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Item 1. Business

2025-03-13 compared with 2024-03-28 · 446 added, 379 removed, 822 unchanged (50% of the section changed)

We are a clinical stage biopharmaceutical company focused on developing off-the-shelf viral immunotherapies that elicit an individualized, systemic anti-tumor immune response to help patients fight cancer.

Our engineered viruses are designed to induce a systemic anti-tumor response due to immunogenic cell death through direct viral-mediated cytotoxicity in cancer cells, thus releasing tumor neo-antigens and creating a pro-inflammatory microenvironment at the site of injection.

Our engineered viruses are designed to induce a systemic anti-tumor response due to induction of immunogenic cell death within the tumor microenvironment, thus releasing tumor neo-antigens and creating a pro-inflammatory microenvironment at the site of injection.

This is intended to lead to in-situ vaccination against the injected tumor and uninjected distant metastases.

Our viral immunotherapy approach utilizes intratumoral administration of genetically engineered viruses to induce tumor cell death and elicit a systemic anti-tumor response.

Our biological multimodal immunotherapy approach utilizes intratumoral administration of genetically engineered viruses to induce tumor cell death and elicit a systemic anti-tumor response.

Local delivery enables us to achieve these effects while aiming to minimize systemic toxicity.

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o A pivotal phase 3 randomized, triple-blinded and placebo-controlled clinical trial in the United States under a Special Protocol Assessment (SPA), with the U.S.

Food and Drug Administration (FDA) evaluating 711 evaluable patients with newly diagnosed, localized prostate cancer who have an intermediate or high-risk for progression.

We completed enrollment of this trial in September 2021, and we expect to report topline data in the fourth quarter of 2024.

Food and Drug Administration (FDA) evaluating patients with newly diagnosed, localized prostate cancer who have an intermediate or high-risk for progression.

The FDA previously granted fast track designation for the use of CAN-2409 for the treatment of localized, primary prostate cancer in combination with radiation therapy to improve the local control rate.

We completed enrollment of this trial in September 2021.

• In December 2024, we announced positive topline data from our phase 3 clinical trial.

This randomized, double-blind, placebo-controlled, multicenter clinical trial enrolled 745 patients (intent to treat population (ITT)) to evaluate the effectiveness and safety of CAN-2409 plus prodrug (valacyclovir) viral immunotherapy in combination with standard of care (SoC) external beam radiation therapy to improve disease-free survival (DFS) in patients with intermediate-to-high-risk, localized prostate cancer.

Patients were randomized 2:1 (496 in CAN-2409+prodrug and 249 in placebo (PBO) +prodrug).

Both arms received standard of care external beam radiation therapy (EBRT) +/- short course androgen deprivation therapy (ADT) (<6 months) and were stratified by NCCN risk group and ADT use.

Three intraprostatic injections of CAN-2409 (5x10 11 v/2mL) or PBO were administered, each followed by 14 days of prodrug.

• The study met its primary endpoint, demonstrating a statistically significant improvement in disease-free survival compared to the control arm.

Key topline results include:

▪ Statistically significant improvement in DFS for CAN-2409 plus radiation therapy (n=496) vs.

radiation therapy alone (n=249).

Treatment with CAN-2409 reduced the risk of prostate cancer recurrence or death by 30%.

Median DFS was not reached for the CAN-2409 treatment arm vs.

86.1 months in the PBO arm (p=0.0155, HR 0.7, 95% CI 0.52 to 0.94)

▪ Prostate cancer specific DFS (exclusion of non-prostate cancer related deaths) demonstrated a greater effect with a 38% decreased risk in the CAN-2409 arm vs.

PBO (p=0.0046;

HR 0.62, 95% CI 0.44 to 0.87)

▪ DFS improvement was observed both in patients receiving short-term ADT and in patients not receiving ADT

▪ Significant increase in the proportion of patients achieving a prostate-specific antigen (PSA) nadir (<0.2 ng/ml) was observed in the treatment arm compared to the placebo control arm (67.1% vs.

58.6%, respectively;

▪ CAN-2409 induced 80.4% pathological complete responses in the 2-year post-treatment biopsies compared to 63.6% observed in the control arm (p=0.0015)

• The median follow-up time for the recruited population was 50.3 months.

The primary outcome measure, DFS, included the evaluation of post-treatment biopsies, performed at two years from the end of radiation, for the presence of tumor recurrence.

Local or systemic recurrence and death from any cause were also part of the primary endpoint.

• CAN-2409 was generally well tolerated, with no new safety signals identified.

The most common CAN-2409-related adverse events were flu-like symptoms, fever and chills, which were generally mild to moderate in severity and self-limited.

• Based on these results, we intend to initiate discussions with the FDA regarding the regulatory pathway for CAN-2409 in intermediate-to-high-risk localized prostate cancer, and we anticipate submitting a biologics license application for CAN-2409 in the fourth quarter of 2026.

o A phase 2 randomized, double blind, placebo-controlled clinical trial in the United States evaluating patients with low-to-intermediate risk, localized prostate cancer undergoing active surveillance.

We completed enrollment of this trial in May 2019, and we expect to report topline data in the fourth quarter of 2024.

We completed enrollment of this trial in May 2019.

• In December 2024, we also reported that the phase 2b clinical trial of monotherapy CAN-2409 in 190 patients with low-to-intermediate risk, localized prostate cancer undergoing active surveillance showed numerical improvement in time to radical treatment and the percentage of patients achieving negative (prostate cancer-free) biopsies at 1-year post-treatment.

However, these differences did not reach statistical significance.

CAN-2409 was generally well tolerated, with no new safety signals identified.

The most common CAN-2409-related adverse events were flu-like symptoms, fever and chills, which were generally mild to moderate in severity and self-limited.

▪ Non-Small Cell Lung Cancer (NSCLC)

o An open-label phase 2 clinical trial in the United States evaluating CAN-2409 plus valacyclovir in combination with continued PD-(L)1 checkpoint inhibitors in approximately 80 patients with stage III/IV NSCLC who have inadequate response to front line PD-(L)1 checkpoint inhibitor treatments.

o An open-label phase 2 clinical trial in the United States evaluating CAN-2409 plus valacyclovir in combination with continued PD-(L)1 checkpoint inhibitors in patients with stage III/IV NSCLC who have inadequate response to front line PD-(L)1 checkpoint inhibitor treatments.

In April 2023, we announced that the FDA granted fast track designation for CAN-2409 plus valacyclovir in combination with pembrolizumab in order to improve survival or delay progression in patients with stage III (not candidates for curative intent) or stage IV NSCLC, who are resistant to first line PD-(L)1 inhibitor therapy and who do not have activating molecular driver mutations or have progressed on directed molecular therapy.

These patients historically have had an expected median overall survival (mOS) of 10-14 months (Reckamp K et al.

These patients historically have had an expected median overall survival (mOS) of <12 months when treated with SoC chemotherapy (Reckamp K et al.

J Clin Onc 2022;40:2295-2306).

The aim of the CAN-2409 immunotherapy antitumor strategy is to raise the tail on the survival curve by increasing the number of long survivors beyond 10-14 months.

o In 2022, we presented data from this phase 2 clinical trial where patients who received two administrations of CAN-2409 plus prodrug and completed the 12-week treatment window that demonstrated:

1) increased infiltration of CD8+ cytotoxic tumor infiltrating lymphocytes in the tumor microenvironment, systemic expansion of effector T cells and increased soluble granzyme B levels in

peripheral blood, 2) favorable changes in the trajectory of tumor progression, 3) decreased tumor size of target lesions in most patients, and 4) reduced size of uninjected tumor lesions (Aggarwal C et al.

Abstract #9037 ASCO June 2022 and Aggarwal C et al.

Candel Virtual R&D Day, December 2022).

These data were further supported in an update released September 2023, based on a data cutoff of August 1, 2023:

▪ 40 patients across Cohort 1 (stable disease at enrollment;

n=5) and Cohort 2 (progressive disease at enrollment;

n=35) were evaluable, as they received two courses of CAN-2409 plus valacyclovir and completed the 12-week treatment window.

▪ While overall survival was not yet mature, we observed an encouraging number of long survivors.

We believe that CAN-2409 may induce a new state of functional immunosurveillance and durable disease control in a subset of the patients.

▪ Of the 40 evaluable patients, 15 patients had lived ≥ 12 months;

of these, 10 patients had lived > 18 months, of whom 70% (7/10) were alive as of last follow up.

All 4 patients (100%) with overall survival > 24 months were alive at last follow up, with the longest reaching 31.7 months.

▪ An additional 18 out of the 40 evaluable patients were also alive but had not yet reached 12 months of follow up.

▪ Notably, many patients treated with CAN-2409 had long survival (≥ 12 months) despite having disease features generally associated with advanced disease and reduced likelihood to benefit from immune checkpoint inhibitor therapy, such as low or negative PD-(L)1 expression, including:

• Amongst patients alive ≥ 12 months with known PD-(L)1 status (14/15), 93% had negative or low PD-(L)1 score (<1 or between 1-49).

• Advanced disease with stage IV in 73% (11/15), lymph node involvement in 73% (11/15), pleural effusion in 40% (6/15), bone metastases in 27% (4/15), adrenal metastases in 20% (3/15), brain metastases in 13% (2/15), liver metastases in 7% (1/15), involvement of 3 or more organs in 13% (2/15), and Eastern Cooperative Oncology Group performance status 1 in 40% (6/15).

▪ There was a significant increase observed in activated central memory, effector-memory, effector T cells, and natural killer (NK) cells after CAN-2409 treatment.

These include CD8+Ki67+IFN g + T cells, CD8+ granzyme B+Ki67+ T cells, CD56+CD16+granzyme B+ NK cells, and gd + T cells.

We also observed an increase in memory B cells after CAN-2409 treatment

▪ We observed an increase in effector/cytotoxic T cells and NK cells in peripheral blood after the second CAN-2409 administration associated with subsequent improved survival (≥ 12 months).

▪ We continued to observe a favorable safety/tolerability profile after CAN-2409 treatment in NSCLC.

There were no dose limiting toxicities or grade 4 or greater treatment related adverse events.

Grade 3 treatment related adverse events were reported in < 10% of patients receiving at least one dose of CAN-2409 (safety population), which we believe compares favorably to current standard of care (SoC) options.

o Candel expects to share topline overall survival data for Cohort 2 in the second quarter of 2024, assuming data are mature at that time.

The aim of the CAN-2409 immunotherapy antitumor strategy is to raise the tail on the survival curve by increasing the number of long survivors beyond 12 months in patients treated with two CAN-2409 injections.

o In May 2024, we announced topline data that showed prolonged overall survival in our phase 2 clinical trial of CAN-2409 plus valacyclovir, together with immune checkpoint inhibitor (ICI) therapy in patients with Stage III/IV NSCLC inadequately responding to ICI [anti-PD-(L)1] therapy (as of an April 1, 2024 data cut-off):

• mOS of 20.6 months was observed following two administrations of CAN-2409 plus valacyclovir in NSCLC patients with progressive disease despite ICI therapy, compared to published results of mOS of 11.6 months observed with SoC docetaxel-based chemotherapy in a similar patient population (Reckamp K et al.

J Clin Onc 2022;40:2295-2306).

Improved mOS was observed in both PD-L1 negative and PD-L1 positive tumors in patients with progressive disease (N=37 patients in cohort 2 for which PD-L1 status at baseline was available).

mOS of 22.0 months was observed across all patients (n=46) who had an inadequate response to ICI and who received two administrations of CAN-2409.

• Treatment with CAN-2409 resulted in systemic activation of the immune response, including increased numbers of effector and cytotoxic T cells as well as elevated levels of inflammatory soluble mediators.

• Activation of the systemic immune response was associated with shrinkage of uninjected lesions (abscopal response).

71.4% of patients with metastatic disease and at least one uninjected tumor (n=35) experienced a beneficial effect from CAN-2409 treatment on both injected and uninjected tumors.

When using a threshold of >5% decrease, more than 60% of patients still showed an abscopal response.

• As of the cut-off date, treatment with CAN-2409 in NSCLC continued to exhibit a generally favorable safety and tolerability profile.

There were no dose-limiting toxicities or grade 4 or higher treatment-related adverse events (TRAEs);

the majority of TRAEs were grade 1 or 2, and there were three grade 3 TRAEs (1 pyrexia, 2 pneumonitis).

• We expect to present updated overall survival data for CAN-2409 in NSCLC in the first quarter of 2025.

▪ Pancreatic Cancer

o We have initiated a randomized phase 2 clinical trial in the United States evaluating CAN-2409 in borderline resectable and locally advanced pancreatic adenocarcinoma.

In December 2023, we announced that the FDA granted fast track designation for CAN-2409 plus valacyclovir for the treatment of patients with pancreatic ductal adenocarcinoma (PDAC) to improve overall survival.

March 2023, in connection with our cost management and dynamic portfolio management initiatives, we elected to pause new enrollment in this randomized phase 2 clinical trial, subject to additional funding.

o We initiated a randomized phase 2 clinical trial in the United States and Mexico evaluating the activity of CAN-2409 in borderline resectable and locally advanced pancreatic ductal adenocarcinoma (PDAC).

Initial positive phase 2 data revealed notable clinical improvements in patients with borderline resectable PDAC following CAN-2409 plus prodrug together with SoC chemoradiation.

In March 2023, in connection with our cost management and dynamic portfolio management initiatives, we elected to pause new enrollment in this randomized phase 2 clinical trial, subject to additional funding.

Despite the pause in new patient enrollment, we presented initial positive interim overall survival and immunological biomarker clinical data at the Society for Immunotherapy of Cancer (SITC) Annual Meeting in the fourth quarter of 2023.

o In a previous phase 1b trial, a statistically significant increase in the number of CD8+ tumor infiltrating lymphocytes was observed.

Initial positive phase 2 data revealed notable improvements in patients with borderline resectable pancreatic ductal adenorcarcinoma (PDAC) following CAN-2409 plus prodrug together with SoC chemoradiation;

the following data were disclosed as of the August 21, 2023 data cutoff

In December 2023, we announced that the FDA granted fast track designation for CAN-2409 plus valacyclovir for the treatment of patients with PDAC to improve overall survival.

In April 2024, we announced updated positive overall survival data and also announced that the FDA has granted orphan drug designation for CAN-2409 for the treatment of pancreatic cancer.

o The following data were disclosed as of the March 29, 2024 data cutoff:

▪ Clinical data highlights:

• Prolonged and sustained survival was observed after experimental treatment with CAN-2409 in patients with borderline resectable PDAC.

• An estimated survival rate of 71.4% at both 24 and 36 months was observed in patients who received CAN-2409 regimen together with SoC chemoradiation prior to surgery, versus only 16.7% estimated survival at 24 and 36 months with SoC chemoradiation prior to surgery

• Importantly, 5 out of 7 patients who received CAN-2409 were still alive at the time of data cutoff, with two patients surviving more than 45 months from enrollment.

Only one patient randomized to control SoC chemotherapy remained alive at data cutoff (alive at 43 months).

• mOS has not been reached yet in patients who received CAN-2409 because most of the patients in the CAN-2409 group were still alive at data cut-off;

mOS was 12.5 months in the control arm.

• Disease course was altered after salvage chemotherapy with improved CA19-9 levels and ongoing survival in CAN-2409 arm, but not in control arm.

• Estimated mOS was 28.8 months in the CAN-2409 group versus 12.5 months in the control group.

• At 24 months, a survival rate of 71.4% was observed in patients receiving CAN-2409 at the time of SoC chemoradiation and surgery, versus only 16.7% in the control group.

At 36 months, a survival rate of 47.6% was estimated in patients who received CAN-2409 versus only 16.7% in the control group.

• Importantly, 4 out of 7 patients who received CAN-2409 were still alive at the time of data cutoff, with 2 patients surviving more than 50.0 months from enrollment.

Only 1 out of 6 patients, randomized to control SoC chemotherapy alone, remained alive at data cutoff (alive at 50.6 months).

▪ Biomarker data analysis demonstrated:

• Consistent and robust activation of immune response after dosing with CAN-2409.

• In pancreatic tissue of patients treated with CAN-2409 plus prodrug together with SoC (but not SoC alone), dense aggregates of CD8+ granzyme B positive cytotoxic T cells, dendritic cells, and B cells were observed in the tumor microenvironment.

• Increased levels of soluble granzymes B and H as well as pro-inflammatory cytokines, including IFN-γ, were observed in peripheral blood after CAN-2409 treatment, but not with control treatment.

These lymphocyte aggregates resemble tertiary lymphoid structures, whose formation in solid tumors is known to be associated with improved prognosis and better response to therapy.

• Increased levels of soluble granzymes B and H as well as pro-inflammatory cytokines, including IFN-γ, were observed in peripheral blood after CAN-2409 treatment, but not after SoC.

▪ Safety analysis:

• CAN-2409 was associated with a favorable tolerability profile.

• Addition of CAN-2409 regimen to SoC was generally well tolerated, with no reported dose-limiting toxicities, including no cases of pancreatitis.

Our lead HSV-based product candidate, CAN-3110, is currently in an ongoing investigator-sponsored phase 1 clinical trial in our initial target indication of recurrent high-grade glioma (HGG).

• Addition of CAN-2409 regimen to SoC was generally well tolerated, with no dose-limiting toxicities, including no cases of pancreatitis.

o In February 2025, we announced the final analysis of this phase 2 clinical trial in borderline resectable PDAC:

▪ Estimated median overall survival after enrollment was 31.4 months in the CAN-2409 group versus only 12.5 months in the control group.

▪ Importantly, 3 out of 7 patients who received CAN-2409 were still alive at the time of data cut-off (February 20, 2025) with survival of 66.0, 63.6, and 35.8 months after enrollment;

survival from the time of diagnosis was 73.5, 68.8 and 41.3 months for these patients.

In contrast, only one out of 6 patients randomized to SoC chemotherapy arm remained alive at the data cutoff;

histologic analysis at resection showed intraepithelial neoplasia associated with improved prognosis in this patient.

▪ Median survival post-progression was 21.2 months in CAN-2409 patients (vs.

7.2 months on the control arm).

▪ Based on these promising findings, the Company has decided to prepare for a larger, late-stage, randomized controlled clinical trial of CAN-2409 in PDAC.

Our lead HSV-based product candidate, CAN-3110, is currently in an ongoing investigator-sponsored phase 1b clinical trial in our initial target indication of recurrent high-grade glioma (HGG).

Patients recruited in this study have previously failed SoC treatment and have a poor prognosis (expected overall survival < 6-9 months).

In February 2024, we announced that the FDA granted fast track designation for CAN-3110 for the treatment of patients with recurrent HGG to improve overall survival.

These patients have failed SoC treatment and have a poor prognosis (expected overall survival < 6-9 months).

Initial overall survival data from this clinical trial was presented in an oral presentation at the ASCO Annual Meeting in June 2021, and additional biomarker data was reported in an oral presentation at the Society for Neuro-Oncology Annual Meeting in November 2021.

During our Research and Development Day in December 2022, we presented updated

data demonstrating that CAN-3110 was well tolerated with no observed dose-limiting toxicity;

achieved 11.6 months mOS with a single dose;

and showed evidence of persistent herpes simplex virus 1 (HSV-1) antigen and HSV-1 replication consistent with mechanism of action as well as robust evidence of immune activation.

In May 2024, we also announced that the FDA granted orphan drug designation for CAN-3110 for the treatment of recurrent HGG.

Initial overall survival data from this clinical trial was presented in an oral presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2021, and additional biomarker data was reported in an oral presentation at the Society for Neuro-Oncology Annual Meeting in November 2021.

During our Research and Development Day in December 2022, we presented updated data demonstrating that a single administration of CAN-3110 was well tolerated with no observed dose-limiting toxicity and achieved 11.6 months mOS.

Furthermore, we showed evidence of persistent herpes simplex virus 1 (HSV-1) antigen and HSV-1 replication consistent with the mechanism of action of CAN-3110 as well as evidence of robust immune activation in the tumor microenvironment and in the peripheral blood of treated patients.

In May 2023, we presented clinical and biomarker data from this ongoing clinical trial in an oral presentation at the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting where we reported mOS in arm A (n=41) ongoing at 11.8 months and mOS in arm B (n=9) ongoing at 12.0 months as of the April 20, 2023 data cutoff.

Safety and tolerability data reported no dose-limiting toxicities in both arm A and arm B.

The safety and tolerability data highlighted the absence of dose-limiting toxicities in both arm A and arm B.

In October 2023, we jointly published an article in Nature that reported extended survival associated with immune activation in patients with recurrent HGG treated with CAN-3110.

Notably, new data reported an increased survival in 66% of patients with positivity for anti-HSV1 antibodies (mOS of 14.2 months).

Immune status was positively associated with survival both in patients with pre-existing HSV1 antibodies (pre-treatment) and in 33% of patients that, while negative at baseline, developed anti-HSV1 antibodies after a single injection of CAN-3110.

Notably, new data reported an increased survival in the 66% of patients with positivity for anti-HSV1 antibodies (mOS of 14.2 months).

Immune status was positively associated with survival both in patients with pre-existing HSV1 antibodies (pre-treatment) and in 33% of patients who, while negative at baseline, developed anti-HSV1 antibodies after a single injection of CAN-3110.

Clinical responses were observed in both injected and uninjected lesions in patients with multifocal disease.

Significant tumor responses in both arm A and arm B were observed, with continued reduction in tumor volume in a patient in arm B approximately one year after CAN-3110 treatment.

Clinical response for this patient, in follow-up as of data cutoff, continued without additional treatment.

Clinical response for this patient continues as of February 2025 without additional treatment.

Analysis of post-treatment samples demonstrated evidence of persistent HSV antigen expression and replication in both injected and uninjected tumor tissue associated with CD8+ T cell infiltration.

The extent of immune activation, measured by gene profiling and quantification of immune cells in post-treatment specimens, was associated with the presence of anti-HSV1 antibodies and survival.

Survival was also associated with the diversity of the T cell repertoire in circulating T cells, suggesting that patients treated with CAN-3110 were able to mount a diverse immune response against the virus and tumor antigens released during the oncolytic process had improved survival.

Survival was also associated with the diversity of the T cell repertoire in circulating T cells, suggesting that patients who were able to mount a diverse immune response against the virus and tumor antigens released during the oncolytic process after CAN-3110 administration, had improved survival.

We are conducting an extension of the clinical trial known as arm C, in which patients with recurrent HGG will receive a repeat dosing regimen of CAN-3110 (up to six injections over four months).

Clinical data from arm C will help evaluate whether multiple injections can increase mOS.

Clinical data from arm C will help evaluate whether multiple injections could further improve survival.

This clinical trial extension is supported by the Break Through Cancer foundation.

We are also designing other novel viral immunotherapy candidates using our proprietary enLIGHTEN Discovery Platform, a systematic, iterative HSV-based discovery platform leveraging human biology and advanced analytics to create new viral immunotherapy candidates for solid tumors.

In October 2022, we entered into a collaboration with the University of Pennsylvania (UPenn) Center for Cellular Immunotherapies to study the impact of novel viral immunotherapy candidates based on our enLIGHTEN Discovery Platform to strengthen the activity of UPenn’s investigational CAR-T cell therapies in difficult to treat solid tumors.

As of February 2025, we have dosed seven patients with multiple injections of CAN-3110 (up to six injections over a period of four months).

In June 2024, a poster presentation at the ASCO Annual Meeting demonstrated that multiple intratumoral injections of CAN-3110 were feasible and well tolerated with no dose-limiting toxicities or severe adverse events observed in the first six patients treated in arm C.

More than 300 core biopsies were obtained from these patients, across the planned dose ranging time points, which were processed for “-omic” analysis,

including single-cell RNA sequencing and cell profiling.

In October 2024, during the 16th Annual International Oncolytic Virotherapy Conference (IOVC), we announced clinical activity and biomarker data for arm C.

The principal investigator of the study reported ongoing improved survival compared to historical controls in patients treated with multiple injections of CAN-3110, with 3 out of 6 patients with recurrent HGG (recurrent glioblastoma) still alive more than one year (12.2, 13.0, and 18.7 months, respectively) after initiation of experimental treatment with CAN-3110.

The data also showed discrepancies between imaging and histologic findings.

Post treatment longitudinal biopsies demonstrated near absence of tumor cells alongside dense lymphocyte infiltrates especially in patients with enhancement on post-treatment MRI scans, suggesting the presence of radiologic pseudo-progression after treatment with CAN-3110.

This data cautions against the evaluation of progression by imaging, restating the importance of survival as the primary endpoint for viral immunotherapy trials.

We expect to present initial median overall survival data for the repeat dosing cohort in the fourth quarter of 2025.

In November 2024, during the SITC 2024 Annual Meeting, we presented data demonstrating the antitumor activity of CAN-3110 in preclinical models of melanoma, a tumor characterized by high Nestin expression, frequent loss-of-function in CDKN2A, and alterations in the Ras-Raf signaling pathway.

This data supports the rationale to expand the evaluation of CAN-3110 into tumors beyond recurrent HGG, creating a potential pipeline in a product.

We are also designing additional novel viral immunotherapy candidates using our proprietary enLIGHTEN Discovery Platform, a systematic, iterative HSV-based discovery platform leveraging human biology and advanced analytics to create new viral immunotherapy candidates for solid tumors.

In October 2022, we entered into a collaboration with the University of Pennsylvania (UPenn) Center for Cellular Immunotherapies to study the impact of novel viral immunotherapy candidates based on Candel's enLIGHTEN Discovery Platform to strengthen the activity of UPenn’s investigational CAR-T cell therapies in difficult to treat solid tumors.

In November 2023, during the SITC 2023 Annual Meeting, we presented two posters describing the key elements of the platform and the development of the first experimental agent from the enLIGHTEN Discovery Platform.

The new agent, Alpha-201 Macro1, is an investigational viral immunotherapy designed to interfere with the CD47/SIRPα pathway and activate innate immune surveillance.

Results demonstrated monotherapy activity following local administration in a preclinical model of lung and breast cancer.

Additional preclinical data presented at SITC confirmed the capability of the enLIGHTEN Advanced Analytics suite to predict optimal gene payload combinations to arm viral vectors, that enable the design of potential combination therapeutics to overcome tumor resistance especially in cancers resistant to ICI treatment.

In March 2024, we announced the acceptance of an abstract at the American Association for Cancer Research's (AACR) 2024 Annual Meeting related to the second candidate from our enLIGHTEN Discovery Platform, a first-in-class multimodal immunotherapy for induction of tertiary lymphoid structures as a novel therapeutic strategy for solid tumors.

We currently own development and commercialization rights for our programs in major markets, including the United States, Europe and Asia, allowing us to control development and seek approval in those areas as we prepare our commercialization efforts.

The first agent based on enLIGHTEN, Alpha-201 Macro1, is an investigational viral immunotherapy designed to interfere with the CD47/SIRPα pathway and activate innate immune surveillance.

Results demonstrated monotherapy activity of this agent following local administration in a preclinical model of lung and breast cancer.

Additional preclinical data presented at SITC confirmed the capability of the enLIGHTEN Advanced Analytics suite to predict optimal gene payload combinations to arm viral vectors, enabling the design of potential combination therapeutics to overcome tumor resistance especially in cancers resistant to immune checkpoint inhibitor treatment.

In April 2024, during the American Association for Cancer Research's 2024 Annual Meeting, we presented data on a second preclinical candidate from the enLIGHTEN Discovery Platform, a first-in-class multimodal immunotherapy for induction of tertiary lymphoid structures, being developed as a novel therapeutic strategy for solid tumors.

Data presented included preclinical in vivo evidence of monotherapy activity of this preclinical candidate as well as activity when administered in combination with immune checkpoint inhibitors (improved survival as compared to PD-1 only treated mice).

In October 2024, during the 16th Annual IOVC, we presented data on a novel biological multimodal therapeutic from the enLIGHTEN TM Discovery Platform, the third preclinical candidate, encoding IL-12 and IL-15.

Data included the ability of this asset to induce expansion and activation of natural killer and CD8+ T cells, resulting in significant inhibition of tumor growth and tumor regression in two different tumor models.

We currently own development and commercialization rights for all our programs in major markets, including the United States, Europe and Asia, allowing us to control development and seek approval in those areas as we prepare our commercialization efforts.

We were incorporated in Delaware in June 2003 as Advantagene, Inc.

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In December 2019, Advantagene licensed substantially all the assets of Periphagen, a company focused on engineering HSV as a gene therapy vector, and in September 2020, licensed CAN-3110 from Mass General Brigham (MGB).

In December 2020, we formally changed our name from Advantagene to Candel Therapeutics, Inc.

In December 2020, we formally changed our name from Advantagene into Candel Therapeutics, Inc.

We completed our initial public offering in July 2021.

Our goal is to develop first-in class and best-in-class viral immunotherapies to transform the lives of cancer patients.

We plan to develop and commercialize our two most advanced product candidates, CAN-2409 and CAN-3110, for the

treatment of a broad range of solid tumor indications, while continuing to build our pipeline through our discovery platform .

Our goal is to develop first-in class and best-in-class biological multimodal immunotherapies to transform the lives of cancer patients.

We plan to develop and commercialize our two most advanced product candidates, CAN-2409 and CAN-3110, for the treatment of a broad range of solid tumor indications, while continuing to build our pipeline through our discovery platform .

Key elements of our strategy include the following:

▪ Advance the late-stage development of, and seek regulatory approval for, our product candidate, CAN-2409, in newly diagnosed, localized prostate cancer.

We are currently conducting a potentially registrational phase 3 clinical trial in intermediate- and high-risk patients in combination with the SoC, radiotherapy.

If approved, we believe CAN-2409 could be a first-in-class drug for localized prostate cancer patients with the potential to significantly increase percentage of patients that achieve disease-free survival or reduce disease progression and recurrence.

▪ Advance the clinical development of CAN-3110 from our HSV platform with tumor-specific enhanced replication potency.

An investigator-sponsored phase 1b clinical trial is ongoing in recurrent HGG.

This trial is evaluating the activity of CAN-3110 in therapy-resistant disease, where we believe a replicating virus may present therapeutic advantages.

Our aim is to improve mOS compared to optimal SoC.

We have recently reported positive topline data on a potentially registrational phase 3 clinical trial in patients with localized, intermediate- and high-risk prostate

cancer in combination with SoC radiotherapy.

If approved, we believe CAN-2409 could be a first-in-class drug for localized prostate cancer patients.

▪ Advance the development of CAN-2409 in stage III/IV NSCLC patients with inadequate responses to SoC immune checkpoint inhibitors (ICI).

A phase 2 clinical trial that evaluates CAN-2409 in combination with ICI is currently underway in NSCLC.

Our aim is to improve mOS compared to optimal SoC (12-14 months).

▪ Advance the development of CAN-2409 in patients with newly diagnosed, localized prostate cancer.

A phase 2 trial that evaluates CAN-2409 as a monotherapy is currently underway in low to moderate risk patients who are under active surveillance.

Our aim is to improve progression-free survival compared to the active surveillance approach.

Our aim is to improve mOS compared to optimal SoC.

▪ Advance the development of CAN-2409 in pancreatic cancer.

We have initiated a randomized phase 2 clinical trial in patients with borderline resectable pancreatic adenocarcinoma.

However, in March 2023, in connection with our cost management and dynamic portfolio management initiatives, we elected to pause new enrollment in this randomized phase 2 clinical trial, subject to additional funding, while we continue to follow the patients who participated in the clinical trial.

We conducted a randomized controlled phase 2 clinical trial in patients with borderline resectable pancreatic adenocarcinoma.

Our aim is to improve mOS compared to SoC.

▪ Advance the development and initiate IND-enabling work of CAN-3110 in a second indication characterized by Nestin expression.

We intend to discuss a new clinical trial designed to explore safety, tolerability and preliminary efficacy in a new indication characterized by Nestin expression (such as breast cancer or melanoma) with the FDA.

▪ Advance the clinical development of CAN-3110 from our HSV platform with tumor-specific enhanced replication potency.

An investigator-sponsored phase 1b clinical trial is ongoing in recurrent HGG.

This trial is evaluating the activity of CAN-3110 in therapy-resistant disease, where we believe a replicating virus may present therapeutic advantages.

Our aim is to improve mOS compared to optimal SoC.

▪ Advance the development of CAN-3110 in a phase 2 clinical trial in rHGG to identify the optimal dosing regimen and improve mOS compared to SoC.

▪ Initiate IND-enabling work for CAN-3110 in a second indication characterized by Nestin expression.

We intend to discuss a new clinical trial designed to explore safety, tolerability and preliminary efficacy in a second indication, for example triple negative breast cancer or melanoma, with the FDA.

▪ Leverage our HSV viral immunotherapy platform to develop additional HSV-based product candidates.

Our new enLIGHTEN Discovery Platform enables rapid vector engineering to generate a range of new candidates in a data driven and indication specific manner.

Our enLIGHTEN Discovery Platform enables rapid vector engineering to generate a range of new candidates in a data driven and indication specific manner, using computational biology and artificial intelligence.

We utilize a key attribute of HSV, a high capacity for genetic cargo, to enable targeted modifications and deploy indication specific genes to the tumor microenvironment.

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We will rely on third party contract manufacturers for commercial-scale manufacturing of both product candidates, CAN-2409 and CAN-3110.

We expect that our cost-of-goods will be substantially lower than cell- and antibody-based therapies because of our high-yield manufacturing process.

For CAN-2409, we have worked with our contract manufacturer (CDMO) to tech transfer, scale up and lock the manufacturing process by performing small scale development runs and a large-scale confirmation run and engineering run.

The CDMO will manufacture a clinical batch which will be used to supply clinical trials after completing an analytical (in vitro) comparability study, and manufacture validation batches to lock the commercial process and enable filing of the biologics license application.

We expect that our cost-of-goods will be substantially lower than that for cell- and antibody-based therapies because of our high-yield manufacturing process.

Conventional cancer therapies (chemotherapy, radiotherapy and surgery) often do not eradicate 100% of the tumor cells, which often leads to tumor progression or recurrence.

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Much focus has been placed on harnessing the effector T cell arm of the immune system for tumor specific immunity.

Adoptive T cell therapy

has shown positive results but with limited activity in solid tumors, and is not scalable for widespread use.

Vaccine approaches range in complexity from peptide antigens to autologous or allogeneic tumor cell products.

The advantage of the single antigen approaches is that they can be easily manufactured and produced, however, they have the fundamental disadvantage of being potentially irrelevant for a patient’s specific tumor or immune system or easily bypassed by resistant clones.

Cellular vaccines are not easily scalable and allogeneic vaccines may not bear the relevant antigens expressed by a patient’s tumor.

Adoptive T cell therapy has shown some positive results but with limited activity in solid tumors and is not scalable for widespread use.

Vaccine approaches range in complexity from peptide or mRNA encoded antigens to autologous or allogeneic tumor cell products.

The advantage of the single antigen approaches is that they can be easily manufactured and produced.

However, they have the fundamental disadvantage of being potentially irrelevant for a patient’s specific tumor or immune system or easily bypassed by resistant clones.

Cellular vaccines are not easily scalable and allogeneic

vaccines may not bear the relevant antigens expressed by a patient’s tumor.

ICIs such as anti-PD-1 and anti-PD-L1 antibodies, have transformed the treatment paradigm for different cancer indications.

However, only approximately 15% to 40% of overall patients respond to such treatment.

However, they do not induce a specific immune response and only approximately 15% to 40% of overall patients respond to such treatment.

We are focused on the development of viral immunotherapy approaches, which are based on an extensive history of research.

Originally, the mechanism of action of those agents was believed to be based only on the ability of the virus to induce cancer cell lysis and to resolve tumors.

Originally, the mechanism of action of agents in this class was believed to be merely based on the ability of the virus to induce cancer cell lysis and to resolve tumors.

Later, it was demonstrated that viral immunotherapy may induce immunogenic cell death.

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With the dramatic emergence of ICIs and immunotherapy as a core treatment modality, the importance of the immunostimulatory aspect of viral-mediated approaches became more widely evident.

The currently understood generalized mechanism of action of viral immunotherapies is unique in combining both an anti-tumor cytotoxic component and an immune-stimulatory component.

Together, these modalities lead to an “in-situ vaccination” effect against the injected tumor followed by an effect on uninjected distant metastases.

The currently understood generalized mechanism of action of viral immunotherapies like CAN-2409 and CAN-3110 is unique in combining both an anti-tumor cytotoxic component and an immune-stimulatory component.

Together, these assets lead to an “in-situ vaccination” effect against the injected tumor followed by an effect on uninjected distant metastases.

Pairing this therapeutic approach with ICI treatment or with radiotherapy is based on a strong mechanistic rationale and has shown promise in experimental models of cancer.

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One of our areas of focus is the conversion of immunologically suppressed “cold” tumors into immunologically active “hot” tumors, thereby increasing their responsiveness to ICI or other therapies, such as radiotherapy.

The Mechanism of Action of Viral Immunotherapy:

The Mechanism of Action of Candel's Viral Immunotherapy:

• Direct anti-tumor cytotoxic activity.

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• Broad stimulation of anti-tumor immunity.

The immunogenic cell death driven by oncolysis results in a potent local and systemic immune stimulation with the increased expression of proinflammatory cytokines, chemokines and adhesion molecules.

This, in turn, promotes the activation of both the innate and adaptive arms of the immune system in the presence of highly immunogenic viral components.

The immunogenic cell death driven by oncolysis results in a potent local and systemic immune stimulation, while adenoviral or HSV viral particles induce increased expression of proinflammatory cytokines, chemokines and adhesion molecules.

Together this promotes the activation of both the innate and adaptive arms of the immune system.

This broad response commonly includes recruitment and activation of antigen-presenting cells and effector immune cells to the site of the tumor.

• Priming of the immune system against tumor antigens.

The lysis of cancer cells leads to the exposure of tumor-specific antigens.

The lysis of cancer cells leads to the exposure of tumor-specific antigens to immune cells.

This early effect, combined with intratumoral immune cell infiltration and activation, leads to antigen presentation and initiation of a local adaptive immune response targeted against a set of tumor antigens expressed by the patient’s cancer cells.

• Development of a systemic immune memory response.

Viral immunotherapy induces the development of a long-lasting systemic immune surveillance against the antigens associated with the injected tumor, and consequently, tumor antigens expressed at metastatic sites.

This leads to a cytotoxic immune response against the distant tumor cells, also known as an abscopal effect.

Viral immunotherapy induces the development of a long-lasting systemic immune surveillance against the multitude of antigens associated with the injected tumor, and consequently, tumor antigens expressed at metastatic sites.

This leads to a systemic cytotoxic immune response against the injected tumor and distant metastases;

the latter is known as an abscopal effect.

Desirable Clinical Properties.

Viral immunotherapy has attributes that are important for cancer therapeutics.

Candel's viral immunotherapy has attributes that are important for cancer therapeutics.

The agents are off-the-shelf and they have been shown to stimulate local and systemic immune responses in most patients, leading to an individualized anti-tumor immune response.

In contrast, individualized cellular immunotherapies require specific manufacturing processes for each individual patient.

The first viral immunotherapy was approved by the FDA in 2015, providing support that additional agents in this class may have similar potential.

Furthermore, safety data shown in several clinical trials of various immunotherapies supports the ability to combine viral immunotherapy with other agents due to the potential for fewer overlapping side effects.

The first viral immunotherapy was approved by the FDA in 2015, providing support that new agents in this class may have similar or better potential.

Furthermore, safety data shown in several clinical trials of various viral immunotherapies supports the ability to combine viral immunotherapy with other therapeutic strategies.

Our Immunotherapy Platforms.

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▪ Off-the-Shelf Product.

A standardized product intended to be available as needed via prescription supports straightforward clinical administration, simplified manufacturing and supply chain management.

A standard product intended to be available as needed via prescription supports straightforward clinical administration, simplified manufacturing and supply chain management.

▪ Intratumoral Route of Administration.

Both of our product candidates are administered by direct injection into the tumor site, and have been shown to result in a systemic immune response.

This approach aims to maximize immune stimulation and minimize systemic toxicity, factors that are believed to be suboptimal with intravenous administration.

This approach aims to

maximize immune stimulation and minimize systemic toxicity, factors that are believed to be suboptimal with intravenous administration.

We believe that directly injecting these viral immunotherapies into a patient’s cancerous tissue helps to optimize the benefit/risk for these agents to be highly immunostimulatory at the site of the tumor, whereas systemically administered agents would need to avoid detection by the body’s immune surveillance mechanisms to avoid rapid destruction before getting to the target tumor.

While our product candidates are administered directly into the tumor, we have observed a systemic anti-tumor immune response in our preclinical studies and clinical trials, resulting in improvement of both injected and uninjected tumors, also known as an “abscopal” effect.

For the indications that we selected, intratumoral administration is a straightforward procedure that is aligned with clinical practice, leveraging SoC medical procedures, such as intra-prostate injection or delivery during diagnostic (bronchoscopy) or therapeutic (neurosurgery) procedures.

Intra-tissue administration is the standard approach in vaccination.

While our product candidates are administered directly into the tumor, we observed a systemic anti-tumor immune response in our preclinical studies and clinical trials, resulting in improvement of both injected and uninjected tumors, also known as an “abscopal” effect.

For the indications that we selected, intratumoral administration is a straightforward procedure that is aligned with normal clinical practice, leveraging routine SoC medical procedures, such as intra-prostate injection, endoscopy, and bronchoscopy for CAN-2409, or stereotactic injection for CAN-3110.

▪ Cost-efficient Manufacturing.

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This allows us to apply this platform to many different tumor types.

▪ Immunogenic Virus Particle.

▪ Pro-inflammatory Virus Particle.

The adenoviral virus particles are strong simulators of the innate immune system, a property that contributes to immune activation at the site of administration.

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▪ Non-Replicating Design .

Engineering the adenovirus to remove replication ability reduces the potential for viral shedding, something which is particularly important in clinical applications such as prostate cancer.

There is no need for in vivo amplification as the virus is highly immunogenic and can be administered at high titers.

Engineering the adenovirus to remove the replication ability reduces the potential for viral shedding, something which is particularly important in clinical applications such as prostate cancer.

There is no need for in vivo amplification as the viral gene construct combined with prodrug is highly immunogenic and can be administered at high titers.

Key attributes of our CAN-3110 platform include:

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This tumor specific replication ability of CAN-3110 is regulated by the expression of ICP34.5, a gene encoding for a protein that permits viral replication even in the presence of the interferon response that is normally able to quell viral infection.

In the CAN-3110 construct, ICP34.5 expression is driven by the expression of Nestin, a protein largely expressed in certain tumors, like gliomas, but not in healthy brain tissue, thereby enabling replication specifically in the context of brain tumors.

We believe our HSV-based platform will allow us to implement additional genetic modifications to leverage the use of CAN-3110 in recurrent HGG and in other tumor types expressing Nestin.

In the CAN-3110 construct, ICP34.5 expression is driven by the expression of Nestin, a protein largely expressed in certain tumors, like HGG, but not in healthy brain tissue, thereby enabling replication specifically in the context of HGG and in other tumors expressing Nestin.

▪ Oncolytic activity combined with immunostimulatory properties.

CAN-3110 is designed to persist and replicate at the site of the tumor.

Viral replication is accompanied by tumor oncolysis, with release of tumor antigens in the microenvironment and activation of a local systemic immune response.

Viral replication is accompanied by tumor oncolysis, with release of tumor antigens in the microenvironment and activation of a local and systemic immune response.

Key attributes of the enLIGHTEN Discovery Platform include:

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▪ Data driven selection of the payload.

The use of advanced analytics on proprietary and publicly available datasets enables us to select what we believe is the best payload for combinatory strategy in a specific

indication, rationalizing our payload selection, de-risking development and maximizing our probability of success .

The use of computational biology and artificial intelligence on proprietary as well as publicly available datasets enables us to select what we believe is the best payload for combinatory strategy in each specific indication, rationalizing our payload selection, de-risking development and maximizing our probability of success .

▪ Use of HSV based on its high capacity for genetic cargos .

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Leveraging these modifications, we can select the best viral vector to deliver the selected payload in a specific indication.

We have an advanced pipeline of late-stage and early-stage clinical trials with our two most advanced product candidates, CAN-2409 and CAN-3110.

We have an advanced pipeline of late-stage and early-stage assets with our two most advanced product candidates, CAN-2409 and CAN-3110 as well as a preclinical pipeline.

CAN-2409, formerly known as gene mediated cytotoxic immunotherapy (GMCI), is our most advanced product candidate.

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First, the direct, cellular killing activity is based on the transformation of valacyclovir into a toxic nucleotide analogue that disrupts DNA synthesis and repair.

This phenomenon occurs preferentially in actively dividing cancer cells, thereby providing tumor specificity.

This phenomenon occurs preferentially in actively dividing cancer cells and cells exhibiting DNA damage, thereby providing tumor specificity.

This DNA repair inhibition is also hypothesized to be the mechanistic explanation behind the encouraging pre-clinical and clinical activity of CAN-2409 in combination with radiotherapy, a treatment known to cause DNA breaks requiring repair for continued cellular survival.

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Consequently, the localized death of tumor cells releases numerous antigens that can be recognized by the patient’s own immune system, thereby training the immune system to recognize, target and destroy cancer cells bearing the same antigens that have spread to other sites in the body.

To date, CAN-2409 has been administered to over 1000 patients with cancer, many of whom are in ongoing, placebo-controlled randomized clinical trials.

To date, CAN-2409 has been administered to over 1000 patients with cancer.

In total, we have conducted more than 10 clinical trials with CAN-2409 in a range of solid tumor indications.

We have seen encouraging clinical activity and a favorable tolerability profile with CAN-2409 in both monotherapy and combination settings with radiotherapy, ICI therapy, androgen deprivation therapy (ADT), chemotherapy and surgery.

We have seen encouraging clinical activity and a favorable tolerability profile with CAN-2409 in both monotherapy and combination settings with radiotherapy, ICI therapy, ADT, chemotherapy and surgery.

Based on the totality of our clinical data generated to date, we are currently pursuing indications in lung, pancreatic, and prostate cancer, which we believe all have great potential to address the unmet need.

We are conducting a phase 3 clinical trial of CAN-2409 under agreement with the FDA through the SPA process in newly diagnosed localized prostate cancer in intermediate- and certain high-risk patients in combination with the SoC that comprises radiotherapy and optional ADT.

Our SPA provides FDA concurrence that our key endpoints and specific critical elements of our trial design are adequate to support a future marketing application if, among other things, we achieve the primary endpoint in the trial.

We have successfully completed a phase 3 clinical trial of CAN-2409 under agreement with the FDA through the SPA process in newly diagnosed localized prostate cancer in intermediate- and certain high-risk patients in combination with the SoC that comprises radiotherapy and optional ADT.

Our SPA provides FDA concurrence that our key endpoints and specific critical elements of our trial design are adequate to support a potential future marketing application.

The clinical trial is randomized, triple-blinded and placebo-controlled.

It targeted enrollment of approximately 700 patients and was fully enrolled with 711 patients in September 2021, with topline data anticipated in the fourth quarter of 2024.

We have also received fast track designation by the FDA for the development of CAN-2409 for the treatment of localized, primary prostate cancer in combination with radiotherapy to improve the local control rate, decrease recurrence and improve disease-free survival.

We expect that if the trial is successful and if we obtain FDA approval, CAN-2409 could be the first new FDA approved pharmacologic treatment available in over 30 years as a first-line therapeutic for the over 100,000 patients who are newly diagnosed with localized prostate cancer each year in the United States.

We have also completed enrollment for a phase 2 clinical trial of CAN-2409 as monotherapy in newly diagnosed prostate cancer patients under active surveillance.

This trial has recruited 187 patients with low-, intermediate- and certain high-risk localized prostate cancer.

We expect to announce topline data in the fourth quarter of 2024.

We believe that this trial, if successful, could position CAN-2409 as a first-line monotherapy treatment for patients with low- and intermediate-risk prostate cancer, thereby meaningfully expanding the addressable patient population.

In NSCLC, we have observed monotherapy activity of CAN-2409 in a phase 1 biomarker focused, window of opportunity clinical trial.

In 2020, we initiated a phase 2 clinical trial evaluating CAN-2409 in combination with PD-(L)1 checkpoint inhibitors for patients with inadequate response to PD-(L)1 ICI.

This open-label clinical trial was originally amended to target enrollment of approximately 80 patients with stage III/IV NSCLC in two separate cohorts.

It targeted enrollment of approximately 700 patients and was fully enrolled with 745 patients randomized (711 of which received at least one study drug injection) in September 2021.

We recently reported positive topline data on this trial, demonstrating that CAN-2409 in combination with SoC radiation+/- short course ADT is able to significantly improve DFS in early prostate cancer compared with SoC radiation+/- short course of ADT alone, with a reduction in cancer recurrence or death of 30% (hazard ratio 0.7).

We have received fast track designation by the FDA for the development of CAN-2409 for the treatment of localized, primary prostate cancer in combination with radiotherapy to improve the local control rate, decrease recurrence and improve disease-free survival.

We expect that if we obtain FDA approval on the basis of the results presented in

December 2024, CAN-2409 could be the first new FDA approved pharmacologic treatment available in over 20 years as a potential first-line therapeutic for the over 100,000 patients who are newly diagnosed with localized prostate cancer each year in the United States.

In NSCLC, we previously observed monotherapy activity of CAN-2409 in a phase 1b biomarker focused, proof of mechanism clinical trial.

In 2020, we initiated a phase 2a clinical trial evaluating CAN-2409 in combination with PD-(L)1 checkpoint inhibitors for patients with inadequate response to PD-(L)1 ICI.

This open-label clinical trial was previously amended to target enrollment of approximately 80 patients with stage III/IV NSCLC in two separate cohorts.

The cohorts are defined based on response to ICI at the time of enrollment.

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Cohort 2 enrolls patients with progressive disease after at least 18 weeks of ICI treatment.

Patients will continue treatment with their initial checkpoint inhibitor and CAN-2409 will be added to their regimen.

The primary efficacy endpoints for this trial are tumor response as measured by RECIST criteria including overall response rate (ORR) and/or disease control rate (DCR).

Patients continue treatment with their initial ICI and two administrations of CAN-2409 are added to the therapeutic regimen.

The original primary efficacy endpoints for this trial are tumor response as measured by RECIST criteria including overall response rate (ORR) and/or disease control rate (DCR), but – consistent with SITC guidelines - there has been an increasing focus on the gold standard endpoint in this population, which is overall survival.

We reported initial data from this trial at the ASCO Annual Meeting in June 2022 and during our Research and Development Day in December 2022.

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a DCR of 77% (20/26) in patients entering the trial with disease progression (cohort 2;

90% of these patients had stage IV disease);

sustained and ongoing clinical responses greater than 1 year;

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and a favorable safety/tolerability data with most treatment-related adverse events being grade 1/2.

In December 2023, the recruitment of this study was paused as we completed target enrollment for cohort 2.

In December 2023, the recruitment of this study was paused as we completed target enrollment for cohort 2, which is the key target population as they have the largest unmet need.

We received FDA fast track designation for CAN-2409 plus valacyclovir in combination with pembrolizumab in order to improve survival or delay progression in patients with stage III/stage IV in NSCLC who are resistant to first line PD-(L)1 inhibitor therapy and who do not have activating molecular driver mutations or have progressed on directed molecular therapy in April 2023.

We anticipate presenting topline overall survival data in the second quarter of 2024.

In a previous phase 1b trial, patients with pancreatic cancer treated with CAN-2409 in addition to SoC demonstrated a greater survival duration over the expected survival of the patients treated with the existing SoC alone in a comparison to historical trial results.

In May 2024, we announced topline data, showing markedly prolonged overall survival in patients who had received two injections of CAN-2409 compared to historical controls.

mOS of 20.6 months was observed following two administrations of CAN-2409 plus valacyclovir in NSCLC patients with progressive disease despite ICI therapy, compared to published results of mOS of 11.6 months observed with SoC docetaxel-based chemotherapy in a similar patient population (Reckamp K et al.

J Clin Onc 2022;40:2295-2306).

Improved mOS was observed in both PD-L1 negative and PD-L1 positive tumors in patients with progressive disease (N=37 patients in cohort 2 for whom PD-L1 status at baseline was available).

mOS of 22.0 months was observed across all patients in cohorts 1 and 2 (n=46), who had an inadequate response to ICI and who received two administrations of CAN-2409.

We confirmed that treatment with CAN-2409 resulted in systemic activation of the immune response, including increased numbers of effector and cytotoxic T cells as well as elevated levels of soluble mediators of inflammation.

Activation of the systemic immune response was associated with shrinkage of uninjected lesions (abscopal response).

71.4% of patients with metastatic disease and at least one uninjected tumor (n=35) experienced a beneficial effect from CAN-2409 treatment on both injected and uninjected tumors.

When using a threshold of >5% decrease, more than 60% of patients still showed an abscopal response.

We also confirmed that treatment with CAN-2409 in NSCLC continued to exhibit a generally favorable safety and tolerability profile as of the cut-off date.

We anticipate presenting updated overall survival data in the first quarter of 2025.

Furthermore, in the group of patients where pre- and post-treatment tumor biopsies were available, a statistically significant increase in the number of CD8+ tumor infiltrating lymphocytes was observed.

We have initiated a randomized phase 2 clinical trial evaluating CAN-2409 in borderline-resectable pancreatic adenocarcinoma.

Next, we have initiated a randomized controlled phase 2aclinical trial evaluating CAN-2409 in borderline-resectable pancreatic adenocarcinoma.

In March 2023, in connection with our cost management and dynamic portfolio management initiatives, we elected to pause new enrollment in this randomized phase 2a clinical trial and first evaluate survival in the patients already enrolled in the clinical trial.

Despite the pause in patient enrollment, we presented initial clinical data in the fourth quarter of 2023.

The initial data showed prolonged and sustained survival in patients treated with CAN-2409 but not in the control arm, We observed a separation of the survival curves with an estimated survival rate of 71% in the treatment arm, compared to 16.7% in the control arm at both 24 and 36 months after treatment.

The initial data showed prolonged and sustained survival in patients treated with CAN-2409 but not in the control arm.

We observed a separation of the survival curves with an estimated survival rate of 71.4% in the treatment arm at 24 months and 47.6% at 36 months, compared to 16.7% in the control arm at both 24 and 36 months after treatment.

We received FDA fast track designation for CAN-2409 plus prodrug (valacyclovir) for the treatment of patients with PDAC to improve overall survival in December 2023.

We expect to present an update of the survival data in the second quarter of 2024.

In April 2024, we announced that the FDA has granted orphan drug designation for CAN-2409 for the treatment of pancreatic cancer.

In April 2024, we also reported topline survival data for the population of patients with borderline resectable PDAC with CAN-2409.

Estimated mOS was 28.8 months in the CAN-2409 group versus only 12.5 months in the control group.

Importantly, 4 out of 7

patients who received CAN-2409 were still alive at the time of data cutoff, with 2 patients surviving more than 50.0 months from enrollment.

Only 1 out of 6 patients, randomized to control SoC chemotherapy alone, remained alive at data cutoff (alive at 50.6 months).

Biomarker data analysis demonstrated consistent and robust activation of immune response after dosing with CAN-2409.

Addition of CAN-2409 regimen to SoC was generally well tolerated, with no dose-limiting toxicities, including no cases of pancreatitis

In February 2025, we presented final data from this randomized clinical trial.

Prolonged and sustained survival was observed after experimental treatment with CAN-2409 compared to the control group in patients with borderline resectable PDAC (n=13):

estimated median overall survival after enrollment was 31.4 months in the CAN-2409 group versus only 12.5 months in the control group.

Median survival post-progression was 21.2 months in patients who received CAN-2409 compared to 7.2 months in the control arm.

Importantly, 3 out of 7 patients who received CAN-2409 were still alive at the time of data cut-off with a survival of 66.0, 63.6, and 35.8 months, respectively, after enrollment;

survival from the time of diagnosis for these patients was 73.5, 68.8, and 41.3 months, respectively.

Of these, the first patient had stage IV metastatic disease detected during surgery, the second had residual tumor present at the resection margin, and the third had adenocarcinoma with negative resection margins.

In contrast, only one out of 6 patients randomized to SoC chemotherapy arm remained alive at the data cutoff (61.2 months from enrollment and 65.5 months from diagnosis);

histologic analysis at resection showed intraepithelial neoplasia without evidence of residual adenocarcinoma in this patient, which is associated with improved prognosis.

Based on these promising findings, the Company has decided to prepare for a larger, late-stage, randomized controlled clinical trial of CAN-2409 in PDAC.

Our second viral immunotherapy platform is based on a novel, next generation, genetically modified HSV that induces tumor specific oncolysis.

The HSV-based platform enables generation of both replication-competent and replication-defective viral product candidates as well as capacity to clone, in the vector, up to five transgenes that will allow us to optimize our virus profile for different tumor settings.

The HSV-based platform enables the generation of both replication-competent and replication-defective viral product candidates as well as the capacity to clone up to five transgenes into the vector that will allow us to optimize the profile of the viral gene construct for different tumor settings.

CAN-3110, our first HSV-based product candidate, has been engineered for enhanced specificity and tumor cell killing, while minimizing toxicity on healthy tissue.

formerly known as rQNestin34.5v.2.

An investigator-sponsored phase 1b clinical trial is ongoing with CAN-3110 in our initial target indication of recurrent HGG and we reported additional biomarker results in November 2021.

CAN-3110 was formerly known as rQNestin34.5v.2.

An investigator-sponsored phase 1b clinical trial is ongoing with CAN-3110 in our initial target indication of recurrent HGG and we reported biomarker results in November 2021.

During our Research and Development Day in December 2022, we presented updated data, demonstrating that the treatment was well tolerated with no observed dose-limiting toxicity.

This was further supported during an oral presentation at the ASGCT Annual Meeting in May of 2023, where we reported mOS of 11.8 months in arm A and 12.0 months in arm B with a single dose, based on a data cutoff date of April 20, 2023.

Additionally, the data showed evidence of immune activation and persistent HSV-1 antigen and HSV-1 replication consistent with the mechanism of action.

During an oral presentation at the ASGCT Annual Meeting in May of 2023, we reported mOS of 11.8 months in arm A and 12.0 months in arm B with a single dose, based on a data cutoff date of April 20, 2023, which is markedly longer than data in historical controls in the same patient population with mOS < 6-9 months.

Additionally, the data showed evidence of immune activation and persistent HSV-1 antigen expression and HSV-1 replication consistent with the mechanism of action.

Clinical and biomarker data for the first 41 patients treated with a single injection of CAN-3110 were published in Nature in October 2023.

The FDA has granted fast track designation to CAN-3110 for the treatment of patients with recurrent HGG to improve overall survival in February 2024.

In May 2024, the FDA awarded Orphan Drug designation to CAN-3110, recognizing its potential in treating HGG.

We are currently evaluating the effects of multiple doses of CAN-3110 in recurrent HGG supported by the Break Through Cancer foundation.

Based on the molecular targeting of CAN-3110, we believe that it could be evaluated in an expanded range of indications in the future, such as other neurologic tumors, melanoma, sarcoma, gastrointestinal stromal tumors, thyroid tumors, and breast cancer.

In October 2024, during the 16th Annual IOVC, we presented clinical activity and biomarker data for arm C.

The principal investigator of the study reported ongoing improved survival compared to historical controls in patients treated with multiple injections of CAN-3110, with 3 out of 6 patients with recurrent HGG still alive more than one year (12.2, 13.0, and 18.7 months, respectively) after initiation of experimental treatment with CAN-3110.

We expect to present initial median overall survival data after repeat dosing of CAN-3110 in the fourth quarter of 2025.

Based on the molecular mechanism of CAN-3110, we believe that it could be evaluated in an expanded range of indications in the future, such as other neurologic tumors, melanoma, sarcoma, gastrointestinal stromal tumors, thyroid tumors, and breast cancer.

In November 2024, during the SITC 2024 Annual Meeting, we presented data demonstrating the antitumor activity of CAN-3110 in preclinical models of melanoma, further supporting the rationale to expand the evaluation of CAN-3110 into tumors beyond rHGG.

In addition, we are pursuing novel discovery programs based on our enLIGHTEN Discovery Platform.

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In March 2024, we announced the acceptance of an abstract at AACR 2024 Annual Meeting related to the second candidate from our enLIGHTEN Discovery Platform, a first-in-class multimodal immunotherapy for induction of tertiary lymphoid structures as a novel therapeutic strategy for solid tumors.

In October 2024, during the 16th Annual IOVC, we presented data on a third

preclinical candidate, a novel multimodal viral therapeutic from the enLIGHTEN TM Discovery Platform encoding IL-12 and IL-15, demonstrating its ability to induce tumor regression in two different tumor models

Market Opportunity

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Localized Prostate Cancer

Prostate cancer is the second leading cause of cancer deaths in men in the United States, representing a high level of medical burden and unmet need.

Prostate cancer is the second most common cause of cancer in men in the United States and many other parts of the world, representing a high level of medical burden and unmet need.

The prostate cancer therapy market is estimated to grow to over $16.1 billion by 2026.

Approximately 200,000 men in the United States are diagnosed with prostate cancer annually, with more than 30,000 deaths each year.

Although most deaths occur in patients with later stage metastatic disease, most prostate cancer patients roughly 150,000 annually in the United States are initially diagnosed in the early stage of disease, of which roughly 105,000 are considered to have intermediate- or high-risk of progression and approximately 45,000 are considered to be low-risk.

For the intermediate- and high-risk patients, the SoC is radical prostatectomy and radiotherapy often in conjunction with androgen deprivation therapy or chemical castration.

These treatments have a high incidence of potentially life altering side effects, including incontinence and erectile dysfunction.

There is therefore a significant unmet need for a novel treatment able to forestall or prevent progression to later stages of disease without the burdensome side effects associated with the current SoC.

Weighing the balance between therapeutic efficacy and side effects linked to therapy, about 10% of the intermediate-risk patients, and approximately 40% of the low-risk patients decide, in consultation with their physicians, to adopt a close monitoring approach known as active surveillance that involves periodic imaging, biomarker evaluation and biopsies.

SoC in this early, localized setting, leaves substantial need unaddressed.

As a result of PSA screening programs, most patients are diagnosed at early stages of disease with low grade, low volume, asymptomatic prostate cancer.

Current screening methods are inadequate to definitively identify which patients are most likely to progress.

As a result of the side effects and complications from currently available treatments, there is a large desire to delay or prevent the need for radical treatment.

As a result, many men with prostate cancer meeting the National Comprehensive Cancer Network (NCCN) guidelines for low-risk prostate cancer choose not to be treated and to undergo an intense monitoring program, known as Active Surveillance (AS), as their preferred initial course of treatment.

However, within 10 years of diagnosis, between 21% and 38% of men will have developed progressive cancer and require invasive treatments.

It has been reported that 21% and 41% of patients initially under AS convert to active treatment based on progression of their disease within two and five years, and approximately 17% of men undergoing AS choose to move to active treatments within 10 years of diagnosis in the absence of any evidence of

progression, underscoring the level of anxiety that patients experience when they carry a diagnosis of untreated prostate cancer and the significant unmet need in this early line of treatment.

To our knowledge, the only FDA-approved pharmacologic intervention indicated for newly diagnosed localized prostate cancer is chemical castration therapy, also known as ADT.

SoC for localized disease is primarily surgery, radiotherapy and/or ADT.

Because ADT has a potentially severe side effect profile, including impotence, hot flashes, mood changes, depression, impact on quality of life, and others, these hormone treatments are reserved only for those patients that present the highest risk of localized or metastatic prostate cancer.

Similarly, surgical prostatectomy can often cause urinary dysfunction and sexual dysfunction that can last years and sometimes be permanent.

Approximately one-third of men with normal baseline function will report an increase in urinary symptoms and urgency after prostatectomy and most men will experience erectile dysfunction after treatment with either surgery or radiation.

We believe CAN-2409 could provide a significant commercial opportunity for therapeutic use in the newly diagnosed, localized prostate cancer patient population, with the goal of reducing progression or recurrence of disease without significant toxicities and with a product that can be administered at outpatient facilities.

Roughly 150,000 men in the United States are diagnosed with early, localized prostate cancer each year, of which roughly 105,000 are considered to have intermediate- or high-risk of progression

For these intermediate- and high-risk patients, the SoC is radical prostatectomy or radiotherapy, often in conjunction with androgen deprivation therapy or chemical castration, with a curative intent.

Still, with current SoC there will be disease recurrence in about ~30% of the patients over time.

Therefore, there is a significant unmet need for a novel treatment able to help prevent recurrence of the disease after radical treatment, avoiding the need for additional androgen deprivation therapy, additional radiotherapy, PSMA-targeted therapy, chemotherapy, or salvage radical prostatectomy (in patients who failed radiotherapy).

These treatments for recurrent prostate cancer after radical therapy may have severe side effects.

For example, androgen deprivation therapy may result in impotence, hot flashes, mood changes, depression, and impaired impact on quality of life.

We believe CAN-2409 could provide a significant commercial opportunity for therapeutic use in the newly diagnosed, localized prostate cancer patient population, with the goal of preventing recurrence of disease without significant toxicities and with a product that can be administered at outpatient facilities.

Non-Small Cell Lung Cancer

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Nonetheless, 60% of these patients will have an inadequate response after one year of ICI treatment, and 80% after three years.

We believe CAN-2409 could provide a significant commercial opportunity for therapeutic use in NSCLC patients with an inadequate response to ICI, if we are able to demonstrate overall survival of more than 12-14 months after treatment per protocol.

Pancreatic Cancer

The American Cancer Society estimates that approximately 64,050 people in the United States (33,130 men and 30,920 women) will be diagnosed with pancreatic cancer in 2023;

about 50,550 people (26,620 men and 23,930 women) will die of pancreatic cancer this year.

The American Cancer Society estimated that approximately 64,050 people in the United States (33,130 men and 30,920 women) were diagnosed with pancreatic cancer in 2023;

about 50,550 people (26,620 men and 23,930 women) will die of pancreatic cancer the same year.

Treatment is with surgery in cases where tumors are resectable, followed by adjuvant chemoradiation;

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For resected patients, while surgery and adjuvant approaches (e.g.

FOLFORINOX) have improved mOS, 5 year survival rates remain modest (20-30%) and most tumors will recur (median recurrence free survival ~1.5 years).

While there is a high level of total clinical research and development activity across pancreatic cancer settings (over 150 investigational products in phase 2 or later development), the majority are targeting metastatic disease.

Physicians have identified a continued unmet need for more effective treatment options across the pancreatic cancer setting, including a need for further approaches which can increase the resectability of borderline / locally advanced patients, and improving cure rates in resected patients.

There are an estimated 18,510 patients with resectable disease, with a sizeable proportion receiving surgery and adjuvant therapy;

there are 12,340 patients with borderline resectable disease and 30,850 with locally advanced tumors (with the majority undergoing neoadjuvant / induction treatment) in the US/EU5.

FOLFORINOX) have improved mOS, 5-year survival rates remain disappointing (20-30%) and most tumors will recur (median recurrence free survival ~1.5 years).

While there is a high level of clinical research and development activity across pancreatic cancer settings (over 150 investigational products in phase 2 or later development), the majority are targeting metastatic disease.

Physicians have identified a continued unmet need for more effective treatment options across the pancreatic cancer setting, in particular a need for improving survival.

There are an estimated 12,340 patients with borderline resectable disease in the US/EU5.

We believe CAN-2409 could provide a significant commercial opportunity for therapeutic use in borderline resectable pancreatic cancer patients, if we are able to confirm the improvement in overall survival two years after initiation of treatment in patients who received CAN-2409 combined with SoC compared to SoC alone.

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Namely, CAN-2409:

▪ Has consistently shown activity in clinical trials across a range of solid tumor types.

▪ Has consistently shown activity in clinical trials across a range of solid tumor types, including a positive randomized, placebo-controlled phase 3 clinical trial in localized prostate cancer.

▪ Has been dosed in more than a thousand patients and has generated favorable tolerability and safety data.

▪ Is engineered to be potently immunogenic but non-replicating with the goal of eliciting a systemic anti-tumor immune response while minimizing the risk for local and systemic toxicity.

▪ Is engineered to be potently immunogenic but non-replicating with the goal of eliciting a systemic anti-tumor immune response against the tumor, while minimizing the risk for local and systemic toxicity.

▪ Can be stored at 4°C, facilitating the use of CAN-2409 in out-patient clinics.

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This form of cell death is immunogenic and exposes tumor antigens that can elicit a further tumor-specific immune response.

Additionally, the virus itself stimulates a marked immuno-inflammatory response.

Key pro-inflammatory cytokines as well as chemokines, adhesion molecules and costimulatory molecules are locally upregulated, resulting in an inflamed (hot) tumor microenvironment, able to further enhance CD8+ cytotoxic tumor infiltrating lymphocyte cell activation and immunization against various released tumor antigens.

Additionally, the adenoviral serotype 5 capsid protein itself stimulates a marked immuno-inflammatory response.

Key pro-inflammatory cytokines as well as chemokines, adhesion molecules and costimulatory molecules are locally upregulated, resulting in an inflamed (hot) tumor microenvironment, able to further enhance CD8+ cytotoxic tumor infiltrating lymphocyte cell activation and in situ immunization against a multitude of released tumor antigens.

This local effect provides a strong mechanistic rationale for the combination of viral immunotherapy with ICIs, such as PD-1 or PD-L1 targeting antibodies.

ICI agents work by unmasking the inhibitory signals provided by PD-L1 ligands on tumor cells when bound to PD-1 receptors on T cells.

By blocking this suppressive signal pharmacologically, it has been demonstrated that T cells can be unleashed to attack cancer cells and that profound clinical benefit can be achieved, but this benefits only a minority of patients.

By blocking this suppressive signal pharmacologically, it has been demonstrated that T cells can be unleashed to attack cancer cells, and that profound clinical benefit can be achieved, but only in a minority of patients.

It has been hypothesized that treatment results can be significantly improved by optimizing recognition of the specific tumor antigens by the patient’s adaptive immune system using viral immunotherapy combined with the non-specific stimulation of T cells induced by ICI treatment.

It appears that a duality of signals is required:

releasing the checkpoint inhibition as described earlier, coupled with the provision of a positive, stimulatory signal to T cells.

The efficient presentation of tumor specific antigens by MHC class I molecules to the immune system provides just such a specific, stimulatory signal.

Viral immunotherapies have been shown to facilitate such cross presentation of tumor antigens and are therefore an attractive complement to PD-1 or PD-L1 checkpoint blockade.

CAN-2409 has not only been shown to induce a specific anti-tumor immune response, but it may also upregulate PD-1 and PD-L1, which could convert non-responders to ICI into responders.

The immune system is highly dynamic, with continuous trafficking of different populations of immune cells throughout the body.

One outcome of this is that when T cells are locally activated and reprogrammed to recognize tumor-specific antigens, they can act systemically to drive an efficient immune response at sites distant from the original tumor.

This abscopal effect may explain the significant effects observed at distant, uninjected sites demonstrated in experimental models of cancers.

Abscopal effect has been shown with CAN-2409 in a mouse model of prostate cancer.

This abscopal effect may explain the significant effects observed at distant, uninjected sites demonstrated in experimental

models of cancers.

For example, an abscopal effect has been shown for CAN-2409 in a mouse model of prostate cancer.

The model employed RM-1, a syngeneic prostate cell line, that was implanted both in the flanks of the mice as well as systemic, via a tail vein injection to mimic metastatic disease, resulting in the emergence of lung tumor nodules.

After intratumor treatment of the flank tumor masses with either CAN-2409 and systemic prodrug, alone or in combination with radiotherapy, we observed a beneficial response in both injected and uninjected metastatic tumor.

Use of CAN-2409 resulted in a 38% mean reduction in tumor volume and, in the combination arm, a reduction of 61% in tumor volume.

Notably, the average number of lung nodules was reduced from 20.5 in the control arm and 22.4 in the mice that

received radiotherapy to 13.0 in the CAN-2409 arm, and to 6.6 when CAN-2409 was combined with radiotherapy.

We have also observed the abscopal response in connection with the experimental treatment of CAN-2409 in patients with NSCLC.

After intratumor treatment of the flank tumor masses with either CAN-2409 plus prodrug, alone or in combination with radiotherapy, we observed a beneficial response in both injected and uninjected metastatic tumors.

Use of CAN-2409 resulted in a 38% mean reduction in tumor volume at the site of injection and, in the combination arm, a reduction of 61% in tumor volume.

Notably, the average number of uninjected lung nodules was reduced from 20.5 in the control arm and 22.4 in the mice that received radiotherapy to 13.0 in the CAN-2409 arm, and to 6.6 when CAN-2409 was combined with radiotherapy, showing both an abscopal (systemic) effect and synergy between CAN-2409 treatment and radiotherapy in a mouse model of prostate cancer.

We have confirmed the abscopal response (systemic anti-tumor immune response) after experimental treatment with CAN-2409 plus prodrug in patients with NSCLC.

We observed regression of uninjected lesions in about two-thirds of evaluable patients presenting with multiple lesions.

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This activity was not observed with T cells from untreated mice, from mice that were treated with a control vector that lacked the thymidine kinase gene, or when the AKR tumor cells were xenografted alone.

These data are consistent with a T cell dependent mechanism of action of CAN-2409.

Additionally, we have shown the induction of CD8+ T cell infiltration at the site of the tumor in patients with prostate cancer, pancreatic cancer, and NSCLC.

Together, data in experimental mouse models of cancer support a T cell dependent mechanism of action for CAN-2409 and provide evidence for in situ vaccination against the tumor, largely based on a CD8+ T cell mediated mechanism.

Accordingly, we have shown the induction of CD8+ T cell infiltration at the site of the tumor in patients with prostate cancer, pancreatic cancer, and NSCLC.

Second Product Candidate - CAN-3110

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▪ Has generated favorable tolerability and safety data, not reaching a dose limiting toxicity in the dose range tested in an ongoing investigator-sponsored phase 1b trial.

▪ Has shown a clinical signal in a difficult to treat brain cancer population, critically defined by a highly immunosuppressive environment.

▪ Has shown a clinical signal in a very difficult to treat brain cancer population, critically defined by a highly immunosuppressive environment.

▪ Has been engineered to replicate in a range of other indications characterized by Nestin expression.

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CAN-2409 for Prostate Cancer

We have completed multiple phase 1 and phase 2 clinical trials in non-metastatic prostate cancer using CAN-2409 as monotherapy and in combination with SoC.

We have completed multiple phase 1b and phase 2 clinical trials in non-metastatic prostate cancer using CAN-2409 as monotherapy and in combination with SoC.

These trials generated favorable tolerability and safety data and also provide evidence to support CAN-2409 immune activation, dosing levels and schedules.

We have administered CAN-2409 to more than 700 patients with localized prostate cancer to date, most of whom are currently in ongoing, placebo-controlled randomized trials.

We have administered CAN-2409 to more than 700 patients with localized prostate cancer to date.

Monotherapy Activity

We have observed what we believe to be a clinical response with CAN-2409 as monotherapy in our phase 1 trials.

We have observed what we believe to be a clinical response with CAN-2409 as monotherapy in our phase 1b and phase 2a clinical trials.

These responses have been consistently observed in patients with prostate cancer, including patients with newly diagnosed, localized disease, as well as those whose cancer was progressing even after radiotherapy.

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We observed in treated samples a 4-fold increase in the number of CD8+ T cells and a 3-fold increase in the number of CD68+ macrophages, demonstrating an immune response after CAN-2409 administration.

In another phase 1/2 clinical trial, patients whose prostate cancer had progressed following radiotherapy and that presented a persistently rising PSA level, were treated with CAN-2409 as monotherapy using six dose levels, ranging from 1x10 8 –1x10 11 viral particles.

In another phase 1b/2a clinical trial, patients whose prostate cancer had progressed following radiotherapy and who presented with a persistently rising PSA level, were treated with CAN-2409 as monotherapy using six dose levels, ranging from 1x108–1x1011 viral particles.

In 27 of the 36 patients recruited a decrease in PSA levels was observed following a single cycle of CAN-2409, as measured by the best PSA decrease in serial assessments within the first 3 months after treatment.

PSA, while an imperfect biomarker for prostate cancer, is still widely employed for patient management in conjunction with biopsy, as rising PSA levels, and in particular PSA doubling time are associated with disease progression.

In that same trial, we observed that the PSA doubling time improved significantly (p=0.0271) from 15.9 months at baseline to 42.5 months after a single cycle of CAN-2409 administration, in this treatment-resistant patient population.

PSA is widely employed for patient management in conjunction with biopsy, as rising PSA levels, and in particular PSA doubling time are associated with disease progression.

In that same clinical trial, we observed that the PSA doubling time improved significantly (p=0.0271) from 15.9 months at baseline to 42.5 months after a single cycle of CAN-2409 administration in this treatment-resistant patient population.

A subset of the patients in this trial also received second or third injection courses of CAN-2409.

In most of those patients, a decrease from pre-administration PSA levels was again observed upon repeated injection.

In most of these patients, another decrease from pre-administration PSA levels was observed upon repeated injection.

We recently completed a phase 2b randomized, double blind, placebo-controlled clinical trial in the United States evaluating the effects of CAN-2409 monotherapy in patients with low-to-intermediate risk, localized prostate cancer undergoing active surveillance.

We randomized 190 patients:

127 to the CAN-2409 arm who received 2 doses of CAN-2409 plus valacyclovir and 63 patients who received PBO plus valacyclovir.

Enrollment of this trial was completed in May 2019.

In December 2024, we reported data showing numerical improvement in time to radical treatment and the percentage of patients achieving negative (prostate cancer-free) biopsies at 1-year post-treatment.

However, these differences did not reach statistical significance.

CAN-2409 was generally well tolerated;

AEs were consistent with prior studies.

The study may have been underpowered for the primary endpoint of progression-free survival.

The Company has decided to deprioritize the development in the active surveillance population.

Combination Therapy

Because of the increasing prevalence of combination therapy for cancer patients, the ability to combine novel agents with SoC treatments without overlapping toxicity is of increasing importance.

We believe that the favorable tolerability and safety data generated for CAN-2409 in our clinical trials is encouraging for our current and future development plans, in combination with other agents but also as a monotherapy in lower risk patient populations that are not willing to undergo more aggressive forms of treatment.

The safety data from our phase 2 clinical trial in prostate cancer patients treated with CAN-2409 in combination with SoC of radiotherapy or androgen deprivation therapy, reported no grade 4 treatment-related adverse events and only single-patient incidence of grade 3 treatment related adverse events.

It was anticipated that flu-like symptoms would be evident, because CAN-2409 is an adenoviral gene construct known to induce a systemic immune response.

Greater than 50% of patients reported fever and/or chills often associated with viral immune activation.

These symptoms, which generally manifested early and transiently, often occurred on the evening of the intratumoral administration of CAN-2409 and resolved by the following morning.

The rates of the gastrointestinal adverse events in this study are consistent with those typically reported by patients undergoing radiotherapy, which is a component of SoC in this population.

Our previous phase 2 clinical trial data informed our agreement with the FDA under the SPA for our ongoing phase 3 clinical trial.

Although the data is limited as we have not conducted head-to-head studies, in our phase 2 clinical trial we observed that intermediate-risk patients who received CAN-2409 in combination with radiotherapy had failure rates that were 75% lower than those reported in four other contemporaneous trials of similar patient populations.

In clinical trials to date, CAN-2409 has been generally well tolerated.

Our previous phase 2a clinical trial data informed our agreement with the FDA under the SPA for our phase 3 clinical trial.

Previously, we observed that intermediate-risk patients who received CAN-2409 in combination with radiotherapy had failure rates that were 75% lower than those reported in four other contemporaneous trials of similar patient populations.

Where these other clinical trials reported freedom from failure rates of between 75%-79%, corresponding to cumulative recurrence rates of 21%-25%, CAN-2409 resulted in a 5% recurrence rate in patients with intermediate-risk prostate cancer.

The median follow-up of patients who received CAN-2409 in this clinical trial was 5.7 years.

The median follow-up of patients who received CAN-2409 in this phase 2a clinical trial was 5.7 years.

Similarly, results in this clinical trial also demonstrated reduced recurrence rates in the low- and high-risk patients enrolled when compared to these other trials.

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In this trial, low-risk patients achieved a PSA of < 2ng/ml in 77% of CAN-2409 treated patients versus 58% in control populations.

The endpoint used in our phase 2 trial was freedom from failure (FFF), defined by the period of time between treatment and the occurrence of a clinical or biochemical failure.

The endpoint used in our phase 2b trial was freedom from failure (FFF), defined by the period of time between treatment and the occurrence of a clinical or biochemical failure.

Under the SPA agreement, we have selected disease-free survival (DFS) as the endpoint for our phase 3 clinical trial.

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This largely overlaps with FFF as it is often triggered by detection of increased PSA levels (i.e., biochemical failure).

We have also reanalyzed our previous phase 2 data using DFS parameters, supporting the implementation of DFS as endpoint in our phase 3 trial.

We have also reanalyzed our previous phase 2a data using DFS parameters, supporting the implementation of DFS as endpoint in our phase 3 trial.

Potentially Registrational Phase 3 Clinical Trial for Localized Prostate Cancer

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Based on the data from our clinical trials to date, we believe that CAN-2409 has the potential, if approved, to be the first new first-line product candidate approved for patients with localized prostate cancer in over 20 years.

We are currently conducting a potentially registrational phase 3 trial for CAN-2409, with agreement, under an SPA with the FDA for a single pivotal trial in newly diagnosed localized prostate cancer in intermediate and high-risk patients in combination with the SoC, radiotherapy.

This phase 3 clinical trial is fully enrolled with 711 patients, randomized 2:1.

Patients receive three investigational treatment courses of CAN-2409, each consisting of four concurrent injections of transrectal or transperineal ultrasound guided administration of CAN-2409 followed by a course of oral valacyclovir.

The first injection course is given at least 15 days but not more than 8 weeks before starting radiation.

The second injection course is given 0-3 days prior to radiotherapy.

The third and final injection course is delivered 15-22 days after the second injections.

A fixed dose of valacyclovir is given for 14 days after each CAN-2409 administration.

SoC external beam radiotherapy is administered to patients throughout the course of the trial with optional ADT as determined by the treating physician.

Trial inclusion criteria are based on patients with localized prostate cancer meeting the NCCN criteria of intermediate-risk or patients presenting only one NCCN high-risk feature.

NCCN intermediate-risk is defined as having at least one of

the following:

We recently reported successful topline data in a potentially registrational phase 3 trial for CAN-2409, under an SPA with the FDA, in newly diagnosed localized prostate cancer in intermediate and high-risk patients in combination with the SoC, radiotherapy.

This phase 3 clinical trial enrolled 745 patients (711 of which received at least one intraprostatic injection of CAN-2409 or PBO), randomized 2:1 to study drug and placebo, respectively.

Patients received three investigational treatment

courses of CAN-2409, each consisting of four concurrent injections of transrectal or transperineal ultrasound guided administration of CAN-2409 followed by a course of oral valacyclovir.

The first injection course was given at least 15 days but not more than 8 weeks before starting radiation.

The second injection course was given 0-3 days prior to radiotherapy.

The third and final injection course was delivered 15-22 days after the second injections.

A fixed dose of valacyclovir was given for 14 days after each CAN-2409 administration.

SoC external beam radiotherapy was administered to patients throughout the course of the trial with a short course (<6 months) ADT as determined by the treating physician.

Trial inclusion criteria were based on patients with localized prostate cancer meeting the NCCN criteria of intermediate-risk or patients presenting only one NCCN high-risk feature.

NCCN intermediate-risk is defined as having at least one of the following:

prostate serum antigen (PSA) of 10-20 ng/ml, Gleason Score of 7, and is staged T2b-T2c via the TNM staging system.

Patients may also exhibit one high-risk characteristic that may consist of a PSA of 20+ ng/ml, a Gleason Score of 8-10, or a cancer that is up to stage T3a, but not more than one of these high-risk factors.

Patients may also have exhibited one high-risk characteristic that may consist of a PSA of 20+ ng/ml, a Gleason Score of 8-10, or a cancer that is up to stage T3a, but not more than one of these high-risk factors.

The SPA specifically defines agreement with the FDA on the statistical design and power of the phase 3 trial as well as the primary endpoint definition.

The SPA states that the trial is adequately designed to provide the necessary data that, depending on the outcome, could support a Biologics License Application (BLA) submission.

The SPA does note the general point for all SPAs, that BLA acceptance and approvability are review issues and that a BLA approval will depend on the quality of actual clinical trial data, the robustness of the effect on the stated primary endpoint, the impact on the secondary endpoints, a favorable assessment of the study conduct, and analysis of safety information and other supportive data.

We have approximately 50 active clinical sites for this clinical trial and have completed enrollment in September 2021 with 711 patients.

The primary endpoint for the clinical trial is DFS.

This trial has been designed to have 90% power, a hazard ratio of 0.5 and an alpha of 0.05.

We are assuming a 15% improvement in the active arm (CAN-2409) as compared to placebo in the rate of events measured according to the DFS definition provided above.

We expect topline data from this phase 3 clinical trial in the fourth quarter of 2024.

Phase 2 Clinical Trial for Active Surveillance

Clinical results to date suggest that CAN-2409 as monotherapy may reduce the rates of biochemical failure for patients with localized prostate cancer.

In the AS setting, we will assess whether CAN-2409 has the potential to delay or prevent tumor progression to a later stage that demands radical treatment.

In May 2019, the Company completed enrollment of 187 patients in its phase 2 clinical trial of CAN-2409 in patients with low-to-intermediate-risk, localized, non-metastatic prostate cancer, randomized 2:1.

The primary endpoint is biopsy-proven progression-free survival (PFS).

Progression is defined as an increase in Gleason grade or increase in tumor volume to > 33%.

As the primary endpoint is event-driven, in February 2023, based on a blinded review of the event rate, the Company determined that additional time is required for patient follow up in order to collect a sufficient number of events.

Based on the current rate of events, the Company currently anticipates topline data to be available in the fourth quarter of 2024.

The SPA does note a general condition for all SPAs, that BLA acceptance and approvability are review issues and that a BLA approval will depend on the quality of actual clinical trial data, the robustness of the effect on the stated primary endpoint, the impact on the secondary endpoints, a favorable assessment of the study conduct, and analysis of safety information and other supportive data.

We utilized approximately 50 clinical sites for this clinical trial and completed enrollment in September 2021 with 745 patients enrolled.

For the primary endpoint of DFS in the ITT population, with a randomization ratio of 2:1, approximately 98 events would provide 90% power to detect a hazard ratio (HR) of 0.5 for prostate cancer recurrence using stratified log-rank test at an alpha level of 0.05.

At study design, it was estimated that randomization of approximately 711 patients would be sufficient to provide the required number of DFS events.

In December 2024, we announced positive topline data from this phase 3 clinical trial after median follow-up time of 50.3 months.

The study met its primary endpoint, demonstrating a statistically significant improvement in disease-free survival compared to the control arm.

Treatment with CAN-2409 reduced the risk of prostate cancer recurrence or death by 30% (p=0.0155, HR 0.7, 95% CI 0.52 to 0.94).

Median DFS was not reached for the CAN-2409 treatment arm vs.

86.1 months in the PBO arm.

Prostate cancer specific DFS (exclusion of non-prostate cancer related deaths) demonstrated a greater effect with a 38% decreased risk in the CAN-2409 arm vs.

PBO (p=0.0046;

HR 0.62, 95% CI 0.44 to 0.87).

DFS improvement was observed both in patients receiving short-term ADT and in patients not receiving ADT.

A significant increase in the proportion of patients achieving a prostate-specific antigen (PSA) nadir (<0.2 ng/ml) was observed in the treatment arm compared to the placebo control arm (67.1% vs.

58.6%, respectively;

CAN-2409 induced 80.4% pathological complete responses in the 2-year post-treatment biopsies compared to 63.6% observed in the control arm (p=0.0015).

CAN-2409 was generally well tolerated;

the most common CAN-2409-related adverse events were flu-like symptoms, fever and chills, which were generally mild to moderate in severity and self-limited.

CAN-2409 for Non-Small Cell Lung Cancer (NSCLC)

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Patients continue treatment with their initial ICI and CAN-2409 was added to their regimen.

The primary efficacy endpoints for this trial are response rate measured by RECIST and/or Disease Control Rate, with overall survival as a key study endpoint.

The primary efficacy endpoints for this trial were response rate measured by RECIST and/or Disease Control Rate, with overall survival as a key study endpoint;

there has been an increasing focus on the gold standard endpoint in this disease, overall survival, consistent with SITC guidelines.

We reported initial data from this trial at the ASCO Annual Meeting in June 2022.

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and favorable safety/tolerability data with most treatment-related adverse events being grade 1/2.

In December 2023, the recruitment of this study was paused as we completed target enrollment for cohort 2.

We anticipate presenting topline overall survival data from this ongoing phase 2 clinical trial in the second quarter of 2024.

In May 2024, we announced topline data that showed prolonged overall survival.

mOS of 20.6 months was observed following two administrations of CAN-2409 plus valacyclovir in NSCLC patients with progressive disease despite ICI therapy, compared to published results of mOS of 11.6 months observed with standard of care docetaxel-based chemotherapy in a similar patient population (Reckamp K et al.

J Clin Onc 2022;40:2295-2306).

Ninety percent of these patients had stage IV disease at inclusion.

Improved mOS was observed in both PD-L1 negative and PD-L1 positive tumors in patients with progressive disease (N=37 patients in cohort 2 for which PD-L1 status at baseline was available).

mOS of 22.0 months was observed across all patients (n=46) who had an inadequate response to ICI and who received two administrations of CAN-2409.

Activation of the systemic immune response was associated with shrinkage of uninjected lesions (abscopal response).

71.4% of patients with metastatic disease and at least one uninjected tumor (n=35) experienced a beneficial effect from CAN-2409 treatment on both injected and uninjected tumors.

When using a threshold of >5% decrease, more than 60% of patients still showed an abscopal response.

We also confirmed that treatment with CAN-2409 in NSCLC continued to exhibit a favorable safety and tolerability profile.

We anticipate presenting updated overall survival data from this ongoing phase 2a clinical trial in the first quarter of 2025.

CAN-2409 for Pancreatic Cancer

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In addition, the study demonstrated that CAN-2409 was generally well-tolerated in combination with SoC.

We are currently conducting a randomized phase 2 clinical trial of CAN-2409 in borderline resectable pancreatic cancer, with a target enrollment of up to 54 patients.

Despite the pause in patient enrollment, we presented initial clinical data in the fourth quarter of 2023, based on a data cutoff date of August 21, 2023.

We are currently conducting a randomized phase 2 clinical trial of CAN-2409 in borderline resectable pancreatic cancer.

In March 2023, in connection with our cost management and dynamic portfolio management initiatives, we elected to pause new enrollment in this randomized phase 2a clinical trial and decided to first evaluate survival in the enrolled patients.

We presented initial clinical data in the fourth quarter of 2023, based on a data cutoff date of August 21, 2023.

The initial data showed prolonged and sustained survival in patients who were treated with CAN-2409 and there was a separation of the survival rates in the treatment and placebo arms.

Estimated survival was 71.4% when 2-3 CAN-2409 courses were added to standard neoadjuvant chemoradiotherapy followed by attempted surgical resection compared to 16.7% with standard neoadjuvant chemoradiotherapy followed by attempted surgical resection alone at both 24 and 36 months after treatment.

We expect to present an update to this survival data in the second quarter of 2024.

CAN-2409 for High-Grade Glioma

Phase 3 Clinical Trial of CAN-2409 in High-Grade Glioma

At our Research & Development Day in December 2022 we announced that we have made a portfolio and resource prioritization decision to pursue CAN-3110 in recurrent HGG, but not to pursue a phase 3 clinical trial of CAN-2409 in high-grade glioma.

The CAN-3110 program in recurrent HGG may serve as an enabling clinical trial for future expansion into earlier stages of HGG as well as other solid tumors outside the brain that are characterized by Nestin expression.

Phase 1 Clinical Trial of CAN-2409 With Opdivo in High-Grade Glioma

We conducted a phase 1b clinical trial in patients with newly diagnosed HGG examining the combination of CAN-2409 and anti-PD-1 nivolumab (Opdivo, BMS) in collaboration with BMS and Adult Brain Tumor Consortium.

This was the first clinical trial to evaluate the combination of CAN-2409 and nivolumab in HGG patients with the goal of enhancing anti-tumor T cell activation and expansion and the potential for better clinical outcome.

Data for this phase 1b clinical trial were presented at the 37th Annual Meeting of Society for Immunotherapy of Cancer (SITC) in Boston in November 2022.

In the trial involving 35 evaluable patients, extensive biomarker analyses demonstrated that the combination of CAN-2409 and nivolumab resulted in a statistically significant expansion of activated tumor-fighting CD4+ and CD8+ T cells effector cells as well as decreased markers of exhaustion on effector cells.

Proteomic analysis by OLINK revealed an increase in pro-inflammatory cytokines, including interferon-gamma, the chemokines CXCL9/10 and CXCL11, MCP-1, MCP-3, and granzyme A.

Systemic immune activation was observed after the single administration of CAN-2409, prior to initiation of nivolumab (week 3 post treatment).

mOS for patients with methylated MGMT promoter was 30.6 months for those who underwent gross total resection (GTR) (n=10) and 12.6 months for those who underwent sub-total resection (STR) (n=5).

mOS for patients with unmethylated MGMT was 13.2 months (GTR) (n=16) and 15.9 months (STR) (n=4), respectively.

Phase 1b/2 Clinical Trial of CAN-2409 Combined with SoC in High-Grade Glioma

In our phase 1b/2 clinical trial in newly diagnosed patients with HGGs, including the difficult-to-treat glioblastoma, CAN-2409 demonstrated a statistically significant increase in patient survival when combined with current SoC over the

current SoC alone (surgery, radiation and temozolomide).

The trial compared the overall survival of 48 enrolled patients treated at 4 clinical sites with CAN-2409 plus SoC against a matched controlled set of 134 patients enrolled at MGB who received only SoC.

The results demonstrated that the mOS of patients receiving SoC alone was 13.5 months while patients receiving CAN-2409 plus SoC was 17.1 months (p=0.0417).

Importantly, a pre-planned analysis on a subset of patients treated surgically with gross total resection (>95% of tumor removed) during surgery (18 patients compared to 44 in the control arm), demonstrated a mOS of 25.1 months in the CAN-2409 arm versus 16.3 months in the SoC group, with approximately a 50% improvement (p=0.0120).

In this patient population, after three years, one in three patients was alive in the CAN-2409 arm compared to 1 in 20 patients in the SoC group.

At the end of the study, three of the patients who received CAN-2409 were alive without progression after 43, 62.1 and 88.5 months.

CAN-2409 was generally well tolerated, with most treatment-related adverse events being grade 1 or 2, and few reports of grade 3 or 4 events.

In April 2024, we announced that the FDA has granted orphan drug designation for CAN-2409 for the treatment of pancreatic cancer.

In April 2024, we also reported topline survival data for the population of patients with borderline resectable PDAC with CAN-2409.

Estimated mOS was 28.8 months in the CAN-2409 group versus 12.5 months in the control group.

Importantly, 4 out of 7 patients who received CAN-2409 were still alive at the time of data cutoff, with 2 patients surviving more than 50.0 months from enrollment.

Only 1 out of 6 patients, randomized to control SoC chemotherapy alone, remained alive at data cutoff (alive at 50.6 months).

Biomarker data analysis demonstrated

consistent and robust activation of immune response after dosing with CAN-2409.

Addition of CAN-2409 regimen to SoC was generally well tolerated, with no dose-limiting toxicities, including no cases of pancreatitis.

In February 2025, we presented final data from this randomized clinical trial.

Prolonged and sustained survival was observed after experimental treatment with CAN-2409 compared to the control group in patients with borderline resectable PDAC (n=13):

estimated median overall survival after enrollment was 31.4 months in the CAN-2409 group versus only 12.5 months in the control group.

Median survival post-progression was 21.2 months in patients who received CAN-2409 compared to 7.2 months in the control arm.

Importantly, 3 out of 7 patients who received CAN-2409 were still alive at the time of data cut-off (February 20, 2025) with a survival of 66.0, 63.6, and 35.8 months, respectively, after enrollment;

survival from the time of diagnosis for these patients was 73.5, 68.8, and 41.3 months, respectively.

In contrast, only one out of 6 patients randomized to SoC chemotherapy arm remained alive at the data cutoff (61.2 months from enrollment and 65.5 months from diagnosis);

histologic analysis at resection showed intraepithelial neoplasia without evidence of residual adenocarcinoma in this patient, which is associated with improved prognosis.

Based on these promising findings, the Company has decided to prepare for a larger, late-stage, randomized controlled clinical trial of CAN-2409 in PDAC.

Opportunities for CAN-2409 in Other Cancer Indications

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At time of recurrence, a mass was evident in the left frontal lobe.

The patient was enrolled in arm B of the phase 1 clinical trial which includes treatment with Cytoxan (24 mg/kg one dose day -2) prior to CAN-3110 injection.

The patient was enrolled in arm B of the phase 1b clinical trial which includes treatment with Cytoxan (24 mg/kg one dose day -2) prior to CAN-3110 injection.

Post-treatment scan demonstrated progressive reduction in enhancement with cavitary necrosis at the site of injection.

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Given the mOS of less than 6-9 months in historical clinical trials of other investigational agents in patients with recurrent HGG, who have failed SoC treatment we believe this is encouraging evidence of clinical activity.

We expect to report additional data, including the potential benefits from multiple injections of CAN-3110, from the ongoing phase 1b clinical trial in the second half of 2024.

In May 2024, we announced that the FDA granted orphan drug designation for CAN-3110 for the treatment of recurrent HGG.

In October 2024, during the 16th Annual IOVC, we

announced clinical activity and biomarker data for arm C.

The principal investigator of the study reported ongoing improved survival compared to historical controls in patients treated with multiple injections of CAN-3110, with 3 out of 6 patients with recurrent HGG still alive more than one year (12.2, 13.0, and 18.7 months, respectively) after initiation of experimental treatment with CAN-3110.

We expect to report initial median overall survival data from the multiple injection cohort of CAN-3110, from the ongoing phase 1b clinical trial in the fourth quarter of 2025.

Collaborations and Other Transactions

We are a party to various license and collaboration agreements under which we license patents, patent applications and other intellectual property to and from third parties.

These licenses impose various diligence and financial payment

obligations on us.

These licenses impose various diligence and financial payment obligations on us.

We expect to continue to enter into these types of license agreements in the future.

We consider the following license and collaboration agreements to be material to our business:

On December 9, 2019, we entered into a series of agreements, including an exclusive license agreement, a novation agreement, an equipment purchase agreement and an intellectual property assignment agreement, collectively the Periphagen Agreements, with Periphagen, whereby we acquired certain assets and licensed certain rights (including specified patent rights and know-how, or the Licensed IP Rights) of Periphagen, primarily consisting of exclusive rights to their technology platform and a portfolio of pre-clinical, development stage virus vectors, as well as certain physical property and equipment.

On December 9, 2019, we entered into a series of agreements, including an exclusive license agreement, a novation agreement, an equipment purchase agreement and an intellectual property assignment agreement, collectively the Periphagen Agreements, with Periphagen, whereby we acquired certain assets and licensed certain rights (including specified patent rights and know-how, or the Licensed IP Rights) of Periphagen, primarily consisting of exclusive rights to their technology platform and a portfolio of preclinical, development stage virus vectors, as well as certain physical property and equipment.

The primary classes of assets are HSV-derived assets expressing neurotrophin-3 (or NT-3 Assets) and other HSV-derived assets (Gene Transfer Neuro-Assets).

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• Disposition Income:

(i) a single digit royalty rate of certain consideration we receive for the grant of a license, assignment or other intellectual property rights related to the NT-3 Assets and (ii) if we consummate a strategic collaboration with certain specified parties to treat non-oncolygic neurological conditions and diseases, either 2nd decile (if consummated within 18 months) or mid-2nd decile to mid-3rd decile (if consummated thereafter) royalty rates of certain consideration we receive for the grant of a license, assignment or other intellectual property rights related to the Gene Transfer Neuro-Assets.

(i) a single digit royalty rate of certain consideration we receive for the grant of a license, assignment or other intellectual property rights related to the NT-3 Assets and (ii) if we consummate a strategic collaboration with certain specified parties to treat non-oncologic neurological conditions and diseases, either 2nd decile (if consummated within 18 months) or mid-2nd decile to mid-3rd decile (if consummated thereafter) royalty rates of certain consideration we receive for the grant of a license, assignment or other intellectual property rights related to the Gene Transfer Neuro-Assets.

If we are required to pay royalties to a third party on any product covered under the Periphagen Agreements, we may credit such royalty payments against the royalties owed to Periphagen in the applicable country, up to a percentage reduction in the mid-2nd decile.

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If we fail to do so, Periphagen may terminate the Periphagen License Agreement for material breach.

On December 15, 2022, Periphagen notified us by letter of its claim that we have failed to use commercially reasonable efforts to complete a human proof of concept clinical trial of an NT-3 Asset under an Exclusive License Agreement dated December 9, 2019 between us and Periphagen (the “Periphagen License Agreement”).

On January 13, 2023, we filed a demand for arbitration against Periphagen with the American Arbitration Association, seeking a declaration that Periphagen’s December 15 letter failed to comply with the dispute and escalation provisions in the Periphagen License Agreement.

On March 10, 2023, Periphagen filed its answer and counterclaims to our demand for arbitration.

In its counterclaims, Periphagen sought a declaration that we have not used commercially reasonable efforts to complete a human proof of concept clinical trial of the NT-3 Asset and a declaration that any further extension of time would not be scientifically or commercially reasonable.

We denied Periphagen’s counterclaims.

On June 7, 2023, the parties entered into an amendment to the Exclusive License Agreement that resolved the dispute and resulted in termination of the arbitration.

See Part I, Item 3 “Legal Proceedings”.

On June 7, 2023, the parties entered into an amendment to the Periphagen License Agreement.

The Periphagen License Agreement expires on the later of December 9, 2069 or the end of the Royalty Term.

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On January 20, 2018, we entered into an exclusive option agreement (the Option Agreement) with MGB.

Pursuant to the Option Agreement, we obtained the exclusive right from MGB to negotiate an exclusive worldwide, royalty-bearing license to develop and commercialize products covered by certain MGB patents, including those patents covering CAN-3110, in the field of gene therapy and vector therapy for the treatment or prevention of cancerous tumors in humans or animals, as such field is further detailed in the Option Agreement (Licensed Field).

Pursuant to the Option Agreement, we obtained the exclusive right from MGB to negotiate a world-wide, royalty-bearing license to develop and commercialize products covered by certain MGB patents, including those patents covering CAN-3110, in the field of gene therapy and oncolytic vector therapy for the treatment or prevention of cancerous tumors in humans or animals, as such field is further detailed in the Option Agreement (the Licensed Field).

In consideration for MGB’s granting of the exclusive option, we paid MGB a non-refundable fee of $40,000.

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On September 15, 2020, we exercised our option and entered into an exclusive patent license agreement with MGB (the MGB License Agreement).

Under the MGB License Agreement, MGB granted to us (a) an exclusive, royalty-bearing license under certain of MGB’s patents to make, have made, use, have used, sell and have sold certain products covered by such licensed patents (the Licensed Products) and otherwise practice processes covered by such licensed patents (Licensed Processes);

Under the MGB License Agreement, MGB granted to us (a) an exclusive, royalty-bearing license under certain of MGB’s patents to make, have made, use, have used, sell and have sold certain products covered by such licensed patents (Licensed Products) and otherwise practice processes covered by such licensed patents (Licensed Processes);

and (b) a non-exclusive, royalty-bearing license under certain other of MGB’s patents to make, have made, use, have used, sell and have sold Licensed Products, but not to sell or have sold Licensed Processes.

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On March 1, 2014, we entered into an exclusive license agreement (the Ventagen Agreement), with Ventagen, LLC (Ventagen).

The Ventagen Agreement provides Ventagen an exclusive license, with rights to grant sublicenses (subject to certain terms and conditions) under any worldwide patent rights and know-how owned or controlled by us during the term of the Ventagen Agreement which cover applicable technology utilizing the delivery method of the herpes derived TK protein to tumors or other tissues via a viral vector (as further specified therein), to research, use, have used, import, have imported, export, have exported, offer for sale, have sold, sell, distribute and market certain products for the prevention or treatment of cancer in humans and any use in animals (or the Field of Use) (Licensed Products), for commercial sale and distribution within Mexico, Belize, Guatemala, Honduras, El Salvador, Costa Rica, Nicaragua, Panama, Colombia and Bolivia (or the Territory).

The Ventagen Agreement provides Ventagen an exclusive license, with rights to grant sublicenses (subject to certain terms and conditions) under any worldwide patent rights and know-how owned or controlled by us during the term of the Ventagen Agreement which cover applicable technology utilizing the delivery method of the herpes derived TK protein to tumors or other tissues via a viral vector (as further specified therein), to research, use, have used, import, have imported, export, have exported, offer for sale, have sold, sell, distribute and market certain products for the prevention or treatment of cancer in humans and any use in animals (or the Field of Use), or the Licensed Products, for commercial sale and distribution within Mexico, Belize, Guatemala, Honduras, El Salvador, Costa Rica, Nicaragua, Panama, Colombia and Bolivia (or the Territory).

Under the Ventagen Agreement, Ventagen agreed to use commercially reasonable efforts to develop and commercialize Licensed Products in the Territory in the Field of Use.

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The large pharmaceutical and biotechnology companies that have commercialized and/or are

developing immuno-oncology treatments for cancer include AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, Merck & Co., Novartis, Pfizer and Genentech.

developing immuno-oncology treatments for cancer include AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, Merck & Co., Novartis, Pfizer, Genentech, and Johnson & Johnson.

Some of the products and therapies developed by our competitors are based on scientific approaches that are the same as or similar to our approach, including with respect to the use of viral immunotherapy with adenovirus and HSV.

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

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

We intend to utilize 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, and partnering opportunities may all influence or alter our commercialization plans.

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Intellectual Property

We believe that approval of our CAN-2409 and CAN-3110 product candidates under a BLA may result in 12 years of data exclusivity in the United States under the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively the ACA), 10 years of market exclusivity in Europe and significant durations in other markets, which would be complementary to any relevant patent exclusivity.

With regard to patent exclusivities, we have or are pursuing patent protection for our CAN-2409 and CAN-3110 product candidates and our enLIGHTEN Discovery Platform.

With regard to our CAN-2409 product candidate, we own a United States patent and a pending patent application that relate to a method of use of CAN-2409 in combination with an immune checkpoint inhibitor.

The issued patent and the pending application, if issued, are expected to expire in 2034.

With regard to our CAN-3110 product candidate, we have rights to issued composition of matter patents in the United States, Australia, Canada, China, Europe, and Japan and patent applications pending in Australia, Europe, and Korea that relate to CAN-3110.

With regard to our CAN-2409 product candidate, we own a U.S.

patent and one pending U.S.

patent application that relate to methods of decreasing tumor burden and micrometastases using CAN-2409 in combination with an immune checkpoint inhibitor.

The issued patent and pending application, if issued, are expected to expire in 2034.

We also own one International patent application filed under the Patent Cooperation Treaty that relates to methods of treating non-squamous non-small cell lung cancer and non-resectable, non-small cell lung cancer using CAN-2409 and one pending U.S.

provisional patent application that relates to methods of treating prostate cancer using CAN-2409.

Patents claiming priority to the International and provisional patent applications, if issued, are expected to expire in 2044 and 2045, respectively.

We also own a pending U.S.

provisional patent application that relates to formulations and methods of manufacture of CAN-2409.

Patents claiming priority to this provisional application, if issued, are expected to expire in 2045.

With regard to our CAN-3110 product candidate, we have exclusively licensed from MGB a patent family that includes issued patents in the United States, Australia, Canada, China, Europe, Japan and Korea, and patent applications pending in Australia and Europe that relate to the composition of matter of the vector used in our CAN-3110 product candidate.

The issued patents and the pending applications, if issued, are expected to expire in 2036.

This patent family is exclusively licensed to us from MGB.

In addition, we have entered into an option agreement with MGB to a pending U.S.

provisional patent application that relates to the use of biomarkers for the selection of cancer patients for treatment with CAN-3110 and for the management of treatment regimens in cancer patients receiving CAN-3110.

The term of patents claiming priority to the provisional patent application, if issued, are expected to expire in 2044.

With regard to our enLIGHTEN Discovery Platform, we have exclusively in-licensed from Periphagen a patent family that includes composition of matter patents in the United States, Europe, and China and pending applications in the United States and China that relate to an HSV vector used in our enLIGHTEN Discovery Platform.

In addition, we

own a pending U.S.

provisional patent application that relates to methods of treating melanoma with CAN-3110.

Patents claiming priority to this provisional patent application, if issued, are expected to expire in 2045.

With regard to our enLIGHTEN Discovery Platform, we have exclusively in-licensed from Periphagen a patent family that includes issued patents in the United States, China, and Europe and patent applications pending in the United States and China that relate to the composition of matter of the HSV vector used in our enLIGHTEN Discovery Platform.

The issued patents and the pending applications, if issued, are expected to expire in 2037.

In addition, we own a pending international patent application filed under the Patent Cooperation Treaty with composition of matter claims that also relate to an HSV vector and candidate payloads used in our enLIGHTEN Discovery Platform and methods of use.

The term of patents claiming priority to the international patent application, if issued, are expected to expire in 2043.

We also own a pending U.S.

provisional patent application that relates to methods of treating certain cancer patients using our HSV vector.

The term of patents claiming priority to the provisional patent application, if issued, are expected to expire in 2044.

In addition, we own a patent family that includes pending patent applications in the United States, Australia, Brazil, Canada, China, Europe, Israel, India, Japan, Korea, Mexico, and Singapore that relate to the HSV vector containing candidate payloads used in our enLIGHTEN Discovery Platform and methods of use.

The pending patent applications, if issued, are expected to expire in 2043.

We also own a pending International patent application filed under the Patent Cooperation Treaty that relates to methods of treating cancer in immune checkpoint inhibitor-refractory patients using our HSV vector.

Patents claiming priority to the International patent application, if issued, are expected to expire in 2044.

Government Regulation

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• a determination by the FDA within 60 days of its receipt of a BLA to accept and file the application;

• satisfactory completion of an FDA pre-license inspection of the manufacturing facility or facilities where the biological product is produced to assess compliance with current good manufacturing practices (cGMPs) to assure that the facilities, methods and controls are adequate to preserve the biological product’s identity, strength, quality and purity;

assure that the facilities, methods and controls are adequate to preserve the biological product’s identity, strength, quality and purity;

• satisfactory completion of an FDA advisory committee review, if applicable;

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The biological product candidate is initially introduced into healthy human subjects and tested for safety.

In the case of some products for severe or life-threatening diseases, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted

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

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

In March 2022, the FDA released a final guidance entitled “Expansion Cohorts:

Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,” which outlines how developers can utilize an adaptive trial design commonly referred to as a seamless trial design in early stages of oncology biological product development (i.e., the first-in-human clinical trial) to compress the traditional three phases of trials into one continuous trial called an expansion cohort trial.

Information to support the design of individual expansion cohorts are included in IND applications and assessed by FDA.

Expansion cohort trials can potentially bring efficiency to biological product development and reduce developmental costs and time.

In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product.

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Failure to exhibit due diligence with regard to conducting required phase 4 clinical trials could result in withdrawal of approval for products.

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

Concurrent with clinical trials, companies may complete additional animal studies and also develop additional information about the chemistry and physical characteristics of the biological product as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

To help reduce the risk of the introduction of adventitious agents with use of biological products, the Public Health Service Act (PHS Act), emphasizes the importance of manufacturing control for products whose attributes cannot be precisely defined.

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Such biological product candidates may be eligible to proceed to registration following an early phase single clinical trial in a limited patient population which may be deemed a pivotal or registrational trial following review of the trial’s design, primary endpoints and results by the applicable regulatory agencies.

Determination of the requirements to be deemed a pivotal or registrational trial is subject to the applicable regulatory authority’s scientific judgement and these requirements may differ in the United States and the European Union.

During all phases of clinical development, regulatory agencies require a sponsor assure extensive monitoring and auditing of all clinical activities, clinical data, and clinical trial investigators.

Annual progress reports detailing the results of the clinical trials, particularly the safety information, must be submitted to the FDA.

During all phases of clinical development, regulatory agencies require that a sponsor assure extensive monitoring and auditing of all clinical activities, clinical data, and clinical trial investigators.

Annual progress reports detailing the results of the clinical trials, particularly the safety information, must be submitted to the FDA and other relevant agencies in Europe and the rest of the world.

Written IND safety reports must be promptly submitted to the FDA and the investigators for serious and unexpected adverse events associated with the use of the study drug, and in some cases, any findings from other studies of the same drug, tests in laboratory animals or in vitro testing that suggest a significant risk for human subjects, or any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

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Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies and clinical trials are submitted to the FDA as part of a BLA requesting approval to market the product for one or more indications.

The BLA must include results of product development, laboratory and animal studies, human clinical trials, information on the manufacture and composition of the product, proposed labeling and other relevant information.

The BLA must include results of product

development, laboratory and animal studies, human clinical trials, information on the manufacture and composition of the product, proposed labeling and other relevant information.

The testing and approval processes require substantial time and effort and there can be no assurance that the FDA will accept the BLA for filing and, even if filed, that any approval will be granted on a timely basis, if at all.

The BLA review typically takes twelve months from the date the BLA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision.

Within 60 days following submission of the application, the FDA reviews the BLA submission to determine if it is substantially complete before the FDA accepts it for filing and full review.

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Under the performance goals and policies implemented by the FDA under the Prescription Drug User Fee Act (PDUFA) for original BLAs, the FDA targets ten months from the filing date in which to complete its initial review of a standard application and respond to the applicant, and six months from the filing date for an application with priority review.

The FDA does not always meet its PDUFA goal dates, and the review process is often significantly extended by FDA requests for additional information or clarification and in some cases, convening of an Advisory Committee.

The FDA does not always meet its PDUFA goal dates, and the review process may be significantly extended by FDA requests for additional information or clarification and in some cases, convening of an Advisory Committee.

This review typically takes twelve months from the date the BLA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision.

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

During the biological product approval process, the FDA also will determine whether a Risk Evaluation and Mitigation Strategy (REMS) is necessary to assure the safe use of the biological product.

During the biological product approval process, the FDA will also determine whether a Risk Evaluation and Mitigation Strategy (REMS) is necessary to assure the safe use of the biological product.

If the FDA concludes a REMS is needed, the sponsor of the BLA must submit a proposed REMS;

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The FDA may delay or refuse approval of a BLA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.

If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, including to subpopulations of patients, which could restrict the commercial value of the product.

commercial value of the product.

Further, the FDA may require that certain contraindications, warnings, precautions or interactions be included in the product labeling.

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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, as noted above, if the second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

Orphan drug status in the European Union (EU) has similar, but not identical, benefits.

Expedited Development and Review Programs

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Breakthrough therapy designation comes with all of the benefits of fast track designation.

The FDA may take other actions appropriate to expedite the development and

review of the product candidate, including holding meetings with the sponsor and providing timely advice to, and interactive communication with, the sponsor regarding the development program.

The FDA may take other actions appropriate to expedite the development and review of the product candidate, including holding meetings with the sponsor and providing timely advice to, and interactive communication with, the sponsor regarding the development program.

A product candidate is eligible for priority review if it treats a serious or life-threatening disease or condition and, if approved, would provide a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious disease or condition.

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Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval.

With respect to oncology products, the FDA may review applications under Real-Time Oncology Review (RTOR) established by the FDA’s Oncology Center of Excellence.

RTOR, which allows an applicant to pre-submit components of the application to allow the FDA to review clinical data before the complete filing is submitted, aims to explore a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible, while maintaining and improving review quality.

Drugs considered for review under RTOR must, among other things, be likely to demonstrate substantial improvements on a clinically relevant endpoint(s) over available therapy, and must have easily interpreted endpoints.

In addition, no aspect of the application should be likely to require a longer review time, such as, for example, a requirement for a new REMS.

To determine eligibility for RTOR, the FDA requires top-line efficacy and safety results from an applicant’s pivotal clinical trial(s), as well as completion of database lock for the clinical trial(s).

The FDA will generally make a decision regarding acceptance into RTOR within twenty (20) business days of receipt of the request from the applicant.

If an applicant is not accepted into RTOR, the applicant will follow routine application submission procedures.

Additionally, a product candidate may be eligible for accelerated approval.

Drug or biological products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval, which means that they may be approved on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on an intermediate clinical endpoint other than survival or irreversible morbidity or mortality, that is reasonably likely to predict irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA generally requires that a sponsor of a drug or biological product receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials, which must be conducted with due diligence, to verify the clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit and, under the Food and Drug Omnibus Reform Act of 2022 (FDORA), the FDA may require, as appropriate, that such trials be underway prior to approval or within a specific time period after the date accelerated approval was granted.

As a condition of approval, the FDA generally requires that a sponsor of a drug or biological product receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials, which must be conducted with due diligence, to verify the clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit and, under the Food and Drug Omnibus Reform Act of 2022 (FDORA), the FDA may require that such trials be underway prior to approval or within a specific time period after the date accelerated approval was granted.

In addition, for products being considered for accelerated approval, the FDA generally requires, unless otherwise informed by the agency, that all advertising and promotional materials, intended for dissemination or publication be submitted to the agency for review.

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Manufacturers of products are required to comply with applicable requirements in the cGMP regulations, including quality control and quality assurance and maintenance of records and documentation.

Manufacturers and other parties involved in the drug supply chain for prescription drug products must also comply with product tracking and tracing requirements and notify the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States.

Other post-approval requirements applicable to biological products, include reporting of cGMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, record keeping requirements, reporting of adverse effects, reporting updated safety and efficacy information, and complying with electronic record and signature requirements.

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Manufacturers must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities, and promotional activities involving the internet.

Discovery of previously unknown problems or the failure to comply with the

applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the market as well as possible civil or criminal sanctions.

Discovery of previously unknown problems or the failure to comply with the applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the market as well as possible civil or criminal sanctions.

Failure to comply with the applicable U.S.

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

Biological product manufacturers and other entities involved in the manufacture and distribution of approved biological products are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMPs, which impose certain procedural and documentation requirements on sponsors and their contract development and manufacturing organizations (CDMOs).

periodic unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMPs, which impose certain procedural and documentation requirements on sponsors and their contract development and manufacturing organizations (CDMOs).

Manufacturers and other parties involved in the drug supply chain for prescription drug and biological products must also comply with product tracking and tracing requirements and for notifying the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States.

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

From time to time, legislation is drafted, introduced, passed in Congress and signed into law that could significantly change the statutory provisions governing the approval, manufacturing, and marketing of products regulated by the FDA.

In addition to new legislation, FDA regulations, guidance, and policies are often revised or reinterpreted by the agency in ways that may significantly affect the manner in which pharmaceutical products are regulated and marketed.

Patent Term Restoration and Marketing Exclusivity

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FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product, and FDA will not approve an application for a biosimilar or interchangeable product based on the reference biological product until 12 years after the date of first licensure of the reference product.

“First licensure” typically means the initial date the particular product at issue was

licensed in the United States.

The FDA may approve multiple “first” interchangeable products so long as they are all approved on the same first day of marketing.

“First licensure” typically means the initial date the particular product at issue was licensed in the United States.

Date of first licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

The BPCIA is complex and continues to be interpreted and implemented by the FDA.

In addition, government proposals have sought to reduce the 12-year reference product exclusivity period.

government proposals have sought to reduce the 12-year reference product exclusivity period.

Other aspects of the BPCIA, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent litigation.

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If the FDA concludes that the applicable criteria have been met, the FDA will issue a PMA for the approved indications, which can be more limited than those originally sought by the applicant.

The PMA can include post-approval conditions that the FDA believes necessary to

ensure the safety and effectiveness of the device, including, among other things, restrictions on labeling, promotion, sale and distribution.

The PMA can include post-approval conditions that the FDA believes necessary to ensure the safety and effectiveness of the device, including, among other things, restrictions on labeling, promotion, sale and distribution.

If the FDA’s evaluation of the PMA or manufacturing facilities is not favorable, the FDA will issue an order denying approval of the PMA or issue a not approvable order.

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The FDA may also determine that additional clinical trials are necessary, in which case the PMA approval may be delayed for several months or years while the trials are conducted and then the data submitted in an amendment to the PMA.

Once granted, PMA approval may be withdrawn by the FDA if compliance with post approval requirements, conditions of approval or other regulatory standards is not maintained or problems are identified following initial marketing.

granted, PMA approval may be withdrawn by the FDA if compliance with post approval requirements, conditions of approval or other regulatory standards is not maintained or problems are identified following initial marketing.

PMA approval is not guaranteed, and the FDA may ultimately respond to a PMA submission with a not approvable determination based on deficiencies in the application and require additional clinical trial or other data that may be expensive and time-consuming to generate and that can substantially delay approval.

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Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application much like the IND prior to the commencement of human clinical trials.

In the EU, for example, an application must be submitted for each clinical trial to each country’s national competent authority (NCA), and at least one independent ethics committee, much like the FDA and an IRB, respectively.

In the EU, for example, an application must be submitted for each clinical trial to each country’s national competent authority, and at least one independent ethics committee, much like the FDA and an IRB, respectively.

Under the Clinical Trials Regulation (EU) No.

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To obtain regulatory approval of a medicinal product in the EU, we must submit a marketing authorization application (MAA).

A centralized marketing authorization is issued by the European Commission through the centralized procedure, based on the opinion of the Committee for Medicinal Products for Human Use (CHMP) of the EMA, and is valid throughout the EU and the additional Member States of the European Economic Area (Iceland, Liechtenstein and Norway) (the EEA).

A centralized marketing authorization is issued by the European Commission through the centralized procedure, based on the opinion of the Committee for Medicinal Products for Human Use (CHMP) of the EMA, and is valid throughout the EU and the additional countries of the European Economic Area (Iceland, Liechtenstein and Norway) (the EEA).

The centralized procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, advanced-therapy medicinal products (i.e.

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The timeframe for the evaluation of an MAA under the accelerated assessment procedure is 150 days, excluding clock stops, but it is possible that the CHMP may revert to the standard time limit for the centralized procedure if it determines that the application is no longer appropriate to conduct an accelerated assessment.

The application used to submit the BLA in the United States is similar to that required in the European Union, although there may be certain specific requirements, for example those set out in Regulation (EC) No 1394/2007 on advanced therapy medicinal products, covering gene therapy, somatic cell therapy and tissue-engineered medicinal products.

Now that the UK (which comprises Great Britain and Northern Ireland) has left the EU, Great Britain is no longer covered by centralized marketing authorizations (under the Northern Ireland Protocol, centralized marketing authorizations currently continue to be recognized in Northern Ireland).

On January 1, 2024, an international recognition framework was put in place by the MHRA, under which the MHRA will have regard to decisions on the approval of marketing authorizations made by the European Medicines Agency and certain other regulators when determining an application for a new Great Britain marketing authorization.

The application used to submit a BLA in the United States is similar to that required in the EU for an MAA, although there may be certain specific requirements, for example those set out in Regulation (EC) No 1394/2007 on advanced therapy medicinal products, covering gene therapy, somatic cell therapy and tissue-engineered medicinal products.

Data and Market Exclusivity

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(2) either (a) such condition affects no more than five (5) in ten thousand (10,000) persons in the EU when the application is made, or (b) it is unlikely that the product, without the benefits derived from orphan status, would generate sufficient return in the EU to justify the necessary investment in its development;

and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the product would be of significant benefit to those affected by that condition, as defined in Regulation (EC) 847/2000.

and (3) there exists no

satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the product would be of significant benefit to those affected by that condition, as defined in Regulation (EC) 847/2000.

Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon the grant of a marketing authorization, entitled to ten years of market exclusivity for the approved therapeutic indication.

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Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The 10-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.

The ten-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.

Additionally, a marketing authorization may be granted to a similar medicinal product for the same indication as an authorized orphan product at any time if:

• the second applicant can establish that its product, although similar to the authorized orphan product, is safer, more effective or otherwise clinically superior;

• the marketing authorization holder of the authorized product consents to a second orphan medicinal product application;

• the marketing authorization holder of the authorized product consents to a second application;

• the marketing authorization holder of the authorized product cannot supply enough orphan medicinal product.

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Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports (PSURs).

• All new MAAs must include a risk management plan (RMP) describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product.

• All new MAAs must include a risk management plan (RMP) describing the risk management system that the company will put in place to prevent or minimize the risks associated with the product.

The regulatory authorities may also impose specific obligations as a condition of the marketing authorization.

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Although general requirements for advertising and promotion of medicinal products are established under EU directives, the details are governed by regulations in each EU Member State and can differ from one country to another.

The aforementioned EU rules are generally applicable in the EEA.

All of the aforementioned EU rules are generally applicable in the EEA.

Reform of the Regulatory Framework in the European Union

The European Commission introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the EU for all medicines (including those for rare diseases and for children).

The European Commission has provided the legislative proposals to the European Parliament and the European Council for their review and approval.

In October 2023, the European Parliament published draft reports proposing amendments to the legislative proposals, which will be debated by the European Parliament.

The European Commission has provided the legislative proposals to the European Parliament and the European Council for their review and approval, and, in April 2024, the European Parliament proposed amendments to the legislative proposals.

Once the European Commission’s legislative proposals are approved (with or without amendment), they will be adopted into EU law.

Brexit and the Regulatory Framework in the United Kingdom

The UK formally left the EU on January 31, 2020, and the UK and the EU have concluded a trade and cooperation agreement or TCA, which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued, but does not provide for wholesale mutual recognition of UK and EU pharmaceutical regulations.

At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the EU regulatory framework currently continues to apply in Northern Ireland).

Except in respect of the EU Clinical Trials Regulation, the regulatory regime in Great Britain therefore largely aligns with current EU medicines regulations, however it is possible that these regimes will diverge more significantly in future now that Great Britain’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of UK and EU pharmaceutical legislation.

However, notwithstanding that there is no wholesale recognition of EU pharmaceutical legislation under the TCA, under a new international recognition framework mentioned above which was put in place by the MHRA on January 1, 2024, the MHRA may take into account decisions on the approval of marketing authorizations from the EMA (and certain other regulators) when considering an application for a Great Britain marketing authorization.

The UK formally left the EU on January 31, 2020.

As a result of the Northern Ireland protocol, following Brexit, the EMA remained responsible for approving novel medicines for supply in Northern Ireland under the EU centralized procedure, and a separate authorization was required to supply the same medicine in Great Britain (England, Wales and Scotland).

On February 27, 2023, the UK government and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”.

This new framework fundamentally changes the existing system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the UK.

In particular, the MHRA will be responsible for approving all medicinal products destined for the UK market (i.e., Great Britain and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland.

A single UK-wide marketing authorization will be granted by the MHRA for all medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.

The Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, so the UK government and the EU will enact legislative measures to bring it into law.

On June 9, 2023, the MHRA announced that the medicines aspects of the Windsor Framework will apply from January 1, 2025.

The Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, and the medicines aspects of the Windsor Framework have applied since January 1, 2025.

This new framework fundamentally changes the previous system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the UK.

In particular, the MHRA is now responsible for approving all medicinal products destined for the UK market (i.e., Great Britain and Northern Ireland), and the EMA no longer has any role in approving medicinal products destined for Northern Ireland under the EU centralized procedure.

A single UK-wide marketing authorization will be granted by the MHRA for all novel medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.

In addition, the new arrangements require all medicines placed on the UK market to be labelled “UK only”, indicating they are not for sale in the EU.

However, although a separate authorization is now required to market medicinal products in the UK, under an international recognition procedure which was put in place by the MHRA on January 1, 2024, the MHRA may take into account decisions on the approval of a marketing authorization from the EMA (and certain other regulators) when considering an application for a UK marketing authorization.

There is now no pre-marketing authorization orphan designation in the UK.

Instead, the MHRA reviews applications for orphan designation in parallel to the corresponding MAA.

The criteria are essentially the same, but have been tailored for the UK market, i.e., the prevalence of the condition in UK (rather than the EU) must not be more than five in 10,000.

Should an orphan designation be granted, the period of market exclusivity will be set from the date of first approval of the product in the UK.

Health Reform

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• The American Taxpayer Relief Act further reduced Medicare payments to several types of providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Due to the Statutory Pay-As-You-Go Act of 2010, estimated budget deficit increases resulting from the American Rescue Plan Act of 2021, and subsequent legislation, Medicare payments to providers will be further reduced starting in 2025 absent further legislation.

however, legislation has been introduced in the U.S.

Congress that would, if enacted, reverse these payment reductions.

In addition to provider payment cuts under Medicare, the American Rescue Plan Act of 2021 also eliminated the statutory Medicaid drug rebate cap, previously set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

These laws and regulations may result in additional reductions in Medicare and other healthcare funding available for healthcare providers and may otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

• On April 13, 2017, the Centers for Medicare & Medicaid Services (CMS) published a final rule that gives states greater flexibility in setting benchmarks for insurers in the individual and small group marketplaces, which may have the effect of relaxing the essential health benefits required under the ACA for plans sold through such marketplaces.

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presidential executive orders, congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

President Biden has also issued multiple executive orders that have sought to reduce prescription drug costs.

In February 2023, HHS also issued a proposal in response to an October 2022 executive order from President Biden that includes a proposed prescription drug pricing model that will test whether targeted Medicare payment adjustments will sufficiently incentivize manufacturers to complete confirmatory trials for drugs approved through FDA’s accelerated approval pathway.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.

At the federal level, President Trump reversed some of President Biden’s executive orders including rescinding Executive Order 14087 entitled “Lowering Prescription Drug Costs for Americans." President Trump may issue new executive orders designed to impact drug pricing.

A number of these and other proposed measures may require authorization through additional legislation to become effective.

Congress and the Trump administration have indicated that they will continue to seek new legislative measures to control drug costs.

At the state level, legislatures have 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.

In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.

This could reduce the ultimate demand for our

drugs or put pressure on our drug pricing, which could negatively affect our business, financial condition, results of operations and prospects.

This could reduce the ultimate demand for our drugs or put pressure on our drug pricing, which could negatively affect our business, financial condition, results of operations and prospects.

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

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In the United States and markets in other countries, patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on third-party payors to reimburse all or part of the associated healthcare costs.

Thus, even if a product candidate is approved, sales of the product will depend, in part, on the extent to which third-party payors, including government health programs in the United States such as Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage, and establish adequate reimbursement levels for, the product.

reimbursement levels for, the product.

In the United States, the principal decisions about reimbursement for new medicines are typically made by CMS, an agency within HHS.

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Governments have shown significant interest in implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products.

Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit a company’s revenue generated from the sale of

any approved products.

Coverage policies and third-party payor reimbursement rates may change at any time.

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Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and new employees, advisors and consultants.

The principal purposes of our equity and cash

incentive plans are to attract, retain and reward personnel through the granting of stock-based and cash-based compensation awards, in order to increase stockholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.

The principal purposes of our equity and cash incentive plans are to attract, retain and reward personnel through the granting of stock-based and cash-based compensation awards, in order to increase stockholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.

Legal Proceedings

From time to time, we may become involved in litigation or other legal proceedings.

On March 10, 2023, Periphagen filed its answer and counterclaims to our demand for arbitration.

We denied Periphagen’s counterclaims.

On June 7, 2023, the parties entered into an amendment to the Exclusive License Agreement that resolved the dispute and resulted in termination of the arbitration.

Aside from the proceeding with Periphagen, we are not currently a party to any litigation or legal proceedings that, in the opinion of our management, are probable to have a material adverse effect on our business.

We are not currently a party to any litigation or legal proceedings that, in the opinion of our management, are probable to have a material adverse effect on our business.

Regardless of outcome, litigation can have an adverse impact on our business, financial condition, results of operations and prospects because of defense and settlement costs, diversion of management resources and other factors.

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Our Internet website address is www.candeltx.com.

Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a), 14, and 15(d) of the Securities Exchange Act of 1934, as amended (the Exchange Act), are available through the “Investors” portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission (SEC).

Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports

filed or furnished pursuant to Sections 13(a), 14, and 15(d) of the Securities Exchange Act of 1934, as amended (the Exchange Act), are available through the “Investors” portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission (SEC).

Information on our website is not part of this Annual Report on Form 10-K or any of our other securities filings unless specifically incorporated herein by reference.

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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