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Item 1. Business

2025-03-21 compared with 2024-03-22 · 323 added, 470 removed, 734 unchanged (52% of the section changed)

Our Business Summary

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, based substantially on discoveries made at and licensed from the University of Texas MD Anderson Cancer Center (MD Anderson) in Houston, Texas.

Business Summary

We are a late-stage pharmaceutical development company currently conducting a pivotal Phase 3 trial evaluating Annamycin, a non-cardiotoxic anthracycline, in combination with Cytarabine for the treatment of subjects with relapsed/refractory acute myeloid leukemia (AML).

This Phase 3 trial should have an interim unblinding of data by the end of 2025, less than a year from its commencement, and an additional unblinding in the first half of 2026.

We believe such early visibility for a pivotal registration-enabling trial is highly unique in that stakeholders will receive preliminary safety and efficacy data in the “MIRACLE” trial (derived from Moleculin R/R AML AnnAraC Clinical Evaluation) within one year of dosing the first subject.

Additionally, we have two portfolios of technologies for hard-to-treat cancers and viruses with clinical and preclinical research funded by investigators at academic institutions.

Each of our three core technologies is based substantially on discoveries made at and licensed from the University of Texas MD Anderson Cancer Center (MD Anderson) in Houston, Texas, and features one or more drugs that have successfully completed a Phase 1 clinical trial.

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

Since our inception, our drugs have completed, are currently in, or have been permitted to proceed in thirteen clinical trials.

Annamycin is our lead molecule and is in three Phase 1B/2 clinical trials - one for treating Acute Myeloid Leukemia (AML) and two for treating Soft Tissue Sarcoma metastasized to the lungs (STS lung metastases, STS lung mets, or Advanced STS).

One of our core management beliefs is that anthracyclines represent the most important treatment for AML and Advanced STS, and we believe Annamycin may, for the first time ever, allow a majority of these patients to benefit from this treatment.

This belief leads us to currently focus mainly on the development of Annamycin.

Our Core Technologies

One is currently beginning a Phase 2B/3 trial.

Since our inception, our drug candidates have completed, are currently in, or have been permitted to proceed in, fourteen clinical trials.

Annamycin is in a class of drugs referred to as Anthracyclines, which are an inhibitor of topoisomerase II, enabling them to cause DNA damage in rapidly replicating tumor cells.

Annamycin, in a unique multilamellar lipid formulation, is our lead molecule and we have recently concluded one Phase 1B/2 clinical trial for treating AML and are embarking on a Phase 3 clinical trial for the treatment of AML, which we believe will be pivotal.

Annamycin was also in two Phase 1B/2 clinical trials for treating Soft Tissue Sarcoma metastasized to the lungs (STS lung metastases, STS lung mets, or Advanced STS).

We believe that our lead drug candidate Annamycin has summarily:

Demonstrated significant efficacy in Phase 1 and 2 cancer clinical trials – specifically relapsed and refractory (R/R) AML with complete remission rates significantly above currently approved second line therapies and STS lung mets with overall survival as a median seventh line therapy comparable to overall survival seen with approved first line monotherapies;

Shown encouraging activity in five different clinical trials (most of which are now complete), funded both internally and externally (through investigator initiated trials);

Shown in its clinical trials to be non-cardiotoxic (N=84) with some patients being safely dosed at five times the typical lifetime maximum allowed anthracycline dose, which potentially enables repeated dosing and consolidation;

Demonstrated in preclinical models, to be more potent than and to avoid cross resistance with some of the most common drugs used to treat AML (as well as many other cancers), including currently approved anthracyclines, Cytarabine and Venetoclax;

Composition of matter patent protection thru 2040 and has orphan drug and fast track status;

No vesicant activity, making it safer to handle and administer as compared to other anthracyclines;

Shown a complete response (CR) rate of 50%, a composite complete response (CRc) rate of 60%, durability of CRc’s of approximately 9 months (and climbing), and an overall survival (OS) rate of approximately 11 months (and climbing) (N=10) in combination with Cytarabine for the treatment of R/R AML as second line therapy to date, which is higher than other currently approved second line therapies for R/R AML

One of our core management beliefs is that anthracyclines represent one of the most important treatments for AML and Advanced STS, and we believe Annamycin may, for the first time ever, allow a majority of these patients to benefit from this treatment.

We believe that such a benefit would be disruptive to the competitive landscape for these markets.

This belief, coupled with our limited resources, leads us to currently focus mainly on the development of Annamycin.

We intend to advance our other drug candidates via investigator led studies – both clinically and preclinically.

Focus and Core Technologies

We are focused on internally funded (“internally” and “externally” funded trials are defined in the Funding Strategy section below) development of our core technologies:

1) 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 R/R AML, and

For the treatment of STS metastasized to the lungs.

2) WP1066 IV:

A better formulation for delivery intravenously of a molecule from the WP1066 portfolio to possibly further support for future externally funded oncology clinical trials.

Such a formulation will require additional preclinical work prior to a clinical trial.

We have established a Recommended Phase 2 Dose 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 and primarily externally funded non-clinical research, with the potential for further studies in the future.

Our core technologies consist of the following programs:

a) Annamycin or L-Annamycin is a “next generation” anthracycline (one of the most common classes of chemotherapy), 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 to be non-cardiotoxic and has shown no cardiotoxicity 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.

Annamycin is demonstrating efficacy in two of its Phase 1B/2 trials as described further below in subjects with AML and Advanced STS.

We believe that Annamycin has potential to fill an unmet need as a second line therapy (2nd line or 2L) in AML and potentially as first line therapy in Advanced STS.

As part of our Annamycin clinical trials, we have engaged an independent expert in assessing cardiotoxicity associated with chemotherapy at the Cleveland Clinic (Expert or Independent Expert).

The data made available to the Expert includes left ventricular ejection fraction (LVEF) as determined by echocardiograms, and ECHO strain imaging, as well as Troponin levels (a biochemical marker of acute heart damage).

“ECHO strain imaging” is a method in echocardiography (medical ultrasound) for measuring regional or global deformation (contraction or beating) of the myocardium (heart muscle).

By strain rate imaging, the simultaneous function of different regions can be displayed and measured.

Cardiac health biomarkers such as blood Troponin levels are considered an indicator of potential long-term heart damage.

The Expert has issued and will continue to issue periodic reports as additional data are provided to him in batches of subject data.

Such data include some data which are preliminary and subject to change.

In our discussions regarding the lack of Annamycin's cardiotoxicity, we rely on the Expert's assessment.

Annamycin benefits from a promising advancement in lipid enabled drug delivery developed in collaboration with and exclusively licensed from MD Anderson.

The unique patent-pending lipid composition allows us to combine a new concept in chemotherapeutic agents within a lipid structure that helps target the delivery of the payload and reduce the potential for toxicity.

In the case of Annamycin, our unique use of lipid technology enables improved tissue/organ distribution, and as demonstrated in multiple clinical trials, dramatically reduced toxicity, including cardiotoxicity.

a) Annamycin or L-Annamycin is a “next generation” anthracycline (one of the most widely used classes of chemotherapy), 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 to be non-cardiotoxic and, with intensive cardiac monitoring, has shown no cardiotoxicity in subjects treated in our five Annamycin clinical trials to date.

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

b) Our WP1066 Portfolio includes WP1066, WP1193 and WP1220, three 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.

These also stimulate a natural immune response to tumors by inhibiting the errant activity of Regulatory T-Cells (TRegs).

WP1066, in oral formulation, has been in two clinical trials, including compassionate use cases.

WP1066 and WP1193 are being tested in preclinical programs in intravenous (IV) formulations.

WP1066 and WP1220 have been in clinical trials in a topical formulation.

WP1066 and WP1220 have both independently successfully completed Phase 1 clinical trials and have demonstrated efficacy as described further below.

c) Our WP1122 Portfolio 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).

We believe such compounds may provide an opportunity to cut off the fuel supply of tumors by taking advantage of their high degree of dependence on glucose in comparison to healthy cells, as well as viruses that also depend upon glycolysis and glycosylation to infect and replicate.

WP1122 has completed a Phase 1 clinical study, successfully establishing a Recommended Phase 2 Dose or RP2D.

We are focused on internally funded (“internally” and “externally” funded trials are defined in the Funding Strategy section below) development of:

1) 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 AML.

2) Annamycin for the treatment of STS metastasized to the lungs.

3) A better formulation for delivery of a molecule from the WP1066 portfolio to possibly further support future externally funded oncology clinical trials.

Such a formulation will require additional preclinical work prior to a clinical trial.

We have established an RP2D for WP1122 to potentially enable future externally funded oncology and virology trials.

Our Clinical Trials

We are currently conducting three Phase 1B/2 trials with Annamycin, two internally funded and one mainly externally funded.

One additional externally funded Phase 1B/2 clinical trial with WP1066 in combination with radiation is planned to begin in 2024.

In terms of developing preclinical data, we conduct research utilizing our own employees, as well as outside consultants, in our own lab, as well as contracted facilities and we sponsor research at MD Anderson, the University of Texas Medical Branch (UTMB), and the University of Warsaw to expand the science of our core technologies and to identify possible combinations with other approved drugs.

We have a National Institutes of Health (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 multiple active INDs/CTAs (Investigational New Drug authorization in the US or Clinical Trial Authorization in Europe).

Under these INDs/CTAs, we have under development, approved, have in progress, or have completed thirteen internally and externally funded clinical trials.

Additionally, we are anticipating advancing Annamycin in combination with Cytarabine for the treatment of AML in a Phase 2B/3 clinical trial beginning in late 2024 or early 2025.

Depending on when MB-107 (our Phase 1B/2 clinical study with Annamycin as a monotherapy treating soft tissue sarcoma pulmonary metastases) concludes, we may see additional partially or fully externally funded clinical research with Annamycin for the treatment of advanced STS.

Below in Table 1 we are summarizing all of the thirteen clinical trials concluded, in progress, or approved/ allowed by the FDA or its European equivalent.

See the discussion following the Table 1 for more detailed information, especially on safety and human activity.

We believe such compounds may provide an opportunity to cut off the energy supply of tumors by taking advantage of their high degree of dependence on glucose in comparison to healthy cells, as well as viruses that also depend upon glycolysis and glycosylation to infect and replicate.

In all our discussions, clinical data (where a CSR or its equivalent has not been published), are considered preliminary and subject to change.

Clinical Trials Summary

As summarized on the next page, we and our external investigators have multiple active INDs/CTAs (Investigational New Drug authorization in the US or Clinical Trial Authorization in Europe).

Under these INDs/CTAs, we have under development, approved, have in progress, or have completed fourteen internally and externally funded clinical trials.

Below in Table 1 we are summarizing those clinical trials that have concluded, are in progress, or are approved/allowed by the FDA or its European equivalent.

See the notes below and the detailed discussion in the sections following Table 1 for more information.

Table 1 - Clinical Summary as of this filing

18 unchanged sentences

no cardiotoxicity reported

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

80% ORR in last cohort

Annamycin in Combination with Cytarabine

MB-106 / R/R AML / Europe

20 subjects recruited to date.

Phase 2 recruiting as 1st line and therapy;

2nd line recruitment stopped at 10 subjects

Seven sites recruiting in Poland and Italy

No cardiotoxicity reported to date

Phase 1B/2 All-Comers (n=18):

CRc rate of 39% & ORR 50%;

As 2nd Line (n=10):

CRc rate of 60% & ORR 70%

22 subjects intent to treat.

2 subjects had an allergic reaction and did not receive full dose.

Enrollment closed.

Trial continues with long-term follow-up.

Seven sites recruited in Poland and Italy.

22 subjects 1 st -7 th line.

4, 10 , and 14 subjects 1 st line.

2nd line, & 2 nd /3 rd line, respectively

No cardiotoxicity observed during the trial.

Held FDA End of Phase 1/2 meeting in June 2024 whereby feedback was received to develop MB-108 MIRACLE trial.

Phase 1B/2 CR 36% All-Comers, CR 43% 2 nd & 3 rd Line;

CR 50% & CRc 60% 2 nd Line;

Durability of all CR’s~12 mos & climbing;

CR’s in Multiple genotypes/mutations;

and post 2 nd line post Venetoclax therapy (60% CRc)

MB-107 / STS Lung Metastases / US

Phase 1 completed;

Phase 2 in progress - treated stopped;

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

Phase 2 completed;

CSR finalized not yet submitted.

RP2D of 330 mg/m 2 identified

No cardiotoxicity reported

Preliminary data - Phase 1 67% (10 of 15) of subjects showed SD or better through 2+ cycles;

Phase 2 (O/S ongoing) 63% (9 of 14) subjects show SD through 2+ cycles

CSR finalized but not submitted.

Final data to be presented by the end of April.

Preliminary OS ~10 mos as median 4 th line.

Annamycin in Combination with Cytarabine

MB-108 / 2 nd Line R/R AML / Global (MIRACLE)

First site initiated

Global trial Annamycin plus Cytarabine vs control arm of Cytarabine plus placebo

No data to date

IIT / STS Lung Metastases / Poland

Phase 1b in progress;

First subject treated in Q4-2022

Study closed to further enrollment.

Investigator led trial weekly dosing regimen versus traditional chemotherapy dosing

1 unchanged sentence

More detail below.

Still in dose escalation phase:

50% have received greater than 2 cycles (~2 months of SD)

No evidence of

cardiotoxicity noted by our independent expert

IIT / Adult GBM / US

6 unchanged sentences

Open to an investigator to lead a study

Trial has not begun

WP1066 in combination with radiation

2 unchanged sentences

Used as reference for next trial

Trial has not begun

WP1066 in combination with radiation therapy

IND allowed for IIT led Adult GBM / US

1B/2 External

Investigator expected to begin recruiting in 2024

Trial has not begun

Site initiation visit was in May 2024

4 subjects enrolled and treat with 1 subject currently on active treatment

No safety data reported to date

No efficacy data reported to date

IIT / Pediatric Brain Tumors / US

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

CSR in process.

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

18 unchanged sentences

Notes for Table 1 :

1) In MB-104 MLFS means "morphological leukemia-free state";

2) In MB-105 we consider complete responses (CR) or complete response with incomplete recovery of the bone marrow (CRi) as where the bone marrow aspirate (BMAs) show leukemic blasts of less than 5%;

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

4) Complete Response Composite (CRc) includes CRs and CRis;

2) Complete Response Composite (CRc) includes CRs and CRi’s;

3) Overall Response Rate (ORR) includes CRc and Partial Response (PR);

6) “Met safety endpoints” means that no drug-related serious and unexpected adverse events occurred as defined in the trial protocol 7) All data presented are preliminary unless a CSR or an investigator's final report has been issued for the trial referenced - specifically the data for MB-106 and MB-107 are preliminary and subject to change;

4) “Met safety endpoints” means that no drug-related serious and no unexpected adverse event (only one serious in MB-105) occurred as defined in the trial protocol 5) All data presented are preliminary (and subject to change) unless a CSR or an investigator's final report has been issued for the trial referenced;

6) With regard to safety and human activity summaries please see the detailed discussion below;

9) MB-106 Phase 1 included “all-comers” or subjects with unlimited lines of prior therapy while Phase 2 included only subjects as 1 st thru 3 rd line of therapy, and 10) MB-107 Phase 2 has no ongoing treatment active and is following nine of fifteen subjects for overall survival (OS).

In the US and Europe, since our inception, we or independent investigators have approval to begin, are currently conducting or have completed thirteen internally or externally funded clinical trials for four of our drug candidates – Annamycin, WP1066, WP1220, and WP1122, as listed above.

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

and, 7) MB-106 Phase 1 included “all-comers” or subjects with unlimited lines of prior therapy while Phase 2 included only subjects as 1 st thru 3 rd line of therapy.

Our Drug Candidate Programs

In the US and Europe, since our inception, we or independent investigators have approval to begin, are currently conducting or have completed fourteen internally or externally funded clinical trials for four of our drug candidates – Annamycin, WP1066, WP1220, and WP1122, as listed above.

All of the clinical trials are or were in the Phase 1 or 2 stage with the exception of MB-108 which is a Phase 2B/3.

Starting in 2021 through 2024, there have been eight "right-to-try" (or their foreign equivalent) uses of Annamycin and WP1066.

Our clinical trials focused on Annamycin in 2024 with two internally funded and one externally funded Phase 1B/2 clinical trials.

We concluded recruitment and treatment in the MB-107 Phase 1B/2 all comers clinical trial using Annamycin as a single agent for the treatment of STS lung mets during 2023.

In this trial we are still monitoring progression free survival (PFS) and overall survival (OS) as we move into 2024.

In our MB-106 Phase 1B/2 all-comers (see discussion below) clinical trial using Annamycin in combination with Cytarabine for the treatment of AML, we concluded recruitment and treatment as 2 nd line therapy on of January 31, 2024, and are continuing recruitment where treatment is either 1 st line (Poland only) or 3 rd line (Poland and Italy) with 20 su bjects recruited thus far out of a planned maximum of 28 subjects.

In using the term "all-comers" for this trial, we did not limit the number of prior therapies for subjects entering the trial in the Phase 1 portion of MB-106.

We concluded recruitment and treatment in the MB-107 Phase 1B/2 all comers clinical trial using Annamycin as a single agent for the treatment of STS lung mets in 2023 and followed for progression free survival (PFS) and OS during 2024.

In our MB-106 Phase 1B/2 all-comers clinical trial using Annamycin in combination with Cytarabine for the treatment of AML, we concluded recruitment and treatment with 22 subjects recruited on an Intent-To-Treat (ITT) basis.

The term "all-comers" for this trial indicates that we did not limit the number of prior therapies for subjects entering the trial in the Phase 1 portion of MB-106.

In the Phase 2 portion we did limit the number of prior therapies to two.

For subjects with one prior therapy, we plan on utilizing the 2 nd line data for an end of Phase 2 meeting with the FDA in the first half of 2024.

Additionally, recruiting and treatment continue for the externally funded Phase 1B/2 clinical trial studying an alternative dosing schedule of Annamycin for the treatment of STS lung mets in Poland, which is discussed further below.

All of these Phase 1B/2 clinical trials are open label, so we periodically announce safety and efficacy data.

We utilized the MB-106 data for an End of Phase 2 (EOP2) meeting with the U.S.

Food and Drug Administration (FDA) in July 2024.

In July 2024, we announced the completion of our EOP2 meeting with the FDA for our Phase 1B/2 clinical trial evaluating Annamycin in combination with Cytarabine for the treatment of subjects with AML as both first line therapy and for subjects who are refractory to or relapsed after induction therapy (MB-106).

We believe that this meeting, based upon the FDA minutes, was a positive discussion and resulted in the design and implementation of a Phase 2B/3 pivotal trial for the treatment of AML patients who are refractory to or relapsed after induction therapy (R/R AML).

The MIRACLE trial will be a global trial, including sites in the US, Europe, Western Asia and the Middle East.

The FDA’s Divisions of Hematologic Malignancies I and Cardiology and Nephrology, as well as related divisions, were involved in the review of the data showing no cardiotoxicity in MB-106 and prior clinical trials.

Consistent with the FDA’s recommendations, in the adaptive MIRACLE trial we plan to utilize a double-blind, placebo-controlled design, where we will compare AnnAraC versus a control arm of high dose cytarabine (HiDAC) plus placebo and we will rely solely on CR (complete remission) at approximately one month as the primary endpoint.

The FDA also wanted to see the durability of response (DoR) as a secondary endpoint and overall survival as an exploratory endpoint, as well as data for patients beyond 2nd line, which is why our plan includes a follow-on MIRACLE2 trial in 3rd line patients starting once the optimum dose is established in the MIRACLE trial.

Based on our discussions with the FDA, we amended in September 2024 our MB-104 investigational new drug application or IND for MB-108.

In the amendment with the new MIRACLE protocol, the trial will, for the first time ever in the US for an AML trial, allow dosing above the lifetime maximum allowable dose (LTMAD) for currently prescribed anthracyclines.

The MIRACLE study, subject to appropriate future filings with and potential additional feedback from the FDA and their foreign equivalents, utilizes an adaptive design whereby the first 75 to 90 subjects will be randomized (1:1:1) in Part A of the trial to receive high dose cytarabine (HiDAC) combined with either placebo, 190 mg/m2 of Annamycin, or 230 mg/m2 of Annamycin, which Annamycin doses were specifically recommended by the FDA in the Company’s end of Phase 1B/2 meeting.

The amended protocol allows for the unblinding of preliminary primary efficacy data (Complete Remission or CR) and safety/tolerability of the three arms once 45 subjects have been evaluated, in addition to unblinding at the conclusion of Part A (at a total of 75 to 90 subjects).

The first unblinding will yield 30 subjects treated with Annamycin (190mg/m2 and 230/m2) and HiDAC compared with 15 subjects from the control arm.

The Company expects to reach the first unblinding (45 subjects) in the second half of 2025, in addition to the second unblinding, which is expected in the first half of 2026.

For Part B of the trial, approximately 220 additional subjects will be randomized to receive either HiDAC plus placebo or HiDAC plus the optimum dose of Annamycin (randomized 1:1).

The selection of the optimum dose will be based on the overall balance of safety, pharmacokinetics and efficacy, consistent with the FDA’s new Project Optimus initiative.

Additionally, recruiting and treatment concluded in 2024 for the externally funded Phase 1B/2 clinical trial studying an alternative dosing schedule of Annamycin for the treatment of STS lung mets in Poland.

The investigator is expected to issue a publication in 2025 on this study.

In February 2023, the externally funded Phase 1 clinical trial with WP1066 for the treatment of pediatric brain tumors concluded.

We expect one externally funded Phase 1B/2 clinical trial for WP1066 in combination with radiation for the treatment of GBM and other brain tumors in 2024.

One more pediatric clinical trial may occur in the future, subject to the results of the other two possible c linical trials.

Human Activity Shown in Our Clinical Trials

The following data regarding human activity are all from our studies.

All data are preliminary and subject to change, unless a clinical study report (CSR) has been published or the investigator-initiated study has concluded and issued its annual report.

“Right-to-try” data are preliminary until published.

Specifically, the data from MB-106 and MB-107 are preliminary and subject to change.

Such activity may or may not be repeated in future clinical trials, including potentially pivotal and/or confirmatory clinical trials.

While we believe such data are encouraging, the FDA or its foreign counterpart will ultimately determine if such data and future data are individually conclusive and support future clinical trials or approval.

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

Annamycin has shown human activity in AML and STS lung mets as follows:

Prior to 2021, our MB-104 US Phase 1 trial for Annamycin as a single agent therapy in relapsed or refractory AML successfully met its safety endpoint (including the absence of cardiotoxicity) and demonstrated human activity in the reduction of circulating bone marrow leukemic 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 relapsed or refractory AML with fifteen subjects receiving the full dose per the protocol and identifying an RP2D and we demonstrated an 80% overall response rate (ORR) in the five subjects in the last cohort.

These subjects with a median age of 65 were heavily pretreated with a median of 6 pr ior therapies.

Three subjects achieved a PR and one achieved a CRi.

Regarding the PRs, two of the three PR subjects’ repeat BMA's had a blast count below 5% at the end of therapy, which we believe qualifies as a CRi under current literature and standards.

We therefore consider the results in the last cohort as 60% CRi and 20% PR with a total of 80% ORR.

During 2023, we started our MB-106 clinical trial with Annamycin in combination with Cytarabine (AnnAraC) for the treatment of AML in an all-comers trial, accepting subjects with a wide range of prior therapies in the Phase 1 portion with a limit of two prior therapies in the Phase 2 portion.

The total recruited to date i s 20 where one subject just began treatment and another subject has not been evaluated for efficacy.

To date we have a composite complete response (CRc) rate of 39% in all subjects (n= 18).

This is comprised of a CR rate of 33% and CRi of 6%.

The 19 th subject, being treated as a 3 rd line therapy, had two BMAs tested where they have been inconclusive, and we are awaiting further testing.

This subject will move the CRc to either 42% or 37% (n=19).

Durability data are developing with one CR and one CRi having relapsed to date.

Durability of CRs is confirmed by repeat BMAs.

The first CR subject was treated in February 2023 and remains durable to date.

The median age of all subje cts recruited is 69, ranging from 19 to 78.

This trial may enroll up to 28 subjects, although recruitment for subjects as 2 nd line therapy ended in January 2024.

The trial continues recruitment for treatment as 1 st line and 3 rd line therapy.

Since we intend to p osition AnnAraC for approval as a 2 nd line therapy, we believe that the most important data from this trial are the results in 2 nd line subjects (excluding subjects who are either 1 st line or 3 rd line and beyond).

When stratified for that population (n=10), the CRc rat e is 60%, being comprised of a CR rate of 50% and a CRi of 10%.

STS Lung Met s:

In 2022 our MB-107 trial treating STS lung metastases demonstrated a preliminary response of stable disease or better in 67% (10 of 15) of subjects – defined as stable disease (SD) or better after two cycles of Annamycin (approximately six weeks) in the 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 64% (9 of 14) of 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 has been documented to be 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).

STS Lung Mets IIT STS Lung M ets:

In late 2022 an investigator-initiated trial (IIT) with Annamycin treating STS lung mets with weekly dosing began.

Six subjects have been enrolled and treated to date (3 in cohort 1 at 35 mg/m2;

3 in Cohort 2 at 60 mg/m2)).

A dose limiting toxicity or DLT was noted.

The cohort was expanded and a 4 th subject in Cohort 2 has been identified, consented in February 2024 and is currently in screening.

The preliminary data to date is 50% (3 of 6) have received greater than 2 cycles (approximately 2 months) of therapy where we have assumed stable disease (SD) through 2 cycles.

One of these three subjects has initiated cycle 5 (where we have assumed SD through 4 cycles).

This is all based on preliminary data from the IIT dosing tracker.

The data is preliminary and subject to change.

We are pending an update from the IIT.

No Cardiotoxicity:

To date, out of th e 82 subjects treated in the MB-104, MB-105, MB-106 and MB-107 trials mentioned above, 63 sub jects’ data have been reviewed by our Independent Expert who has reported seeing no signs or symptoms of cardiotoxicity among the subjects reviewed.

In March 2024, we were notified of an increase in one subject's troponin levels and the Expert opined that the subject had other factors relatable to the increase in the troponins and deemed this event unrelated to Annamycin.

Data are sent periodically to our Independent Expert to be reviewed and we intend to have all subjects' data reviewed.

Clinical data where a CSR or its equivalent has not been published are considered preliminary and subject to change.

WP1066 has shown the following human activity:

In an IIT of WP1066 in an oral formulation (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.

In the IIT pediatric trial, two subjects (n=8) received at least 4 cycles (each cycle = 28 days) prior to progression.

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

The CSR for this study was issued in 2021 for a clinical trial of WP1220, another drug candidate which is a topical formulation in the WP1066 Portfolio, studied for the topical treatment of cutaneous T-cell lymphoma (CTCL) and 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 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.

Our Drug Candidate Programs

An externally funded Phase 1B/2 clinical trial for WP1066 in combination with radiation for the treatment of GBM began treating subjects in 2024.

Preclinical studies have begun on an intravenous formula of WP1066 to determine which molecule within the WP1066 portfolio will be best suited for future trials.

Internally funded preclinical studies at MD Anderson were initiated in 2023 and ongoing thru 2025.

Additionally, externally funded preclinical work is being performed at Emory University and along with the data from the clinical trial at Northwestern University, should set the stage for additional pediatric studies at Emory University in the future.

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

We successfully completed a Phase 1 clinical study of WP1122 in 2023.

Annamycin Program

One of our core management beliefs is that anthracyclines represent the most important treatment for AML and Advanced STS, and we believe Annamycin may allow, for the first time ever, a majority of these patients to benefit from this treatment.

This belief leads us to currently focus mainly on the development of Annamycin.

To further explain this, 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.

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 and clinical trials support this intended design.

The lack of cardiotoxicity and the potential for efficacy of Annamycin have been demonstrated i n 82 s ubjects treated to date.

The efficacy data have been generated, mainly in 2023.

To that end, we believe that Annamycin has potential to fill an unmet need as a second line therapy (2 nd line) in AML and potentially as a first line therapy (1 st line) in Advanced STS.

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

The lack of cardiotoxicity and the potential for efficacy of Annamycin have been demonstrated in 84 subjects treated to date.

Based upon the efficacy and safety data to date, we believe that Annamycin has potential to fill an unmet need as a second line therapy (2 nd line) in AML and potentially as a first line therapy (1 st line) in both AML and Advanced STS.

The FDA and the EMA (European Medicines Agency) have granted Orphan Drug Designation (ODD) to Annamycin for the treatment of AML.

Additionally, the FDA has granted ODD for Annamycin for the treatment of soft tissue sarcoma.

Such designation means, in part, these agencies believe we have established a medically plausible basis for using the drug for those indications.

The FDA also granted Fast Track-Designation (FTD) for Annamycin for both the treatment of AML and Soft Tissue Sarcoma.

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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 reproducing cancer cells.

Acute leukemia is one of a number of cancers that are usually treated with anthracyclines in "fit" patients.

In the case of acute leukemia, anthracyclines are typically used in “induction therapy,” where the goal is often to induce sufficient remission of patients’ blood-born tumor cells to allow for a potentially curative bone marrow transplant.

Acute leukemia is one of a number of cancers that are usually treated with anthracyclines in patients who are considered to be “fit” enough to undergo such therapy.

In the case of acute leukemia, anthracyclines are typically used in “induction therapy,” where the goal is often to induce sufficient remission of patients’ bloodborne tumor cells to allow for a potentially curative bone marrow transplant.

Two key factors limit the safety and effectiveness of anthracyclines:

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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.

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

In addition, the effectiveness of currently approved anthracyclines is limited by their propensity for succumbing to “multidrug resistance.” This can occur where, as a natural defense mechanism, transmembrane proteins acting as transporters (one type of which is referred to as a “P-glycoprotein pump” or an “ABCB1 transporter”;

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We believe that the encouraging preliminary efficacy being demonstrated in our clinical trials in 2 nd line AML therapy may, in part, be the result of Annamycin's ability to avoid MDR1 mechanisms.

As part of our Annamycin clinical trials, we have engaged an independent expert at the Cleveland Clinic to assess cardiotoxicity associated with chemotherapy (Expert or Independent Expert).

The data made available to the Expert include left ventricular ejection fraction (LVEF) as determined by echocardiograms, and ECHO strain imaging, as well as serum Troponin levels (a biochemical marker of acute heart damage).

“ECHO strain imaging” is a method in echocardiography (medical ultrasound) for measuring regional or global deformation (contraction or beating) of the myocardium (heart muscle).

By strain rate imaging, the simultaneous function of different regions can be displayed and measured.

Cardiac health biomarkers such as blood Troponin levels are considered an indicator of potential long-term heart damage.

The Expert has issued and will continue to issue periodic reports as additional data are provided to him in batches of subject data.

Such data include some data which are preliminary and subject to change.

In our discussions regarding the lack of Annamycin's cardiotoxicity, we rely on the Expert's assessment.

Annamycin in preclinical studies has shown a lack of cardiotoxicity and this also has been shown in our clinical trials to date, as reported by our Expert.

Clinical data where a CSR or its equivalent has not been published are considered preliminary and subject to change.

Our Expert has issued and will continue to issue periodic reports as additional data are provided in batches of subject data.

To date, we have received a several independent assessments for the absence of cardiotoxicity in subjects treated with Annamycin.

We now have independent assessments covering 63 subjects that have been treated with Annamycin in four different clinical trials in the U.S.

To date, we have received several independent assessments for the absence of cardiotoxicity in subjects treated with Annamycin.

We now have independent assessments covering 84 subjects that have been treated with Annamycin in five different clinical trials in the U.S.

and Europe with no evidence of cardiotoxicity.

To date, 62 of all 82 s ubjects treated (which includes the 63 subjects independently assessed) were treated above the FDA’s lifetime maximum anthracycline limit of 550 mg/m 2 , with 1 subject having been treated with 3420 mg/m 2 (or roughly six times the FDA approved lifetime anthracycline exposure) of standard anthracyclines and Annamycin and there has been no evidence of cardiotoxicity.

To date of the 77 subjects treated in our internally funded trials, 56 were treated above the FDA’s lifetime maximum anthracycline limit of 550 mg/m 2 , with one subject having been treated with 3420 mg/m 2 (or roughly five times the FDA approved lifetime anthracycline exposure) of standard anthracyclines and there has been no evidence of cardiotoxicity.

After review of the data provided, the Independent Expert, in their most recent report and as stated in previous reports, concluded that there was no evidence of cardiotoxicity.

In March 2024, we were notified of an increase in one subject’s troponin levels seven weeks post cycle one and prior to initiation of a second cycle.

Immediately post the second treatment the troponin levels decreased.

All of the relevant subject's data were reviewed by our Expert.

In the report of the Expert, the subject had other factors relatable to the increase in the troponins and deemed this event unrelated to the study drug Annamycin.

We consider all data, including this data, preliminary and subject to change until a CSR is published.

We believe the Expert's 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.

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Anthracyclines are an important class of first line tools for physicians and while effective, their maximum lifetime dose in patients is limited due to concerns over cardiotoxicity.

The following discussion, which includes estimates based on current literature and our discussions with key opinion leaders, suggests that approximately 60% of AML patients continue to have a significant unmet need.

This is based on the reality that effective treatment options are limited.

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While the standard of care treatment can be complex, regionally variable (especially since not all current AML drugs are approved in all countries), and highly individualized (based on a range of factors including gene mutations), all AML patients are initially categorized based on their ability to undergo intensive chemotherapy.

As a result, we estimate around 50% of patients are deemed “Fit” for standard intensive first-line treatment and the other 50% are deemed “Un-Fit.”

Those who are deemed “Fit” are most often treated with the “standard” induction therapy of three days of intravenous daunorubicin or equivalent anthracycline, and seven days of intravenous cytarabine, also known as Ara-C.

We estimate that only about 36% of these patients, or approximately 18% of overall AML patients, will have a durable CR to first line therapy, meaning the cancerous cells in their bone marrow have been reduced to 5% or less.

As a result, we estimate around 50% of patients are deemed “Fit” for standard intensive first-line treatment and the other 50% are deemed “UnFit.”

This first line regimen is often referred to as “7+3.” We estimate that only about 36% of these patients, or approximately 18% of overall AML patients, will have a durable CR as a result of first line therapy, meaning the cancerous cells in their bone marrow have been reduced to 5% or less.

At this point, they either qualify for a bone marrow transplant or hope for the remission to become long lasting.

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However, since so few patients actually get to this point, we estimate that only a minor subset (approximately 14%) of all AML patients reach this positive outcome, through the standard first-line pathway for “fit” patients.

The 50% of patients who are deemed “Un-Fit” for first-line intensive chemotherapy treatment are usually treated with a combination of Venetoclax and azacytidine, also known as “Ven-Aza”.

The 50% of patients who are deemed “Unfit” for first-line intensive chemotherapy treatment are usually treated with a combination of Venetoclax and azacytidine, also known as “Ven-Aza”.

The success rate, as we estimate, in this group of patients is only around 37%, or approximately 19% of all AML patients, achieving a durable CR and qualifying for a BMT or achieving long-term remission.

Similarly, we estimate that as many as 80% of these responding patients will benefit from a bone marrow transplant or experience lasting remission.

But again, this means that only a small subset of the deemed “Un-Fit” patients, approximately 15% of all AML patients, achieve this positive outcome.

While this success rate appears as good or better than 7+3 in “Fit” patients, it generally takes much longer and considering the limited remaining life expectancy for AML patients, the faster regimen is favored whenever patients are considered “Fit.” Similarly, we estimate that as many as 80% of these responding patients will benefit from a bone marrow transplant or experience lasting remission.

But again, this means that only a small subset of the deemed “Unfit” patients, approximately 15% of all AML patients, achieve this positive outcome.

Additionally, a study of AML subjects who were refractory to or relapsed after receiving Venetoclax plus a hypomethylating agent regimen (such as azacitidine) as 1 st line therapy demonstrated a dismal outcome upon failure of this regimen with a median OS of just 2.4 months.

Of those subjects that, upon Venetoclax regimen failure and received salvage therapy, only 12.5% and 4% achieved a CRc and a CR, respectively (A.

Cortes, Et al, “Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and Venetoclax regimens, Haematologica online, vol.

106 No.3 (2021)).

In recent years, new targeted therapies have been approved (mostly in the US) and have become available to 2 nd line patients (those patients for whom the 1 st line therapies discussed above have failed), adding a new alternative.

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Five such drugs have been approved to date, but each is only relevant to a subset of AML patients who happen to have the requisite genetic mutation and response rates are relatively low.

We estimate that only about 21% of 2nd line patients will achieve a durable CR which means only another 11% of the AML population is given a chance to beat their disease with a successful bone marrow transplant or lasting remission.

We estimate that only about 21% of those 2nd line patients who happen to have the requisite genetic profile will achieve a durable CR, which means only another 11% of the AML population is given a chance to beat their disease with a successful bone marrow transplant or lasting remission.

This leaves, based on our estimates, about 58% of all AML patients who will ultimately succumb to their disease.

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Annamycin Clinical Trials – AML

We have studied Annamycin in three internally funded AML clinical trials, one of which is still under way.

We have studied Annamycin in three internally funded AML clinical trials.

These trials are MB-104, MB-105, and MB-106.

In MB-105 and MB-106, we began seeing what we believe to be potentially significant efficacy in AML.

Below is a discussion of these three trials with a focus on the most recent two.

Below in Table 2 is a summary of the preliminary responses in the concluded MB-105 monotherapy trial and the MB-106 combination therapy trial to date, both for the treatment of AML.

Table 2 - Summary of Annamycin Responses in MB-105 & MB-106 AML Studies as of Marc h 19, 2024

Study MB-105 Monotherapy - Last Cohort at 240 mg/m 2 (RP2D)

Study MB-106 Combination Therapy– Phase 1B/2 All Lines (Range 1-7)

Study MB-106Combination Therapy– Phase 1B/21 st Line

Study MB-106Combination Therapy– Phase 1B/2 As 2 nd Line Only

Annamycin - Single Agent

Ara-C + Annamycin "5+3"

Ara-C + Annamycin“5+3"

Subjects Not Yet Evaluable

Subjects Evaluable To Date

Subjects Evaluable Not Dosed Per Protocol

Median Prior Therapies

Median Age - Years (Range)

Complete Responses (CR)

CR with incomplete recovery (CRi)

Total Complete Response(s) (CRc)

Complete Response (CR) Rate

Complete Response Composite (CRc) Rate

Partial Responses (PRs)

CRc Relapsed To Date

Durability of CR

Notes for Table 2 :

1) Data from MB-105 is showing only the five subjects treated per protocol in the last cohort and are shown as this cohort was at the recommended phase 2 dose or RP2D.

2) Data from MB-106 is for intent to Treat subjects;

3) Data from MB-106 is preliminary and subject to change;

4) Durability is developing;

and 5) The 19 th subject, being treated as a 3 rd line therapy, had two BMAs tested where they have been inconclusive, and we are awaiting further testing.

This subject will move the CRc in the “MB-106 Phase 1B/2 All Lines" column to either 42% or 37% (n=19).

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 completed in 2020.

In MB-105 and MB-106, we saw what we believe to be potentially significant efficacy in AML.

With that data in July 2024, we announced the completion of our EOP2 meeting with the FDA for our Phase 1B/2 clinical trial evaluating Annamycin in combination with Cytarabine (also known as “Ara-C” and for which the combination of Annamycin and Ara-C is referred to as AnnAraC) for the treatment of subjects with AML as both first line therapy and for subjects who are refractory to or relapsed after induction therapy (MB-106).

Based upon the FDA minutes, we designed and began implementation of a Phase 2B/3 pivotal trial for the treatment of AML patients who are refractory to or relapsed after induction therapy.

This MIRACLE trial will be a global trial, including sites in the US, Europe, Western Asia and the Middle East.

The MIRACLE study is a Phase 2B/3 clinical trial whereby data from the 2B portion will be combined with the Phase 3 portion.

This trial is more fully discussed below.

A Phase 1 clinical trial of Annamycin as a single agent for the treatment of R/R AML in the US was successfully completed in 2020.

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.

Our Independent Expert, as discussed above, noted that after review of the data for the subjects in this trial there were no signs of cardiotoxicity.

Our independent Expert, an oncologist who specializes in cardiotoxicity of anthracyclines at the Cleveland Clinic, noted that after review of the data for the subjects in this trial there were no signs of cardiotoxicity.

As a result of discussions with the FDA after MB-104, 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.

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A total of 20 subjects were enrolled in this trial.

Significant adverse events (AE’s) > grade 3 in this trial (n=20) were:

Per the CSR, drug related serious adverse events significant adverse events (AE’s) > grade 3 in this trial (n=20) were:

neutropenia 80%, thrombocytopenia 75%, anemia 75%, febrile neutropenia 30%, and pancytopenia 10%.

Drug related serious adverse events (SAE’s) were:

thrombocytopenia and anemia 25% each, febrile neutropenia 20%, neutropenia 10%, and mucosal inflammation, neutropenic infection, hepatocellular injury, hypotension, hepatotoxicity, sepsis and infusion related reaction 5% each.

Additionally, our Expert noted that after review of the data for the nineteen of the twenty subjects in this trial there were no signs of cardiotoxicity.

neutropenia 65%, thrombocytopenia 50%, anemia 40%, febrile neutropenia 30%, pancytopenia 10%, and leukopenia, hepatocellular injury, hepatotoxicity, anaphylactic reaction, sepsis, and hypotension 5% each.

Additionally, our Expert noted that after review of the data for nineteen of the twenty subjects in this trial there were no signs of cardiotoxicity.

One subject who received a partial dose of Annamycin and left the trial had no post-treatment evaluations performed.

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However, in two of the PRs, as noted by the site, subjects' bone marrow blast counts were successfully decreased to below 5%, however these subjects were still designated as a PR by the sub-investigator at that site.

We include these subjects as CRis since their results met the definition of CRi per the protocol and thus believe that a CRi rate of 60% would be more accurate.

As a part of our ongoing sponsored research at MD Anderson, animal testing 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.

As a part of our ongoing sponsored research at MD Anderson, animal testing indicated that the combination of Annamycin with Ara-C 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.

For animals treated with AnnAraC, median survival ranged from 56 to 76 days.

Additionally, when looking at median 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 supported initiation of clinical development of the combination of Annamycin and Ara-C in AML patients.

This combination was achieved via a promising advancement in lipid enabled drug delivery developed in collaboration with and exclusively licensed from MD Anderson.

The unique patented lipid composition allows us to combine a new concept in chemotherapeutic agents within a lipid structure that helps target the delivery of the payload and reduce the potential for toxicity.

In the case of Annamycin, our unique use of lipid technology enables improved tissue/organ distribution and, as demonstrated in multiple clinical trials, dramatically reduced toxicity, including avoiding cardiotoxicity.

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Beyond that, we believed 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 currently limiting the use of anthracycline-based intensive chemotherapy.

Thus, we began focusing our efforts on a clinical trial studying AnnAraC for the treatment of AML in Europe.

On May 2, 2023, we announced successful completion of the first cohort in our Phase 1B portion of our Phase 1B/2 clinical trial using Annamycin in combination with Cytarabine for the treatment of AML.

This study is utilizing a “5+3” regimen where Annamycin is administered with three days of infusion along with the five days of infusion of Cytarabine.

Thus, we focused our efforts on a clinical trial studying AnnAraC for the treatment of AML in Europe.

Below in Table 2 is a summary of the preliminary responses in the MB-106 combination therapy trial to date.

Table 2 - Summary of Annamycin Responses in MB-106 AML Studies as of March 1, 2025

Study MB-106 Combination Therapy – Phase 1B/2 All Lines (Range As 1 st -7 th Line)

Study MB-106Combination Therapy – Phase 1B/2 (As 2 nd & 3 rd Line)

Study MB-106Combination Therapy – Phase 1B/2 (As 2 nd Line Only)

Ara-C + Annamycin "5+3"

Ara-C + Annamycin “ 5+3"

Subjects Evaluable Not Dosed Per Protocol

Median Age - Years (Range)

Complete Responses

CR with incomplete recovery (CRi)

Total Complete Response(s)

Partial Responses (PRs)

Durability of CRc’s to date (mos)

Median OS to date (mos)

Notes for Table 2 :

1) Data from MB-106 is for intent to Treat subjects;

2) Data from MB-106 is preliminary and subject to change;

3) Durability and OS are developing;

and, 4) Durability is measured from the date of CR assessed to relapse date or date of the last update to the database.

In May 2023, we announced successful completion of the first cohort in our Phase 1B portion of our Phase 1B/2 clinical trial using Annamycin in combination with Cytarabine for the treatment of AML.

This study utilized a “5+3” regimen where Annamycin is administered with three days of infusion along with the five days of infusion of Cytarabine.

As we noted, this combination strategy is similar to the familiar “7+3” induction therapy that is considered to be a standard of care in AML, where seven days of Cytarabine infusions are paired with three days of an approved anthracycline (typically, daunorubicin).

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Annamycin was dosed at 190 mg/m 2 , along with Cytarabine at 2.0 g/m 2 /day for five days (total dose of 10g/m 2 ).

The median number of prior therapies for these three subjects in the first cohort was five (range of one to six).

One subject, who was 78 years of age at the time of the study initiation and enrolled after a single prior multi-year therapy, achieved a CR that has continued to be durable at 12 months.

This subject has received a second and recently a third course of treatment, during the ensuing 11 months, at the direction of the treating physician.

This subject has not experienced a relapse to date.

The other two subjects were shown to have disease progression.

At the recommendation of the safety review committee, we deemed the first cohort dose as safe and opened the second cohort with the Annamycin dose being increased to 230 mg/m 2 .

On August 7, 2023, we successfully completed the second cohort at 230 mg/m 2 of Annamycin in this combination study.

In August 2023, we successfully completed the second cohort at 230 mg/m 2 of Annamycin in this combination study.

Four subjects were treated in this cohort, one is believed to be relapsed from one or more prior therapies and three are believed to be refractory to up to three prior therapies.

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At the recommendation of the safety review committee, we deemed the second cohort dose as safe and as the recommended expansion phase dose and opened recruitment, including for both first line therapy and for subjects who are refractory to or relapsed after induction therapy, to the Phase 2 portion of the trial.

The median number of prior therapies for the three evaluable subjects in the second cohort was two (range of one to three) and the median age was 67.

One subject, who was 64 years of age at the time of enrollment into the study with one prior therapy, was deemed a CR (complete response), which was shown to be durable at approximately three months, at which point the subject proceeded to a bone marrow transplant.

The other two subjects were shown to have disease progression.

On October 2, 2023, we announced the initial subjects had been treated in the Phase 2 portion of MB-106.

To date, 20 subjects have been enrolled in the full MB-106 Phase 1B/2 study.

At the end of January 2024, we completed recruiting the desired number of 2 nd line subjects and began preparation for an End of Phase 2 (EoP2) meeting with the FDA.

In addition, we expanded the MB-106 study protocol to include 1st line subjects to provide data to enable the designing of a potential confirmatory Phase 3 post-approval study, however we do not expect the addition of this cohort to delay our EoP2 meeting.

At the end of January 2024, we completed recruiting the desired number of 2 nd line subjects and began preparation for an End of Phase 2 meeting with the FDA.

In addition, we expanded the MB-106 study protocol to include 1st line subjects to provide data to enable the designing of a potential confirmatory Phase 3 post-approval study.

Our current planned pathway for approval for Annamycin in combination with Cytarabine for the treatment of AML is as a 2 nd line therapy.

Therefore, our focus is primarily on securing an accelerated approval pathway for the treatment of 2 nd line subjects (those who were relapsed from or refractory to a 1st line AML therapy, regardless of whether the subject was deemed “fit” or “unfit”).

As mentioned previously, the MB -106 clinical trial with Annamycin in combination with Cytarabine for the treatment of AML is an “all-comers” (as discussed above) trial, accepting subjects with a wide range of prior therapies.

The total subjects recruited to date is 20 where one first-line subject just began treatment and another third-line subject has not yet been fully evaluated.

Currently, we have a composite complete response (CRc) rate of 39% in all evaluable subjects (n= 18).

This is comprised of a CR rate of 33% and CRi rate of 6%.

We believe that the most important subgroup in this trial to be subjects for whom AnnAraC is their 2 nd line of therapy.

When stratified for that population (n=10), the CRc rate is 60% being comprised of a CR rate of 50% and a CRi rate of 10%.

The 19 th subject, being treated as a 3 rd line therapy, had two BMAs that were inconclusive, and we are awaiting further testing.

This subject will move the CRc for the full trial to either 42% or 37% (n=19), depending on the final assessment of the BMA.

Durability data are developing wi th one CR having relapsed to date with 4.5 months of durability.

T he first CR subject was treated in February 2023 and remains durable to date.

Durability of CRc's is confirmed by repeat bone marrow aspirates (BMAs).

The median age of all subjects recruited is 69, ra nging from 19 to 78.

This trial may enroll up to 28 subjects with recruitment for subjects as 2 nd line therapy having ended in January 2024.

The trial continues recruitment for treatment as 1 st line and 3 rd line therapy.

The first CR subject was treated in February of 2023 and has not relapsed to date, having received a third course of AnnAraC in February 2024.

One CR has relapsed to date as noted in Table 2 above.

The relapse occurred at the same study site where a subsequent review of the anti-microbial standard of care for patients during the peri-chemotherapy infusion period was not consistent with the standard of care recommended by the leading medical organizations.

This site also had a significantly greater rate of infections than was reported at the other study sites.

These infections precluded the use of an additional course of chemotherapy, which has been utilized in most patients who have achieved a durable CR or CRi at the other MB-106 study sites.

We believe that this lack of additional courses of AnnAraC may (and we stress "may") have contributed to the only relapse in MB-106 following a CR and the only death to a CRi subject to date.

The death was not deemed disease progression and occurred after a series of infections.

This subject was scheduled for a BMT.

We have also begun recruiting 1 st line subjects into this trial to provide data for a possible future confirmatory Phase 3 clinical trial in 1 st line patients.

The first two subjects for whom AnnAraC was considered 1 st line therapy have been treated, and upon evaluation it was determined that the treatment resulted in a CR for one of the subjects.

The other subject was deemed a treatment failure, withdrew from our study, received a different therapy, and subsequently expired.

Currently, the median age of the recruited subjects in MB- 106 is 69 years (range of age is 19 to 78 years) with a median number of prior therapies for AML of 1 (range of 0 to 6).

The trial has recruited 20 subjects to date with 2 (1 from the 2 nd line of therapy population) subjects withdrawing from the trial due to adverse events and 1 other subject not yet having a bone marrow aspirate fully evaluable.

We may recruit up to 28 subjects in the Phase 1B/2 clinical trial, however, having already recruited the desired number of 2 nd line subjects to support our EoP2 meeting with the FDA, we may elect to complete this trial with fewer than 28 subjects.

At our current rate of progress, we expect to conclude the trial and report topline data in 1H 2024.

There continues to be no evidence of cardiotoxicity as reported by an independent Expert’s reports following assessments of 4 su bjects' data from this trial (included in the Expert evaluations of 63 subjects from all our Annamycin clinical trials).

The balance of the subjects in the trial will be reviewed by the Independent Expert in the near future.

Later in 2024, we closed all recruitment.

We continue to follow subjects that remain in the study for OS and durability of CR/CRc’s, as well as safety data.

As mentioned previously, the Phase 1b portion of the MB-106 clinical trial with Annamycin in combination with Cytarabine for the treatment of AML was an “all-comers” (as discussed above) trial, accepting subjects with a wide range of prior therapies.

The Phase 2 portion was open to being 1 st thru 3 rd line of therapy.

The total subjects recruited was 22.

The results of the trial to date are shown in Table 2 above.

These data are preliminary and subject to change once the CSR is published.

No evidence of cardiotoxicity was noted by the Expert following assessments of the MB-106 data.

In all subjects enrolled to date (n=22) in MB-106 adverse events (Grade < 3) are as follows:

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the second adverse event was due to an allergic reaction to cytarabine.

The CR/CRis have been spread across 3 different sites in two different countries (Poland and Italy) and 7 out of 9 sites participating in the study have recruited subjects to date.

We have been and intend to continue reporting top-line results in all of our clinical trials on a quarterly basis or when a recruiting or regulatory milestone is achieved.

Top-line results will include reporting of any drug-related adverse events (AEs) and assessment of cardiotoxicity, as described above.

Top-line results will also include the number of partial responses (PRs) and complete responses (CRs), 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, and a PR means the subject's BMA reduced by 50% and resulted in a blast count of 25% or less.

The strategy to begin the next AML study, which we intend to be a pivotal study, is to approach the FDA or its foreign equivalent for Annamycin to be a 2 nd line therapy and design an accelerated approval pivotal trial, with a follow-on confirmatory Phase 3 trial.

As mentioned above, we have now concluded the recruitment of subjects for 2 nd line treatment in MB-106, enabling evaluation of the necessary data for submission to the regulatory authorities as support for such a trial.

The data above regarding human activity are all from our studies and are preliminary and subject to change, unless a clinical study report (CSR) has been published or the investigator-initiated study has concluded and issued its annual report.

“Right-to-try” data are preliminary until published.

Such activity may or may not be repeated in future clinical trials, including potentially pivotal and/or confirmatory clinical trials.

While we believe such data are encouraging, the FDA or its foreign counterpart will ultimately determine if such data and future data are individually conclusive and supports future clinical trials or approval.

Annamycin Clinical Trials – STS Lung Metastases

The CR/CRc’s have been spread across 4 different sites in two different countries (Poland and Italy) and 7 out of 9 sites participating in the study have recruited subjects to date.

We believe the FDA minutes, reflect a positive discussion and the meeting resulted in the design and implementation of a Phase 2B/3 pivotal trial for the treatment of AML patients who are refractory to or relapsed after induction therapy.

This MIRACLE trial will be a global trial, including sites in the US, Europe, Western Asia and the Middle East.

The FDA’s Divisions of Hematologic Malignancies I and Cardiology and Nephrology, as well as related divisions, were involved in the review of the data showing no cardiotoxicity in MB-106.

Consistent with the FDA’s recommendations, in the adaptive MIRACLE trial we plan to utilize a double-blind, placebo-controlled design, where we will compare AnnAraC versus the control arm of high dose cytarabine (HiDAC) plus placebo and we will rely solely on CR (complete remission) at approximately one month as the primary endpoint.

The FDA also wanted to see the durability of response (DoR) and overall survival as secondary endpoints, as well as data for patients beyond 2nd line, which is why our plan includes a follow-on MIRACLE2 trial in 3rd line patients starting once the optimum dose is established in the MIRACLE trial.

Based on our discussions with the FDA, we amended in November 2024 our MB-104 investigational new drug application or IND for MB-108.

In the amendment with the new MIRACLE protocol, the trial will allow, for the first time in the US for AML subjects, dosing above the lifetime maximum allowable dose for currently prescribed anthracyclines.

Subsequently, in February 2025 we received FDA feedback and guidance on our IND amendment, noted above, that allowed a reduction in the size of our Phase 3 pivotal trial protocol to 220.

With their feedback and our response, all the major aspects of the trial remain unchanged.

Guidance from FDA included a recommendation to alter the statistical plan that reduced the initially proposed size of Part B of our trial by approximately 10%.

Moreover, the nature of the feedback helps us move forward quickly to open sites in the US, in addition to the non-US sites we are expecting to open.

Any reduction in recruitment helps to shorten the time to completion of the trial.

On February 3, 2025, and February 27, 2025, we received additional comments and information requests from the FDA about the amended IND.

We believe that we addressed those issues in our responses on February 17, 2025 and March 6, 2025, respectively.

On March 14, 2025, we received an additional information request, with a requested response date of March 28, 2025.

We cannot be assured that our responses will be adequate for the FDA to continue to allow the amended IND to proceed, or that there will not be additional requests for information.

Because we are amending an existing IND, there is no required time for the FDA to respond to our submissions, but neither is a response required for us to proceed with the MIRACLE trial.

As with all clinical trials, if at any time the FDA believes there is a safety issue that merits it, the agency may put the MIRACLE trial on clinical hold.

The amended protocol allows for the unblinding of preliminary primary efficacy data (Complete Remission or CR) and safety/tolerability of the three arms at 45 subjects, in addition to the conclusion of Part A (at 75 to 90 subjects).

This early unblinding will yield 30 subjects having received Annamycin (190 mg/m2 and 230 mg/m2) and HiDAC and 15 subjects receiving HiDAC plus placebo.

The Company expects to reach the first unblinding (45 subjects) in the second half of 2025, in addition to the second unblinding, which is expected in the first half of 2026.

This accelerated estimated timeline is due to the positive response the Company received in meetings during December with potential investigators regarding recruitment for the trial.

For Part B of the trial, approximately 220 additional subjects will be randomized to receive either HiDAC plus placebo or HiDAC plus the optimum dose of Annamycin (randomized 1:1).

The selection of the optimum dose will be based on the overall balance of safety, pharmacokinetics and efficacy, consistent with the FDA’s new Project Optimus initiative.

Data from the control arm and the optimum dose of Annamycin in the Phase 2B portion of the trial will be combined with the data for the Phase 3 portion of the trial in determining efficacy and safety.

The Organotropic Nature of Annamycin

Nonclinical research at MD Anderson has demonstrated that Annamycin has an organotropic nature enabling it to hyperaccumulate in certain key organs, including the liver, spleen, pancreas and lungs as compared with existing anthracyclines such as doxorubicin.

This could prove to be especially valuable for primary tumors in or tumors that eventually metastasize to these organs.

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

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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 had suggested a possible significant therapeutic benefit of Annamycin against metastatic osteosarcoma.

In February 2021, we also announced that a preclinical study in animals had 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.

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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.

Annamycin Clinical Trials – STS Lung Metastases

It is estimated that there are approximately 36,000 new cases of STS in the seven major markets (US, EU5 and Japan) each year.

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Although the lungs tend to be a major site of relapse, when we began our own clinical trial MB-107 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.

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Subjects who had stable disease at the time of study discontinuation will continue to be followed for progression free response and overall survival.

In the Phase 1B portion of the trial, subjects were treated from 210 mg/m 2 to 390 mg/m 2 in a single dose of Annamycin.

In the Phase 2 portion of the trial, an exploratory RP2D of 360 mg/m 2 was initiated for the first 3 subjects and a final RP2D of 330 mg/m 2 was determined and 15 subjects were treated.

All subjects had pulmonary metastases from soft tissue sarcoma and at least one prior therapy.

There was no limit on how many prior therapies a subject could have prior to entering this study.

Most subjects were heavily treated with other therapies prior to entering our trial with our treatment representing the fourth median therapy for all subjects in the Phase 1B and Phase 2 portion of the trial (range of two to twelve ).

As of March 1,2024, as reported by the investigation sites, nine subjects in Phase 2 are alive whose OS is currently below the Phase 2 median OS, so OS data are not available at this time for that phase.

Below in Table 3 is a summary of progression free survival for evaluable subjects, as discussed further below, by groupings and median overall survival for all subjects evaluable in Phase 1B:

MB-107 Summary as of March 1, 2024

Progression Free Survival Months (mos)

Phase 1B All Subjects

Phase 2 All Subjects

All Subjects Treated at < 330 mg/m 2

All Subjects with 2 or Fewer Prior Therapies ( < 2PT)

All Subjects < 330 mg/m 2 & < 2PT

Median O/S mos

Overall survival (OS);

Not available for Phase 2 subjects at this time, as data continues to develop (N/A)

In the Phase 1B portion of the trial, subjects were treated from 210 mg/m 2 to 390 mg/m 2 .

In the Phase 2 portion of the trial, an exploratory RP2D of 360 mg/m 2 was initiated for the first 3 subjects and a final RP2D of 330 mg/m 2 was determined and 15 subjects were treated.

Including the 3 subjects treated at the same dose in the Phase 1B portion of this trial, this equates to seventeen total subjects measurable for efficacy at the 330 mg/m 2 dose level.

Including all measurable subjects at all dose levels in the Phase 1B portion of the trial, thirty-two subjects were treated with at least one cycle in this study and twenty-seven received at least two cycles of treatment.

For the Phase 2 subjects, the median time to entering the MB-107 trial from the time of initial diagnosis is estimated, based on clinical data to date, to be approximately 20 months, and these subjects have been mostly heavily treated previously for STS lung mets prior to entering our study.

Once all data are collected, we plan a more in-depth presentation of the topline data for this study in 2024.

Based on the data as shown in Table 3 above, we believe the following observations are in order:

Very few trials for subjects with such advanced (median = 20 months from initial diagnosis;

all with lung metastases in MB-107) disease progression have been published, making comparisons to historical performance difficult.

With this in mind, median OS for subjects in the Phase 1B portion of this study is currently at 11.3 months, which we believe is notable based on current literature.

Overall median PFS for the trial is 2.3 months (range 1.2 to 6.9 months) with seven subjects discontinuing early due to thrombocytopenia.

Five of these subjects negatively impacted this median PFS, which we believe was exacerbated by the extreme advanced stage of the patients and their being weakened by prior therapies.

Median PFS improved to 3.1 months for lower doses of Annamycin ( ≤ 330 mg/m 2 ) versus the maximum dose used in the trial and for subjects who had fewer prior therapies or PT ( < 2).

These data suggest to us that Annamycin may be best positioned as a first line alternative to the current standard of care with an anthracycline and where an anticipated combination of high patient response rate, significant improvement in OS and the absence of cardiotoxicity may improve patient outcomes.

The data above regarding human activity are all from our studies and are preliminary and subject to change, unless a CSR has been published or the investigator-initiated study has concluded and issued its annual report.

“Right-to-try” data are preliminary until published.

Such activity may or may not be repeated in future clinical trials, including potentially pivotal and/or confirmatory clinical trials.

Most subjects were heavily treated with other therapies prior to entering our trial with our treatment representing the seventh median therapy for all subjects in the Phase 1B and Phase 2 portion of the trial (range of two to twelve).

A total of 36 subjects, 19 and 17 subjects for Phase 1B and Phase 2 portions of the study respectively, were recruited for MB-107.

In the first quarter of 2025, we completed the CSR for MB-107 as median OS had been reached in 2024.

We anticipate announcing these results by the end of April.

IIT STS Lung Mets or Rutkowski Trial NIO-0002 :

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The grant-funded clinical trial is led by Prof.

Piotr Rutkowski, MD, PhD, Head of Department of Soft Tissue/Bone Sarcoma and Melanoma at MSCNRIO, and it will be operated independently of our study in the US.

The trial has 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.

Six subjects have been enrolled and treated to date (three in cohort 1 at 35 mg/m2;

three in Cohort 2 at 60 mg/m2)).

A DLT was noted.

The cohort was expanded and a fourth subject in Cohort 2 has been identified, consented in February 2024 and is currently in screening.

The preliminary data to date is 50% (3 of 6) have received greater than two cycles (approximately 2 months) of therapy where we have assumed stable disease (SD) through two cycles.

One of these three subjects has initiated cycle 5 (with us assuming SD through four cycles).

This is all based on a preliminary data from the IIT dosing tracker.

Piotr Rutkowski, MD, PhD, Head of Department of Soft Tissue/Bone Sarcoma and Melanoma at MSCNRIO, and it is operated independently of our study in the US.

Recruitment in this trial has closed and subjects are being followed for safety and efficacy data.

This trial began dosing subjects in late 2022 with 8 subjects across 2 dose cohorts enrolled.

The trial had a dosing regimen of once per week rather than once every 21 days as in the US trial (three in cohort 1 at 35 mg/m2;

five in Cohort 2 at 60 mg/m2)).

The preliminary data to date are 63% (5 of 8) have received greater at least two cycles (approximately 2 months) of therapy where we have assumed stable disease (SD) through two cycles and 38% (3 of 8) subjects received 4 cycles (with us assuming SD through four cycles).

This is based on a preliminary data.

The data are preliminary and subject to change.

Previously, this trial was facilitated by WPD Pharmaceuticals (WPD), based in Poland.

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 its sublicense.

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.

The WP1066 Portfolio Program

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molecules targeting the modulation of key oncogenic transcription factors.

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.

In 2019, the FDA granted ODD for WP1066 for the treatment of glioblastoma, which means the agency believes, in part, that 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), represents a novel class of agents capable of hitting multiple targets, including the activated form of a key oncogenic transcription factor, STAT3.

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

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

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

The third cohort dosing was deemed safe at 8mg/kg.

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The WP1122 Portfolio Program

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.

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

These new compounds are 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 stop the fuel supply of tumors by taking advantage of their high level of dependence on glucose in comparison to healthy cells.

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Additionally, based on independent preclinical data, we believe this technology has the potential to impact hard to treat viruses that also rely heavily on glycolysis and glycosylation.

Due to the COVID-19 pandemic, we looked to establish a RP2D for WP1122 in a Phase 1 clinical trial and certain countries had established accelerated COVID-19 focused programs for Phase 1 trials such as the United Kingdom.

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 the 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.

This was followed by a Phase 3 study and an approval in May 2021, by Drugs Controller General India (DCGI) for emergency use of 2-DG as an adjunct therapy in subjects with moderate to severe 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 Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom 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 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.

Due to the COVID-19 pandemic, we established a recommended Phase 2 dose for WP1122 in a Phase 1 clinical in the United Kingdom.

Clinical Trial with WP1122

In 2021, we received authorization from the MHRA to commence a Phase 1a clinical trial of WP1122 in the United Kingdom.

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.

In 2022, we determined with the data from the Phase 1a trial 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.

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Potential Clinical Trial for GBM with WP1122

On December 1, 2021, we announced that the FDA allowed our IND application to study WP1122 for the treatment of GBM to go forward.

In 2021, we announced that the FDA allowed our IND application to study WP1122 for the treatment of GBM to go forward.

With this IND cleared, we seek a partner to conduct an externally funded Phase 1 open label, single arm, dose escalation study of the safety, pharmacokinetics, and efficacy of oral WP1122 in adult subjects with GBM.

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Working Environment

Our headquarters and laboratory are in Houston, Texas, and our workforce, as of year-end 2023, consisted of eighteen full and part-time employees, in the US which are leveraged with other service providers and contractors worldwide working in a primarily virtual environment.

Our headquarters and laboratory are in Houston, Texas, and our workforce, as of year-end 2024, consisted of 17 full and part-time employees, in the US which are leveraged with other service providers and contractors worldwide working in a primarily virtual environment.

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

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In the event of prolonged business interruptions due to geopolitical events, we could incur significant losses, require substantial recovery time and experience significant expenditures in order to resume our business or clinical operations.

While having operations in neighboring Poland, we have no operations directly in Russia or Ukraine, but we do not and cannot know if the current uncertainties in these geopolitical areas, which are unfolding in real-time, will escalate and result in broad economic and security conditions or rationing of medical supplies or production facilities, which could limit our ability to conduct clinical trials or result in material implications for our business.

While having operations in neighboring Poland, we have no operations directly in Russia.

However, we do plan to have some of our MIRACLE trial treat subjects in Ukraine in 2025.

We do not and cannot know if the current uncertainties in these geopolitical areas, which are unfolding in real-time, will escalate and result in broad economic and security conditions or rationing of medical supplies or production facilities, which could limit our ability to conduct clinical trials or result in material implications for our business.

In addition, our insurance policies typically contain a war exclusion of some description, and we do not know how our insurers are likely to respond in the event of a loss alleged to have been caused by geopolitical uncertainties.

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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.

We have obtained worldwide, exclusive licenses or options to license 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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Where MD Anderson jointly owns patent applications with us, we are responsible for prosecution and maintenance of those patents and patent applications at our expense.

If we choose to not prosecute or maintain patents in certain geographical areas, MD Anderson has the right to pursue those rights separate from us.

To date, no geographical areas in which we have chosen to not prosecute or maintain such patents have been pursued to date separately from us by MD Anderson.

As new discoveries arise with respect to our drug candidates, we and MD Anderson seek to protect our rights to those inventions by filing new patent applications.

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

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, 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.

On April 9, 2024, the United States Patent and Trademark Office (USPTO) issued U.S.

Patent number 11,951,118 titled, “ Preparation of Preliposomal Annamycin Lyophilizate ” (the ‘118 patent’) to Moleculin and The University of Texas System Board of Regents.

Additionally on May 14, 2024, the USPTO issued an additional patent (U.S.

Patent number 11,980,634) titled “ Method of Reconstituting Liposomal Annamycin ” (the ‘634 patent’).

We have global, exclusive licenses MD Anderson’s interests to both patents.

The ‘118 patent provides claims to compositions that contain Annamycin, and the ‘634 patent provides claims to liposomal Annamycin suspension compositions, both with a base patent term extending until June 2040, subject to extension to account for time required to fulfill regulatory requirements for FDA approval.

Moleculin’s novel candidate for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma lung metastases (STS lung mets) uses a unique lipid-based delivery technology.

In addition to the issued ‘118 and expected ‘634 U.S.

patents, we have additional patent applications pending in the US and in major jurisdictions worldwide.

p-STAT3 Inhibitors

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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, China, Europe, Israel, India, Japan and South Korea.

Foreign counterparts to the US patents are issued outside the US including in Europe.

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

We have rights to three issued US patents which claim compositions of WP1220, as well as foreign counterparts issued in China, Eurasia, Europe, Japan, Mexico, New Zealand, Singapore and Ukraine.

We have rights to three issued US patents which claim compositions of WP1220, as well as foreign counterparts.

These patents have an international filing date in June 2009.

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We have rights to an issued US patent with claims to compositions of WP1122 and methods for treating cancer using WP1122, with an international filing date in June 2009.

We also have rights to foreign counterparts issued in China, Europe, and Japan.

We also have rights to foreign counterparts.

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.

In an effort to reduce costs, we are in the process of replacing our licenses on WP1122 with an option on WP1122 with MD Anderson.

Such discussions are being held in conjunction with extending our sponsored research with MD Anderson.

There can be no assurance that this process will result in our satisfaction.

FDA Designations

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Overview of The Market for Our Oncology Drugs

The American Cancer Society (https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2024-cancer-facts-figures.ht ml) estimates that cancer continues to be the second most common cause of death in the US, after heart disease.

The American Cancer Society (https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2025-cancer-facts-figures.html ) estimates that cancer continues to be the second most common cause of death in the US, after heart disease.

A total of 2.0 million new cancer cases and 618,120 deaths from cancer are expected to occur in the US in 2025 , which is about 1,693 d eaths a day.

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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, world-wide annual revenues generated from anthracyclines have been estimated to approximate $1 billion .

The approved anthracyclines most commonly used are daunorubicin and doxorubicin and world-wide annual revenues, mostly generic, generated from anthracyclines were estimated in 2023 to approximate $1.3 billion (https://www.globenewswire.com/news-release/2025/01/13/3008751/28124/en/Liposomal-Doxorubicin-Market-Research-and-Forecast-Report-2024-2032-Growing-Investments-and-Collaborations-Personalised-Medicine-Trends-Market-Penetration-inEmergingEconomies.html#:~:text=The%20global%20liposomal%20doxorubicin%20market,USD%202%20billion%20by% 202032.) and is expected to grow to $2 billion by 2032.

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

One industry report estimates that annual drug revenues generated from the demand for AML-related therapies in the United States, United Kingdom, France, Germany, Italy and Spain were in the range of $153 million in 2016, and it is estimated that this number is increasing with the increase in approved AML treatments – estimated to rise to $1.6 billion by 2025.

Of this worldwide amount, the US market is estimated to comprise the largest sha re.

Leukemia is a cancer of the white blood cells and acute forms of leukemia can manifest quickly and leave patients with limited treatment options.

AML is the most common type of acute leukemia in adults.

It occurs when a clone of leukemic progenitor white blood cells proliferates in the bone marrow, suppressing the production of normal blood cells.

Currently, the only viable option for acute leukemia patients is a bone marrow transplant, also known as a hematopoietic stem cell transplant, which is successful in a significant number of patients.

However, in order to qualify for a bone marrow transplant, the patient’s leukemia cells must be decreased to a sufficiently low level.

This usually begins with a therapy referred to as “7+3,” which consists of combining seven injections of Cytarabine with 3 infusions of an anthracycline to induce remission (a complete response, or “CR”).

This therapy had not improved since it was first used in the 1970s and we estimate that this induction therapy had a success rate of about 20% to 25%.

A revision to this therapy was approved in the form of a drug called Vyxeos, which combines Cytarabine and an anthracycline (daunorubicin) into a single liposomal injection given 3 times.

This improvement appears to have increased the level of CRs to 34% and the overall survival by 3.5 months.

Unfortunately, the current clinically approved anthracyclines (including Vyxeos) are cardiotoxic (i.e., can damage the heart), which can limit the dosage amount that may be administered to patients.

Additionally, the tumor cells often present de novo or develop resistance to the first-line anthracycline, through what is called “multidrug resistance,” enabling the tumor cells to purge themselves of the available anthracyclines.

Consequently, in the majority of these patients there remains no effective therapy for inducing remission sufficient to enable a potentially curative bone marrow transplant and unfortunately most patients will succumb quickly to their leukemia.

If a patient’s leukemia reappears before they can be prepared for a bone marrow transplant, they are considered to have “relapsed.” If a patient fails to achieve a sufficient response from the induction therapy to qualify for a bone marrow transplant, they are considered to be “refractory” (resistant to therapy).

Until more recent new drug approvals, palliative care or focus on overall survival versus curative treatment was the predominant treatment modality for patients not suitable for traditional chemotherapy.

In 2019, AbbVie’s Venclexta was 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 (Un-Fit) for intensive induction chemotherapy due to co-existing medical conditions.

In addition, 5 different targeted therapies have been approved in the U.S.

for treatment of relapsed or refractory (2 nd Line) AML patients.

Despite these advancements, we believe approximately 60% of AML patients will either not qualify for or will not succeed with these available treatments, leaving a significant unmet need.

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.

Of this worldwide amount, the US market is estimated to comprise the largest share.

We believe that pursuing approval as a second line induction therapy for adult relapsed or refractory AML patients is the shortest path to regulatory approval, but we also believe that one of the most important potential uses of Annamycin is in the treatment of children with either AML or ALL (acute lymphoblastic leukemia, which is more common in children).

Accordingly, we also intend to pursue approval for pediatric use in these conditions when practicable.

Soft tissue sarcoma is a broad term for cancers that start in soft tissues (muscle, tendons, fat, lymph and blood vessels, and nerves).

Soft tissue sarcoma is a broad term for cancers that start in soft tissues (muscle, tendons, fat, bone, lymph and blood vessels, and nerves).

These cancers can develop anywhere in the body but are found mostly in the arms, legs, chest, and abdomen.

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

We believe that the market size of STS with lung metastases in the seven major markets is expected to rise from $177 million in 2017 to reach $198 million by 2030.

According to our estimates, the highest market size of STS with lung metastases was estimated in the United States, followed by Germany.

We believe that the market size of STS globally was $1.58 billion in 2024 and is expected to grow to $2.57 billion by 2030.

According to our estimates, the highest market size of STS with lung metastases was estimated in the United States, followed by Germany (https://finance.yahoo.com/news/2025-research-soft-tissue-sarcoma-124900301.html).

The market of STS with lung metastases is categorized into first-line and second-line therapies.

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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 became 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.

Market for Our WP1066 (STAT3) Portfolio

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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.

CTCL is a neoplastic transformation of T-lymphocytes and most often occurs between the ages of 40 and 60.

Unlike other forms of non-Hodgkin lymphoma, CTCL is initially manifested as skin lesions (mycosis fungoides "MF"), but later stages involve lymph nodes, circulating tumor cells in the blood, as well as viscera.

MF is considered a low-grade cutaneous lymphoma which we estimate accounts for more than half of primary CTCLs.

Early-stage MF (Stages I and II;

~70% of subjects) is generally treated with skin-directed treatments (topical therapy) using systemic drugs that do not have significant side effects as secondary treatments.

Advanced-stage MF requires more aggressive (systemic) therapies due to more extensive involvement of tissues and organs.

Treatment is based mainly on a recently published European Organization for Research and Treatment of Cancer (EORTC) guideline.

A consensus guideline for clinical endpoints and response criteria to be incorporated into clinical trials was published.

However due to the rarity of this disease, it has been difficult to perform randomized studies.

There is currently no cure for this disease.

The incidence of CTCL is approximately 16,000 worldwide in 2020 (US + EU 48%) and estimated to be growing to 18,000 by 2026.

Asia has the highest incidence (38%).

Prevalence is estimated to be 42,000 in US & EU growing to 45,000 with prevalence in Japan growing to a total of 49,000 by 2026.

Since this is a chronic disease, we believe introduction of a new topical therapy that is more effective and less toxic than currently available topical drugs (if that is what is shown) would be important to this market.

The US market was estimated to represent $40 million in annual sales in 2020, yet consists of technologies that are as much as 40 years old.

Our WP1220 proof of concept trial for the treatment of CTCL was conducted in 5 subjects, including the treatment of a total of 11 lesions and concluded with a lesion objective response rate (ORR) of 45%, no adverse events and 55% stable disease, resulting in 100% clinical benefit.

60% of the subjects responded with a PR.

We believe that a significant unmet need remains for early stage (Stages IA through IIA) CTCL, and therefore, we believe a meaningful opportunity exists for WP1220.

Market for Our WP1122 Portfolio

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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.

We have a license or an option to all of our technology from MD Anderson, and we also sponsor research there as well.

In an effort to reduce costs, we are in the process of replacing our licenses on WP1122 with an option on WP1122 with MD Anderson.

Such discussions are being held in conjunction with extending our sponsored research with MD Anderson.

There can be no assurance that this process will result in our satisfaction.

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.

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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, 2023 and 2022, respectively.

Total expenses under these agreements we re $0.2 and $0.3 million, for the years ended December 31, 2024 and 2023, 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 2025.

We have a sponsored research agreement with MD Anderson that currently runs until the end of the first quarter of 2025 and is expected to be extended, however there can be no assurance that this effort will be successful.

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

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Soft-tissue sarcomas which have metastasized to the lungs are extremely difficult to treat.

There are an estimated 13,600 new cases of soft-tissue sarcoma diagnosed each year, and of those that metastasize, approximately 70% of metastases occur to the lungs.

The current standard of care consists of anthracycline therapy or newer-generation drugs such as pazopanib.

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Government Regulation

Government authorities at the federal, state and local level in the US, and in analogous levels in other countries extensively regulate, among other things, the development, testing, manufacture, quality control, safety, effectiveness, approval, labeling, packaging, storage, distribution, import, export, record-keeping, reporting, promotion, advertising, distribution, marketing and export and import of products such as those we are developing.

Government authorities at the federal, state and local level in the US, and in analogous levels in other countries extensively regulate products such as those we are developing, including the conditions under which such products are approved for use, their safety and effectiveness, and how they are developed, tested, manufactured, packaged and labeled, promoted, stored and distributed.

The pharmaceutical drug product candidates that we develop must be approved by the FDA before they may be marketed and commercially distributed in the US, and by regulators in other countries before being marketed and commercially distributed there.

In the United States, the FDA regulates pharmaceutical products such as our product candidates under the Federal Food, Drug, and Cosmetic Act and implementing regulations.

In the United States, the FDA regulates pharmaceutical products such as our product candidates under the Federal Food, Drug, and Cosmetic Act (FDCA) and implementing regulations.

Pharmaceutical products are also subject to other federal, state and local statutes and regulations.

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 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.

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, placing a clinical trial on hold, 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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Submission to the FDA of an Investigational New Drug application, or IND, which must become effective before human clinical trials may begin;

Performance of adequate and well-controlled human clinical trials according to the FDA’s regulations commonly referred to as good clinical practices (GCP) and any additional requirements for the protection of human research subjects and their health information, to establish the safety and efficacy of the proposed pharmaceutical product for its intended use;

Submission to the FDA of an NDA for marketing approval that includes substantial evidence of safety and effectiveness from results of clinical trials, as well as the results of preclinical testing, detailed information about the chemistry, manufacturing and controls, and proposed labeling and packaging for the product;

Performance of adequate and well-controlled human clinical trials according to the FDA’s regulations commonly referred to as good clinical practices (GCP) and additional requirements for the protection of human research subjects and their health information, to establish the safety and effectiveness of the proposed product;

Submission to the FDA of an NDA seeking marketing approval that includes substantial evidence of safety and effectiveness from results of clinical trials, as well as the results of preclinical testing, detailed information about the chemistry, manufacturing and controls, and proposed labeling and packaging for the product;

Review of the product candidate by an FDA advisory committee, if applicable;

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IND Application.

Clinical trials involve the administration of the product candidate to healthy volunteers or subjects with the targeted disease under the supervision of qualified investigators, generally physicians not employed by or under the clinical trial sponsor’s control.

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.

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Additionally, a manufacturer of an investigational drug for a serious disease or condition is required to make available, such as by posting on its website, its policy on evaluating and responding to requests for individual patient access to such investigational drug.

This requirement applies on the earlier of the first initiation of a Phase 2 or Phase 3 trial of the investigational drug or, as applicable, 15 days after the drug receives a designation as a breakthrough therapy, fast track product, or regenerative medicine advanced therapy.

NDA Submission and Review.

The results of product development, preclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the pharmaceutical product candidate, proposed labeling and other relevant information are submitted to the FDA as part of an NDA seeking approval to market the product.

Under the Prescription Drug User Fee Act (PDUFA), as amended, the submission of an NDA is subject to the payment of a substantial fee, although the fee may be waived under certain circumstances, which may or may not be applicable to us or our partners for any of our product candidates.

In addition, under the Pediatric Research Equity Act, as amended, an NDA or supplement to an NDA generally must contain data to assess the safety and effectiveness of the product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may grant deferrals for submission of data or full or partial waivers depending on the designated pathway for submission.

The submission of an NDA is subject to the payment of a substantial fee, although the fee may be waived under certain circumstances, which may or may not be applicable to us or our partners for any of our product candidates.

In addition, an NDA or supplement to an NDA generally must contain data to assess the safety and effectiveness of the product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may grant deferrals for submission of data or full or partial waivers in certain circumstances.

The FDA first examines a submitted NDA to determine if the application is sufficiently complete to be accepted for review.

If not, the agency may refuse to file the NDA, informing the sponsor of inadequacies to be addressed in a resubmitted application.

In this event, the NDA must be resubmitted with the additional information.

The resubmitted application also is subject to review before the FDA accepts it for filing.

Once an NDA is accepted for filing, the FDA begins an in-depth review of the application.

Pursuant to goals established under PDUFA, the FDA aims to complete the review within 10 months of the 60-day filing date, which would be within 12 months of the date of submission, but that deadline is extended in certain circumstances, including by FDA requests for additional information or clarification.

The resubmitted application is also subject to an initial review before the FDA accepts it for filing.

After accepting an NDA for filing, the FDA conducts an in-depth review of the application.

Pursuant to goals established in statute, the FDA aims to complete the review within 12 months of the date of NDA submission, but that deadline is extended in certain circumstances, including by FDA requests for additional information or clarification.

The FDA also has programs intended to expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical needs and/or provide benefits over existing therapies.

They include:

Priority Review, under which FDA aims to complete the NDA review within eight months of the date of submission;

Priority Review, under which the FDA aims to complete the NDA review within eight months of the submission;

Accelerated Approval, where a product may be approved on the basis of data demonstrating an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit;

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The FDA review of an NDA focuses on determining, among other things, whether the proposed product candidate is safe and effective for its intended use, and whether the product candidate is being manufactured in accordance with cGMP to assure and preserve the product candidate’s identity, strength, quality and purity.

The FDA may refer applications for novel pharmaceutical products or pharmaceutical products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

The FDA may refer certain applications to an advisory committee for a recommendation whether, and under what conditions, the application should be approved.

The FDA carefully considers an advisory committee’s recommendations, but is not bound by them.

The FDA may also determine that a risk evaluation and mitigation strategy (REMS) is necessary to assure the safe use of the product.

Among other things, a REMS can include restrictive conditions under which the product may be distributed, which may have a negative impact on the product’s commercial success.

A REMS may include restrictions on the conditions under which the product is distributed, which may have a negative impact on the product’s commercial success.

If the FDA concludes that a REMS is needed, the NDA sponsor must submit a proposed REMS, and the product will not be approved until FDA determines that the proposed REMS is adequate.

The FDA usually will inspect the facilities at which the product candidate is manufactured, and will not approve the product candidate unless the agency determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

The FDA usually inspects facilities at which the product candidate is manufactured, and will not approve the product candidate unless the agency determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving an NDA, the FDA will typically inspect one or more clinical trial sites to assure compliance with IND study requirements and GCP.

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The NDA review and approval process is lengthy and difficult, and may involve FDA requests for additional data or information, which may extend the process and/or lead the agency to refuse to approve the application.

This is the case even if requested data or information are submitted, because data are not always conclusive and the FDA may interpret data differently than the sponsor does.

If it decides not to approve an NDA, the FDA will issue a complete response letter, which usually describes the specific deficiencies in the NDA and may include recommended actions the applicant might take for the FDA to reconsider the application.

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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 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 the agency has instead continued 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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ependymoma, medulloblastoma, diffuse intrinsic pontine glioma, or atypical teratoid rhabdoid tumor, provided that related statutory sunset provisions are extended.

The federal Food, Drug and Cosmetic Act (FDCA) also provides for a grant of five-year exclusivity with approval of a product containing a new chemical entity (NCE), which generally means that the active moiety has never before been approved in any drug.

During this exclusivity period, which runs from the date of the product’s approval, FDA may not accept for filing any Abbreviated New Drug Application (ANDA) for a generic version of the product or any 505(b)(2) NDA (generally an NDA that relies on data that are not the sponsor’s and for which the sponsor has not obtained a right of reference) for a product with the same active moiety.

There are circumstances under which the follow-on application can be submitted at four years, and there are provisions that operate to preclude approval of the application for an additional period of time.

Also, NCE exclusivity does not block approval of a “full” NDA (generally, an NDA in which the data are the sponsor’s or for which the sponsor has obtained a right of reference).

The NCE exclusivity scheme is complicated and evolving;

for that reason, although we believe that some of our products will qualify for five-year NCE exclusivity, we cannot be certain that will receive such exclusivity, or that if we do, the exclusivity will effectively protect our market position.

Hatch-Waxman Act

The Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-Waxman Act) establishes two abbreviated approval pathways for pharmaceutical products that are in some way follow-on versions of already approved products.

The Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-Waxman Act) amended the FDCA to establish two abbreviated approval pathways for pharmaceutical products that are in some way follow-on versions of already approved products.

Generic Drugs.

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505(b)(2) NDAs.

As discussed above, if a product is similar, but not identical, to an already approved product, it may be submitted for approval via an NDA under section 505(b)(2) of the FD&C Act.

As discussed above, if a product is similar, but not identical, to an already approved product, it may be submitted for approval via an NDA under section 505(b)(2) of the FDCA.

Unlike an ANDA, this does not excuse the sponsor from demonstrating the proposed product's safety and effectiveness.

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A "Paragraph IV" certification is an assertion that the patent does not block approval of the later product, either because the patent is invalid or unenforceable or because the patent, even if valid, is not infringed by the new product.

Once the FDA accepts for filing an ANDA or 505(b)(2) application containing a Paragraph IV certification, the applicant must within 20 days provide notice to the RLD or listed drug NDA holder and patent owner that the application has been submitted, and provide the factual and legal basis for the applicant's assertion that the patent is invalid or not infringed.

If the NDA holder or patent owner files suit against the ANDA or 505(b)(2) applicant for patent infringement within 45 days of receiving the Paragraph IV notice, the FDA is prohibited from approving the ANDA or 505(b)(2) application for a period of 30 months or the resolution of the underlying suit, whichever is earlier.

If the RLD has NCE exclusivity and the notice is given and suit filed during the fifth year of exclusivity, the regulatory stay extends until 7.5 years after the RLD approval.

The FDA may approve the proposed product before the expiration of the regulatory stay if a court finds the patent invalid or not infringed or if the court shortens the period because the parties have failed to cooperate in expediting the litigation.

Regulatory Exclusivities.

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If a product is a "new chemical entity," or NCE — generally meaning that the active moiety has never before been approved in any drug — there is a period of five years from the product's approval during which the FDA may not accept for filing any ANDA or 505(b)(2) application for a drug with the same active moiety.

An ANDA or 505(b)(2) application may be submitted after four years, however, if the sponsor of the application makes a Paragraph IV certification.

Also, NCE exclusivity does not block approval of a “full” NDA (generally, an NDA in which the data are the sponsor’s or for which the sponsor has obtained a right of reference).

The NCE exclusivity scheme is complicated and evolving;

for that reason, although we believe that some of our products will qualify for five-year NCE exclusivity, we cannot be certain we will receive such exclusivity, or that if we do, the exclusivity will effectively protect our market position.

A product that is not an NCE may qualify for a three-year period of exclusivity if the NDA contains new clinical data, (other than bioavailability studies) derived from studies conducted by or for the sponsor, that were necessary for approval.

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Additionally, the exclusivity applies only to the conditions of approval that required submission of the clinical data.

If the RLD has NCE exclusivity and the notice is given and suit filed during the fifth year of exclusivity, the regulatory stay extends until 7.5 years after the RLD approval.

In connection with the submission of our NDA for product in February 2023, we provided Paragraph IV certification notices to the NDA holder and patent owner of the two unexpired Orange Book-listed patents covering the reference product.

As noted above, these parties have 45 days from receiving the Paragraph IV certification notices to file a patent infringement suit which would prohibit the FDA from approving our NDA for up to 30-months.

If the RLD has NCE exclusivity and the notice is given and suit filed during the fifth year of exclusivity, the regulatory stay extends until 7.5 years after the RLD approval.

Patent Term Restoration.

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Only one patent claiming each approved product is eligible for restoration and the patent holder must apply for restoration within 60 days of approval.

Patent and Trademark Office (USPTO) in consultation with the FDA, reviews and approves the application for patent term restoration.

In consultation with the FDA, the U.S.

Patent and Trademark Office (USPTO) reviews and approves the application for patent term restoration.

In the future, we may be able to apply for extension of patent term for one or more of our currently licensed patents or any future owned patents to add patent life beyond its current expiration date, depending upon the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.

We cannot be certain that any of our product candidates will qualify for patent term restoration or, if so, for how long the patent term will be extended.

Post-Approval Requirements

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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.

The Hatch-Waxman Amendments permit a patent restoration term of up to five years as compensation for the patent term lost during product development and the FDA regulatory review process for a product the approval of which is the first permitted commercial marketing of the active pharmaceutical ingredient.

However, patent term restoration cannot extend the remaining term of a patent beyond a date 14 years after the product’s approval date.

The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of an NDA plus the time between the submission date of an NDA and the approval of that application.

Only one patent applicable to an approved pharmaceutical product is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent unless an extension is obtained.

The US Patent and Trademark Office, in consultation with the FDA, reviews and renders a decision on the application for any patent term extension or restoration.

We cannot be certain that any of our product candidates will qualify for patent term restoration or, if so, for how long the patent term will be extended.

Pharmaceutical Coverage, Pricing and Reimbursement

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Even if favorable coverage and reimbursement status is attained for one or more products for which we may receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

At the federal level, in July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs.

In response to Biden’s executive order, on September 9, 2021, HHS released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles.

In addition, the Inflation Reduction Act (IRA), among other things, (1) directs HHS to negotiate the price of certain high-cost, single-source drugs and biologics covered under Medicare and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

The IRA permits HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

These provisions will take effect progressively starting in fiscal year 2023, although the Medicare drug price negotiation program is currently subject to legal challenges.

HHS has and will continue to issue and update guidance as these programs are implemented.

It is currently unclear how the IRA will be implemented but is likely to have a significant impact on the pharmaceutical industry.

The ACA substantially changed the way healthcare is financed by both governmental and private insurers and significantly impacts the pharmaceutical industry.

The ACA is intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against healthcare fraud and abuse, add new transparency requirements for healthcare and health insurance industries, impose new taxes and fees on pharmaceutical manufacturers and impose additional health policy reforms.

Further, the Inflation Reduction Act (IRA), among other things, (1) directs HHS to negotiate the price of certain high-cost, single-source drugs and biologics covered under Medicare and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

Under the IRA, certain categories of drugs are excluded from price negotiations, including drugs that receive orphan drug designation as the only FDA-approved indication.

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This could reduce the ultimate price that we receive for Annamycin, which could negatively affect our business, results of operations, financial conditions, and prospects.

Further, in response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the Center for Medicare and Medicaid Innovation which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

We expect that changes or additions to the ACA, IRA or their implementing regulations or guidance, changes to the Medicare and Medicaid programs, changes regarding the federal government’s authority to directly negotiate drug prices and changes stemming from other healthcare reform measures, especially with regard to healthcare access or financing or other legislation in individual states, could have a material adverse effect on the healthcare industry and our business.

At the state level, individual states in the United States have also increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

Additionally, some individual states have begun establishing Prescription Drug Affordability Boards to review high-cost drugs and, in some cases, set upper payment limits.

Legally mandated price controls on payment amounts by third-party payors or other restrictions could harm our business, results of operations, financial condition, and prospects.

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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