, the holders of such intellectual property rights may be able to block our ability

to commercialize such product candidates or practice our methods unless we obtain a license under the intellectual property rights or

until any applicable patents expire or are determined to be invalid or unenforceable.