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Item 1. Business

2025-03-13 compared with 2024-03-14 · 512 added, 484 removed, 902 unchanged (52% of the section changed)

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Cisplatin and vinblastine sulfate are both generic and available to purchase in bulk supply commercially.

The United States Food & Drug Administration (the “FDA”) has approved both drugs as intravenous agents for several types of cancers.

The United States Food & Drug Administration (“FDA”) has approved both drugs as intravenous agents for several types of cancers.

Cisplatin was first approved in 1978 for testicular cancer, and is also approved in ovarian and bladder cancer.

The drug is also used widely in several other cancers including pancreatic and bile duct cancer.

Vinblastine sulfate was first approved in 1965, and is also approved in generalized Hodgkin’s disease, lymphocytic lymphoma, advanced carcinoma of the testis, and certain types of sarcoma.

Vinblastine sulfate was first approved in 1965, and is also approved in generalized Hodgkin’s disease, lymphocytic lymphoma, advanced carcinoma of the testis, and certain types of sarcomas.

The drug is also used in breast and lung cancer.

In 2017, we initiated a Phase 1/2 dose escalation study (“IT-01”) using INT230-6 in the United States under an investigational new drug application (“IND”) authorized by the FDA and in Canada under a preclinical trial application (“CTA”) approved by Health Canada (“HC”).

In 2017, we initiated our first trial, a Phase 1/2 dose escalation study (“IT-01 Study”) using INT230-6 in the United States under an investigational new drug application (“IND”) authorized by the FDA and in Canada under a preclinical trial application (“CTA”) approved by Health Canada.

The study tested the safety and efficacy of INT230-6 in patients with refractory or metastatic cancers, and enrolled 110 patients in three arms:

(i) INT230-6 used as a monotherapy, (ii) INT230-6 in combination with Merck’s Keytruda® (pembrolizumab), and (iii) INT230-6 in combination with Bristol Myers Squibb’s (“BMS”) Yervoy® (ipilimumab).

We completed enrollment of IT-01 in June 2022, locked the IT-01 database in February 2023 and finalized the clinical study report in September 2023.

We completed enrollment of the IT-01 Study in June 2022, locked the IT-01 Study database in February 2023 and finalized the clinical study report in September 2023.

We delivered the combination-specific reports and other information to our partners in the fourth quarter of 2023.

In 2021, we initiated a Phase 2 randomized study that tested INT230-6 as a monotherapy treatment in early-stage breast cancer for patients not suitable for presurgical chemotherapy (the “INVINCIBLE-2 Study” or “IT-02”).

In 2021, we initiated our second trial, a Phase 2 randomized study that tested INT230-6 as a monotherapy treatment in early-stage breast cancer for patients not suitable for presurgical chemotherapy (the “INVINCIBLE-2 Study”).

The study enrolled 91 subjects and the database was locked in November 2023.

The key endpoint was whether INT230-6 could reduce a patient’s cancer compared to no treatment, which is the current standard of care (“SOC”), or a saline injection.

The key endpoint was whether INT230-6 could reduce a patient’s cancer compared to no treatment, which is the current standard of care (“SOC”) for the majority of patients with early-stage breast cancer, or a saline injection.

Substantial reduction of cancer presurgically in aggressive forms of cancer has been shown to correlate with delaying disease recurrence.

Other endpoints of the INVINCIBLE 2 Study were to understand the percentage of necrosis that can be achieved in tumors for a given dose, especially tumors larger than 2 centimeters in longest diameter, and whether either a local or whole-body anti-cancer immune response could be induced.

The key endpoints of the INVINCIBLE 2 Study were to understand the percentage of necrosis that can be achieved in tumors of varying sizes for a given dose,

especially for tumors larger than 2 centimeters in longest diameter.

We also sought to determine whether a local or whole-body anti-cancer immune response could be induced.

The INVINCIBLE-2 Study demonstrated a high order of necrosis in presurgical breast cancer tumors in the period from diagnosis to surgery, with some patients experiencing greater than 95% necrosis of the tumor.

Data from the INVINCIBLE-2 Study demonstrated that INT230-6 had a favorable safety profile.

An increase of certain types of immune cells (CD4+ and NK T-cells) in the tumor and blood was also shown.

There was also an increase of certain types of immune cells (CD4+ and NK T-cells) in the tumor and blood.

Additionally, there was an increase in the T-cells repertoire relative to control.

In mid-2024, we intend on initiating a Phase 3 open-label, randomized study testing the superiority INT230-6 used as monotherapy compared to the standard of care drugs in 2nd and 3rd line treatment for certain soft tissue sarcoma subtypes (the “INVINCIBLE-3 Study” or “IT-03”).

We plan to enroll 333 patients with an endpoint of overall survival.

Also in mid-2024, we intend on initiating a Phase 2/3 program testing INT230-6 in combination with the SOC treatment (chemotherapy/immunotherapy) compared to SOC alone in women with triple negative breast cancer in presurgical (neoadjuvant) breast cancer (“IT-04”).

The endpoint for the Phase 2 portion of the trial is the change in the pathological complete response rate for the combination compared to the SOC alone.

We expect to begin the Phase 2 portion of the study in mid-2024, which will provide data to size the Phase 3 portion of the study.

We have also successfully developed Phase 3 quality analytical methods for the three INT230-6 components and successfully manufactured a large-scale batch of INT230-6.

In July 2024, we initiated and dosed our first patient in a Phase 3 open-label, randomized study (the “INVINCIBLE-3 Study”) testing INT230-6 as a monotherapy compared to the SOC drugs in second-and third-line treatment for certain soft tissue sarcoma subtypes.

This study has been authorized by the FDA, Health Canada, the European Medicines Authority, and Australia's Therapeutics Goods Administration.

The trial is enrolling patients and is being conducted in eight countries:

the US, Australia, Canada, France, Germany, Italy, Poland, and Spain.

Up to 60 sarcoma-focused hospitals and other centers are expected to participate from these countries.

We plan to enroll 333 patients and expect to complete enrollment in the first half of 2026, with an endpoint of overall survival.

In October 2024, in collaboration with the Swiss Group for Clinical Cancer Research SAKK ("SAKK"), we initiated and dosed our first patient in a Phase 2 study (the “INVINCIBLE-4 Study”) to treat patients with localized triple-negative breast cancer (“TNBC”).

We plan to enroll 54 patients and expect to complete enrollment by the end of the first quarter of 2026, and the endpoint is the change in the pathological complete response rate for the combination compared to the SOC alone.

We have also successfully developed Phase 3 quality analytical methods for the three INT230-6 components and successfully manufactured multiple large-scale batches of INT230-6.

In a meeting with the FDA in the fourth quarter of 2023, we agreed on a chemical manufacture and control (“CMC”) plan for Phase 3 and product registration for our three key ingredients and INT230-6.

If we successfully execute the agreed upon plan, the CMC portion of a New Drug Application (“NDA”) should be acceptable to the FDA for product approval and registration (subject to final NDA review).

If we successfully execute the agreed-upon plan, we expect that the CMC portion of a New Drug Application (“NDA”) should be acceptable to the FDA for product approval and registration (subject to final NDA review).

Our pipeline is focused on realizing the full potential of INT230-6 in metastatic and local disease settings to help cancer patients with major unmet medical need.

We are exploring the use of INT230-6 across multiple cancer types (including those types that do not normally respond to immunotherapy) and “hot” tumors (cancer types that are more likely to respond to immunotherapy).

Based on data generated in IT-01 and the INVINCIBLE-2 studies, our current forward pipeline consists of:

• A Phase 3 open-label, randomized study testing the superiority INT230-6 used as monotherapy compared to the standard of care drugs in 2nd and 3rd line treatment for certain soft tissue sarcoma subtypes.

For every three patients enrolled, two will receive INT230-6 and one will receive SOC drug(s) chosen by the investigators depending on the type of sarcoma.

The Company is working with several contracted vendors to initiate the Phase 3 trial.

We plan to enroll 333 patients with an endpoint of overall survival.

In September 2023, we announced that the FDA granted orphan drug designation for the treatment of soft tissue sarcoma to the three active moieties comprising INT230-6:

Our current pipeline consists of:

• INVINCIBLE-3 Study , a Phase 3 open-label, randomized study testing the superiority INT230-6 used as monotherapy compared to the standard of care drugs in 2nd and 3rd line treatment for certain soft tissue sarcoma subtypes.

In September 2023, the FDA granted orphan drug designation for the treatment of soft tissue sarcoma to the three active moieties comprising INT230-6:

cisplatin, vinblastine sulfate, and the diffusion enhancer SHAO.

• A Phase 2/3 study testing INT230-6 in combination with the SOC treatment (chemotherapy/immunotherapy) compared to the SOC alone in women with triple negative breast cancer in presurgical (neoadjuvant) breast cancer.

The endpoint for the Phase 2 portion of the trial is the change in the pathological complete response rate for the combination compared to the SOC alone.

• INVINCIBLE-4 Study , a two cohort Phase 2 randomized, controlled study testing INT230-6 in combination with the SOC treatment (chemotherapy/immunotherapy) (cohort A) and the SOC alone (cohort B) in women in presurgical (neoadjuvant) TNBC.

This is a two-cohort noncomparative trial with null hypotheses (H0):

pathological complete response (“pCR”) rate ≤ 0.6, and (H1):

pCR rate ≥ 0.8.

• A Phase 2 clinical study in metastatic triple negative breast cancer, contingent on raising additional capital to fund the study.

In 2018, we received Fast Track Designation by the FDA to use INT230-6 in metastatic triple negative breast cancer for patients whose cancer has progressed following one or two prior drug treatments.

In addition, we plan to continue to research and test new product candidates with improved immune activating properties.

Through research studies conducted in animals, we have identified a promising product candidate currently designated as INT33X.

We believe that the INT33X product candidate development program will most likely lead to the creation of new patents and other intellectual property.

As part of our development program for INT33X, we will first conclude our on-going research studies in mice, after which we will finalize the exact product candidate composition before proceeding with clinical development.

Our Partnerships

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After nearly two years of dosing a combination of Keytruda and INT230-6, patients showed comparable safety to INT230-6 monotherapy.

In addition, only three grade 3 immune-related adverse events reported in patients receiving the combination of INT230-6 with Keytruda.

We completed study dosing in December 2022, finalized the clinical study report, tables, listings and figures for the Keytruda cohorts and provided the study information to Merck in December 2023.

Subjects enrolled in the single arm combination with pembrolizumab received a diagnosis of cancer progression following a median of 3 prior lines of therapy.

The median OS in the All Treated Population was 4.7 months (95% CI:

Only three grade 3 immune-related adverse events reported in patients receiving the combination.

We completed study dosing in December 2022 and provided the study information to Merck in December 2023.

• Bristol Myers Squibb.

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In our IT-01 Study, we treated 18 patients in this combination arm, and there was only one grade 3 immune-related adverse event (colitis) reported.

We completed study dosing in December 2022, finalized the clinical study report, tables, listings and figures for the Yervoy cohorts and provided the study information to BMS in December 2023.

The median OS for the IT-01 combination cohort was not reached (NA) (95% CI:

7.2, NA) in the All Treated Population.

We completed study dosing in December 2022 and provided the study information to BMS in December 2023.

In May 2024, we entered into a collaboration agreement with SAKK to conduct our INVINCIBLE-4 Study.

SAKK is a decentralized academic research institute that has been conducting clinical trials of cancer treatments in all major Swiss hospitals since 1965.

It federates a large network of research groups with a Competence Center in Bern in charge of coordinating the clinical operations.

It also works with selected cooperative groups abroad, particularly on rare forms of cancer.

SAKK's aim is to advance existing cancer treatments, investigate the efficacy and tolerability of new treatments (radiotherapy, medicines and surgery), and set new standards in treatment.

22 Swiss hospitals are full members of SAKK.

Our Clinical Data

INT230-6 has already generated anti-cancer evidence of activity as a single agent in clinical studies.

INT230-6 has generated anti-cancer evidence of activity as a single agent in clinical studies.

Localized and abscopal effects have been observed in several patients.

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No maximum tolerated dose had been reached.

In our study IT-01 in metastatic patients, most adverse events were minor grade 1 or 2;

In our IT-01 Study in metastatic patients, most adverse events were minor grade 1 or 2;

a total of 15 patients out of 110 (13.6%) had a grade 3 even related to the drug regimen (INT230-6 alone or combined with the two immunotherapies).

The primary grade 3 events were pain, anemia, rash, fatigue vomiting, dehydration and dizziness.

There was 1 laboratory-based grade 4 adverse event that resolved quickly, a decrease in the number of neutrophils, the most common type of white blood cell that contributes toward the healing of damaged tissues and resolving infections.

There was 1 laboratory-based grade 4 adverse event that resolved quickly, a decrease in the

number of neutrophils, the most common type of white blood cell that contributes toward the healing of damaged tissues and resolving infections.

There were no grade 5 adverse events.

Please see Table 1 and 2 in the “ Results from IT-01 Phase 1/2 Clinical Trial ” portion of our “ Business ” section on page 67 of this report for more information.

We believe the safety profile consisted of mainly low grade related adverse events because the drug primarily stays in the tumor and the potent agents did not travel throughout the body.

Measurement of the

amount of the drugs seen in the blood (pharmacokinetics or PK) indicated that more than 95% of the drug that was dosed remained in the tumor.

Measurement of the amount of the drugs seen in the blood (pharmacokinetics or PK) indicated that more than 95% of the drug that was dosed remained in the tumor.

Our Manufacturing Capabilities

We work with clinical manufacturing organizations.

In the fourth quarter of 2023, we successfully developed the Phase 3 quality analytical methods for measurement of the key INT230-6 components, validated those methods and manufactured our fourth current Good Manufacturing Practice (“cGMP”) clinical batch of the drug product that met specifications.

During the fourth quarter, the Company requested and was granted a meeting that was held with the FDA to review the INT230-6 CMC for INT230-6.

We do not own or operate facilities for drug manufacturing, storage and distribution, or testing.

We work with clinical manufacturing organizations to manufacture the clinical supplies of our current and any future product candidates.

In 2023, we successfully developed the Phase 3 quality analytical methods for measurement of the key INT230-6 components, validated those methods and had manufactured our fourth current Good Manufacturing Practice (“cGMP”) clinical batch of the drug product that met specifications.

During the fourth quarter of 2023, the Company requested and was granted a meeting that was held with the FDA to review the INT230-6 CMC for INT230-6.

The CMC discussion focused on the tasks necessary to initiate the Phase 3 study and future product registration as part of a potential New Drug Application (“NDA”).

During the meeting, the Company and the FDA agreed upon a plan for the CMC set of activities for the active pharmaceutical ingredients and the drug product (INT230-6) necessary for the NDA.

To commence the Phase 3 sarcoma program, we engaged contract research organizations to help manage the Phase 3 sarcoma study.

We believe that INVINCIBLE-3 will be the first local therapy (though with systemic immune activating properties) to be tested as a single agent in metastatic disease compared to active SOC IV or oral agents.

Our Proprietary Drug Discovery platform, DfuseRx SM

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We intend to apply our deep understanding of our novel drug delivery technology to create a range of new direct killing and immune-activating products candidates while focusing on our lead clinical programs.

If successful, we hope to fundamentally change the way cancer is treated for multiple cancer types in both the metastatic and presurgical disease settings.

If successful, we hope to fundamentally change treatment for multiple cancer types in both the metastatic and presurgical disease settings.

We seek to build a company that develops and commercializes a new medicine and treatment methodology.

By applying a disciplined focus on product development, we seek to transform the lives of cancer patients and change the very essence of cancer treatment.

Our objective is for patients to overcome their cancer without harm, to live a long life with high quality and to eliminate the fear of disease recurrence.

Our objective is for patients to overcome their cancer without harm, to live a long life with high quality and to eliminate the fear of disease recurrence or the therapy itself.

We maintain a culture of high integrity that embraces the patient and their caregivers.

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Key elements of our strategy include:

• To focus our resources to aggressively pursue the research and development of our novel medicine to transform patient lives.

• To always remember that taking care of and benefiting the patient is the most important element to being successful.

• To effectively manage costs by outsourcing research and development to qualified, academic, private or government laboratories to leverage third-party expertise, while maintaining internal know-how, expertise and intellectual property.

• To build an internal team of experienced industry veterans that can work independently and who know how to get the product development job done.

• To create a large body of rigorous data, publications, presentations, collaborations and training materials about the new product candidates.

• To continuously communicate to the medical community and patients of the power of our new approach.

• To continue our commitment to precision medicine and personalized care for each and every patient.

• To assure that our technology is fully understood, explored, and used as designed.

• focusing our resources to aggressively pursue the research and development of our novel medicine to transform patient lives.

• providing high-quality care of the patient is a critical element to being successful.

• effectively managing costs by outsourcing research and development to qualified, academic, private or government laboratories to leverage third-party expertise, while maintaining internal know-how, expertise and intellectual property.

• building an internal team of experienced industry veterans that can work independently and who know how to get the product development job done.

• creating a large body of rigorous data, publications, presentations, collaborations and training materials about the new product candidates.

• continuously communicating to the medical community and patients of the power of our new approach.

• continuing our commitment to precision medicine and personalized care for each and every patient.

• assuring that our technology is fully understood, explored, and used as designed.

Market Opportunities for Our Product Candidates

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For example, the majority of breast cancer tumors identified are local to the breast or are regional.

As a result, there are 170,000 lumpectomies performed in the U.S.

Roshni Rao, Chief, Breast surgery program, at New York-Presbyterian/Columbia University Medical Center wrote in the Cancer Letter that “although lumpectomy is the best option for many breast cancer patients, with 170,000 procedures performed annually, it is not perfect.

According to Breast Cancer Facts and Stats 2024, 66% of breast cancer cases are diagnosed at the localized stage.

All too often, a post-operative pathology report shows that while the surgeon may have removed the entire tumor, a second surgical procedure is needed to clean up lingering cancer cells.

Known as re-excision, it occurs in roughly 20% to 25% of cases, on average.

critical for surgeons and their patients to have access to the latest innovations, once demonstrated effective by clinical research, be used wherever and whenever possible.” Our drug candidate’s potential to kill cancer quickly prior to surgery and engage an anti-cancer immune response may provide a higher percentage of patients a greater five-year event-free survival for a number of tumor types.

It is critical for surgeons and their patients to have access to the latest innovations, once demonstrated effective by clinical research, be used wherever and whenever possible.” Our drug candidate’s potential to kill cancer quickly prior to surgery and engage an anti-cancer immune response may provide a higher percentage of patients a greater five-year event-free survival for a number of tumor types.

Breast Cancer

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women (about 13%) will develop invasive breast cancer over the course of her lifetime.

In 2024, there will be an estimated 313,510 new cases of invasive breast cancer diagnosed in women;

2790 new cases diagnosed in men, and an additional 56,500 new cases of ductal carcinoma in situ diagnoses in women.

(Siegel et al., 2024).

According to the American Cancer Society, in 2025, there are expected to be approximately 316,950 new cases of invasive breast cancer diagnosed in women in the United States;

2800 new cases diagnosed in men, and an additional 59,080 new cases of ductal carcinoma in situ diagnoses.

Breast cancer is the most commonly diagnosed cancer among American women.

Breast cancer became the most common cancer globally as of 2021, accounting for 12% of all new annual cancer cases worldwide, according to the World Health Organization.

Approximately 11 – 17% of breast cancers test negative for estrogen receptors, progesterone receptors, and excess human epidermal growth factor receptor 2 (HER2) protein, qualifying them as triple negative (“TNBC”).

Breast cancer accounted for 11% of all new annual cancer cases worldwide, according to Globaocan’s Global Cancer Statistics 2022.

Approximately 11 – 17% of breast cancers test negative for estrogen receptors, progesterone receptors, and excess human epidermal growth factor receptor 2 (“HER2”) protein, qualifying them as TNBC.

TNBC is considered to be more aggressive and have a poorer prognosis than other types of breast cancer, mainly because there are fewer available targeted medicines especially for women have tumors above 2 cm in longest diameter.

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There are many types of soft tissue tumors, and not all of them are cancerous.

There are many types of sarcoma;

however, the three most common are bone sarcoma (referred to as osteosarcoma), leiomyosarcoma, undifferentiated pleomorphic sarcoma and liposarcoma.

There are many types of sarcomas;

however, the four most common are bone sarcoma (referred to as osteosarcoma), and soft tissue sarcomas (“STS”) leiomyosarcoma, undifferentiated pleomorphic sarcoma and liposarcoma.

Leiomyosarcoma is a type of sarcoma that grows in the smooth muscles.

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In females, there is also smooth muscle in the uterus.

When sarcoma is metastatic prognosis is poor;

even with chemotherapy, half of people diagnosed with metastatic disease die within 15 months.

Each year, 12,000 people in the U.S.

and 1,150 in Canada are newly diagnosed with soft tissue sarcomas.

About 3,000 patients have bone sarcomas.

When sarcoma is metastatic, prognosis is poor, even with chemotherapy.

Half of people diagnosed with metastatic disease STS in the second or third line setting of the major 3 STS subtypes die within 15 months.

An analysis of SEER data shows that 14,500 people in the U.S.

have metastatic soft tissue sarcomas of the 3 main subtypes

Chemotherapy Treatment

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Almost all current anti-cancer drug therapies load drug throughout the entire body including classic chemotherapy before surgery (neoadjuvant), after surgery (adjuvant), targeted therapy, antibodies or antibody drug conjugates, liposomal or nanoparticle delivered drugs.

Many cancer cells in tumors are located away from blood vessels (referred to have hypoxic regions) and systemic administration of chemotherapy is ineffective at delivering the needed amounts of the medicine to all parts of the tumor.

Many cancer cells in tumors are located away from blood vessels (referred to as hypoxic regions) and systemic administration of chemotherapy is ineffective at delivering the needed amounts of the medicine to all parts of the tumor.

A significant limitation of the current chemical-based anti-cancer treatments is proper drug delivery.

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Immunotherapy

There has been much excitement over the past decade about the promise of immunotherapy in treating cancer.

These novel product candidates are designed to mobilize an immune system to attack cancer.

The field of cancer immunotherapy has become the primary focus of treatment for many tumor types.

There is significant interest from pharmaceutical companies, physicians and patients in advancing new, immune-based treatment concepts.

Today, some patients with formerly fatal cancers are experiencing long term survival benefits with immune-based treatments.

Agents that stimulate or block various types of immune cells have generated much excitement and promise in treating cancer.

These novel product candidates mobilize the immune system against cancer.

There had been significant interest from pharmaceutical companies, physicians and patients in advancing new, immune-based treatment concepts as patients with formerly fatal cancers experienced long-term survival benefits with immune-based treatments.

Immunotherapy has shown promise against the most mutated cancers such as melanoma, renal cell carcinoma, squamous cell carcinomas and subsets of lung cancers.

Often these new immune stimulating drugs work in patients having high levels of specific markers,

such as the percentage of a protein on the surface of the cancer cell known as PD-L1 or the number of genetic mutations that may have caused the cancer referred to as a tumor’s mutational burden.

However, once promising immunotherapies, such as TIGIT and LAG3, have failed to provide significant improvements over the current PD-1, PD-L1, and CTLA-4 therapies.

Many cancers, however, are also unresponsive to immunotherapy.

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Thus, the immune therapies induce side effects.

To enable more patients to benefit from immunotherapy, new technologies that are able to improve recognition of the cancer by the immune system, or disrupt the tumor’s ability to evade immune cells, are critical and strongly needed.

To enable more patients to benefit from immunotherapy, new

technologies that are able to improve recognition of the cancer by the immune system, or disrupt the tumor’s ability to evade immune cells, are critical and strongly needed.

Challenges Facing Current Treatments

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Cancer also can cloak itself from the immune cells and create barriers to reduce their influx into the tumor.

Our Treatment Approach

Our treatment concept pioneers a new approach to treating cancer — kill tumors in the body ( in situ ) to create from the patient’s own cancer a recognizable, high-quality material (referred to as antigen) for better immune cell engagement against the cancer (immunological cell kill).

Our Treatment Approach Versus Current Methods

Current systemic treatment regimens administer either a fixed amount or a set dose based on weight or via an algorithm based on weight and height, such as specific surface area.

There is no correlation between height and weight and outcome;

however, there is a correlation with survival based on a patient’s number of metastatic sites and amount of bulk disease (total tumor burden).

Our treatment concept pioneers a new dosing approach to treating cancer — kill tumors in the body ( in situ ) to create from the patient’s own cancer a recognizable, high-quality material (referred to as antigen) for better immune cell engagement against the cancer (immunological cell kill).

Our new concept uses a delivery molecule to enable the dispersal of potent drugs throughout the tumor that can also diffuse into the cancer cells.

This process effectively loads the tumor with strong killing agents, which are retained within the cells.

The active agents themselves used in our product candidate also have properties that improve immune recognition of the cancer.

The active agents themselves used in our product candidate also have properties that improve immune recognition of cancer.

At the right dose our product candidates can completely saturate an injected tumor delivering high concentrations of drug into the cancer cells and killing the entire tumor.

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Our clinical data suggests that not all tumors need be injected for long term disease control.

Through our novel, drug treatment technology, we hope to transform the lives of patients with cancer.

Figure 1 compares current systemic treatment approaches with our treatment.

Figure 1 – Current Dosing Methods

Through our novel drug treatment and new dosing approach, we hope to transform the lives of patients with cancer.

Our objectives are to increase patient longevity, reduce side effects, remove the fear of treatment, empower the patient, and minimize the risk of disease recurrence.

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(i) cisplatin, a proven anti-cancer cytotoxic agent, (ii) vinblastine sulfate, also a proven anti-cancer cytotoxic agent, and (iii) SHAO, a penetration enhancing amphiphilic molecule.

Both cisplatin and vinblastine sulfate have direct cancer cell killing and immune activating mechanisms of action.

The SHAO chemical structure is shown in Figure 2 below.

When injected into tumors, INT230-6 can kill the tumors.

Our safety studies show that if the drug is (accidentally) injected into healthy tissue there is no observation of damage.

Our in vivo safety studies show that if the drug is injected into healthy tissue there is no observation of tissue damage (skin, liver or peritoneum).

The drug agents enter the blood stream at low doses.

The unique amphiphilic SHAO compound formulated product candidate increases the dispersion of the drug throughout the tumor following intratumoral injection.

Our technology is novel and unique.

For those familiar with drug delivery technologies in cancer, it is important to understand that our product candidate is not a liposome, not a nanoparticle nor an emulsion.

INT230-6 is a 100% water-

based formulation with tissue dispersion properties that do not destroy cancer cell membranes.

We are unaware of any previous anti-cancer drug or prior intratumoral preparation with similar characteristics.

Figure 1 – Chemical Structure of SHAO

The SHAO molecule facilitates drug dispersion throughout the tumor.

The molecule allows the tumor to absorb the killing agents and facilitates their diffusion into the cancer cells.

Once in the cancer cell one drug cisplatin binds the DNA and causes the cell apoptosis (death) whereas the other agent, vinblastine sulfate, destroys the cell’s tubulin to shut down replication.

Our technology is novel and unique, and is not a liposome, a nanoparticle, or an emulsion.

INT230-6 is a 100% water-based formulation with tissue dispersion properties that do not destroy cancer cell membranes.

Figure 2 – INT230-6

The SHAO molecule facilitates drug dispersion throughout the tumor and facilitates their diffusion into the cancer cells.

Once in the cancer cell one drug cisplatin binds the DNA and causes the cell apoptosis (death) whereas the other

agent, vinblastine sulfate, destroys the cell’s tubulin to shut down replication.

Data in humans suggests that when administered at the proper drug dose to tumor volume ratio, a significant portion of the injected tumor can be killed on a single dose.

In addition, there is evidence (in both animals and humans) that for certain cancers there is an activation of the immune system.

Our novel intratumoral (IT) technology is different than other IT approaches in four important ways:

There is evidence (in both animals and humans) that there is an activation of the immune system for certain cancers.

Our novel technology is different than other IT approaches in four important ways:

1) We recognized that the composition of a tumor is highly unfavorable to direct injection of water-based products because the tumor has a high fat content and is under surrounding pressure.

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4) Our product candidate has potential to kill tumors in a manner and could be used before surgery immediately after diagnosis or for treatment of cancers where there are no therapeutic agents or suitable local treatments available.

INT230-6 in Animals

Our first research studies in mice were conducted with organizations that provide services under contract, referred to as contract research organizations (“CROs”).

Our Company collaborated with the Vaccine Branch of the National Cancer Institute (NCI) in Bethesda, MD.

The research with the NCI was established after the National Institutes of Health awarded our Company a cooperative research and development agreement (CRADA).

The program was quite successful and culminated with the publication of a paper in July 2019 that we jointly authored with the NCI.

Preclinical Data

Our first research studies in mice were conducted with contract research organizations (“CROs”).

The Company collaborated with the Vaccine Branch of the National Cancer Institute (“NCI”) in Bethesda, MD.

The research with the NCI was established after the National Institutes of Health awarded us a CRADA.

The program culminated with the publication of a paper in July 2019 that was jointly authored with the NCI.

In that publication, we reported that INT230-6 treatment resulted in regression from baseline in 100% of the tumors and complete response in up to 90%.

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The liquid mostly leaked from the tumor.

However, the formulation that

incorporated SHAO was readily and rapidly absorbed by the tumor in a dose dependent manner as shown in Figure 2 below.

However, the formulation that incorporated SHAO was readily and rapidly absorbed by the tumor in a dose dependent manner as shown in Figure 3 below.

Figure 3 – Comparison of drug dispersion/absorption in tumors with and without our DfuseRx technology.

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The data was generated by our partners at the National Cancer Institute and under our CRADA and published (OncoImmunology 2019 Vol 8 No 10;

Preclinical Good Laboratory Practice (GLP) Safety of INT230-6

Preclinical Good Laboratory Practice Safety of INT230-6

During a meeting in 2014 with the FDA we reached agreement on an accelerated safety and manufacturing program.

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In the United States, the FDA regulates drug and device products under the Federal Food, Drug, and Cosmetic Act and its implementing regulations.

We filed our IND application for our study IT-01 entitled “A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects with Advanced Refractory Cancers” and held a meeting with senior FDA officials in November 2016.

We filed our IND application for our IT-01 Study entitled “A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects with Advanced Refractory Cancers” and held a meeting with senior FDA officials in November 2016.

In December 2016, the FDA provided us a “Study May Proceed” letter.

We also met formally with the HC in a CTA meeting in 2016.

We filed the CTA and held meetings with senior HC officials.

We also met formally with the Health Canada in a CTA meeting in 2016.

We filed the CTA and held meetings with senior Health Canada officials.

Health Canada provided us a “No Objection” letter in early 2017.

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Dose for a given tumor is set based on its size.

IT-01 Phase 1/2 Clinical Trial

Study IT-01, was completed in 2023.

Clinical Trials

Phase 1/2 Refractory or Metastatic Cancer (“IT-01 Study”)

The IT-01 Study, was completed in 2023.

The study design permitted our product candidate to be tested in several different cancer patient populations with dosing into both superficial e.g.

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We tested our product candidate in over 20 different cancer types.

IT-01, is listed on clinicaltrials.gov;

The hospitals that enrolled patients in the United States were:

the Sydney Kimmel Cancer Center at Johns Hopkins, The Fox Chase Cancer Center at Temple University, the University of Southern California’s Norris Cancer Center, LA County and HOAG Presbyterian Hospitals of the University of Southern California medical system, the UMASS Memorial in Worchester Massachusetts, Columbia Presbyterian in New York, the Princess Margaret Hospital which is part of the University Health Network in Toronto, and the Houston Methodist.

In 2019 we partnered with Merck and in 2020 we partnered with BMS.

We treated 30 patients having various cancers using INT30-6 with Merck’s Keytruda ® (pembrolizumab) and 18 patients with BMS’s Yervoy ® (ipilimumab).

A schematic of the final Phase 2 study’s three dosing cohorts is shown in Figure 4 below.

The final data and clinical study reports were provided to the partners in December 2023.

Figure 4 — Schema of the 3 final dosing groups for the metastatic study IT-01.

Results from IT-01 Phase 1/2 Clinical Trial

The Phase 1/2 study treated refractory patients, who failed multiple lines of therapy.

One hundred ten (110) subjects were treated in IT-01.

One hundred ten (110) subjects were treated in the IT-01 Study.

The results of the escalation portion, which included up to 175 mL per session every two weeks, indicated a favorable safety profile of INT230-6 with or without immunotherapy, with only 7 patients out of 64 on INT230-6 alone experiencing grade 3 related adverse events.

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The majority of treatment related adverse events have been low grade (grade 1 or 2).

A total of 15 patients out of 110 (13.6%) had at least one grade 3 adverse event in study IT-01.

A total of 15 patients out of 110 (13.6%) had at least one grade 3 adverse event in the IT-01 Study.

The primary grade 3 events have been pain, fatigue vomiting anemia, rash, dehydration and dizziness.

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Data that measured the circulating levels of the key ingredients has been generated from the ongoing study in metastatic patients.

The amount of vinblastine sulfate seen in

plasma of patients is much lower than a lesser dose given IV.

The amount of vinblastine sulfate seen in plasma of patients is much lower than a lesser dose given IV.

Cisplatin is reduced to metal rapidly and is challenging to measure in blood even for IV dosing.

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Thus, IT dosing INT230-6 compares favorably to the toxicities normally associated with cisplatin and vinblastine sulfate when given intravenously at comparable doses.

Figure 5 — Free vinblastine (VIN) levels and platinum metal in blood plasma over time for intratumorally (IT) administered INT230-6.

Figure 6 — Free vinblastine levels and platinum metal in blood plasma over time for intratumorally administered INT230-6.

Cytotoxic components in INT230-6 have minimal systemic exposure and short half-life.

Most of the active drug remains in the tumor as a result INT230-6 appears to have favorable safety data to date.

RECIST (Response Evaluation Criteria in Solid Tumors) for Efficacy

Response Evaluation Criteria in Solid Tumors (“RECIST”) for Efficacy

A standard way to measure how well a cancer patient responds to a treatment is based on whether tumors shrink, stay the same, or get bigger.

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Tumor Death (Necrosis)

Investigators report significant necrosis (reduced contrast uptake in the CT image) in many injected tumors including adrenocortical, breast, chordoma, colon, head and neck (H&N), lung, sarcoma and squamous cell.

Cisplatin causes apoptotic cell death leading to necrotic tissue, and vinblastine sulfate destroys tubulin, which is needed for cell replication.

Investigators report significant necrosis (dead tissue as evidenced by reduced contrast uptake in the CT image) in many injected tumors including adrenocortical, breast, chordoma, colon, head and neck, lung, sarcoma and squamous cell.

Figure 7 below is an example of a squamous cell tumor that became necrotic by the 2-month scan.

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Dosing is completed just prior to their first scan when the increase in tumor diameter is most likely to be highest.

As noted above, RECIST measurements of whether a patient’s cancer is stable, decreasing or progressing are based on the changes in the tumor’s longest diameter.

As noted above, RECIST

measurements of whether a patient’s cancer is stable, decreasing or progressing are based on the changes in the tumor’s longest diameter.

An increase in longest diameter above a threshold would indicate progression.

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Figure 10 shows the scan of a sarcoma patient’s tumor pre- and post-dosing.

diameter declines by 15%, while the second longest diameter declines 42%.

The longest diameter declines by 15%, while the second longest diameter declines 42%.

Using RECIST criteria, this patient would have been classified as having stable disease, whereas the World Health Organization, which uses the two longest diameters, would classify this patient as having had a partial response, which is a better outcome.

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Disease Control Rate

Even though RECIST was deemed to be less accurate for measuring efficacy a secondary objective of IT-01 was to assess the preliminary efficacy of INT230-6 by measuring the disease control rate (DCR) based on the (RECIST) and immune RECIST (iRECIST) criteria.

The DCR rates for the study are shown below.

Even though RECIST was deemed to be less accurate for measuring efficacy, a secondary objective of the IT-01 Study was to assess the preliminary efficacy of INT230-6 by measuring the disease control rate (shown below) based on the RECIST and immune RECIST (“iRECIST”) criteria.

Monotherapy cohorts

Disease Control Rate a

Disease Control Rate

Total (all subjects) (N = 64), n (%)

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100 (39.8, 100;

Prior treatment b

Prior treatment

Yes (N = 31), n (%)

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Efficacy is not usually the primary objective.

Most patients in Phase 1 studies have low survival expectations that ranges from 3 to 8 months depending on the type of cancer and patient’s incoming health.

Most patients in Phase 1 studies have low survival expectations that ranges from 3 to 8 months depending on the type of cancer and the patient’s incoming health.

(see Chau, N., BMC Cancer volume 11, Article number:

Over the past two decades the development of a prognostic score to predict survival of patients treated in Phase 1 studies has been completed and validated by the Royal Marsden Hospital (RMH) in the United Kingdom.

The score, which ranges from 0 to 3, is highly correlated of overall survival (OS) outcomes.

A score of 0 suggests longest potential survival and a 3 worst.

Many studies show that subjects enrolled in Phase 1 have survival of under 6 months when RMH scores greater than or equal to 1.

In our study IT-01 patients were enrolled whose cancer progressed following treatment using all approved and some experimental therapies suitable for their specific disease.

The score, which is comprised of 3 risk factors (number of metastatic sites, size of tumors and nutritional levels).

Scores range from 0 to 3, and are highly correlated with overall survival (“OS”).

A score of 0 suggests the longest potential survival, and a score of 3 is the worst.

Many studies show that subjects enrolled in Phase 1 have a survival of under 6 months when RMHI scores greater than or equal to 1.

Over 75% of patients in our study had a score of 1 or 2.

In our IT-01 Study, patients were enrolled whose cancer progressed following treatment using all approved and some experimental therapies.

Forty-three (43%) of patients had previous had an IV form of a platinum-based drug including cisplatin.

Forty-four percent (44%) had previously received an anti-PD-1 antibody.

Efficacy data from 64 patients enrolled in IT-01 is available from patients receiving INT230-6 alone (referred to as monotherapy).

Efficacy data from 64 patients enrolled in the IT-01 Study is available from patients receiving INT230-6 alone (referred to as monotherapy).

There were over 820 different tumor injections conducted over the course of the trial with over 502 being into visceral deep tumors.

Study IT-01 was a Phase 1/2 dose escalation (i.e.

The IT-01 Study was a Phase 1/2 dose escalation (i.e.

the Phase 1 basket portion) and Phase 2 (expansion of specified cancer types).

These types of studies are primarily testing safety in the Phase 1 and determining whether there is an efficacy signal in the expansion compared to historical data.

There was no control arm in IT-01 and no randomization.

Therefore, there is no comparator to determine the significance of any given endpoint.

There was no control arm in the IT-01 Study and no randomization though patients were enrolled with random tumor burdens and random cancer types.

Therefore, there is no formal comparator to determine the significance of any given endpoint.

See Table below for the patient population.

Final INT230-6 monotherapy population (n=64) in IT-01

Final INT230-6 monotherapy population (n=64) in the IT-01 Study

Type of Cancer

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Adrenocortical carcinoma, Anal, Bladder, Cervical, Eccrine, Lung, Metastatic Cancer of Unknown Primary, Pseudomyxoma peritonei, Renal, and Thyroid.

Patients receiving a monotherapy dose of INT230-6 above 40 percent of their TTB measured in cubic centimeters had a statistically significantly longer survival than patients who received treatment to less than 40% of their TTB.

Patients receiving a monotherapy dose of INT230-6 above 40 percent of their TTB measured in cubic centimeters had statistically significantly longer survival than patients who received treatment to less than 40% of their TTB.

The subjects receiving a dose >40% of their total incoming tumor burden also lived much longer than would be expected for patients in a Phase 1/2 basket study.

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however, this Phase 2 population size was also too small to properly assess effectiveness of INT230-6.

As a result, we have determined that overall survival, an endpoint preferred by the FDA for cancer clinical trials, is the most appropriate metric to prove efficacy of our drug candidate to treat metastatic disease.

Study IT-01 also indicates that soft tissue sarcoma, at cancer type with high unmet medical need, would be a suitable disease for a Phase 3 trial to evaluate the efficacy of INT230-6.

In our metastatic study survival appears to be impacted by the total dose a patient received relative to number and size of their tumors.

Patients receiving a higher percentage of drug (mL) relative to their TTB (cm 3 ) remained on study longer regardless of the cancer type.

A patient’s TTB is calculated by adding up the volumes of all reported tumors.

Simply stated, the more drug given to more tumors, the more likely a subject would be alive longer, though not all tumors need be treated.

Killing more of a patient’s cancer is beneficial.

Based on the analysis of strong absorption of our drug by the tumor and the ignition of the immune system, we have determined that overall survival was most appropriate for our Phase 3 study.

OS is the FDA’s preferred endpoint for cancer clinical trials to prove efficacy.

The probability of survival for a given population can be plotted.

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This result is shown in the red curve and is comparable to survival expected in historical Phase 1 basket studies (See Chau, N., BMC Cancer volume 11, Article number:

Patients that received a dose of INT230-6 to greater than 40% of their TTB had a ~63% chance of being alive at 1 year and the

median overall survival was 18.7 months.

Patients that received a dose of INT230-6 to greater than 40% of their TTB had a ~63% chance of being alive at 1 year and the median overall survival was 18.7 months.

These results indicate that survival improves for those dosed to greater than 40% of their TTB compared to those receiving under 40%.

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the sample size is small and the average values for the green curve was lower.

Figure 10 — Kaplan Meier Estimates of Sarcoma Patient-Survival Dosing INT230-6 in study IT-01

Figure 11 — Kaplan Meier Estimates of Sarcoma Patient-Survival Dosing INT230-6 in the IT-01 Study

Exploratory analysis of dose relative to TTB was conducted.

Many tumors, including all under 1 cm in diameter, were not reported and so TTB is likely underestimated.

In the IT-01 Study, survival appears to be impacted by the total dose a patient received relative to the number and size of their tumors.

Patients receiving a higher percentage of INT230-6 (mL) relative to their TTB (cm 3 ) remained in the study longer regardless of the cancer type.

The analysis using 40% of tumor burden was arbitrary;

however, the conclusion from the data is that the more INT230-6 that was administered and the more tumors injected, the more likely a subject would be alive longer for a given tumor burden.

In the Phase 3 study, the physicians are advised to treat as many tumors as are safe to inject.

Biomarker Analysis

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Our technology disperses potent killing agents throughout tumors and enables the potent killing agents to diffuse into the cancer cell without damage to the cell membrane.

When the tumor’s cancer cells are no longer alive, the ability of the immune system to identify the cancer and mount a response can be increased.

We collect tumor tissue before and after dosing of our drug candidate from patients injected tumors.

When the tumor’s cancer cells are dying or no longer alive, the ability of the immune system to identify the cancer and mount a response can be increased.

In our prior studies, we collected tumor tissue before and after dosing of our drug candidate from patients injected tumors.

We analyze for live and dead cancer cells (referred to as necrotic cells).

Our data shows that our drug candidate can kill cancer cells over a couple of weeks and activate an immune response.

We have observed these effects in multiple cancers.

INT230-6 injections were conducted on the first treatment cycle’s first day (referred to as C1D0) and on the fourteenth day (C1D14).

Our data shows that our drug candidate can kill cancer cells over a few days to a few weeks and activate an immune response.

We have observed these effects in multiple cancer types.

In the IT-01 Study, INT230-6 injections were conducted on the first treatment cycle’s first day (“C1D0”) and on the fourteenth day (“C1D14”).

Pre and post-dose biopsies from the same injected tumor were obtained on C1D0 and again 28 days later just prior to the 3 rd dose on the first day of the second treatment cycle (“C2D0”).

To determine the percentage of viable tumor cells and necrotic (dead) cancer cells pre and post two treatments, we conducted analysis on the collected tissue following haemotoxylin and eosin (“H&E”) staining.

To determine the percentage of viable tumor cells and necrotic (dead) cancer cells pre and post two treatments, we conducted analysis on the collected tissue following hemotoxylin and eosin (“H&E”) staining.

H&E tissue analysis helps identify different types of cells and provides important information about the pattern, shape, and structure of cells in a tissue sample.

For many patients, we observed substantial reductions of cancer following the two injections of INT230-6 alone.

Below are data on cell killing and immune activation from the two cancer types, breast cancer and sarcoma, for which we are planning Phase 3 programs.

Below are data on cell killing and immune activation from the two cancer types, breast cancer and sarcoma.

We also use immunohistochemistry (“IHC”) staining to help assess cancer and various immune cell populations, as well as the degree of cancer cell proliferation in the treated tumors.

Necrosis Results in Breast Cancer

Figure 11 shows tissue taken from a breast cancer patient.

Figure 12 shows tissue taken from a metastatic breast cancer patient from the IT-01 Study.

The pre-dose C1D0 samples stained positive (dark purple) indicating significant amounts of cancer throughout the sample.

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Immune Response in Breast Cancer

In preclinical studies, our technology reduces the cancer levels substantially and causes the influx of immune cells into the tumor.

In preclinical studies, our technology reduces cancer levels substantially and causes an influx of immune cells into the tumor.

The below images from a breast cancer patient confirm that this effect also occurs in humans.

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We observe infiltrating immune cells in the tumor.

In Figure 12 (below) the first panel (Image A) there is extensive cancer as the blue color seen is for 4´,6-diamidino-2-phenylindole, a blue-fluorescent DNA stain (DAPI) and the marker of live and proliferating cancer.

The green and yellow colored cells are immune cells.

The second panel (Image B) shows that at 28 days after the first dose there is a markedly reduced amount of live cancer (less blue stain).

In addition, the green/yellow stained cells, representing CD4 and CD8 T-cells, are increased dramatically throughout the entire tissue.

In Figure 13 (below) the first panel (Image A) shows extensive cancer (blue color) (DAPI) and a marker of live and proliferating cancer.

The green and yellow colors represent immune cells.

The second panel (Image B) shows that 28 days after two doses there is a markedly reduced amount of live cancer (less blue stain).

In addition, the green/yellow stained cells, representing CD4 and CD8 T-cells, are increased throughout the entire tissue.

Figure 13 — IHC Staining of breast cancer tissue for immune cell infiltration pre- and post-dosing of INT230-6

Necrosis Results in Sarcoma

Several patients with metastatic soft tissue sarcomas have been enrolled in the study.

As was seen with breast cancer and multiple other tumor types, there were substantial reductions of cancer in the biopsies pre and post in sarcoma patients.

Several patients with metastatic soft tissue sarcomas were enrolled in the IT-01 Study.

As was seen with breast cancer and multiple other tumor types, there were substantial reductions of cancer in the biopsies pre- and post-dosing.

As shown in Figure 14.

Image A is the stained tissue sample (pre-dose) that shows significant cancer (dark purple cells) throughout the tissue sample.

Image B is the stained tissue sample taken on day 28 after two doses of INT230-6 (day 0 and day 14) that shows significant reduction in the cancer (Magnification 3.7x).

Image B is the stained tissue sample taken on day 28 after two doses of INT230-6 (day 0 and day 14) that shows significant reduction in the live cancer (Magnification 3.7x).

Figure 14 — Images from match pair biopsied soft tissue sarcoma subject 010-001 pre- and post-two INT230-6 injections

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We also measured DAPI and activated T-cells from a sarcoma tumor.

The results again confirm that for this non-immunogenic tumor type, there is also a substantial reduction of tumor cells as seen by the decrease in the marker post INT230-6 treatment.

Figure 14 shows the influx for sarcoma patients into the tumor of CD4 and CD8 T-cells at 28 days following the first dose.

The results again confirm that for this non-immunogenic tumor type, there is also a substantial reduction of cancer cells as seen by the decrease in the marker post INT230-6 treatment.

Figure 15 shows the influx into the tumor of CD4 and CD8 T-cells at 28 days following the first dose.

Figure 15 — Staining of biopsied sarcoma tumor tissue pre and post dosing of INT230-6

Image A - Predose

Image A - Pre-dose

Image B - Post-dose

Results of the H&E analysis as well as the multiplex IHC staining show substantial cancer cell reduction, decreases in proliferation, and increased immune infiltration after INT230-6 dosing.

The totality of the data indicate the drug has the ability to kill cancer and increase the immune response in multiple sarcoma types.

The results of the H&E analysis and the multiplex IHC staining show substantial cancer cell reduction, decreases in proliferation, and increased immune infiltration after INT230-6 treatment.

The totality of the data indicate the drug has the ability to kill cancer and increase the immune response in sarcomas.

INT230-6 Efficacy in Soft Tissue Sarcoma

Sarcomas are a rare and heterogeneous group of solid tumors derived from mesenchymal cell origin.

Although single agent or combination anthracycline-based chemotherapy provides some benefit for the treatment of advanced sarcomas, prognosis is still unfavorable with median overall survival of 12 – 16 months and there is significant unmet medical need.

By the time subjects fail approved therapies and enter Phase 1 studies patients’ median overall survival is typically 3 – 8 months (see Subbiah, V Scientific Reports | 6:35448 | DOI:

10.1038/srep35448) depending on certain risk factors such those found in the RMHI score.

Thirty patients with sarcoma were treated in study IT-01.

Although single agent or combination anthracycline-based chemotherapy provides some benefit for the treatment of advanced sarcomas, prognosis is still unfavorable with median overall survival in the second and third line setting of 11 to 16 months and there is significant unmet medical need.

By the time subjects fail approved therapies and enter Phase 1 studies patients’ median overall survival is typically 8 to 10 months (see Subbiah, V Scientific Reports | 6:35448 | DOI:

10.1038/srep35448) depending on certain risk factors such those found in the RMHI score, and sarcoma subtype.

Thirty patients with sarcoma were treated in the IT-01 Study.

Fifteen received INT230-6 monotherapy and 15 received INT230-6 with immunotherapy.

Enrolled subjects receiving INT230-6 had a median of 3 (0, 8) prior therapies, median age

of 64 and 13% were ECOG 0, 80% ECOG 1.

Enrolled subjects receiving INT230-6 had a median of 3 (0, 8) prior therapies, median age of 64 and 13% were ECOG 0, 80% ECOG 1.

Those receiving the combination with ipilimumab had a median of 4 (0, 9) prior therapies, median age of 64 and 38% were ECOG 0, with 62% ECOG 1.

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The INT230-6 dose delivered at a single visit was up to 242 mL (112 mg of cisplatin, 24.2 mg of vinblastine sulfate) into one or more tumors.

The VIN given exceeded the typical 5.1 mg starting IV dose for an average size person.

The vinblastine given exceeded the typical 5.1 mg starting IV dose for an average size person.

The CIS given was equivalent to a typical IV dose.

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The most common treatment-related adverse events (TRAEs) in evaluable monotherapy subjects were localized pain, fatigue, decreased appetite, nausea, most of which were low grade.

Please see Table 1 in the “ Results from IT-01 Phase 1/2 Clinical Trial ” portion of our “ Business ” section on page 67 of this report for more information.

We compared our Phase 1/2 basket study survival data in soft tissue sarcoma (“STS”) to overall survival data generated from three published clinical Phase 1/2 basket trials in sarcoma.

In our trial, IT-01, fifteen (15) STS patients received only INT230-6 monotherapy and 11 have received the combination with ipilimumab.

In our IT-01 Study, fifteen (15) STS patients received only INT230-6 monotherapy and 14 have received the combination with ipilimumab.

The 3 studies used were:

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al., Scientific Reports | 6:35448 2016, Evaluation of Novel Targeted Therapies in Aggressive Biology Sarcoma Patients after progression from US FDA approved Therapies.

Each of these publications report use of the Royal Marsden Hospital index (RMHI).

Each of these publications report use of the RMHI.

As noted above the RMHI is validated score predictive of overall survival for cancer patients in basket studies.

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CI (4.8 – 10.4) CI (6.3 – 11.8) (CI (8.1 – 14.2)*

* 44% of Subbiah study subjects had a RMHI score of 0 versus 26% in Sponsor’s study IT-01

* 44% of Subbiah study subjects had a RMHI score of 0 versus 26% in Sponsor’s IT-01 Study

Though the sarcoma subtype mix between the 3 literature study populations is not matched exactly, mOS from the Jones, Cassier and Subbiah studies are similar.

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Subjects in our study primarily had a RMHI score of 1 (33%) or 2 (40%).

To be more confident that we are matching the population when comparing our drug to the Subbiah population, we created a synthetic Kaplan-Meier (KM) control curve from the Subbiah dataset that approximated our patients’ RMHI score distribution (Figure 16 below).

To be more confident that we are matching the population when

comparing our drug to the Subbiah population, we created a synthetic Kaplan-Meier control curve from the Subbiah dataset that approximated our patients’ RMHI score distribution (Figure 17 below).

We chose Subbiah as the dataset, because it was the study that reported the longest survival of the three Sarcoma studies, and would be the most conservative data to serve as the basis for a synthetic control.

Our drug is dosed based on a patient’s total measured volumetric tumor burden.

From our mouse studies we found that a dose volume to tumor volume ratio of 1 to 4 could nearly saturate a tumor.

The average TTB of patients entering the trial was 200cc.

However, when our study was initiated, the dose was limited to 5 mL per month to establish the maximum tolerated dose and generate safety data.

This early dose to tumor ratio proved to be inadequate to treat most tumors.

As a result, most early patients were under treated and the survival seen early in the study was typical of survival rates normally seen in Phase 1 basket trials.

As we moved through the dose escalation Phase of our trial and generated favorable safety data, the dose amount frequency and loading into the tumor was escalated.

We observed that if a cumulative drug dose volume equal to 40% or more of the total reported presenting tumor burden was administered over 5 sessions every two weeks with maintenance, patients showed evidence of clinical efficacy as overall survival increased.

For the INT230-6 monotherapy STS patients (N=15) with a median of 3 prior lines of therapy our median OS was 21.4 months with a confidence interval of 6.4 to 42.0 months (this dataset includes those subjects dosed with considerably less than 40% of their TTB).

In those subjects receiving a dose greater than or equal to 40% of their TTB (N=11), the OS was not reached with ~400 days of median follow-up.

Subjects receiving less than 40% of their TTB had a median survival of 4.0 months.

We calculated the KM synthetic control derived from the Subbiah basket trial matched to study IT-01 sarcoma population’s RMHI scores for all INT230-6 monotherapy patients that predicted our sarcoma patients should have had a median survival of 6.7 months.

We calculated the Kaplan-Meier synthetic control derived from the Subbiah basket trial matched to the IT-01 Study sarcoma population’s RMHI scores for all INT230-6 monotherapy patients that predicted our sarcoma patients should have had a median survival of 6.7 months.

Figure 17 — Survival of INT230-6 monotherapy sarcoma patients

Estimates of sarcoma subject survival using INT230-6 based on dose per TTB from study IT-01 compared to a synthetic control are shown in the table below.

Estimates of sarcoma subject survival using INT230-6 based on dose per TTB from the IT-01 Study compared to a synthetic control are shown in the table below.

INT230-6 Dosed

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4.0 6.7 21.3 Not reached with 400 days of median follow-up

IT-02, The INVINCIBLE-2 Study in Presurgical Breast Cancer

Phase 2 Presurgical Breast Cancer Study (“INVINCIBLE-2 Study”)

In March 2021, we began a Phase 2 Randomized, Window of Opportunity trial evaluating clinical and biological effects of intratumoral INT230-6 against no treatment (the SOC) in early-stage breast cancer patients awaiting surgery.

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The key efficacy endpoints were to (i) compare necrosis levels in tumors based on size and dose compared to saline control, (ii) the percentage of subjects having a greater than 50% reduction of viable cancer cells in their tumor compared to control, and (iii) the percentage of subjects who achieve a cell cycle arrest, defined as a reduction in the proportion of cells staining positive for Ki67, a widely used marker of cancer cell proliferation for systemic therapy.

According to our estimates using the National Cancer Database (NCBD), approximately 40% of patients diagnosed with breast cancer annually, there are nearly 100,000 that have no therapeutic treatment following diagnosis.

According to our estimates using the National Cancer Database, approximately 40% of patients diagnosed with breast cancer annually, there are nearly 100,000 that have no therapeutic treatment following diagnosis.

Women undergoing surgery typically wait approximately 2 to 6 weeks to have the procedure.

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The Ontario Institute of Cancer Research analyzed subject immune responses, Ki67 and conducted immune biomarker analysis.

Ozmosis Research Inc., a Toronto-based CRO, managed the data and study in Canada.

Ozmosis Research

Inc., a Toronto-based CRO, managed the data and study in Canada.

Intensity funded the trial and provided INT230-6 supply.

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In the control groups, no subjects achieved an MPR (n=29).

IT-02 (The INVINCIBLE-2 Study) Tumor Necrosis via Diffusion

Tissue taken via biopsy from tumor in our metastatic study IT-01 shows that viable cancer cells are significantly reduced.

Tumor Necrosis via Diffusion

Tissue taken via biopsy from tumor in the IT-01 Study shows that viable cancer cells are significantly reduced.

However, in our INVINCIBLE 2 study, surgeons also removed the entire breast cancer tumor following INT230-6 injection.

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Both tumors shown with high grade (3) proliferative tumors.

IT-02 (The INVINCIBLE-2 Study) Immune Activation

Immune Activation

Intensity presented positive INT230-6 data in patients with early-stage breast cancer in a podium poster spotlight discussion at the 2023 SABCS on December 8, 2023.

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T-cells are an important systemic component of the adaptive immune system that aid in the destruction of invaders.

Immune repertoire refers to all the unique T-cell receptor (TCR) and B-cell receptor (BCR) genetic rearrangements.

Immune repertoire refers to all the unique T-cell receptor (“TCR”) and B-cell receptor genetic rearrangements.

Only lymphocytes that encounter an antigen with the right receptor to bind to it will be activated and proliferate during an immune response, forming a clone of cells with identical antigen receptors for attack.

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Both of these study findings support the hypothesis that IT INT230-6 prior to SOC neoadjuvant therapy could increase pCR rates in high-risk patients.

Planned Clinical Programs

Phase 3 Metastatic Soft Tissue Sarcoma (INVINCIBLE-3 Study)

Given the positive data on survival seen in our metastatic study in sarcoma patients, we plan to conduct a single Phase 3 study in 2 nd /3 rd line treatment for locally advanced, recurrent, inoperable, or metastatic non-diffuse soft tissue sarcoma with overall survival as the primary endpoint.

The current Phase 3 study design plans to enroll subjects who will be randomized 2 to 1 to either INT230-6 for 5 doses Q2 weeks with maintenance dosing every 9 weeks for 2 years or the SOC.

Phase 3 Metastatic Soft Tissue Sarcoma Study (“INVINCIBLE-3 Study”)

In July 2024, we initiated and dosed our first patient in the INVINCIBLE-3 Study, a phase 3 study in 2 nd /3 rd line treatment for locally advanced, recurrent, inoperable, or metastatic non-diffuse soft tissue sarcoma with overall survival as the primary endpoint in a subset of advanced soft tissue sarcoma patients (leiomyosarcoma, liposarcoma and undifferentiated pleomorphic sarcoma).

These subtypes comprise over 80% of the sarcoma populations.

This study has been authorized by the FDA, Health Canada, the European Medicines Authority, and Australia's Therapeutics Goods Administration.

The trial is enrolling patients and is being conducted in eight countries:

the US, Australia, Canada, France, Germany, Italy, Poland, and Spain.

Up to 60 sarcoma-focused hospitals and other centers are expected to participate from these countries.

The INVINCIBLE-3 Study will randomize patients 2 to 1 to either INT230-6 for 5 doses Q2 weeks with maintenance dosing every 9 weeks for 2 years or the SOC.

The three drugs most used for soft tissue sarcoma will be the control SOC at the investigator’s choice depending on the type of sarcoma.

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The final analysis will be based on 80% of events (266 deaths).

A protocol synopsis was developed and submitted to the FDA.

On October 14, 2021, we met with the FDA to discuss the Phase 3 protocol and reached alignment on the Phase 3 study design, patient population and statistical approach..

In November 2023, we submitted our IND to the FDA with the proposed full protocol.

In December 2023, we received the Study May Proceed Letter from the FDA for our phase 3 trial in less than 30 days from the IND submission.

Figure 20 shows the survival curves from five recent Phase 3 studies using now approved SOC drugs for sarcoma, and also shows the expected Phase 3 survival for 1) the blended control based on the likely mix of sarcoma types (green curve) and 2) the expected INT230-6 Phase 3 survival curve that was generated based on our clinical results in sarcoma (navy blue curve).

See Figure 21 below for INVINCIBLE-3 Study schema.

Figure 21 — The INVINCIBLE-3 Study schema comparing INT230-6 to the approved 2 nd or 3 rd line standard of care drugs

Figure 22 shows the survival curves from five recent Phase 3 studies using now approved SOC drugs for sarcoma, and also shows the expected Phase 3 survival for 1) the blended control based on the likely mix of sarcoma types (green curve) and 2) the INT230-6 survival curve based on the IT-01 Study results for sarcoma patients only (navy blue curve).

The references showing the Phase 3 data for the SOC controls are;

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It is notable that despite different regimens and sarcoma subtype distributions, the overall survival is consistent for the current SOC drugs.

Our Phase 2 program enrolled sarcoma patients with mixed subtypes whose cancer progressed despite a median of 3 prior treatments.

We plan to enroll a similar mix of sarcoma patients;

in Phase 3, however, no patient will have progressed on more than 2 treatments.

Thus, patients in our planned Phase 3 study should be healthier than those treated in our Phase 2 study.

Over 25% of patients in our Phase 2 study were well underdosed, and based on the tumor necrosis levels seen in IT-02, the dose loading into the tumor was insufficient for high levels of necrosis in the prior studies.

In the planned Phase 3 study, underdosing of patients will be less likely to occur, given dosing of INT230-6 can be as high as 175mL from day 1.

Patients in the planned Phase 3 program shall also receive long term maintenance treatment of INT230-6 every 12 weeks, which mostly did not occur for many patients in our Phase 2 program.

Figure 20 — Survival curves of standard of care drugs and INT230-6 based on Phase 2

Our IT-01 Study enrolled sarcoma patients with mixed subtypes whose cancer progressed despite a median of 3 prior treatments.

We plan to enroll a similar mix of sarcoma patients in the INVINCIBLE-3 Study, however, no patient will have progressed on more than 2 treatments.

Thus, patients in the INVINCIBLE-3 Study should be healthier than those treated in our IT-01 Study, where over 25% of patients were well underdosed, and based on the tumor necrosis levels observed.

In the INVINCIBLE-3 Study, underdosing of patients will be less likely, given dosing of INT230-6 can be as high as 175mL from day 1, and patients will also receive long term maintenance treatment of INT230-6 every 12 weeks.

Figure 22 — Overall survival curves of standard of care drugs from phase 3 trials, and INT230-6 survival curve based on IT-01 Study sarcoma patient results.

The survival curves from five recent Phase 3 studies using now approved standard of care drugs for sarcoma.

The figure also shows the expected Phase 3 survival for 1) the blended control based on the likely mix of sarcoma types (green curve) and 2) the expected INT230-6 Phase 3 survival curve that was generated based on our clinical results in sarcoma (navy blue curve), which was conducted in a less healthy sarcoma population.

Figure 21 — The expected Phase 3 study schema comparing INT230-6 to the approved 2 nd or 3 rd line standard of care drugs

The current Phase 3 design proposes an endpoint of overall survival in a subset of advanced soft tissue sarcoma patients (leiomyosarcoma, liposarcoma and undifferentiated pleomorphic sarcoma).

These subtypes comprise over 80% of the sarcoma populations.

We plan to enroll two subjects in the INT230-6 group per one subject of any of the three SOC used drugs which will depend on the patient’s type of sarcoma.

INT230-6 will be dosed every 2 weeks for 5 doses with maintenance every 12 weeks.

The SOC drugs will be dosed at their approved regimens in each country.

We anticipate 9 countries in North America, Europe and the Pacific will participate in this study.

Phase 2/3 Pre-surgical (Neoadjuvant) Triple Negative Breast (INVINCIBLE-4 or IT-04)

In November 2020, we met with the FDA to discuss use of our drug prior to surgery for breast cancer patients at high risk of disease recurrence such as those with triple negative breast cancer for potential accelerated approval.

The figure also shows the expected Phase 3 survival for 1) the blended control based on the likely mix of sarcoma types (green curve) and 2) the INT230-6 survival curve based on the IT-01 Study results for sarcoma patients only (navy blue curve), which was conducted in a less healthy sarcoma population.

Phase 2 Pre-surgical (Neoadjuvant) Triple Negative Breast Cancer Study (“INVINCIBLE-4 Study”)

In October 2024, in collaboration with SAKK, we initiated and dosed our first patient in the INVINCIBLE-4 Study, a phase 2 study to treat patients with localized TNBC.

The INVINCIBLE-4 Study is a randomized open-label, multicenter study to determine the clinical activity, safety, and tolerability of INT230-6 in patients with tumors greater than two centimeters having early-stage, operable TNBC.

These patients undergo SOC treatment, which consists of pembrolizumab, anthracyclines, carboplatin, cyclophosphamide, and paclitaxel.

The primary endpoint is pCR in the primary tumor and affected lymph nodes.

Patients will be randomized one to one to receive a regimen of two doses of INT230-6 followed by SOC, or SOC alone.

The study is expected to enroll 54 patients in up to 16 centers in Switzerland and France.

The FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint.

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The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.

The surrogate endpoint we discussed with the FDA was pathological complete response.

In November 2020, we met with the FDA to discuss use of our drug prior to surgery for breast cancer patients at high risk of disease recurrence such as those with TNBC for potential accelerated approval.

The surrogate endpoint we discussed with the FDA was pCR, defined as the absence of residual invasive and in situ cancer on H&E evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy.

pCR is an accepted FDA criteria for triple negative breast cancer for accelerated approval.

Preoperative or neoadjuvant systemic chemotherapy, once reserved for patients with locally advanced breast cancer in whom the goal was to render large breast cancers operable, has become increasingly common.

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Finally, the neoadjuvant setting offers investigators the unique opportunity to examine modulation of tissue, imaging, and other biomarkers from the time of biopsy to the time of definitive breast surgery following preoperative systemic therapy.

Pathological complete response (“pCR”) is an accepted FDA criteria for triple negative breast cancer for accelerated approval.

pCR is defined as the absence of residual invasive and in situ cancer on H&E evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy.

On July 26, 2021, the FDA approved pembrolizumab (brand name Keytruda) for high-risk, early-stage, triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

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The data on percent tumor necrosis form the phase 2 INVINCIBLE-4 Study will indicate how much necrosis can be induced upfront.

Following receipt of the final data from the phase 2 INVINCIBLE-4 Study, we plan to request another meeting with the FDA to review a Phase 3 randomized trial in neoadjuvant breast cancer with pCR improvement as the endpoint.

The design of the Phase 2/3 study for presurgical use would be to add INT230-6 injection(s) in front of the SOC, which is chemotherapy with pembrolizumab, in TNBC and/or HER2+ versus SOC.

The first endpoint would be for accelerated approval using Pathological Complete Response (pCR).

Data for approval could be obtained 4 months post enrollment of the last patient.

For full drug approval we would continue to enroll to show that the addition of INT230-6 to the SOC could lead to event free survival (EFS).

The full approval endpoint would likely be at 3 years post-enrollment of the full EFS study.

The Phase 2 design of the program is shown in Figure 22 below.

Figure 22 — The expected Phase 2 and 3 study schema comparing INT230-6 to the approved 2 nd or 3 rd line standard of care drugs

Phase 2 Metastatic Triple Negative Breast Cancer (contingent on additional capital raises) .

The Phase 2 design of the INVINCIBLE-4 Study is shown in Figure 23 below.

Figure 23 — The INVINCIBLE-4 Study schema comparing INT230-6 to the approved 2 nd or 3 rd line standard of care drugs

Phase 2 Metastatic Triple Negative Breast Cancer Study (contingent on additional capital raises)

The FDA designation of INT230-6 for Fast Track was made in 2018 as response to our proposed development program evaluating INT230-6 for the treatment of patients with relapsed or metastatic triple negative breast cancer.

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Sacituzumab extended median overall survival to 10.9 months versus 4.9 months with chemotherapy (HR:

With a small sample size in study IT-01 INT230-6 either as monotherapy or with pembrolizumab has shown in refractory metastatic breast cancer (all types) a median overall survival of 12 months (n=9), and in subset of just m TNBC subjects, a median overall survival of approximately 12.5 months.

With a small sample size in the IT-01 Study, INT230-6 either as monotherapy or with pembrolizumab has shown in refractory metastatic breast cancer (all types) a median overall survival of 12 months (n=9), and in subset of just m TNBC subjects, a median overall survival of approximately 12.5 months.

INT230-6 Phase 2/3 study design would consist of metastatic TNBC patients whose cancer has progressed following 1 to 2 lines of prior therapy.

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The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs such as those we are developing.

We, along with our vendors, collaboration partners, CROs and contract manufacturers, will be required to navigate the various preclinical, clinical,

manufacturing and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval of our product candidate.

We, along with our vendors, collaboration partners, CROs and contract manufacturers, will be required to navigate the various preclinical, clinical, manufacturing and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval of our product candidate.

The process of obtaining regulatory approvals of drugs and ensuring subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.

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The process required by the FDA before our product candidate is approved for therapeutic indications and may be marketed in the United States generally involves the following:

• completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with Good Laboratory Practice, or GLP, requirements;

• completion of extensive nonclinical studies in accordance with applicable regulations, including studies conducted in accordance with good laboratory practice (“GLP”) requirements;

• submission to the FDA of an IND, which must become effective before clinical trials may begin and must be updated annually or when significant changes are made;

• approval by an Institutional Review Board, or IRB, or independent ethics committee at each clinical trial site before each trial may be initiated;

• performance of adequate and well-controlled clinical trials in accordance with Good Clinical Practice, or GCP requirements and other clinical trial-related regulations to establish the safety and efficacy of the proposed drug product candidate for its intended purpose;

• approval by an institutional review board (“IRB”) or independent ethics committee at each clinical trial site before each trial may be initiated;

• performance of adequate and well-controlled clinical trials in accordance with good clinical practice (“GCP”) requirements and other clinical trial-related regulations to establish the safety and efficacy of the proposed drug product candidate for its intended purpose;

• preparation and submission to the FDA of a NDA after completion of all pivotal trials;

• a determination by the FDA of its receipt of an NDA, to file the application for review;

• a determination by the FDA after its receipt of an NDA, to file the application for review;

• satisfactory completion of one or more FDA pre-approval inspections of the manufacturing facility or facilities where the product will be produced to assess compliance with cGMP requirements, to assure that the facilities, methods and controls are adequate to assure the drug product’s identity, strength, quality and purity;

• potential FDA audit of the clinical trial sites that generated the data in support of the NDA;

• potential FDA audit of the clinical trial sites that generated the data in support of the NDA to confirm compliance with GCP requirements and data integrity;

• payment of user fees for FDA review of the NDA;

• FDA review and approval of the NDA, including consideration of the views of any FDA advisory committee, prior to any commercial marketing or sale of the drug product in the United States.

• FDA review and approval of the NDA, including satisfactory completion of an FDA advisory committee review of the product candidate, if applicable, prior to any commercial marketing or sale of the drug product in the United States.

Preclinical and clinical trials for drug products

Before testing any drug in humans, the product candidate must undergo rigorous preclinical testing.

Before testing any drug in humans, the product candidate must undergo rigorous preclinical, or nonclinical, testing.

Preclinical studies include laboratory evaluations of chemistry, formulation and stability, as well as in vitro and animal studies to assess safety and in some cases to establish the rationale for therapeutic use.

The conduct of preclinical studies is subject to federal and state regulations and requirements, including GLP requirements for safety and toxicology studies.

The Consolidated Appropriations Act for 2023, signed into law on December 29, 2022, (P.L.

117-328) amended the FDCA to specify that nonclinical testing for drugs may, but is not required to, include in vivo animal testing.

According to the amended language, a sponsor may fulfill nonclinical testing requirements by completing various in vitro assays (e.g., cell-based assays, organ chips, or microphysiological systems), in silico studies (i.e., computer modeling), other human or non-human biology-based tests (e.g., bioprinting), or in vivo animal tests.

The conduct of preclinical studies is subject to federal and state regulations and requirements, including GLP requirements for safety and toxicology studies as well as the U.S.

Department of Agriculture’s Animal Welfare Act, if applicable.

The results of the preclinical studies, together with manufacturing information and analytical data must be submitted to the FDA as part of an IND.

An IND is a request for authorization from the FDA to administer an investigational product to humans, and must become effective before clinical trials may begin.

An IND is a request for authorization from the FDA to administer an investigational drug product to humans and must become effective before clinical trials may begin.

The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies.

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and any available human data or literature to support the use of the investigational product.

The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises concerns or questions about the conduct of the clinical trial, including concerns that human research subjects will be exposed to unreasonable health risks, and imposes a clinical hold.

The IND automatically becomes effective 30 days after receipt by the FDA, unless the agency, within the 30-day time period, raises concerns or questions about one or more proposed clinical trials, including concerns that human research subjects will be exposed to unreasonable health risks, and imposes a clinical hold.

In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.

Some long-term preclinical testing may continue after the IND is submitted.

Accordingly, submission of an IND may or may not result in FDA authorization to begin a trial.

A separate submission to an existing IND must also be made for each successive clinical trial conducted during product development of a product candidate, and the FDA must grant permission, either explicitly or implicitly by not objecting, before each clinical trial can begin.

The clinical-stage of development involves the administration of the product candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCP requirements, which include the requirements that all research subjects provide their

informed consent for their participation in any clinical trial.

Some long-term nonclinical testing may continue after the IND is submitted.

A separate submission to an existing IND must also be made for each successive clinical trial conducted during development of a product candidate, and the FDA must grant permission, either explicitly or implicitly by not objecting, before each clinical trial can begin.

For cancer patients, the Phase 1 usually involves patients whose cancer has progressed following all approved therapies for that particular cancer.

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Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.

Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable related to the anticipated benefits.

The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative, and must monitor the clinical trial until completed.

The FDA, the IRB, or the sponsor may suspend or discontinue a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk.

Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

There also are requirements governing the reporting of ongoing clinical trials and completed clinical trials to public registries.

Information about applicable clinical trials, including clinical trials results, must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website.

Disclosure of the results of such trials can be delayed in some cases for up to two years after the date of completion of the trial.

Some clinical trials also include oversight by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may recommend that the sponsor halt the clinical trial if the data safety monitoring board determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

There also are requirements governing the reporting of certain ongoing clinical trials and completed clinical trials to public registries.

Information about applicable clinical trials, including trial results, must be submitted to the NIH within specific timeframes for publication on the ClinicalTrials.gov data registry.

Sponsors of clinical trials registered with NIH are obligated to disclose the results of such trials, but such disclosure can be delayed in some cases for up to two years after the date of completion of the trial.

Failure to timely register a covered clinical trial or to submit trial results as provided for in the law can give rise to civil monetary penalties and also prevent the non-compliant party from receiving future grant funds from the federal government.

Both the NIH and the FDA have signaled willingness to enforce requirements under the NIH’s Final Rule on ClinicalTrials.gov registration and reporting requirements.

Starting in 2021, the FDA has issued Notices of Non-Compliance to several companies in connection with ClinicalTrials.gov.

We have conducted our trials in Canada under a Clinical Trial Agreement with Health Canada, the regulatory authority in Canada.

While we plan to conduct any international clinical trials under appropriate country filings in the future, a sponsor who wishes to conduct a clinical trial outside of the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND.

The FDA will accept a well-designed and well-conducted foreign clinical study not conducted under an IND if the study was conducted in accordance with GCP requirements, and the FDA is able to validate the data through an onsite inspection if deemed necessary.

Department of Health and Human Services’ final rule and NIH’s complementary policy on ClinicalTrials.gov registration and reporting requirements became effective in 2017, and the government has brought enforcement actions against clinical trial sponsors that fail to comply with such requirements.

We have conducted our trials in Canada under a clinical trial authorization from Health Canada, the regulatory authority in Canada.

While we plan to conduct any international clinical trials we sponsor under appropriate country filings in the future, a sponsor who wishes to conduct a clinical trial outside of the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND.

The FDA will accept as support for an IND or application for marketing approval a well-designed and well-conducted foreign clinical study not conducted under an IND if the study was conducted in accordance with GCP requirements, and the FDA is able to validate the data through an onsite inspection if deemed necessary.

Clinical trials to evaluate therapeutic indications to support NDAs for marketing approval are typically conducted in three sequential phases, which may overlap.

• Phase 1 — Phase 1 clinical trials involve initial introduction of the investigational product into healthy human volunteers or patients with the target disease or condition.

These studies are typically designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, evaluate the side effects associated with increasing doses, and, if possible, to gain early evidence of effectiveness.

As noted above for new cancer treatments such as ours, the Phase 1 involves patients whose cancer has progressed following all approved therapies for that particular cancer not healthy volunteers.

• Phase 2 — Phase 2 clinical trials typically involve administration of the investigational product to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.

• Phase 1 — The investigational product is introduced into healthy human volunteers or patients with the target disease or condition.

These studies are typically designed to test the safety, dosage tolerance, absorption, metabolism, distribution and excretion of the investigational product in humans, evaluate the side effects associated with increasing doses, and, if possible, to gain early evidence of effectiveness.

As noted above for new cancer treatments such as ours, or other severe or life-threatening diseases, especially where the product may be too inherently toxic to ethically administer to healthy volunteers, initial human testing is often conducted with patients.

• Phase 2 — This phase typically involve administration of the investigational product to a limited patient population with a specified disease or condition to identify possible adverse side effects and safety risks, preliminarily evaluate the efficacy, and to determine dosage tolerance, optimal dosages and dosing schedule.

Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.

• Phase 3 — Phase 3 clinical trials typically involve administration of the investigational product to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites.

These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval.

Generally, one or two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA.

• Phase 3 — These clinical trials typically involve administration of the investigational product to an expanded patient population, generally at multiple geographically dispersed trial sites, to further evaluate dosage, clinical efficacy and safety.

Such trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide, if appropriate, an adequate basis for product approval and labeling.

Generally, two adequate and well-controlled Phase 3 clinical trials, or in certain cases one large multicenter trial with robust results, are required by the FDA to support approval of an NDA.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.

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In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

Progress reports detailing the results of the clinical trials, among other information, must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA and the investigators fifteen days after

the trial sponsor determines the information qualifies for reporting for serious and unexpected suspected adverse events, findings from other studies or animal or in vitro testing that suggest a significant risk for human participants exposed to the investigational product and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

A pivotal trial is a clinical trial that is believed to satisfy FDA requirements for the evaluation of a product candidate’s safety and efficacy such that it can be used, alone or with other pivotal or non-pivotal trials, to support regulatory approval.

Generally, pivotal trials are Phase 3 trials, but they may be Phase 2 trials if the design provides a well-controlled and reliable assessment of clinical benefit, particularly in an area of unmet medical need.

Congress also recently amended the FDCA, as part of the Consolidated Appropriations Act for 2023, in order to require sponsors of a Phase 3 clinical trial, or other “pivotal study” of a new drug to support marketing authorization, to design and submit a diversity action plan for such clinical trial.

The action plan must include the sponsor’s diversity goals for enrollment, as well as a rationale for the goals and a description of how the sponsor will meet them.

Sponsors must submit a diversity action plan to the FDA by the time the sponsor submits the relevant clinical trial protocol to the agency for review.

The FDA may grant a waiver for some or all of the requirements for a diversity action plan.

It is unknown at this time how the diversity action plan may affect Phase 3 trial planning and timing, but if the FDA objects to a sponsor’s diversity action plan or otherwise requires significant changes to be made, it could delay initiation of the relevant clinical trial.

trial sponsor determines the information qualifies for reporting for serious and unexpected suspected adverse events, findings from other studies or animal or in vitro testing that suggest a significant risk for human participants exposed to the investigational product and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

The sponsor must also notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than seven calendar days after the sponsor’s initial receipt of the information.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the drug characteristics of the product candidate and finalize a process for manufacturing the drug product in commercial quantities in accordance with cGMP requirements.

Concurrent with clinical trials, companies usually complete additional nonclinical studies and must also develop additional information about the drug characteristics of the product candidate and finalize a process for manufacturing the drug product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product candidate and manufacturers must develop, among other things, methods for testing the identity, strength, quality and purity of the final drug product.

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NDA Submission and Review by the FDA

We intend to seek data exclusivity or market exclusivity for INT230-6.

Assuming successful completion of the required clinical testing, the results of the preclinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications.

An NDA is a request for approval to market a new drug for one or more specified indications.

Assuming successful completion of all required clinical testing in accordance with applicable regulatory requirements, detailed information on the product candidate’s is submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications.

The NDA must include all relevant data available from pertinent pre-clinical and clinical studies, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things.

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To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of the FDA.

FDA approval of an NDA must be obtained before a chemical drug may be marketed in the United States.

In addition, under the Pediatric Research Equity Act, or PREA, an NDA or supplement to an NDA must contain data to assess the safety and effectiveness of the drug 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 Food and Drug Administration Safety and Innovation Act requires that a sponsor who is planning to submit a marketing application for a drug product that includes a new clinically active component, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan (PSP) within sixty days after an end-of-Phase 2 meeting or as may be agreed between the sponsor and the FDA.

The FDA may grant deferrals for submission of pediatric data or full or partial waivers.

FDA approval of an NDA must be obtained before a drug product may be marketed in the United States.

In addition, under the Pediatric Research Equity Act (“PREA”), an NDA or supplement to an NDA, for a new active ingredient, indication, dosage form, dosage regimen, or route of administration must contain data that are adequate to assess the safety and effectiveness of the drug 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.

A sponsor who is planning to submit a marketing application for a drug product that includes a new clinically active component, new indication, new dosage form, new dosing regimen or new route of administration must submit an initial Pediatric Study Plan (“PSP”) within sixty days after an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of the pivotal clinical trial.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including trial objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

The FDA and the sponsor must reach an agreement on the PSP.

A sponsor can submit amendments to an agreed upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from pre-clinical studies, early phase clinical trials or other clinical development programs.

The FDA may, on its own initiative or at the sponsor’s request, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adult populations, or full or partial waivers from the pediatric data requirements.

Unless otherwise required by regulation, PREA does not apply to any drug product for an indication for which orphan designation has been granted.

The FDA reviews all submitted NDAs before it accepts them for filing, and may request additional information rather than accepting the NDA for filing.

The FDA reviews all submitted NDAs to ensure that they are sufficiently complete for substantive review before it accepts them for filing, and may request additional information rather than accepting the NDA for filing.

The FDA must make a decision on accepting an NDA for filing within 60 days of receipt, and such decision could include a refusal to file by the FDA.

If the FDA refuses to file the NDA and requests additional information, the application must be resubmitted with the requested information.

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

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

The FDA reviews an NDA to determine, among other things, whether the product is safe and effective and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued identity, strength, quality and purity.

Under the goals and polices agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, the FDA targets ten months, from the filing date, in which to complete its initial review of an original NDA and respond to the applicant, and six months from the filing date of an original NDA filed for priority review.

The FDA does not always meet its PDUFA goal dates for standard or priority NDAs, and the review process is often extended by FDA requests for additional information or clarification.

The FDA reviews an NDA to determine, among other things, whether the product is safe and effective for the proposed indication and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued identity, strength, quality and purity.

Under the goals and polices agreed to by the FDA under the Prescription Drug User Fee Act (“PDUFA”), the FDA targets ten months, from the filing date, in which to complete its initial review of an original NDA and respond to the applicant, and six months from the filing date of an original NDA is granted priority review.

The FDA does not always meet its PDUFA goal dates for standard or priority NDAs, and the

review process is often extended by FDA requests for additional information or clarification and the sponsor’s process to respond to such inquiries.

As a result, the NDA review process can be quite lengthy.

Further, under PDUFA, as amended, each NDA must be accompanied by a substantial user fee, and the sponsor of an approved NDA is also subject to an annual program fee for each approved drug product.

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Fee waivers or reductions may be available in certain circumstances, including a waiver of the application fee for the first application filed by a small business.

Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

The FDA may refer an application for a new drug product to an advisory committee.

An advisory committee is a panel of independent experts, including clinicians and other scientific experts, which reviews, evaluates and provides a

recommendation as to whether the application should be approved and under what conditions.

Additionally, no application user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

During its review of an NDA, the FDA may refer an application for a new drug product to an advisory committee.

An advisory committee is a panel of independent experts, including clinicians and other scientific experts, which reviews, evaluates and provides 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.

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Additionally, before approving an NDA, the FDA may inspect one or more clinical trial sites to assure compliance with GCP and other requirements and the integrity of the clinical data submitted to the FDA.

The FDA also may require submission of a Risk Evaluation and Mitigation Strategy, or REMS, as a condition for approving the NDA to ensure that the benefits of the product outweigh its risks.

The FDA also may require submission of a Risk Evaluation and Mitigation Strategy (“REMS”) as a condition for approving the NDA to ensure that the benefits of the product outweigh its risks.

The REMS could include medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, or other risk-minimization tools.

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter or a Complete Response Letter.

A Complete Response Letter indicates that the review cycle of the application is complete and the application is not ready for approval.

A Complete Response Letter will usually describe all of the deficiencies that the FDA has identified in the NDA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the Complete Response Letter without first conducting required inspections, testing submitted product lots, and/or reviewing proposed labeling.

In issuing the Complete Response Letter, the FDA may recommend actions that the applicant might take to place the NDA in condition for approval, including requests for additional information or clarification.

Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

The FDA determines the requirement for a REMS, as well as the specific REMS provisions, on a case-by-case basis.

If the FDA concludes a REMS plan is needed, the sponsor of the NDA must submit a proposed REMS plan.

The FDA will not approve an NDA without a REMS plan, if required.

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA will issue either an approval letter or a Complete Response Letter (“CRL”).

A CRL indicates that the review cycle of the application is complete and the application will not be approved in its present form.

A CRL will usually describe all of the deficiencies that the FDA has identified in the NDA.

The deficiencies identified may be minor, for example, requiring labeling changes, or major, for example, requiring additional clinical trials.

In issuing the CRL, the FDA may recommend actions that the applicant might take to place the NDA in condition for approval, including requests for additional information or clarification.

If a CRL is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application.

However, even with submission of the additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter.

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

Even if the FDA approves a product, depending on the specific risk(s) to be addressed, the FDA may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a product’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product.

Even if the FDA approves a drug product, depending on the specific risk(s) to be addressed, the FDA may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a product’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, any of which can materially affect the potential market and profitability of the product.

The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs.

After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes, and additional labeling claims, are subject to further testing requirements and FDA review and approval.

Expedited Development and Review Programs for Drugs

The FDA maintains several programs intended to facilitate and expedite development and review of new drugs to address unmet medical needs in the treatment of serious or life-threatening diseases or conditions.

These programs include Fast Track Designation, Breakthrough Therapy designation, priority review and Accelerated Approval.

A new drug product is eligible for Fast Track Designation if it is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address unmet medical needs for such disease or condition.

Fast Track Designation applies to the combination of the product and the specific indication for which it is being studied.

Fast Track Designation provides increased opportunities for sponsor interactions with the FDA during preclinical and clinical development, in addition to the potential for rolling review once a marketing application is filed, meaning that the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

Fast Track, Breakthrough Therapy and Priority Review

The FDA maintains several programs designed to facilitate and expedite development and review of certain new drugs that are intended for the treatment of serious or life-threatening diseases or conditions and that demonstrate the potential to address unmet medical needs or represent a significant improvement over existing therapies.

These programs include fast track designation, breakthrough therapy designation, and priority review.

A new drug product is eligible for fast track designation if it is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address an unmet medical need by providing a therapy where none exists or a therapy that may be superior to existing therapies based on efficacy or safety factors.

Fast Track Designation provides increased opportunities for more frequent sponsor interactions with the FDA during product development to help facilitate

and expedite the development and review process.

In addition, the FDA may initiate a rolling review once a marketing application is filed, meaning that the agency may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

In addition, a new drug product may be eligible for breakthrough therapy designation if it is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug, alone or in combination with one or more other drugs or biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

Breakthrough therapy designation provides all the features of fast track designation in addition to intensive guidance on an efficient development program beginning as early as Phase 1, and FDA organizational commitment to expedited development, including involvement of senior managers and experienced review staff in a cross-disciplinary review, where appropriate.

Any product submitted to the FDA for approval, including a product with Fast Track or Breakthrough Therapy designation, may also be eligible for additional FDA programs intended to expedite the review and approval process, including priority review and Accelerated Approval.

A product is eligible for priority review if it is intended to treat a serious or life-threatening disease or condition, and if approved, would provide a significant improvement in safety or effectiveness.

For original NDAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date (compared with ten months under standard review).

A product intended to treat serious or life-threatening diseases or conditions may receive Accelerated Approval upon a determination that the product has 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 on irreversible morbidity or mortality which is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

Accelerated Approval is usually contingent on a sponsor’s agreement to conduct additional post-approval studies to verify and describe the product’s clinical benefit.

The FDA may withdraw approval of a drug approved under Accelerated Approval if, for example, the sponsor fails to conduct the confirmatory trials in a timely manner or the confirmatory trial fails to verify the predicted clinical benefit of the product.

In addition, unless otherwise informed by the FDA, the FDA currently requires, as a condition for Accelerated Approval, that all advertising and promotional materials that are intended for dissemination or publication within 120 days following marketing approval be submitted to the agency for review during the pre-approval review period, and that after 120 days following marketing approval, all advertising and promotional materials must be submitted at least 30 days prior to the intended time of initial dissemination or publication.

Fast Track Designation, Breakthrough Therapy designation, priority review and Accelerated Approval do not change the scientific or medical standards for approval or the quality of evidence necessary to support approval but may expedite the development or review process.

Finally, the FDA may grant priority review to a product candidate intended to treat a serious or life-threatening disease or condition, and if approved, would provide a significant improvement in safety or effectiveness over existing therapies.

The FDA determines at the time that the NDA is submitted, on a case-by-case basis, whether the proposed drug product represents a significant improvement in treatment, prevention or diagnosis of disease when compared with other available therapies.

Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes, or evidence of safety and effectiveness in a new subpopulation.

A priority review designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for taking action on a NDA from ten months to six months for an original application from the date of filing.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decided that the time period for FDA review or approval will not be shortened.

Furthermore, fast track designation, breakthrough therapy designation and priority review do not change the scientific or medical standards for approval or the quality of evidence necessary to support approval and may not ultimately expedite the development or review process.

Accelerated Approval

In addition, products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval from the FDA and may be approved on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

The FDA may also grant accelerated approval for such a drug or biologic when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality (“IMM”), and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA will require that a sponsor of a drug receiving accelerated approval perform post-marketing clinical trials to verify and describe the predicted effect on IMM or other clinical endpoint, and the product may be subject to expedited withdrawal procedures.

Drugs and biologics granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.

For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.

Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints.

An intermediate clinical endpoint is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug or biologic, such as an effect on IMM.

The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints, but has indicated that such endpoints generally may support accelerated approval when the therapeutic effect measured by the endpoint is not itself a clinical benefit and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate long-term clinical benefit of a drug or biologic.

The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a drug or biologic, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly.

For example, accelerated approval has been used extensively in the development and approval of drugs and biologics for treatment of a variety of cancers in which the goal of therapy is

generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large clinical trials to demonstrate a clinical or survival benefit.

The accelerated approval pathway is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the drug’s clinical benefit.

As a result, a product candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to establish the effect on the clinical endpoint.

Failure to conduct required post-approval studies, or to confirm the predicted clinical benefit of the product during post-marketing studies, would allow the FDA to withdraw approval of the drug.

Congress recently provided FDA with additional statutory authority to mitigate potential risks to patients from continued marketing of ineffective drugs previously granted accelerated approval.

Under the act’s amendments to the FDCA, FDA may require the sponsor of a product granted accelerated approval to have a confirmatory trial underway prior to approval.

The sponsor must also submit progress reports on a confirmatory trial every six months until the trial is complete, and such reports are published on FDA’s website.

The amendments also give FDA the option of using expedited procedures to withdraw product approval if the sponsor’s confirmatory trial fails to verify the claimed clinical benefits of the product.

All promotional materials for product candidates being considered and approved under the accelerated approval program are subject to prior review by the FDA.

Post-Approval Requirements for Drugs

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Although physicians may prescribe approved products for off-label uses, manufacturers may not market or promote such uses.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, including not only by our employees but also by agents of us or those speaking on our behalf, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, including not only by a manufacturer’s employees but also by its agents or those speaking on its behalf, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties, including liabilities under the False Claims Act where products carry reimbursement under federal health care programs.

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For example, the FDA may require post-market testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

In addition, drug manufacturers and their subcontractors involved in the manufacture and distribution of approved products are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMP, which impose certain procedural and documentation requirements upon us and our contract manufacturers.

FDA may also condition approval of a drug product on the development and approval of a REMS.

A REMS could include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of products.

Product approvals may be withdrawn for non-compliance with regulatory standards or if problems occur following initial marketing.

In addition, drug manufacturers and their subcontractors involved in the manufacture of approved products are required to register their establishments with the FDA and certain state agencies and are subject to periodic scheduled or unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMP regulations, which impose certain procedural and documentation requirements upon us and our contract manufacturers.

Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented.

FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting requirements upon us and any third-party manufacturers that we may decide to use.

FDA regulations also require investigation and correction of any deviations from cGMP requirements and impose reporting requirements upon us and any third-party manufacturers that we may decide to use.

Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance.

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There is also a continuing, annual program fee for any marketed product.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information, requirements for post-market studies or clinical trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS.

Once a drug product is granted marketing approval, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information, requirements for post-market studies or clinical trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS.

Other potential consequences include, among other things:

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• consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act, or PDMA, which regulates the distribution of drugs and drug samples at the federal level, and sets minimum standards for the registration and regulation of drug distributors by the states.

Both the PDMA and state laws limit the distribution of prescription pharmaceutical product samples and impose requirements to ensure accountability in distribution.

The Drug Supply Chain Security Act, or DSCSA, was enacted with the aim of building an electronic system to identify and trace certain prescription drugs distributed in the United States, including most biological products.

The DSCSA mandates phased-in and resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors and dispensers over a ten‑year period, which culminated in November 2023.

After an additional one-year stabilization period to give entities subject to the DSCSA additional time to finalize interoperable tracking systems and to ensure supply chain continuity, the applicable requirements under the DSCSA became fully enforceable as of November 27, 2024.

From time to time, new legislation and regulations may be implemented that could significantly change the statutory provisions governing the approval, manufacturing and marketing of products regulated by the FDA.

For example, FDA released proposed regulations in February 2022 to amend the national standards for licensing of wholesale drug distributors by the states;

establish new minimum standards for state licensing third-party logistics providers;

and create a federal system for licensure for use in the absence of a state program, each of which is mandated by the DSCSA.

It is impossible to predict whether further legislative or regulatory changes will be enacted, or FDA regulations, guidance or interpretations changed or what the impact of such changes, if any, may be.

Orphan Designation and Exclusivity

Under the Orphan Drug Act, the FDA may grant orphan drug designation, or ODD, to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with either a patient population of fewer than 200,000 individuals in the United States, or a patient population greater of than 200,000 individuals in the United States when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the United States will be recovered from sales in the United States of that drug or biologic.

Under the Orphan Drug Act, the FDA may grant orphan drug designation (“ODD”) to a drug intended to treat a rare disease or condition, defined as a disease or condition with either a patient population of fewer than 200,000 individuals in the United States, or a patient population greater of than 200,000 individuals in the United States when there is no reasonable expectation that the cost of developing and making available the drug in the United States will be recovered from sales in the United States of that drug or biologic.

ODD must be requested before submitting an NDA.

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In addition, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

We filed for orphan drug status with the FDA in December 2021, responded to clarifications from the FDA in March 2022, and received orphan drug designation for all three components of INT230-6—SHAO, cisplatin and vinblastine—for soft tissue sarcoma in June 2022.

This designation makes INT230-6 eligible for seven years of marketing exclusivity if it receives marketing approval for the treatment of soft tissue sarcoma.

A drug product can also obtain pediatric market exclusivity in the United States.

Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms.

This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.

The data from such study do not need to show the product to be effective in the pediatric population studied;

Pediatric exclusivity, if granted, adds six months of marketing protection to the term of any existing regulatory exclusivity periods or listed patents.

This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted if any NDA sponsor submits pediatric data that fairly responds to a Written Request from the FDA for such data.

The data do not need to show the product to be effective in the pediatric population studied;

rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted.

Although this is not a patent term extension, it effectively extends the regulatory period during which the FDA cannot approve another application.

We filed for orphan drug status with the FDA in December 2021, responded to clarifications from the FDA in March 2022, and received orphan drug designation for all three components of INT230-6 SHAO, cisplatin and vinblastine, for soft tissue sarcoma in June 2022.

This designation

grants the company seven years of marketing exclusivity following approval in the soft tissue sarcoma for any of our products containing any one of these three ingredients.

The issuance of a Written Request by the FDA does not require the sponsor to undertake the described studies.

The Hatch-Waxman Act and Marketing Exclusivity

Under the Drug Price Competition and Patent Term Restoration Act of 1984, otherwise known as the Hatch-Waxman Amendments to the FDCA, Congress authorized the FDA to approve generic drugs that are the same as drugs previously approved by the FDA under the NDA provisions of the statute and also enacted Section 505(b)(2) of the FDCA.

To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application, or ANDA, to the agency.

In support of such applications, a generic manufacturer may rely on the preclinical and clinical testing conducted for a drug product previously approved under an NDA, known as the reference listed drug (RLD).

Specifically, in order for an ANDA to be approved, the FDA must find that the generic version is identical to the RLD with respect to the active ingredients, the route of administration, the dosage form, and the strength of the drug.

In contrast, Section 505(b)(2) permits the filing of an NDA where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference.

A Section 505(b)(2) applicant may eliminate the need to conduct certain preclinical or clinical studies, if it can establish that reliance on studies conducted for a previously approved product is scientifically appropriate.

Under the Drug Price Competition and Patent Term Restoration Act of 1984, otherwise known as the Hatch-Waxman Act, Congress authorized the FDA to approve generic drugs based on innovator or “reference” drugs previously approved by the FDA.

Congress also enacted Section 505(b)(2) of the FDCA, which provides a hybrid drug approval pathway combining features of a traditional NDA and a generic drug application.

To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application (“ANDA”) to the agency.

An ANDA is a comprehensive submission that contains, among other things, data and information pertaining to the active pharmaceutical ingredient, bioequivalence, drug product formulation, specifications and stability of the generic drug, as well as analytical methods, manufacturing process validation data and quality control procedures.

ANDAs are “abbreviated” because they cannot include preclinical and clinical data to demonstrate safety and effectiveness.

Instead, in support of such applications, a generic manufacturer may rely on the preclinical and clinical testing conducted for a drug product previously approved under an NDA, known as the reference listed drug (“RLD”).

At the same time, the FDA must also determine that the generic drug is “bioequivalent” to the innovator drug.

Under the statute, a generic drug is bioequivalent to a RLD if “the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug.” Upon approval of an ANDA, the FDA indicates whether the generic product is “therapeutically equivalent” to the RLD in the agency publication, Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book.

Physicians and pharmacists consider a therapeutic equivalent generic drug to be fully substitutable for the RLD.

In addition, by operation of certain state laws and numerous health insurance programs, the FDA’s designation of therapeutic equivalence often results in substitution of the generic drug without the knowledge or consent of either the prescribing physician or patient.

In contrast, Section 505(b)(2) enables the applicant to rely, in part, on the FDA’s prior findings of safety and efficacy data for an existing product, or published literature, in support of its application.

Section 505(b)(2) NDAs may provide an alternate path to FDA approval for new or improved formulations or new uses of previously approved products;

for example, an applicant may be seeking approval to market a previously approved drug for new indications or for a new patient population that would require new clinical data to demonstrate safety or effectiveness.

Section 505(b)(2) permits the filing of an NDA where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference.

A Section 505(b)(2) applicant may eliminate the need to conduct certain nonclinical or clinical studies, if it can establish that reliance on studies conducted for a previously approved product is scientifically appropriate.

Unlike the ANDA pathway used by developers of bioequivalent versions of innovator drugs, which does not allow applicants to submit new clinical data other than bioavailability or bioequivalence data, the 505(b)(2) regulatory pathway does not preclude the possibility that a follow-on applicant would need to conduct additional clinical trials or nonclinical studies;

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In seeking approval of an NDA or a supplement thereto, the NDA sponsor is required to list with the FDA each patent with claims that cover the sponsor’s product or an approved method of using the product.

Upon approval of an NDA, each of the patents listed in the application for the drug is published in the FDA publication Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book.

Upon approval of an NDA, each of the patents listed in the application for the drug is published in the Orange Book.

When an ANDA applicant submits its application to the FDA, the applicant is required to certify to the FDA concerning any patents listed in the Orange Book for the RLD, except for patents covering methods of use for which the follow-on applicant is not seeking approval.

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A certification that the new product will not infringe the RLD’s listed patents or that such patents are invalid is called a Paragraph IV certification.

If the follow-on applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA and patent holders for the RLD once the applicant’s NDA has been accepted for filing by the FDA.

The NDA and patent holders may then initiate a legal challenge to the Paragraph IV certification.

The filing of a patent infringement lawsuit within 45 days of their receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA or 505(b)(2) NDA until the earlier of 30 months after the receipt of the Paragraph IV notice, expiration of the patent or a decision in the infringement case that is favorable to the ANDA or 505(b)(2) applicant.

The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification.

The filing of a patent infringement lawsuit within 45 days of the receipt of a Paragraph IV certification notice automatically prevents the FDA from approving the ANDA or 505(b)(2) NDA until the earlier of 30 months after the receipt of the Paragraph IV notice, expiration of the patent, settlement of the lawsuit, or a decision in the infringement case that is favorable to the ANDA or 505(b)(2) applicant.

Alternatively, if the listed patent holder does not file a patent infringement lawsuit within the required 45-day period, the follow-on applicant’s ANDA or 505(b)(2) NDA will not be subject to the 30-month stay.

In addition, under the Hatch-Waxman Amendments, the FDA may not approve an ANDA or 505(b)(2) NDA until any applicable period of non-patent exclusivity for the referenced RLD has expired.

These market exclusivity provisions under the FDCA also can delay the submission or the approval of certain applications.

The FDCA provides a five-year

period of non-patent marketing exclusivity within the United States to the first applicant to gain approval of an NDA for a drug containing a new chemical entity.

A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.

During the exclusivity period, the FDA may not accept for review an ANDA or a 505(b)(2) NDA submitted by another company for another version of such drug where the applicant does not own or have a legal right of reference to all the data required for approval.

The FDCA provides a five-year period of non-patent data exclusivity within the United States to the first applicant to gain approval of an NDA for a drug containing a new chemical entity (“NCE”).

For the purposes of this exclusivity provision, a drug is an NCE if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the physiological or pharmacological action of the drug substance.

In cases where such NCE exclusivity has been granted, an ANDA or 505(b)(2) NDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a paragraph IV certification, in which case the applicant may submit its application four years following the original product approval.

However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement.

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Five-year and three-year exclusivity also will not delay the submission or approval of a traditional NDA filed under Section 505(b)(1) of the FDCA.

However, an applicant submitting a traditional NDA would be required to either conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

However, an applicant submitting a traditional NDA would be required to conduct, or obtain a right of reference to, all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Patent Term Extension

After NDA approval, owners of relevant drug patents may apply for up to a five-year patent term extension.

The allowable patent term extension is calculated as half of the drug’s testing phase — the time between when the IND becomes effective and NDA submission — and all of the review phase — the time between NDA submission and approval, up to a maximum of five years.

The time can be shortened if the FDA determines that the applicant did not pursue approval with due diligence.

The total patent term after the extension may not exceed 14 years.

For patents that might expire during the application phase, the patent owner may request an interim patent extension.

An interim patent extension increases the patent term by one year and may be renewed up to four times.

For each interim patent extension granted, the post-approval patent extension is reduced by one year.

The director of the Patent and Trademark Office (PTO) must determine that approval of the drug covered by the patent for which a patent extension is being sought is likely.

Interim patent extensions are not available for a drug for which an NDA has not been submitted.

Other Regulatory Matters

Manufacturing, sales, promotion and other activities of drug products following approval, where applicable, or commercialization are also subject to regulation by numerous regulatory authorities in the United States in addition to the FDA, which may include the Centers for Medicare & Medicaid Services, or CMS, other divisions of the Department of Health and Human Services, or HHS, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments and governmental agencies.

A patent claiming a prescription drug or medical device for which FDA approval is granted may be eligible for a limited patent term extension under the FDCA, which permits a patent restoration of up to five years for patent term lost during product development and the FDA regulatory review provided that certain statutory and regulatory requirements are met.

The length of the patent term extension is related to the length of time the drug or medical device is under regulatory review while the patent is in force.

The restoration period granted on a patent covering a new FDA-regulated medical

product is typically one-half the time between the date a clinical investigation on human beings is begun and the submission date of an application for premarket approval of the product, plus the time between the submission date of an application for approval of the product and the ultimate approval date.

Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date.

Only one patent applicable to an eligible FDA-approved product is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent in question.

A patent that covers multiple products for which approval is sought can only be extended in connection with one of the marketing approvals.

Patent and Trademark Office, or USPTO, reviews and approves the application for any patent term extension or restoration in consultation with the FDA.

If a patent relating to a drug product might expire during the NDA review and approval phase, the patent owner may request an interim patent term extension.

An interim patent term extension increases the patent term by one year and may be renewed up to four times.

For each interim patent term extension granted, the post-approval patent term extension is reduced by one year.

The Director of the USPTO must determine that approval of the drug covered by the patent for which an interim patent term extension is being sought is likely.

Other Healthcare Laws

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In the United States, these laws include, without limitation, state and federal anti-kickback, false claims, physician transparency, and patient data privacy and security laws and regulations, including but not limited to those described below.

• The federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, paying, receiving or providing any remuneration (including any kickback, bribe, or certain rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid;

a person or entity need not have actual knowledge of the federal Anti-Kickback Statute or specific intent to violate it in order to have committed a violation.

• The federal Anti-Kickback Statute (“AKS”), which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, paying, receiving or providing any remuneration (including any kickback, bribe, or certain rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, lease, order, arrangement or recommendation of, any good, facility, item or service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid;

a person or entity need not have actual knowledge of the AKS or specific intent to violate it in order to have committed a violation.

Violations are subject to civil and criminal fines and penalties for each violation, plus up to three times the remuneration involved, imprisonment, and exclusion from government healthcare programs;

• The federal civil and criminal false claims laws, including the civil False Claims Act, or FCA, which prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment or approval that are false, fictitious or fraudulent;

• The federal civil and criminal false claims laws, including the civil False Claims Act (“FCA”), which prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment or approval that are false, fictitious or fraudulent;

knowingly making, using, or causing to be made or used, a false statement or record material to a false or fraudulent claim or obligation to pay or transmit money or property to the federal government;

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Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.

In addition, the government may assert that a claim that includes items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the civil False Claims Act.

The government may assert that a claim that includes items or services resulting from a violation of the AKS constitutes a false or fraudulent claim for purposes of the civil False Claims Act.

The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery.

When an entity is determined to have violated the federal civil False Claims Act, the government may impose civil fines and penalties for each false claim, plus treble damages, and exclude the entity from participation in Medicare, Medicaid and other federal healthcare programs;

When an entity is determined to have violated the FCA, the government may impose civil fines and penalties for each false claim, plus treble damages, and exclude the entity from participation in Medicare, Medicaid and other federal healthcare programs;

• The federal civil monetary penalties laws, which impose civil fines for, among other things, the offering or transfer or remuneration to a Medicare or state healthcare program beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of services reimbursable by Medicare or a state health care program, unless an exception applies;

• The Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil liability for knowingly and willfully executing a scheme, or attempting to execute a scheme, to defraud any healthcare benefit program, including private payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, or falsifying, concealing or covering up a material fact or making any materially false statements in connection with the delivery of or payment for healthcare benefits, items or services.

Similar to the federal Anti-Kickback Statute, a person or entity need not have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;

• HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, imposes, among other things, specified requirements on covered entities and their business associates relating to the privacy and security of individually identifiable health information including mandatory contractual terms and required implementation of technical safeguards of such information.

• The Health Insurance Portability and Accountability Act of 1996 (“HIPAA”) imposes criminal and civil liability for knowingly and willfully executing a scheme, or attempting to execute a scheme, to defraud any healthcare benefit program, including private payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, or falsifying, concealing or covering up a material fact or making any materially false statements in connection with the

delivery of or payment for healthcare benefits, items or services.

Similar to the AKS, a person or entity need not have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;

• HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”), and their respective implementing regulations, imposes, among other things, specified requirements on covered entities and their business associates relating to the privacy and security of individually identifiable health information including mandatory contractual terms and required implementation of technical safeguards of such information.

HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates in some cases, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions;

• The Physician Payments Sunshine Act, enacted as part of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the ACA, imposed new annual reporting requirements for certain manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, for certain payments and “transfers of value” provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

• The Physician Payments Sunshine Act, enacted as part of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (collectively, the “ACA”), imposed new annual reporting requirements for certain manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, for certain payments and “transfers of value” provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain advanced non-physician healthcare practitioners, and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

In addition, many states also require reporting of payments or other transfers of value, many of which differ from each other in significant ways, are often not pre-empted, and may have a more prohibitive effect than the Sunshine Act, thus further complicating compliance efforts;

Effective January 1, 2022, these reporting obligations will extend to include transfers of value made in the previous year to certain non-physician providers such as physician assistants and nurse practitioners;

• Federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers;

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state and foreign laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government or otherwise restrict payments that may be made to healthcare providers;

state and foreign laws

that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers, and restrict marketing practices or require disclosure of marketing expenditures and pricing information;

state and foreign laws that govern the privacy and security of health information in some circumstances.

These data privacy and security laws may differ from each other in significant ways and often are not pre-empted by HIPAA, which may complicate compliance efforts.

state and foreign laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers, and restrict marketing practices or require disclosure of marketing expenditures and pricing information;

state and foreign laws that govern the privacy and security of health information in some circumstances, which may differ from each other in significant ways and often are not pre-empted by HIPAA, which may complicate compliance efforts.

The distribution of drug products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.

Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

Federal and state enforcement bodies have increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

It is possible that governmental authorities will conclude that our business practices do not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.

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

In the European Union and other countries outside of the United States, pricing and reimbursement schemes vary widely from country to country.

Some countries provide that drug products may be marketed only after a reimbursement price has been agreed to.

Additionally, some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate to currently available therapies.

In certain jurisdictions, cross-border imports from low-priced markets exert competitive pressure that may reduce pricing within a country.

Any country that has price controls or reimbursement limitations for drug products may not allow favorable reimbursement and pricing arrangements.

Healthcare Reform

In the United States and some foreign jurisdictions, there have been, and likely will continue to be, a number of legislative and regulatory changes and proposed changes regarding the healthcare system directed at broadening the availability of healthcare, improving the quality of healthcare, and containing or lowering the cost of healthcare.

For example, in March 2010, the United States Congress enacted the ACA, which, among other things, includes changes to the coverage and payment for products under government health care programs.

The ACA includes provisions of importance to our potential product candidate that:

• created an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic products, apportioned among these entities according to their market share in certain government healthcare programs;

• expanded eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;

• expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic drugs and revising the definition of “average manufacturer price,” or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices;

• addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;

• expanded the types of entities eligible for the 340B drug discount program;

• established the Medicare Part D coverage gap discount program by requiring manufacturers to provide point-of-sale-discounts off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;

• created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.

Since its enactment, there have been numerous judicial, administrative, executive, and legislative challenges to certain aspects of the ACA.

For example, the Tax Cuts and Jobs Act of 2017 (the Tax Act) was enacted, which includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” On December 14, 2018, a U.S.

District Court Judge in the Northern District of Texas ruled that the individual mandate is a critical and inseverable feature of the ACA, and therefore, because it was repealed as part of the Tax Act, the remaining provisions of the ACA are invalid as well.

Additionally, on December 18, 2019, the U.S.

Court of Appeals for the 5 th Circuit ruled that that the individual mandate was unconstitutional and remanded the case back to the District Court to determine whether the remaining provisions of the ACA are invalid as well.

Supreme Court held in a 7 – 2 opinion that the states and individuals that brought the lawsuit challenging the ACA’s individual mandate do not have standing to challenge the law.

The Supreme Court did not reach the merits of the challenge, but the decision ends the case.

It is also unclear how the Supreme Court ruling, other such litigation, and the healthcare reform measures of the Biden administration will impact the ACA or our business.

Other legislative changes have been proposed and adopted in the United States since the Affordable Care Act was enacted.

In August 2011, the Budget Control Act of 2011, among other things, included aggregate reductions of Medicare payments to providers of 2% per fiscal year, which went into effect in April 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2031 unless additional Congressional action is taken.

The Coronavirus Aid, Relief, and Economic Security Act, or CARES Act, which was signed into law on March 27, 2020, designed to provide financial support and resources to individuals and businesses affected by the COVID-19 pandemic, suspended these reductions from May 1, 2020 through December 31, 2020, and extended the sequester by one year, through 2030.

In addition, in January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single-source and innovator multiple-source drugs, beginning January 1, 2024.

These laws may result in additional reductions in Medicare, Medicaid and other healthcare funding.

Moreover, payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives.

For example, CMS may develop new payment and delivery models, such as bundled payment models.

In addition, recently there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their commercial products, which has resulted in several Congressional inquiries and proposed and enacted state and federal legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for pharmaceutical products.

For example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to prescription drug pricing and importation.

As a result, the FDA also released a final rule in September 2020, effective November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada.

Further, in November 2020, the U.S.

Department of Health and Human Services, or HHS, finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been postponed by Congress and HHS to January 1, 2032.

The CMS also issued an interim final rule that would have established a Most Favored Nation, or MFN, Model for Medicare Part B drug payments.

This regulation would have substantially changed the reimbursement landscape as it based Medicare Part B payment for 50 selected drugs on prices in foreign countries instead of average sales prices (ASP) and established a fixed add-on payment in place of the current 6 percent (4.3 percent after sequestration) of ASP.

The MFN drug payment amount was expected to be lower than the current ASP-based limit because U.S.

drug prices are generally the highest in the world.

However, CMS issued a final rule on December 29, 2021 that rescinded the MFN Model interim final rule.

In December 2020, CMS issued a final rule implementing significant manufacturer price reporting changes under the Medicaid Drug Rebate Program, including regulations that affect manufacturer-sponsored patient assistance programs subject to pharmacy benefit manager accumulator programs and Best Price reporting related to certain value-based purchasing arrangements.

On May 21, 2021, an industry group sued CMS, claiming that the change to the Best Price rule exceeds CMS’s statutory authority and is contrary to the Medicaid Rebate statute, and on May 17, 2022, the U.S.

District Court for the District of Columbia vacated the Best Price rule.

In August 2022, President Biden signed the Inflation Reduction Act of 2022 (IRA) into law.

This statute marks the most significant action by Congress with respect to the pharmaceutical industry since adoption of the ACA in 2010.

Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap;

imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (beginning October 1, 2022);

and replaces the Medicare Part D coverage gap discount program with a new discounting program (beginning in 2025).

The IRA permits the Secretary of the Department of Health and Human Services (HHS) to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

On March 15, 2023, and June 30, 2023, HHS issued guidance regarding implementation of the Medicare drug price negotiation program in initial price applicability year 2026.

HHS stated it would provide additional information in the future related to implementation for initial price applicability years 2027 and beyond.

Some provisions of the IRA may be subject to legal challenge.

Several manufacturers and industry groups have challenged the drug price negotiation program for Medicare Parts B and D in federal court.

These lawsuits are ongoing, and additional lawsuits may be filed in the future.

It is unknown whether such litigation or other litigation, if brought, will be successful.

For these and other reasons, it is currently unclear how the IRA will be effectuated, and while the impact of the IRA on the pharmaceutical industry cannot yet be fully determined, it is likely to be significant.

On May 23, 2023, CMS issued a proposed rule that would modify many Medicaid Drug Rebate Program requirements and implement a drug price verification survey.

It is unclear whether the proposed rule will be finalized and whether the final rule will differ from the proposed rule.

It is also unclear to what extent these regulations or any future legislation or regulations will have on our business, including our ability to generate revenue and achieve profitability.

On May 30, 2018, the Right to Try Act was signed into law.

The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval.

Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.

There is no obligation for a drug manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.

Outside the United States, ensuring coverage and adequate payment for a product also involves challenges.

Pricing of prescription pharmaceuticals is subject to government control in many countries.

Pricing negotiations with government authorities can extend well beyond the receipt of regulatory approval for a product and may require a clinical trial that

compares the cost-effectiveness of a product to other available therapies.

The conduct of such a clinical trial could be expensive and result in delays in commercialization.

In the United States and some foreign jurisdictions, there have been, and likely will continue to be, a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product and therapeutic candidates, restrict or regulate post-approval activities, and affect the ability to profitably sell product and therapeutic candidates that obtain marketing approval.

The FDA’s and other regulatory authorities’ policies may change and additional government regulations may be enacted that could prevent, limit or delay regulatory approval of our product and therapeutic candidates.

In addition, future legislative and regulatory proposals may materially impact the ability of the FDA and other regulatory agencies to operate as they have historically operated.

We cannot be sure whether additional legislative changes will be enacted, or whether any of the FDA’s regulations, guidances or interpretations will be changed, or what the impact of such changes on the agency and its scientific review staff, if any, may be.

For example, the next FDA user fee reauthorization package is expected to enter stakeholder negotiations beginning in mid-2025, with any agreement sent to Congress in early 2027 for purposes of initiating the legislative process.

Reauthorization of the prescription drug user fee program would need to be finalized by Congress by the end of September 2027 in order to avoid a disruption in FDA’s review goals for NDAs and other activities supported by user fees assessed against industry.

If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements

or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we otherwise may have obtained and we may not achieve or sustain profitability, which would adversely affect our business, prospects, financial condition and results of operations.

The containment of healthcare costs has become a priority of federal and state governments, and the prices of therapeutics have been a focus in this effort.

government, state legislatures and foreign governments have shown significant interest in implementing cost-containment programs to limit the growth of government-paid healthcare costs, including price controls, restrictions on reimbursement, and requirements for substitution of generic and biosimilar products for branded prescription medicines, respectively.

In recent years, the U.S.

Congress has considered reductions in Medicare and Medicaid reimbursement levels, including for medicines administered by physicians.

The Centers for Medicare and Medicaid Services (CMS), also has authority to revise reimbursement rates and to implement coverage restrictions for most drugs and biologics.

Cost reduction initiatives and changes in coverage implemented through legislation or regulation could decrease utilization of and reimbursement for any approved products we may market in the future.

While Medicare regulations apply only to pharmaceutical benefits for Medicare beneficiaries, private payors often follow Medicare coverage policy and payment limitations in setting their own reimbursement rates.

Therefore, any reduction in reimbursement that results from federal legislation or regulation may result in a similar reduction in payments from private payors.

The ACA was enacted in March 2010 and has had a significant impact on the healthcare industry in the United States by expanding coverage for the uninsured while at the same time containing overall healthcare costs.

With regard to biopharmaceutical products, the ACA, among other things, addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, increased the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extended the rebate program to individuals enrolled in Medicaid managed care organizations, established annual fees on manufacturers of certain branded prescription drugs, and created a new Medicare Part D coverage gap discount program.

We expect that future changes or additions to the ACA, the Medicare and Medicaid programs, and changes stemming from other healthcare reform measures, especially with regard to healthcare access, financing or other legislation in individual states, could have a material adverse effect on the healthcare industry in the United States.

Additionally, on December 20, 2019, the Further Consolidated Appropriations Act for 2020 was signed into law (P.L.

116-94) and includes a piece of bipartisan legislation called the Creating and Restoring Equal Access to Equivalent Samples Act of 2019 or the “CREATES Act.” The CREATES Act aims to address the concern articulated by both the FDA and others in the industry that some brand manufacturers have improperly restricted the distribution of their products, including by invoking the existence of a REMS for certain products, to deny generic product developers access to samples of brand products.

Because generic product developers need samples of an RLD to conduct certain comparative testing required by the FDA, some have attributed the inability to timely obtain samples as a cause of delay in the entry of generic products.

To remedy this concern, the CREATES Act establishes a private cause of action that permits a generic product developer to sue the brand manufacturer to compel it to furnish the necessary samples on “commercially reasonable, market-based terms.” Although lawsuits have been filed under the CREATES Act since its enactment, those lawsuits have settled privately;

therefore to date no federal court has reviewed or opined on the statutory language and there continues to be uncertainty regarding the scope and application of the law.

For a drug product to receive federal reimbursement under the Medicaid or Medicare Part B programs or to be sold directly to U.S.

government agencies, the manufacturer must extend discounts to entities eligible to participate in the 340B Drug Pricing Program.

The maximum amount that a manufacturer may charge a 340B covered entity for a given product is the average manufacturer price, or AMP, reduced by the rebate amount paid by the manufacturer to Medicaid for each unit of that product.

As of 2010, the ACA expanded the types of entities eligible to receive discounted 340B pricing, although, under the current state of the law, with the exception of children’s hospitals, these newly eligible entities will not be eligible to receive discounted 340B pricing on orphan drugs.

In addition, as 340B drug pricing is determined based on AMP and Medicaid rebate data, the revisions to the Medicaid rebate formula and AMP definition described above could cause the required 340B discount to increase.

Moreover, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.

For example, the 2021 Consolidated Appropriations Act signed into law on December 27, 2020 incorporated extensive healthcare provisions and amendments to existing laws, including a requirement that all manufacturers of drug products covered under Medicare Part B report the product’s average sales price to CMS beginning on January 1, 2022, subject to enforcement via civil money penalties.

In August 2022, the Inflation Reduction Act of 2022, or the IRA, became law.

Among other things, the IRA has multiple provisions that may impact the prices of drug products that are both sold into the Medicare program and throughout the United States.

For example, a manufacturer of a drug or biological product covered by Medicare Parts B or D must pay a rebate to the federal government if the drug product’s price increases faster than the rate of inflation.

This calculation is made on a product-by-product basis and the amount of the rebate owed to the federal government is directly dependent on the volume of a drug product that is paid for by Medicare Parts B or D.

Additionally, starting in payment year 2026, CMS will negotiate drug prices annually for a select number of single source Part D drugs without generic or biosimilar competition.

CMS will also negotiate drug prices for a select number of Part B drugs starting for payment year 2028.

If a drug product is selected by CMS for negotiation, it is expected that the revenue generated from such drug will decrease.

CMS has begun to implement these new authorities and entered into the first set of agreements with drug and biological product manufacturers for negotiated prices of 10 products, which will become applicable for payment year 2026.

However, the IRA’s impact on the pharmaceutical industry in the United States remains uncertain, in part because multiple large pharmaceutical companies and other stakeholders (e.g., the U.S.

Chamber of Commerce) have initiated federal lawsuits against CMS arguing the program is unconstitutional for a variety of reasons, among other complaints.

Those lawsuits are currently ongoing.

Individual states in the United States have also increasingly passed legislation and implemented regulations designed to control pharmaceutical 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.

For example, in recent years, several states have formed prescription drug affordability boards (PDABs).

Much like the IRA’s drug price negotiation program, these PDABs have attempted to implement upper payment limits (UPLs) on drugs sold in their respective states in both public and commercial health plans.

For example, in August 2023, Colorado’s PDAB announced a list of five prescription drugs that would undergo an affordability review.

The effects of these efforts remain uncertain pending the outcomes of several federal lawsuits challenging state authority to regulate prescription drug payment limits.

In December 2020, the U.S.

Supreme Court held unanimously that federal law does not preempt the states’ ability to regulate pharmaceutical benefit managers (“PBMs”) and other members of the healthcare and pharmaceutical supply chain, an important decision that may lead to further and more aggressive efforts by states in this area.

The FTC in mid-2022 also launched sweeping investigations into the practices of the PBM industry that could lead to additional federal and state legislative or regulatory proposals targeting such entities’ operations, pharmacy networks, or financial arrangements.

Significant efforts to change the PBM industry as it currently exists in the U.S.

may affect the entire pharmaceutical supply chain and the business of other stakeholders, including pharmaceutical product developers like us.

In the European Union, pricing and reimbursement schemes vary widely from country to country.

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Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate to currently available therapies or so-called health technology assessments, in order to obtain reimbursement or pricing approval.

For example, the European Union provides options for its member states to restrict the range of products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

European Union member states may approve a specific price for a product or they may instead adopt a system of direct or indirect controls on our profitability for placing the product on the market.

For example, the EU provides options for its member states to restrict the range of products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

EU member states may approve a specific price for a product, or they may instead adopt a system of direct or indirect controls on our profitability for placing the product on the market.

Other member states allow companies to fix their own prices for products but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions.

Recently, many countries in the European Union have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to manage healthcare expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the European Union.

Many countries in the EU have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to manage healthcare expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the EU.

The downward pressure on healthcare costs in general, particularly prescription products, has become intense.

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Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained.

Reference pricing used by various European Union member states, and parallel trade, i.e., arbitrage between low-priced and high-priced member states, can further reduce prices.

Reference pricing used by various EU member states, and parallel trade, i.e., arbitrage between low-priced and high-priced member states, can further reduce prices.

There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries.

We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative or executive action, either in the United States or abroad.

We expect that additional federal, state, and foreign healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in limited coverage and reimbursement and reduced demand for our products, once approved, or additional pricing pressures.

Compliance with Other Federal and State Laws or Requirements;

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To market any product outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization or identification of an alternate regulatory pathway, manufacturing, commercial sales and distribution of our product candidates.

For instance, in the European Economic Area, or the EEA (comprised of the 26 EU Member States plus Iceland, Liechtenstein and Norway, with the UK having left the EU in January of 2020), medicinal products must be authorized for marketing by using either the centralized authorization procedure or national authorization procedures.

• Centralized procedure — If pursuing marketing authorization of a product candidate for a therapeutic indication under the centralized procedure, following the opining of the EMA’s Committee for Medicinal Products for Human Use, or, CHMP, the European Commission issues a single marketing authorization valid across the EEA.

The centralized procedure is compulsory for human medicines derived from biotechnology processes or advanced therapy medicinal products (such as gene therapy, somatic cell therapy and tissue engineered products), products that contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other immune dysfunctions, viral diseases, and officially designated orphan medicines.

For instance, in the European Economic Area (“EEA”) (comprised of the 27 EU Member States plus Iceland, Liechtenstein and Norway, medicinal products must be authorized for marketing by using either the centralized authorization procedure or national authorization procedures.

• Centralized procedure — If pursuing marketing authorization of a product candidate for a therapeutic indication under the centralized procedure, following the opining of the EMA’s Committee for Medicinal Products for Human Use (“CHMP”), the European Commission issues a single marketing authorization valid across the EEA.

immune dysfunctions, viral diseases, and officially designated orphan medicines.

For medicines that do not fall within these categories, an applicant has the option of submitting an application for a centralized marketing authorization to the EMA, as long as the medicine concerned contains a new active substance not yet authorized in the EEA, is a significant therapeutic, scientific or technical innovation, or if its authorization would be in the interest of public health in the EEA.

Under the centralized procedure the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP.

Under the centralized procedure the maximum timeframe for the evaluation of a marketing authorization application by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP.

Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation.

The timeframe for the evaluation of an MAA under the accelerated assessment procedure is 150 days, excluding clock stops.

The timeframe for the evaluation of a marketing authorization application under the accelerated assessment procedure is 150 days, excluding clock stops.

• National authorization procedures — There are also two other possible routes to authorize products for therapeutic indications in several countries, which are available for products that fall outside the scope of the centralized procedure:

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Following this, additional marketing authorizations can be sought from other EU countries in a procedure whereby the countries concerned recognize the validity of the original, national marketing authorization.

In the EEA, new products for therapeutic indications that are authorized for marketing (i.e., reference products) qualify for eight years of data exclusivity and an additional two years of market exclusivity upon marketing authorization.

Only products for which marketing authorizations have been granted may be promoted in the EU.

A marketing authorization is valid for five years in principle and the marketing authorization may be renewed after the initial five-year period on the basis of a re-evaluation of the risk-benefit balance by the EMA or by the competent authority of the authorizing member state.

To this end, the marketing authorization holder must provide the EMA, or the applicable competent authority, with a consolidated version of the file in respect of quality, safety and efficacy, including all variations introduced since the marketing authorization was granted, at least six months before the marketing authorization ceases to be valid.

Once renewed, the marketing authorization is valid for an unlimited period, unless the European Commission, or the applicable competent authority, decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal.

Any marketing authorization which is not followed by the actual placing of the drug on the market in the EEA (in case of centralized procedure) or on the market in the authorizing member state within three years after authorization ceases to be valid (the so-called sunset clause).

New products for therapeutic indications that are authorized for marketing (i.e., reference products) in the EU qualify for eight years of data exclusivity and an additional two years of market exclusivity upon marketing authorization.

The data exclusivity period prevents generic or biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the EU during a period of eight years from the date on which the reference product was first authorized in the EU.

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Similar to the United States, the various phases of non-clinical and clinical research in the European Union are subject to significant regulatory controls.

The Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on GCP and the related national implementing provisions of the individual EU Member States govern the system for the approval of clinical trials in the European Union.

Under this system, an applicant must obtain prior approval from the competent national authority of the EU Member States in which the clinical trial is to be conducted.

Furthermore, the applicant may only start a clinical trial at a specific study site after the competent ethics committee has issued a favorable opinion.

The clinical trial application must be accompanied by, among other documents, an investigational medicinal product dossier (the Common Technical Document) with supporting information prescribed by Directive 2001/20/EC, Directive 2005/28/EC, where relevant the implementing national provisions of the individual EU Member States and further detailed in applicable guidance documents.

In April 2014, the new Clinical Trials Regulation, (EU) No 536/2014 (Clinical Trials Regulation) was adopted.

The Clinical Trials Regulation will be directly applicable in all the EU Member States, repealing the current Clinical Trials Directive 2001/20/EC.

Conduct of all clinical trials performed in the European Union will continue to be bound by currently applicable provisions until the new Clinical Trials Regulation becomes applicable.

In 2014, the Clinical Trials Regulation, (EU) No 536/2014 (“Clinical Trials Regulation”) was adopted, and it became effective on January 31, 2022.

The Clinical Trials Regulation is directly applicable in all the EU Member States, as it repealed the Clinical Trials Directive 2001/20/EC, which previously governed the application process to obtain authorization for and the performance of clinical trials in the EU.

The extent to which ongoing clinical trials will be governed by the Clinical Trials Regulation will depend on when the Clinical Trials Regulation becomes applicable and on the duration of the individual clinical trial.

If a clinical trial continues for more than three years from the day on which the Clinical Trials Regulation becomes applicable the Clinical Trials Regulation will at that time begin to apply to the clinical trial.

The new Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the European Union.

The Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the European Union.

The main characteristics of the regulation include:

a streamlined application procedure via a single-entry point, the Clinical Trials Information System, or CTIS, a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;

and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts.

a streamlined application procedure via a single-entry point, the Clinical Trials Information System (“CTIS”), a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;

and a harmonized procedure for the assessment of applications

for clinical trials, which is divided in two parts.

Part 1 is assessed by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned).

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However, overall related timelines will be defined by the Clinical Trials Regulation.

On the basis of the results of an independent audit of the CTIS, on April 21, 2021, the EMA Management Board confirmed to the European Commission that the CTIS is fully functional.

Based on this, January 31, 2022 was fixed as the date of applicability of the Clinical Trials Regulation (EU) No 536/2014.

The collection and use of personal health data in the European Union, previously governed by the provisions of the Data Protection Directive, is now governed by the General Data Protection Regulation, or the GDPR, which became effective on May 25, 2018.

Use of CTIS became mandatory for new clinical trial application submissions as of February 1, 203.

The collection and use of personal health data in the European Union, previously governed by the provisions of the Data Protection Directive, is now governed by the General Data Protection Regulation (“GDPR”), which became effective on May 25, 2018.

While the Data Protection Directive did not apply to organizations based outside the EU, the GDPR has expanded its reach to include any business, regardless of its location, that provides goods or services to residents in the EU.

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GDPR grants individuals the opportunity to object to the processing of their personal information, allows them to request deletion of personal information in certain circumstances, and provides the individual with an express right to seek legal remedies in the event the individual believes his or her rights have been violated.

Further, the GDPR imposes strict rules on the transfer of personal data out of the European Union to the United States or other regions that have not been deemed to offer “adequate” privacy protections.

Failure to comply with the requirements of the GDPR and the related national data protection laws of the European Union Member States, which may deviate slightly from the GDPR, may result in fines of up to 4% of global revenues, or €20,000,000, whichever is greater.

Further, the GDPR only permits exports of data outside of the EU where the country where the recipient is located is deemed to have adequate data privacy laws by the European Commission or where there is a suitable data transfer solution in place to safeguard personal data (e.g., the EU Commission approved Standard Contractual Clauses).

On July 10, 2023, the European Commission adopted an adequacy decision for a new mechanism for transferring data from the EU to the United States – the EU-US Data Privacy Framework, which provides EU individuals with several new rights, including the right to obtain access to their data, or obtain correction or deletion of incorrect or unlawfully handled data.

The adequacy decision followed the signing of an executive order introducing new binding safeguards to address transfers of personal data from the EU to the United States.

Notably, the new obligations were geared to ensure that data can be accessed by U.S.

intelligence agencies only to the extent necessary and proportionate and to establish an independent and impartial redress mechanism to handle complaints from Europeans concerning the collection of their data for national security purposes.

The European Commission will continually review developments in the United States along with its adequacy decision.

Adequacy decisions can be adapted or even withdrawn in the event of developments affecting the level of protection in the applicable jurisdiction.

Future actions of EU data protection authorities are difficult to predict.

Failure to comply with the requirements of the GDPR and the related national data protection laws of the European Union Member States, which may deviate slightly from the GDPR, may result in fines of up to 4% of annual global turnover, or €20,000,000, whichever is greater.

As a result of the implementation of the GDPR, we may be required to put in place additional mechanisms ensuring compliance with the new data protection rules.

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Should we utilize third party distributors, compliance with such foreign governmental regulations would generally be the responsibility of such distributors, who may be independent contractors over whom we have limited control.

In July 2023, we signed a lease to move into 2,686 square feet of office space at 1 Enterprise Drive, Suite 430, Shelton, Connecticut (the “Shelton Lease”) to improve recruiting of staff and to reduce costs.

The Shelton Lease commenced on September 1, 2023 and has a 5.5 year term.

The initial payments for base rent are zero for the first

six months, $2,910 for each of the next six months, and gradually increase to $3,275 per month for the final months of the lease.

The Company has an option to cancel this lease after 36 months.

Commercialization

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Manufacturing

We do not own or operate facilities for drug manufacturing, storage and distribution, or testing.

We work with clinical manufacturing organizations to manufacture the clinical supplies of our current and any future product candidates.

We have established an operations leadership team with extensive experience in manufacturing drugs based on amphiphilic agents, and in the construction, validation, approval and operation of facilities designed to manufacture these products.

We have established an operations leadership team with extensive experience in manufacturing of the SHAO and INT230-6 product candidate.

We have established an operations leadership team with extensive experience in manufacturing of the SHAO and INT230-6

product candidate.

Our team has developed a reproducible manufacturing process for SHAO and our product candidates.

In 2016 we produced our first batch of INT230-6 under FDA regulated cGMP and have scaled up the product successfully.

In 2016, our first batch of INT230-6 was produced under FDA regulated cGMP and scaled up successfully.

We generated and continue to generate stability data showing that INT230-6 had acceptable stability through 36 months using validated analytical methods.

The development and commercialization of new product candidates is highly competitive.

We face competition from major pharmaceutical, specialty pharmaceutical and biotechnology companies among others with respect to INT230-6 and will face similar competition with respect to any product candidates that we may seek to develop or commercialize in the future.

We face competition from major pharmaceutical, specialty pharmaceutical and biotechnology companies among others and will face similar competition with respect to any product candidates that we may seek to develop or commercialize in the future.

We compete in pharmaceutical, biotechnology and other related markets that develop immune-oncology therapies for the treatment of cancer.

There are other companies working to develop new drugs, immunotherapies and other approaches for the treatment of cancer including divisions of large pharmaceutical and biotechnology companies of various sizes.

The large pharmaceutical and biotechnology companies that have commercialized and/or are developing immune-based treatments for cancer include AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, Inc., Merck & Co., Novartis, Pfizer and Genentech, Inc.

In addition, other companies have oncology divisions including large companies such as Eli Lilly and GlaxoSmithKline or and several smaller midsize organizations.

Some of the products and therapies developed by our competitors are based on scientific approaches that are the similar to our approach, including with respect to the use of intratumoral delivery or activation of the immune system.

The large pharmaceutical and biotechnology companies that have commercialized and/or are developing immune-based treatments for cancer include Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, Inc., Merck & Co., Merck KGA, Novartis, Pfizer Regeneron and Roche (Genentech, Inc.) In addition, other companies have oncology divisions including large companies such as Eli Lilly and GlaxoSmithKline or and several smaller midsize organizations.

Other competitive products and therapies are based on entirely different approaches.

We are aware that Oncorus, Inc., Replimune Group, Inc., Amgen Inc., ImmVira Co., Ltd., IconOVir Bio, Inc., and FerGene, Inc., among others, are developing immunotherapies that may have utility for the treatment of indications that we are targeting.

We are aware that Replimune Group, Inc., Amgen Inc., ImmVira Co., Ltd., IconOVir Bio, Inc., and FerGene, Inc., among others, are developing immunotherapies that may have utility for the treatment of indications that we are targeting.

Potential competitors also include academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing and commercialization.

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Our competitors also may obtain FDA or foreign regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

The key competitive factors affecting the success of all our product candidates, if approved, are likely to be their efficacy, safety, convenience and

price, if required, the level of biosimilar or generic competition and the availability of reimbursement from government and other third-party payors.

The key competitive factors affecting the success of all our product candidates, if approved, are likely to be their efficacy, safety, convenience and price, if required, the level of biosimilar or generic competition and the availability of reimbursement from government and other third-party payors.

Intellectual Property

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and all external major pharmaceutical markets.

Four foreign patent applications are pending.

Our three United States Patent and Trademark Office (“PTO”) issued patents are as follows;

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US Patent Application Number 17/108,099 is directed to a method of treating cancer, with a filing date of December 1, 2020.

We are prosecuting patents in every major market and have been granted patents in Australia, Canada, China, the 27 European Union countries (national phase filings were made for Austria, Belgium, Cypress, Czech Republic, Denmark, Finland, France, Germany, Greece, Italy, Ireland, Liechtenstein, Luxembourg, Macedonia, Malta, Monaco, the Netherlands, Norway, Poland, Portugal, Romania, San Marino, Singapore, Spain, Sweden, Switzerland, Turkey, and the United Kingdom), Israel, Japan, Macau, Russia, Singapore, South Africa, and South Korea.

Patent applications are pending in Brazil, Chile, Mexico and India.

Each application and issued patent has multiple claims directed to technology, methods, formulations and our lead product candidates.

We are prosecuting patents in every major market and have been granted patents in Australia, Brazil, Canada, China, 27 European countries (Austria, Belgium, Cypress, Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Liechtenstein, Luxembourg, Macedonia, Malta, Monaco,

Netherlands, Norway, Poland, Portugal, Romania, San Marino, Spain, Sweden, Switzerland, Turkey, and the United Kingdom), India, Israel, Japan, Macau, Mexico, Russia, Singapore, South Africa and South Korea.

Each application and issued patent have multiple claims directed to technology, methods, formulations and our lead product candidates.

Together with trade secrets, know-how and continuing technological innovation, we believe that our IP position is thorough, novel, non-obvious and has been reduced to practice.

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Employees and Human Capital Resources

As of March 1, 2024, we had seventeen employees and contractors, including one with an M.D.

As of March 1, 2025, we had sixteen employees and contractors, including one with an M.D.

and one with a Ph.D.

degree, consisting of two part-time and five full-time and employees, and ten contractors.

degree, consisting of two part-time and five full-time employees, and nine contractors.

We have never had a work stoppage, and none of our employees is represented by a labor organization or under any collective-bargaining arrangements.

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Talent Attraction and Engagement

We seek to foster community, inclusion, and diversity throughout the organization by identifying talent culture adds, with a targeted emphasis on the value and contributions of each employee.

Our talent attraction strategy includes utilizing employee referrals and networks, with a generous referral award, job boards, including those focused on diverse talent, and partnerships with organizations representing underrepresented communities.

All job descriptions are thoroughly reviewed for consistent and inclusive language.

Our talent attraction strategy includes utilizing employee referrals and networks, with a generous referral award, and job boards.

We retain our talent through open and honest communication.

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In addition to salaries, we offer dynamic competitive compensation programs that are in line with our peers and industry.

To reward employee contributions and enable them to share in the success of the Company, all employees receive generous and attainable incentive compensation beyond their base salary and equity compensation opportunities.

To reward employee contributions and enable them to share in our success, all employees receive generous and attainable incentive compensation beyond their base salary and equity compensation opportunities.

We offer a 401(k) with employer match, employer-subsidized insurance benefits which are both robust and cost effective, flexible spending accounts, and employee assistance programs, among many other employee benefits.

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Our website and the information on, or that can be accessed through our website, will not be deemed to be incorporated by reference into this Annual Report on Form 10-K or any other report we file or furnish to the SEC.

We make available on our website, free of charge, our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission, or the SEC.

Our SEC reports can be accessed through the Investors section of our internet website.

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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