Monopar Therapeutics Stock

Monopar Therapeutics Inc. operates as a clinical stage biopharmaceutical company.

The company is focused on developing proprietary therapeutics designed to extend life or improve quality of life for cancer patients. The company is building a drug development pipeline through the licensing and acquisition of therapeutics in late preclinical and clinical development stages. The company leverages its scientific and clinical experience to help reduce the risk and accelerate the clinical development of the company's drug product candidates.

During 2022, the company expanded the number of clinical trial sites in its global Phase 2b/3 clinical trial of the company's lead product candidate, Validive (clonidine hydrochloride mucobuccal tablet; clonidine HCI MBT), for the prevention of chemoradiotherapy ('CRT')-induced severe oral mucositis ('SOM') in patients with oropharyngeal cancer ('VOICE' trial). The company has active sites in the U.S., Spain, France, Germany, and Poland; and has completed enrollment of the Phase 2b portion of the clinical trial with a go/no go interim analysis decision from the company's independent data monitoring committee anticipated by the end of March 2023. The company also continued enrolling in its U.S.-based open-label, Phase 1b clinical trial of camsirubicin for the treatment of advanced soft tissue sarcoma ('ASTS').

The company also, in collaboration with its partner, NorthStar Medical Radioisotopes, LLC, continues to move forward with the development of MNPR-101 for radiopharmaceutical use in advanced cancers. Finally, the company continues to develop MNPR-202, an analog of camsirubicin designed to potentially treat doxorubicin- and camsirubicin-resistant cancers, which is being tested in preclinical models by the company's collaborator, the Cancer Science Institute of Singapore at the National University of Singapore.

Product Candidates

Validive (clonidine hydrochloride mucobuccal tablet; clonidine HCI MBT)

Validive is designed to be used prophylactically to prevent SOM in patients undergoing CRT for oropharyngeal cancer ('OPC'). SOM is a painful and debilitating inflammation and ulceration of the mucous membranes lining the oral cavity and oropharynx in response to chemoradiation. The majority of patients receiving CRT to treat their OPC develop SOM, which remains one of the most common and devastating side effects of treatment in this indication. The potential clinical benefits to preventing SOM in patients include: reduced treatment discontinuations leading to potentially improved overall survival outcomes; reduced mouth and throat pain avoiding the need for feeding tube intervention; decreased long-term and often permanent debilitation arising from swallowing difficulties, neck and throat spasms, and lung complications due to food aspiration; and decreased reliance on pain medication. The company's mucobuccal tablet ('MBT') formulation is a novel delivery system for clonidine that allows for prolonged and enhanced local delivery of drug in the regions of mucosal radiation damage in patients with OPC. Validive has been granted fast track designation in the U.S., orphan drug designation in the EU, and has global intellectual property patent protection through mid-2029 not accounting for possible patent extensions.

In September 2017, the company exercised an option to license Validive from Onxeo S.A., the company that developed Validive through its Phase 2 clinical trial. In the completed Phase 2 clinical trial, Validive demonstrated clinically meaningful efficacy signals within the 64-patient OPC population randomized to placebo, Validive 50 µg dose and Validive 100 µg dose. The absolute incidence of SOM in OPC patients who received a dose of Validive 100 µg once per day was reduced by 26.3% (incidence rate of 65.2% in placebo, 45.0% in Validive 50 µg group, and 38.9% in Validive 100 µg group). The median time to onset of SOM was 37 days in the placebo cohort; 45 days in the Validive 50 µg cohort and no median time of onset was reached in the Validive 100 µg group since fewer than half of this cohort of patients developed SOM. There was also a 37.8% reduction in the median duration of the SOM for the Validive 100 µg group versus placebo (41.0 days placebo group, 34.0 days Validive 50 µg group, and 25.5 days Validive 100 µg group) in patients that developed SOM. Median duration of SOM across all patients, inclusive of both those that did and did not develop SOM, was 17 days in the placebo group and 0 days in each of the Validive 50 and 100 µg groups. A positive dose response was seen in each of these three clinical endpoints. Additionally, patients in the Validive cohorts in the Phase 2 clinical trial demonstrated a safety profile similar to that of placebo. Onxeo's promising preclinical studies and Phase 2 clinical trial have informed the design and conduct of an effective Phase 2b/3 and, if required, second confirmatory Phase 3 clinical program.

In February 2021, the company dosed the first patient in the company's Phase 2b/3 VOICE trial. In August 2021, the company successfully reached the company's original target of 20 activated clinical trial sites for the Phase 2b portion of the 2b/3 Validive VOICE trial, and in September 2021 the company received authorization to proceed with the VOICE clinical trial in multiple countries in Europe. In 2022, the company completed enrollment of the Phase 2b portion of the VOICE trial and commenced enrolling the Phase 3 portion. As of March 10, 2023, the company had 81 clinical sites activated and enrolling patients in the U.S. and Europe. To be prepared for a positive go/no-go decision based on the interim analysis, anticipated to occur by the end of March 2023, the company continues to activate additional sites globally. To complete the VOICE clinical program, including, if required, completing a second Phase 3 confirmatory clinical trial, the company will require additional funding in the millions or tens of millions of dollars (depending on if the company has consummated a collaboration or partnership or neither for Validive), which the company is planning to pursue within the next 12 months.

SOM typically arises in the immune tissue at the back of the tongue and throat, which comprise the oropharynx, and consists of acute severe tissue damage and pain that prevents patients from swallowing, eating and drinking. Validive stimulates the alpha-2 adrenergic receptor (alpha-2AR) on macrophages (white blood cells present in the immune tissues of the oropharynx) suppressing pro-inflammatory cytokine expression. Validive exerts its effects locally in the oral cavity and oropharynx over a prolonged period of time through its unique MBT formulation. Patients who develop SOM are also at increased risk of developing late onset toxicities, including trismus (jaw, neck, and throat spasms), dysphagia, and lung complications, which are often irreversible and lead to increased hospitalization and the need for further interventions sometimes years after completion of CRT. The prevention of SOM by Validive will have the potential to reduce treatment discontinuation and/or treatment delays potentially leading to improved survival outcomes and reducing or eliminating these long-term morbidities resulting from CRT.

The OPC target population for Validive is the most rapidly growing segment of head and neck cancer ('HNC') patients, with an estimated greater than 40,000 new cases of OPC in the U.S. alone in 2023. The growth in OPC is driven by the increasing prevalence of oral human papilloma virus ('HPV') infections in the U.S. and around the world.

Validive is an MBT of clonidine. The MBT formulation was developed to enhance drug delivery to the oral mucosa while minimizing systemic absorption. The Validive tablet is tasteless and odorless and is self-administered once daily by affixing it to the outside of the patient's upper gum where it dissolves slowly over a period of several hours, resulting in the extended release of clonidine into the oral cavity and oropharynx, the sites of SOM following CRT for OPC. Validive treatment begins on the first day of CRT and continue daily through the last day of radiation.

The majority of patients receiving CRT to treat their OPC develop SOM, which is one of the most common and devastating side effects of treatment in this indication.

While not designed by the company, Onxeo's promising preclinical studies and Phase 2 clinical trial have informed the design and conduct of an effective Phase 2b/3 VOICE clinical trial.

In response to COVID-19 and its effects on clinical trials, in 2020, the company adjusted its clinical development plan accordingly to fit what is feasible in the current environment. The company simplified the design of the previously planned Phase 3 clinical trial for Validive for the prevention of CRT-induced severe oral mucositis in patients with oropharyngeal cancer ('VOICE'), to a seamless Phase 2b/3 design. This design is based on a binary primary endpoint, incidence of SOM, and minimizes touch points with the clinical trial sites and patients. Validive is a once daily self-administered mucoadhesive tablet which can be taken in the patient's home setting. The VOICE trial (NCT04648020) is a randomized, placebo-controlled and double blinded global clinical trial with trial sites in the U.S., Spain, France, Germany and Poland. In 2022, the company completed enrollment of the Phase 2b portion of the VOICE trial and commenced enrollment in the Phase 3 portion. As of March 10, 2023, the company had 81 clinical sites activated and enrolling patients in the U.S. and Europe.

The blinded interim analysis of clinical data from the Phase 2b patient cohort of the trial, to be performed by an independent data monitoring committee, will be used to guide the company as to whether or not to continue enrolling the Phase 3 portion of the trial. This analysis should be completed and reported out by the end of March 2023. To be prepared for a positive go/no-go decision based on the interim analysis, the company continues to activate additional sites globally. The entire trial has been designed to enroll up to 260 evaluable patients. This modification in design allowed the company to activate and commence dosing the VOICE trial in early 2021 without requiring near-term financing.

Assuming a positive result of the go/no go interim analysis decision anticipated by the end of March 2023, to complete the Phase 3 portion of the VOICE clinical program, including, if required, completing a second Phase 3 confirmatory clinical trial, the company will require additional funding in the millions or tens of millions of dollars (depending on if the company has consummated a collaboration or partnership or neither for Validive), which the company is planning to pursue within the next 12 months. Validive has been granted fast track designation in the U.S., orphan drug designation in the EU, and has global intellectual property patent protection through mid-2029 not accounting for possible patent extensions.

Validive Mechanism of Action

Validive is designed to deliver high local concentrations of clonidine, an agonist of alpha-2AR, to the oral cavity and oropharynx, the site of irradiation in the treatment of OPC. In the oropharynx, alpha-2AR is expressed on macrophages, immune cells that produce inflammatory cytokines, the molecules that are responsible for the development of SOM, in response to CRT. Several published clinical reports have demonstrated that chemoradiation treatment substantially increased salivary cytokine levels and a recent study demonstrated that these were positively associated with the formation of SOM in patients with head and neck cancer. Patients with HPV+ OPC demonstrate an increased accumulation of macrophages in the tumor microenvironment compared to patients with OPC that were negative for human papilloma virus ('HPV-'), thus further priming HPV+ OPC patients for the development of SOM. The alpha-2AR regulates the expression of cytokines by macrophages, and clonidine reduces this cytokine production. Macrophages are the primary immune cells in the oropharynx that express alpha-2AR, making clonidine's mechanism of cytokine suppression macrophage selective and distinct from the mechanism of other anti-inflammatory drugs. Further, Validive delivers clonidine to the mucosal surface, the site most affected by chemoradiation treatment in OPC. This results in high salivary concentrations of clonidine, minimizing systemic absorption, and allowing for maximal exposure the at-risk oral mucosa and the OPC microenvironment to drug. Preclinical studies and a Phase 2 clinical trial of Validive have provided data that support Validive's mechanism of action and therapeutic potential for reducing the incidence of SOM in patients with OPC, improving oral mucositis-related symptoms, and decreasing CRT-related adverse events, while exhibiting a favorable safety profile and high compliance rate in patients.

Validive Phase 2 Clinical Trial Data

In October 2015, the results from an international Phase 2 clinical trial of Validive were announced, demonstrating promising signs of clinical activity and safety compared to placebo. The trial enrolled 183 HNC patients and was conducted in more than thirty centers in Europe and the United States. Patients who had undergone surgical resection of their head and neck cancer with curative intent and who were planned to receive at least 50 Gray (Gy) of radiation in combination with chemotherapy, regardless of anatomical location of disease, were included in this study. This global, multi-center, double-blind, randomized, placebo-controlled, three-arm study (NCT01385748) compared the efficacy and safety of Validive 50 µg and 100 µg to placebo in patients with HNC receiving CRT. Of the 183 HNC patients, 64 had OPC (placebo = 24, Validive 50 µg = 21, Validive 100 µg = 19). Validive and placebo were administered once daily beginning 1 to 3 days prior to CRT and continuing until the end of chemoradiation.

The Phase 2 clinical trial data support the development of Validive for the prevention of SOM in OPC patients.

The company's review of the Phase 2 clinical trial data suggests that the effect of Validive was much greater in OPC compared to non-OPC patients. The Phase 2 data along with the mechanism of action of Validive provide a rationale for developing Validive for the treatment of chemoradiation induced SOM in OPC patients as a first indication.

Validive Phase 1 Clinical Trial Data

A Phase 1 clinical trial in 36 healthy volunteers comparing the pharmacokinetics of the systemic (oral tablet) clonidine HCl with clonidine MBT (local and sustained delivery of clonidine to oral mucosa and oropharynx - Validive's formulation) was completed. This was a single-center, Phase 1, single-blind randomized, three-period, three-sequence, single-dose crossover study was conducted between August and November 2015. Healthy volunteers receiving Validive had far less systemic exposure to clonidine with the 50 µg and 100 µg clonidine MBTs (Validive) versus 100 µg clonidine HCl tablets (swallowed oral tablet). In contrast, levels of clonidine in saliva in volunteers receiving a single dose of 50 µg and 100 µg clonidine MBT (Validive) was much greater than saliva levels in volunteers receiving a single dose of 100 µg clonidine HCl tablets. Additionally, no significant effects on blood pressure were observed with the clonidine MBTs (Validive). Blood pressure effects were tested because clonidine is known to lower blood pressure when absorbed systemically. These results are consistent with the expectation that the MBT formulation (Validive) is designed to release clonidine in the oral cavity and oropharynx, as opposed to distributed systemically.

Validive Preclinical Data

The anti-inflammatory properties of clonidine were studied in a human oral mucosa organotypic culture model, as pro-inflammatory cytokines are believed to drive the development of SOM. Samples of healthy non-keratinized human oral mucosa were obtained from patients undergoing surgery. The experimental oral mucosa pro-inflammatory process was mediated by the addition of neuropeptide substance P ('SP') to the culture medium. The addition of SP on human gingiva induced a significant increase in TNF-alpha, an important pro-inflammatory molecule involved in mucositis pathogenesis. Overall, on human gingiva stimulated by SP, a concentration dependent decrease in TNF-alpha production was observed with clonidine, which was statistically significant at 3 µg/ml clonidine; see below:

Camsirubicin (5-imino-13-deoxydoxorubicin; formerly MNPR-201, GPX-150)

The company's second product candidate, camsirubicin, is a novel analog of doxorubicin which has been designed to reduce the cardiotoxic side effects generated by doxorubicin while retaining anti-cancer activity. A Phase 2 clinical trial for camsirubicin has been completed in patients with advanced (e.g., unresectable or metastatic) soft tissue sarcoma ('ASTS'). Average life expectancy for these patients is 12-15 months. In this study, 52.6% of patients evaluable for tumor progression demonstrated clinical benefit (partial response or stable disease), which was proportional to dose and consistently observed at higher cumulative doses of camsirubicin (>1000 mg/m2). Camsirubicin was very well tolerated in this study and underscored the ability to potentially administer camsirubicin without restriction of cumulative dose in patients with ASTS.

Camsirubicin is a proprietary doxorubicin analog that is selective for topoisomerase II-alpha. Doxorubicin is used to treat adult and pediatric solid and blood (hematologic) cancers, including soft tissue sarcomas, breast, gastric, ovarian and bladder cancers, leukemias and lymphomas. Despite clinical studies demonstrating the anti-cancer benefit of higher cumulative doses of doxorubicin, the clinical efficacy of doxorubicin has historically been limited by the risk of patients developing irreversible, potentially life-threatening cardiotoxicity. For example, several clinical studies completed in the 1990s demonstrated that concurrent doxorubicin (60 mg/m2, 8 cycles) and paclitaxel gave a 94% overall response rate in patients with metastatic breast cancer but led to 18% of these patients developing congestive heart failure. Reduction of doxorubicin to 4-6 cycles of treatment decreased the incidence of congestive heart failure, but also reduced response rates to 45-55%. In a clinical study looking at dose response, sarcoma patients on the high dose (75 mg/m2) doxorubicin had a response rate of 37% compared to just 18% in the low dose (45 mg/m2) doxorubicin group. With the cumulative dose restriction on doxorubicin, the median progression free survival for ASTS patients is approximately 6 months, with median overall survival of 12-15 months. There is a significant unmet opportunity to develop a replacement for doxorubicin that can be dosed higher and for longer to improve anti-tumor activity.

Camsirubicin has been engineered specifically to retain the anticancer activity of doxorubicin while minimizing its toxic effects on the heart. Similar to doxorubicin, the antitumor effects of camsirubicin are mediated through the stabilization of the topoisomerase II complex after a DNA strand break and DNA intercalation leading to tumor cell apoptosis (cell death). Inhibiting the topoisomerase II-alpha isoform is desired for the anti-cancer effect, while inhibiting the topoisomerase II-beta isoform has been demonstrated to mediate, at least in part, the cardiotoxicity associated with all anthracycline drugs used in the clinic. Camsirubicin is substantially more selective than doxorubicin for inhibiting topoisomerase II-alpha versus topoisomerase II-beta. This selectivity may partly explain the minimal cardiotoxicity that has been observed for camsirubicin in preclinical and clinical studies as of December 31, 2022. These attributes provide a strong rationale for developing camsirubicin as a monotherapy, as well as in combination with other anticancer agents, without potential restrictions on cumulative dose, and offer the opportunity to pursue a large market opportunity for camsirubicin in a broad spectrum of cancer types.

Based on the encouraging clinical results as of December 31, 2022, in September 2021, the company commenced an open-label, Phase 1b dose escalation trial of camsirubicin plus growth factor support (pegfilgrastim/G-CSF) in the U.S. as first-line treatment for patients with ASTS. The aim is to administer camsirubicin without restricting cumulative dose, thereby potentially improving efficacy by keeping patients who are responding on treatment. These are patients who are not candidates for surgery or radiation treatment, and are largely made up of patients with metastatic disease. Doxorubicin is the current standard of care in the first-line setting for these patients. Although this Phase 1b is designed to determine the maximum tolerated dose of camsirubicin, given the historical dose-dependent anti-tumor response repeatedly demonstrated with doxorubicin, efficacy measurements are being tracked in these patients as the dose is increased. In November 2021, the first dose level of camsirubicin had been completed, with a positive recommendation from the trial safety review committee to proceed to the next higher dose level. The company is presently enrolling patients at the fifth dose level. The fifth dose level is over twice the highest dose reached in any prior camsirubicin clinical trial (650 mg/m2 versus 265 mg/m2) and no drug-related cardiotoxicity has been observed as of December 31, 2022 up to the current dose-level. The open-label Phase 1b camsirubicin dose-escalation trial is planning to enroll additional cohorts until the maximum tolerable dose is reached. In November 2022, the company presented an abstract and poster of the Phase 1b clinical trial data at the Connective Tissue Oncology Society Annual Meeting in Vancouver, BC.

The company anticipates topline results in the camsirubicin Phase 1b clinical trial by the end of 2023 and the company has sufficient funds to advance the trial through that date. However, if camsirubicin reaches higher dose levels than the company is anticipating, the Phase 1b clinical trial may still be dosing patients beyond the end of 2023 and topline results may be deferred. Although the company would likely consider this a positive development, it is possible that the company would require additional funding to complete an extended Phase 1b clinical trial in this situation. Regardless, additional funding is expected to be required to support further development through and beyond the company's ongoing Phase 1b clinical trial.

In June 2019, the company entered into a clinical collaboration with Grupo Español de Investigación en Sarcomas ('GEIS'). GEIS is an internationally renowned non-profit organization focused on the research, development and management of clinical trials for sarcoma, that has worked with many of the leading biotech and global pharmaceutical companies. Following completion of the company's Phase 1b clinical trial, the company continues to expect that GEIS will sponsor and lead a multi-country, randomized, open-label Phase 2 clinical trial evaluating camsirubicin head-to-head against doxorubicin, the current first-line treatment for ASTS. The Phase 2 clinical trial is estimated to enroll 170 ASTS patients with the primary endpoint of the trial being progression-free survival, with secondary endpoints, including response rate, overall survival and incidence of treatment-emergent adverse events. The company will provide study drug to GEIS and supplemental financial support for the clinical trial. In addition to camsirubicin's orphan drug designation in the U.S. by the FDA, the European Commission also granted orphan drug designation for camsirubicin for the treatment of soft tissue sarcoma in the EU in November 2019.

Camsirubicin Clinical Data

Several clinical studies of camsirubicin have been completed.

In October 2013, a Phase 1 dose escalation study conducted at the University of Iowa completed enrollment of 24 patients who received one of eight different dose levels of camsirubicin ranging from 14 to 265 mg/m2. No evidence of irreversible cardiotoxicity was observed in any of these patients, including 4 patients who received prior anthracycline (doxorubicin or related molecules) treatment. Stable disease was observed in 55.0% of patients in this Phase 1 study, including 3 out of 4 patients with leiomyosarcoma, which is a type of soft tissue sarcoma that originates in connective tissue and smooth muscle most commonly in the uterus, stomach and small intestine. No growth factor support (G-CSF) was given to patients, and the limiting toxicity was neutropenia.

In January 2015, a multi-center open label single arm Phase 2 clinical trial was initiated in doxorubicin-naïve patients with ASTS. This Phase 2 clinical trial enrolled 22 patients and was completed in August 2016. Camsirubicin was administered intravenously at 265 mg/m2 every 3 weeks for up to 16 doses, with all patients being given growth factor support, and there was clear indication of anticancer activity at this well-tolerated dose and schedule. The majority of patients (52.6%) evaluable for tumor progression demonstrated clinical benefit (stable disease or partial response), which was proportional to dose and consistently observed at higher cumulative doses of camsirubicin (>1000 mg/m2). The progression-free survival at 6 months was 38%, higher than the 6-month PFS of doxorubicin in three of the more recent studies, which showed 23%, 25%, and 33% 6-month PFS for doxorubicin. Camsirubicin was very well tolerated in this study and underscored the potential ability to administer camsirubicin without restriction for cumulative dose in patients with ASTS. Under compassionate use access, one patient received 20 cycles of camsirubicin (cumulative dose 5,300 mg/m2). Apart from one patient who developed febrile neutropenia and severe leukopenia, there were no grade 4 toxicities reported and no grade 3 side effects other than anemia. A transient decrease in left ventricular ejection fraction ('LVEF') was observed in four patients treated with camsirubicin. These decreases in LVEF in camsirubicin treated patients were not serious adverse events and were transient, with LVEF subsequently returning to normal levels in all four subjects. Despite some subjects in this study receiving camsirubicin for up to 20 cycles, effects on cardiac function were of no clinical significance and there was no evidence of irreversible heart failure in any subject.

Camsirubicin Preclinical Data

In preclinical studies, camsirubicin showed a lack of acute, as well as chronic functional cardiotoxicity and did not cause the cardiac histopathologic lesions observed with doxorubicin in a chronic rabbit model.

Camsirubicin demonstrated limited effect on cardiac contractility, in-line with control

Chronic IV administration of camsirubicin two times per week into rabbits over the course of 13 weeks also showed a lack of cardiotoxicity of camsirubicin when compared to doxorubicin ('DOX'). Echocardiography was performed weekly to obtain left ventricular fractional shortening ('LVFS') measurements to assess cardiac function. At sacrifice, all six doxorubicin-treated rabbits showed cardiac dysfunction by echocardiography, and LVFS was significantly different from control values (p<0.001). In contrast, none of the camsirubicin-treated rabbits exhibited cardiac dysfunction by echocardiography at any time during the study.

MNPR-101 for Radiopharmaceutical Use

The company's third program is based on MNPR-101 (formerly huATN-658), a novel first-in-class humanized monoclonal antibody to the urokinase plasminogen activator receptor ('uPAR'), for its use as a radiopharmaceutical in advanced cancers. uPAR is highly expressed in tumors while healthy tissue rarely, if ever, expresses uPAR. The expression of uPAR on diseased cells and tissues allows for selective targeting of MNPR-101, which may be modified to carry imaging and therapeutic payloads.

MNPR-101 represents a novel approach for drug targeting of uPAR as it does not interfere with normal binding of uPA to uPAR. It instead blocks the CD11b (alpha-M)-uPAR interaction.

Based upon the anticipated non-overlapping toxicity and distinct mechanism of action, MNPR-101 has the potential to be used in combination with existing cancer therapies. The selective expression of uPAR in tumors underpins the company's expectation that MNPR-101 will be well-tolerated and amenable to a radiopharmaceutical treatment approach.

MNPR-101-Zr as a Potential Imaging Agent

MNPR-101-Zr is being developed as an imaging agent for the diagnosis and surveillance of multiple cancer types. In February 2023, the company announced that based on promising recently generated preclinical imaging results with MNPR-101-Zr showing high uptake across multiple cancer types, the company and NorthStar were committing to additional funding with the aim of initiating a first-in-human imaging study with MNPR-101-Zr as early as the end of this year.

MNPR-101-Zr is a zirconium-89 labeled version of MNPR-101. Positron emission tomography ('PET') imaging of preclinical mouse models for triple-negative breast, colorectal, and pancreatic tumors displayed high and selective uptake of MNPR-101-Zr in these uPAR-expressing tumors.

These proof-of-concept studies provide support for a first-in-human PET imaging study with MNPR-101-Zr and a future therapeutic study using actinium-225 labeled radioimmunotherapeutic version of MNPR-101. Overall, the imaging results demonstrate the potential utility of MNPR-101 as a precision targeting agent for both imaging and therapy in multiple cancer indications.

MNPR-101 RIT

Also pursuant to the company's collaboration with NorthStar, the company continues to develop potential radioimmunotherapeutics ('RITs') based on MNPR-101. The company's collaboration combines NorthStar's expertise in the innovative production, supply, and distribution of important medical radioisotopes with the company's expertise in therapeutic drug development. NorthStar and the company has filed provisional composition of matter patents covering the actinium-based radiopharmaceutical drug candidate (MNPR-101-PCTA-Ac-225). The company is evaluating pathways to initiating a first-in-human study with this drug candidate.

MNPR-202 and Related Analogs

In June 2021, the company entered into a collaboration agreement with the Cancer Science Institute of Singapore ('CSI Singapore'), one of Asia's premier cancer research centers, at the National University of Singapore ('NUS') (consistently ranked as one of the world's top universities) to evaluate the activity of MNPR-202 and related analogs in multiple types of cancer. MNPR-202 was designed to retain the same potentially non-cardiotoxic backbone as camsirubicin but is modified at other positions which may enable it to work in certain cancers that are resistant to camsirubicin and doxorubicin. In December 2020, the company announced the issuance of its composition of matter U.S. patent (US10,450,340) covering MNPR-202 and related analogs. CSI Singapore has tested MNPR-202 in preclinical cancer models with promising results and is conducting additional preclinical studies with MNPR-202. In December 2022, in collaboration with Dr. Anand Jeyasekharan of CSI Singapore, the company presented an abstract and poster of the preclinical data of MNPR-202 at the American Society of Hematology 64th Annual Meeting in New Orleans, LA.

License, Development and Collaboration Agreements

Onxeo S.A.

In June 2016, the company executed an agreement with Onxeo S.A., a French public company, which gave the company the exclusive option to license (on a world-wide exclusive basis) Validive (clonidine hydrocholoride mucobuccal tablet; clonidine HCI MBT) a mucoadhesive tablet of clonidine based on the Lauriad mucoadhesive technology.

Grupo Español de Investigación en Sarcomas ('GEIS')

In June 2019, the company executed a clinical collaboration with GEIS for the development of camsirubicin in patients with ASTS. Following completion of the Phase 1b clinical trial in the U.S. that the company initiated in the third quarter of 2021 with the first patient dosed in October 2021, the company continues to expect that GEIS will sponsor and lead a multi-country, randomized, open-label Phase 2 clinical trial to evaluate camsirubicin head-to-head against doxorubicin, the current first-line treatment for ASTS.

XOMA Ltd.

To humanize the company's MNPR-101 antibody, the company has 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.

Intellectual Property Portfolio and Exclusivity

Validive

The company licenses all intellectual property related to Validive from Onxeo S.A., a French public company. Validive is covered by 57 issued patents in 31 jurisdictions, including the U.S., EU, Japan, and other Asian countries; and has orphan drug designation in the EU, as well as Fast Track designation from the FDA. These patents are method of use patents that cover the use of Validive to prevent and/or treat inflammation and inflammatory pain of the mucosa, including cancer therapy-induced mucositis; the use of clonidine or clonidine derivatives for the prevention or treatment of adverse side effects of chemotherapy; and clonidine and/or clonidine derivatives for use in the prevention of skin injury resulting from radiotherapy, and have been assigned to the company pursuant to its license agreement with Onxeo. The latest patent expires in 2035 not accounting for possible extensions.

In November 2020, the company announced a series of recently issued patents for Validive (clonidine HCl mucobuccal tablet). These patents, including U.S. Patent No. 10,675,271, provide claims covering 'Clonidine and/or clonidine derivatives for use in the prevention and/or treatment of adverse side effects of chemotherapy'. These patents expand the potential use of Validive in cancer patients, beyond the earlier allowed claims for the prevention of oral mucositis in patients receiving CRT. Specifically, they provide protection for the potential ability of Validive to prevent or treat common chemotherapy-associated side effects, such as asthenia and fatigue and would provide protection should the company determine in the future to conduct additional Validive development activities related to adverse side effects of chemotherapy beyond oropharyngeal cancer.

Camsirubicin

Camsirubicin (GPX-150) is covered by manufacturing process patents. The company has a patent for chemical synthesis technology that efficiently converts cardiotoxic '13-keto' anthracyclines, such as doxorubicin, daunorubicin, epirubicin, and idarubicin into novel, patentable, and most likely less-cardiotoxic '5-imino-13-deoxy' analogs. A novel chemical composition of an intermediate for this synthesis is also patented. In addition, the company has a patent covering the combination of camsirubicin with paclitaxel for the treatment of cancer, plus covering the method of use of these two drugs for this purpose. The company's camsirubicin patent portfolio contains eight issued U.S. patents (two of which have expired) and one U.S. pending patent application. The company has certain corresponding patents and applications in twenty-nine foreign jurisdictions, including the U.S., EU, Japan, and other Asian countries. The process patents for the synthesis of camsirubicin intermediates will expire in 2024 and the patents covering the combination use of camsirubicin and its analogs with taxanes will expire in 2026. The patent covering novel, potentially more potent analogs of camsirubicin expires in 2038. The company may pursue patent term extensions where appropriate. The company has obtained patent protection around the intermediates and process used to manufacture camsirubicin and the company expects to obtain Hatch-Waxman exclusivity (applicable to new chemical entities) for 5 years that will prevent generic competition. The company has also obtained U.S. and EU orphan drug status in soft tissue sarcoma with additional orphan cancer indications expected to follow.

In December 2020, the company announced the issuance of a U.S. patent (US 10,450,340) covering compositions of matter (2-pyrrilino camsirubicin) for a novel family of camsirubicin analogs. This patent, which expands the company's camsirubicin intellectual property portfolio, is expected to expire in 2038 not including any patent term extensions. The patent broadens the company's camsirubicin portfolio and creates a pipeline that has been designed to retain the potentially favorable non-cardiotoxic chemical backbone of camsirubicin and the potent broad-spectrum antitumor activity of doxorubicin. Further, preclinical evidence suggests that this new family of 2-pyrrilino camsirubicin analogs could be active in doxorubicin-resistant tumor cells, which may enable use in cancer types beyond those possible with camsirubicin.

MNPR-101

The company's patent portfolio for its MNPR-101 antibody (huATN-658), as well as its epitope, consists of two issued U.S. composition of matter and their methods of use patents and corresponding (granted and pending) patents and patent applications in twenty-two foreign jurisdictions, including the European Union, Japan, and other Asian countries. These patents are owned by the company. The patents covering the composition of matter of MNPR-101 will expire in 2025 and the patents covering the MNPR-101 epitope will expire in 2027. Being a novel biologic, it 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 countries. The Radio-Immuno-Therapeutic derivative of MNPR-101 (uPRIT) patent, if granted expires in 2041.

MNPR-101 for Radiopharmaceutical Use

In collaboration with NorthStar, the company filed a provisional patent application entitled 'Precision Radioimmunotherapeutic Targeting of the Urokinase Plasminogen Activator Receptor (uPAR) for the Treatment of Severe COVID-19 Disease' with the 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 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. Advanced COVID-19 patients frequently develop severe, life-threatening, pulmonary inflammation as a result of a viral induced cytokine storm. The development of this cytokine storm is associated with a high rate of mortality in severe COVID-19 patients, even when oxygen support and mechanical ventilation are utilized. uPRITs have been designed with the goal of selectively eradicating the aberrantly activated immune cells responsible for causing cytokine storm and its harmful systemic effects.

In May 2021, the company and NorthStar filed a provisional patent application with the USPTO titled 'Bio-Targeted Radiopharmaceutical Compositions Containing Ac-225 and Methods of Preparation.' Radiopharmaceutical therapy is a promising approach to treat cancer and other diseases using radioactive isotopes bound with proteins/antibodies to target and kill cells. If validated through further evaluation, it could potentially improve efficacy and safety and enhance manufacturing efficiency of actinium-based radiopharmaceuticals, the full potential of which are presently constrained by the price and scarcity of Ac-225.

Also in May 2021, the company and NorthStar filed a provisional composition of matter patent application titled 'Urokinase Plasminogen Activator Receptor-Targeted Radiopharmaceutical' covering a radiotherapeutic consisting of the company's proprietary antibody MNPR-101 bound to Ac-225 via the isotope binding agent PCTA. This RIT 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 uPA receptor expression.

Sales and Marketing

The company has retained worldwide commercial rights for the company's product candidates. If the company's product candidates receive marketing approval, the company plans to commercialize them in the U.S. and potentially in Europe with the company's own focused, specialty sales force to be developed. The company would expect to conduct most of the buildout of this organization following approval in the U.S. or following similar marketing authorizations in Europe of any of the company's product candidates. The company expects to explore commercialization of Validive and potentially other product candidates in certain markets outside the U.S., including the EU, utilizing a variety of collaboration, distribution and other sales and marketing arrangements with one or more third parties.

Government Regulation and Product Approval

The pharmaceutical product candidates that the company develops must be approved by the FDA before they may be legally marketed in the U.S.

Research and Development

During the year ended December 31, 2022, the company's research and development expenses were $7,592,000.

History

The company was founded in 2014. It was incorporated as a Delaware limited liability company in 2014 under the name Monopar Therapeutics, LLC. In 2015, the company converted to a Delaware corporation and changed its name to Monopar Therapeutics Inc.