What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2026-03-12 compared with 2025-03-13 · 548 added, 425 removed, 843 unchanged (54% of the section changed)

1 unchanged sentence

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 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.

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

Local administration is designed to achieve these therapeutic effects while minimizing systemic exposure and associated toxicity.

The immune cells induced by these viral immunotherapies are believed to target patients’ specific tumor antigens, potentially improving responses in immunologically “hot” tumors while at the same time infiltrating the tumor microenvironment, transforming non-inflamed “cold” tumors with limited immune response into “hot” tumors.

While our product candidates are administered directly into the tumor, we have observed systemic immune response in our preclinical studies and clinical trials that may indicate the potential of our product candidates to induce systemic immune response against distal, uninjected tumors, also known as an “abscopal” effect.

While our product candidates are administered directly into the tumor, we have observed systemic immune responses in our preclinical studies and clinical trials that may indicate the potential of our product candidates to induce systemic immune response against distal, uninjected tumors, also known as an “abscopal” effect.

We believe viral immunotherapy is among the most promising cancer treatment modalities today.

1 unchanged sentence

We have established two clinical off-the-shelf viral immunotherapy platforms based on novel, genetically modified adenovirus and herpes simplex virus (HSV) constructs, respectively.

Our most advanced product candidate, CAN-2409, is an off-the-shelf adenovirus product candidate which is administered in conjunction with the prodrug valacyclovir, that has generated promising clinical activity across a range of solid tumor indications.

CAN-2409 is currently being studied in the following ongoing clinical trials:

Our most advanced product candidate, aglatimagene besadenovec (referred to herein as aglatimagene and previously as CAN-2409), is an off-the-shelf adenovirus product candidate, administered in conjunction with the prodrug valacyclovir, and has generated promising clinical activity across a range of solid tumor indications.

Aglatimagene is being studied in the following ongoing clinical trials:

▪ Prostate Cancer

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.

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

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.

The FDA granted Fast Track Designation for the use of aglatimagene for the treatment of localized, primary prostate cancer in combination with radiation therapy to improve the local control rate.

o The primary goal of curative treatment for localized prostate cancer is complete tumor eradication, as outlined by National Comprehensive Cancer Network (NCCN) guidelines.

However, up to 30% of intermediate- to high-risk patients experience recurrence despite radical therapy, and salvage treatments often carry significant side effects and limited efficacy.

Recurrence beyond two years post-treatment is strongly linked to need for salvage anti-cancer therapies, higher rates of metastasis, and prostate cancer-specific mortality after prolonged follow up (>10 years).

Studies also show that patients prioritize the perception of being cancer-free and are often willing to risk long-term complications to achieve this.

Fear of recurrence remains prevalent, especially after biochemical failure (Hoffman RM et al.

Cancer 2003;97:1653-62 ;

Jayadevappa R et al.

J Clin Oncol 2019;37:964-73 ;

Nilsson R et al.

Eur Urol Open Sci 2021;25:44-51).

Therefore, this study aimed to assess whether adding aglatimagene plus valacyclovir to standard of care (SoC) radiotherapy could improve disease-free survival (DFS) in patients pursuing curative treatment, a primary endpoint established in the SPA with the FDA.

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)

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

Patients were randomized 2:1 (496 in aglatimagene + prodrug and 249 in placebo + 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 aglatimagene (5x10 11 vp/2mL) or placebo were administered, each followed by 14 days of prodrug.

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

1 unchanged sentence

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.

The study met its primary endpoint, demonstrating a statistically significant improvement in DFS in patients in the aglatimagene arm compared to the placebo arm.

Key topline results include:

• The primary endpoint, as agreed with the FDA under a SPA, was met:

statistically significant improvement in DFS for aglatimagene plus radiation therapy (n=496) vs.

placebo plus radiation therapy (n=249) (p=0.0155;

0.52 to 0.94).

Median DFS was not reached for the aglatimagene treatment arm vs.

86.1 months in the placebo arm.

• This result was supported by secondary and exploratory endpoints:

o Statistically significant improvement in prostate cancer-specific DFS (exclusion of non-prostate cancer related deaths) in the aglatimagene arm vs.

placebo (p=0.0046;

HR 0.62, 95% CI 0.44 to 0.87)

o Exploratory subset analysis showed that improvement in prostate cancer-specific DFS was observed, independent of the use of short-term ADT and independent of the type of EBRT (conventional EBRT vs.

moderate hypofractionated EBRT)

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

58.6%, respectively;

o Statistically significant increase in the proportion of patients with a pathological complete response in 2-year post-treatment biopsies (80.4% in the aglatimagene arm vs.

63.6% in the control arm;

• Aglatimagene was generally well tolerated.

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

There was no increase in serious adverse events after aglatimagene administration vs.

• In May 2025, after submission of these topline data to the FDA, we announced that the FDA granted Regenerative Medicine Advanced Therapy (RMAT) Designation for aglatimagene for the treatment of newly diagnosed, localized prostate cancer in patients with intermediate- to high-risk disease.

• In June 2025, the results from the positive phase 3 clinical trial of aglatimagene in patients with intermediate- to high-risk, localized prostate cancer were presented in an oral session at the Annual Meeting of the American Society of Clinical Oncology (ASCO).

• In September 2025, we presented subgroup analysis of the phase 3 clinical trial during the Annual Meeting of the American Society for Radiation Oncology (ASTRO).

The data demonstrated that the effect of aglatimagene on prostate-specific DFS was independent of the type of radiotherapy used (conventional EBRT vs.

moderate hypofractionated EBRT).

For moderate EBRT, the hazard ratio (HR) was 0.52 (95% CI:

0.30–0.93), and for conventional EBRT, the HR was 0.76 (95% CI:

Subgroup analyses of prostate cancer-specific DFS demonstrated that aglatimagene outperformed standard of care across all categories, with HRs ranging from 0.49 in patients with intermediate-risk favorable prostate cancer to 0.69 in patients with high-risk disease.

• We expect to announce supportive data on prostate cancer-specific outcomes (prostate cancer-specific DFS, time to salvage anti-cancer therapy, and time to metastasis) after extended follow-up in the second quarter of 2026.

• In addition, in the third quarter of 2026, we expect to present novel immunological biomarker data in patients with localized prostate cancer.

• We are in ongoing dialogue with the FDA in preparation for the Company’s anticipated submission of a Biologics License Application (BLA) for aglatimagene in prostate cancer 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.

• 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.

• In December 2024, we reported that this phase 2 clinical trial of aglatimagene monotherapy in 190 patients with low- to intermediate-risk, localized prostate cancer undergoing active surveillance showed a trend toward 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, which might be explained by 1) the fact that the study was not statistically powered for the primary endpoint (progression-free survival), 2) ~70% of patients had low-risk disease (which makes it more difficult to detect a treatment effect), 3) patients received only 2 administrations of aglatimagene rather than 3 as used in the phase 3 clinical trial described above, and 4) patients did not receive radiotherapy (preclinical models of prostate cancer have shown synergy between aglatimagene and radiotherapy in this specific indication).

Aglatimagene was generally well tolerated.

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

o We have initiated a phase 2a, open-label, multi-center study evaluating biomarkers and biodistribution and shedding of aglatimagene plus valacyclovir in men with localized, intermediate-risk prostate cancer who are planning to receive EBRT.

The study aims to recruit up to 45 patients (30 in the treatment arm and 15 in the control arm treated with EBRT alone).

Biosamples (blood, urine, semen) will be collected at specified timepoints.

We anticipate that this data will be submitted as part of the BLA filing in the fourth quarter of 2026.

▪ 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 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 <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 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.

o An open-label phase 2a clinical trial in the United States evaluating aglatimagene 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 aglatimagene plus valacyclovir in combination with pembrolizumab in order to improve survival or delay progression in patients with unresectable stage III 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 <12 months when treated with SoC second-line chemotherapy (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.

The aim of the aglatimagene immunotherapy antitumor strategy is to improve overall survival beyond the median of 12 months in patients treated with two aglatimagene injections and raise the long tail of survival.

o In March 2025, we announced overall survival data from this phase 2a clinical trial of aglatimagene in NSCLC:

▪ In patients with an inadequate response to immune checkpoint inhibitor (ICI) treatment who received 2 aglatimagene plus valacyclovir courses (Cohort 1+2, per protocol population, n=46), mOS was 24.5 months.

▪ In patients with progressive disease, despite ICI treatment (Cohort 2, per protocol population, n=41), mOS was 21.5 months, which is markedly longer than the 9.8–11.8 months of survival reported in published literature in a similar patient population receiving standard of care of docetaxel second-line chemotherapy (Paz-Ares LG et al, J Clin Oncol 2024;42:2860-2872 ;

Ahn MJ et al, J Clin Onc 2024;43:260-272).

▪ 37% of patients with progressive disease at enrollment were still alive > 24 months after aglatimagene treatment at the time of the March 3, 2025 data cut, suggesting a long tail of survival.

14/15 patients with overall survival > 24 months and 9/9 patients with overall survival > 30 months had non-squamous NSCLC.

▪ In patients with non-squamous NSCLC and progressive disease despite ICI (Cohort 2, per protocol population, n=33), observed mOS was 25.4 months after aglatimagene treatment.

▪ Aglatimagene continued to exhibit a generally favorable safety and tolerability profile during the extended follow-up period.

o Based on these positive findings, we plan to initiate a pivotal phase 3 clinical trial of aglatimagene in patients with progressive, metastatic, non-squamous NSCLC despite ICI treatment in the second quarter of 2026.

o We expect to announce updated data on OS including data on long-term survival and biomarker analysis from the phase 2a clinical trial in the first quarter of 2026.

▪ Pancreatic Cancer

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.

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.

• 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 within the tumor microenvironment.

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:

• 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.

o We conducted a randomized controlled phase 2a clinical trial in the United States and Mexico evaluating the activity of aglatimagene in borderline resectable pancreatic ductal adenocarcinoma (PDAC).

In December 2023, we announced that the FDA granted Fast Track Designation for aglatimagene plus valacyclovir for the treatment of patients with PDAC to improve overall survival.

In April 2024, we announced updated positive overall survival data and supportive biomarker data and also announced that the FDA has granted Orphan Drug Designation for aglatimagene for the treatment of PDAC.

In July 2025, we announced that the European Medicines Agency (EMA) has granted Orphan Designation for aglatimagene for the treatment of pancreatic cancer.

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

▪ Estimated median overall survival after enrollment was 31.4 months in the aglatimagene group versus 12.5 months in the control group.

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

survival from the time of diagnosis was 73.5, 68.8 and 41.3 months, respectively, 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).

▪ Median post-progression survival was 21.2 months in the aglatimagene arm vs.

6.4 months in the control arm.

▪ In October 2025, we decided to pause on further clinical development of aglatimagene in PDAC, in the context of portfolio prioritization, unless externally funded through a grant or other non-dilutive external funding.

Our lead HSV-based product candidate, linoserpaturev (referred to previously as CAN-3110), is currently being evaluated in an ongoing investigator-sponsored phase 1b clinical trial in the 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.

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.

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 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.

In October 2023, we published an article in Nature that reported extended overall survival associated with immune activation in patients with recurrent HGG treated with linoserpaturev.

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

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 continues as of February 2025 without additional treatment.

Significant tumor responses were observed in both arm A and arm B of this study.

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 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).

In February 2024, we announced that the FDA granted Fast Track Designation for linoserpaturev for the treatment of patients with recurrent HGG to improve overall survival.

In May 2024, we also announced that the FDA granted Orphan Drug Designation for linoserpaturev for the treatment of recurrent HGG.

In November 2024, during the Society for Immunotherapy of Cancer (SITC) Annual Meeting, we presented data demonstrating the antitumor activity of linoserpaturev 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 potential to expand the evaluation of linoserpaturev into tumors beyond recurrent HGG, creating a potential pipeline in a product.

We are conducting an extension of the clinical trial (arm C), in which patients with recurrent glioblastoma receive a repeat dosing regimen of linoserpaturev (up to six injections over four months).

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.

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 October 2024, at the 16th Annual International Oncolytic Virotherapy Conference (IOVC), we presented initial clinical and biomarker data from Arm C of the linoserpaturev trial.

The principal investigator reported improved survival compared to historical controls in patients who received multiple injections of linoserpaturev.

Post-treatment longitudinal biopsies showed a near absence of tumor cells with dense lymphocyte infiltration, particularly in patients with post-treatment MRI enhancement, consistent with radiologic pseudo-progression.

These findings were reported in a Science Translational Medicine manuscript published in October 2025, which followed two patients from Arm C through 97 serial tumor biopsies.

Serial brain biopsy samples showed extensive immune-mediated remodeling of the tumor microenvironment after linoserpaturev administration, characterized by dense lymphocyte infiltration and extensive tumor necrosis (death).

One patient achieved a complete pathological response, with clearance of tumor cells from post-treatment biopsies.

In contrast, MRI scans for both patients showed apparent tumor enlargement (pseudo-progression), underscoring that conventional imaging criteria may underestimate linoserpaturev’s immunologic activity.

These results illustrate the limitations of conventional imaging in evaluating the response to viral immunotherapy in glioblastoma and highlight the importance of overall survival data, supported by histology, in this indication.

In October 2025, we also announced updated OS data for Arm A and Arm B as of August 15, 2025.

The updated mOS was 11.8 months for arm A (n=41) (CI:

8.3–14.9) and 12.0 months for arm B (n=9) (CI:

10.0–NA), respectively, after a single injection of linoserpaturev.

One patient from arm A and one patient from arm B were still alive after prolonged follow-up (59.2 and 42.4 months, respectively, after linoserpaturev administration).

At the time of data cutoff, 9 patients in arm C had received multiple administrations of linoserpaturev.

At the 1×10⁸ plaque-forming unit (PFU) dose, 3 patients received 4 injections, 1 patient received 5 injections, and 2 patients received 6 injections.

At the 1×10⁷ PFU dose, 1 patient received 4 injections, and 2 patients received 5 injections.

Median follow-up was 8.9 months.

Four out of 9 patients were alive at the time of data cutoff (range 3.1-28.2 months after initiation of linoserpaturev treatment).

Five patients had died, of which 3 died more than one year after initiation of linoserpaturev treatment (range 5.5-21.8 months).

We have recently completed enrollment in arm C, and expect to present mature mOS data and an update on long-term survivors in the fourth quarter of 2026.

In January 2026, we received clearance for an IND that will support enabling work for a potential future randomized controlled phase 2 dose regimen finding study of linoserpaturev in recurrent glioblastoma.

We have also designed 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 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.

6 unchanged sentences

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 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 these areas as we prepare our commercialization efforts.

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

(Advantagene).

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 into Candel Therapeutics, Inc.

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

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

We completed our initial public offering in July 2021.

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 .

We plan to develop and commercialize our two most advanced product candidates, aglatimagene and linoserpaturev, 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 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.

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

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 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 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.

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

We 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.

We plan to submit a BLA in the fourth quarter of 2026.

We believe that, if approved, aglatimagene could be a first-in-class drug for localized prostate cancer patients.

We are approaching our preparations for commercialization of aglatimagene in prostate cancer with the same discipline and flexibility that guides our manufacturing strategy:

building specialized partner networks around aglatimagene that can be scaled and reconfigured as conditions evolve.

We plan to implement a capital-efficient commercialization model focused on establishing strong relationships with leading investigators, high-volume treatment centers, patient advocacy organizations, and payers to support disease awareness, appropriate patient identification, and patient access.

Our largely externalized, collaborative framework integrates our internal clinical and scientific expertise with specialized external capabilities in commercial readiness, distribution, market access, and launch execution.

As market conditions, geographic scope, and product maturity warrant, we may selectively internalize certain commercial capabilities, including building a targeted sales organization, where doing so enhances strategic control, operating leverage, and long-term value creation.

This approach is designed to enable launch readiness while preserving strategic flexibility, cost discipline, and meaningful long-term economic participation.

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

A phase 2 clinical trial that evaluates aglatimagene in combination with ICI has demonstrated improvement in mOS compared to historical control patients treated with second line docetaxel chemotherapy.

In the second quarter of 2026, we plan to initiate a phase 3 study in patients with progressive, metastatic, non-squamous NSCLC despite ICI treatment that will randomize participants to two courses of aglatimagene plus valacyclovir plus continued ICI vs.

SoC docetaxel-based chemotherapy.

▪ Perform enabling work for a potential future randomized controlled phase 2 clinical trial of linoserpaturev in recurrent HGG to potentially identify the optimal dosing regimen and improve mOS compared to SoC.

We recently obtained clearance for an IND.

▪ Leverage our enLIGHTEN Discovery Platform to enable rapid vector engineering, generating 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.

2 unchanged sentences

In order to advance treatment options for a large number of patients, we may partner with other companies with complementary resources to maximize the value of our current and future product candidates.

Such partnerships may allow us to pair CAN-2409, CAN-3110, and our future product candidates with other novel agents owned by strategic partners.

Such partnerships may allow us to pair aglatimagene, linoserpaturev, and future product candidates with other novel agents owned by strategic partners.

Partnerships may also help realize the full potential of our product candidates in markets where we are unlikely to pursue development or commercialization on our own.

1 unchanged sentence

▪ Ensure commercial-scale manufacturing of our product candidates .

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

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 will rely on third party contract manufacturers for commercial-scale manufacturing of both product candidates, aglatimagene and linoserpaturev.

For aglatimagene, we have worked with our contract manufacturer (CDMO) to tech transfer, scale up and finalize the manufacturing process for potential commercialization of aglatimagene.

The CDMO has performed small scale development runs and has scaled up the process to manufacture four successful and consistent large-scale runs to date.

Additionally, the CDMO has manufactured a clinical batch, using the commercial manufacturing process, which will be used to supply clinical trials, after

completing an in vitro analytical comparability study.

We expect to use this material in our phase 3 clinical trial in NSCLC.

Our selected CDMO is getting ready to validate the commercial manufacturing process by executing process validation batches to potentially enable filing of a BLA.

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.

10 unchanged sentences

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.

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, they do not induce a specific immune response and 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 patients respond to such treatment.

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

1 unchanged sentence

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

This effect may be enhanced by the pro-inflammatory effects of the viral capsid proteins.

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 like CAN-2409 and CAN-3110 is unique in combining both an anti-tumor cytotoxic component and an immune-stimulatory component.

This effect may be enhanced by the pro-inflammatory effects of viral capsid proteins.

With the 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 like aglatimagene and linoserpaturev 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.

3 unchanged sentences

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 Candel's Viral Immunotherapy:

The Mechanism of Action of Candel's Viral Immunotherapy Candidates:

• Direct anti-tumor cytotoxic activity.

Tumor-specific viral-mediated oncolysis is achieved by both precise delivery of the engineered virus to the tumor as well as the virus’ ability to selectively replicate within a cancer cell.

Tumor-specific viral-mediated oncolysis is achieved by both precise delivery of the engineered virus to the tumor as well as the virus’ ability to selectively target a cancer cell.

Various approaches have been applied in different programs to increase the specificity and potency of viral toxicity aimed at tumor cells, including genetic modifications and use of prodrugs.

11 unchanged sentences

Desirable Clinical Properties.

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.

We believe Candel's viral immunotherapy candidates have 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 patients, leading to an individualized anti-tumor immune response.

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

9 unchanged sentences

▪ 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.

Both of our clinical 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.

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.

1 unchanged sentence

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.

13 unchanged sentences

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:

Key attributes of our linoserpaturev platform include:

▪ Capacity for selective replication in the tumor.

There is a strong rationale for use of a replication-competent virus that is designed to provide potent oncolysis and viral amplification in tumors characterized by high volume or located in less anatomically accessible areas, such as recurrent HGG.

We have engineered CAN-3110 to selectively replicate only within tumors.

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 HGG, but not in healthy brain tissue, thereby enabling replication specifically in the context of HGG and in other tumors expressing Nestin.

We have engineered linoserpaturev to selectively replicate only within tumors.

This tumor specific replication ability of linoserpaturev 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 linoserpaturev 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.

Linoserpaturev 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 and systemic immune response.

6 unchanged sentences

▪ Amenable to engineered modifications.

Our knowledge of virus biology allows us to make modifications, such as those already present in CAN-3110 to target certain tumor types.

Our knowledge of virus biology allows us to make modifications, such as those already present in linoserpaturev to target certain tumor types.

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 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.

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

Aglatimagene is our most advanced product candidate.

It is a replication-defective adenovirus that has been genetically modified to express the gene encoding the HSV-thymidine kinase enzyme.

3 unchanged sentences

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.

Second, adenoviral capsid proteins themselves also directly trigger an immuno-inflammatory response through the establishment of a proinflammatory tumor microenvironment, resulting in the expression of proinflammatory cytokines, chemokines, and adhesion molecules that contribute to the optimal conditions to immunize against the tumor antigens that are released in the tumor microenvironment as a direct result of the formed toxic nucleotide analogues.

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

Second, adenoviral capsid proteins also directly trigger an immuno-inflammatory response through the establishment of a proinflammatory tumor microenvironment, resulting in the expression of proinflammatory cytokines, chemokines, and adhesion molecules that contribute to the optimal conditions to immunize against the tumor antigens that are released in the tumor microenvironment as a direct result of the formed toxic nucleotide analogues.

Together, this results in the recruitment, activation, and proliferation of anti-tumor effector cells, in particular CD8+ cytotoxic T cells.

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.

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, 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 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 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.

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, aglatimagene has been administered to over 1,000 patients with cancer.

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

We have seen encouraging clinical activity and a favorable tolerability profile with aglatimagene 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 and prostate cancer, where we believe our product candidates have potential to address the unmet needs of patients.

We have successfully completed a phase 3 clinical trial of aglatimagene 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 with the FDA reflects the agency's concurrence that our primary endpoint and other specific critical elements of our trial design are adequate to support a potential marketing application.

The clinical trial was randomized, double-blind and placebo-controlled.

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

We reported positive topline data on this trial in December 2024, demonstrating that aglatimagene in combination with SoC radiation+/- short course ADT was able to significantly improve DFS in early prostate cancer compared with SoC radiation+/- short course of ADT alone, with a statistically significant improvement of DFS of 30% (hazard ratio 0.7).

We have received Fast Track Designation by the FDA for the development of aglatimagene for the treatment of localized, primary prostate cancer in combination with radiotherapy to improve the local control rate, decrease recurrence and improve DFS.

In May 2025, after submission of the topline data to the FDA, we announced that the FDA granted Regenerative Medicine Advanced Therapy (RMAT) Designation to aglatimagene for the treatment of newly diagnosed, localized prostate cancer in patients with intermediate- to high-risk disease.

In June 2025, the results from the positive phase 3 clinical trial of aglatimagene in patients with intermediate- to high-risk, localized prostate cancer were presented in an oral session at the ASCO Annual Meeting.

In September 2025, we presented subgroup analysis of the phase 3 clinical trial during the ASTRO Annual Meeting.

The data demonstrated that the efficacy of aglatimagene on DFS and prostate-specific DFS was independent of the type of radiotherapy used (conventional EBRT vs.

moderate hypofractionated EBRT).

For moderate EBRT, the hazard ratio (HR) was 0.52 (95% CI:

0.30–0.93), and for conventional EBRT, the HR was 0.76 (95% CI:

We expect to announce supportive data on prostate cancer-specific outcomes (prostate cancer-specific DFS, time to salvage anti-cancer therapy, and time to metastasis) after extended follow-up in the second quarter of 2026.

In addition, we expect to announce immunological biomarker data in localized prostate cancer in the third quarter of 2026.

We are in ongoing dialogue with the FDA in preparation for the Company’s anticipated submission of a Biologics License Application for aglatimagene in prostate cancer in the fourth quarter of 2026.

We expect that if we obtain FDA approval on the basis of the results presented in December 2024, aglatimagene could be the first new FDA approved pharmacologic treatment available in over 20 years as a potential first-line therapeutic for the over 150,000 patients who are newly diagnosed with localized prostate cancer each year in the United States.

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

In 2020, we initiated a phase 2a clinical trial evaluating aglatimagene 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.

2 unchanged sentences

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

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

Patients continue treatment with their initial ICI and two administrations of aglatimagene 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.

12 unchanged sentences

increased infiltration of CD8+ T cells in the tumor microenvironment;

systemic expansion of effector T cells and increase in soluble granzyme B levels in the peripheral blood;

systemic expansion of effector T cells and increase in soluble granzyme B levels in the peripheral

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, 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.

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.

We received FDA Fast Track Designation for aglatimagene 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.

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

mOS of 20.6 months was observed following two administrations of aglatimagene 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.

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 aglatimagene.

We confirmed that treatment with aglatimagene 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.

71.4% of patients with metastatic disease and at least one uninjected tumor (n=35) experienced a beneficial effect from aglatimagene 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.

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 clinical trial results.

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

In March 2025, we announced overall survival data from this phase 2a clinical trial of aglatimagene in NSCLC.

In patients with an inadequate response to ICI treatment who received 2 aglatimagene plus valacyclovir courses (Cohort 1+2, per protocol population, n=46), mOS was 24.5 months.

In patients with progressive disease, despite ICI treatment (Cohort 2, per protocol population, n=41), mOS was 21.5 months, which is markedly longer than the 9.8–11.8 months of survival reported in published literature in a similar patient population receiving standard of care of docetaxel second-line chemotherapy (Paz-Ares LG et al, J Clin Oncol 2024;42:2860-2872 ;

Ahn MJ et al, J Clin Onc 2024;43:260-272).

37% of patients with progressive disease at enrollment were still alive > 24 months after aglatimagene treatment at the time of the March 3, 2025 data cut, suggesting a long tail of survival.

14/15 patients with overall survival > 24 months and 9/9 patients with overall survival > 30 months had non-squamous NSCLC.

In patients with non-squamous NSCLC and progressive disease despite ICI (Cohort 2, per protocol population, n=33), observed mOS was 25.4 months after aglatimagene treatment.

Aglatimagene continued to exhibit a generally favorable safety and tolerability profile during the extended follow-up period.

Based on these positive findings, we plan to initiate a pivotal phase 3 clinical trial of aglatimagene in patients with progressive, metastatic, non-squamous NSCLC despite ICI treatment in the second quarter of 2026.

We expect to announce updated data on OS including a long-term survival and novel biomarker data analysis based on the phase 2a trial in the first quarter of 2026.

In a previous phase 1b trial, patients with pancreatic cancer treated with aglatimagene 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 clinical trial results.

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.

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

Next, we initiated a randomized controlled phase 2a clinical trial evaluating aglatimagene in patients with 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.

The initial data showed prolonged and sustained survival in patients treated with aglatimagene 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.

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.

We received FDA Fast Track Designation for aglatimagene plus prodrug (valacyclovir) for the treatment of patients with PDAC to improve overall survival in December 2023.

In April 2024, we announced that the FDA has granted Orphan Drug Designation for aglatimagene for the treatment of pancreatic cancer.

Orphan Designation was also granted by the European Medicines Agency (EMA) in July 2025.

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

Estimated mOS was 28.8 months in the aglatimagene group versus only 12.5 months in the control group.

Importantly, 4 out of 7 patients who received aglatimagene 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

Biomarker data analysis demonstrated

consistent and robust activation of immune response after dosing with aglatimagene.

Addition of aglatimagene 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;

Prolonged and sustained survival was observed after experimental treatment with aglatimagene 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 aglatimagene group versus only 12.5 months in the control group.

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

Importantly, 3 out of 7 patients who received aglatimagene 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.

2 unchanged sentences

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.

In October 2025, we decided to pause on further clinical development of aglatimagene in PDAC, in the context of portfolio prioritization, unless externally funded through a grant or other non-dilutive external funding.

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 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.

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.

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

Linoserpaturev was formerly known as rQNestin34.5v.2.

An investigator-sponsored phase 1b clinical trial is ongoing with linoserpaturev 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.

1 unchanged sentence

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.

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

The FDA has granted Fast Track Designation to linoserpaturev 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 linoserpaturev, recognizing its potential in treating HGG.

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

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.

The principal investigator of the study reported ongoing improved survival compared to historical controls in patients treated with multiple injections of linoserpaturev, 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 linoserpaturev.

We are conducting an extension of the clinical trial (arm C), in which patients with recurrent glioblastoma receive a repeat dosing regimen of linoserpaturev (up to six injections over four months).

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.

In October 2024, at the 16th Annual International Oncolytic Virotherapy Conference (IOVC), we presented initial clinical and biomarker data from Arm C of the linoserpaturev trial.

The principal investigator reported improved survival compared to historical controls in patients who received multiple injections of linoserpaturev.

Post-treatment biopsies showed a near absence of tumor cells with dense lymphocyte infiltration, particularly in patients with post-treatment MRI enhancement, consistent with radiologic pseudo-progression.

These findings were reported in a Science Translational Medicine paper published in October 2025, which described 97 serial tumor biopsies from two patients who received linoserpaturev.

Follow-up samples revealed extensive immune-mediated remodeling of the tumor microenvironment, characterized by dense lymphocyte infiltration and extensive tumor necrosis (death).

One patient achieved a complete pathological response, with clearance of tumor cells from post-treatment biopsies.

These results underscore the limitations of conventional imaging in evaluating the response to viral immunotherapy and highlight the importance of overall survival data, supported by histology.

In October 2025, we also announced updated OS data for Arm A and Arm B as of August 15, 2025.

The updated mOS was 11.8 months for arm A (n=41) (CI:

8.3–14.9) and 12.0 months for arm B (n=9) (CI:

10.0–NA) respectively, after a single injection of linoserpaturev.

One patient from arm A and one patient from arm B were still alive after prolonged follow-up (59.2 and 42.4 months, respectively, after linoserpaturev administration).

At the time of data cutoff, 9 patients in arm C had received multiple administrations of linoserpaturev.

At the 1×10⁸ plaque-forming unit (PFU) dose, 3

patients received 4 injections, 1 patient received 5 injections, and 2 patients received 6 injections.

At the 1×10⁷ PFU dose, 1 patient received 4 injections, and 2 patients received 5 injections.

Median follow-up was 8.9 months.

Four out of 9 patients were alive at the time of data cutoff (range 3.1-28.2 months after initiation of linoserpaturev treatment).

Five patients had died, of which 3 died more than one year after initiation of linoserpaturev treatment (range 5.5-21.8 months).

We have now completed recruitment for Arm C and expect to present mature mOS data and an update on long-term survivors in the fourth quarter of 2026.

Based on the molecular mechanism of linoserpaturev, 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 linoserpaturev in preclinical models of melanoma, further supporting the rationale to expand the evaluation of linoserpaturev into tumors beyond recurrent HGG.

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

4 unchanged sentences

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.

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

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

4 unchanged sentences

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

The primary goal of curative treatment for localized prostate cancer is complete tumor eradication, as outlined by National Comprehensive Cancer Network (NCCN) guidelines.

However, up to 30% of intermediate- to high-risk patients experience recurrence despite radical therapy, and salvage treatments often carry significant side effects and limited efficacy.

Studies also show that patients prioritize the perception of being cancer-free and are often willing to risk long-term complications to achieve this.

Fear of recurrence remains prevalent, especially after biochemical failure (Hoffman RM et al.

Cancer 2003;97:1653-62;

Jayadevappa R et al.

J Clin Oncol 2019;37:964-73;

Nilsson R et al.

Eur Urol Open Sci 2021;25:44-51).

Approximately 300,000 men in the United States are diagnosed with prostate cancer annually, with more than 30,000 deaths each year.

Roughly 200,000 men in the United States are diagnosed with early, localized prostate cancer each year, of which roughly 150,000 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.

For these intermediate- and high-risk patients, the SoC is radical prostatectomy or radiotherapy, the latter 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.

2 unchanged sentences

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.

We believe aglatimagene 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 as well as local and

metastatic disease progression, without significant toxicities and with a product that can be administered at outpatient facilities.

Non-Small Cell Lung Cancer

7 unchanged sentences

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 months after treatment.

We believe aglatimagene 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 months after treatment.

Pancreatic Cancer

8 unchanged sentences

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.

We believe aglatimagene 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 aglatimagene combined with SoC compared to SoC alone.

High-Grade Glioma

7 unchanged sentences

New agents to treat patients with recurrent HGG are urgently needed.

We believe CAN-3110 provides a significant opportunity for therapeutic use in recurrent HGG based on the results published in Nature in October 2023, showing nearly doubling of the expected mOS after just a single injection of CAN-3110.

We believe linoserpaturev provides a significant opportunity for therapeutic use in recurrent HGG based on the results published in Nature in October 2023, showing nearly doubling of the expected mOS after just a single injection of linoserpaturev.

Our Product Candidates

Initial Product Candidate - CAN-2409

We believe the adenovirus-based CAN-2409 has advantageous properties that differentiate from other viral immunotherapies.

Namely, CAN-2409:

Initial Product Candidate - Aglatimagene

We believe our adenovirus-based product candidate aglatimagene has advantageous properties that differentiate from other viral immunotherapies.

Namely, aglatimagene:

▪ 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.

▪ Has been dosed in more than a thousand patients and has shown a generally favorable tolerability and safety profile to date.

▪ 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.

▪ Can be stored at 4°C for up to 6 months, facilitating the use of aglatimagene in out-patient clinics.

This aspect is particularly favorable in indications such as prostate cancer, where patients are often monitored in individual private practices.

CAN-2409 (international non-proprietary name:

Aglatimagene besadenovec is an adenovirus-based replication-defective engineered gene construct encoding the thymidine kinase gene derived from the herpes simplex virus.

9 unchanged sentences

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.

This local effect provides a strong mechanistic rationale for the combination of aglatimagene 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.

1 unchanged sentence

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.

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.

Aglatimagene 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.

For example, an abscopal effect has been shown for 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 aglatimagene 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 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.

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

Use of aglatimagene 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 aglatimagene arm, and to 6.6 when aglatimagene was combined with radiotherapy, showing both an abscopal (systemic) effect and synergy between aglatimagene 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 aglatimagene plus prodrug in patients with NSCLC.

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

The activity of CAN-2409 treatment has been shown to be dependent on CD8+ T cell involvement in studies in mouse models that evaluated permutations of CAN-2409 treatment and T cell depletion.

Furthermore, T cells from mice that were successfully treated with CAN-2409 and prodrug were shown to be sufficient to inhibit tumor growth when mixed with AKR tumor model cells and implanted subcutaneously in mouse flanks.

The activity of aglatimagene treatment has been shown to be dependent on CD8+ T cell involvement in studies in mouse models that evaluated permutations of aglatimagene treatment and T cell depletion.

Furthermore, T cells from mice that were successfully treated with aglatimagene and prodrug were shown to be sufficient to inhibit tumor growth when mixed with AKR tumor model cells and implanted subcutaneously in mouse flanks.

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.

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.

Together, data in experimental mouse models of cancer support a T cell dependent mechanism of action for aglatimagene 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

CAN-3110 is a modified HSV with specific properties that can be leveraged in diverse clinical indications.

Namely, CAN-3110:

Second Product Candidate - Linoserpaturev

Linoserpaturev is a modified HSV with specific properties that can be leveraged in diverse clinical indications.

Namely, linoserpaturev:

▪ Is engineered to provide oncolysis through replication specifically in Nestin expressing cancer cells.

▪ Has demonstrated statistically significant survival benefit in preclinical models of brain cancer.

▪ 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 very difficult to treat brain cancer population, critically defined by a highly immunosuppressive environment.

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

▪ Has shown an activity 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.

▪ Is derived from our HSV-based platform that also provides the potential to support expansion of our pipeline with novel agents.

CAN-3110 is an engineered HSV where the expression of ICP34.5, the gene responsible for viral replication, has been placed under the control of a tumor-specific Nestin promoter.

Linoserpaturev is an engineered HSV where the expression of ICP34.5, the gene responsible for viral replication, has been placed under the control of a tumor-specific Nestin promoter.

Nestin is a cytoskeletal protein that is overexpressed in glioma cells, but it is absent in the healthy adult brain.

In CAN-3110, ICP34.5 expression is controlled by the Nestin promotor enabling viral replication selectively in tumor cells.

In linoserpaturev, ICP34.5 expression is controlled by the Nestin promotor, enabling viral replication selectively in tumor cells.

This replication-competent HSV construct provides tumor-specific cytolytic activity, while sparing healthy cells that do not express Nestin.

This modification of the viral genome of CAN-3110 enables us to maintain the function of ICP34.5, an HSV protein that allows virus replication even in the presence of a suppressive interferon response, under strict control and only in tumor cells.

This modification of the viral genome of linoserpaturev enables us to maintain the function of ICP34.5, an HSV protein that allows virus replication even in the presence of a suppressive interferon response, under strict control and only in tumor cells.

ICP34.5 is deleted in other HSV oncolytic viruses that may be less tumor selective with an intent of achieving a favorable safety profile, which may result in viruses characterized by poor replication ability and a limited ability to generate an effective anti-tumor immune response.

Our Clinical Trials

CAN-2409 for Prostate Cancer

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.

Aglatimagene for Prostate Cancer

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

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

We have administered aglatimagene 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 1b and phase 2a clinical trials.

We have observed what we believe to be a clinical response with aglatimagene 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.

In newly diagnosed patients with localized prostate cancer, analysis of biopsies following monotherapy CAN-2409 treatment revealed a change in glandular architecture, necrosis and increased immune cell infiltration as compared to baseline biopsy.

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 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.

In newly diagnosed patients with localized prostate cancer, analysis of biopsies following monotherapy aglatimagene treatment revealed a change in glandular architecture, necrosis and increased immune cell infiltration as compared to baseline biopsy.

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 aglatimagene administration.

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 aglatimagene 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 aglatimagene, as measured by the best PSA decrease in serial assessments within the first 3 months after treatment.

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 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 aglatimagene administration in this treatment-resistant patient population.

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

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.

In December 2024, we completed a phase 2b randomized, double blind, placebo-controlled clinical trial in the United States evaluating the effects of aglatimagene 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.

127 to the aglatimagene arm who received 2 doses of aglatimagene 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.

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;

Aglatimagene 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.

Also, it is difficult to demonstrate therapeutic efficacy in patients with low-risk disease.

The Company has decided to deprioritize the development of aglatimagene 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 where indicated.

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

We believe that the favorable tolerability and safety data generated for aglatimagene in our clinical trials is encouraging for our current and future development plans, in combination with other agents where indicated.

In clinical trials to date, aglatimagene 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 phase 2a clinical trial was 5.7 years.

Previously, we observed that intermediate-risk patients who received aglatimagene 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%, aglatimagene resulted in a 5% recurrence rate in patients with intermediate-risk prostate cancer.

The median follow-up of patients who received aglatimagene 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.

Furthermore, a pathological complete response (pCR) was observed in 93% of the biopsies available at 2yrs (37%-73% in control populations).

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

1 unchanged sentence

The DFS definition requires an objective detection of tumor progression.

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

This largely overlaps with FFF as biopsy and/or imaging studies are often triggered by detection of increased PSA levels (i.e., biochemical failure).

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

We are developing CAN-2409 as a potential therapeutic option that avoids the long-term severe side effects of hormone therapy or surgical interventions.

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 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.

We are developing aglatimagene as a potential therapeutic option that could prevent or delay symptoms due to local and metastatic disease progression as well as the long-term severe side effects of salvage anti-cancer therapies, such as hormone therapy or surgical interventions.

Based on the data from our clinical trials to date, we believe that aglatimagene 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 recently reported successful topline data in a potentially registrational phase 3 trial for aglatimagene, 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 aglatimagene or PBO), randomized 2:1 to study drug and placebo, respectively.

Patients received three investigational treatment courses of aglatimagene, each consisting of four concurrent injections of transrectal or transperineal ultrasound guided administration of aglatimagene 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.

1 unchanged sentence

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.

A fixed dose of valacyclovir was given for 14 days after each aglatimagene 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.

7 unchanged sentences

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.

The study met its primary endpoint, demonstrating a statistically significant improvement in disease-free

survival compared to the control arm.

Treatment with aglatimagene improved DFS by 30% (p=0.0155, HR 0.7, 95% CI 0.52 to 0.94).

Median DFS was not reached for the aglatimagene 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.

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

PBO (p=0.0046;

3 unchanged sentences

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)

To assess the potential for CAN-2409 to trigger local and systemic immune activation and produce a “hot” tumor phenotype, we designed and completed a clinical trial in patients with surgically resectable lung cancer.

In this proof of mechanism phase 1 clinical trial, dose escalation of intratumoral neoadjuvant CAN-2409 was followed by tumor resection three weeks later.

The specific goal was to obtain biological data to better understand the impact of CAN-2409 on the tumor microenvironment, with a specific focus on intratumoral CD8+ tumor infiltrating lymphocyte cell activation and function while also assessing the effects on the systemic immune response.

The effects of CAN-2409 were evaluated by comparing post-injection specimens to an internal control consisting of each patient’s own pre-treatment needle biopsy and blood samples, and an external cohort of matched patients who underwent standard surgical resection without CAN-2409.

The results showed evidence of significant intratumoral and systemic immune activation after experimental CAN-2409 monotherapy treatment.

Analysis of peripheral blood mononuclear cells, both before and after CAN-2409 administration, demonstrated a significant increase in expression of proliferation and activation markers including HLA-DR, CD38 and Ki67 three weeks after CAN-2409 initiation.

aglatimagene 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).

Aglatimagene was generally well tolerated;

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

In September 2025, we presented subgroup analysis of the phase 3 clinical trial during the 2025 ASTRO Annual Meeting.

The data demonstrated that the efficacy of aglatimagene on DFS and prostate-specific DFS was independent of the type of radiotherapy used (conventional EBRT vs.

moderate hypofractionated EBRT).

For moderate EBRT, the hazard ratio (HR) was 0.52 (95% CI:

0.30–0.93), and for conventional EBRT, the HR was 0.76 (95% CI:

Aglatimagene for Non-Small Cell Lung Cancer (NSCLC)

To assess the potential for aglatimagene to trigger local and systemic immune activation and produce a “hot” tumor phenotype, we designed and completed a clinical trial in patients with surgically resectable lung cancer.

In this proof of mechanism phase 1b clinical trial, dose escalation of intratumoral neoadjuvant aglatimagene was followed by tumor resection three weeks later.

The specific goal was to obtain biological data to better understand the impact of aglatimagene on the tumor microenvironment, with a specific focus on intratumoral CD8+ tumor infiltrating lymphocyte cell activation and function while also assessing the effects on the systemic immune response.

The effects of aglatimagene were evaluated by comparing post-injection specimens to an internal control consisting of each patient’s own pre-treatment needle biopsy and blood samples, and an external cohort of matched patients who underwent standard surgical resection without aglatimagene.

The results showed evidence of significant intratumoral and systemic immune activation after experimental aglatimagene monotherapy treatment.

Analysis of peripheral blood mononuclear cells, both before and after aglatimagene administration, demonstrated a significant increase in expression of proliferation and activation markers including HLA-DR, CD38 and Ki67 three weeks after aglatimagene initiation.

Other relevant findings in this clinical trial included an increase in markers of T cell activation such as PD-1 and CTLA-4, which are targets of ICI that have been approved for use in NSCLC.

In this NSCLC phase 1 clinical trial, two patients experienced grade 3 dehydration with renal insufficiency, two patients presented grade 3 urinary retention and six patients were observed to have a grade 4 low lymphocyte count.

Of significant interest, one patient, a 70 year-old male with a 14.8 cm stage IIIA sarcomatoid carcinoma, exhibited a nearly 50% decrease in tumor volume at 3 weeks after CAN-2409 monotherapy treatment.

Collectively, these results lead us to believe that CAN-2409 could provide an opportunity to improve ICI response rates in patients with NSCLC by eliciting additional immune activation in lung cancer patients.

CAN-2409 and Checkpoint Combination Phase 2 Clinical Trial for NSCLC in Patients with Inadequate Response to ICI

In 2020, we initiated a phase 2 clinical trial of CAN-2409 in NSCLC patients with inadequate response to ICI that has enrolled patients receiving SoC ICI (plus chemotherapy if indicated) in combination with two courses of CAN-2409 plus continued ICI.

In this NSCLC phase 1b clinical trial, two patients experienced grade 3 dehydration with renal insufficiency, two patients presented grade 3 urinary retention and six patients were observed to have a grade 4 low lymphocyte count.

Of significant interest, one patient, a 70 year-old male with a 14.8 cm stage IIIA sarcomatoid carcinoma, exhibited a nearly 50% decrease in tumor volume at 3 weeks after aglatimagene monotherapy treatment.

Collectively, these results led us to believe that aglatimagene could provide an opportunity to improve clinical outcomes in patients with NSCLC and an inadequate response to ICI by eliciting additional and specific immune activation.

Aglatimagene and Checkpoint Combination Phase 2 Clinical Trial for NSCLC in Patients with Inadequate Response to ICI

In 2020, we initiated a phase 2 clinical trial of aglatimagene in NSCLC patients with inadequate response to ICI that has enrolled patients receiving SoC ICI (plus chemotherapy if indicated) in combination with two courses of aglatimagene plus continued ICI.

This open label clinical trial, as amended, targeted enrollment of approximately 80 patients with stage III/IV NSCLC in two separate cohorts.

1 unchanged sentence

Cohort 1 addresses patients with stable disease and Cohort 2 enrolled patients with progressive disease after at least 18 weeks of ICI treatment.

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

Patients continued treatment with their initial ICI and aglatimagene was added to their regimen.

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.

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

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

7 unchanged sentences

an overall response rate of 13% (4/30) across cohorts 1 and 2;

durable disease stabilization translating into encouraging preliminary evidence of progression-free survival;

durable disease stabilization translating

into encouraging preliminary evidence of progression-free survival;

consistent induction of local and systemic cytotoxic T cell response;

3 unchanged sentences

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.

mOS of 20.6 months was observed following two administrations of aglatimagene 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).

1 unchanged sentence

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.

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 aglatimagene.

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.

71.4% of patients with metastatic disease and at least one uninjected tumor (n=35) experienced a beneficial effect from aglatimagene 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

In a previous phase 1b clinical 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.

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

In March 2025, we announced overall survival data from this phase 2a clinical trial of aglatimagene in NSCLC.

In patients with an inadequate response to immune checkpoint inhibitor (ICI) treatment who received 2 aglatimagene plus valacyclovir courses (Cohort 1+2, per protocol population, n=46), mOS was 24.5 months.

Ahn MJ et al, J Clin Onc 2024;43:260-272).

37% of patients with progressive disease at enrollment were still alive > 24 months after aglatimagene treatment at the time of the March 3, 2025 data cut, suggesting a long tail of survival.

14/15 patients with overall survival > 24 months and 9/9 patients with overall survival > 30 months had non-squamous NSCLC.

In patients with non-squamous NSCLC and progressive disease despite ICI (Cohort 2, per protocol population, n=33), observed mOS was 25.4 months after aglatimagene treatment.

Aglatimagene continued to exhibit a generally favorable safety and tolerability profile during the extended follow-up period.

We expect to announce updated data on OS and a long-term survival analysis in the first quarter of 2026.

Aglatimagene for Pancreatic Cancer

In a previous phase 1b clinical trial, patients with pancreatic cancer treated with aglatimagene 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.

Furthermore, in the subset 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.

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.

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

Next, we conducted a randomized phase 2a clinical trial of aglatimagene 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.

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.

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

Estimated survival was 71.4% when 2-3 aglatimagene 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 received FDA Fast Track Designation for aglatimagene plus prodrug (valacyclovir) for the treatment of patients with PDAC to improve overall survival in December 2023.

In April 2024, we announced that the FDA granted Orphan Drug Designation for aglatimagene for the treatment of pancreatic cancer.

Orphan Designation was also granted by the EMA in July 2025.

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

Estimated mOS was 28.8 months in the aglatimagene group versus 12.5 months in the control group.

Importantly, 4 out of 7 patients who received aglatimagene 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.

Biomarker data analysis demonstrated consistent and robust activation of immune response after dosing with aglatimagene.

Addition of aglatimagene 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;

Prolonged and sustained survival was observed after experimental treatment with aglatimagene 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 aglatimagene group versus only 12.5 months in the control group.

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

Importantly, 3 out of 7 patients who received aglatimagene 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.

2 unchanged sentences

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

In addition to patients with prostate, lung, pancreatic, and brain cancer, CAN-2409 has been dosed in small early-stage exploratory clinical trials in patients with ovarian cancer, malignant pleural effusion, pediatric brain cancer and retinoblastoma, supporting the tolerability and safety profile described above.

CAN-3110 for Recurrent High-grade Glioma

Our first HSV-based product candidate, CAN-3110, is in an ongoing investigator-sponsored phase 1b clinical trial in recurrent HGG.

Taken together, the data supports the potential of aglatimagene across various solid tumors.

Opportunities for Aglatimagene in Other Cancer Indications

In addition to patients with prostate, lung, pancreatic, and brain cancer, aglatimagene has been dosed in small early-stage exploratory clinical trials in patients with ovarian cancer, malignant pleural effusion, pediatric brain cancer and retinoblastoma, supporting the tolerability and safety profile described above.

Linoserpaturev for Recurrent High-grade Glioma

Our first HSV-based product candidate, linoserpaturev, is in an ongoing investigator-sponsored phase 1b clinical trial in recurrent HGG.

This is an open-label, dose-escalation clinical trial in patients who have failed SoC.

The primary objective of this clinical trial is to analyze the safety of CAN-3110 use in patients with recurrent HGG.

The primary objective of this clinical trial is to analyze the safety of linoserpaturev use in patients with recurrent HGG.

No dose-limiting toxicities were observed in doses ranging from 1x10 6 to 1x10 10 PFU in half-log increments.

More than 55 patients have been treated.

Immunohistology studies showed persistent presence of HSV antigen and infiltration by CD8+ cytotoxic tumor infiltrating lymphocytes post treatment, providing support for the expected mechanism of action of CAN-3110.

We are particularly encouraged by the clinical course of a few patients who received a single injection with CAN-3110 as monotherapy upon recurrence of glioblastoma.

One patient, originally diagnosed with multicentric glioblastoma and initially treated with SoC surgical resection followed by temozolomide and radiotherapy has been treated with CAN-3110 monotherapy, upon recurrency with development of two lesions visualized on MRI.

Sixty-three patients have been treated.

Immunohistologic studies showed persistent presence of HSV antigen and infiltration by CD8+ cytotoxic tumor infiltrating lymphocytes post treatment, providing support for the expected mechanism of action of linoserpaturev.

We are particularly encouraged by the clinical course of a few patients who received a single injection with linoserpaturev as monotherapy upon recurrency of glioblastoma.

One patient, originally diagnosed with multicentric glioblastoma and initially treated with SoC surgical resection followed by temozolomide and radiotherapy received linoserpaturev monotherapy, upon recurrency with development of two lesions visualized on MRI.

One lesion, in the frontal region, had developed at the site of the initially resected mass.

The second, larger mass was a new lesion.

The patient received CAN-3110 via stereotactic administration into the injected lesion.

The patient received linoserpaturev via stereotactic administration into the injected lesion.

At day 56 post-injection, there was a visible decrease in the volume of both masses.

2 unchanged sentences

A second patient initially diagnosed with methylated grade IV HGG located in the temporal lobe underwent 2 consecutive resections and treatment with chemoradiation for rapid progressive disease.

The patient was injected with CAN-3110 (10E8 pfus), at the site of the original lesion.

The patient was injected with linoserpaturev (10E8 pfus), at the site of the original lesion.

An MRI scan performed at day 91 showed increased enhancement at the site of injection.

The patient underwent an additional resection, but, importantly, histological report showed mainly inflammatory tissue with high density of tumor infiltrating lymphocytes.

The patient did not have detectable disease, in absence of any additional treatment for more than 2 years and passed away as passenger of a motor vehicle accident on day 717 post CAN-3110 treatment.

Another patient, originally diagnosed with grade IV astrocytoma, was treated with CAN-3110 for a recurrence following first-line therapy with subtotal resection, chemoradiation and adjuvant temozolomide.

The patient underwent an additional resection, but, importantly, histologic report showed mainly inflammatory tissue with high density of tumor infiltrating lymphocytes.

The patient did not have detectable disease, in absence of any additional treatment for more than 2 years and passed away as passenger of a car accident on day 717 post linoserpaturev treatment.

Another patient, originally diagnosed with grade IV astrocytoma, was treated with linoserpaturev for a recurrence following first-line therapy with subtotal resection, chemoradiation and adjuvant temozolomide.

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

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.

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 linoserpaturev injection.

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

The patient remains clinically stable as of February 2024 and has not required additional therapies in the two years post CAN-3110 treatment.

The patient remains clinically stable as of February 2026 and has not required additional therapies in the two years post linoserpaturev treatment.

We find these case reports to be encouraging because of the unusually favorable disease course experienced by these patients with recurrent HGG who had previously failed SoC treatment, in absence of concurrent therapies.

2 unchanged sentences

mOS 12.0 months).

Prolonged survival after CAN-3110 treatment was associated with HSV-1 seropositivity as well as with changes in T cell fractions and TCRβ diversity.

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.

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.

Prolonged survival after linoserpaturev treatment was associated with HSV-1 seropositivity as well as with changes in T cell fractions and TCRβ diversity.

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

In May 2024, we announced that the FDA granted Orphan Drug Designation for linoserpaturev 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 linoserpaturev, 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 linoserpaturev.

In October 2025, we also announced updated OS data for Arm A and Arm B as of August 15, 2025.

The updated mOS was 11.8 months for arm A (n=41) (CI:

8.3–14.9) and 12.0 months for arm B (n=9) (CI:

10.0–NA), respectively, after a single injection of linoserpaturev.

One patient from arm A and one patient from arm B were still alive after prolonged follow-up (59.2 and 42.4 months, respectively, after linoserpaturev administration).

At the time of data cutoff, 9 patients in arm C had received multiple administrations of linoserpaturev.

At the 1×10⁸ plaque-forming unit (PFU) dose, 3 patients received 4 injections, 1 patient received 5 injections, and 2 patients received 6 injections.

At the 1×10⁷ PFU dose, 1 patient received 4 injections, and 2 patients received 5 injections.

Median follow-up was 8.9 months.

Four out of 9 patients were alive at the time of data cutoff (range 3.1-28.2 months after initiation of linoserpaturev treatment).

Five patients had died, of which 3 died more than one year after initiation of linoserpaturev treatment (range 5.5-21.8 months).

We have recently completed recruitment of Arm C and we expect to present mature mOS data and an update on long-term survivors in the fourth quarter of 2026.

The FDA previously granted Fast Track Designation and Orphan Drug Designation to linoserpaturev in recurrent HGG based on an earlier data cut.

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.

We are a party to various license, royalty 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.

1 unchanged sentence

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

On February 19, 2026, we entered into a purchase and sale agreement (the RTW Purchase Agreement) with funds managed by RTW Investments, LP (RTW).

Under the terms of the RTW Purchase Agreement, RTW has agreed to pay us $100 million (the RTW Purchase Price) upon the marketing approval of aglatimagene for the treatment of intermediate-risk and high-risk localized prostate cancer by the FDA in exchange for a tiered royalty on future net sales of aglatimagene in the United States.

RTW will be entitled to a 4.67% royalty on the portion of annual net sales in the United States that is less than or equal to $1 billion, and a 1.33% royalty on the portion of annual net sales in the United States, exceeding $1 billion.

The 4.67% tier will increase to 6.67% if annual net sales do not achieve certain specified levels (the Ratchet), subject to a cure opportunity by us (provided that such Ratchet and cure opportunity may each subsequently occur more than once).

The royalty payments become payable following the first commercial sale of aglatimagene in the United States and end upon RTW’s receipt of $250 million in royalty payments (the RTW Royalty Cap).

If we undergo a change of control with, or sell aglatimagene and all of the aglatimagene rights to, a third party, the RTW Purchase Agreement provides the Company and RTW with an option for us to pay certain specified amounts to terminate the RTW Purchase Agreement, depending upon the timing for such transaction, up to the RTW Royalty Cap (the Buy-Out Option).

If either party exercises the Buy-Out Option, the RTW Purchase Agreement will automatically terminate upon payment of the specified amount.

The transaction is subject to certain closing conditions, including that FDA approval must occur by a specified date, conditions related to our indebtedness and other customary closing conditions.

The RTW Purchase Agreement also contains customary representations, warranties and indemnities on the part of us and RTW and customary covenants on the part of us, including around our indebtedness as well as licensing and other activities related to aglatimagene and its rights.

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.

24 unchanged sentences

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 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).

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 linoserpaturev, 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.

22 unchanged sentences

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), 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).

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.

6 unchanged sentences

Ventagen retains an irrevocable, perpetual, paid up, royalty-free license, with rights of sublicense to use, have used, lease, import and export, offer to sell, sell, have sold, product, distribute and market Licensed Products in each country in the Territory after the expiration of the Royalty Term in such country.

Certain of our current stockholders own 49.5% of the voting stock of Ventagen, but we do not hold any management position or run the day-to-day operations of Ventagen.

See “Certain Relationships and Related Person Transactions.”

The development and commercialization of new product candidates is highly competitive.

We face competition from major pharmaceutical, specialty pharmaceutical and biotechnology companies among others with respect to CAN-2409 and CAN-3110 and will face similar competition with respect to any product candidates that we may seek to develop or commercialize in the future.

We face competition from major pharmaceutical, specialty pharmaceutical and biotechnology companies among others with respect to aglatimagene and linoserpaturev and will face similar competition with respect to any product candidates that we may seek to develop or commercialize in the future.

We compete in pharmaceutical, biotechnology and other related markets that develop immuno-oncology therapies for the treatment of cancer.

There are other companies working to develop viral immunotherapies for the treatment of cancer, including divisions of large pharmaceutical and biotechnology companies of various sizes.

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

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

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, 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.

8 unchanged sentences

Our competitors also may obtain FDA or foreign regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

The key competitive factors affecting the success of all our product candidates, if approved, are likely to be their efficacy, safety, convenience and price, if required, the level of biosimilar or generic competition and the availability of reimbursement from government and other third-party payors.

The key competitive factors affecting the success of all our product candidates, if approved, are likely to be their efficacy, safety, convenience and

price, if required, the level of biosimilar or generic competition and the availability of reimbursement from government and other third-party payors.

Commercialization

5 unchanged sentences

We have established an operations leadership team with extensive experience in manufacturing biologics based on viruses, including viral immunotherapy products and gene therapy products, and in the construction, validation, approval and operation of facilities designed to manufacture biologics.

We have secured a third-party contract manufacturing organization for clinical and commercial-scale manufacturing of our CAN-2409 and CAN-3110 product candidates.

We have secured a third-party contract manufacturing organization for clinical and commercial-scale manufacturing of our aglatimagene and linoserpaturev product candidates.

We rely and expect to continue to rely on such contract manufacturing organizations to produce our biologic candidates, and if approved, biological products.

Intellectual Property

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 U.S.

With regard to patent exclusivities, we have or are pursuing patent protection for our clinical aglatimagene and linoserpaturev product candidates and our enLIGHTEN Discovery Platform.

With regard to our aglatimagene 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.

patent application that relate to methods of decreasing tumor burden and micrometastases using aglatimagene 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 one pending International patent application filed under the Patent Cooperation Treaty (International application) that relates to methods of treating non-squamous non-small cell lung cancer and non-resectable, non-small cell lung cancer using aglatimagene, one International application that relates to methods of treating non-resectable, non-small cell lung cancer by administering aglatimagene to a disease positive lymph node, and one pending International application that relates to methods of treating prostate cancer using aglatimagene.

Patents claiming priority to the International applications relating to lung cancer, if issued, are expected to expire in 2044.

Patents claiming priority to the International application relating to prostate cancer, if issued, are expected to expire in 2045.

We also own a pending U.S.

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

provisional patent application that relates to formulations and methods of manufacture of aglatimagene.

Patents claiming priority to this provisional application, if issued, are expected to expire in 2046.

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.

With regard to our linoserpaturev 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 Europe that relate to the composition of matter of the vector used in our linoserpaturev product candidate.

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

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.

In addition, we own a pending International patent application that relates to methods of treating melanoma with linoserpaturev.

Patents claiming priority to this International 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.

7 unchanged sentences

The FD&C Act and corresponding regulations govern, among other things, the research, development, clinical trial, testing, manufacturing, quality control, approval, safety, efficacy, labeling, packaging, storage, record keeping, distribution, reporting, marketing, promotion, export and import, advertising, post-approval monitoring, and post-approval reporting involving biological products.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources and we may not be able to obtain the required regulatory approvals.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the

expenditure of substantial time and financial resources and we may not be able to obtain the required regulatory approvals.

Further, even if we obtain the required regulatory approvals for our products, pharmaceutical companies are subject to myriad federal, state, and foreign healthcare laws, rules, and regulations governing all aspects of our operations, including, but not limited to, our relationships with healthcare professionals, healthcare institutions, distributors of our products, and sales and marketing personnel;

11 unchanged sentences

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

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 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;

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

9 unchanged sentences

Such authorization must be secured prior to interstate shipment and administration.

In support of a request for an IND, the clinical trial sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol to the FDA as part of the IND.

In support of a request for an IND, the clinical trial sponsor must submit the results of the preclinical tests, together with manufacturing

information, analytical data, any available clinical data or literature and a proposed clinical protocol to the FDA as part of the IND.

An IND must become effective before human clinical trials may begin.

27 unchanged sentences

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 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.

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.

13 unchanged sentences

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.

28 unchanged sentences

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.

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

16 unchanged sentences

Expedited Development and Review Programs

The FDA has various programs, including fast track designation, breakthrough therapy designation, accelerated approval and priority review, that are intended to expedite or simplify the process for the development and FDA review of drugs and biologics that are intended for the treatment of serious or life-threatening diseases or conditions.

The FDA has various programs, including Fast Track Designation, Breakthrough Therapy Designation, accelerated approval, Regenerative Medicine Advanced Therapy (RMAT) Designation, and priority review, that are intended to expedite or simplify the process for the development and FDA review of drugs and biologics that are intended for the treatment of serious or life-threatening diseases or conditions.

To be eligible for Fast Track Designation, new drugs and biological product candidates must be intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

5 unchanged sentences

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 may be eligible for RMAT Designation if:

(1) it is a cell therapy, therapeutic tissue engineering product, human cell or tissue product, or combination product using any such therapies or products;

(2) it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition;

and (3) there is preliminary clinical evidence that indicates the product candidate has the potential to address unmet medical needs for such disease or condition.

This program is intended to facilitate efficient development and review of RMATs and includes all of the features of Breakthrough Therapy Designation, including early interactions to discuss potential surrogate or intermediate endpoints.

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.

3 unchanged sentences

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.

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 that such trials be underway prior to approval or within a specific time period after the date accelerated approval was granted.

17 unchanged sentences

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

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).

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).

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.

2 unchanged sentences

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.

22 unchanged sentences

The BPCIA is complex and continues to be interpreted and implemented by the FDA.

government proposals have sought to reduce the 12-year reference product exclusivity period.

In addition, 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.

14 unchanged sentences

In July 2016, the FDA issued a draft guidance document intended to further assist sponsors of therapeutic products and sponsors of in vitro companion diagnostic devices on issues related to co-development of these products.

The FDA generally requires companion diagnostics intended to select the patients who will respond to cancer treatment to obtain approval of a PMA for that diagnostic contemporaneously with approval of the therapeutic.

The FDA generally requires companion diagnostics intended to select the patients who will respond to cancer treatment to obtain marketing approval or clearance for that diagnostic contemporaneously with approval of the therapeutic.

The review of these in vitro companion diagnostics in conjunction with the review of therapeutic candidates such as those we are developing involves coordination of review by the FDA’s Center for Biologics Evaluation and Research and by the FDA’s Center for Devices and Radiological Health.

The PMA process, including the gathering of clinical and pre-clinical data and the submission to and review by the FDA, can take several years or longer.

It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling.

PMA applications are also subject to an application fee.

PMAs for certain devices must generally include the results from extensive pre-clinical and adequate and well-controlled clinical trials to establish the safety and effectiveness of the device for each indication for which FDA approval is sought.

In particular, for a diagnostic, the applicant must demonstrate that the diagnostic produces reproducible results when the same sample is tested multiple times by multiple users at multiple laboratories.

In addition, as part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the Quality System Regulation (QSR) which imposes elaborate testing, control, documentation and other quality assurance requirements.

If the FDA evaluations of both the PMA application and the manufacturing facilities are favorable, the FDA will either issue an approval letter or a not-approvable letter, which usually contains a number of conditions that must be met in order to secure the final approval of the PMA, such as changes in labeling, or specific additional information, such as submission of final labeling, in order to secure final approval of the PMA.

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.

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.

A not approvable letter will outline the deficiencies in the application and, where practical, will identify what is necessary to make the PMA approvable.

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.

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.

Historically, the FDA required premarket approval applications (PMAs) for nearly all companion diagnostics for cancer therapies.

In January 2024, the FDA announced its intention to initiate the reclassification process for most in vitro diagnostics, including companion diagnostics.

22 unchanged sentences

Under the Clinical Trials Regulation (EU) No.

536/2014, which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022, a single application is now made through the Clinical Trials Information System (CTIS) for clinical trial authorization in up to 30 EU/EEA countries at the same time and with a single set of documentation.

536/2014 (CTR), which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022, a single application is now made through the Clinical Trials Information System (CTIS) for clinical trial authorization in up to 30 EU/EEA countries at the same time and with a single set of documentation.

The assessment of applications for clinical trials is divided into two parts (Part I contains scientific and medicinal product documentation and Part II contains the national and patient-level documentation).

Part I is assessed by a coordinated review by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned) of a draft report prepared by a Reference Member State.

Part II is assessed separately by each Member State concerned.

16 unchanged sentences

In the EU, upon receiving a marketing authorization, innovative medicinal products approved on the basis of a complete and independent data package qualify for eight years of data exclusivity and an additional two years of market exclusivity.

If granted, data exclusivity prevents generic or biosimilar applicants from referencing the innovator’s pre-clinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the EU, during a period of eight years from the date on which the reference product was first authorized in the EU.

Data exclusivity prevents generic or biosimilar applicants from referencing the innovator’s pre-clinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the EU, during a period of eight years from the date on which the reference product was first authorized in the EU.

During the additional two-year period of market exclusivity, a generic or biosimilar MAA can be submitted and authorized, and the innovator’s data may be referenced, but no generic or biosimilar product can be placed on the EU market until the expiration of the market exclusivity.

1 unchanged sentence

There is no guarantee that a product will be considered by the EMA to be an innovative medicinal product, and products may not qualify for data exclusivity.

Even if a product is considered to be an innovative medicinal product so that the innovator gains the prescribed period of data exclusivity, another company may market another version of the product if such company obtained a marketing authorization based on an MAA with a complete and independent data package of pharmaceutical tests, preclinical tests and clinical trials.

authorization based on an MAA with a complete and independent data package of pharmaceutical tests, preclinical tests and clinical trials.

Orphan Designation and Exclusivity

Products receiving orphan designation in the EU can receive ten years of market exclusivity, during which time no “similar medicinal product” may be placed on the market.

Products receiving Orphan Designation in the EU are eligible for ten years of market exclusivity for the approved indication, during which time no “similar medicinal product” for the same indication may be placed on the market, subject to certain limited exceptions.

A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

5 unchanged sentences

(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.

12 unchanged sentences

The MAA for the product must include the results of pediatric clinical trials conducted in accordance with the PIP, unless a waiver applies, or a deferral has been granted by the PDCO of the obligation to implement some or all of the measures of the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults, in which case the pediatric clinical trials must be completed at a later date.

Products that are granted a marketing authorization with the results of the pediatric clinical trials conducted in accordance with the PIP are eligible for a six month extension of the protection under an SPC (provided an application for such extension is made at the same time as filing the SPC application for the product, or at any point up to 2 years before the SPC expires) even where the trial results are negative.

Products that are granted a marketing authorization with the results of the pediatric clinical trials conducted in accordance with the agreed PIP are eligible for a six month extension of the protection under an SPC (provided an application for such extension is made at the same time as filing the SPC application for the product, or at any point up to 2 years before the SPC expires) even where the trial results are negative.

In the case of orphan medicinal products, a two-year extension of the orphan market exclusivity may be available.

4 unchanged sentences

• The holder of a marketing authorization must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance, who is responsible for oversight of that system.

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 to prevent or minimize the risks associated with the product.

obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports (PSURs).

• 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, in accordance with applicable EU requirements.

The regulatory authorities may also impose specific obligations as a condition of the marketing authorization.

Such risk-minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies.

RMPs and PSURs are routinely available to third parties requesting access, subject to limited redactions.

RMPs and certain PSUR information may be made available to third parties requesting access, subject to limited redaction of confidential commercial information and personal data.

• All advertising and promotional activities for the product must be consistent with the approved summary of product characteristics (SmPC) and therefore all off-label promotion is prohibited.

4 unchanged sentences

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, 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.

In April 2024, the European Parliament adopted its position on the legislative proposals and, in June 2025, the Council of the European Union adopted its position.

A common position on the text has been agreed upon on December 11, 2025, in the context of subsequent inter-institutional trilogue negotiations.

The proposed revisions remain to be adopted, and are not expected to become applicable before 2028.

Brexit and the Regulatory Framework in the United Kingdom

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”.

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.

Following the end of the Brexit transition period on January 1, 2021 and the implementation of the Windsor Framework on January 1, 2025, the United Kingdom (UK) is not generally subject to EU laws in respect of medicines.

The EU laws that have been transposed into UK law through secondary legislation remain applicable in the UK, however, new legislation such as the (EU) CTR is not applicable in the UK.

As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) is the UK's standalone medicines and medical devices regulator.

As a result of the Northern Ireland Protocol, different rules applied in Northern Ireland than in England, Wales, and Scotland (together, "Great Britain", or GB), which continued to follow the EU regulatory regime for a period following Brexit.

However, on January 1, 2025 a new arrangement called the "Windsor Framework" came into effect and reintegrated Northern Ireland under the regulatory authority of the MHRA with respect to medicinal products.

The Windsor Framework removes EU licensing processes and EU labeling and serialization requirements in relation to Northern Ireland and introduces a UK-wide licensing process for medicines.

In particular, the MHRA is now responsible for approving medicinal products placed on the UK market (i.e., Great Britain and Northern Ireland), and the EMA no longer has a role in UK marketing authorizations.

A single UK-wide MA will be granted by the MHRA for 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, for packs placed on the UK market on or after January 1, 2025, a "UK Only" label, indicating they are not for sale in the EU.

However, although separate authorization is now required to market medicinal products in the UK, since January 1, 2024, the MHRA may rely on the International Recognition Procedure (IRP) when reviewing certain types of MAAs.

Pursuant to the IRP, the MHRA will take into account the expertise and decision-making of trusted regulatory partners (e.g.

the medicines regulatory authorities in Australia, Canada, Switzerland, Singapore, Japan, the U.S.A.

and the EMA in the EU) when considering an application for a UK MA.

There is no pre-MA orphan designation in the UK.

Instead, the MHRA reviews applications for orphan designation with the corresponding MA application.

The criteria are essentially the same, but have been tailored for the UK market, i.e., the prevalence of the condition in the 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.

3 unchanged sentences

pharmaceutical industry.

The ACA, among other things, subjects biological products to potential competition by lower-cost biosimilars, increases the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program extends the rebate program to individuals enrolled in Medicaid managed care organizations, establishes annual fees and taxes on manufacturers of certain branded prescription drugs, and creates a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition to coverage under Medicare Part D for the manufacturer’s outpatient drugs.

brand drugs to eligible beneficiaries during their coverage gap period, as a condition to coverage under Medicare Part D for the manufacturer’s outpatient drugs.

Other legislative changes have been proposed and adopted in the United States since the ACA was enacted:

4 unchanged sentences

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 were further reduced starting on January 1, 2025.

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.

11 unchanged sentences

Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one Orphan Designation and for which the only approved indication is for that disease or condition.

If a product receives multiple orphan designations or has multiple approved indications, it may not qualify for the orphan drug exemption.

Under the One Big Beautiful Bill Act of 2025, this restriction was eliminated;

and effective for the 2028 initial price applicability year, all orphan drugs, regardless of the number of orphan drug designations or indications, are exempt from the Medicare drug price negotiation program.

The implementation of the IRA is currently subject to ongoing litigation challenging the constitutionality of the IRA’s Medicare drug price negotiation program.

6 unchanged sentences

Congress and the Trump administration have indicated that they will continue to seek new legislative measures to control drug costs.

On April 15, 2025, the Trump Administration published Executive Order 14273, “Lowering Drug Prices by Once Again Putting Americans First,” which generally directs the federal government to take measures to reduce drug prices, including eliminating the so-called “pill penalty” under the Inflation Reduction Act that creates a distinction between small molecule and large molecule products for purposes of determining when a drug may be eligible for drug price negotiation.

On May 12, 2025, the Trump Administration published Executive Order 14297, “Delivering Most-Favored-Nation Prescription Drug Pricing to American Patients” which generally, among other things, directs the federal government to establish and communicate most-favored-nation (MFN) price targets to pharmaceutical manufacturers to bring prices for American patients in line with comparably developed nations.

Further, the Executive Order directs the federal government to support regulatory paths to allow direct-to-patient sales for companies that meet these targets.

It also states that the Administration will take additional aggressive action (for example, examining whether marketing approvals should be modified or rescinded or opening the door for individual drug importation waivers) should manufacturers fail to offer American consumers the MFN lowest price.

It also directs the Secretary of Commerce and the U.S.

Trade Representative to “take all necessary and appropriate action to ensure foreign countries are not engaged in any act, policy, or practice that may be unreasonable or discriminatory or that may impair United States national security .

including by suppressing the price of pharmaceutical products below fair market value in foreign countries.” Notably, a similar “Most Favored Nation” pricing rule enacted under the first Trump Administration was subject to an injunction resulting from judicial challenges to the rule, which was formally rescinded by the former Biden Administration in August 2021.

On November 6, 2025, the Centers for Medicare & Medicaid Services (CMS) announced a new drug payment model designed to make MFN-level prices available to state Medicaid programs via manufacturer rebates.

Referred to as the “GENErating cost Reductions fOr U.S.

Medicaid Model” (GENEROUS), the initiative is designed to run from 2026 through 2030 and is voluntary for both manufacturers and state Medicaid programs.

Under the model, participating states will be able to access MFN-level prices for participating manufacturers’ drugs through CMS-negotiated supplemental rebates tied to an MFN net price benchmark.

On December 19, 2025, the CMS proposed a mandatory Center for Medicare and Medicaid Innovation (CMMI) drug payment model to test whether alternative methods for calculating Medicare rebates, based on international pricing metrics rather than inflation-based metrics, reduce costs for Medicare fee-for-service (FFS) beneficiaries and the Medicare program while preserving quality of care.

The Guarding U.S.

Medicare Against Rising Drug Costs (GUARD) Model, would test an alternative approach to calculating rebates for certain Medicare Part D products using international pricing benchmarks.

The GUARD Model would begin on January 1, 2027, and run through December 31, 2033.

Further, on December 19, 2025, CMS proposed the Global Benchmark for Efficient Drug Pricing Model (GLOBE) for Medicare Part B, would require manufacturers of specified single source drugs and sole source biologics to pay incremental rebates based on international benchmark prices, with participation triggered for products meeting CMS’s spending and eligibility criteria.

As proposed, GLOBE would begin a five-year performance period on October 1, 2026.

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.

Certain states are also pursuing cost containment efforts through Prescription Drug Affordability Boards (PDABs) and similar entities.

While many PDABs have been granted authority to promote drug price transparency and reporting, some states have granted PDABs more expansive authority, including to set Upper Payment Limits (UPLs) on select, high price drugs.

The adoption and implementation of UPLs may put downward pressure on drug prices and impact our company’s future revenues.

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.

105 unchanged sentences

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