Monopar Therapeutics

You should read the following discussion in conjunction with our financial statements as of December 31, 2024, and the notes to such financial statements included elsewhere in this Annual Report on Form 10-K.

Overview

Monopar Therapeutics Inc. (“Monopar,” the “Company,” “we,” “us,” and “our” and similar terms mean Monopar Therapeutics Inc. and its subsidiaries except where the context otherwise requires) is a clinical-stage biopharma company developing an innovative treatment for Wilson disease and novel radiopharmaceuticals for oncology. Our Wilson disease product candidate is ALXN1840, a late-stage, investigational once-daily, oral medicine. Our radiopharmaceutical program consists of MNPR-101, a proprietary humanized monoclonal antibody that is being developed across multiple product candidates, conjugated with different radioisotopes, for the treatment of advanced solid tumors expressing urokinase plasminogen activator receptor (“uPAR”). MNPR-101-Zr is our clinical-stage radiodiagnostic imaging agent comprised of MNPR-101 conjugated to zirconium-89; MNPR-101-Lu is our clinical-stage radiotherapeutic comprised of MNPR-101 conjugated to lutetium-177; and MNPR-101-Ac is our late-preclinical stage radiotherapeutic comprised of MNPR-101 conjugated to actinium-225.

We build our drug development pipeline through both in-house efforts and licensing of late preclinical and clinical-stage therapeutics, leveraging our scientific and clinical expertise to mitigate risk and to accelerate development.

Our Product Pipeline

Our Product Candidates

ALXN1840 for Wilson Disease

ALXN1840 (bis-choline tetrathiomolybdate) is an investigational once-daily, orally-administered drug candidate in development for the treatment of Wilson disease, a rare and progressive genetic condition in which the body’s pathway for removing excess copper is compromised. Over time this excess copper results in the build-up of toxic copper levels in the liver, brain, and other organs, leading to damage that greatly impacts a patient's life. Patients can develop a wide range of symptoms, including liver disease and psychiatric or neurological manifestations, such as personality changes, tremors and difficulty walking, swallowing or talking. In some cases, the damage and loss of function may be irreversible. ALXN1840 is a novel small molecule designed to selectively and tightly bind and remove copper from the body’s tissues and blood. ALXN1840 has been granted Orphan Drug Designation and Fast Track designation in the U.S. and orphan designation in the EU.

Wilson disease affects 1 in 30,000 live births in the U.S. There are an estimated 10,000 Wilson disease patients in the U.S., with an estimated 5,000 patients currently diagnosed and being treated with standard-of-care (“SoC”).

Alexion completed a pivotal Phase 3 clinical trial of Wilson disease patients on ALXN1840, which met its primary endpoint in assessing copper mobilization over 48 weeks, defined as daily mean Area Under the Effect Curve (“AUEC”) for directly measured non-ceruloplasmin-bound copper (“dNCC”). In the trial, 214 patients were enrolled, and the trial was randomized, rater-blinded, and multi-centered, designed to evaluate the efficacy and safety of ALXN1840 versus SoC in patients with Wilson disease aged 12 years and older. Patients taking ALXN1840 experienced rapid copper mobilization, with a response at 4 weeks and sustained through the 48 weeks. The primary endpoint demonstrated three-times greater copper mobilization with ALXN1840 compared to the SoC arm (Least Square Mean Difference (“LSM Diff”) 2.18 µmol/L; p< 0.0001), including in patients who had been treated previously with SoC for an average of 10 years.

Additionally, data from patients in the Phase 3 clinical trial who exhibited at the time of study entry an incomplete and/or intolerant response (“IIR”) to prior treatment on SoC showed that more patients on ALXN1840 as compared to SoC in the trial exhibited improved neurological symptoms (45% vs. 20%, respectively) and fewer exhibited worsened neurological symptoms (5% vs. 17%, respectively) when assessed on a reported Minimal Clinically Important Difference (“MCID”) scale. These data suggest ALXN1840 may reduce the risk of neurological worsening when compared to SoC.

Alexion terminated the ALXN1840 program in Wilson disease based on its review of results from Phase 2 mechanistic trials, and discussions with regulatory authorities. Their analysis of the Phase 2 mechanistic trials was that they failed to demonstrate net-negative copper balance in Wilson disease patients during short-term treatment with ALXN1840 and to reduce hepatic copper concentration after treatment with ALXN1840. The decision not to progress the ALXN1840 program in Wilson disease was not related to any safety signals.

Following Alexion’s decision, in October 2024, we entered into an exclusive worldwide license for the program and assumed responsibility for all future global development and commercialization activities. In the near term, we will be focusing on assembling a regulatory package and submitting an NDA. We expect to submit an NDA to the FDA inearly 2026.

MNPR-101 for Radiopharmaceutical Use

The radiopharmaceutical space has had numerous positive developments and announcements over the past 18 months, from acquisitions to clinical data to reimbursement rates to commercial demand. Since December 2023, four significant acquisitions have been publicly announced or completed with upfront payments ranging from approximately $1 billion to over $4 billion (BMS/RayzeBio, AstraZeneca/Fusion Pharma, Eli Lilly/POINT BioPharma, and Novartis/Mariana Oncology).

MNPR-101 is our proprietary humanized monoclonal antibody that we are developing for advanced solid tumors expressing uPAR. This novel first-in-class radiopharmaceutical program aims to identify and selectively bind to and kill the tumors expressing uPAR, while minimizing damage to healthy tissue. The program uses MNPR-101 to target uPAR as a means to accurately deliver radioisotope payloads to the tumors.

uPAR is highly expressed in multiple types of tumors, including breast, pancreatic, and colorectal cancers but not on most normal cells. For example, it is estimated that the tumors and/or tumor associated cells in 97% of breast, 89% of bladder, 87% of pancreatic and 85% of colorectal cancer patients express uPAR. Moreover, several Phase 1 PET imaging studies in advanced cancer patients show that uPAR can be clearly detected in tumors, making it a potentially attractive target for radiopharmaceuticals.

We have demonstrated promising preclinical data to-date for our MNPR-101 radiopharmaceutical program. Positron emission tomography (“PET”) imaging data of preclinical human tumor xenograft mouse models for triple-negative breast, colorectal, and pancreatic tumors expressing uPAR display high, selective and durable uptake of MNPR-101-Zr, our imaging agent. Additionally, preclinical triple-negative breast and pancreatic cancer mouse model studies with MNPR-101 conjugated to therapeutic radioisotopes lutetium-177 and actinium-225 have shown promising anti-tumor activity. Overall, the preclinical imaging and therapeutic efficacy study results demonstrate the potential utility of MNPR-101 as a precision targeting radiopharmaceutical agent for both imaging and therapy in multiple cancer types. We are currently actively enrolling our Phase 1 imaging/dosimetry and our therapeutic clinical trials in Australia for MNPR-101-Zr and MNPR-101-Lu in patients with advanced cancer, respectively.

MNPR-101-Zr Phase 1 Imaging and Dosimetry Clinical Trial

In February 2024, we received Human Research Ethics Committee (“HREC”) clearance in Australia to commence a first-in-human Phase 1 imaging and dosimetry clinical trial for MNPR-101-Zr in patients with advanced solid tumors. The trial, which is anticipated to enroll approximately 12 patients, utilizes total body positron emission tomography–computed tomography (“PET/CT”) imaging to assess tumor uptake, normal organ biodistribution, and safety. The study is being conducted at Melbourne Theranostic Innovation Centre (“MTIC”), headed by Professor Rodney Hicks, MBBS(Hons), MD, FRACP, FICIS, FAAHMS, and uses one of the world's most sensitive clinical total-body PET/CT scanners, the Siemens Biograph Vision Quadra, to image the targeting ability of MNPR-101-Zr in cancer patients.

In April 2024, we launched the Phase 1 trial, and in July 2024, we announced the enrollment of our first patient. In September 2024, we announced positive early clinical data validating the tumor-targeting ability of MNPR-101-Zr, which was then presented at the European Association of Nuclear Medicine (“EANM”) Annual Congress 2024. The results of a total-body PET image taken at 168 hours (7 days) post-administration of MNPR-101-Zr in the first uPAR-positive patient enrolled in the trial demonstrated the specificity, durability, and uptake of MNPR-101-Zr in the metastatic tumors relative to normal tissue (see the images below). The regions of higher uptake also aligned with the locations of the previously observed metastatic tumors on conventional F-fluorodeoxyglucose (“FDG”) PET imaging. These results suggest a favorable targeting profile for MNPR-101. We continue to enroll patients for the MNPR-101-Zr Phase 1 clinical trial.

MNPR-101-Lu Phase 1a Therapeutic Clinical Trial

Following encouraging Phase 1 clinical data regarding tumor uptake, biodistribution, and safety of MNPR-101-Zr, we decided to evaluate the efficacy in humans of a therapeutic version of MNPR-101. For our initial MNPR-101-RIT candidate, we selected the beta-emitting radioisotope lutetium-177. In August 2024, we received regulatory clearance in Australia to commence a first-in-human Phase 1a clinical trial of our novel uPAR-targeted radiopharmaceutical therapy MNPR-101-Lu in patients with advanced solid tumors. We initiated the trial in October 2024, and it is currently active and enrolling. In order to be dosed with the therapeutic, the patient’s cancer is imaged using MNPR-101-Zr with a PET/CT scanner, and only those patients with scans showing sufficient uPAR expression are dosed in the therapeutic clinical trial.

MNPR-101-Ac Therapeutic Preclinical Development

In addition to our clinical product candidates, we are developing MNPR-101-Ac, a late-preclinical stage radiotherapeutic candidate comprised of MNPR-101 conjugated to alpha-emitting radioisotope actinium-225. MNPR-101-Ac is being developed for the treatment of advanced solid tumors.

** Additional Radiopharmaceutical Opportunities**

We are also exploring opportunities to expand our radiopharmaceutical pipeline, primarily through internal development efforts. In October 2024, we announced a filing of a provisional patent application for new radiopharmaceutical compounds and a family of linkers used to connect radioisotopes with targeting agents, including our uPAR-targeting antibody MNPR-101. This provisional patent application and a subsequent utility patent filing could enable us to use these linkers to create new proprietary radiopharmaceuticals to pursue well-established cancer targets.

** License,** Development and Collaboration Agreements

Alexion, AstraZeneca Rare Disease

On October 23, 2024, the Company executed a License Agreement with Alexion, pursuant to which Alexion granted us an exclusive worldwide license for the development and commercialization of ALXN1840, a drug candidate for Wilson disease. As initial upfront consideration for the License Agreement, we issued Alexion 387,329 shares (representing 9.9% of our outstanding shares at the time) of our common stock and agreed to make an upfront cash payment of $4.0 million. A cash payment of $1.0 million was paid at the time of signing and the remaining $3.0 million was paid in January 2025, pursuant to the terms of the License Agreement. We agreed to an anti-dilution provision that entitled Alexion to receive additional shares at no cost to maintain their 9.9% ownership until we raised the next $25.0 million of common stock, subject to a maximum of 705,015 shares unless we obtained stockholder approval. Pursuant to the anti-dilution right, we issued an additional 157,188 shares of our common stock to Alexion. No further obligations exist pursuant to Alexion's anti-dilution right.

Additionally, we are obligated to make milestone payments of up to $94.0 million for the achievement of regulatory approval and sales related milestones. In addition, the Company is obligated to pay tiered royalties based on net sales in the low- to mid-double digit range. We have also given Alexion the right of first negotiation regarding any rights should we intend to sublicense ALXN1840. Furthermore, we will have to pay Alexion a percentage in the mid-double digits of any sublicensing income received by us. As part of this License Agreement, we have assumed an agreement from Alexion, under which we will also owe a third-party single digit millions in cash milestone payment upon regulatory approval in Europe and a single digit percentage royalty on net sales in Europe.

NorthStar Medical Radioisotopes, LLC (“NorthStar”)

In June 2024, we entered into a long-term, non-exclusive master supply agreement with NorthStar under which NorthStar will provide us with the therapeutic radioisotope actinium-225 (“Ac-225”). The original collaboration agreement was amended at that time to clarify certain economic and other terms related to jointly developed intellectual property rights for our MNPR-101 for radiopharmaceutical use. We have acquired these rights from NorthStar, together with certain broad, jointly-developed intellectual property pertaining to MNPR-101, giving us full ownership and title to our lead MNPR-101 radiopharmaceutical platform. We will jointly share ownership of the filed patent application on the use of PCTA as a linker with Ac-225, which has shown that MNPR-101 has superior binding and yield with Ac-225 over the current industry-leading linker, DOTA.

To humanize our MNPR-101 antibody, we have taken a non-exclusive license to XOMA (US) LLC’s humanization technology and know-how. Humanization involves replacing most of the non-critical parts of the mouse sequence of an antibody with the human sequence to minimize the ability of the human immune system to recognize this antibody as foreign. As such, MNPR-101 has been engineered to be 95% human sequence using the XOMA technology. Under the terms of the non-exclusive license with XOMA Ltd., we are to pay only upon the achievement of clinical, regulatory and sales milestones, potentially totaling $14.925 million. The agreement does not require the payment of sales royalties. As of March 14, 2025, we had not reached any milestones and had not been required to pay XOMA Ltd. any funds under this license agreement. The first milestone payment is payable upon first dosing of a human patient in a Phase 2 clinical trial. We are currently conducting Phase 1 clinical trialsand cannot reliably predict when we will be able to commence a Phase 2 clinical trial, if at all.

Intellectual Property Portfolio and Exclusivity

An important part of our strategy is obtaining patent protection to help preserve the proprietary nature of our product candidates, and to prevent others from developing similar competitive agents. Our patent portfolio includes issued patents and pending patent applications in the U.S. and in foreign countries. Our general practice is to seek patent protection in major markets worldwide.

ALXN1840

Pursuant to the terms of our license agreement with AstraZeneca for ALXN1840, we obtained the intellectual property portfolio for ALXN1840, including exclusive license and prosecution of over 86 patent applications granted, published, or pending in over 30 countries worldwide. ALXN1840 has orphan drug designation for the treatment of Wilson disease in the U.S. and EU as well as Fast Track designation from the FDA. In the U.S., these include 5 granted patents, 6 published patent applications, and 2 private and pending applications with the earliest expiration expected in 2038. The patents cover methods of treatment and dosing of ALXN1840 for Wilson disease, methods of manufacture for tetrathiomolybdate, and certain drug product formulations.

MNPR-101

Our patent portfolio for our MNPR-101 antibody as well as its epitope consists of two issued U.S. composition of matter and their methods of use patents and corresponding issued patents in Japan. The U.S. patent covering the composition of matter of MNPR-101 will expire in 2027 with the corresponding Japanese patent expiring in 2025, and the U.S. patent covering the MNPR-101 epitope will expire in 2029 with corresponding Japanese patent expiring in 2027. Being a novel biologic, MNPR-101 is eligible for 12 years of exclusivity in the U.S. under the Biologics Price Competition and Innovation Act (“BPCI Act”), and it will benefit from varying durations of similar exclusivity in numerous other count ries. The earliest to expire of the patent applications for radiopharmaceutical derivatives of MNPR-101, if granted, would expire in 2041.

Patent life determination depends on the date of filing of the application and other factors as promulgated under the patent laws. In most countries, including the U.S., the patent term is generally 20 years from the earliest claimed filing date (the priority date) of a non-provisional patent application in the applicable country, not taking into consideration any potential patent term adjustment that may be filed in the future or any regulatory extensions that may be obtained. Some of our patents are currently near expiration and we may pursue patent term extensions for these where appropriate. See “Risk Factors – Risks Related to our Intellectual Property.”

MNPR-101 for Radiopharmaceutical Use

Radiopharmaceutical therapy is a promising approach to treat cancer and other diseases using radioactive isotopes, such aslutetium-177 and actinium-225 bound with proteins/antibodies to target and kill cells.

In collaboration with NorthStar, we filed a provisional patent application entitled “Precision Radioimmunotherapeutic Targeting of uPAR for Treatment of Severe COVID-19 Disease” with the U.S. Patent and Trademark Office (“USPTO”) on June 15, 2020. A full international application (International Application Number PCT/US2021/037416) that claims priority to the provisional filing date was filed under the Patent Cooperation Treaty (“PCT”) on June 15, 2021. This application covers novel compositions and uses of imaging and cytotoxic radioisotopes attached to antibodies that bind to uPAR, thereby creating precision targeted radiotherapeutics, also known as uPRITs, for the treatment of severe COVID-19 and other respiratory diseases.

In May 2021, we and NorthStar filed a provisional patent application with the USPTO titled “Bio-Targeted Radiopharmaceutical Compositions Containing Ac-225 and Methods of Preparation.”A full international patent application (International Application Number PCT/US2022/0378956) titled, “Trivalent Radioisotope Bio-Targeted Radiopharmaceutical, Methods of Preparation and Use” that claims priority to the provisional filing date was filed under the PCT on May 20, 2022.

Also in May 2021, we and NorthStar filed a provisional composition of matter patent application titled “Urokinase Plasminogen Activator Receptor-Targeted Radiopharmaceutical,” which covers a radiotherapeutic consisting of our proprietary antibody MNPR-101 bound to Ac-225 via the isotope binding agent PCTA. A full international patent application (International Application Number PCT/US2022/0409751) titled, “Urokinase Plasminogen Activator Receptor-Targeted Radiopharmaceutical” that claims priority to the provisional filing date was filed under the PCT, also on May 20, 2022. This radiopharmaceutical demonstrated 98% radiochemical purity and high stability and has the potential to be a highly selective, potent treatment for a variety of cancers, severe COVID-19, and other diseases characterized by aberrant uPAR expression.

On June 11, 2024, Monopar and Northstar announced that the companies amended and extended their radiopharmaceutical collaboration. As part of the amended agreement, Monopar received all rights and title to the PCT/US2021/037416, PCT/US2022/0409751, and joint ownership with certain exclusive rights of PCT/US2022/0409751.

In April 2024, Monopar announced the filing of a provisional patent protecting certain MNPR-101 radiopharmaceutical optimization inventions, and in October 2024, Monopar announced a further addition to its radiopharmaceutical intellectual property portfolio with a provisional patent filing on new radiopharmaceutical compounds and linkers.

Manufacturing

ALXN1840

We do not currently own or operate manufacturing facilities for the production or testing of ALXN1840, nor do we have plans to develop our own manufacturing operations in the foreseeable future. We expect to depend on third-party contract manufacturers for all our required raw materials, Active Pharmaceutical Ingredients (“API”), and finished drug products. We plan on utilizing elements of the existing supply chain that was used in the most recent clinical studies for ALXN1840, and we are in discussions to engage these vendors as our contract manufacturers for the supply of API and drug product.

MNPR-101

We do not currently own or operate manufacturing facilities for the production or testing of our MNPR-101 radiopharmaceutical program. We presently depend on third-party contract manufacturers for all our required raw materials, API, and finished drug products for our preclinical and clinical studies. We are having clinical batches of MNPR-101-Zr and MNPR-101-Lu manufactured by external vendors for use in treating patients in our Phase 1 imaging and dosimetry trial, therapeutic trial and compassionate use protocols. In addition, we are in the process of setting up a radiopharmaceutical laboratory and exploring potential manufacturing operations.

Wilson Disease Competition

While there is no cure for Wilson disease, the FDA has approved several therapeutic agents for the treatment of Wilson disease. Treatment approaches include chelation therapies and Zinc supplements which prevents dietary copper absorption. Chelation therapies utilize chelators, which are drugs that bind to metals and minerals in the bloodstream to allow them to be excreted by the body. Existing chelation therapies are penicillamine-based products, which include Cuprimine (Bausch Health Companies Inc.) and Depen (Meda Pharmaceuticals Inc., a Viatris company), and trientine-based products, which include Syprine (Bausch Health Companies Inc.) and Cuvrior (Orphalan SA). Zinc acetate is marketed as Galzin in the U.S. and as Wilzin in Europe (rights to both geographies belong to Eton Pharmaceuticals, Inc). Gene therapy is also being investigated as a potential therapeutic application for the treatment of Wilson disease by addressing the mutated ATP7B copper transporter gene. We are aware of two gene therapies that are in clinical development for the treatment of Wilson disease: UX701 (Ultragenyx Pharmaceutical Inc.) and VTX-801 (Vivet Therapeutics).

Oncology Market Competition

The pharmaceutical industry in general, and the oncology therapeutics sector in particular, are characterized by intense competition. We face competition from both pharmaceutical and biotechnology companies, many of which are larger and better financed than us. We also face competition from academic and government laboratories in our efforts to develop and commercialize new oncology therapeutics. The therapeutics that we are developing, if successfully commercialized, will have to compete with existing therapeutics already on the market and novel therapeutics currently in development, as well as new therapeutics that may be discovered and developed in the future. Our product candidates will also have to compete with alternate treatment modalities, such as improvements in radiation treatments, which are also subject to continuous innovation and improvement. Additional information can be found in the section entitled “Risk Factors – Risks Related to Our Business Operations and Industry.”

MNPR-101 Radiopharmaceutical Program Competition

Our MNPR-101 radiopharmaceutical program, including MNPR-101-Zr for imaging and MNPR-101-Lu and MNPR-101-Ac for therapy, is susceptible to all the competitive factors listed above under Oncology Market Competition. In addition to the current standard of care for patients with advanced cancers, we consider our most direct competitors to be companies that are developing targeted radiopharmaceuticals for the treatment of cancer. There are several companies that are developing radiopharmaceuticals for cancers including, but not limited to: Novartis AG, Bayer AG, Bristol Myers Squibb, Eli Lilly and Company, Actinium Pharmaceuticals, Inc., Johnson & Johnson, Telix Pharmaceuticals Limited, Lantheus Holdings, Inc., AstraZeneca, and Genentech, as well as numerous early-stage companies that are developing a wide range of targeted radiopharmaceuticals for advanced cancers. For the uPAR-targeted radiopharmaceuticals, CuraSight, a Danish biotech company, is currently developing a clinical-stage non-antibody-based uPAR radiodiagnostic and radiotherapeutic pair which binds to a different epitope on uPAR as compared to MNPR-101.

Government Regulation and Product Approval

Government authorities in the U.S., at the federal, state and local level, and in other countries such as Australia, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of products such as those we are developing. The pharmaceutical product candidates that we develop must be approved by the FDA and the Therapeutics Goods Administration (“TGA”) before they may be legally marketed in the U.S. and Australia, respectively. See “Risk Factors – Risks Related to Clinical Development and Regulatory Approval.”

U.S. Pharmaceutical Product Development Process

In the U.S., the FDA regulates pharmaceutical products under the Federal Food, Drug and Cosmetic Act (“FDCA”) and implements regulations. Pharmaceutical products are also subject to other federal, state and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development, approval or after approval process may subject an applicant to administrative or judicial enforcement. FDA enforcement could result in refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls, product seizures, total or partial suspension of production or distribution injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us. The process required by the FDA before a non-biological pharmaceutical product may be marketed in the U.S. generally involves the following:

The lengthy process of seeking required approvals and the continuing need for compliance with applicable statutes and regulations require the expenditure of substantial resources, and make approvals inherently uncertain.

Before testing any compounds with potential therapeutic value in humans, the pharmaceutical product candidate enters the preclinical testing stage. Preclinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as well as in-vitro and animal studies to assess the potential safety and activity of the pharmaceutical product candidate. These early proof-of-principle studies are done using sound scientific procedures and thorough documentation. The conduct of single and repeat dose toxicology and toxicokinetic studies in animals must comply with federal regulations and requirements, including GLP. The sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA has concerns and notifies the sponsor. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical study can begin. If resolution cannot be reached within the 30-day review period, either the FDA places the IND on clinical hold, or the sponsor withdraws the application. The FDA may also impose clinical holds on a pharmaceutical product candidate at any time before or during clinical studies due to safety concerns or non-compliance. Accordingly, it is not certain that submission of an IND will result in the FDA allowing clinical studies to begin, or that, once begun, issues will not arise that may suspend or terminate such clinical studies.

During the development of a new drug, sponsors are given opportunities to meet with the FDA at certain points. These points may be prior to submission of an IND, at the end of Phase 2, and before an NDA or BLA is submitted. Meetings at other times may be requested. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the sponsor to ask specific questions to the FDA, for the FDA to provide advice, and for the sponsor and FDA to reach agreement on the next phase of development. Sponsors typically use the end of Phase 2 meeting to discuss their Phase 2 clinical results and present their plans for the pivotal Phase 3 clinical (registration) trial(s) that they believe will support approval of the new drug. A sponsor may be able to request a Special Protocol Assessment (“SPA”), the purpose of which is to reach agreement with the FDA on the Phase 3 clinical trial protocol design and analyses that will form the primary basis of an efficacy claim.

According to FDA guidance for industry on the SPA process, a sponsor which meets the prerequisites may make a specific request for an SPA and provide information regarding the design and size of the proposed clinical trial. The FDA’s goal is to evaluate the protocol within 45 days of the request to assess whether the proposed trial is adequate, and that evaluation may result in discussions and a request for additional information. An SPA request must be made before the proposed trial begins, and all open issues must be resolved before the trial begins. If a written agreement is reached, it will be documented and made part of the IND record. The agreement will be binding on the FDA and may not be changed by the sponsor or the FDA after the trial begins except with the written agreement of the sponsor and the FDA or if the FDA determines that a substantial scientific issue essential to determining the safety or efficacy of the drug was identified after the testing began.

Clinical studies involve the administration of the pharmaceutical product candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the clinical study sponsor’s control. Clinical studies are conducted under protocols detailing, among other things, the clinical study objectives, dosing procedures, subject selection and exclusion criteria, how the results will be analyzed and presented and the parameters to be used to monitor subject safety. Each protocol must be submitted to the FDA as part of the IND. Clinical studies must be conducted in accordance with GCP guidelines. Further, each clinical study must be reviewed and approved by an independent institutional review board (“IRB”), at, or servicing, each institution at which the clinical study will be conducted. An IRB is charged with protecting the welfare and rights of study participants and is tasked with considering such items as whether the risks to individuals participating in the clinical studies are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the informed consent form that must be provided to each clinical study subject or his/her legal representative and monitors the clinical study until completed.

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

Concurrent with clinical studies, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the pharmaceutical product as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the pharmaceutical product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final pharmaceutical product. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the pharmaceutical product candidate does not undergo unacceptable deterioration over its shelf life.

U.S. Review and Approval Processes

The results of product development, preclinical studies and clinical studies, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the pharmaceutical product, proposed labeling and other relevant information are submitted to the FDA as part of an NDA or BLA requesting approval to market the product. The submission of an NDA or BLA is subject to the payment of substantial user fees; a waiver of such fees may be obtained under certain limited circumstances.

In addition, under the Pediatric Research Equity Act (“PREA”), an NDA, BLA or a supplement thereof must contain data to assess the safety and effectiveness of the pharmaceutical product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may grant deferrals for submission of data or full or partial waivers. Unless otherwise required by regulation, PREA does not apply to any pharmaceutical product for an indication for which orphan designation has been granted.

The FDA reviews all NDAs and BLAs submitted before it accepts them for filing and may request additional information rather than accepting an NDA or BLA for filing. Once a submission is accepted for filing, the FDA begins an in-depth review of the NDA or BLA. Under the goals and policies agreed to by the FDA under the Prescription Drug User Fee Act (“PDUFA”), the FDA has 10 months in which to complete its initial review of a standard NDA or BLA and respond to the applicant, and six months for a priority NDA or BLA. The FDA does not always meet its PDUFA goal dates for standard and priority NDAs or BLAs. The review process and the PDUFA goal date may be extended by three months if the FDA requests, or if the NDA or BLA sponsor otherwise provides additional information or clarification regarding information already provided in the submission within the last three months before the PDUFA goal date.

After the NDA or BLA submission is accepted for filing, the FDA reviews the NDA or BLA application to determine, among other things, whether the proposed product is safe and effective for its intended use, and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality and purity. The FDA may refer applications for novel pharmaceutical products or pharmaceutical products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions. During the pharmaceutical product approval process, the FDA also will determine whether a risk evaluation and mitigation strategy (“REMS”) is necessary to assure the safe use of the pharmaceutical product. If the FDA concludes that a REMS is needed, the sponsor of the NDA or BLA must submit a proposed REMS; the FDA will not approve the NDA or BLA without a REMS, if required.

Before approving an NDA or BLA, the FDA will inspect the facilities at which the product is manufactured. The FDA will not approve the product unless it determines that the manufacturing processes and facilities are compliant with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA or BLA, the FDA will typically inspect one or more clinical sites as well as the site(s) where the pharmaceutical product is manufactured to assure compliance with GCP and cGMP, respectively. If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information. In addition, the FDA will require the review and approval of product labeling.

The NDA and BLA review and approval process is lengthy and difficult, and the FDA may refuse to approve an NDA or BLA if the applicable regulatory criteria are not satisfied or may require additional clinical data or other data and information. Even if such data and information are submitted, the FDA may ultimately decide that the NDA or BLA does not satisfy the criteria for approval. Data obtained from clinical studies are not always conclusive and the FDA may interpret data differently than the sponsor's interpretations of the same data. The FDA will issue a complete response letter if the agency decides not to approve the NDA or BLA. The complete response letter usually describes all of the specific deficiencies in the NDA or BLA identified by the FDA. The deficiencies identified may be minor (for example, requiring labeling changes) or major (for example, requiring additional clinical studies). Additionally, the complete response letter may include recommended actions that the applicant might take to place the application in an updated condition for approval. If a complete response letter is issued, the applicant may either resubmit the NDA or BLA, addressing all the deficiencies identified in the letter, or withdraw the application.

If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling. In addition, the FDA may require Phase 4 testing which involves clinical studies designed to further assess pharmaceutical product safety and effectiveness and may require testing and surveillance programs to monitor the safety of the approved product that has been commercialized.

Regulatory Framework in Australia

The Therapeutic Goods Administration (“TGA”), through the Therapeutic Goods Act 1989 (the “Act”) and the Therapeutic Goods Regulations, is responsible for the efficacy, quality, safety and timely availability of drugs and medical devices in Australia. The mission statement of the TGA is “To ensure the safety, quality and efficacy of therapeutic goods available in Australia at a standard equal to that of comparable countries, and that premarket assessment of therapeutic goods is conducted within a reasonable time.” The TGA administers two pathways for clinical trials, the Clinical Trials Notification (“CTN”) and Clinical Trials Approval (“CTA”) schemes. These schemes provide avenues through which unapproved therapeutic goods may be lawfully supplied for use solely for experimental purposes in humans. The choice of which route to use (CTN or CTA) lies firstly with the Australian clinical trial sponsor and then with the Human Research Ethics Committee (“HREC”) that approves the protocol.

Clinical trials of medicines and biologics typically proceed through 'phases' of development, which are generally as follows: Phase 1 (human pharmacology), Phase 2 (therapeutic exploratory), and Phase 3 (therapeutic confirmatory). Phase 4 may be conducted for post-marketing surveillance or resolution of treatment uncertainties. Clinical development pathways are becoming less rigid with respect to phase, seamless adaptive trial designs and other cross-phase studies. Under the CTN and CTA schemes, the use of therapeutic goods in the trial must be in accordance with the Guideline for Good Clinical Practice, the National Statement and the protocol approved by the HREC responsible for monitoring the conduct of the trial. The trial sponsor must also comply with the requirements of any other relevant Commonwealth and/or state and territory legislation in relation to clinical trials and the supply of therapeutic goods.

A company or organization wishing to supply a therapeutic good in Australia must apply for market authorization from the TGA. The TGA assesses the application, and if market authorization is granted, the therapeutic good is entered on the Australian Register of Therapeutic Goods (“ARTG”). The TGA uses three pathways to evaluate a prescription medicine: the standard pathway, the priority review pathway and the provisional approval pathway. The TGA is required by statute to complete its evaluation for approval of a medicine in the standard pathway within 255 working days. The priority review pathway has a target timeframe of 150 working days and allows for a faster assessment of vital and life-saving prescription medicines. Sponsors of promising new prescription medicines (with only preliminary clinical data available) can seek fast-tracked registration through the provisional approval pathway. All pathways require evidence that the medicines are made according to Good Manufacturing Practice (“GMP”). GMP describes principles and procedures to ensure therapeutic goods are of high quality. The TGA inspects Australian (and some overseas) manufacturers to ensure compliance with GMP standards.

The evaluation and approval process of a new medicine in Australia generally follows:

Therapeutic goods generally need to be entered on the ARTG before they can be sold in Australia. However, there are several ways that patients can gain access to products that have not been approved for use in Australia:

Other International Regulations

In addition to regulations in the U.S. and Australia, there are a variety of foreign regulations governing clinical studies and commercial sales and distribution of our future product candidates. Whether or not FDA or HREC approval is obtained for a product, approval of a product must be obtained by the comparable regulatory authorities of foreign countries before clinical studies or marketing of the product can commence in those countries. The approval process varies from country to country, and the time may be longer or shorter than that required for FDA or HREC approval. The requirements governing the conduct of clinical studies, product licensing, pricing and reimbursement vary greatly from country to country. In addition, certain regulatory authorities in select countries may require us to repeat previously conducted preclinical and/or clinical studies under specific criteria for approval in their respective country, which may delay and/or greatly increase the cost of approval in certain markets targeted for approval by us.

Under the European Union (“EU”) regulatory systems, marketing applications for pharmaceutical products are typically submitted under a centralized procedure to the European Medicines Agency (“EMA”). The centralized procedure provides for the granting of a single marketing authorization that is valid for all EU member states. The EMA also has designations for Orphan Drugs, which, if applicable, can provide for faster review, lower fees and more access to advice during drug development. While the marketing authorization in the EU is centralized, the system for clinical studies (application, review and requirements) is handled by each individual country. Approval to run a clinical study in one country does not guarantee approval in any other country. The pharmaceutical industry in Canada is regulated by Health Canada. A New Drug Submission (“NDS”) is the equivalent of a U.S. NDA and must be filed to obtain approval to market a pharmaceutical product in Canada. Marketing regulations and reimbursement are subject to national and provincial laws. In Japan, applications for approval to manufacture and market new drugs must be approved by the Ministry of Health, Labor and Welfare. Nonclinical and clinical studies must meet the requirements of Japanese laws. Results from clinical studies conducted outside of Japan must be supplemented with at least a bridging clinical study conducted in Japanese patients.

In addition to regulations in Europe, Canada, Japan, Australia and the U.S., there are a variety of foreign regulations governing clinical studies, commercial distribution and reimbursement of future product candidates which we may be subject to as we pursue regulatory approval of ALXN1840, the MNPR-101 radiopharmaceutical program, or any future product candidates internationally.

Compliance with Environmental Laws

Historically, we have not operated our own laboratory or manufacturing facilities. As a result, we have not incurred any costs of compliance with environmental laws. However, we are in the process of setting up a radiopharmaceutical laboratory and exploring potential manufacturing operations. As a result, we would be subject to regulation under various state and federal environmental and worker safety laws, including the Occupational Safety and Health Act, the Resource Conservation and Recovery Act, the Comprehensive Environmental Response, Compensation and Liability Act and the Toxic Substances Control Act, each as amended from time to time. These and other laws and their implementing regulations govern our manufacture, use, storage, handling, transport and disposal of various biological, chemical, radioactive and other hazardous substances used in our operations and the wastes generated by those activities. We cannot eliminate the risk of accidental contamination or discharge and any resultant injury from these substances. We may face liability for any injury or contamination that results from our use or the use by third parties of those substances, and such liability may exceed our insurance coverage and our total assets. While our environmental and worker safety compliance costs have not had a material adverse effect on our results of operations, there can be no assurance that such costs will not be material in the future or that such future compliance will not have a material adverse effect on our business and operational results.

Employees

Our operations are currently managed by six individuals (including our executive chairman and our Acting Chief Medical Officer), of whom two have a PhD, two have an MD, two have an MBA, one has an MS in health economics and policy, one has an MS in electrical engineering and one has an MS in legal studies. They have worked at industry leading companies such as BioMarin Pharmaceutical Inc., Raptor Pharmaceuticals, Abbott Laboratories, Onyx Pharmaceuticals, and Amgen. As of March 14, 2025, we had sixteen employees; fourteen of whom were full-time. We anticipate hiring additional employees in regulatory affairs, clinical operations, and other departments, to help manage regulatory submissions, clinical studies, manufacturing, business development and corporate strategy. In addition, to complement our internal expertise, we have contracts with medical and scientific consultants, manufacturers, laboratories, and contract research and development organizations that specialize in various aspects of drug development including clinical development, preclinical development, manufacturing, quality assurance, and regulatory affairs.

Corporate Information

We were formed as a Delaware limited liability company in December 2014, with the name Monopar Therapeutics, LLC. In December 2015, we converted to a Delaware C corporation. Our principal executive offices are located at 1000 Skokie Blvd, Suite 350, Wilmette, IL 60091. Our telephone number is (847) 388-0349. Our corporate website is located atwww.monopartx.com. Any information contained in, or that can be accessed through our website, is not incorporated by reference in this Annual Report on Form 10-K.

Trademark Notice

All trademarks, service marks and trade names in this Annual Report on Form 10-K are the property of their respective owners. We have omitted the® and ™ designations, as applicable, for the trademarks used herein.

Available Information

Our corporate website is located atwww.monopartx.com. The reference to these website addresses does not constitute incorporation by reference of the information contained on the websites and should not be considered part of this Annual Report on Form 10-K.

We intend to satisfy any disclosure requirement under Item 5.05 of Form 8-K regarding an amendment to, or waiver from, a provision of our Code of Business Conduct and Ethics by posting such information on our website as specified above.