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Item 1. Business

2023-03-22 compared with 2022-03-24 · 352 added, 508 removed, 602 unchanged (59% of the section changed)

BUSINESS 

Overview 

We are a clinical stage pharmaceutical company with a growing pipeline of clinical programs for the treatment of highly resistant cancers and viruses.

We have three core technologies, based substantially on discoveries made at and licensed from MD Anderson Cancer Center (MD Anderson) in Houston, Texas.

We have six drug candidates, three of which have now shown human activity in clinical trials.

Core Technologies

We are a clinical stage pharmaceutical company with a growing pipeline, including Phase 2 clinical programs for hard-to-treat cancers and viruses. We have three core technologies, each of which have had one or more drugs successfully complete a Phase 1 clinical trial 1 , based substantially on discoveries made at and licensed from MD Anderson Cancer Center (MD Anderson) in Houston, Texas.

Three of our six drug candidates have shown human activity in clinical trials and are currently in Phase 1b/2 or Phase 2 clinical trials.

Since our inception, our drugs have been in, are currently in, or have received approval to proceed in eleven clinical trials.

Our Core Technologies

Our core technologies consist of the following:

a) Annamycin, a “next generation”

anthracycline designed to be different than currently approved anthracyclines by eliminating cardiotoxicity and avoiding the multidrug resistance mechanisms that can limit the efficacy of the approved products.

(Annamycin has shown no cardiotoxicity in subjects treated to date in Moleculin’s clinical trials);

a) Annamycin or L-Annamycin is a “next generation”

anthracycline designed to be different than currently approved anthracyclines, which are limited in utility because of cardiotoxicity risks and their susceptibility to multidrug resistance mechanisms.

Annamycin was designed to avoid multidrug resistance and has shown no cardiotoxicity 2  in subjects treated in clinical trials to date.

Furthermore, we have demonstrated safe dosing beyond the dose limitations imposed by regulatory authorities upon currently prescribed anthracyclines due to their inherent cardiotoxicity;

b) our WP1066 Portfolio, which includes WP1066 and WP1220, two of several Immune/Transcription Modulators in the portfolio designed to inhibit p-STAT3 (phosphorylated signal transducer and activator of transcription) among other transcription factors associated with tumor activity, while also stimulating a natural immune response to tumors by inhibiting the errant activity of Regulatory T-Cells (TRegs);

and c) our WP1122 Portfolio, which contains compounds (including WP1122, WP1096, WP1097) designed to exploit the potential uses of inhibitors of glycolysis such as 2-deoxy-D-glucose (2-DG), which we believe may provide an opportunity to cut off the fuel supply of tumors by taking advantage of their high level of dependence on glucose in comparison to healthy cells.

Clinical Trials

In the US and Europe, we have completed or are currently conducting clinical trials for three of our drug candidates –

Annamycin, WP1066, and WP1220.

All trials are or were in the Phase 1 portion, except the WP1220 trial, which was a proof-of-concept clinical trial.

c) our WP1122 Portfolio, which contains compounds (including WP1122, WP1096, and WP1097) designed to exploit the potential uses of inhibitors of glycolysis such as 2-deoxy-D-glucose (2-DG), which we believe may provide an opportunity to cut off the fuel supply of tumors by taking advantage of their high level of dependence on glucose in comparison to healthy cells, as well as viruses that depend upon glycolysis and glycosylation to infect and replicate.

Our Focus  

We are focused on internally funded (“internally”

and “externally”

funded trials are defined in the Funding Strategy section below) development of:

1) Annamycin for the treatment of Soft Tissue Sarcoma metastasized to the lungs (STS lung metastases or STS lung mets)

2) Annamycin in combination with Cytarabine (also known as Ara-C, the combination with Annamycin of which is referred to as AnnAraC) for the treatment of Relapsed or Refractory Acute Myeloid Leukemia (R/R AML or AML).

3) Developing a better delivery mechanism for WP1066 to further support current and possibly future externally funded oncology clinical trials. 

We have also recently established a Recommended Phase 2 Dose (RP2D) for WP1122 to potentially enable future externally funded oncology and virology trials.

Beyond this, we support development of our core technologies through several externally funded clinical trials with the potential for others in the near-term.

Our Clinical Trials

In the US and Europe, we or external investigators have approved, are currently conducting or have completed eleven i nternally or externally funded clinical trials for four of our drug candidates –

Annamycin, WP1066, WP1220, and WP1122 since inception.

All clinical trials are or were in the Phase 1 or 2 stage.

During 2021, we had four active clinical trials evaluating either Annamycin or WP1066 in the US and Europe.

In 2021 and early 2022, there were also three “right-to-try”

This increased to six a ctive or just completed trials in 2022 involving Annamycin, WP1066, and WP1122.

In 2021 and 2022, there were five “right-to-try”

(or their foreign equivalent) uses of Annamycin and WP1066.

Of the four clinical trials active in 2021, two of those are internally funded trials (the difference between “internally”

and “externally”

funded trials is discussed below) of Annamycin.

One is studying relapsed and refractory acute myeloid leukemia (AML) in Europe, and one is investigating soft tissue sarcoma metastasized to the lungs (STS lung metastases) in the US.

The other two trials are externally funded studies of WP1066 in brain tumors, both in the US, one of which was terminated during the year because the Principal Investigator in that trial moved to a new institution. We successfully concluded an internally funded Phase 1 AML clinical trial in Europe in early 2022, establishing a Recommended Phase 2 Dose (RP2D) for Annamycin as a single agent.

We are in the process of locking the database and beginning the completion of the Clinical Study Report (CSR) for that study.

During 2021, we filed applications or began recruiting for four clinical trials in the US and Europe.

The investigational new drug (IND) application in the US for a Phase 1b/2 trial of Annamycin for the treatment of STS lung metastases was filed in late 2020 with the US Food and Drug Administration (FDA).

The IND went into effect in early 2021 and this trial began recruiting subjects shortly thereafter.

In 2021, we also filed and received clearance for an IND for a Phase 1 trial for WP1122 treating glioblastoma multiforme (GBM) in adults, and consistent with our strategy of leveraging external funding for many of our clinical trials, we intend to seek opportunities for an investigator-initiated clinical trial in cancer patients in 2022.

We also filed in October 2021 a clinical trial application (CTA) to commence a Phase 1a clinical trial of WP1122 in the United Kingdom for the treatment of COVID-19 for which we later received the appropriate authorization to proceed.

In early March 2022, we filed an amended protocol with both the Riverside Ethics Committee and Medicines and Healthcare Products Regulatory Agency (MHRA).

The amendment updated the level of dilution of the oral solution to ensure that WP1122 is fully dissolved in a wider range of pharmacy environments. We believe that the risk/benefit aspect of the study was not affected by this change.

Once this amendment is approved, we expect this internally funded trial to begin in the first half of 2022.

We also filed a CTA in Poland in November 2021 for a Phase 1/2 trial for the treatment of relapsed and refractory AML with a combination of Annamycin and Cytarabine (AnnAraC) for which we received Central Ethics approval in December 2021.

Upon receipt of approval from the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products (URPL), we plan to proceed with this trial. This trial builds on the safety and dosage data from the two successfully concluded single agent Annamycin AML Phase 1 trials in the US and Europe and is supported by preclinical animal data from our ongoing sponsored research at MD Anderson.

The AnnAraC trial is expected to begin during the first half of 2022.

In addition to the trials described above, we expect that an investigator sponsored trial will be initiated in Europe in 2022 to study an alternative dosing regimen for Annamycin in the treatment of STS lung metastases. During 2022, we may also have another investigator led trial outside of the US (partially internally funded) focused on the use of WP1122 for the treatment of subjects with COVID-19.

The volatility and unpredictability of COVID-19 incidence in various countries may limit our ability to recruit certain subjects and could make it infeasible for us to conduct a Phase 2 clinical trial on a timely basis, or at all.

As mentioned earlier, the WP1066 brain tumor trial at MD Anderson was terminated in 2021, as the original lead physician investigator moved to another institution.

We expect another externally funded Phase 1/2 investigator led trial to replace the MD Anderson trial in 2022.

That trial’s IND will likely reference our WP1066 GBM IND filed in early 2022, once cleared by the FDA.

We expect this new trial to investigate WP1066 in combination with radiation for the treatment of adult brain tumors.

As summarized and explained further below, we expect up to ten clinical trials (or more, if we proceed with a COVID-19 trial in addition to the UK trial) to be active or concluded by the end of 2022.

Three of the six clinical trials active in 2022 are internally funded trials of Annamycin and one is an internally funded Phase 1 clinical trial for WP1122 setting a RP2D.

Moving into 2023, we are actively recruiting in three clinical trials in a Phase 1b/2 or Phase 2 stage and have recently concluded one trial.

These three currently active clinical trials are open label so we expect to be able to announce any human activity that is being demonstrated in these trials during 2023. In February 2023, the externally funded Phase 1 clinical trial with WP1066 for the treatment of pediatric brain tumors concluded.

We expect up to three externally funded Phase 1b/2 clinical trials for WP1066 in the treatment of GBM and other brain tumors in 2023.

During 2022, we or external investigators filed applications or began recruiting f or five  internally or externally funded clinical trials in the US and Europe.

Annamycin - The clinical trial application (CTA) in Poland for a Phase 1b/2 trial of Annamycin in combination with Cytarabine

 or AnnAraC f or the treatment of AML was allowed in 2022.

This trial was later approved to expand into Italy in 2022 and dosing subjects began there i

n March 2023.

With preclinical data in mice demonstrating a 68% improvement in activity in AML with AnnAraC over Annamycin alone combined with the human activity demonstrated in the highest dosing cohort in the single agent AML clinical trial, we concluded our single agent Annamycin clinical trial treating AML and focused on this combination trial.

Annamycin - An investigator sponsored trial (externally funded) was initiated in Poland in 2022 to study an alternative dosing regimen for Annamycin in the treatment of STS lung mets.

This trial began administering drug to subjects in late 2022. 

WP1066 - In 2022, an investigational new drug (IND) application we filed in the US for a Phase 1 clinical trial studying WP1066 for treating glioblastoma multiforme (GBM) in adults went into effect.

Consistent with our strategy of leveraging external funding for many of our clinical trials, we intend to seek to capitalize on external funding with opportunities for an investigator-initiated clinical trial in adult cancer patients in 2023.

We supplied drug product to an externally funded pediatric brain tumor trial with WP1066 up to its conclusion in February 2023.

WP1122 - Our Phase 1a clinical trial of WP1122 in the United Kingdom for the treatment of COVID-19 began recruiting in 2022, and we completed the trial in late 2022, establishing an RP2D.

We are in the process of completing this trial - locking the database and finalizing a clinical study report (CSR).

This RP2D will possibly aid in future externally funded trials for the treatment of certain viruses and cancers as we look for investigator led studies.

WP1122 - In 2022, we filed an IND with the FDA that then went into effect, allowing us to proceed with a clinical trial using WP1122 for the treatment of GBM.

This may lead to an oncology investigator-initiated trial (IIT).

Additionally, an investigator filed independently a CTA in Brazil in 2022 to study WP1122 for the treatment of moderate to severe COVID-19.

Based on current COVID-19 epidemiology, we do not expect this externally funded trial to be conducted.

Additionally, we are in discussions with research institutions in the US, Asia, and South America regarding possible externally funded trials or programs involving WP1066 and WP1122.

1  Subject to publishing final Clinical Study Report

2  In discussions of “no cardiotoxicity”

of Annamycin, management’s beliefs are based on an expert’s opinion based their review of certain clinical trial subject data including LVEF, ECHO strain analyses, and cardiac biomarkers –

troponin’s I & T

In terms of developing preclinical data, we have our own lab and consultants with our employees conducting research and, we sponsor research at MD Anderson to expand the science of our core technologies and possible combinations with other approved drugs.

We have a National Institutes of Health or NIH funded preclinical study with WP1096 (from the WP1122 portfolio) for the treatment of the Tacaribe Arenavirus.

As summarized below, we and our external investigators have an IND/CTA in process, approved, are in progress, or have completed eleven internally and externally funded clinical trials.

Additionally, we are anticipating additional clinical trials in 2023.

See the following discussion for more detailed information, especially on safety and human activity.

Clinical Summary as of this filing 3

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noted as External)

Safety Summary

Activity Summary

MB-104 / R/R AML / US

Phase 1 concluded and CSR completed.

Phase 1 concluded and CSR published.

Phase 2 start awaits further data from other trials

Maximum Dose allowed per protocol 120 mg/m 2

Met safety endpoints; no cardiotoxicity

Met safety endpoints; no cardiotoxicity demonstrated

14.3% MLFS (subtherapeutic dose level when compared to MB-105)

MB-105 / R/R AML / Poland

Phase 1 concluded and database lock is in process

Phase 1 concluded and published CSR Jan 2023

Maximum Dose and RP2D 240 mg/m 2

Met safety endpoints;

no cardiotoxicity

60% ORR in last cohort (2 PRs and 1 CRi)

no cardiotoxicity demonstrated

80% ORR in last cohort (3 PRs and 1 CRi)

MB-107 / STS Lung Metastases / US

cohort 4 at 390 mg/m 2 ; cohort expanded due to DLT

Recruiting and estimate expansion phase in 2022

No cardiotoxicity

Some subjects exhibited stable disease with one PR as best overall response to date

Phase 1 completed;

Phase 2 in progress

Treating Phase 2 subjects and estimate completion of Phase 2 in 2023

No cardiotoxicity demonstrated

Preliminary data - Phase 1 60% (9 of 15) of subjects showed SD or better through 2+ cycles;

Phase 2 (ongoing) 67% (4 of 6) subjects show SD through 2+ cycles

Annamycin in Combination with Cytarabine

MB-106 / R/R AML / Europe

Expected to begin recruiting Phase 1 in 2022

CTA submitted, awaiting approval

Not applicable as trial has not started (N/A)

Phase 1b in progress;

First subject treated in March 2023

Five sites recruiting in Poland and Italy

No cardiotoxicity demonstrated

No data to date as subjects have just begun treatment

IIT / STS Lung Metastases / Poland

Expect to begin Phase 1b recruiting in 2022

Investigator led trial with a different dosing regimen than MB-107

Phase 1b in progress;

First subject treated in Q4-2022

Investigator led trial with a weekly dosing regimen versus traditional chemotherapy dosing as in MB-107

To date, 2 subjects dosed in Cohort 1 (35 mg/m2) with no DLTs nor activity noted

No human activity demonstrated to date

IIT / Adult GBM / US

Terminated by site

Closed prior to completion by site

Investigator left for another institution

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No activity demonstrated. RP2D or MTD not established.

WP1066 in combination with radiation

IND approved for GBM

Exploring for an investigator to lead a study

Trial has not begun

WP1066 in combination with radiation 

IIT / Adult GBM / US

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To be led by investigator with prior experience with WP1066

Trial has not begun

IIT / Pediatric Brain Tumors / US

In Dose Level 3 at 8mg/kg

Ongoing recruitment

Concluded in February 2023 with a dose level at 8mg/kg

Concluded 10 subjects enrolled and treated over 3 dose levels up to 8 mg/kg

No drug related serious adverse events noted

1 DIPG patient had a temporary clinical response

1 DIPG subject had a temporary clinical response

MB-201 / CTCL / Poland

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MB-301 / COVID-19 / UK

Expect to begin in first half of 2022

First in human trial for WP1122

1  This is a summary of the detailed discussion below and does not include compassionate use/right-to-try usage of our drug candidates.

Completed and CSR in process;

Established RP2D

Drug at RP2D was tolerable and safe

Met safety endpoints

N/A as in healthy volunteer subjects

IND approved for GBM

1b/2 External

Exploring for an investigator to lead a study

Trial has not begun

This is a summary of the detailed discussion below and does not include compassionate use/right-to-try usage of our drug candidates.

Terms are defined elsewhere in this document including “internal”

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means that no drug-related serious and unexpected adverse events occurred as defined in the trial protocol. All data presented are preliminary unless a CSR has been issued for the trial referenced.

With regard to safety and human activity summaries please see the detailed discussion below.

Human Activity

The following data regarding human activity are all from Phase 1 studies, except where noted as early Phase 2 data.

Such information is early in the clinical trial process.

Such activity may or may not be repeated in future Phase 2 or 3 clinical trials. While we believe such data is encouraging, the FDA or its foreign counterpart will ultimately determine if such data and future data is individually conclusive.

Three of our drug candidates have shown activity in humans to date.

Prior to 2021, a US Phase 1 trial for Annamycin in AML successfully met its safety endpoint (including the absence of cardiotoxicity) and demonstrated human activity in the reduction of circulating bone marrow blasts despite the trial being conducted at what were expected to be subtherapeutic dosages (not exceeding 120 mg/m 2 ) based on the European AML study.

This US study’s CSR was issued in 2021.

In the final cohort of the European Phase 1 single-agent Annamycin trial, where the RP2D was determined to be 240 mg/m 2 , there was a preliminary objective response rate (ORR) of 60% (three out of five) in subjects receiving a full course of treatment.

In an investigator-initiated trial (IIT) trial of WP1066 (our lead inhibitor of p-STAT3) for the treatment of pediatric brain tumors, both a clinical and an objective response was demonstrated in a patient with diffuse interstitial pontine glioma (DIPG), one of several indications for which WP1066 has been granted a “rare pediatric disease”

designation, which could potentially qualify WP1066 for a priority review voucher upon approval of a New Drug Application (NDA).

The CSR issued in 2021 for a clinical trial of WP1220, another drug candidate in the WP1066 Portfolio, for the topical treatment of cutaneous T-cell lymphoma (CTCL) documented in 60% of subjects (3 out of 5) PR that was confirmed by a subsequent evaluation one month later with one of the subjects having a near total resolution of their lesions (93% decrease).

Annamycin has shown the following human activity:

Prior to 2021, our MB104 US Phase 1 trial for Annamycin in AML successfully met its safety endpoint (including the absence of cardiotoxicity) and demonstrated human activity in the reduction of circulating bone marrow blasts despite the trial being conducted at what were expected to be subtherapeutic dosages (not exceeding 120 mg/m2) based on the European AML study.

This US study’s CSR was issued in 2021. 

In 2022 we completed our MB-105 Phase 1 single agent trial for Annamycin in AML with fifteen subjects receiving the full dose per the protocol and identifying an RP2D and we demonstrated an 80% ORR in the five subjects in the last cohort.

Three subjects were a PR and one was a CRi.

Regarding the PRs, two of the three PR subjects’

repeat bone marrow aspirate assessments (BMA) showed a blast count below 5% at the end of therapy.

In 2022 our MB107 trial treating STS lung metastases demonstrated a preliminary response of stable disease or better in 60% –

defined as stable disease (SD) or better after two cycles of Annamycin (approximately six weeks) in Phase 1 portion of the study.

Our median progression free survival (PFS) was 2.6 months for subjects receiving the study drug dose per the Phase 1 protocol.

In the ongoing Phase 2 portion of the trial, we have demonstrated to date a preliminary response of 67% (4 of 6) subjects showing SD through 2 or more cycles.

This is in a subject population where the median progression free survival time in patients with soft tissue sarcoma with metastases (not just lung metastases) that have failed initial systemic therapy is approximately 1.6 to 2.0 months, without effective therapy which includes subjects treated with a placebo.

Comandone, F.

Petrelli, A Boglione, S.

Salvage Therapy in Advanced Adult Soft Tissue Sarcoma.

The Oncologist 2017;22:1518–1527).

WP1066 has shown the following human activity:

In an investigator-initiated trial of WP1066 (our lead inhibitor of p-STAT3) for the treatment of pediatric brain tumors, both a clinical and an objective response were demonstrated in a subject with diffuse intrinsic pontine glioma (DIPG), one of several indications for which WP1066 has been granted a “rare pediatric disease”

designation, which could potentially qualify WP1066 for a priority review voucher if the FDA were to approve a New Drug Application (NDA) for treatment of that disease.

WP1220 (part of the WP1066 portfolio) has shown the following activity:

The CSR issued in 2021 for a clinical trial of WP1220, another drug candidate in the WP1066 Portfolio, studied for the topical treatment of cutaneous T-cell lymphoma (CTCL) documented a PR (the target lesion decreasing 50% or more) in 60% of subjects (three out of five) that was confirmed by a subsequent evaluation one month later with one of the subjects having a near total resolution of their lesions (93% decrease).

The median time to PR was 56 days.

Stable disease was the best response documented for remaining 40% of subjects (2 out of 5), resulting in clinical benefit for 100% of subjects.

Stable disease was the best response documented for the remaining 40% of subjects (two out of five), resulting in clinical benefit for 100% of subjects.

All subjects (100%) survived up to 112 days of follow-up.

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By “externally funded”

we mean that the preclinical work is performed by external collaborators and for the clinical trials are physician-sponsored or IITs.

we mean that the preclinical work is performed by external collaborators and the clinical trials are physician-sponsored or IITs.

For externally funded research, any grant funds that support such preclinical work or clinical trials and most of the associated expenses do not flow through our financial statements.

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Additionally, we are seeking collaborative partners to further clinical research on all three of our core programs.

Specifically, we have ongoing discussions with potential partners to support a Phase 2 clinical trial of WP1220 in CTCL.

The ultimate course of action depends on the outcome of additional regulatory and preclinical work.

These trials may be internally or externally funded, depending on the timing and nature of the studies.

Utilizing our sponsored research, we are further evaluating WP1122 and other molecules in that portfolio (WP1096 and WP1097) for the treatment of COVID-19 and other viruses.

These discussions, unless otherwise described herein, are preliminary.

Working Environment

Our headquarters and laboratory are in Houston, Texas, and our workforce, as of year-end 2021, consisted of twenty-one full and part-time employees, including contractors devoting more than 20 hours per week, in the US and Europe, which are leveraged with other service providers and contractors worldwide working in a primarily virtual environment, even prior to the COVID-19 pandemic.

This number increased to twenty-two in early 2022.

We do not have manufacturing facilities and all manufacturing activities are contracted out to third parties.

Our headquarters and laboratory are in Houston, Texas, and our workforce, as of year-end 2022, consisted of nineteen full and part-time employees, in the US and Europe, which are leveraged with other service providers and contractors worldwide working in a primarily virtual environment, even prior to the COVID-19 pandemic. We do not have manufacturing facilities and all manufacturing activities are contracted out to third parties.

Additionally, we do not have a sales organization.

Our overall strategy is to seek the best value for our shareholders either via potential outlicensing or collaborative opportunities with other pharmaceutical companies with existing marketing, sales and distribution or via the development of contracted marketing, sales and distribution capability if and when our drugs are approved.

The spread of COVID-19 has caused significant volatility in US and international markets, including Poland, where we conduct some of our clinical trials, and Italy, where our drug supply is produced.

There has been limited temporary interruption of our drug supply, and the ability to monitor activities were limited at most Polish clinics where we are conducting trials, which could delay our ability to collect data and authorize new subject recruitment.

Additionally, we believe COVID-19 has materially slowed the ability of approved sites to recruit subjects for our trials in Poland.

Although, the impact of the pandemic appears to be lessened, this continues to be a volatile situation that could continue to improve or worsen at any time.

The spread of COVID-19 caused significant volatility in US and international markets, including Poland, where we conduct some of our clinical trials, and Italy, where our Annamycin drug supply is produced.

In 2022, there was limited temporary interruption of our drug supply, and the ability to monitor activities were limited at most Polish clinics where we are conducting trials. Although, most of the impact of the pandemic appears to have abated, this continues to be a volatile situation that could continue to improve or worsen at any time.

Some of our European sites still cite the lack of staff as a reason for slow recruitment.

Furthermore, there is significant uncertainty around the breadth and duration of business disruptions related to COVID-19, including the impact on the US and international economies and, as such, we are therefore unable to determine if those circumstances will have a material impact to our operations.

Additionally, war, terrorism, geopolitical uncertainties (such as the current crisis in Ukraine) and other business interruptions could cause damage to, disrupt or cancel the conduct of our clinical trials on a global or regional basis, which could have a material adverse effect on our business, clinical sites or vendors with which we do business.

Additionally, war, terrorism, geopolitical uncertainties (such as the current war in Ukraine) and other business interruptions could cause damage to, disrupt or cancel the conduct of our clinical trials on a global or regional basis, which could have a material adverse effect on our business, clinical sites, drug suppliers or vendors with which we do business.

Such events could also decrease the availability of subjects interested or able to enroll in our clinical trials or make it difficult or impossible for us to deliver products and services to our clinical investigational sites.

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We cannot determine whether these events will materially impact our overall business and operations, recruitment, and our drug supply in the future.

Mission and Strategy Overview

We are a clinical stage pharmaceutical company with a growing pipeline of clinical development programs for the treatment of highly resistant cancers and viruses.

For cancers, these include AML, GBM, STS lung metastases, pancreatic cancer, CTCL, other vital organ metastases, and others.

With regard to viruses, our current focus is the possible treatment of COVID-19, its variants and potential future coronaviruses, while additional preclinical work has demonstrated possible activity against HIV, Zika, and Dengue fever.

Our Mission and Strategy

We are a clinical stage pharmaceutical company with a growing pipeline, including Phase 2 clinical programs for hard-to-treat cancers and viruses. We have three core technologies, each of which have had one or more drugs successfully complete a Phase 1 clinical trial 4 , based substantially on discoveries made at and licensed from MD Anderson in Houston, Texas.

Three of our six drug candidates have shown human activity in clinical trials and are currently in Phase 1b/2 or Phase 2 clinical trials.

Since our inception, our drugs have been in, are currently in, or have received approval to proceed in eleven clinical trials.

With regard to viruses, preclinical work has demonstrated possible activity against COVID-19, HIV, Zika, and Dengue fever.

Our diverse pipeline of technologies was built around the recognition that many highly resistant tumors tend to have a common set of traits, including an increase in multidrug resistance mechanisms, an evasion of the natural immune system, a marked upregulation of certain key oncogenic transcription factors and an increased dependence on glycolysis for energy production.

Many of these traits are also common to certain viruses and we believe each of these elements may be addressed by the unique and innovative mechanisms introduced by one or more of our three core technologies.

Many of these traits are also common to the replication of certain viruses and we believe each of these elements may be addressed by the unique and innovative mechanisms introduced by one or more of our three core technologies.

As detailed within, although we have conducted a significant amount of preclinical and early-stage clinical work that we consider promising, there is no guarantee that any future study will be conducted or will be successful, or that our product candidates, if approved, will ultimately be successfully commercialized.

We believe our technologies may provide an opportunity to help the many patients in need of alternative therapies, both as single agents and in combination with numerous existing technologies that often fail as tumors present immediate or acquired resistance.

We believe showing even modest improvements in highly resistant cancers and viruses may lead to approval pathways that may potentially reduce the time and capital required to ultimately realize success.

We believe showing even modest improvements in hard-to-treat cancers and viruses may lead to approval pathways that may potentially reduce the time and capital required to ultimately realize success.

Our technology is licensed from MD Anderson via exclusive licenses, which are discussed in more detail below.

In February 2019, we announced our sublicensing agreement to WPD Pharmaceuticals (WPD), an entity associated with one of our cofounders and the chair of our science advisory board, Dr.

Waldemar Priebe.

WPD recently announced their facilitation of a grant equivalent to $1.5 million to the Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO) to fund a Phase 1b/2 clinical trial of Annamycin for the treatment of STS lung metastases.

The grant-funded clinical trial is led by Prof.

In 2021, our then sublicensee, WPD Pharmaceuticals (WPD), announced their facilitation of a grant equivalent to $1.5 million to the Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO) to fund a Phase 1b/2 clinical trial of Annamycin for the treatment of STS lung metastases.

The grant-funded clinical trial, which has begun treatment of subjects, is led by Prof.

Piotr Rutkowski, MD, PhD, Head of Department of Soft Tissue/Bone Sarcoma and Melanoma at the MSCNRIO in Warsaw, Poland.

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Additionally, we are independently exploring other grant funded opportunities.

This increase in potential outside funding should allow us to concentrate our internal resources primarily on Annamycin, WP1122, and alternate methods of delivery for WP1066.

In March 2023, WPD assigned their rights and duties related to the grant-funded trial at MSCNRIO to us as part of the termination of their sublicense as described further below.

This increase in potential outside funding should allow us to concentrate our internal resources primarily on Annamycin, alternate methods of delivery for WP1066, and WP1122.

This allows us to prioritize our internal funding to core clinical trials that we think may lead to an approval pathway and/or a strategic licensing opportunity.

Accordingly, we have increased our focus on clinical trial pathways for Annamycin, which is now in clinical trials for two different indications.

We have now seen human activity in three drug candidates, some of which that we think are capable of supporting an approval pathway with continued positive developments in their respective clinical trials.

We continue to internally fund our WP1122 antiviral program, as we now have an approved CTA for a Phase 1 clinical trial intended to establish an RP2D, however the volatility and unpredictability of COVID-19 incidence in various countries may limit our ability to recruit certain subjects and could make it infeasible for us to conduct a Phase 2 clinical trial on a timely basis, or at all. In addition, the FDA recently cleared an IND for the study of WP1122 in GBM and we intend to identify investigators interested in collaborating on the potential oncology indications for this drug candidate.

Intellectual Property

We have obtained worldwide, exclusive licenses from MD Anderson Cancer Center (MD Anderson) to issued US patents and pending US patent applications for each of our drug candidates, as well as pending foreign patent applications or issued foreign patents.

We have now seen human activity in three drug candidates, some of which we think may be capable of supporting an approval pathway with continued positive developments in their respective clinical trials.

Subject to database lock and completion of a CSR, we are concluding our internally funded WP1122 antiviral program which established an RP2D. This will potentially support future externally funded virology or oncology clinical trials.

Additionally, an IND for the study of WP1122 in GBM went into effect in 2022 and we intend to identify investigators interested in collaborating on the potential oncology indications for this drug candidate.

Our Intellectual Property and FDA Designations

We have obtained worldwide, exclusive licenses from MD Anderson to issued US patents and pending US patent applications for each of our drug candidates, as well as pending foreign patent applications or issued foreign patents.

With respect to certain patents or patent applications, we are co-owners with MD Anderson, in which instances we have exclusively licensed MD Anderson’s rights in those patents or patent applications.

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In the US, regulatory exclusivity can range from three (3) years for a product with a previously approved active pharmaceutical ingredient to seven (7) years for a novel product designated as an Orphan Drug.

We have obtained Orphan Drug designation (ODD) from the FDA for Annamycin for the treatment of AML and intend to seek ODD for Annamycin and other product candidates for other orphan diseases for which we seek to develop these drugs.

We have obtained Orphan Drug designation (ODD) from the FDA for Annamycin for the treatment of AML and STS;

for WP1066 for the treatment of GBM;

and, for WP1122 for the treatment of GBM.

We have other FDA designations as discussed below. Detailed discussion of potentially relevant regulatory exclusivities can be found under Regulatory Exclusivities below.

The following provides a general description of our patent portfolio and is not intended to represent an assessment of claim limitations or claim scope.

4  WP1122 Phase 1 Clinical Study Report has not been published and safety results are preliminary.

We have pending patent applications directed to the synthetic processes for lyophilized Annamycin and for reconstitution of our Annamycin drug product candidate.

We have exclusively licensed MD Anderson’s rights in these applications, which are co-owned by MD Anderson and us.

The applications are pending in jurisdictions worldwide, including but not limited to Australia, Brazil, Canada, China, European Patent Organization, Japan and the US Both applications have a filing date of June 25, 2020.

The applications are pending in jurisdictions worldwide, including but not limited to Australia, Brazil, Canada, China, European Patent Organization, Japan, Israel, India, South Korea, Mexico, and the US.

Both applications have a filing date of June 25, 2020.

We also have rights to a patent application, filed on November 23, 2020, directed to the use of Annamycin for the treatment of certain lung cancers.

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These patents claim WP1066 and other molecules, as well as methods of treating disease using WP1066.

Foreign counterparts to the US patents are issued in Canada, Europe, Israel, India, Japan and South Korea.

Foreign counterparts to the US patents are issued in Canada, China, Europe, Israel, India, Japan and South Korea.

These patents have an international filing date in December 2004, and in certain instances have had the patent term adjusted.

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In addition, we have rights to US and foreign patent applications directed to the treatment of viral diseases with WP1122 and other anti-metabolites including WP1096 and WP1097, with a filing date in March 2021.

Our Drug Candidate Programs

FDA Designations

To further enhance our intellectual property, we have the following FDA designations for our drug candidates as shown.

The importance of these designations is discussed further below in the section titled Regulatory Exclusivities .

Drug Candidate

FDA ODD - Indication

FDA Fast Track - Designation (FTD)

FDA Rare Pediatric Disease Priority Review Voucher (PRV) Program

Yes – AML, Soft Tissue Sarcoma

Yes – Ependymoma, diffuse intrinsic pontine glioma (DIPG), medulloblastoma and atypical teratoid rhabdoid tumor

Our Drug Candidate Programs 

Annamycin Program

We consider Annamycin to be a "next generation" anthracycline, unlike any currently approved anthracyclines, as it is designed to avoid multidrug resistance mechanisms and cardiotoxicity (the efficacy of all currently approved anthracyclines is limited by both multidrug resistance and cardiotoxicity).

Our preclinical studies support this intended design and, to date, we have demonstrated no signs of cardiotoxicity in our three Phase 1 clinical trials utilizing Annamycin as assessed, as recently as January 2022, by an expert in cardiotoxicity associated with chemotherapy at the Cleveland Clinic.

Additionally, we reported from our clinical trials evidence that Annamycin may have a substantially lower incidence of alopecia (hair loss) than currently prescribed anthracyclines such as doxorubicin.

The FDA granted Orphan Drug Designation (ODD) to Annamycin for the treatment of AML and for soft tissue sarcomas, which means the agency believes we have established a medically plausible basis for using the drug for those indications.

Additionally, Fast Track Designation was also granted by the FDA for Annamycin for both the treatment of AML and STS lung metastases.

A drug that receives Fast Track designation is eligible for some or all of the following:

We consider Annamycin to be a "next generation" anthracycline, unlike any currently approved anthracyclines, as it is designed to avoid multidrug resistance mechanisms and cardiotoxicity, recognizing that the efficacy of all currently approved anthracyclines is limited by both multidrug resistance and cardiotoxicity.

Our preclinical studies support this intended design and an independent expert in chemotherapy-associated cardiotoxicity at the Cleveland Clinic issued a report indicating no signs of cardiotoxicity in our three Phase 1 Annamycin clinical trials in forty-two subjects, as recently as November 2022.

Additionally, we reported from our clinical trials evidence that Annamycin may have a substantially lower incidence of alopecia (hair loss) than currently prescribed anthracyclines.

The FDA granted ODD to Annamycin for the treatment of AML and for soft tissue sarcomas, which means the agency believes we have established a medically plausible basis for using the drug for those indications.

The FDA also granted FTD for Annamycin for both the treatment of AML and STS lung metastases.

A drug that receives FTD is eligible for some or all of the following:

More frequent meetings with FDA to discuss the drug's development plan and ensure collection of appropriate data needed to support drug approval;

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Eligibility for other FDA expedited programs, if relevant criteria are met;

New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed.

NDA review usually does not begin until the sponsor has submitted the entire application to the FDA

Rolling review by FDA of the NDA, rather than waiting until every section of the NDA is complete before beginning review of the application, which is the typical process.

Annamycin Clinical Trials –

A Phase 1 clinical trial of Annamycin as a single agent for the treatment of relapsed and refractory (R/R) AML in the US was successfully concluded in 2020.

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The FDA established the LTMAD because of concerns about cardiotoxicity associated with currently approved anthracyclines when administered above the LTMAD.

An updated independent safety review in early 2022 of certain preliminary data of the first 30 subjects in our three Annamycin clinical trials (treating both AML and STS lung metastases) concluded there was no evidence of cardiotoxicity.

19 of the 30 subjects evaluated had been treated above the LTMAD and none have shown evidence of any cardiotoxicity.

As a result of discussions with the FDA, we focused our continuing efforts on establishing an RP2D for Annamycin in our Phase 1/2 single agent R/R AML clinical trial Europe, which was ongoing throughout 2021.

An updated independent safety review in late 2022 of certain preliminary data of the first forty-two subjects in our three Annamycin clinical trials (treating both AML and STS lung metastases) concluded there was no evidence of cardiotoxicity.

Thirty-two of the forty-two subjects reviewed (across three of our trials –

MB-104, MB-105 and MB-107), following administration of Annamycin, received more than the LTMAD and none have shown evidence of any cardiotoxicity per our expert review.

As a part of our ongoing sponsored research at MD Anderson, animal testing has indicated that the combination of Annamycin with Ara-C (AnnAraC) provides a synergistic effect that is more effective in AML mouse models than either drug alone.

These data were presented at the 62nd Annual Meeting & Exposition of the American Society for Hematology (ASH) under the title:

"High Efficacy of Liposomal Annamycin (L-ANN or L-Annamycin) in Combination with Cytarabine (AnnAraC) in Syngeneic p53-null AML Mouse Model."

This study was conducted in a highly aggressive AML mouse model where median survival is approximately 13 days.

For animals treated with AnnAraC, median survival ranged from 56 to 76 days, thus expanding median survival by 585%, with some animals having no signs of any tumors after treatment. Additionally, when looking at median overall survival (OS) for the mice in the study, AnnAraC demonstrated a 68% improvement in the OS compared to Annamycin as a single agent and a 241% increase in OS compared to Cytarabine alone.

We believe these experiments support initiation of clinical development of the combination of Annamycin and Ara-C in AML patients.

Although Annamycin has already shown human activity as a single agent in its two Phase 1 AML clinical trials and has shown no signs of cardiotoxicity, the observed synergy in vitro and confirmatory in vivo data suggest that the AnnAraC could be more effective in a clinical setting than Annamycin as a single agent.

This would be consistent with the current practice to use Ara-C in combination with other anthracyclines.

The current first-line therapy for AML patients is the combination of an anthracycline and Ara-C in a regimen referred to as "7+3" where Ara-C is administered daily for 7 days in parallel with 3 daily doses of an anthracycline.

Simply substituting Annamycin for the currently used anthracycline in a similar 7+3 regimen would represent a familiar and well-practiced treatment modality.

Beyond that, we believe it would have the added advantages that Annamycin has been shown in published research to be active against tumor cells resistant to doxorubicin and, importantly, has the potential to remove the concern for cardiotoxicity, a significant toxic side effect of currently used anthracyclines.

Thus, we are now focusing our efforts on an AnnAraC trial for the treatment of AML in Europe.

As a result of discussions with the FDA, we focused our continuing efforts on establishing an RP2D for Annamycin in our Phase 1/2 single agent R/R AML clinical trial in Europe.

In February 2022, we successfully concluded the Phase 1 portion of that trial and established the RP2D of 240 mg/m2.

In that trial we continue to demonstrate no signs in cardiotoxicity in subjects treated.

In the final cohort , five subjects received a full course of Annamycin and demonstrated an ORR of 60% with two partial responses (PRs) and one complete response with incomplete recovery of neutrophils and/or platelets (CRi). In light of recent preclinical research suggesting that the combination of Annamycin with Cytarabine (AnnAraC) may be more effective for R/R AML patients than Annamycin as a single agent, we have elected to begin the process of commencing a Phase 1/2 clinical trial in Europe evaluating AnnAraC rather than to expend resources on the expansion (Phase 2) arm of the single agent trial. 

These preclinical animal studies showed that AnnAraC was 68% more effective (median overall survival or OS) than Annamycin as a single agent and 241% more effective than Cytarabine (also known as Ara-C) alone.

Accordingly, we filed a CTA with the URPL in Poland in November 2021 for a Phase 1/2 trial treating AML with AnnAraC and received approval in December 2021 from the Bioethics Committee of the Medical University of Karol Marcinkiewicz in Poznań

(Ethics Committee).

We are in correspondence with the URPL and expect to receive their approval and to begin this trial in the first half of 2022.

We can provide no assurance that such approval will be received.

We received clearance from the FDA to proceed with a Phase 1b/2 clinical trial of Annamycin as a potential treatment for soft tissue sarcomas (STS) metastasized to the lungs.

Our preclinical work on Annamycin demonstrated activity against certain cancers (including STS) metastasized to the lungs.

In the final cohort, five subjects received a full course of Annamycin and demonstrated an ORR of 80% with three partial responses (PRs) and one complete response with incomplete recovery of neutrophils and/or platelets (CRi). In two of the PRs the BMA's were below 5% but were still designated as a PR by the sub-investigator at that site.

In light of the preclinical research suggesting that the combination of AnnAraC may be more effective for R/R AML patients than Annamycin as a single agent, we have elected to begin the process of commencing a Phase 1/2 clinical trial in Europe evaluating AnnAraC rather than to expend resources on the expansion (Phase 2) arm of the single agent trial. These preclinical animal studies showed that AnnAraC was 68% more effective (median overall survival or OS) than Annamycin as a single agent and 241% more effective than Cytarabine alone.

Such preclinical results may not be replicated in human clinical trials.

We have been and intend to continue reporting top-line results by cohort in all of our Annamycin clinical trials, with each announcement also including an update on any other related trials.

Top-line results will include reporting of any drug-related adverse events (AEs) and assessment of cardiotoxicity, including ECHO (echocardiogram) scans measuring change in ejection fraction and measuring certain blood troponin levels, which is considered a biomarker for potential long-term cardiovascular impairment.

Top-line results will also include the number of partial responses (PRs), complete responses (CRs) and subjects deemed capable of progressing to a potentially curative bone marrow transplant, which we term "bridge to transplant" (BTs), each of which is essentially a function of the magnitude of reduction in a subject's BMA.

For purposes of these clinical trials, a CR means that the subject's BMA reduced to 5% or less with recovery of neutrophils (or white blood cells) and platelets, CRi means a CR where there was incomplete recovery of neutrophils and/or platelet counts, a PR means the subject's BMA reduced by 50% and resulted in a blast count of 25% or less, and a BT means subjects are deemed capable of progressing to a potentially curative bone marrow transplant.

Annamycin Clinical Trials –

STS Lung Metastases

We announced in April 2019 that our ongoing sponsored research at MD Anderson demonstrated that Annamycin can significantly improve survival in an aggressive form of triple negative breast cancer metastasized to the lungs in animal models.

We know that Annamycin was previously shown to be significantly more potent than doxorubicin in both Lewis lung carcinoma in animal models or in vivo and small cell lung cancer in vitro models.

In addition to seeing activity in animal models of triple negative breast cancer metastasized to the lungs, we are also seeing activity in colon cancer metastasized to the lungs.

The particular animal models used in our testing are considered to represent very aggressive forms of cancer.

Furthermore, a poster entitled, "Liposomal annamycin inhibition of lung localized breast cancer," was presented at the San Antonio Breast Cancer Symposium held in December 2019.

The published poster (https://www.moleculin.com/san-antonio-bc-symposium-poster/) shows substantially increased survival in both triple negative breast cancer and colon cancer lung metastases animal models.

It should also be noted that treatment with Annamycin resulted in long-term survival of a significant number of animals, even when cancer was reintroduced into the animals post initial treatment, suggesting the development of beneficial immune memory.

A reduction in tumor growth was demonstrated as well as a reversal of tumor activity resulting in an almost complete reduction of tumor burden.

Such preclinical results may not be replicated in human clinical trials.

We announced in early 2021 that Annamycin demonstrated consistently high antitumor activity in tested animal models of different types of lung-localized cancers, including sarcoma.

These promising findings correlate with a high uptake of Annamycin to the lungs in animal models.

We found in our studies that the Annamycin uptake is over 30-fold higher than that of doxorubicin, the primary first-line chemotherapy for soft tissue sarcoma. The limited pulmonary uptake of doxorubicin in animal models may help explain its limited activity against STS lung metastases in humans. Additionally, our clinical data to date show no cardiotoxicity associated with the use of Annamycin, and the published research demonstrate Annamycin’s ability to avoid multidrug resistance mechanisms, both of which are often treatment-limiting effects of anthracyclines (which includes doxorubicin) in this setting. Taken together, these factors suggest that Annamycin could represent an important treatment to help address a significant unmet need in patients with STS lung metastases.

In February 2021, we announced that a preclinical study in animals has suggested a possible significant therapeutic benefit of Annamycin against metastatic osteosarcoma.

As of day 130 of the study, the survival rate for animals treated with Annamycin was 100%, compared with only 10% for untreated animals.

Computerized tomography scans demonstrated that animals treated with Annamycin exhibited suppression of tumor growth and not a single death was observed in the treated animals, whereas observed tumor burden was believed to have contributed to the rapid death of 90% of untreated animals.

We believe these data are a promising indication of the possibility of Annamycin’s impact on other cancers metastasized to the lungs.

We caution that these are preclinical animal data and we can provide no assurance that we will see similar results in our clinical trials, let alone ultimately obtain approval of Annamycin for this use.

It is estimated that there are approximately 36,000 new cases of STS in the seven major markets (US, EU5 and Japan) each year. Our clinical advisors estimate that approximately half of all STS patients will eventually develop lung metastases from their primary tumor. Although first-line treatments such as surgical resection, chemotherapy and radiation may provide initial therapeutic benefit for approximately one third of those patients, there are no approved or emerging second-line therapies for the remaining patients who relapse or are refractory. Although the lungs tend to be a major site of relapse, when we began our own clinical trial using Annamycin against STS lung metastases, we were aware of only a very few active clinical trials specifically targeting STS lung metastases, indicating that Annamycin currently faces limited competition in this area of development.

Along with the results in STS lung metastases, our animal models have shown activity in other lung metastases, including osteosarcoma, colorectal and triple negative breast cancer, as well as meaningful concentration levels of Annamycin in the liver, spleen and pancreas. Additionally, when tested in a highly aggressive AML mouse model, Annamycin significantly reduced tumor burden in the spleen, lungs and liver, leading to an increase in survival. Based on these promising preclinical data, we believe the ultimate market opportunity for Annamycin could be larger than just STS lung metastases. As such, we may expand our clinical trials into these areas in the near term using externally funded trials.

In December 2020, the FDA allowed our IND to go into effect to study Annamycin for the treatment of soft tissue sarcoma lung metastases.

This allowed us to begin a Phase 1b/2 clinical trial in the US for patients with STS lung metastases after first-line therapy for their disease.

This allowed us to begin a Phase 1b/2 clinical trial in the US for subjects with STS lung metastases after first-line therapy for their disease.

The trial began in the first half of 2021.

In December 2021, we reported preliminary interim results from this clinical trial as we concluded the safety review of the third cohort and opened the fourth cohort in a dose escalation trial, which continues to document preliminary clinical activity for this drug.

We are currently in the fourth cohort and have expanded the cohort due to a dose limiting toxicity (DLT).

The first three subjects in this cohort preliminarily exhibited stable disease per the protocol after two cycles and continued in the study.

Due to the DLT, the fourth cohort is being expanded to enroll an additional three subjects at this dose level. In the absence of any additional DLTs at this dose level, we have the option to continue escalation to explore the fifth cohort at 450 mg/m 2 dose level or to declare the RP2D to be 390 mg/m 2 .

Additionally, we announced in February 2021 promising preclinical studies involving Annamycin targeting osteosarcoma metastasized to the lungs.

Via our sponsored research, we plan to further investigate the treatment of other cancer metastases and other cancers such as liver, colorectal, and pancreatic cancers among others.

Prior Development

We took over the development of Annamycin after two prior drug development companies, Callisto Pharmaceuticals and Aronex Pharmaceuticals, ceased development work for various clinical and business reasons, leading to the termination of their INDs by the FDA.

The basis for our decision to proceed notwithstanding the most recent prior developer’s abandoning the project is that we believed the actual clinical data as reported by Dr.

Robert Shepard, our Chief Medical Officer and the prior developer’s Chief Medical Officer at the time of the clinical trials, to the 2009 Annual Meeting of the American Society of Clinical Oncology (ASCO), and as further reported by the Principal Investigators of the clinical trials in a peer-reviewed journal article (Clin Lymphoma Myeloma Leuk.

doi:10.1016/j.clml.2013.03.015.), supported further clinical evaluation.

In addition, the conclusion published in the 2013 Clinical Lymphoma, Myeloma & Leukemia Journal article was that “Single agent nanomolecular liposomal annamycin appears to be well-tolerated and (demonstrates) evidence of clinical activity as a single agent in refractory adult ALL.”

As reported in both the ASCO presentation and the 2013 journal article referenced, the definition of efficacy is based on the following Response Criteria:

“Response criteria were achievement of CR defined as ≤5% blasts, granulocyte count of ≥1×10 9 /L, and a platelet count of ≥100×10 9 /L.

Partial remission was defined the same as CR, except for the presence of 6% to 25% blasts.

Hematologic improvement was defined as for CR but platelet count of ≥1×10 9 /L.”

The summary of subject response from the 2013 journal article reads:

“After determining the MTD, a 10-patient phase IIA was conducted.

Eight of the patients completed one cycle of the three days of treatment at the MTD.

Of these, five (62%) demonstrated encouraging anti-leukemic activity with complete clearing of circulating peripheral blasts.

Three of these subjects also cleared bone marrow blasts with one subsequently proceeding onto successful stem cell transplantation.

The other two subjects developed tumor lysis syndrome and unfortunately expired prior to response assessment.”

In our review of these trials, we confirmed that the activity demonstrated in this summary corresponds with a “Partial Remission”

as described in the Response Criteria and that the three subjects who “cleared bone marrow blasts”

correspond with “CR”

(Complete Response).

The Callisto trial was the second trial to study Annamycin in acute leukemia.

The first trial was sponsored by Aronex Pharmaceuticals.

When Callisto acquired the technology and made changes in manufacturing methods, they had to conduct another Phase 1 dose ranging trial.

Both trials yielded some human activity with Annamycin in AML but at different MTDs.

We believe the different MTDs were due to subtle differences in the manufacturing and reconstitution processes of Aronex and Callisto, mainly regarding liposomes.

The production of liposome formulated anthracyclines is very sensitive to subtle changes in production method and starting materials.

It is partly for this reason that, more than 10 years later and with entirely new contractors, we had to run additional Phase 1 dose ranging studies and the technology we assisted in developing yielded additional new patent applications for formulation and reconstitution of Annamycin.

The Importance of No Cardiotoxicity

We have received multiple reports from an independent expert cardiology assessment and the last such report in January 2022 continued to confirm the absence of any cardiotoxicity relating to treatment with Annamycin in our three Phase 1 clinical trials to date.

That report updated the independent safety review of certain preliminary data for the first 30 subjects in our clinical trials in the US and Europe with Annamycin targeting AML and the STS lung metastases which concluded there was no evidence of cardiotoxicity.

The review included analysis of ejection fraction, echo strain and certain troponin levels intended to assess the potential for both acute and chronic heart damage.

In 2022, we expanded the fourth cohort due to a dose limiting toxicity (DLT) and then in late 2022, we concluded the Phase 1b portion of the study.

Fifteen subjects were enrolled and treated per the protocol in four cohorts to determine the maximum tolerable dose and/or the RP2D and followed for safety and efficacy.

Each cohort had three subjects, except for the fourth cohort, which (per the protocol) was expanded to six subjects after a DLT occurred in a single subject.

The Company concluded the Phase 1b portion after the fourth cohort of 390 mg/m2 was documented to be safe.

Based on findings from the Phase 1b position of the trial, 360 mg/m2 demonstrated it may be tolerated by subjects initially, however continued treatment was deemed at risk to be delayed or interrupted due to adverse events (primarily myelosuppression, which is anticipated with high doses of anthracycline therapy), hence lowering the dose from 360 mg/m2 to 330 mg/m2 was contemplated in advance of beginning the Phase 2 expansion pending results from the first three subjects in the RP2D evaluation phase.

Adverse events (AE), primarily myelosuppression, in the first three subjects at 360 mg/m2 led us to lower the RP2D to 330 mg/m2 in October 2022, which we believe will enable continued treatment of subjects with fewer interruptions.

The median progression free survival time in patients with soft tissue sarcoma with metastases (not just lung metastases which is believed to be even shorter) that have failed initial systemic therapy is approximately 1.6 to 2.0 months, without effective therapy which includes subjects treated with a placebo.

Comandone, F.

Petrelli, A Boglione, S.

Salvage Therapy in Advanced Adult Soft Tissue Sarcoma.

The Oncologist 2017;22:1518–1527) In this context, we believe Annamycin has the potential to bring a new and effective treatment option to patients with this significant unmet need.

In the fifteen subjects treated per protocol in the escalating dose cohorts, there was an overall response rate in nine subjects or 60% –

defined as stable disease or better in the subjects STS lung metastases after at least two cycles of Annamycin (approximately six weeks).

Our median progression free survival (PFS) was 2.6 months in the Phase 1 portion of the study.

PFS will be monitored in the Phase 2 portion, as well.

This data is encouraging but preliminary and may not be borne out by further study.

To date in the Phase 2 portion of the study, fourteen subjects have been identified, recruited, or dosed out of a total planned twenty-five to twenty-eight subjects.

Of these eleven have begun receiving doses and six have been dosed two cycles and received their end of cycle two scans.

Four of these or 67% were noted as stable disease or better with one of the subjects continuing with the study drug.

The main reason for subjects not continuing is due to myelosuppression due to the study drug, keeping in mind that most of these subjects have had multiple prior treatments for STS and some have received close to the LTMAD prior to entering the study.

All four subjects will continue to be monitored for PFS while in the study.

The one subject continuing with the study drug has not experienced myelosuppression.

We have recently discussed with investigators that they may reduce the dose of the study drug after the first cycle, per the protocol, as to possibly allow more subjects to continue receiving the study drug.

This data is preliminary and subject to change.

The Importance of Lower Cardiotoxicity of Annamycin Versus Other Anthracyclines

We have received multiple reports from an independent expert cardiology assessment and the last such report in late 2022 continued to confirm the absence of any cardiotoxicity relating to treatment with Annamycin in our three Phase 1 clinical trials to date.

To be clear, where we mention “no cardiotoxicity”

of Annamycin, management’s beliefs are based on this expert’s opinion based on their review of certain clinical trial subject data.

The expert’s report updated the independent safety review of certain preliminary data for the first forty-two subjects in our Annamycin clinical trials in the US and Europe targeting AML and the STS lung metastases which concluded there was no evidence of cardiotoxicity.

The expert’s reviews included analysis of ejection fraction, echo strain and certain troponin levels (I & T) intended to assess the potential for both acute and chronic heart damage. We believe these expert reports are particularly relevant in light of a recently published retrospective study showing that the incidence of heart failure more than doubles for cancer patients treated with anthracyclines compared to cancer patients not receiving anthracyclines (C Larson, et al.

Anthracycline and Heart Failure in Patients Treated for Breast Cancer or Lymphoma, 1985-2010.

JAMA Network Open.

2023;6(2):e2254669.

doi:10.1001/jamanetworkopen.2022.54669).

With the subject population that we are experiencing in our Annamycin trials (multiple prior therapies, many elderly), we believe that there is a high likelihood that a cardiac event will occur that we will not be able to disassociate from our study drug.

Additionally, we reported evidence that Annamycin may have a substantially lower incidence of alopecia (hair loss) than currently prescribed anthracyclines such as doxorubicin.

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And, in part because of the emphasis placed on alternatives to chemotherapy, we believe that not enough has been done to improve chemotherapeutic agents to make them safer, especially with regard to cardiotoxicity (damage to the heart), and more effective.

Anthracyclines are a class of chemotherapy drugs designed to destroy the DNA (by creating iron-mediated free oxygen radicals, damaging the DNA and cell membranes, and inhibiting topoisomerase II) of rapidly producing cancer cells.

Acute leukemia is one of a number of cancers that are usually treated with anthracyclines.

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This is a particularly significant risk for pediatric leukemia patients, whose life spans can be severely shortened by the induction therapy intended to cure them of acute leukemia.

In the animal model recommended by the FDA as an indicator of human cardiotoxicity, the non-liposomal (free) form of Annamycin has been shown to be significantly less likely than doxorubicin to create heart lesions in mice, and the liposomal formulation (L-Annamycin) has been shown in these same models to have reduced cardiotoxicity to the point where it is unlikely to cause harm to human patients.

If this same characteristic continues to be shown in humans, it may allow Annamycin to be used more aggressively to help patients achieve remission.

This would be especially valuable in the case of pediatric acute leukemia (both AML and ALL) because of the potential impact of cardiotoxicity on long-term survival.

In our clinical trials for Annamycin, we are collecting data to further validate the design intent of Annamycin to have little or no cardiotoxicity.

Unless otherwise noted, all of our references to Annamycin refer to the liposomal form (L-Annamycin).

In our clinical trials for Annamycin, we are collecting data to further validate the design intent of Annamycin to have no cardiotoxicity as reviewed by our expert review.

In addition, the effectiveness of currently approved anthracyclines is limited by their propensity for succumbing to “multidrug resistance.”

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A laboratory study has suggested that Annamycin may resist being expelled by P-glycoprotein pumps and similar multidrug resistance transporters, which may mean the drug circumvents multidrug resistance.

This characteristic has been shown in pre-clinical testing to allow for higher drug uptake in diseased cells, which we believe could allow for more effective induction therapy with less risk to the patient, especially in relapsed patients.

Annamycin as a Single Agent in AML

The prior development history of Annamycin in acute leukemia suggested that a possible approval pathway exists by positioning Annamycin as a single agent for the treatment of R/R AML.

Notwithstanding the recent approval of multiple drugs for this indication, most of these drugs are targeted therapies that are helpful to only a small percentage of the overall AML patient population.

A significant unmet need still exists for those patients that are refractory to or relapse from the traditional first-line induction therapy (known as “7+3”) designed to induce remission of AML and, in some cases, prepare patients for a curative bone marrow transplant.

Unfortunately, the majority of AML patients do not respond adequately to the current first-line therapies.

In addition, approximately 40% of AML patients are deemed “unfit”

for 7+3 due to the intensity of this chemotherapy.

We estimate that a significant portion of those patients are deemed unfit because of the potential for cardiotoxicity inherent in the anthracyclines currently used in 7+3.

Given its lack of cardiotoxicity, single agent Annamycin may also provide a viable treatment alternative for such patients.

Hence our initial clinical trials in R/R AML, as discussed more fully below, were focused on Annamycin as a single agent, and establishing an RP2D, which we were able to establish in early 2022.

Annamycin in Combination with Cytarabine (also known as Ara-C) in AML

These data were presented at the 62nd Annual Meeting & Exposition of the American Society for Hematology (ASH) under the title:

"High Efficacy of Liposomal Annamycin (L-ANN) in Combination with Cytarabine in Syngeneic p53-null AML Mouse Model."

This study was conducted in a highly aggressive AML mouse model where median survival is approximately 13 days.

For animals treated with AnnAraC, median survival ranged from 56 to 76 days, thus expanding median survival by 585%, with some animals, after treatment, having no signs of any tumors. Additionally, when looking at median overall survival (OS), AnnAraC demonstrated a 68% improvement in the OS compared to Annamycin as a single agent and a 241% increase in OS compared to Cytarabine alone.

We believe these experiments support initiation of clinical development of the combination of Annamycin and Ara-C in AML patients.

Although Annamycin has already shown human activity as a single agent in its two Phase 1 AML clinical trials and has shown no signs of cardiotoxicity, the observed synergy in vitro and confirmatory in vivo data suggest that the combination of Annamycin and Ara-C could be more effective in a clinical setting than Annamycin as a single agent.

This would be consistent with current practice to use Ara-C in combination with an anthracycline like Annamycin.

Simply substituting the currently used anthracycline in a similar 7+3 regimen with Annamycin would represent a familiar and well-practiced treatment modality.

Thus, we are now focusing our efforts on an AnnAraC trial for the treatment of AML in Europe in the first half of 2022.

Annamycin as a Single Agent in STS Lung Metastases

We know that Annamycin was previously shown to be significantly more potent than doxorubicin in both Lewis lung carcinoma in vivo and small cell lung cancer in vitro models.

In addition to seeing activity in animal models of triple negative breast cancer metastasized to the lungs, we are also seeing activity in colon cancer metastasized to the lungs.

The particular animal models used in our testing are considered to represent very aggressive forms of cancer.

Furthermore, a poster entitled, "Liposomal annamycin inhibition of lung localized breast cancer," was presented at the San Antonio Breast Cancer Symposium held in December 2019.

A reduction in tumor growth was demonstrated as well as a reversal of tumor activity resulting in an almost complete reduction of tumor burden.

We announced in early 2021 that Annamycin demonstrated consistently high antitumor activity in vivo in tested animal models of different types of lung-localized cancers, including sarcoma.

These promising findings correlate with surprisingly high uptake of Annamycin to the lungs in animal models.

In February 2021, we announced that a preclinical study in animals has confirmed a significant therapeutic benefit of Annamycin against metastatic osteosarcoma.

As of day 130 of the study, the survival rate for animals treated with Annamycin was 100%, compared with only 10% for untreated animals.

We believe these data are a promising indication of the possibility of Annamycin’s impact on other cancers metastasized to the lungs.

We caution that these are preclinical animal data and we can provide no assurance that we will see similar results in our clinical trials.

It is estimated that there are approximately 36,000 new cases of STS in the seven major markets (US, EU5 and Japan) each year. Our clinical advisors estimate that approximately half of all STS patients will eventually develop lung metastases from their primary tumor. Although first-line treatments such as surgical resection, chemotherapy and radiation may provide initial therapeutic benefit for approximately one third of those patients, there are no approved or emerging second-line therapies for the remaining patients who relapse or are refractory. Although the lungs tend to be a major site of relapse, when we began our own clinical trial using Annamycin against STS lung metastases, we were aware of only two active clinical trials specifically targeting STS lung metastases, indicating that Annamycin currently faces limited competition in this area of development.

Clinical Trials for Annamycin  

In 2022, we expect there will be three clinical trials ongoing that involve Annamycin for the treatment of R/R AML or STS lung metastases.

We recently concluded our Annamycin single agent AML trial in Europe, safely establishing an RP2D, and are now focusing on a European Phase 1/2 AML trial with AnnAraC (combination of Annamycin with Ara-C) which we believe will begin in the first half of 2022.

Additionally, our Phase 1b/2 clinical trial in the US for the treatment of STS lung metastases is ongoing, and a third investigator led trial with Annamycin treating STS lung metastases using a different dosing regimen than the US trial should begin in Poland during the second half of 2022.

This is in addition to the successfully completed US Phase 1 clinical trial of single agent Annamycin treating R/R AML.

US R/R AML Trial

We filed our IND application for a Phase 1/2 trial in the US with Annamycin for the treatment of R/R AML, with the clinical strategy of increasing the prior developers’

MTD mentioned above, in February 2017, which was allowed in September 2017.

The FDA required us to limit dosages to subjects to a lifetime maximum anthracycline exposure of 550 mg/m 2 in this trial which in effect limited the maximum dose in our trial to 120 mg/m 2 .

Subject treatment began in the US in March 2018.

In February 2020, we announced that our open label, single arm US Phase 1 portion of a Phase 1/2 trial had concluded its second cohort and met its primary objective of demonstrating the safety of Annamycin in treating relapsed or refractory AML. At that time, we received an independent expert cardiology assessment confirming the absence of cardiotoxicity in the first 19 subjects treated with Annamycin in both our US and European Phase 1 clinical trials.

The FDA requested that we demonstrate that Annamycin could be safely administered to subjects up to the lifetime maximum allowable level of anthracycline (LTMAD) established by the FDA and the trial met this primary endpoint.

The FDA established the LTMAD because of concerns about cardiotoxicity associated with currently approved anthracyclines when administered above the LTMAD.

An updated independent safety review in early 2022 of certain preliminary data of the first 30 subjects in our three Annamycin clinical trials concluded there was no evidence of cardiotoxicity.

Importantly, 19 of the 30 subjects evaluated were treated above the LTMAD.

As stated in our CSR, one of seven (or 14.3%) subjects achieved a morphological leukemia-free state (MLFS).

MLFS is defined as <5% blasts in the bone marrow with no blasts with Auer rods and no extramedullary disease.

This was at what we viewed as a subtherapeutic dose level when compared to MB-105.

As a result of discussions with the FDA, we focused on establishing an RP2D in our single agent R/R AML trial in Europe (discussed below), which we have recently announced, and, as requested by the FDA, we continue to generate additional safety and efficacy data prior to considering continuation of our US R/R AML trial.

European R/R AML Trial

In August 2017, we met with the European Medicines Agency (EMA) to discuss a CTA (Clinical Trial Authorization) in Europe for the study of Annamycin for the treatment of R/R AML.

In December 2017, the Ethics Committee in Poland approved our Phase 1/2 trial of Annamycin for the treatment of relapsed or refractory AML.

A final approval was required by the Polish National Office which was received in June 2018.

This enabled our Phase 1/2 clinical trial there to study Annamycin for the treatment of relapsed or refractory AML to begin.

The EMA did not impose a lifetime maximum anthracycline exposure limit in this trial.

In the final cohort of this trial, subjects were treated at 240 mg/m 2 .

Two subjects were preliminarily reported to have DLT events which were later classified as adverse events (AEs) following a review by the Safety Review Committee of the protocol DLT definitions.

However due to the preliminary DLT designation at the time, the cohort was expanded and eventually enrolled a total of eight subjects, with five receiving the full course of Annamycin.

An amendment to the Annamycin clinical trial protocol allowed for a change in the DLT criteria as it relates to transient grade 3 elevations and allowed dosing of three additional subjects in the 240 mg/m 2 cohort.

Of the eight subjects that were dosed three subjects experienced AEs or SAEs.

One fully resolved and another resolved to a grade 2 in the same day. One subject treated experienced an SAE (grade 2 infusion reaction) not currently listed in the investigator brochure (IB) therefore this is a Suspected Unexpected Serious Adverse Reaction (SUSAR) that required reporting to regulatory bodies, which was done.

In this cohort the eight subjects received an average of approximately seven prior regimens, representing heavily treated subjects.

Of the five receiving a full course of Annamycin at 240 mg/m 2 , a 60% ORR was experienced with two PRs and one CRi.

Coupling these data with the preclinical animal studies showing AnnAraC having greater efficacy than Annamycin or Cytarabine alone, as mentioned above, we established 240 mg/m 2 as the RP2D for this trial and switched our focus to initiating the combination study.

We also continued to see no signs of cardiotoxicity with all but three subjects having been reviewed by the expert, as mentioned above.

These last three subjects will be included in future updated reviews by the expert.

With these data we successfully concluded the Phase 1 portion of this trial in February of 2022 and will now focus on treating AML utilizing AnnAraC, as discussed more fully below.

While this will establish an RP2D for Annamycin in this single agent AML trial and will assist in establishing the starting dose in our planned trial using AnnAraC in treating AML, we do not believe it will limit the dose escalation in either the AnnAraC or STS trials, which are both discussed in more detail below.

Plans for a Phase 1/2 Trial of AnnAraC in AML in Europe

Based on the preclinical data discussed above, we are preparing to start a new clinical trial for the treatment of relapsed or refractory AML with the combination of Annamycin with Ara-C. We expect this clinical trial to begin in the first half of 2022.

We intend for our planned study of AnnAraC in AML to have a similar trial design to the recently concluded Phase 1/2 study of Annamycin as a single agent in AML. We believe safety data from our current single agent trial will enable us to begin the combination trial at a higher starting dose of Annamycin in the Phase 1 portion that our starting does in our monotherapy AML trial.

As part of these plans in 2021, we filed a CTA in Poland for a Phase 1/2 trial treating AML with a combination of Annamycin and Cytarabine (AnnAraC) and received approval in December 2021 from the Bioethics Committee of the Medical University of Karol Marcinkiewicz in Poznań

(Ethics Committee) and we expect allowance from the URPL in time to begin this trial in the first half of 2022. However, we cannot provide assurance that such approval will be received. This trial builds on the safety and dosage data from the two prior single agent Annamycin AML Phase 1 trials in the US and Europe that have been successfully concluded.

We also utilized preclinical animal data from our sponsored research conducted simultaneous with our clinical trials to support this new combination trial.

In that animal study Annamycin in combination with Cytarabine demonstrated a 68% improvement in the median overall survival (OS) compared to Annamycin as a single agent and a 241% increase in OS compared to Cytarabine alone.

Study Design for R/R AML -

We have been studying Annamycin in both the US and Europe in Phase 1/2 open label, single arm clinical trials to assess the safety and efficacy of Annamycin as a single agent for the treatment of adults with relapsed or refractory AML.

The US and European trials had essentially the same study design, consisting of a Phase 1 intended to establish a "Recommended Phase 2 Dose" (RP2D), to which the studies may then proceed in the Phase 2 portion.

The Phase 1 portion of the studies provided for escalating doses in cohorts of 3 subjects each, with each successive cohort receiving the next higher dose level until "dose limiting toxicities" prevent further increases.

Cohorts 1, 2, 3 and 4 in Europe received a dose of 120, 150, 180 and 210 mg/m 2 , respectively, and the results allowed us to advance to Cohort 5 with dosing at 240 mg/m 2 .

Refer to the discussion above for an update on this trial.

Cohort 1 in the US started at 100 mg/m 2 , and the results supported moving to Cohort 2 at 120 mg/m 2 , which has now been fully recruited, treated, and evaluated.

Our US Phase 1 trial met its primary endpoint, demonstrating the safety of Annamycin in treating AML when delivered to subjects at or below the lifetime maximum anthracycline dose established by the FDA.

The primary safety signal was the absence of cardiotoxicity, a serious and often treatment-limiting issue prevalent with currently approved anthracyclines.

The European trial benefited from a more aggressive dose escalation scheme than was allowed in the US trial and, as a result, reached higher dose levels. 

We have been and intend to continue reporting top-line results by cohort in all of our Annamycin clinical trials, with each announcement also including an update on any other related trials.

Top-line results will include reporting of any drug-related adverse events (AEs) and assessment of cardiotoxicity, including ECHO (echocardiogram) or MUGA (MUGA stands for multiple-gated acquisition and is also known as radionuclide ventriculography (RVG, RNV) or radionuclide angiography (RNA);

it is a type of nuclear imaging test intended to show how well the heart is pumping) scans measuring change in ejection fraction and measuring certain blood troponin levels, which is considered a biomarker for potential long-term cardiovascular impairment.

For purposes of these clinical trials, a CR means that the subject's bone marrow blasts reduced to 5% or less (with CRi meaning a CR where there was incomplete recovery of white blood cell and/or platelet counts), a PR means the subject's bone marrow blasts reduced by 50% and resulted in a blast count of 25% or less, and a BT means subjects are deemed capable of progressing to a potentially curative bone marrow transplant.

Safety of Annamycin in R/R AML Subjects -

Our US Phase 1 trial met its primary endpoint, demonstrating the safety of Annamycin in treating R/R AML when delivered to subjects at or below the lifetime maximum anthracycline dose established by the FDA.

The primary safety signal was the absence of cardiotoxicity, a serious and often treatment-limiting issue prevalent with currently approved anthracyclines.

Additionally, we recently concluded our European R/R AML trial, as discussed above, and not only set an RP2D but also met the trial’s primary safety signal with the absence of cardiotoxicity.

As discussed above, this was determined by echocardiograms, as well as cardiac health biomarkers, principally certain blood troponin levels, which are considered an indicator of potential long-term heart damage.

The data showed no cardiotoxicity in all of the subjects evaluated in the both Phase 1 trials.

An updated independent safety review in early 2022 of certain preliminary data of the first 30 subjects in our three Annamycin Phase 1 clinical trials, which again concluded there was no evidence of cardiotoxicity.

Importantly, 19 of the 30 subjects have been treated above the LTMAD.

Compared to previous studies of other anthracyclines, we believe this is an important event.

For example, a review published in Cardiovascular Drugs and Therapy (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346598/) reported that 65% of patients who received the equivalent of 550 mg/m 2 of doxorubicin (a current standard of care anthracycline) exhibited sub-clinical cardiotoxicity, defined as a reduction in left ventricular ejection fraction >10% points to a value <50%.

In the 5 subjects mentioned above who were treated in our European trial above 550 mg/m 2 , no evidence of cardiotoxicity was detected.

The same published review also suggested that a better long-term indicator of cardiotoxicity may be the measurement of an increase in a biomarker called troponin.

When measured as an early biomarker of cancer therapy-related cardiotoxicity, troponin rise occurs consistently in 21% - 40% of patients after treatment with current standard of care anthracycline chemotherapy and, per the published review, such an increase in troponin is associated with an increased risk of heart disease later in life.

Overall, some form of cardiotoxicity, short-term or long-term, occurs in 65% of such patients.

Of the 30 subjects treated thus far in all three of our Annamycin clinical trials and where safety has been assessed, none has shown a clinically significant increase in troponin levels, again supporting the absence of cardiotoxicity. As previously noted, although these data are, in our view, promising, there remains significant additional clinical investigation to be done, and there can be no guarantee of the future results. 

US STS Lung Metastases Trials

Our preclinical work on Annamycin demonstrated activity against certain cancers metastasized to the lungs, including soft tissue sarcoma (STS), osteosarcoma and triple negative breast cancer.

In December 2020, we disclosed that the FDA allowed our IND to go into effect to study Annamycin for the treatment of soft tissue sarcoma lung metastases.

This allowed us to begin a Phase 1b/2 clinical trial in the US for subjects with this indication after first-line therapy for their disease.

This trial began in June of 2021.

We also disclosed in December 2020 that the FDA had granted ODD to Annamycin for the treatment of soft tissue sarcomas, in addition to the existing ODD for Annamycin in relapsed or refractory AML.

Also, in December 2021, we reported preliminary interim results from our US Phase 1b/2 clinical trial as we concluded the safety review of the third cohort and opened the fourth cohort in the dose escalation portion of trial, which continues to document preliminary human activity for this drug.

The Phase 1b/2 study is a US multi-center, open-label, single-arm study that in Phase 1b will determine the MTD and/or the RP2D and safety of Annamycin.

The Phase 2 portion of the study will explore the efficacy of Annamycin as a single agent at the RP2D for the treatment of subjects with STS with lung metastases for whom prior chemotherapy has failed, and for whom new chemotherapy is considered appropriate.

A minimum of three subjects will be enrolled in each cohort of the Phase 1b portion of the study until an MTD is identified, after which there will be a determination of the RP2D based on an assessment of both safety and efficacy.

Up to 25 subjects will be enrolled at the RP2D in Phase 2 to further evaluate efficacy.

Three of the six subjects in the first two cohorts reached four or more months with stable disease or better.

In a patient population where the median progression free survival time in patients with soft tissue sarcoma with metastases that have failed initial systemic therapy is approximately 1.6 to 2.0 months, without effective therapy which includes subjects treated with a placebo.

Comandone, F.

Petrelli, A Boglione, S.

Salvage Therapy in Advanced Adult Soft Tissue Sarcoma.

The Oncologist 2017;22:1518–1527), we believe Annamycin has the potential to bring a new and effective treatment option to patients with this significant unmet need.

We are also encouraged by the pace of recruitment to date for this trial.

The summary of interim data from the first four cohorts of the study are as follows:

First Cohort (210 mg/m 2 ):

Two subjects had stable disease up to 6 cycles (4.5 months) but were then discontinued due to progressive disease.

One subject discontinued after the first cycle.

The end of study scan was performed, and stable disease was observed.

However, the subject discontinued from the study because the initiation of the second cycle was delayed greater than 6 weeks from the previous dose.

Second Cohort (270 mg/m 2 ):

In one subject, the scan at the end of the second cycle showed that there was a partial response (PR, >30% reduction in tumor size), and this was stable when the subject was scanned at the end of cycle 4.

The subject subsequently discontinued from the study due to that subject electing to undergo surgical resection to potentially eradicate disease.

One subject was discontinued from the study after 2 cycles after the end of cycle 2 scan revealed progressive disease.

One subject received 1 cycle of treatment but discontinued treatment for reasons unrelated to Annamycin.

The end of study scan revealed progressive disease.

Third Cohort (330 mg/m 2 ):

One subject discontinued after the first cycle. An interim, unscheduled scan revealed progressive disease and the subject was discontinued from the study.

One subject was discontinued from the study after 2 cycles as a scan after the end of cycle 2 revealed progressive disease.

One subject received 2 cycles and end of cycle 2 scans showed stable disease. However, subject withdrew consent from the study to pursue local standard of care.

Fourth Cohort (390 mg/m 2 ):

Efficacy data for the fourth cohort are incomplete as not all subjects have received their scans.

One subject received 2 cycles and end of Cycle 2 scans showed Stable Disease. The subject currently continues on study with Cycle 3.

One subject is currently in Cycle 2.

This subject experienced a DLT of febrile neutropenia.

It did resolve and the subject continued in the study.

End of Cycle 2 scans showed Stable Disease. The subject currently continues on study with Cycle 3.

One subject received 2 cycles and end of Cycle 2 scans showed Stable Disease. The subject currently continues on study with Cycle 3.

The statements above are based on interim data and should be considered preliminary and subject to change.

We have now completed initial enrollment in the fourth cohort of the Phase 1b portion of the study with dosing increased to 390 mg/m 2 and expect to announce that cohort’s full preliminary results in the near term.

Due to the DLT noted above, the fourth cohort is being expanded to enroll an additional three subjects at this dose level. In the absence of any additional DLTs at this dose level, we have the option to continue escalation to explore the fifth cohort at 450 mg/m 2 dose level or to declare the RP2D to be 390 mg/m 2 .

If a second DLT occurs at the 390mg/m 2 dose level, three subjects may be enrolled into one additional dose level at 360mg/m 2 to confirm the MTD/RP2D.

If the fifth cohort is deemed safe, we may continue to escalate until an MTD is reached.

Therefore, up to twenty-one subjects or more may be enrolled in the Phase 1b portion of the study, unless a determination is made to add additional cohorts beyond the fifth cohort or we establish an RP2D.

Although significant further study is necessary, this characteristic has been shown in pre-clinical testing to allow for higher drug uptake in diseased cells, which we believe could allow for more effective induction therapy with less risk to the patient, especially in relapsed patients.

We are also collaborating with WPD and physicians in Poland and are currently pursuing a physician-sponsored clinical trial in Europe.

WPD announced their facilitation of a grant equivalent to $1.5 million USD to the Maria Sklodowska-Curie National Research Institute to fund a Phase 1b/2 clinical trial of Annamycin for the treatment of STS lung metastases. The grant-funded clinical trial will be led by Prof.

Piotr Rutkowski, MD, PhD, Head of Department of Soft Tissue/Bone Sarcoma and Melanoma at the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, and it will be operated independently of our study in the US.

The trial will use a dosing regimen of once per week rather than once every 21 days as in the US trial.

We expect this trial to begin in 2022.

US STS Lung Metastases Trial - Study Design

In Phase 1b, Annamycin is administered as an intravenous (IV) infusion over 2 hours on Day 1, followed by 20 days off (1 cycle = 21 days).

Subjects visit the study site every 21 days (±3 days) at which time safety monitoring, including adverse events (AEs), a physical examination, laboratory evaluations (clinical chemistry, complete blood count), vital signs, weight measurements, Eastern Cooperative Oncology Group (ECOG) performance status, and electrocardiograms (ECGs) are performed, followed by an IV infusion of study drug.

Cardiac function is followed by echocardiogram (ECHO) scans at screening, at the end of the first two cycles and then every other cycle thereafter, at the end of treatment visit, and if feasible, during follow up at 6 months (±1 month) and 1 year (±1 month) after study drug discontinuation.

As long as the Investigator considers that the benefits of treatment with Annamycin continue to outweigh the risks, treatment will continue every 21 days until tumor progression is observed or unacceptable toxicity occurs.

Tumor response is monitored every 6 weeks (±1 week) from Cycle 1 Day 1 during treatment, at the End of Treatment visit, and then every 3 months (±1 month) until disease progression using RECIST 1.1 criteria.

Those subjects who leave the study after a maximum response is achieved and who do not start another therapy will be followed every 3 months (±1 month) for progression-free survival (PFS).

If a subject receives further therapy after discontinuing from the study, they will only be followed for overall survival (OS) and if feasible, follow-up ECHO scans at 6 months (±1 month) and 1 year (±1 month) will be conducted after study drug discontinuation.

Piotr Rutkowski, MD, PhD, Head of Department of Soft Tissue/Bone Sarcoma and Melanoma at the Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO) in Warsaw, Poland, and it will be operated independently of our study in the US.

The trial will have a dosing regimen of once per week rather than once every 21 days as in the US trial.

This trial began dosing subjects in late 2022.

To date, two subjects have been dosed in Cohort 1 (35 mg/m2) with no DLTs nor activity noted with recruitment continuin g. In March of 2023, WPD assigned their rights and duties related to the grant-funded trial at MSCNRIO to us as part of WPD’s termination of their sublicense as described further below.

The WP1066 Portfolio Program

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In 2019, the FDA granted ODD for WP1066 for the treatment of glioblastoma, which means the agency believes we have established a medically plausible basis for using the drug to treat glioblastoma.

We believe our WP1066 Portfolio (including lead drug candidates WP1066 and WP1220) we believe, represents a novel class of agents capable of hitting multiple targets, including the activated form of a key oncogenic transcription factor, STAT3.

We believe our WP1066 Portfolio (including lead drug candidates WP1066 and WP1220), represents a novel class of agents capable of hitting multiple targets, including the activated form of a key oncogenic transcription factor, STAT3.

A substantial body of published research has identified STAT3 as a master regulator of a wide range of tumors and has linked the activated form, p-STAT3, with the survival and progression of these tumors.

For this reason, it is believed that targeted inhibition of p-STAT3 may be an effective way to reduce or eliminate the progression of these diseases.

During 2021, we have been working on developing an appropriate IV formulation for WP1066 or its analogs.

As a result of these studies, we believe that the lead molecule WP1066 may be our best candidate for intravenous administration and efforts to identify and optimize the best strategy for IV delivery are currently underway.

Additionally, we determined that the stability of WP1732, another molecule in the WP1066 Portfolio was less than satisfactory and, as such, in March 2021 we terminated our license for WP1732 with MD Anderson.

Since 2021, we have been working on developing an appropriate IV formulation for WP1066 or its analogs.

As a result of these studies, we believe that the lead molecule WP1066 may be our best candidate for intravenous administration or additional oral avenues and efforts to identify and optimize the best strategy for delivery are currently underway.

We also determined that the stability of WP1732, another molecule in the WP1066 Portfolio was less than satisfactory and, as such, in March 2021 we terminated our license for WP1732 with MD Anderson.

We however retain an option to re-license WP1732 from MD Anderson in the future.

The high level of anticancer activity demonstrated in multiple tumors in animal models by WP1066 is potentially related to its ability to also inhibit such important key oncogenic transcription factors such as c-Myc and HIF-1α.

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We intend to pursue additional study to build on this preclinical evidence and preliminary animal model data.

Recently published research papers have presented several findings that may point to new opportunities for our WP1066 class of drugs.

Published research papers have presented several findings that may point to new opportunities for our WP1066 class of drugs.

One such article suggested that our STAT3 inhibitor WP1066 abrogated PD-L1/2 expression in cancer cells and may be a useful agent in addition to checkpoint inhibitor immunotherapy in cancer patients (J Clin Exp Hematop, 57(1), 21-25, 2017).

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WP1066 is our flagship Immune/Transcription Modulator.

It has been the subject of over 50 peer-reviewed articles and its activity against p-STAT3 has now been validated in independent labs around the globe.

It has been the subject of over 50 peer-reviewed articles and its activity against p-STAT3 has now been validated in independent labs around the world.

This discovery was inspired by a naturally occurring compound (caffeic acid) in propolis (from honeybees).

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Clinical Trials for the WP1066 Portfolio

In 2021, two trials were underway with WP1066.

The first trial was a physician-sponsored Phase 1 trial of WP1066 in adult subjects with recurrent malignant glioma and brain metastasis from melanoma which the FDA allowed to proceed in December 2017.

In July 2018, this trial opened for recruitment in the US.

This dose-escalation Phase 1 brain tumor clinical trial via a physician-sponsored IND with MD Anderson Cancer Center has generated pharmacokinetic data for orally dosed WP1066.

Those data demonstrated sufficient bioavailability of our drug via oral administration to show the presence of WP1066 in blood plasma on a dose-dependent basis.

In early 2021, investigators at MD Anderson began the fourth cohort in the dose escalation phase.

In the first quarter of 2021, we were notified that the physician sponsoring the MD Anderson trial was leaving MD Anderson.

MD Anderson has chosen to terminate this trial.

We are actively pursuing the process to file our own IND for WP1066 so physician sponsored trials can reference our IND, although we can provide no assurance as to when, or if, this filing will be completed.

Another physician-sponsored Phase 1 trial is being considered for the treatment of adult GBM with WP1066 in combination with radiation, although no assurances can be given that such trial will begin.

In July 2020 we announced that a peer-reviewed article published in Clinical Cancer Research (Clin Cancer Res June 30 2020 DOI:10.1158/1078-0432.CCR-19-4092) reported findings that WP1066, used in combination with traditional whole brain radiation therapy (WBRT) resulted in long-term survivors and enhanced median survival time relative to monotherapy in mice with implanted human brain tumors.

The paper can be accessed at:

https://clincancerres.aacrjournals.org/content/early/2020/06/30/1078-0432.CCR-19-4092.full-text.pdf

The study was performed by lead author Martina Ott, Ph.D., Instructor of Neurosurgery, senior author Amy Heimberger, M.D., professor of Neurosurgery, and a team of researchers at The University of Texas MD Anderson Cancer Center.

In this study, C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood-brain barrier penetrant inhibitor of the STAT3 pathway, or the two in combination.

The role of the immune system was evaluated using tumor rechallenge strategies, immune incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and nanostring gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment.

The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs.

control p<0.0001).

Immunological memory appeared to be induced, because mice were protected during subsequent tumor rechallenge.

The therapeutic effect of the combination was completely lost in immune incompetent animals.

Nanostring analysis and immunofluorescence revealed immunological reprogramming in the brain tumor microenvironment specifically affecting dendritic-cell antigen presentation and T cell effector functions.

The study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the central nervous system by inducing dendritic-cell and T cell interactions in the brain tumor, which seems to be a requirement for a fully functional immune response

This study is consistent with preliminary data we announced previously.

Importantly, the study indicated the potential that the combination of STAT3 inhibition with whole brain radiotherapy had the capacity to enhance the therapeutic effect against established tumors as well as developing immune memory that appears to prevent recurrence.

With this preclinical data, we believe that another physician-sponsored Phase 1 trial could be considered for the treatment of GBM with WP1066 in combination with radiation, although no assurances can be given that such trial will begin.

At the 2009 annual meeting of the Society for Neuro Oncology (SNO), Emory University researchers reported encouraging activity in animals with their in vitro pediatric brain tumor models using WP1066.

At the 2019 annual meeting of the Society for Neuro Oncology (SNO), Emory University researchers reported encouraging activity in animals with their in vitro pediatric brain tumor models using WP1066.

Based on these data, they filed and received clearance to proceed with an IND for a trial to treat children with recurrent or refractory malignant brain tumors with WP1066.

This trial is being conducted at the Aflac Cancer & Blood Disorders Center at Children's Healthcare of Atlanta.

The Emory trial for pediatric brain tumors has now treated three subjects in the first two cohorts of the Phase 1 dose escalation portion of physician-sponsored clinical trial for the treatment of pediatric brain tumors with WP1066.

One subject has been treated in the third cohort at the dose level of 8mg/kg.

Two more subjects will be treated at this dose level.

Emory University has amended its protocol to allow dosing at 16 mg/kg after these two additional subjects have been dosed, and the third cohort dosing has been deemed safe.

In that trial, one of the subjects in the first cohort with DIPG showed an apparent response to the treatment with both clinical improvement and radiologic reduction of tumor size.

We caution that these is preliminary data, and no conclusions should be drawn from this single event. 

In February 2023, the Emory trial for pediatric brain tumors concluded treating three subjects in the three cohorts of the Phase 1 dose escalation portion of physician-sponsored clinical trial for the treatment of pediatric brain tumors with WP1066.

The third cohort dosing was deemed safe at 8mg/kg. In that trial, one of the subjects in the first cohort with DIPG showed an apparent response to the treatment with both clinical improvement and radiologic reduction of tumor size.

We caution that this is preliminary data, and no conclusions should be drawn from this single event.

It is our belief that Emory will continue with its study of WP1066 into a Phase 2 program later this year.

An analog of WP1066, referred to as WP1220, was previously the subject of an IND (WP1220 was referred to as “MOL4239”

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Notwithstanding its limitations in treating psoriasis, our pre-clinical research in multiple CTCL cell lines has suggested that WP1220 may be effective in inhibiting CTCL.

Based on these data, we are pursuing discussions with various pharmaceutical companies to further development of this molecule.

Based on these data, we are pursuing discussions with various pharmaceutical companies for further development of this molecule.

CTCL is a potentially deadly form of skin cancer for which there are limited treatment options. 

Clinical Activity WP1220 –

In August 2019, we completed full enrollment in a proof-of-concept clinical trial in Poland to study WP1220 for the treatment of CTCL.

Clinical Activity WP1220 

In August 2019, we completed full enrollment in a Phase 1b clinical trial in Poland to study WP1220 for the treatment of CTCL.

Polish authorities approved our CTA for this use in January 2019, and the trial began enrolling subjects in March 2019.

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This Phase 1 study was designed to demonstrate the safety and efficacy of WP1220 after topical treatment of CTCL.

Of 5 subjects enrolled, 11 lesions were assessed according to the CAILS scoring system.

The only related adverse event (AE) was mild contact dermatitis in one subject that the Investigator deemed was not related to the drug.

4 of the 5 subjects improved in CAILS scores on index lesions, with one exhibiting stable disease, with a median reduction of 56% (range 25-94%).

3 of the subjects exhibited a PR.

Improvement was noted within 7 days of treatment initiation and maintained 1 month after discontinuation.

Of the 11 lesions, 45% exhibited a CR or a 50% or more reduction in CAILS and 55% exhibited stable disease with 100% showing a clinical benefit. Independent dermatologic review based on photographic documentation was conducted and corroborated these findings.

Of five subjects enrolled, eleven lesions were assessed according to the CAILS scoring system.

The only related AE was mild contact dermatitis in one subject that the Investigator deemed was not related to the drug.

Four of the five subjects improved in CAILS scores on index lesions, with one exhibiting stable disease, with a median reduction of 56% (range 25-94%).

Three of the subjects exhibited a PR.

Improvement was noted within seven days of treatment initiation and maintained 1 month after discontinuation.

Of the eleven lesions, 45% exhibited a CR or a 50% or more reduction in CAILS and 55% exhibited stable disease with 100% showing a clinical benefit. Independent dermatologic review based on photographic documentation was conducted and corroborated these findings.

Although this was a small proof-of-concept clinical trial, WP1220, topically applied, had no safety issues and appeared to be effective in MF.

We believe this is the first demonstration in humans suggesting that inhibition of p-STAT3 with topical therapy has efficacy in CTCL. As a result of this, we continue to actively seek third-party collaborations to begin a Phase 2a/2b trial with approximately 60 subjects.

IV Formulation for the WP1066 Portfolio

The topical application WP1220 does not appear to result in systemic exposure to the drug, which is desirable in the case of a topical drug targeting a dermatologic condition, however, WP1066 is currently administered orally with the intent of systemic uptake.

Although preliminary data from physician-sponsored brain tumor trials indicate that the oral administration of WP1066 does result in detectable levels of WP1066 in plasma, we believe our opportunity for successful development of a p-STAT3 inhibitor would be expanded if we were able to develop a compound capable of intravenous (IV) administration. In 2020, we began developing IV formulation methods for WP1066 that might address its lack of solubility.

We believe this is the first demonstration in humans suggesting that inhibition of p-STAT3 with topical therapy may have efficacy in CTCL. As a result of this, we continue to actively seek third-party collaborations to begin a Phase 2 trial with approximately sixty subjects.

Alternate Formulation for the WP1066 Portfolio

The topical application WP1220 does not appear to result in systemic exposure to the drug, which is desirable in the case of a topical drug targeting a dermatologic condition. WP1066, however, is currently administered orally, with an undesirable taste profile, with the intent of systemic uptake.

Although preliminary data from physician-sponsored brain tumor trials indicate that the oral administration of WP1066 results in detectable levels of WP1066 in plasma, we believe our opportunity for successful development of a p-STAT3 inhibitor would be expanded if we were able to develop a compound capable of a different oral delivery or intravenous (IV) administration. In 2020, we began developing IV formulation methods for WP1066 that might address its lack of solubility.

We also invested in research to identify molecular analogs that may be more soluble and, therefore, easier to develop for IV administration.

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The WP1122 Portfolio Program

WP1122 Portfolio Program Overview

We have a license agreement with MD Anderson pursuant to which we have been granted a royalty-bearing, worldwide, exclusive license for the patent and technology rights related to our WP1122 Portfolio and similar molecules focused on inhibitors of glycolysis and glycosylation.

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The prognosis for such patients can be particularly grim and the treatment options available to their physicians are among the most limited of any cancer.

The American Cancer Society has estimated 24,530 new cases of brain and other nervous system cancers will occur in the United States in 2021, resulting in 18,600 deaths.

The American Cancer Society has estimated 24,810 new cases of brain and other nervous system cancers will occur in the United States in 2023, resulting in 18,990 deaths (https://www.cancer.org/latest-news/facts-and-figures-2023.html - as of January 2023).

Despite the severity and poor prognosis of these tumors, there are few FDA-approved drugs on the market. 

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Accordingly, we filed and subsequently received clearance for an IND to study WP1122 in GBM as described below.

An early 2021 study of 2-DG in COVID-19 subjects was conducted by the Institute of Nuclear Medicine and Allied Sciences (INMAS), a lab of Defense Research and Development Organization (DRDO), in collaboration with Dr Reddy's Laboratories (DRL), Hyderabad, India.

An early 2021 study in India of 2-DG in COVID-19 subjects was conducted by the Institute of Nuclear Medicine and Allied Sciences (INMAS), a lab of Defense Research and Development Organization (DRDO), in collaboration with Dr Reddy's Laboratories (DRL), Hyderabad, India.

INMAS-DRDO scientists initiated a Phase 2 clinical trial on 2-DG in COVID-19 subjects in May 2020 during the first wave of the pandemic.

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Doi:10.4103/jfmpc.jfmpc_1338_21).

Given that WP1122 is prodrug of 2-DG designed to improve its circulation time and tissue/organ uptake, we consider this human data regarding 2-DG to be potentially relevant to the potential for WP1122 to be useful in treating COVID-19.

Given that WP1122 is a prodrug of 2-DG designed to improve its circulation time and tissue/organ uptake, we consider this human data regarding 2-DG to be potentially relevant to the potential for WP1122 to be useful in treating COVID-19.

The MHRA had access to this and other data in approving our CTA, as discussed below, and did not require an animal testing model.

Clinical Trial for COVID-19 with WP1122

On April 6, 2021, we announced the engagement of IQVIA Biotech, a contract research organization (CRO) to manage our efforts to begin potential clinical trials of WP1122 for the treatment of COVID-19.

On October 19, 2021, we announced that we received authorization from the MHRA to commence a Phase 1a clinical trial of WP1122 in the United Kingdom.

Furthermore, we also announced that we received a favorable opinion from the London - Riverside Research Ethics Committee in the UK to begin the study, which is expected to be conducted at the Medicines Evaluation Unit in Manchester, United Kingdom.

In early March 2022, we filed an amended protocol with both the Riverside Ethics Committee and the MHRA.

The amendment updated the dilution of the oral solution to achieve full dissolution of WP1122. No risk/benefit to the study was affected because of this change.

Once this amendment is approved, we plan to begin this trial in the first half of 2022.

The Phase 1a study in healthy human volunteers will investigate the effects of a single ascending dose (SAD) and multiple days of ascending dosing (MAD) of WP1122 administered as an oral solution.

Dose escalation will take place in sequential SAD cohorts, and MAD will start as soon as SAD has completed at least 3 dosing cohorts in which WP1122 is found to be safe and well-tolerated.

This study in healthy volunteers will explore safety and pharmacokinetics (PK), and subsequent clinical development will be in subjects infected with SARS-CoV-2 to further evaluate safety and establish a favorable risk/benefit profile.

The Company expects to enroll approximately 80 healthy volunteers in the United Kingdom.

The primary endpoint (SAD and MAD) for the study is safety and tolerability, which will be assessed by the frequency of adverse events (AEs), serious adverse events, treatment-emergent adverse events, and AEs of special interest.

These will be presented by severity and seriousness, system organ class, preferred term and cohort.

Clinically significant changes from baseline in clinical laboratory values, physical examination, vital signs, and electrocardiograms will be documented.

The secondary endpoint (SAD and MAD) of the study will be the assessment of PK parameters of WP1122 and its 3 active metabolites.

Total duration of study participation for each subject will be up to 4 weeks during SAD and up to 5 weeks during MAD.

The Phase 1a study in healthy human volunteers investigated the effects of a single ascending dose (SAD) and multiple days of ascending dosing (MAD) of WP1122 administered as an oral solution. 

On October 14, 2022, we provided an update on the preliminary results from the second MAD cohort of our Phase 1a study of WP1122.

This cohort consisted of an initial 4 subjects, who were scheduled to be dosed daily for 7 days with 64 mg/kg/day of WP1122 or placebo in the dose escalation trial evaluating the safety and PK of WP1122.

In conjunction with the study SRC, we stopped the second MAD cohort when 2 subjects experienced non-serious adverse events that, although asymptomatic, met the stoppage criteria in the protocol.

Although we considered the potential to open a third MAD cohort (2a) to dose subjects at a reduced dose level of 48mg/kg/day for 7 days, we subsequently determined that the primary objectives of this Phase 1a study had already been met by establishing a safe and tolerable dose and that continued testing with healthy volunteers would not be a wise use of resources.

In late October 2022, after further review of the data and in discussions with our clinical team, we determined that the maximum tolerated dose (MTD) for WP1122 is a daily cumulative dose of 32 mg/kg in two divided doses for seven days, and we concluded the Phase 1a study of WP1122.

We believe this will advance future studies of WP1122 in antiviral and oncology indications.

With an IND active for WP1122 for the treatment of glioblastoma and a COVID-19 investigator sponsored trial in Brazil in the approval process, we have concluded that advancing WP1122 in these indications will occur only if external funds are available.

With respect to the COVID-19 investigator led trial in Brazil, we doubt that this trial will occur due to the current epidemiology of COVID-19.

We will begin to close out the Phase 1a study and generate the clinical study report.

Potential Clinical Trial for GBM with WP1122

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Such a trial would enable parallel development of WP1122 as a cancer therapy.

Consistent with our strategy of leveraging external funding for many of our clinical trials, we intend to seek opportunities for an investigator-initiated clinical trial of WP1122 in cancer patients in 2022.

There is no assurance that we will be successful in finding an investigator with access to externally sourced funds.

Additionally, we will rely on external collaborations for testing other molecules in the WP1122 portfolio against other hard to treat viruses such as HIV, Dengue fever, and Zika.

Overview of The Market for Our Oncology Drugs

The American Cancer Society (https://www.cancer.org/latest-news/facts-and-figures-2022.html - as of March 2022) estimates that cancer continues to be the second most common cause of death in the US, after heart disease.

A total of 1.9 million new cancer cases and 609,360 deaths from cancer are expected to occur in the US in 2022, which is about 1,670 deaths a day.

Overview of The Market for Our Oncology Drugs 

The American Cancer Society (https://www.cancer.org/latest-news/facts-and-figures-2023.html - as of January 2023) estimates that cancer continues to be the second most common cause of death in the US, after heart disease.

A total of 1.9 million new cancer cases and 609,820 deaths from cancer are expected to occur in the US in 2023, which is about 1,670 deaths a day.

These statistics do not include either basal cell or squamous cell skin cancers because US cancer registries are not required to collect information on these cancers.

These numbers also do not account for the effect the COVID-19 pandemic has likely had on cancer diagnoses and deaths because they are projections based on reported cases through 2018 and deaths through 2019.

Market for Annamycin

Digestive, reproductive, breast and respiratory cancers comprise most of expected cancer diagnoses in 2022, while cancers like leukemia and brain tumors are considered “rare diseases.”

Leukemia in particular, can be divided into acute, chronic and other, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) comprising 26,710 of the estimated 60,650 n ew cases expected in the United States in 2022. T he National Cancer Institute estimates that cancer-related direct medical costs in the US wer e $183 billion in 2015 and are projected to increase to $246 billion by 2030, a 34% i ncrease based only on population growth and aging.

However, the projection is likely an underestimate because of the growing cost of prescription medicines, with the list price for many now more than $100,000 ann ually.

Per the American Cancer Society, digestive, reproductive, breast and respiratory cancers comprise most of expected cancer diagnoses in 2023, while cancers like leukemia and brain tumors are considered “rare diseases.”

Leukemia in particular, can be divided into acute, chronic and other, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) comprising 26,920 of the estimated 59,610 n ew cases expected in the United States in 2023. T he National Cancer Institute estimates that cancer-related direct medical costs in the US wer e $208.9 billion in 2020, which is likely an underestimate because it does not account for the growing cost of treatment;

for example, the list price for many prescription medicines is now more than $100,000 annually.

Our lead drug candidate, Annamycin, is in a class of drugs referred to as anthracyclines, which are chemotherapy drugs designed to destroy the DNA of targeted cancer cells.

The approved anthracyclines most commonly used are daunorubicin and doxorubicin and, prior to the expansion of their generic equivalents, annual revenues generated from anthracyclines have been estimated in the range of $770 million.

Acute leukemia is one of a number of cancers that are treated with anthracyclines.

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(resistant to therapy).

Palliative care or focus on overall survival versus curative treatment has become the focus for patients not suitable for traditional chemotherapy.

AbbVie’s Venclexta is approved by the FDA in combination with a hypomethylating agent (azacitidine or decitabine) or low-dose AraC (LDAC) for the treatment of newly diagnosed AML in patients who are 75 years of age or older, or for those ineligible for intensive induction chemotherapy due to co-existing medical conditions.

While a confirmatory Phase 3 trial (VIALE-C) evaluating Venclexta + LDAC failed to meet an OS endpoint, a larger confirmatory trial evaluating Venclexta + azacitidine demonstrated a survival advantage (15 months vs 10 months) and supported regulatory approvals in the EU (May 2021) and Japan (March 2021).

Together, this group of relapsed and refractory AML patients constitutes our primary focus for treatment with Annamycin and our intent is to pursue FDA approval for Annamycin as a second-line induction therapy for adult relapsed or refractory AML patients.

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The lungs are the most frequent site of metastasis from soft-tissue sarcomas.

From several studies, it has been estimated that approximately 30% of the STS cases develop lung metastases.

It has been estimated that as high as approximately 50% of the STS cases develop lung metastases.

Effective systemic therapies for metastatic STS are currently limited;

when possible, surgical removal of the lung metastases (known as pulmonary metastasectomy, PM) is the preferred treatment.

Metastasectomy and/or chemotherapy are the most common treatments offered to patients with metastatic sarcoma.

Pulmonary metastasectomy, either video-assisted or through a formal thoracotomy, has been shown to increase overall survival in select populations of both osseous and soft tissue sarcoma patients.

when possible, surgical removal of the lung metastases (known as pulmonary metastatectomy, PM) is the preferred treatment.

However, guidelines for the performance of PM for STS do not exist and decisions to operate are often made on an individual basis (American Association for Thoracic Surgery (AATS).

(2016, May 16).

Increasing survival in soft tissue sarcoma patients with lung metastases undergoing resection.

ScienceDaily.

Retrieved March 3, 2023 from www.sciencedaily.com/releases/2016/05/160516181330.htm).

Metastatectomy and/or chemotherapy are the most common treatments offered to patients with metastatic sarcoma.

Pulmonary metastatectomy, either video-assisted or through a formal thoracotomy, has been shown to increase overall survival in select populations of both osseous and soft tissue sarcoma patients.

The market is expected to grow as a result of factors like an increase in the patient pool.

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Given this backdrop, we believe the best initial pathway for Annamycin is to pursue the second-line treatment of STS lung metastasis.

Based on our research, we believe that there were approximately 60,000 pancreatic cancer diagnoses and 48,000 deaths in the US last year. Incidence of pancreatic cancer in the US is expected to grow to 90,000 by 2040. While pancreatic cancer only accounts for 3.2% of all cancer diagnoses, it has the highest mortality rate of all cancers and is the third leading cause of cancer-related deaths in the US, behind lung and colon cancer.

The most effective treatment for pancreatic cancer is surgery, but only 20% of cases are eligible for a surgical approach. The 80% of non-resectable pancreatic cancers are typically treated with chemotherapy and other pharmacotherapies. Global sales of drugs used for the treatment of pancreatic cancer, including Abraxane, Lynparza and Tarceva, exceeded $3 billion in 2020, though this figure includes sales for treatment of other cancers as well.

Abraxane will become generic in 2022 which should impact this number.

Per the American Cancer Society, in 2023, an estimated 64,050 new cases of pancreatic cancer will be diagnosed in the US and 50,550 people will die from the disease.

While pancreatic cancer only accounts for 3.3% of all cancer diagnoses, it has the highest mortality rate of all cancers and is the third leading cause of cancer-related deaths in the US, behind lung and colon cancer.

The most effective treatment for pancreatic cancer is surgery, but fewer than 20% of cases are eligible for a surgical approach. The 80% of non-resectable pancreatic cancers are typically treated with chemotherapy and other pharmacotherapies. Global sales of drugs used for the treatment of pancreatic cancer, including Abraxane, Lynparza and Tarceva, exceeded $3 billion in 2020, though this figure includes sales for treatment of other cancers as well.

Abraxane will become generic in 2023 which should impact this number.

There is a tremendous amount of clinical development activity in pancreatic cancer, with 551 trials ongoing, of which 32 were late-stage.

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Gliomas (mainly glioblastoma and astrocytomas) account for 78% of malignant tumors.

Diffuse Interstitial Pontine Glioma (DIPG) - also called:

Diffuse Intrinsic Pontine Glioma (DIPG) - also called:

Pontine Glioma or Brainstem Glioma –

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In December 2020, we announced that the FDA had approved our request for a "Rare Pediatric Disease" designation for our drug candidate WP1066.

The designation may entitle us to receive a transferrable Priority Review Voucher (PRV) upon approval of an NDA for one of three indications, including DIPG, medulloblastoma and atypical teratoid rhabdoid tumor.

The designation may entitle us to receive a transferrable Priority Review Voucher upon approval of an NDA for one of three indications, including DIPG, medulloblastoma and atypical teratoid rhabdoid tumor.

We believe that the early activity we are seeing in WP1066 is both surprising and encouraging.

The approval of these three Rare Pediatric Disease designations is a reminder of just how important our efforts are to potentially help children with brain tumors.

These vouchers are issued upon drug approval of the rare disease indication from the FDA and once issued, can be transferred to other drug developers. PRVs have historically had significant value and have recently been sold for up to $100 million or more. 

These vouchers are issued upon drug approval of the rare disease indication from the FDA and once issued, can be transferred to other drug developers. PRVs have historically had significant value and management believes have a value up to $100 million or more. 

Additionally, WP1220 which is in the WP1066 Portfolio, has shown activity in a clinical trial for the treatment of CTCL.

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Due to difficulties in diagnosis, the intrinsic aggressive nature of pancreatic cancers, and the sparse systemic treatment options available, only approximately 4% of patients diagnosed with pancreatic adenocarcinoma will be alive five years after diagnosis.

We believe that WP1122 may also be effective at treating COVID-19. Hundreds of drug candidates have been tested in COVID-19 since the disease became pandemic in early 2020. Many approved COVID-19 therapies, such as therapeutic antibodies and anti-the viral drugs molnupiravir and nirmatrelvir, have demonstrated activity against SARS-CoV-2, the virus which causes COVID-19. Other therapies, such as the JAK inhibitor baricitinib, act on host-based mechanisms, importantly by reducing inflammation. WP1122 is being evaluated to act by both host-based and viral mechanisms. Many experts believe that COVID-19 will eventually become endemic, and that a dynamic similar to influenza will emerge. In this scenario, we estimate that there could be approximately 4 million cases of COVID-19 in the US annually by 2027. Should WP1122 prove effective at treating COVID-19, of which there is no assurance, we expect that contract sales to governments will have an important role in the market. 

Our License Agreements

Sponsored Research and License Agreements with MD Anderson

We have licensed all of our technology from MD Anderson, and we also sponsor research there as well.

Under license agreements associated with Annamycin, the WP1122 Portfolio, and the WP1066 Portfolio, all described below, we are responsible for certain license, milestone and royalty payments over the course of the agreements.

Under license agreements associated with Annamycin, the WP1122 Portfolio, and the WP1066 Portfolio, we are responsible for certain license, milestone and royalty payments over the course of the agreements.

Annual license fees, prior to the first sale of a licensed product, can be as high as $0.1 million depending upon the anniversary.

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Royalty payments can range in the single digits as a percent of net sales on drug products or flat fees as high as $0.6 million, depending upon certain terms and conditions.

Not all of these payments are applicable to every drug. Total expenses under these agreements were $0.3 million for the years ended December 31, 2021 and 2020, respectively.

Not all of these payments are applicable to every drug. Total expenses under these agreements we re $0.3 million for the years ended December 31, 2022 and 2021, respectively.

For more information about our license agreements, see Footnote 8 - Commitments and Contingencies included in our Consolidated Financial Statements set forth in this report.

We have a sponsored research agreement with MD Anderson that currently runs until the end of December 2024.

The expenses recognized under the MD Anderson agreement with regards to the sponsored research agreement were $0.7 million a nd $0.6 million for the year ended December 31, 2021 and 2020, respectively.

In July 2021, we amended the sponsored research agreement for total payment of $0.2 million to support the continuation of the project.

On June 29, 2017, we entered into a patent and technology license agreement with MD Anderson licensing certain technology related to the method of preparing Liposomal Annamycin and on December 17, 2021 we entered into an amendment to this agreement to include certain technology related to the method of reconstituting Liposomal Annamycin.

On December 2, 2021, we entered into a patent and technology license agreement with MD Anderson licensing certain technology related to lung targeted therapies with Annamycin.

The terms and payments of which are included in the summary above.

The terms of these agreements extend until the later of 20 years from the effective date of the agreements, or the expiration of the last-to-expire licensed patent.

In addition, commencing on the four-year anniversary of each agreement, MD Anderson has the right to remove any jurisdiction from such agreement, upon 90 days’

notice, if we have not commercialized or are not using commercially reasonable efforts actively and effectively to attempt to commercialize a licensed invention in such jurisdiction.

WP1066 Portfolio

The rights and obligations to a June 2010 Patent and Technology License Agreement entered into by and between Moleculin LLC and MD Anderson (the “2010 Agreement”) have been assigned to us.

Therefore, we have obtained a royalty-bearing, worldwide, exclusive license to intellectual property rights, including patent rights, related to our WP1066 drug product candidate.

On February 3, 2022, we entered into a new patent and technology license agreement (the “2022 Agreement”) with MD Anderson licensing certain technology related to WP1066 checkpoint inhibitors.

In consideration for these agreements, we must make payments to MD Anderson including an up-front payment, milestone payments and minimum annual royalty payments for sales of products developed under the license agreement.

Annual maintenance fee payments will no longer be due upon marketing approval in any country of a licensed product under the 2010 Agreement.

One-time milestone payments are due upon commencement of the first Phase III study for a licensed product within the United States, Europe, China or Japan;

upon submission of the first NDA for a licensed product in the United States;

and upon receipt of the first marketing approval for sale of a licensed product in the United States.

The term of the 2010 Agreement extends until the later of 15 years from the effective date of the agreement, or the expiration of the last-to-expire licensed patent.

The term of the 2022 Agreement extends until the later of 20 years from the effective date of the agreement, or the expiration of the last-to-expire licensed patent.

In addition, MD Anderson may terminate the 2022 Agreement if we fail to file for an IND for a Phase 1 study before February 2, 2025 in the United States, France, Germany, Italy, Spain, the United Kingdom or China.

WP1122 Portfolio

The rights and obligations to an April 2012 Patent and Technology License Agreement entered into by and between IntertechBio and MD Anderson (the “2012 Agreement”) have been assigned to us.

Therefore, we have obtained a royalty-bearing, worldwide, exclusive license to intellectual property, including patent rights, related to our WP1122 Portfolio and to our drug product candidate, WP1122.

On December 3, 2021, we entered into a new patent and technology license agreement (the “2021 Agreement”) with MD Anderson licensing certain technology related to WP1122 anti-viral treatments.

The terms and payments of these agreements are included in the summary above.

The 2012 Agreement was amended in May 2020 to provide for extension of a certain milestone requirement and allowed for us to extend such milestone upon our request and extension payment. The initial milestone required us to file an IND with the FDA for a Phase I study by February 20, 2021.

We extended the deadline for this milestone to August 20, 2021 by paying an extension fee.

On August 3, 2021, we filed a CTA in the United Kingdom to commence a Phase 1a clinical trial of WP1122.

MD Anderson agreed that this CTA filing would further extend the deadline to file an IND with the FDA for a Phase I study until February 2022.

In December 2021, we submitted an IND for the treatment of GBM with WP1122 to the FDA, thus meeting the IND filing milestone.

The term of the 2012 agreement extends until the later of 15 years from the effective date of the agreement, or the expiration of the last-to-expire licensed patent.

In addition, MD Anderson may terminate the 2012 agreement if we fail to commence a Phase 1 study for a licensed product prior to November 20, 2022;

or if we fail to commence a Phase 2 study for licensed product prior to November 20, 2024.

The term of the 2021 agreement extends until the later of 20 years from the effective date of the agreement, or the expiration of the last-to-expire licensed patent.

In addition, MD Anderson may terminate the 2021 agreement if we fail to file an IND or its foreign equivalent for a Phase 1 study for a licensed product prior to December 3, 2024;

or if we fail to commence a Phase 1 study for licensed product prior to December 3, 2026.

We believe that the filing and clearance of a WP1122 Phase 1 clinical trial for COVID-19 in the UK and subsequent start of that trial will meet these milestone requirements.

In addition, the Company also has Sponsored Research Agreements with other universities, one in the US and one in Europe.

The expenses recognized under the agreements, mainly related to MD Anderson, were $1.1 million and $0.7 million for the years ended December 31, 2022 and 2021, respectively. 

WPD Licensing Agreement

On December 20, 2021, we amended our sublicense agreement with WPD Pharmaceuticals (WPD), originally entered into on February 19, 2019, pursuant to which we sublicensed to WPD certain intellectual property rights, including rights to Annamycin, its WP1122 portfolio, and its WP1066 portfolio, which sublicense was previously amended on March 22, 2021 (as amended, the “WPD Agreement”).

Since February 2019, we were party to a sublicense agreement with WPD Pharmaceuticals (WPD), pursuant to which we sublicensed to WPD certain intellectual property rights, including rights to Annamycin, its WP1122 portfolio, and its WP1066 portfolio (as amended, the “WPD Agreement”).

WPD is affiliated with Dr.

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Under the WPD Agreement, we granted WPD a royalty-bearing, exclusive license to research, develop, manufacture, have manufactured, use, import, offer to sell and/or sell products in the field of human therapeutics under the licensed intellectual property in the countries of Poland, Estonia, Latvia, Lithuania, Belarus, Ukraine, Moldova, Romania, Armenia, Azerbaijan, Georgia, Slovakia, Czech Republic, Hungary, Uzbekistan, Kazakhstan, Greece, Austria, Russia, Netherlands, Turkey, Belgium, Switzerland, Sweden, Portugal, Norway, Denmark, Ireland, Finland, Luxembourg, Iceland (licensed territories).

Pursuant to the WPD Agreement, WPD agreed that it must use Commercially Reasonable Development Efforts (CRDE) to develop and commercialize products in the licensed territories.

For purposes of the WPD Agreement, the term CRDE means the expenditure, either directly or through the guarantees of grants, by or on behalf of WPD or any of its affiliates of at least:

(i) $2,500,000 during the first four (4) years (the “Initial Hurdle Date”) immediately following the date of the original agreement, or February 19, 2019, on the research, development and commercialization of sublicensed products in the licensed territories;

and (ii) a minimum of $2,100,000 annually for each of the five (5) years after the Initial Hurdle Date on the research and development of sublicensed products in the licensed territories.

The total minimum required total CRDE is $14.0 million.

During the term of the WPD Agreement, to the extent we are required to make any payments to MD Anderson pursuant to our license agreements with MD Anderson, whether a milestone or royalty payment, as a result of the research and development or sale of a sublicensed product, WPD shall be required to advance or reimburse us for such payments.

In further consideration for the rights granted by us to WPD under the WPD Agreement, WPD agreed to pay us a royalty percentage at a rate equal to the royalty rate owed MD Anderson under our license agreements with MD Anderson plus an additional royalty (the “override royalty percentage”) equal to 1.0% of net sales of any sublicensed products, provided, however, if WPD spends:

(i) more than $14.0 million in CRDE, the override royalty percentage will decrease to 0.75% of net sales;

or (ii) more than $17.0 million in CRDE, the override royalty percentage will decrease to 0.5% of net sales.

With certain exceptions, the WPD Agreement will remain in full force and effect until the expiration of the last patent within the sublicensed patents.

Notwithstanding the foregoing, we have the right, in our sole discretion, to terminate the WPD Agreement in whole, or to materially amend the agreement by removing a portion of the sublicensed subject matter, in connection with certain fundamental transactions or in connection with the granting to an unaffiliated third party of a license or sublicense to all or to a material portion of the sublicensed subject matter within all or substantially all of the licensed territories (such event, the “buyback event”) by making a payment to WPD based on the percentage of licensed territories involved in the buyback event as compared to the overall world healthcare spend and the extent to which WPD has satisfied its CRDE requirements.

On December 19, 2021, we consented to allow WPD, upon a default to a third-party lender that had advanced funds to WPD (the “Lender”), to assign the WPD Agreement to the Lender, subject to certain conditions and subject to the Lender granting us the right to terminate the WPD Agreement upon any assignment as follows.

If the assignment occurs, we have the right at any time during the remaining term of the WPD Agreement to terminate the agreement by paying the Lender $1.7 million (the “Termination Fee”) in the form of $1.0 million in cash and the issuance to Lender of our common stock valued at the remaining balance due (based on valuing each share of common stock issued at the greater of $3.00 per share or 30% less than the five day trading average of the common stock for the five trading days prior to the date the notice of termination is delivered;

provided that if the assignment occurs and if we do not exercise the above termination right within 90 days of the Assignment Date:

(i) the Initial Hurdle Date will be extended for a period of 3 years;

and (ii) the Termination Fee shall increase (A) $2.0 million prior to the later of March 1, 2023 or 105 days from the assignment date;

(B) $2.2 million prior to the later of March 1, 2024 or one year and 105 days from the assignment date;

or, (C) $2.4 million thereafter.

Upon any assignment, we will pay the Lender $0.2 million to cover legal and transaction fees related to the termination.

In March 2023, we and WPD agreed to terminate the WPD Agreement.

Pursuant to the termination, we agreed to pay WPD (or its designees) $700,000 in cash and shares of our common stock valued at $800,000.

In connection with the termination, WPD agreed to assign all of its rights and obligations to us related to the Phase 1b/2 clinical trial of Annamycin for the treatment of STS lung metastases being conducted at Maria Sklodowska-Curie National Research Institute.

With the termination of the WPD Agreement, we now hold the worldwide rights to all of our licensed intellectual property, other than the rights related to non-human animals.

Animal Life Sciences Licensing Agreement

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With certain exceptions, the ALI Agreement will remain in full force and effect until the expiration of the last patent within the sublicensed patents.

Prior Sublicenses

In 2015, we entered into certain patent and technology development and license agreements with Dermin sp.

In connection with such agreements, certain intellectual property rights related to Annamycin, our WP1122 portfolio, and our WP1066 portfolio were licensed to Dermin and Dermin was granted a royalty-bearing, exclusive license to manufacture, have manufactured, use, import, offer to sell and/or sell products in the field of human therapeutics under the licensed intellectual property in certain countries in Europe and Asia.

In July 2019, Dermin assigned its rights under the foregoing license agreements to an affiliated entity, Exploration Invest Pte Ltd.

(Exploration).

On July 30, 2019, we and Exploration entered into an agreement pursuant to which we issued Exploration shares of Company common stock valued at $0.5 million (based on the greater of the closing price of the common stock on the date of the agreement or the 10-day average closing price prior to the date of the agreement) in exchange for the modifying the license agreements to:

(i) limit the licensed territory solely to Poland;

and (ii) limit the patent rights and technology rights licensed to Exploration to the patent rights and technology rights that existed on the date the original license agreements were entered into with Dermin.

In February 2022, we entered into a termination agreement with Exploration pursuant to which Exploration agreed to terminate all the above licenses for a one-time payment of $400,000.

As of the date hereof, all the above licenses have been terminated.

Corporate History

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With these results, Jazz Pharmaceuticals acquired Celator in 2016 and obtained FDA approval.

More recently, a new drug called venetoclax, which is indicated for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in combination with certain antibody therapies, has been found to be effective for the treatment of AML.

More recently, a new drug called Venetoclax, has been approved for the treatment of AML, targeting patients over 75 years of age or not suitable for typical chemotherapy.

We believe that such treatment is focused on overall survival and not complete remission or bridge to transplant.

Drugs attempting to target a subset of AML patients who present with specific gene mutations, such as one referred to as FLT3, have recently received FDA approval, but by definition serve only subsets of the AML population.

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Obtaining regulatory approvals and complying with post-approval requirements generally is expensive, labor-intensive and time-consuming.

Failure to comply with the applicable requirements may subject an applicant to administrative or judicial enforcement action, which could include refusal to permit clinical trials, refusal to approve an application, withdrawal of an approval, issuance of a warning letter, product recall, product seizure, suspension of production or distribution, fines, refusals of government contracts, and restitution, disgorgement or civil or criminal penalties.

Failure to comply with the applicable requirements may subject an applicant to administrative or judicial enforcement action, which could include refusal to permit clinical trials to be conducted, refusal to approve an application, withdrawal of an approval, issuance of a warning letter, product recall, product seizure, suspension of production or distribution, fines, refusals of government contracts, and restitution, disgorgement or civil or criminal penalties.

Any agency or judicial enforcement action could have a material adverse effect on us.

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Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, 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.

Each protocol for trials conducted in the US must be submitted to the FDA as part of the IND.

Clinical trials must be conducted in accordance with FDA’s good clinical practice, or GCP, regulations, which are intended to safeguard study subjects and support the validity of the resultant data.

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Such post-approval requirements can materially impact a product’s commercial prospects. Post-approval modifications to a drug product, such as changes in indications, labeling or manufacturing processes or facilities, may require development and submission of additional information or data in a new or supplemental NDA, which would also require prior FDA approval.

Regulatory Exclusivities.

The Orphan Drug Act provides incentives for the development of drugs intended to treat rare diseases or conditions, which generally are diseases or conditions affecting less than 200,000 individuals in the US.

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During that period, the FDA generally may not approve any other application for product with the same active moiety for the same use, although there are exceptions, most notably when the later product is shown to be clinically superior to the product with orphan drug exclusivity.

A court decision in 2021 broadened the scope of ODE, but the impact of that decision is yet to be determined.

A court decision in 2021 broadened the scope of ODE, but the ultimate impact of that decision is yet to be determined, as FDA has stated that it does not intend to apply the court decision to other products, and will instead continue to apply the narrower scope that has long been the agency’s approach.

ODD and ODE are also available from the European Union (EU).

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In addition, changes to the manufacturing process generally require prior FDA approval before being implemented and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval.

Patent Term Restoration 

If we receive FDA approval of our pharmaceutical product candidates, and depending upon the timing, duration and specifics of the FDA approval of the use of our pharmaceutical product candidates, some of our product candidates covered by US patents may be eligible for limited patent term restoration under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments.

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In addition to regulations in Europe and the United States, we will be subject to a variety of foreign regulations governing clinical trials and commercial distribution of our future drugs.

As of December 31, 2021 our workforce consisted of twenty-one full and part-time employees and contractors devoting more than 20 hours per week, in the US and Europe. We leverage our work force with other service providers and contractors worldwide, working in a primarily virtual environment, even prior to the COVID-19 pandemic.

Our workforce contained thirteen full-time employees and four part-time employees.

As of December 31, 2022 our workforce consisted of nineteen fu ll and part-time employees devoting more than 20 hours per week, in the US. We leverage our work force with other service providers and contractors worldwide, working in a primarily virtual environment, even prior to the COVID-19 pandemic.

Our workforce contained fifteen full-time employees and four p art-time employees.

Access to Information

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business