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Item 1. Business

2026-03-27 compared with 2025-03-13 · 509 added, 604 removed, 810 unchanged (58% of the section changed)

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Intratumoral (“IT”) treatment, or treatment designed to contain a drug inside a tumor without spreading to the rest of the body, has been an objective of clinicians since discovery of chemotherapeutic agents.

The challenge with IT treatment approaches is that a tumor’s lipophilic, high fat, dense and pressurized microenvironment is incompatible with and does not absorb water-based products.

We believe that this drug delivery challenge limits the effectiveness of prior and current IT treatments, which involve injecting aqueous drugs into a tumor without sufficient consideration of the tumor environment (regardless of the drug’s mechanism or approach, i.e.

The challenge with IT treatment approaches is that a tumor’s stromal, high-fat, dense, poorly vascularized, and pressurized microenvironment is incompatible with and does not absorb water-based products.

We believe that this drug delivery challenge limits the effectiveness of prior and current IT treatments, which have involved injecting aqueous drugs into a tumor without sufficient consideration of the tumor environment.

The problem of the incompatibility of the tumor’s environment is independent of any water-based drug’s mechanism or approach, i.e.

the stimulation of an inflammatory response or efforts to attract immune cells into a hostile live tumor.

Accordingly, there remains a continued unmet need for the development of direct IT therapies for solid tumors that provide high local killing efficacy coupled with nontoxic systemic anti-cancer effects.

We believe we have created a product candidate with the necessary chemistry to overcome this local delivery challenge.

We believe we have created a product candidate with the necessary chemistry to overcome this local delivery challenge within the tumor.

Evidence shows the mechanism of tumor killing achieved by our drug candidate also leads to systemic immune activation and T-cell repertoire expansion in certain cancers.

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The drug is also used in breast and lung cancer.

Our Clinical Programs

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.

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(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 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.

Data from a cohort of only sarcoma patients whose cancer continued to progress following 3 prior therapies showed a median overall survival of 21.3 months.

Typical median survival for these severe sarcomas is 7.6 to 9.7 months.

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.

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

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 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 determined that our 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.

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

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.

Based on the data from the IT-01 Study, 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 333-patient study with an endpoint of overall survival has been authorized by the FDA, Health Canada, the European Medicines Authority, and Australia's Therapeutics Goods Administration.

In March 2025, we paused new site activations and patient enrollments due to funding constraints.

Prior to this pause, the trial had enrolled 21 patients.

We will continue to treat all patients enrolled in this study in cooperation with our third-party contract research organizations to reduce ongoing costs during this pause.

Once sufficient funding is obtained, we plan to restart site activations and patient enrollment in the INVINCIBLE-3 Study.

In October 2024, in collaboration with the Swiss Cancer Group ("SCI"), formerly the Swiss Cancer Group for Clinical Cancer Research 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”).

The endpoint is the change in the pathological complete response rate for the combination compared to the SOC alone.

In September 2025, we paused new patient enrollment to revise the dosing regimen for patients receiving INT230-6 in Cohort A due to some patients in Cohort A experiencing localized skin irritation near the tumor site.

A protocol amendment was submitted to the Swissmedic and the Swiss Ethics Committee to use a lower drug volume per tumor volume ratio and a single injection of INT230-6.

Full approval to resume enrollment was granted on March 26, 2026, and we plan to resume enrollment in the second quarter of 2026.

We are currently targeting to complete enrollment by the end of 2027 and will likely add resources to help sites enroll new patients.

In the event we are unable to obtain sufficient additional funding, we may have to delay the completion of the INVINCIBLE-4 Study until such funding is obtained.

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.

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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 Lead Product Candidate:

Our lead product candidate, INT230-6, is primarily comprised of three components:

(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 1 below.

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 bloodstream at low doses.

Pharmacokinetic results showed that greater than 95 percent of the active agents remain in the tumor.

The SHAO compound increases the dispersion of the drug throughout the tumor following intratumoral injection.

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 1 – INT230-6

The SHAO molecule facilitates drug dispersion throughout the tumor and facilitates the diffusion of the two cytotoxic agents into the cancer cells.

Once in the cancer cell, cisplatin binds the DNA and causes the cell apoptosis (death) whereas 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.

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

Cisplatin also increases cancer cells’ binding to T-cells, and vinblastine sulfate can promote the maturation of immune dendritic cells in the local environment.

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.

To be effective, an IT drug must disperse, be absorbed by the tumor and enter the cancer cell.

Without our unique formulation chemistry, water soluble drugs are not readily dispersed or absorbed by a tumor.

2) Our delivery technology is based on a proven science that uses amphiphilic molecules to transport drugs through tissue.

The active drug agents in our lead product candidate (cisplatin and vinblastine sulfate) are established, commercial, potent killing agents with immune stimulating properties that as of now are only used as IV products.

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

Cisplatin binds to DNA to cause apoptotic cell death and also attracts and binds T-cells via TL9 receptors.

Vinblastine sulfate destroys tubulin to stop replication and also induces dendritic cell maturation.

3) Unlike other IT products, our product candidates have multiple opportunities well beyond skin tumors, such as melanoma.

Our lead product candidate, INT230-6, has shown the ability to kill tumors deep in the body such as in the liver, lung, and peritoneum.

The product candidate has also demonstrated ability to kill tumors from several cancer types with abscopal effects and increased overall survival compared to historical results in Phase 1/2 studies.

4) Our product candidate has potential to kill tumors 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.

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

patient 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 those compounds 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 cancer.

Our product candidates can saturate an injected tumor delivering high concentrations of drug into the cancer cells and killing the entire tumor.

This process removes the cancer’s cloaking system, decreases the barriers to immune influx and activates a body-wide anti-cancer immune response to attack the uninjected tumors and unseen metastases.

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

Figure 2 compares current systemic treatment approaches with our treatment.

Figure 2 – Comparison of our Approach to 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.

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).

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.

Based on the data from the first two studies, we initiated a Phase 3 program in metastatic sarcoma and a Phase 2 study in presurgical TNBC.

INVINCIBLE-3 Study - Phase 3 Randomized Controlled Metastatic Soft Tissue Sarcoma Study

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 locally advanced, recurrent, inoperable, or metastatic non-diffuse subset of advanced soft tissue sarcoma patients (leiomyosarcoma, liposarcoma and undifferentiated pleomorphic sarcoma) with overall survival as the primary endpoint.

These subtypes comprise over 70% of the sarcoma populations.

The INVINCIBLE-3 Study will randomize patients 2 to 1 to either INT230-6 for 5 doses Q2 weeks with maintenance dosing every 12 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.

Our Phase 3 study is designed to be 90% powered to detect a difference hazard value of 0.65 in overall survival between the INT230-6 treatment group and the control group with 333 patients enrolled.

The study will have 3 interim data reviews.

The first at 20% of events (deaths) for futility only, the second at 40% of events, and the third at 60% of events.

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

See Figure 3 for INVINCIBLE-3 Study schema.

In December 2023, FDA provided us with a study may proceed letter.

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.

• 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.

In September 2024, the European Medicines Agency (“EMA”) accepted our study application via our filing in the clinical trials information system (“CTIS”).

The INVINCIBLE-3 Study has been authorized by the FDA, Health Canada, the European Medicines Authority, and Australia's Therapeutics Goods Administration.

The trial is being conducted in 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.

In July 2024, we initiated and dosed our first patient in the INVINCIBLE-3 Study.

In March 2025, we paused new site activations and patient enrollments due to funding constraints.

Prior to this pause, the trial enrolled 21 patients.

We will continue to treat all patients enrolled in this study in cooperation with our third-party contract research organizations to reduce ongoing costs during this pause.

Once sufficient funding is obtained, we plan to restart site activations and patient enrollment in the INVINCIBLE-3 Study.

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

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

No patient will have progressed on more than 2 prior treatments.

The standard of care drugs have a mOS ranging from 11 to 15 months (Figure 4).

In the INVINCIBLE-3 Study, underdosing of patients will be less likely, given dosing of INT230-6 can be as high as 160mL from day 1, and patients will also receive long-term maintenance treatment of INT230-6 every 12 weeks.

Figure 4 — Overall survival curves of standard of care drugs from phase 3 trials in second or third line

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

INVINCIBLE-4 Study - Phase 2 Randomized Presurgical Triple Negative Breast Cancer Study

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”).

Cohort A doses INT230-6 prior to the SOC, which is the Keynote 522 regimen, over a period of 6 months prior to surgery.

The primary endpoint is the increase in pathological complete response rate (“pCR”) and systemic safety compared with the SOC regimen.

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

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

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.

Our Partnerships

• The National Cancer Institute (“NCI”).

In May 2014, we were awarded a Collaboration Research and Development Agreement (“CRADA”) by the National Institute of Health’s National Cancer Institute.

The research sought to understand the mechanism of action of INT230-6 and test the drug in several models in the NCI’s laboratories.

The program resulted in a peer-reviewed publication titled Intratumorally delivered formulation, INT230-6, containing potent anti-cancer agents induces protective T-cell immunity and memory , which appeared in the journal OncoImmunology 2019 Vol 8 No 10;

15 and that was jointly authored by us and the NCI.

The data for the paper was generated entirely by the NCI in their laboratories and reported the critical role of T-cells in promoting complete tumor regression using our drug candidate and that INT230-6 was synergistic with anti-PD-1 (programmed death receptor 1) and anti-Cytotoxic T Lymphocyte-Associated Antigen 4 (“CTLA-4”) antibodies.

In June 2019, we entered into an agreement with Merck to evaluate the combination of INT230-6 with Keytruda ® (pembrolizumab), Merck’s anti-PD-1 therapy, in patients with advanced solid malignancies, including pancreatic, bile duct, squamous cell and non-MSI high colon cancers.

In our IT-01 Study, we treated 30 patients with this combination arm.

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

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.

In April 2020, we entered into an agreement with BMS to evaluate the safety and efficacy of INT230-6 with Yervoy ® (ipilimumab), BMS’s CTLA-4 immune checkpoint inhibitor, in patients with breast (17%), liver (5%), and advanced sarcoma cancer (78%).

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.

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.

See Figure 5 for INVINCIBLE-4 Study schema.

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.

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.

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

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 criterion 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.

There are several potential reasons to consider neoadjuvant treatment for early-stage breast cancer.

Giving chemotherapy preoperatively permits breast conservation in some patients who would otherwise require a mastectomy and may improve cosmetic preservation or restoration of physical appearance.

Preoperative therapy also provides a real-time evaluation of tumor response to permit discontinuation of ineffective therapy.

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.

As shown in Figure 8 below from the INVINCIBLE 2 Study, INT230-6 can cause a large tumor to become necrotic on a single dose without toxicity other than minor pain at the injection site.

Combining one or two doses upfront of INT230-6 with the SOC neoadjuvant therapy (pembrolizumab with anthracycline, cyclophosphamide and taxane) could potentially increase the pCR rate significantly to allow for accelerated approval especially in the more challenging tumors greater than or equal to 2 cm.

Further use of INT230-6 may allow for the elimination of the anthracycline and could reduce the toxicity of current chemotherapy regimen while obtaining an increase in pCR.

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

Figure 5 — The INVINCIBLE-4 Study schema comparing INT230-6 to the approved 2 nd or 3 rd line standard of care drugs

In October 2024, in collaboration with the SCI, we initiated and dosed our first patient in the INVINCIBLE-4 Study.

In September 2025, we paused new patient enrollment to revise the dosing regimen for patients receiving INT230-6 in Cohort A due to patients in Cohort A experiencing localized skin irritation near the tumor site.

Prior to this pause, fourteen (14) patients had been treated with seven (7) in each cohort.

The expected enrollment is sixty-one (61) patients.

In March 2026, a protocol amendment was submitted to the Swissmedic and the Swiss Ethics Committee to use a lower drug volume per tumor volume ratio and a single injection of INT230-6.

Full approval to resume enrollment was granted on March 26, 2026, and we plan to resume enrollment in the second quarter of 2026.

We are currently targeting to complete enrollment by the end of 2027 and may add resources to help sites enroll new patients.

In the event we are unable to obtain sufficient additional funding, we may have to delay the completion of the INVINCIBLE-4 Study until such funding is obtained.

We also reported the following preliminary observations on the fourteen patients treated to date:

pCR Data Observations

A pCR was achieved in five (5) of seven (7) patients (71.4%) who received injections of INT230-6 prior to SOC.

Six (6) patients received two (2) injections and one patient, who achieved a pCR, received one (1) injection.

A pCR was achieved in two (2) of six (6) patients (33%) who received the SOC alone, with one patient still to be evaluated.

Safety Data Observations

There has been a total of fourteen (14) grade 3 or higher adverse events, only one of which was considered a common immune-related side effect of checkpoint immunotherapy.

There has been a total of twenty-five (25) SOC-related grade 3 adverse events, of which four (4) were considered common or rare side effects of immune checkpoint inhibitors (three grade 3 and one grade 4).

Our Completed Clinical Trials

Phase 1/2 Study IT-01

The primary objectives of Phase 1 trials are to define the safety or toxicity profile of a new drug and to determine the dose for further evaluation in Phase 2 trials.

Patients enrolled in Phase 1 are therefore placed at risk of toxicity, in exchange for an undefined and limited clinical benefit.

Furthermore, patients who are considered for Phase 1 trials may be regarded as vulnerable because their physical condition may be deteriorating due to advanced cancer malignancy for which no further standard treatment options exist.

Efficacy is not usually the primary objective.

Most patients in Phase 1 studies have low survival expectations that range 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 in the United Kingdom (the Royal Marsden Hospital Index, or “RMHI”).

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 2017 IT-01 Study (the “IT-01 Study”), patients were enrolled whose cancer progressed following treatment using all approved and some experimental therapies.

Forty-three percent (43%) of patients had previously 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 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.

We initiated our first trial, dose escalation study using INT230-6 in the United States under an IND authorized by the FDA and in Canada under a 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 BMS Yervoy® (ipilimumab).

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 October of 2025, the Lancet Discovery Group’s journal, eBioMedicine, published our first clinical manuscript reporting results of our first-in-human trial with INT230-6 alone.

The manuscript included the following data results:

In heavily pretreated patients with advanced disease having over 20 different types of cancer, whose cancer had progressed following multiple prior lines of therapy.

intratumoral INT230-6 achieved the following:

• A disease control rate of 75% (48/64 patients) and a median overall survival (“mOS”) of 11.9 months.

In an exploratory analysis comparing patients receiving INT230-6 at a total dose (in mL) at a cumulative amount greater than 40% of the patient’s total tumor burden (“TTB”) compared to those treated with less than 40% of their TTB, the results were as follows:

◦ The disease control rate was 83.3% (40/48) compared to 50% (8/16);

◦ Median overall survival was 18.7 months (95% CI:

11.5–23.5) compared to 3.1 months (95% CI:

1.6–5.9) with a hazard ratio (HR) of 0.17 (95% CI:

0.081–0.342);

P<0.0001 (see Figure 3 below);

◦ Improved survival was consistent across a range of low to high tumor burden and tumor sizes.

• Approximately 20% of patients in the >40% group had uninjected tumors shrink, abscopal effects.

• Fifteen of 64 patients survived for more than 21 months.

• INT230-6 induced a qualitative decrease in proliferating cancer cells in injected tumors and a qualitative increase in activated T-cells infiltrating the tumor microenvironment.

• No dose-limiting toxicities were reported among 64 monotherapy patients;

seven patients had a grade 3 (10.9%) with no grade 4 or 5 treatment-related adverse events.

• Pharmacokinetic results showed that greater than 95% of the active cytotoxic agents remained in the injected tumors.

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

Figure 6 below illustrates the survival for all monotherapy INT230-6 subjects.

Treating the severe refractory population with only our drug candidate, approximately 50% of patients would be expected to be alive at one year (blue curve) with an mOS of 11.9 months.

Subjects dosed an amount of INT230-6 that was less than 40% of their TTB had a mOS of 3.1 months.

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 an approximately 63% chance of being alive at 1 year and the median overall survival was 18.7 months.

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

While there were no

differences statistically in the two populations with regards to incoming tumor burden, the sample size is small and the average values for the green curve were lower.

Figure 6 — Patient-Survival Dosing INT230-6 for All Monotherapy INT230-6 Patients 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, our 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.

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 in the second and third line setting of 11 to 16 months.

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).

Survival depends on certain risk factors, such as those found in the RMHI score (high lactate dehydrogenase, the number of metastatic sites, and low serum albumin levels), and sarcoma subtype.

Thirty (30) patients with sarcoma were treated in the IT-01 Study.

Fifteen (15) received INT230-6 monotherapy and fifteen (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.

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.

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 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:

• Jones Cancer Chemother Pharmacol (2011) 68:423 – 429, Clinical benefit of early Phase clinical trial participation for advanced sarcoma patients.

• Cassier et al., Annals of Oncology 25:

1222 – 1228, 2014 Outcome of patients with sarcoma and other mesenchymal tumours participating in Phase I trials:

a subset analysis of a European Phase I database.

• Subbiah et 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 RMHI.

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

A subject obtains 1 point depending on their number of metastatic sites, pre-dose plasma lactase dehydrogenase level and albumin concentrations.

Each of the 3 studies report the median overall survival results for subjects for various RMHI values as shown in the table below and Figure 7.

Median OS in Phase 1 Basket studies

Jones Cassier Subbiah

Median OS 7.6 months 9.1 months 9.6 months

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 IT-01 Study

We estimated the RMHI score for each patient receiving only INT230-6 in our study.

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

We created a synthetic Kaplan-Meier control curve.

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.

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

Figure 7 shows the actual median overall survival for INT230-6 patients receiving INT230-6 alone, which was 21.3 months (blue curve).

Those patients receiving a higher dose relative to their tumor (>40%) burden had not yet reached median overall survival prior to the end of the study with over 400 days of median follow-up .

Figure 7 — Survival of INT230-6 monotherapy sarcoma patients from Study IT-01

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

(months) Synthetic Control

(2 prior lines)

(months) INT230-6 all

(months) INT230-6

Dosed >40% of TTB

Median overall survival, CI

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

INVINCIBLE-2 Study - Phase 2 Randomized Controlled Study in Presurgical Breast Cancer

In 2021, we initiated our second and now completed clinical 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 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.

We determined that a local or whole-body anti-cancer immune response could be induced.

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

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 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.

The study completed enrollment and the database was locked in November 2023.

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, 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.

The trial was a two-part Phase 2, randomized, open label, multi-center study that has completed enrollment of 91 patients with early-stage breast cancer.

In part 1, twenty-nine patients were randomized 2:1 to treatment or no treatment.

Those in treatment received either up to three doses of INT230-6 on days 1, 8 and 15 post diagnosis or no treatment, the current SOC prior to resection.

Part 2 of the study randomized patients 2:1 to one intratumoral injection of either INT230-6 or saline solution.

IT-02 was conducted under the direction and supervision of Principal Investigator, Dr.

Angel Arnout.

The Ottawa Hospital conducted all subject enrollment, treatment and pathology for necrosis.

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.

Intensity funded the trial and provided INT230-6 supply.

There were no milestone payments, royalties or other compensation to be paid to any party.

The agreement provided that each party will solely own any inventions generated in the clinical trial that relate solely to intellectual property owned by that party.

In the INVINCIBLE-2 Study, the treatment group had a highly statistically significant increase in necrosis (tumor death) compared to the saline control group of 19% for the treatment group versus 1.3% for the saline control group (p=0.0002).

For tumors with diameter of 2 cm or higher in longest diameter the treatment group had an average of 24% necrosis in 42 subjects vs.

0.8% for the saline control group in 8 subjects (p=0.0007) .

In the study nine (9) subjects in INT230-6 treatment groups had a major pathological response (MPR) with a mean of 79.4% tumor necrosis.

MPR is defined as having less than or equal to 50% residual cancer in the tumor (i.e.

≥50% of the tumor became necrotic).

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

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.

At the San Antonio Breast Cancer Symposium (“SABCS”) in December 2023 images showed that up to >95% of an entire large tumor greater than 4.3 cm can be killed on a single INT230-6 injection at the proper dose (in milliliters) relative to the size of the tumor (in centimeters).

This result is seen in Figure 8 panel A and B.

An ER+PR+HER2+ 3.9 cm grade 3 invasive ductal breast cancer tumor was treated on day 1 with 7.4 cc of INT230-6.

Seven days later with another 14.8 cc.

The tumor was then resected another seven days later.

In panel B, a ER+PR+Her2- 4.4 cm diameter invasive lobular breast cancer tumor was treated with one dose of 21.3 mL of INT230-6, then resected 20 days later.

The INT230-6 was able to kill 85% of the ductal tumor from Panel A.

However, in the second panel, the drug was able to diffuse throughout nearly the entire tumor.

The boundary of

the tumor is shown by the black dotted lines and the red dotted lines show the extent of the necrosis.

Pathology conducted on the excised tumor showed that there was only a small percentage of viable cancer cells in one area of the 4.4 cm tumor after a single dose of INT230-6 of 21.4 mL.

More than 95% of the tumor was necrotic (dead) or ghost cells (cells without a nucleus).

These images show that diffusion distance is proportional to the amount given on a single dose.

In panel C we show high necrosis after surgery of a subject with a 3.3 invasive ductal cancer, who received one INT230-6 dose of 13.3 mL.

This patient’s tumor was characterized as having sheet-like necrosis to and just beyond the tumor edge.

Figure 8 Panels A and B — Showing the extent of the entire tumor and the area of dead cancer for various doses of drug;

greater than 95% of the total tumor volume was killed by a single dose injections of INT230-6.

Figure 8 Panels C and D — 100% necrosis with correspond H&E staining

In the above figure the entire breast tumor has been removed.

The black or blue dotted line shows the extent of the tumor, and red dotted line shows the extent of the necrotic (dead cancer) after treatment with INT230-6.

For a given tumor diffusion distance and thus tumor killing is proportional to the amount of drug dosed.

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

INT230-6 demonstrated a favorable safety profile and was well tolerated and patient interest in the new treatment was high.

Enrollment in the INVINCIBLE-2 study was rapid.

We believe patients are highly interested in a product that can potentially destroy the majority of their tumor rapidly while waiting for their surgery and with the possibility to induce a systemic anti-cancer immune response.

Surgery proceeded on time or without difficulty from the INT230-6 IT treatment.

Adverse events are minimal — mainly transient, low-grade pain at the injection site.

Our Clinical Data

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These results have been observed in combination with lower toxicities over a period of several months and post-treatment.

• Increased Survival Observed in Metastatic Disease.

Preliminary data presented at the American Society of Clinical Oncology (“ASCO”) the Society for Immunotherapy of Cancer (“SITC”) and the Connective Tissue Oncology Society (“CTOS”) for sarcoma in 2022 and 2023 indicated that patients receiving INT230-6 appear to live longer compared to historical data for subjects in phase 1/2 sarcoma studies.

• Increased Survival Observed in Metastatic Disease Relative to Studies Having Similar Patient Populations.

In addition to the Lancet eBioMedicine paper, our clinical research has been selected for poster and oral presentations multiple times at the American Society of Clinical Oncology (“ASCO”) the Society for Immunotherapy of Cancer (“SITC”), the SABCS, and the Connective Tissue Oncology Society (“CTOS”) beginning in 2020, indicating that patients receiving INT230-6 appear to live longer compared to historical data for subjects in phase 1/2 sarcoma studies.

• Acceptable Safety Profile of the New Drug/Treatment Approach to Date.

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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.

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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 Partnerships

National Cancer Institute (“NCI”).

In 2014, we were awarded a Collaboration Research and Development Agreement (“CRADA”) by the National Institute of Health’s National Cancer Institute.

The research sought to understand the mechanism of action of INT230-6 and test the drug in several models in the NCI’s laboratories.

15 and that was jointly authored by us and the NCI.

In 2019, as part of our IT-01 Study, we entered into a supply agreement with Merck to evaluate the combination of INT230-6 with Keytruda ® (pembrolizumab), Merck’s anti-PD-1 therapy, in patients with advanced solid malignancies, including pancreatic, bile duct, squamous cell and non-MSI high colon cancers.

In our IT-01 Study, we treated 30 patients with this combination arm.

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

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.

It is our intent to publish the data from the combination arms from the IT-01 Study with Merck.

• Bristol Myers Squibb.

In 2020, as part of our IT-01 Study, we entered into an agreement with BMS to evaluate the safety and efficacy of INT230-6 with Yervoy ® (ipilimumab), BMS’s CTLA-4 immune checkpoint inhibitor, in patients with breast (17%), liver (5%), and advanced sarcoma cancer (78%).

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.

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.

• Swiss Cancer Institute and UniCancer.

In 2024, as part of our INVINCIBLE-4 Study, presurgical breast cancer study in Switzerland and France, we partnered with the Swiss Cancer Institute (in Switzerland) and UniCancer (in France) who act as Sponsors of the Phase 2 TNBC trial in their respective countries.

The Swiss Cancer Institute is a research institution dedicated exclusively to independent, multicenter cancer research in Switzerland, who conduct comprehensive research in all types of cancer and across all disciplines.

Unicancer is the only French hospital federation 100% dedicated to the fight against cancer.

Through its health cooperation group, Unicancer is also the only national hospital network exclusively specialized in oncology.

It brings together 18 French Comprehensive Cancer Centres.

Our Manufacturing Capabilities

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Our technology platform allows us to identify novel product formulations and test the products’ activity in animal or test tube models of cancer.

Using our platform technology, we evaluated several potential formulations comprising various amphiphilic molecules that act as cancer cell penetration enhancers.

We tested formulations using our technology with many potent, anti-cancer drugs (with different mechanisms of action) in various combinations under several conditions to discover our lead product candidate, INT230-6.

We believe our treatment approach may overcome some of the inherent problems of treating cancer with less toxicity.

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taking care of the patient will benefit all stakeholders.

Key elements of our strategy include:

• 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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Cancer cells adapt to evade and thwart immune cells in several ways and can thus grow unchecked.

According to the American Cancer Society, in 2025 there will be an estimated 2 million new cancer cases diagnosed and over 618,000 cancer deaths in the United States.

According to the American Cancer Society, in 2026 there will be an estimated 2.1 million new cancer cases diagnosed and over 626,000 cancer deaths in the United States, which is 1,700 deaths per day.

An increase of more than 8,000 deaths from 2025.

Cancer is the second most common cause of death in the U.S.

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have metastatic soft tissue sarcomas of the 3 main subtypes

Chemotherapy Treatment

Unmet Medical Need for Improved Cancer Treatments

There is a high unmet medical need for improved cancer treatments.

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Another challenge for systemic approaches is poor absorption or cellular mechanisms in the cancer cell to remove the drugs.

Immunotherapy

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.

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 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 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 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.

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

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.

Our Lead Product Candidate:

Our lead product candidate, INT230-6, is primarily comprised of three components:

(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.

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, 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.

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.

To be effective, an IT drug must disperse, be absorbed by the tumor and enter the cancer cell.

Without our unique formulation chemistry water soluble drugs are not readily dispersed or absorbed by a tumor.

2) Our delivery technology is based on a proven science that uses amphiphilic molecules to transport drugs through tissue.

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

Cisplatin binds to DNA to cause apoptotic cell death and also attracts and binds T-cells via TL9 receptors.

Vinblastine sulfate destroys tubulin to stop replication and also induces dendritic cell maturation.

3) Unlike other IT products, our product candidates have multiple opportunities well beyond skin tumors, such as melanoma.

Our lead product candidate, INT230-6, has shown the ability to kill tumors deep in the body such as in the liver, lung, and peritoneum.

The product candidate has also demonstrated ability to kill tumors from several cancer types with abscopal effects and increased overall survival compared to historical results in Phase 1/2 studies.

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.

Preclinical Data

Early Research Showed Proof-of-Concept

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

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Thus, immunological T-cell memory was induced by INT230-6.

INT230-6 is Synergistic with Checkpoint Blockade

Nature has created checkpoints on the immune system to regulate the activity of the immune cells.

These pathways are crucial for self-tolerance to prevent the immune system from attacking healthy cells indiscriminately.

Large pharmaceutical companies such as Merck, Roche, AstraZeneca, Pfizer, Regeneron and BMS have developed new types of anti-cancer anti-body drugs with the ability to modify and block the checkpoints on the immune system.

Our results show strong benefit in regressing tumors with the combination of INT230-6 and checkpoint inhibitors which leads to improve survival.

The data showed the combination of our product candidate with either anti-PD-1 or CTLA-4 antibodies in a dual tumor (metastatic) cancer mouse resulted in additive benefit.

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

As part of our own research, we formulated cisplatin in water without the SHAO and added a noncolloidal dye.

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INT230-6 is well absorbed and distributed throughout tumors (right side images) compared to the drug alone in water which leaks out (left side images).

Data published in the International Journal of Molecular Sciences June 2020 doi.org/10.3390/ijms21124493.

In addition to formulation experiments we conducted growth inhibition experiments using large tumors (>300 mm 3 ) and treated with low drug doses.

Typically, research conducted by other companies developing cancer products use small tumors (25 to 100 mm 3 ).

Such companies also often use large drug doses in their studies with drug amounts that are five to fifty-fold above our dose amounts.

Our product candidate can completely eradicate murine tumors, an effect that is termed a complete response (“CR”).

Most competitors show only a slowing down of the tumor’s growth rate over time.

INT230-6 regresses tumors over time as shown in Figure 4 panel A and extends animal life compared to the drugs given alone intratumorally at the same dose without our technology.

In addition, our drug candidate shows superior efficacy given intratumorally compared to dosing the drugs intravenously.

Often animals with a CR are permanently protected against the cancer.

This means upon re-inoculation with the same cancer new tumors do not grow.

The protective effect happens whether the cancer cells are reinoculated under the skin or administered intravenously indicating a broad systemic immune protection.

Through our research collaboration with the NCI, we generated data regarding the mechanism of action for our lead product candidate.

INT230-6 shows direct tumor killing and immune cell activation.

The direct tumor cell death is caused by action of the two potent agents (cisplatin and vinblastine sulfate).

Data generated to date indicates infiltration of dendritic cells into the tumor which can present antigen to activate CD8 and CD4 immune T-cells against the cancer.

Survival and tumor eradication are mostly driven by CD8+ T-cells.

Thus, our product candidate generates high quality, vaccine-like antigen from the attenuated tumors to promote the immune activation.

The Company also published data showing increases in dendritic cells, macrophage, T-cells and Natural Killer (“NK”) cells 10 days after intratumoral treatment in mouse colon tumors.

Selective immune depletion of CD4 and CD8 abrogates the therapeutic effect.

Figure 3 panel B that shows the influx of various immune cell into the tumor microenvironment.

The scope of the NCI studies was to assess growth inhibition, survival and immune activation.

Naïve mice were SC challenged with 1 × 10 6 C26 cells into the right flank.

Vehicle or INT230-6 (0.5 mg/ml cisplatin, 0.1 mg/ml vinblastine sulfate, 10 mg/ml IT-006 cell penetration enhancer also referred to as SHAO) were intratumorally (“IT”) administered into 300 mm 3 (approx.

8.5 mm in diameter, 100 μl/400 mm 3 C26 tumor) SC tumors (n = 10/group) for 5 sequential days (day 0 to 4) and tumor growth was monitored.

The fraction 5/10 indicates the number of complete responders.

The log rank test indicates a significant difference between the groups (p<0.0001).

Figure 4 — Mouse data showing tumor reduction and immune activation

In Panel A on the left, 100% of animals receiving INT230-6 treatment for 5 days have a slight increase followed by a decrease from baseline, with 50% of animals having a complete response compared to no treatment controls with no decrease or complete responders (data generated by the NCI see OncoImmunology 2019 Vol 8 No 10;

Panel B cell staining shows an increase in the immune infiltrates.

Data from Int.

2020, 21, 4493.

INT230-6 is Synergistic with Checkpoint Blockade

Nature has created checkpoints on the immune system to regulate the activity of the immune cells.

These pathways are crucial for self-tolerance to prevent the immune system from attacking healthy cells indiscriminately.

Large pharmaceutical companies such as Merck, Roche, AstraZeneca, Pfizer and BMS have developed new types of anti-cancer anti-body drugs with the ability to modify and block the checkpoints on the immune system.

Our results show strong benefit in regressing tumors with the combination of INT230-6 and checkpoint inhibitors which leads to improve survival.

The data showed the combination of our product candidate with either anti-PD-1 or CTLA-4 antibodies in a dual tumor (metastatic) cancer mouse resulted in additive benefit.

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 Safety of INT230-6

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

We successfully completed the needed tasks to begin clinical testing that included conducting pharmacology studies (showing activity of the drug), toxicology studies in two animal species, analytical methods development, manufacturing scale up, and regulatory submissions.

All these steps were completed by 2015.

The data showed that the use of SHAO did not change or increase the toxicity of cisplatin or vinblastine sulfate.

Analytical results showed the two drugs remain unchanged chemically when INT230-6 is stored properly, which is in a standard freezer at -20°C.

Clinical Regulatory Interactions

Our data was accepted for publication in the International Journal of Molecular Sciences June 2020 doi.org/10.3390/ijms21124493.

Regulatory Interactions

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 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 Health Canada in a CTA meeting in 2016.

We first started interactions with the FDA in 2014 and agreed on a preclinical

The FDA provided us a “Study May Proceed” letter.In 2023 the U.S.

FDA reviewed our Phase 3 program.

We met with the chemical, manufacturing and Controls division and developed a plan for registration of our drug product, INT230-6.

In addition our Phase 3 protocol was reviewed in detail by several groups with the FDA (clinical, pharmacological, safety, etc.) in December of 2023.

Our protocol was approved, and we received a Study May Proceed letter for the INVINCIBLE-3 trial.

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

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

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As we have progressed our study, we filed several amendments since 2017 and have received “No Objection Letters” each time from Health Canada.

We have been treating patients continuously under both our IND and CTA since May 2017.

The regulatory agencies agreed to permit setting the drug dose based on tumor volumes rather than using alternatives such as dose based on a patient’s height and weight.

Our belief is that using the patients’ total tumor burden (“TTB”) instead of body size is a more personalized and precise approach to ensure that patients receive an appropriate dose for their unique cancer burden.

We have been treating patients continuously under both our IND and CTA since May 2017.After submission of our Phase 3 trial protocol and relevant materials to Health Canada, we received a No-objection letter for the INVINCIBLE-3 trial.

The European Medicines Agency (EMA) uses the Clinical Trials Information System (CTIS) for all submission.

The CTIS is the mandatory, centralized, web-based portal for submitting and managing clinical trial applications (initial, amendments, renewals) in the EU/EEA since January 31, 2023.

It streamlines workflows for sponsors and regulators, offering a single submission point for up to 30 countries and a public, searchable database for transparency, requiring compliance with strict EU Clinical Trial Regulation (536/2014) guidelines.

Both our Phase 3 INVINCIBLE-3 and INVINCIBLE-4 trials were submitted to the EMA via the CTIS program.

In 2024, the CTIS generated a unique EU Trial Number for our accepted INVINCIBLE-3 study submission.

In 2025, the CTIS generated a unique EU Trial Number for our accepted INVINCIBLE-4 study submission.

Our clinical trial submission for our Phase 3 dossier was made under the Clinical Trial Notification (CTN) scheme.

Once the Human Research Ethics Committee (“HREC”) reviewed the clinical information Australia's Therapeutic Goods Administration (“TGA”) provided, acknowledgment of the acceptance by HREC for the study in 2024 allowed the trial to proceed.

All regulatory agencies agreed to permit setting the drug dose based on tumor size rather than using alternatives such as dose based on a patient’s height and weight.

Our belief is that using the patients’ TTB instead of body size is a more personalized and precise approach to ensure that patients receive an appropriate dose for their unique cancer burden.

Better dosing could lead to maximized efficacy with minimized side effects.

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

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.

squamous cell, thyroid, breast, head and neck, lymph, skin, and deep body cancers such as those found in pancreatic, uterus, liver, kidneys, colon, bile duct, fat, muscles (sarcoma) and lung.

The clinical trial sought to determine the safety and potential efficacy of dosing INT230-6 directly into several different types of cancers.

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

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

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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 the 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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This effect is independent of the cancer type and highly reproducible.

As would be expected, the amount of the vinblastine seen in the plasma when given intratumorally was less than 5% of the blood concentrations had the drug been given intravenously.

As would be expected, the

amount of the vinblastine seen in the plasma when given intratumorally was less than 5% of the blood concentrations had the drug been given intravenously.

Our two highest average doses of INT230-6 were 118 mL and 80 mL.

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Publications show the plasma concentration of a standard dose of vinblastine sulfate (6.5 mg for an average sized person) can be estimated.

Based on pharmacokinetic studies of vinblastine in the literature (Links, M., Cancer Investigation Volume 17, 1999 – issue 7479-485), we estimated a vinblastine plasma level of 240 ng/mL at 6 hours for an IV dose of ~5.1 mg.

Comparing our blood plasma concentration profile for vinblastine at various doses to the data from the Links cancer investigation indicates that >95% to 99% of the drug remained or degraded in the tumor post injection depending on the dose.

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

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.

Efficacy assessments for evaluating changes in tumor size in clinical trials are typically conducted with standardized oncology response criteria, for example, Response Evaluation Criteria in Solid Tumors known as RECIST or a newer version 1.1 (RECIST 1.1).

Efficacy in Metastatic Disease

A standard way to measure how well a cancer patient responds to treatment is to see whether tumors shrink, stay the same, or grow larger.

Efficacy assessments of changes in tumor size in clinical trials are typically conducted using standardized oncology response criteria, for example, Response Evaluation Criteria in Solid Tumors (“RECIST”) or its newer version 1.1 (RECIST 1.1).

There are additional guidelines for immunotherapeutic trials (“iRECIST”).

These criteria measure the change in longest diameter of tumors to assess drug response.

An increase in longest diameter of > 20% is considered progressive disease.

The rationale behind this is that tumors should generally become smaller.

These criteria measure changes in the longest diameter of tumors to assess drug response.

An increase in the longest diameter of > 20% is considered progressive disease.

The rationale is that tumors should generally become smaller.

The main benefit of iRECIST is to afford physicians the opportunity to confirm progression with a follow-up scan of the tumors 1 to 2 months later.

However, both RECIST 1.1 and iRECIST criteria were designed only to assess response to systemic therapies.

Our study initially employed RECIST 1.1, and subsequently, iRECIST methods for determining the efficacy of INT230-6.

Our IT-01 Study initially used RECIST 1.1, and subsequently, iRECIST methods for determining the efficacy of INT230-6.

INT230-6 induced tumor regression in both injected and non-injected lesions in several patients.

However, tumors often increased in the longest diameter prior to shrinking using our drug, which we attribute to three factors.

However, when using our drug, tumors often increased in the longest diameter prior to shrinking, which we attribute to three factors.

The first is high absorption by the tumor of our drug.

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Finally, tumors can become cystic.

We have reported these data at major medical conferences (ASCO 2021, 2022, 2023, CTOS 2022, 2023) to indicate that RECIST methodology may be an inaccurate measure of clinical benefit for intratumoral INT230-6.

We have reported these data at major

medical conferences (ASCO 2021, 2022, 2023, CTOS 2022, 2023) to indicate that RECIST methodology may be an inaccurate measure of clinical benefit for intratumoral INT230-6.

Tumor Death (Necrosis)

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Figure 11 — Images showing that INT230-6 induces tumor necrosis (death) in the injected tumors.

The patient in these images had a squamous cell carcinoma.

His cancer continued to progress after 2 surgeries, radiation, and chemotherapy.

The patient enrolled in our study in January 2018 with two 10 cm 3 deep tumor nodules in his upper arm muscle.

The hospital recommended total arm and shoulder amputation.

This subject received 4 intratumoral injections equal to 100% of his 2 tumors’ volume.

The drug was dosed at ratio of 1 mL per 4 cc of tumor.

In the red circle in the left panel there is bright contrast indicating active cancer.

At the first scan on May 15, 2018, there was an increase in tumor size, significant necrosis (lack of contrast) and inflammation observed (right panel).

This patient has retained his arm and shoulder and is alive as of the last follow up visit in December 2022.

The patient in these images had a two sarcoma tumors at the base of his spine.

The first was 6.15cm in longest diameter, and the second was 14.4cm.

His cancer continued to progress after 2 surgeries, radiation, chemotherapy, and immunotherapy (PD-1 antibody).

The patient enrolled in our study in March 2018.

This subject received multiple intratumoral injections over several years.

In the baseline scan shown in the left panel, there is significant uptake of a contrast agent that shows dense, live, active cancer.

The first two scans showed a significant increase in size;

however, there was evidence of necrosis and cyst formation.

By the third scans on October 30, 2018, there was a decrease in tumor size, significant necrosis (lack of contrast) and inflammation observed (right panel).

This patient was alive at the end of the study in 2023 without visibly active cancer.

Abscopal Effects

In the metastatic study several subjects showed tumor size reduction of non-injected lesions in lymph nodes, liver, lung, perineum, and retroperitoneal areas (i.e.

In the IT-01 Study, several subjects showed tumor size reduction of non-injected lesions in lymph nodes, liver, lung, perineum, and retroperitoneal areas (i.e.

abscopal effects to visceral lesions).

The apparent abscopal effect was seen primarily in patients that received a dose greater than 40% of their TTB.

Abscopal effect rates may be even higher than known.

Sites did not report existing tumors under 1 cm in diameter.

In addition, many tumors above 1 cm were not followed and unreported.

We captured images from all subjects to be able to determine the true abscopal effect in all subjects at a future time and this analysis is in progress.

Shrinkage of uninjected bystander tumors (abscopal effects) was observed in tracked tumors in patients injected with IT INT230-6.

Most patients (90%) with an abscopal response were dosed at ≥40% of their TTB (9/48 [19%]).

In addition, 36% of patients with sarcoma dosed at >40% of their TTB had an abscopal effect;

however, these rates may be underestimated, as not all tumors were measured per RECIST 1.1 and uninjected tumors (<1 cm) were not recorded.

The maximum reduction from baseline in tracked tumor diameters ranged from 2% to 37.5% .

Figure 12 below shows uninjected tumor diameter changes over time of patients with confirmed reports of abscopal effects.

Figure 8 — Change in longest diameter of uninjected tumors over time (abscopal effects) monotherapy subjects only.

Figure 12 — Maximum change in longest diameter of uninjected tumors over time (abscopal effects) monotherapy subjects only.

Abscopal effects have been observed in ten patients after IT administration of INT230-6.

Of these, nine patients were dosed at ≥40% of their total tumor burden.

Tumor Diameter and Corresponding Volume

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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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Visualizing a change in 3 dimensions also shows the limitations of using RECIST methods for determining efficacy for intratumoral INT230-6.

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

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.

Figure 10 — Scan showing change in two longest diameters of an injected sarcoma tumor at the base of the spine.

We believe that RECIST measurements (longest diameter) are inappropriate to capture efficacy with INT230-6.

As a result, overall survival, the FDA’s gold standard efficacy endpoint, is a better measure of INT230-6’s performance in metastatic cancer.

Disease Control Rate

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

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

75.0 (62.6, 85.0;

Dosed ≥ 40% TTB (N = 48), n (%)

83.3 (69.8, 92.5;

Dosed < 40% TTB (N = 16), n (%)

50.0 (24.7, 75.3;

Sarcoma only (N = 15), n (%)

93.3 (68.1, 99.8;

Dosed ≥ 40% TTB (N = 11), n (%)

90.9 (58.7, 99.8;

Dosed < 40% TTB (N = 4), n (%)

100 (39.8, 100;

Prior treatment

Yes (N = 31), n (%)

74.2 (55.4, 88.1;

No (N = 33), n (%)

75.8 (57.7, 88.9;

Survival — Phase 1 Basket Studies

The primary objectives of Phase 1 trials are to define the safety or toxicity profile of a new drug and to determine the dose for further evaluation in Phase 2 trials.

Patients enrolled in Phase 1 are therefore placed at risk of toxicity, in exchange for an undefined and limited clinical benefit.

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 the patient’s incoming health.

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

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 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.

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).

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 the IT-01 Study

Type of Cancer

Patients Monotherapy

10 Other a <4% each

Skin (Melanoma/Merkle)

Squamous cell carcinoma

Head and neck

Cholangiocarcinoma

a Others include:

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 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.

These data indicate a potentially active drug.

Given the small size of the population, the heterogeneity of the cancers and variability of the incoming tumor burdens, the high and low dose groups may have been different in a way that we may not have been able to measure.

We observed a strong overall survival signal in just sarcoma patients;

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

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.

Figure 11 panel A below illustrates the survival for all monotherapy INT230-6 subjects.

See Table below for the patient population.

Treating only with our drug candidate, approximately 50% of patients would be expected to be alive at one year (blue curve) with a median overall survival (“mOS”) expected of 11.9 months.

Subjects dosed an amount of INT230-6 that was less than 40% of their TTB had a mOS of 3.1 months.

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.

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

While there were no differences statistically in the two populations with regards to incoming tumor burden;

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

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.

Determination of progression will be using density measured criteria.

Biomarker Analysis

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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).

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

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

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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 hemotoxylin 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 hematoxylin 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.

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

Reduction of Live Cancer Observed in Breast Cancer

Figure 14 shows the reduction of live cancer cell tissue taken from a metastatic breast cancer patient from the IT-01 Study pre and post-dosing of INT230-6.

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

However, 28 days later C2D0, there was almost no cancer observed in the collected tissue.

However, 28 days later C2D0, there was almost no cancer observed in the collected biopsy tissue.

Magnification is 400µ.

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Immune Response in Breast Cancer

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.

INT230-6 causes an influx of immune cells into the tumor mice.

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

Applying a special set of stains to the biopsied tissue enables the measurement of immune cells inside the tumor.

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Figure 15 — 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 were enrolled in the IT-01 Study.

Reduction of Live Cancer Observed in Sarcoma

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

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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.

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.

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.

The sarcoma types were leiomyosarcoma, liposarcoma, pleomorphic sarcomas, chondrosarcoma, chordoma, spindle cell sarcoma, fibrosarcoma, osteosarcoma, myofibroblastic sarcoma, desmoid type, and Kaposi sarcoma.

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 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.

Safety in sarcoma population remained favorable.

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.

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 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:

• Jones Cancer Chemother Pharmacol (2011) 68:423 – 429, Clinical benefit of early Phase clinical trial participation for advanced sarcoma patients.

• Cassier et.

al., Annals of Oncology 25:

1222 – 1228, 2014 Outcome of patients with sarcoma and other mesenchymal tumours participating in Phase I trials:

a subset analysis of a European Phase I database.

• Subbiah et.

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 RMHI.

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

A subject obtains 1 point depending on their number of metastatic sites, pre-dose plasma lactase dehydrogenase level and albumin concentrations.

Each of the 3 studies report the median overall survival results for subjects for various RMHI values as shown in the table below.

Median OS in Phase 1 Basket studies

Jones Cassier Subbiah

Median OS 7.6 months 9.1 months 9.6 months

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 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.

Subbiah reports the overall survival of sarcoma patients for a given RMHI score (Figure 16 below) from the publication shows the strong correlation between RMHI score and overall survival.

Figure 16 — Overall Survival based on RMHI scores in soft tissue sarcoma (Subbiah data)

We were able to estimate the RMHI score in our study for each patient receiving only INT230-6.

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 control curve from the Subbiah dataset that approximated our patients’ RMHI score distribution (Figure 17 below).

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 the IT-01 Study compared to a synthetic control are shown in the table below.

INT230-6 Dosed

(months) Synthetic Control

(2 prior lines)

(months) INT230-6 all

(months) INT230-6

Dosed >40% of TTB

Median overall survival, CI

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

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

The study completed enrollment and the database was locked in November 2023.

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

The trial was a two-part Phase 2, randomized, open label, multi-center study that has completed enrollment of 91 patients with early-stage breast cancer.

In part 1, twenty-nine patients were randomized 2:1 to treatment or no treatment.

Those in treatment received either up to three doses of INT230-6 on days 1, 8 and 15 post diagnosis or no treatment, the current SOC prior to resection.

Part 2 of the study randomized patients 2:1 to one intratumoral injection of either INT230-6 or saline solution.

IT-02 was conducted under the direction and supervision of Principal Investigator, Dr.

Angel Arnout.

The Ottawa Hospital conducted all subject enrollment, treatment and pathology for necrosis.

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.

Intensity funded the trial and provided INT230-6 supply.

There were no milestone payments, royalties or other compensation to be paid to any party.

The agreement provided that each party will solely own any inventions generated in the clinical trial that relate solely to intellectual property owned by that party.

In study IT-02, the treatment group had a highly statistically significant increase in necrosis (tumor death) compared to the saline control group of 19% for the treatment group versus 1.3% for the saline control group (p=0.0002).

For tumors with diameter of 2 cm or higher in longest diameter the treatment group had an average of 24% necrosis in 42 subjects vs.

0.8% for the saline control group in 8 subjects (p=0.0007) .

In the study nine (9) subjects in INT230-6 treatment groups had a major pathological response (MPR) with a mean of 79.4% tumor necrosis.

MPR is defined as having less than or equal to 50% residual cancer in the tumor (i.e.

≥50% of the tumor became necrotic).

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

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.

This result is seen in Figure 18 panel A and B.

An ER+PR+HER2+ 3.9 cm grade 3 invasive ductal breast cancer tumor was treated on day 1 with 7.4 cc of INT230-6.

Seven days later with another 14.8 cc.

The tumor was then resected another seven days later.

In panel B, a ER+PR+Her2- 4.4 cm diameter invasive lobular breast cancer tumor was treated with one dose of 21.3 mL of INT230-6, then resected 20 days later.

The INT230-6 was able to kill 85% of the ductal tumor from Panel A.

However, in the second panel, the drug was able to diffuse throughout nearly the entire tumor.

The boundary of the tumor is shown by the black dotted lines and the red dotted lines show the extent of the necrosis.

Pathology conducted on the excised tumor showed that there was only a small percentage of viable cancer cells in one area of the 4.4 cm tumor after a single dose of INT230-6 of 21.4 mL.

More than 95% of the tumor was necrotic (dead) or ghost cells (cells without nucleus).

These images show that diffusion distance is proportional to the amount given on a single dose.

In panel C we show high necrosis after surgery of a subject with a 3.3 invasive ductal cancer, who received one INT230-6 dose of 13.3 mL.

This patient’s tumor was characterized as having sheet-like necrosis to and just beyond the tumor edge.

Figure 18 Panels A and B — Showing the extent of the entire tumor and the area of dead cancer for various doses of drug;

greater than 95% of the total tumor volume was killed by a single dose injections of INT230-6.

Figure 18 Panels C and D — 100% necrosis with correspond H&E staining

In the above figure the entire breast tumor has been removed.

The black or blue dotted line shows the extent of the tumor, and red dotted line shows the extent of the necrotic (dead cancer) after treatment with INT230-6.

For a given tumor diffusion distance and thus tumor killing is proportional to the amount of drug dosed.

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

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.

INT230-6 demonstrated a systemic increase in the median diversity of T-cell repertoire in patients’ blood compared to baseline that was also much larger than a control saline injection and again showed that a single injection of INT230-6 can induce up to >95% necrosis of a tumor.

Immune Cell Activation

INT230-6 demonstrated an increase in CD4 T-cells and NK cells within tumors and gene expression profiling revealed a treatment effect of up-regulation of immune pathways expressed by T-cell activation, lymphocyte activation and inflammatory responses.

INT230-6 demonstrated a favorable safety profile and was well tolerated and patient interest in the new treatment was high.

There was a reduced in Ki67 for the drug and control.

Live cancer cells are needed to evaluate Ki67.

Several subjects’ tumors receiving INT230-6 had such high necrotic percentages that measurement of Ki67 was not possible.

Those subject’s samples were therefore noted as unevaluable.

This result biased the Ki67 outcome against the drug and indicated that Ki67 was an inappropriate marker for INT230-6.

Enrollment in the study was rapid.

Surgery proceeded on time or without difficulty by the INT230-6 IT treatment.

Adverse events are minimal — mainly transient, low-grade pain at the injection site.

An analysis of differential gene expression comparing pre-and post-treated tumor tissue samples in the control group compared to the drug treated group showed that over 200 more immune related genes were activated pre- and post-treatment compared to the controls.

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Figure 18 — Relative abundance levels of immune cells present in the breast cancer tumor compared to current standard of care (no treatment controls.

Each bar demonstrates the immune cell abundance in a specific patient separated by cancer subtype, the left panel is the baseline cell population and the right panel is the post INT230-6 treatment.

Each bar represents a patient and demonstrates the immune cell abundance in a specific patient, the left panel is the baseline cell population and the right panel is the post INT230-6 treatment.

There was a relative increase in abundance of CD4 T naïve (light green) and NK cells (darker green) in the majority of patients post treatment.

In addition, INT230-6 demonstrated a systemic increase in the median diversity of the T-cell repertoire in patients’ blood compared to baseline that was much larger than a control saline injection as seen in Figure 19.

The adaptive immune system is one of the body’s most powerful defenses.

By being able to adapt, the body’s immune cells can be trained to attack undesirable cells or viruses anywhere in the body.

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 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.

A greater diversity of T-cell repertoire means there is higher likelihood for a T-cell to bind to the foreign entity (e.g.

cancer cells) and increase the specific T-cell clonal population to destroy the invader.

Sequencing of the TCR beta chain CDR3 regions from all plasma samples and analyzed TCR repertoire diversity using the Shannon diversity index.

TCR diversity was higher post-treatment compared to the pre-treatment.

Boxes depict the interquartile range with the line in the boxes showing the median, and the lines outside the boxes show the first or third quartiles of fraction as shown in Figure 20.

Figure 20 — Increase in clonal diversity in blood of all treated patients, with much bigger difference in INT230-6 drug treated vs saline groups

The INVINCIBLE 2 study demonstrated feasibility, safety, tolerability and immune activation of presurgical IT injections in breast cancer patients.

Preliminary data show histologic evidence of up to 95% tumor necrosis in varying

biologic subtypes including lobular carcinoma.

There was also an increase in immune activation.

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.

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.

Our Phase 3 study is designed to be 90% powered to detect a difference hazard value of 0.65 in overall survival between the INT230-6 treatment group and the control group with 333 patients enrolled (2:1 randomization to either INT230-6 treatment or control therapy).

The study will have 3 interim data reviews.

The first at 20% of events (deaths) for futility only, the second at 40% of events, and the third at 60% of events.

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

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;

for trabectadin:

2019 Aug 1;125(15):2610-2620;

for eribulin:

Schöffski et.

2016 Apr 16;387(10028):1629-37;

and for pazopanib:

van der Graaf et.

2012 May 19;379(9829):1879-86.

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

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 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.

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

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

There are several potential reasons to consider neoadjuvant treatment for early-stage breast cancer.

Giving chemotherapy preoperatively permits breast conservation in some patients who would otherwise require mastectomy and may improve cosmesis, or the preservation or restoration of physical appearance, in existing candidates for breast conservation.

Preoperative therapy also provides a real-time evaluation of tumor response to permit discontinuation of ineffective 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.

The efficacy of pembrolizumab in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with pembrolizumab as a single agent was investigated in KEYNOTE-522, a randomized, multicenter, double-blind, placebo-controlled trial conducted in patients with newly diagnosed previously untreated high-risk early-stage triple-negative breast cancer.

Patients were enrolled regardless of tumor PD-L1 expression.

Patients were randomized (2:1) to pembrolizumab in combination with chemotherapy or placebo in combination with chemotherapy.

The main efficacy outcome measures were pathological complete response rate and event free survival.

The pathological complete response rate was only 63% for patients who received pembrolizumab in combination with chemotherapy compared with 56% for patients who received chemotherapy alone.

However, that 7% increase in the pCR for pembrolizumab plus chemotherapy compared to chemotherapy alone was sufficient to result in a meaningful event free survival rate at 3 years for the 1200 patient Keynote 522 population.

This in turn resulted in pembrolizumab receiving full approval for neoadjuvant and adjuvant use in triple negative breast cancer.

At the same time, in Keynote 522 eighty percent (80%) of patients had a grade 3 or higher adverse event and 0.6% of patients died from the treatment.

As shown in Figure 18 above from the INVINCIBLE 2 Study INT230-6 can cause >95% of a large tumor to become necrotic on a single dose without toxicity other than minor pain at the injection site.

Further use of INT230-6 may allow for the elimination of the anthracycline or cyclophosphamide and could reduce the toxicity of current chemotherapy regimen while obtaining an increase in pCR.

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

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.

Metastatic TNBC patients have a poor prognosis, with a median overall survival of 13.3 months with treatment first line.

Recently approved treatments including Lynparza (PARP inhibitor) and Tecentriq (PD-L1 inhibitor).

Those treatments target a specific subset of patients, with BRCA 1 or 2 and PD-L1 positive markers, respectively.

Our target population would be more inclusive.

Continuing chemotherapy treatment until disease progression is currently the SOC for patients with metastatic TNBC, with no preferred chemotherapy regimens established at this time.

Gilead presented data at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #1080) for second line use of sacituzumab (Trodelvy).

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

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.

The Phase 2 study would be approximately 60 patients with INT230-6 arm and a control arm cohort design of patients using investigators choice of therapy.

The endpoints would be median overall survival.

Patients would receive 5 doses of INT230-6 every two weeks delivered IT with a maintenance dosing.

The protocol will be designed to allow us to determine, within 12 months following completion of enrollment, whether INT230-6 has the potential to offer clinical benefit.

A combination of INT230-6 with a checkpoint antibody (e.g.

pembrolizumab or ipilimumab) within the randomized Phase 2 may be considered.

From the results of the ongoing Phase 2, the company would make a strategic decision to use either monotherapy or combination with a checkpoint and size the final study accordingly.

Phase 3 would be randomized 2 to 1 against investigators choice of treatment.

Additional subjects could be added to the Phase 2 portion to complete the Phase 3 program.

A clinical Phase 2/3 program in metastatic breast will be when sufficient capital is available post-initiation of the sarcoma Phase 3 study and the Phase 2/3 program in neoadjuvant breast cancer.

Government Regulation

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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 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.

In December 2022, Congress 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.

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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.

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

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

Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters and criteria to be used in monitoring safety and evaluating effectiveness.

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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.

Sponsors of clinical trials registered with the 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.

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.

Both the NIH and the FDA have 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.

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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.

• Phase 2 — This phase typically involves 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.

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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.

In December 2022, Congress 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.

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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.

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.

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 15 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.

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 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.

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.

Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life and to identify appropriate storage conditions for the product candidate.

NDA Submission and Review by the FDA

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.

Assuming successful completion of all required clinical testing in accordance with applicable regulatory requirements, detailed information on the product candidate 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 preclinical 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.

Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a product’s use or from a number of alternative sources, including studies initiated by investigators.

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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.

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 preclinical 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.

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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.

Under the goals and policies 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 if 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.

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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.

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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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.

In September 2025, the FDA began publishing CRLs, with trade secret and confidential commercial information redacted, soon after issuing them to the respective sponsors, breaking with long standing agency tradition of publishing CRLs with approval documentation after the product is approved.

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

If and when the 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.

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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.

Fast Track, Breakthrough Therapy and Priority Review

Fast Track, Breakthrough Therapy, Priority Review and Commissioner’s National Priority Voucher

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.

These programs include fast track designation, breakthrough therapy designation, priority review, and the Commissioner’s National Priority Voucher program.

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.

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.

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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.

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 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.

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 an NDA from ten months to six months for an original application from the date of filing.

In 2025, the FDA created a new pilot program called the Commissioner’s National Priority Voucher (“CNPV”) with the goal of radically expediting the drug and biological product review and approval process.

The agency may award a CNPV to a company or a specific product candidate that demonstrates alignment with certain national health priorities.

The FDA aims to take action on a marketing application for which a CNPV is used within one to two months after the filing date.

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.

Furthermore, none of these programs changes 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

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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.

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.

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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.

Congress amended the FDCA in December 2022 to provide FDA with additional statutory authority to mitigate potential risks to patients from continued marketing of ineffective drugs previously granted accelerated approval.

Under the amendments, 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.

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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.

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.

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.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act (“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.

The Drug Supply Chain Security Act (“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 resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors and dispensers.

The DSCSA also replaced certain provisions from the PDMA pertaining to wholesale distribution of prescription drugs with a more comprehensive statutory scheme, requiring uniform national standards for wholesale distribution and, for the first time, for third-party logistics providers.

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 (“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.

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 of greater 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.

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.

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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.

To the extent a Section 505(b)(2) applicant is relying on studies conducted for an already approved product, such an applicant is also required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would.

To the extent a Section 505(b)(2) applicant is relying on studies conducted for an already approved product, such

an applicant is also required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would.

Specifically, any applicant who subsequently files an ANDA or 505(b)(2) NDA that references the drug listed in the Orange Book must certify to the FDA that with respect to each published patent, (i) the required patent information has not been filed by the original applicant of the RLD;

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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.

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.

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.

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• 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 (“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.

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;

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Therefore, coverage and reimbursement for drug products can differ significantly from payor to payor.

The process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved.

The process for determining whether a third-party payor will provide coverage for a product may be separate from

the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved.

Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs.

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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.

For example, negotiations on the next FDA user fee reauthorization package began in mid-2025, and the resulting agreement is expected to be sent to Congress in early 2027 for purposes of initiating the legislative process.

Reauthorization of the prescription drug user fee program must 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.

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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.

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.

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Therefore, any reduction in reimbursement that results from federal legislation or regulation may result in a similar reduction in payments from private payors.

Furthermore, recent U.S.

federal actions include initiatives incorporating “most favored nation” (international reference pricing) concepts for certain prescription drugs, as well as agency testing of new payment models that could tie Medicare reimbursement or manufacturer rebates to prices in specified reference countries.

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.

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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.

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 was enacted to address the concern articulated by both the FDA and others in the industry that some brand manufacturers had 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 attributed the inability to timely obtain such 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;

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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.

Additionally, 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.

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 announcing the first round of negotiated “maximum fair” prices for the first 10 drug products in August 2024, which will become applicable for payment year 2026.

The second round of negotiated prices for 15 drug products was announced in November 2025, and CMS published the next group of drug products selected for negotiation in January 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.

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Those lawsuits are currently ongoing.

Separately, the Trump Administration announced the creation of a government website called TrumpRx, which will allow consumers to purchase certain drugs at reduced prices as negotiated between the drug manufacturers and the administration.

As of December 2025, the Trump Administration secured deals with five major drug manufacturers to offer certain drugs at most-favored-nation prices.

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.

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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.

Furthermore, 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.

In mid-2022, the FTC launched sweeping investigations into the practices of the PBM industry, and published interim reports with its findings in mid-2024 and January 2025, that also appear to be contributing to additional federal and state legislative and regulatory proposals, as well as enforcement action and private litigation, targeting PBM operations, pharmacy networks, and financial arrangements.

In February 2026, President Trump signed into law several PBM regulatory reforms as part of a federal budget package, including but not limited to requirements for PBMs to pass back 100% of rebates and fees to commercial health plan sponsors;

to provide extensive informational disclosures related to patients’ coverage and benefits;

and to accept only bona fide service fees from drug companies when providing services under Medicare Part D.

The Department of Labor (“DOL”) also issued a proposed rule in January 2026 that would mandate specific PBM fee disclosures to self-insured plan fiduciaries under the Employment Retirement Income Security Act (“ERISA”).

If finalized as proposed, the DOL rule would also allow plan fiduciaries to audit those PBM disclosures to confirm accuracy.

Additional proposals and legislative changes aimed at PBMs and their business practices are likely to continue to be introduced and considered in Congress and by executive agencies.

Significant efforts to change the PBM industry as it currently exists in the U.S.

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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.

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.

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Poison Prevention Packaging Act.

Manufacturing, labeling, packaging, distribution, sales, promotion and other activities also are potentially subject to federal and state consumer protection and unfair competition laws, among other requirements to we may be subject.

The distribution of pharmaceutical 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.

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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 (“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.

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 opinion of the EMA’s Committee for Medicinal Products for Human Use (“CHMP”), the European Commission issues a single marketing authorization valid across the EEA.

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.

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The ten-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

In April 2023 the European Commission issued a legislative proposal to revise and replace the existing general pharmaceutical legislation, which was subsequently finalized and adopted in December 2025.

The revisions will significantly change several aspects of drug development and approval in the EU.

Similar to the United States, the various phases of non-clinical and clinical research in the European Union are subject to significant regulatory controls.

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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 Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the European Union.

The Clinical Trials Regulation was adopted 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 (“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.

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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The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the concerned EU Member State.

However, overall related timelines will be defined by the Clinical Trials Regulation.

Use of CTIS became mandatory for new clinical trial application submissions as of February 1, 203.

However, overall related timelines are defined by the Clinical Trials Regulation.

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.

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We currently have no sales, marketing or commercial product distribution capabilities and have no experience as a company commercializing products.

However, if necessary, we intend to hire appropriately to build the necessary infrastructure and capabilities over time for the United States, and potentially other regions, following further advancement of our product candidates.

Clinical data, the size of the addressable patient population, the size of the commercial infrastructure and manufacturing needs may all influence or alter our commercialization plans.

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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.

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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 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.

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 (Amgen).

Some of the products and therapies developed by our competitors are based on scientific approaches that are similar to our approach, including with respect to the use of intratumoral delivery or activation of the immune system (Amgen).

Other competitive products and therapies are based on entirely different approaches.

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Intellectual Property

We have a robust intellectual property position with 18 issued patents (with 3 of such patents being issued in the US).

We have a robust intellectual property position with 19 issued patents (with 4 of such patents being issued in the U.S.).

We have the ability to enforce our patent claims in 41 countries including the U.S.

and all external major pharmaceutical markets.

Our three United States Patent and Trademark Office (“PTO”) issued patents are as follows;

(i) US Patent Number 9,351,997 is directed to a method of treating cancer, with a registration date of May 31, 2016 and an expiration date of December 6, 2033, (ii) US Patent Number 9,636,406 is directed to a method of treating cancer, with a registration date of May 2, 2017 and an expiration date of September 15, 2033, and (iii) US Patent Number 10,888,618 is directed to a method of treating cancer, with a registration date of January 12, 2021 and an expiration date of September 15, 2033.

We also have one U.S.

patent application pending.

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, 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.

Our four United States Patent and Trademark Office (“PTO”) issued patents are as follows;

(i) US Patent Number 9,351,997 is directed to a method of treating cancer, with a registration date of May 31, 2016 and an expiration date of December 6, 2033, (ii) US Patent Number 9,636,406 is directed to a method of treating cancer, with a registration date of May 2, 2017 and an expiration date of September 15, 2033, (iii) US Patent Number 10,888,618 is directed to a method of treating cancer, with a registration date of January 12, 2021 and an expiration date of September 15, 2033, and (iv) US Patent Number 12,496,345 is directed to a method of treating cancer and an intratumoral formulation, with a registration date of December 16, 2025 and an expiration date of September 15, 2033.

We are prosecuting patents in every major market and have been granted patents in Australia, Brazil, Canada, China, 27 European countries (Austria, Belgium, Cyprus, 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 has 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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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