What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2026-03-12 compared with 2025-03-06 · 342 added, 211 removed, 620 unchanged (47% of the section changed)

We are a diversified clinical-stage company developing therapeutics designed to treat cancer and related diseases in areas of high unmet need.

As a result of the acquisition in March 2022 of Theriva Biologics, S.L.

(“VCN”, formerly named VCN Biosciences, S.L.), described in more detail below (the “Acquisition”), we transitioned our strategic focus to oncology through the development of VCN’s new oncolytic adenovirus platform designed for intravenous and intravitreal delivery to trigger tumor cell death, to improve access of co-administered cancer therapies to the tumor, and to promote a robust and sustained anti-tumor response by the patient’s immune system.

As a result of the Company’s acquisition of Theriva Biologics, S.L.

(“VCN”, formerly named VCN Biosciences, S.L.), in March 2022, as described in more detail below (the “Acquisition”), we transitioned our strategic focus to oncology through the development of VCN’s new oncolytic adenovirus platform designed for intravenous and intravitreal delivery to trigger tumor cell death, to improve access of co-administered cancer therapies to the tumor, and to promote a robust and sustained anti-tumor response by the patient’s immune system.

Our lead product candidate, VCN - 01 (zabilugene almadenorepvec), is a clinical stage oncolytic human adenovirus that is modified for tumor - selective replication and to express an enzyme, PH20 hyaluronidase.

VCN - 01 has been evaluated in a Phase 2b clinical study for the treatment of pancreatic cancer (“VIRAGE”), and a Phase 1 clinical study for the treatment of retinoblastoma, as well as various other Phase 1 clinical studies for the treatment of other solid tumors including head and neck squamous cell carcinoma.

Prior to the Acquisition, our focus was on developing therapeutics designed to treat gastrointestinal (GI) diseases which included our clinical development candidates:

(1) SYN-004 (ribaxamase) which is designed to degrade certain commonly used intravenous (IV) beta-lactam antibiotics within the GI tract to prevent microbiome damage thereby preventing overgrowth and infection by pathogenic organisms such as Clostridioides difficile infection (CDI), and vancomycin resistant Enterococci (VRE), and reducing the incidence and severity of acute graft-versus-host-disease (aGVHD) in allogeneic hematopoietic cell transplant (HCT) recipients, and (2) SYN-020, a recombinant oral formulation of the enzyme intestinal alkaline phosphatase (IAP) produced under cGMP conditions and intended to treat both local GI and systemic diseases.

As part of our strategic transformation into an oncology focused company, we are exploring value creation options for our SYN-004 and SYN-020 assets, including out-licensing or partnering.

(1) SYN-004 (ribaxamase), which is designed to degrade certain commonly used intravenous (IV) beta-lactam antibiotics within the GI tract to prevent microbiome damage, thereby preventing overgrowth and infection by pathogenic organisms such as Clostridioides difficile infection (CDI) and vancomycin resistant Enterococci (VRE), and reducing the incidence and severity of acute graft-versus-host-disease (aGVHD) in allogeneic hematopoietic cell transplant (HCT) recipients, and (2) SYN-020, a recombinant oral formulation of the enzyme intestinal alkaline phosphatase (IAP) produced under current good manufacturing practices (“cGMP”) conditions and intended to treat both local GI and systemic diseases.

In February 2026, we entered into a license agreement (the “Rasayana License Agreement”) with Rasayana Therapeutics, Inc.

(“Rasayana”), pursuant to which we granted Rasayana an exclusive worldwide license with the right to grant sublicenses to research, develop, manufacture and commercialize any Product (as such term is defined in the Rasayana License Agreement), which includes SYN-020, comprising, containing, or covered by the Licensed IP (as such term is defined in the Rasayana License Agreement) and/or devised, developed, or produced using the Licensed IP.

Pursuant to the terms of the Rasayana License Agreement, Rasayana will assume all responsibility and costs for the development and commercialization of the Products.

We believe that this arrangement will provide us with potential to derive value from our SYN-020 asset, without the need for us to continue to invest additional working capital into the further development of the product candidate, thereby allowing us to focus our efforts and expenditures on the development of our oncology assets.

Additionally, as part of our strategic transformation into an oncology focused company, we are exploring value creation options for our SYN-004 asset, including out-licensing or partnering.

Our Current Product Pipeline

1 unchanged sentence

allo-HCT allogeneic hematopoietic cell transplant.

CSR clinical study report.

HNSCC head and neck squamous cell carcinoma.

2 unchanged sentences

For other abbreviations see the text.

¹Final Phase 1b/2a study cohort contingent on grant funding or partnership.

²Pursuant to the Rasayana License Agreement, commencing February 7, 2026, Rasayana is responsible for all development and commercialization efforts, including all costs related thereto, of SYN-020, and is obligated to use commercially reasonable efforts to meet certain specified development milestones, as more particularly set forth in the Rasayana License Agreement.

Additional products with preclinical proof-of-concept include SYN-006 (carbapenemase) to prevent aGVHD, CDI, and microbiome damage in patients treated with carbapenem antibiotics and SYN-007 (ribaxamase) DR to prevent antibiotic associated diarrhea with oral β-lactam antibiotics.

²Depending on funding/partnership.

SYN-004 may enter a U.S.

Food and Drug Administration (“FDA”)-agreed Phase 3 clinical trial for the treatment of CDI.

Our Current Oncology-Focused Pipeline

2 unchanged sentences

This novel class of anticancer agents has unique mechanisms of action compared to other cancer drugs.

Oncolytic viruses (“OV”) exploit the fact that cancer cells contain mutations that cause them to lose growth control and form tumors.

Once inside a tumor cell, oncolytic viruses exploit the tumor cell machinery to generate thousands of additional copies of the virus, which then kill the tumor cell and spread to neighboring cells, causing a chain reaction of cell killing.

Oncolytic viruses (“OVs”) exploit the fact that cancer cells contain mutations that cause them to lose growth control and form tumors.

Once inside a tumor cell, OVs exploit the tumor cell machinery to generate thousands of additional copies of the virus, which then kill the tumor cell and spread to neighboring cells, causing a chain reaction of cell killing.

This infection and tumor cell killing by OVs also alerts the immune system, which can then attack the virus infected tumor cells to help destroy the tumor in some instances.

Our OV product candidates are engineered to efficiently infect and selectively replicate to a high extent in tumor cells versus normal host cells, which enables intravenous delivery.

By contrast, many other oncolytic viruses in clinical development today are administered by direct injection into the tumor.

By contrast, many other OVs in clinical development today are administered by direct injection into the tumor.

Intravenous delivery has the potential to expand the therapeutic effect of OVs because the virus can infect both the primary tumor and tumor metastases throughout the body.

Our first product candidate VCN-01, is a clinical stage oncolytic human adenovirus that is modified to express an enzyme, PH20 hyaluronidase, that is designed to degrade hyaluronan in the tumor stroma, which helps the virus and other molecules to penetrate and spread throughout the tumor.

Our lead product candidate VCN-01 (zabilugene almadenorepvec), is a clinical stage oncolytic human adenovirus that is modified to express an enzyme, PH20 hyaluronidase, that is designed to degrade hyaluronan in the tumor stroma, which helps the virus and other

molecules to penetrate and spread throughout the tumor.

VCN-01 can be used alone or in combination with other cancer therapies, such as chemotherapy and immunotherapy, for difficult to treat cancers.

An expanding intellectual property portfolio supports our oncology programs, and because our products are characterized as biologics with Orphan Drug designation in our target indications, if approved by the FDA they will be further protected by data and/or market exclusivity.

VCN-01 — An oncolytic human type-5 adenovirus engineered for intravenous administration and to express a tumor matrix degrading enzyme (PH20 hyaluronidase) that facilitates the entry of therapeutics and immune cells into tumors

VCN-01 (zabilugene almadenorepvec) — An oncolytic human type-5 adenovirus engineered for intravenous administration and to express a tumor matrix degrading enzyme (PH20 hyaluronidase) the goal of which is to facilitate the entry of therapeutics and immune cells into tumors

VCN-01 is a genetically modified oncolytic adenovirus that has been engineered to contain four independent genetic modifications on the backbone of the wild-type human adenovirus serotype 5 (HAd5) genome.

7 unchanged sentences

Expression of PH20 by VCN-01 is designed to degrade the hyaluronic acid within the tumor stroma and to improve virus spread throughout the tumor.

Based upon the foregoing, we believe our oncolytic virus platform, exemplified by VCN-01, represents a new and potentially powerful form of therapy to be combined with tumor cell killing, anti-tumor immunity and stroma destruction after intravenous delivery.

Based upon the foregoing, we believe our OV platform, exemplified by VCN-01, represents a new and potentially powerful form of therapy to be combined with tumor cell killing, anti-tumor immunity and stroma destruction after intravenous delivery.

The VCN-01 product candidate is provided as a sterile liquid concentrate that is diluted for infusion or injection.

1 unchanged sentence

Our initial indication for clinical development is unresectable metastatic pancreatic cancer, a disease for which there is currently no cure and only limited therapeutic options.

VCN-01 has been administered to 142 patients across multiple Phase 1 clinical trials and the Phase 2 VIRAGE trial, including patients with pancreatic cancer, head and neck squamous cell carcinoma, ovarian cancer, colorectal cancer, and retinoblastoma.

At the time of the filing of this Annual Report, VCN-01 has been administered to 142 patients across multiple Phase 1 clinical trials and the Phase 2 VIRAGE trial, including patients with pancreatic cancer, head and neck squamous cell carcinoma, ovarian cancer, colorectal cancer, and retinoblastoma.

Pancreatic Ductal Adenocarcinoma

Cancer of the pancreas consists of two main histological types:

cancer that arises from the ductal (exocrine) cells of the pancreas or, much less often, cancers may arise from the endocrine compartment of the pancreas.

cancer that arises from the ductal (exocrine) cells of the pancreas or, much less often, cancers that may arise from the endocrine compartment of the pancreas.

Pancreatic ductal adenocarcinoma (“PDAC”) accounts for more than 90% of all pancreatic tumors.

11 unchanged sentences

Surgery is the only treatment that offers the prospect of long term-survival;

however, the 5-year survival for the limited number of patients in whom resection is possible remains low (20 – 30 %).

Patients with advanced disease are managed with chemotherapy.

however, the 5-year survival rate for the limited number of patients in whom resection is possible remains low (20 – 30 %).

Patients with advanced disease are often managed with chemotherapy.

In recent years, the combination of gemcitabine with albumin-bound paclitaxel (GA), and the combination of folic acid, 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) have emerged as the standard of care.

In 2024, liposomal irinotecan (ONIVYDE®), which was previously approved for second line PDAC in combination with fluorouracil and leucovorin, was approved in the United States and Europe as first line therapy for metastatic PDAC when administered along with oxaliplatin 5-FU and leucovorin (the NALIRIFOX regimen).

In 2024, liposomal irinotecan (ONIVYDE®), which was previously approved for second line PDAC in combination with fluorouracil and

leucovorin, was approved in the United States and Europe as first line therapy for metastatic PDAC when administered along with oxaliplatin 5-FU and leucovorin (the NALIRIFOX regimen).

However, the results are still very poor and new therapeutic interventions are needed.

The increase is particularly evident in younger people.

In recent years, the prevalence of PDAC has increased, which increase has been particularly evident in younger people.

The rising incidence of pancreatic cancer and its current economic burden place increased pressure to improve outcomes for patients.

In May 2011, the Committee for Orphan Medicinal Products (“COMP”) from the European Medicines Agency (“EMA”) recommended granting Orphan Medicinal Product Designation to VCN-01 for the treatment of pancreatic cancer and in June 2011, the European Commission confirmed the designation under Regulation (“EC”) No 141/2000 of the European Parliament and of the Council.

In May 2011, the Committee for Orphan Medicinal Products (“COMP”) from the European Medicines Agency (“EMA”) recommended granting Orphan Medicinal Product Designation to VCN-01 for the treatment of pancreatic cancer and in June 2011, the European Commission (“EC”) confirmed the designation under Regulation No 141/2000 of the European Parliament and of the Council.

In June 2023, the FDA granted Orphan Drug designation to VCN-01 for the treatment of pancreatic cancer.

In May 2024, the FDA granted Fast Track designation to VCN-01 for the treatment of pancreatic cancer.

Phase 1a/Proof of Concept Trial of VCN-01 by intratumoral administration in PDAC

In September 2019, VCN presented a poster at the European Society for Molecular Oncology (“ESMO”) annual meeting describing initial mechanism of action data from a multicenter, Phase 1 dose escalation study of intratumoral (“IT”) VCN-01 administered to pancreatic cancer patients in combination with standard doses/schedules of either gemcitabine or nab-paclitaxel plus gemcitabine (NCT02045589).

The study was conducted at three hospitals in Spain and 8 patients with confirmed histologic diagnosis of unresectable PDAC amenable to endoscopic ultrasound guided (“EUS”) injection were treated with 3 injections (coincide with 1 st day of the chemotherapy cycles) at two different dose levels of VCN-01 (six patients had metastatic disease and two had locally advanced disease).

Phase 1a/Proof of Concept Trial of VCN-01 (zabilugene almadenorepvec) by intratumoral administration in PDAC

In September 2019, VCN presented a poster at the European Society for Medical Oncology (“ESMO”) annual meeting describing initial mechanism of action data from a multicenter, Phase 1 dose escalation study of intratumoral (“IT”) VCN-01 administered to pancreatic cancer patients in combination with standard doses/schedules of either gemcitabine or nab-paclitaxel plus gemcitabine (NCT02045589).

The study was conducted at three hospitals in Spain and 8 patients with confirmed histologic diagnosis of unresectable PDAC amenable to endoscopic ultrasound guided (“EUS”) injection were treated with 3 injections (coinciding with 1 st day of the chemotherapy cycles) at two different dose levels of VCN-01 (6 patients had metastatic disease and 2 had locally advanced disease).

The treatment regimen was generally well-tolerated.

11 unchanged sentences

10.1136/jitc-2021-003254.

Phase 1 Trial of intravenous VCN-01 with or without nab-paclitaxel plus gemcitabine in patients with solid tumors and PDAC

In March 2022, we announced the peer-reviewed publication of a Phase 1, multicenter, open-label, dose-escalation study investigating the safety, tolerability and biodistribution of intravenous VCN-01 oncolytic adenovirus with or without standard-of-care (SoC) chemotherapy (gemcitabine/nab-paclitaxel) in patients with advanced solid tumors (NCT02045602).

Phase 1 Trial of intravenous VCN-01 (zabilugene almadenorepvec) with or without nab-paclitaxel plus gemcitabine in patients with solid tumors and PDAC

In March 2022, we announced the peer-reviewed publication of data from a Phase 1, multicenter, open-label, dose-escalation study investigating the safety, tolerability and biodistribution of intravenous VCN-01 oncolytic adenovirus with or without standard-of-care (SoC) chemotherapy (gemcitabine/nab-paclitaxel) in patients with advanced solid tumors (NCT02045602).

The data, published in the Journal for ImmunoTherapy of Cancer, suggests that intravenous treatment with VCN-01 is feasible and has been well tolerated, with encouraging biological and clinical activity.

11 unchanged sentences

A second viral peak in plasma and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients.

Increased levels of immune biomarkers (IFNγ, sLAG3, IL-6, IL-10) were found after VCN-01 administration.

Increased levels of immune biomarkers (IFNγ, sLAG3, IL-6, IL-10) were found

after VCN-01 administration.

In patients with pancreatic adenocarcinoma, the overall response rate (ORR) was 50% for Part II and 50% for Part III, as assessed by the investigators.

6 unchanged sentences

VCN-01 appeared to convert the typically immunosuppressive tumor microenvironment of pancreatic adenocarcinomas into an enhanced inflammatory microenvironment (IDO, CD28, PD-1, CTL signature up-regulation, and collagen formation) after treatment.

Phase 2 Trial of intravenous VCN-01 with or without nab-paclitaxel plus gemcitabine in patients with solid tumors and PDAC

In January 2023, we dosed the first patients in VIRAGE, the Phase 2b randomized, open-label, placebo-controlled, multicenter clinical trial of systemically administered VCN-01 in combination with standard-of-care (SoC) chemotherapy (gemcitabine/nab-paclitaxel) as a first line therapy for patients with newly-diagnosed metastatic pancreatic ductal adenocarcinoma.

The study is being conducted at approximately 17 sites in the US and EU.

Two doses of VCN-01 are included in the treatment arm:

the 1st dose is administered on day 1, then one week later 3 cycles of gemcitabine and nab-paclitaxel as standard of care is administered.

The second VCN-01 dose is administered 7 days before the 4th cycle of chemotherapy (approximately 90 days after the first VCN-01 dose), followed by additional cycles of gemcitabine/nab-paclitaxel chemotherapy.

Phase 2 Trial of intravenous VCN-01 (zabilugene almadenorepvec) with nab-paclitaxel plus gemcitabine in patients with PDAC

In January 2023, we dosed the first patients in VIRAGE, the Phase 2b randomized, open-label, multicenter clinical trial of systemically administered VCN-01 in combination with SoC chemotherapy (gemcitabine/nab-paclitaxel) as a first line therapy for patients with newly-diagnosed metastatic pancreatic ductal adenocarcinoma.

The study was conducted at approximately 17 sites in the US and EU.

Two doses of VCN-01 were included in the treatment arm:

the 1st dose was administered on day 1, then one week later 3 cycles of gemcitabine and nab-paclitaxel as standard of care was administered.

The second VCN-01 dose was administered 7 days before the 4th cycle of chemotherapy (approximately 90 days after the first VCN-01 dose), followed by additional cycles of gemcitabine/nab-paclitaxel chemotherapy.

Patient dosing was initiated in the U.S.

in July 2023 and on September 23, 2024, we announced that we have achieved our target patient enrollment of 92 evaluable patients in the VIRAGE Phase 2b clinical trial.

Thirty-six patients have received their second doses of intravenous VCN-01, which were well tolerated and demonstrated the expected VCN-01 adverse event profile.

Topline data for the VIRAGE Phase 2b clinical trial is anticipated for Q2 2025.

in July 2023 and, on September 23, 2024, we announced that we achieved our target patient enrollment of 92 evaluable patients in the VIRAGE Phase 2b clinical trial.

Thirty - six patients received their second doses of intravenous VCN-01, which were well tolerated and demonstrated the expected VCN-01 adverse event profile.

Positive topline data for the VIRAGE Phase 2b clinical trial from the first-line treatment of 96 newly-diagnosed metastatic PDAC patients was announced in the second quarter of 2025 and is described below.

On January 30, 2024, the accumulated clinical data from patients enrolled across 6 sites open in the U.S.

7 unchanged sentences

On May 23, 2024, we announced that the FDA granted Fast Track Designation (FTD) to lead clinical candidate VCN-01 in combination with gemcitabine and nab-paclitaxel to improve progression-free survival and overall survival in patients with metastatic pancreatic adenocarcinoma.

On June 1, 2024, we presented the design of VIRAGE trial in a poster at the American Society of Clinical Oncology (ASCO) Annual Meeting 2024 Congress held and in Chicago (Illinois) from May 31- June 4, 2024.

The poster discussed the objectives, endpoints and key inclusion and exclusion criteria included in the trial protocol, together with the treatment schedule for each arm of the study.

On December 5, 2024 we announced the outcomes of a Type D meeting with the FDA to obtain guidance on the design of a Phase 3 clinical study of VCN-01 in combination with standard-of-care chemotherapy for the treatment of PDAC.

FDA advised that the optimal path forward for the VCN-01 PDAC program is to conduct a stand-alone Phase 3 study of VCN-01 with gemcitabine/nab-paclitaxel.

The FDA provided general agreement with our proposed design for a Phase 3 clinical study and indicated that inclusion of additional standard-of-care chemotherapy for PDAC was not necessary as it would complicate the study design and analysis.

On December 5, 2024, we announced the outcomes of a Type D meeting with the FDA to obtain guidance on the design of a potential Phase 3 clinical study of VCN-01 in combination with SoC chemotherapy for the treatment of metastatic PDAC (“mPDAC”).

The FDA advised that the optimal path forward for the VCN-01 PDAC program is to conduct a stand-alone Phase 3 study of VCN-01 with gemcitabine/nab-paclitaxel.

The FDA provided general agreement with our proposed design for a Phase 3 clinical study and indicated that inclusion of additional SoC chemotherapy for mPDAC was not necessary as it would complicate the study design and analysis.

The FDA meeting also highlighted the FDA’s preferences regarding certain statistical elements of confirmatory clinical studies, including methods for sample size estimation and the study population(s) used for data analysis.

On February 4 th , 2025, we received Scientific Advice from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) on the design of a Phase 3 clinical study of VCN-01 in combination with standard-of-care chemotherapy for the treatment of metastatic PDAC.

Consistent with feedback from the FDA, CHMP advised that a marketing authorization application (MAA) for VCN-01 in metastatic PDAC could be supported by positive results from a randomized, controlled, stand-alone Phase 3 study comparing VCN-01 combined with gemcitabine/nab-paclitaxel to gemcitabine/nab-paclitaxel standard-of-care alone.

The Scientific Advice also included CHMP suggestions regarding the study populations, inclusion/exclusion criteria, randomization and blinding, priority endpoints, and proposed statistical strategies for data analysis.

An additional note from the EMA Committee for Orphan Medicinal Products (COMP) noted that the potential benefit of VCN-01 with gemcitabine/nab-paclitaxel in a Phase 3 trial will be compared with the therapeutic effects of the other approved standard-of-care chemotherapies (FOLFIRINOX, NALIRIFOX) when considering maintenance of the Orphan Medicinal Product status of VCN-01 at the time of an MAA.

On February 4, 2025, we received Scientific Advice from the Committee for Medicinal Products for Human Use (“CHMP”) of the European Medicines Agency (“EMA”) on the design of a potential Phase 3 clinical study of VCN-01 in combination with SoC chemotherapy for the treatment of mPDAC.

Consistent with feedback from the FDA, CHMP advised that a marketing authorization application (“MAA”) for VCN-01 in mPDAC could be supported by positive results from a randomized, controlled, stand-alone Phase 3 study comparing VCN-01 combined with gemcitabine/nab-paclitaxel to gemcitabine/nab-paclitaxel SoC alone.

The Scientific Advice also included CHMP suggestions regarding the study populations, inclusion/exclusion criteria, randomization and blinding, priority

endpoints, and proposed statistical strategies for data analysis.

An additional comment from the EMA Committee for Orphan Medicinal Products (“COMP”) noted that the potential benefit of VCN-01 with gemcitabine/nab-paclitaxel in a Phase 3 trial will be compared with the therapeutic effects of the other approved SoC chemotherapies (FOLFIRINOX, NALIRIFOX) when considering maintenance of the Orphan Medicinal Product status of VCN-01 at the time of an MAA.

On March 31, 2025, we announced that a second Independent Data Monitoring Committee (“IDMC”) review of data from the VIRAGE Phase 2b clinical trial in newly-diagnosed mPDAC found that VCN-01 was well tolerated in combination with SoC chemotherapy (gemcitabine/nab-paclitaxel) and the adverse event (“AE”) profile was as expected for the patient population and the medications being studied.

The VCN-01 AE profile was consistent with that observed in prior clinical trials.

The most common VCN-01 related AEs (pyrexia, flu-like illness, vomiting, nausea, and elevated transaminases) were transient and reversible.

These AEs were observed to be less frequent and of reduced CTCAE grade after the second VCN-01 dose (administered on day 92) compared to the first VCN-01 dose (administered on day 1).

The IDMC noted that the overall type and number of AEs in the VCN-01 treatment group was as expected for the pancreatic cancer population, the duration of treatment, and the administration of an oncolytic virus.

On May 7, 2025, we announced positive topline outcomes from the VIRAGE Phase 2b clinical trial evaluating our lead product candidate VCN-01 (zabilugene almadenorepvec) plus SoC chemotherapy gemcitabine/nab-paclitaxel as a first line therapy for patients with mPDAC for whom gemcitabine/nab-paclitaxel is the recommended first-line treatment option.

Topline outcomes for the analysis of the VIRAGE trial includes the following data for first-line treatment of the 96 newly-diagnosed metastatic PDAC patients dosed in the clinical trial:

● In the primary endpoint analysis, the 48 patients treated with at least one dose of gemcitabine/nab-paclitaxel SoC had a median OS) of 8.6 months, while the 48 patients treated with VCN-01 followed by at least one dose of gemcitabine/nab-paclitaxel SoC had a median OS of 10.8 months [Hazard Ratio (HR) = 0.57, 95% CI 0.34-0.96, p=0.0546].

● The improvements in OS in the VCN-01+SoC treatment arm compared to the SoC control arm were reflected in increased progression free survival (PFS) [median PFS 7.0 vs 4.6 months;

HR = 0.55, 95% CI 0.34-0.88, p= 0.0105].

● The median duration of response (“DoR”) was 5.4 months (n=15) in the SoC control arm, while the median DoR in the VCN-01+SoC treatment arm was doubled to 11.2 months (n=19, HR = 0.22, 95% CI 0.08-0.62, p=0.0035).

The increase in OS was greater for patients who received 2 doses of VCN-01 and 4 or more cycles of gemcitabine/nab-paclitaxel SoC (n=34) compared with patients who received 4 or more cycles of gemcitabine/nab-paclitaxel SoC (n=29) [median OS 14.8 and 11.6 months respectively;

HR=0.44, 95% CI:

0.21-0.92, p=0.046], suggesting that the second dose of VCN-01 (administered 3 months after the first dose) provides a meaningful additional benefit in this treatment subgroup.

On October 20, 2025, expanded mPDAC data from the VIRAGE Phase 2b trial (NCT05673811) were presented in oral communication at the ESMO 2025 Annual Congress, which took place in Berlin, Germany.

Results from the VIRAGE Phase 2b trial included in the abstract for the presentation titled “VIRAGE trial:

randomized Phase IIb, open-label, study of Nab-Paclitaxel and Gemcitabine with/without intravenous VCN-01 in Patients with Metastatic Pancreatic Cancer (mPDAC )” are set forth below:

112 patients were randomized.

Patients in the modified intent to treat (“mITT”) population received at least 1 dose of gemcitabine/nab-paclitaxel (“GA”) standard of care chemotherapy (GA, Arm I) or VCN-01 (Arm II).

Patients in the full analysis set (“FAS”) population received at least 1 dose of gemcitabine/nab-paclitaxel SoC chemotherapy (GA;

Arm I) or VCN-01 followed by at least 1 dose of GA (Arm II).

Definitions -mo.

OS (overall survival).

PS or PFS (progression free survival).

DoR (duration of response).

ORR (objective response rate).

HR (hazard ratio).

CI (confidence interval).

Compared to patients who started GA cycle 4 alone (Arm I), patients who received 2 VCN-01 doses and started GA cycle 4 (Arm II) showed greater improvement in OS (14.8 vs 11.6 months;

95% CI 0.21 - 0.92;

P =0.046) and PFS (11.2 vs 7.4 months;

95% CI 0.25 - 0.91;

VCN-01 administration was well tolerated.

All VCN- 01-related serious adverse events (n=13) were resolved, the most common being flu-like symptoms (13,2%), transaminase increase (5.7%) and drug-induced liver injury (3.8%).

Viral genome analysis confirmed the bioactivity of the second VCN-01 dose.

This study met its primary endpoints.

Patients receiving VCN-01 + GA had improved OS, PFS and DoR compared to GA standard of care.

Design of the Phase 3 Trial of intravenous VCN-01 with nab-paclitaxel plus gemcitabine in patients with mPDAC

On December 29, 2025, we announced the receipt of additional Scientific Advice (the “Additional Scientific Advice”) from the CHMP of the EMA on the design of a Phase 3 clinical trial of lead clinical candidate VCN-01 in combination with gemcitabine/nab-paclitaxel standard-of-care (SoC) chemotherapy for the first-line treatment of metastatic PDAC.

CHMP advised that a potential future marketing authorization application (MAA) for VCN-01 in metastatic PDAC could be supported by Theriva’s proposed clinical development strategy comprising a single, high-quality, double-blinded, randomized, placebo-controlled Phase 3 trial if it demonstrates a compelling benefit-risk ratio with VCN-01 plus gemcitabine/nab-paclitaxel SoC compared to gemcitabine/nab-paclitaxel SoC alone.

The Additional Scientific Advice included agreement on the proposed sample size, and the use of an adaptive design to potentially optimize trial timelines and outcomes.

Inclusion/exclusion criteria, primary endpoint (overall survival), secondary endpoints (including progression free survival, duration of response, and patient reported outcomes) were also accepted.

Importantly, CHMP recognized the increased improvement in overall survival rate of patients receiving 2 doses of VCN-01 in the VIRAGE study, and agreed with the proposed dosing of VCN-01 and gemcitabine/nab-paclitaxel in repeated “macrocycles”, enabling more than 2 doses of VCN-01 to be administered in the Phase 3 trial.

They further suggested that more frequent dosing of VCN-01 could be considered.

An End-of-Phase 2 meeting with the FDA is planned for first half of 2026, aiming to finalize the design of a pivotal multinational Phase 3 clinical trial in PDAC.

Retinoblastoma

3 unchanged sentences

In the US, retinoblastoma shows an incidence rate of 3.3 per 1,000,000 with only about 200 to 300 children diagnosed per year according to the American Cancer Society.

Bilateral retinoblastoma (Rb1 germinal mutation) represents 25-35% of the cases while unilateral retinoblastoma (sporadic mutation) accounts for 65-75%.

retinoblastoma (Rb1 germinal mutation) represents 25-35% of the cases while unilateral retinoblastoma (sporadic mutation) accounts for 65-75%.

While retinoblastoma is a highly curable disease in the US, with a current disease-free survival rate of >95%, the clinical challenge for those who treat retinoblastoma is to preserve life and to prevent the loss of an eye, blindness and other serious effects of treatment that reduce the patient’s life span or the quality of life.

7 unchanged sentences

In February 2022, the FDA granted Orphan Drug designation to VCN-01 for the treatment of retinoblastoma.

Phase 1 Trial of intravitreal VCN-01 in patients with retinoblastoma

Phase 1 Trial of intravitreal VCN-01 (zabilugene almadenorepvec) in patients with retinoblastoma

During the third quarter of 2017, VCN entered into a Clinical Trial Agreement with Hospital Sant Joan de Déu (Barcelona, Spain) to conduct an investigator sponsored Phase 1 clinical study evaluating the safety and tolerability of two intravitreal injections of VCN-01 in patients with intraocular retinoblastoma refractory to systemic, intra-arterial or intravitreal chemotherapy, or radiotherapy, in whom enucleation was the only recommended treatment (NCT03284268).

Patients received two intravitreal injections of VCN-01, 14 days apart, at a dose of either 2 x 10 9 vp/eye (n=1) or 2 x 10 10 vp/eye (n=8).

The clinical database for the study has now been locked and the clinical study report is being prepared.

The trial has concluded and the clinical study report has been completed.

On April 23, 2024, we announced positive topline data from this study, with agreement by the study Monitoring Committee that the study had a positive outcome.

VCN-01 was well tolerated after intravitreal administration at the 2 doses and the most frequently reported treatment-related adverse events were Grade 1 or 2.

There were no dose limiting toxicities and no ocular or systemic toxicities equal to or greater than Grade 3 during the evaluation period.

● Some degree of ocular inflammation and associated turbidity was observed after VCN-01 injection.

Inflammation was managed, and vitreous haze improved in some cases, by local and systemic administration of anti-inflammatory drugs.

● VCN-01 does not appear to change the retinal function, and selective VCN-01 replication in retinoblastoma cells has been observed by immunohistochemical analysis.

● Replication within retinoblastoma tumors over time was detected

● Intravitreal VCN-01 demonstrated promising antitumor activity:

o Four patients presented a response characterized by unequivocal improvement in vitreous seed density.

o Eye enucleation was avoided in 3 patients to date, one of whom has retained their eye after 4 years of follow-up.

Per the terms of the clinical trial agreement, the determination by the study Monitoring Committee that the study had a positive outcome means we received an exclusive, worldwide technology license, and related patents from Hospital Sant Joan de Déu for the treatment of pediatric patients with advanced retinoblastoma and we will pay to Hospital Sant Joan de Déu the amount of three hundred twenty thousand, two hundred and sixty five Euros (€320,265) or approximately $334,000, upon receipt by us of the final clinical study report.

Per the terms of the clinical trial agreement, the determination by the study Monitoring Committee that the study had a positive outcome means we received an exclusive, worldwide technology license, and related patents from Hospital Sant Joan de Déu for the treatment of pediatric patients with advanced retinoblastoma and we are obligated to pay to Hospital Sant Joan de Déu the amount of three hundred twenty thousand, two hundred and sixty five Euros (€320,265) or approximately $334,000, half of which has been paid and the remaining half is expected to be paid upon invoice receipt.

A pre-Investigational New Drug (“IND”) meeting with the FDA was held on December 19, 2023 to discuss the path forward for VCN-01 as an adjunct to chemotherapy in pediatric patients with advanced retinoblastoma.

3 unchanged sentences

If a Biologics License Application for VCN-01 for the treatment of retinoblastoma is approved by the FDA by September 30, 2029, we may be eligible to receive a Priority Review Voucher.

Previously, the FDA granted orphan drug designation to VCN-01 for treatment of retinoblastoma.

On October 11, 2024, the European Commission adopted the European Medicines Agency (EMA) recommendation to grant Orphan Medicinal Product Designation to VCN-01 for the treatment of retinoblastoma

VCN-01 in combination with Immunomodulatory therapeutics

On October 11, 2024, the European Commission adopted the EMA recommendation to grant Orphan Medicinal Product Designation to VCN-01 for the treatment of retinoblastoma and the European Commission confirmed the designation under Regulation No 141/2000 of the European Parliament and of the Council.

On May 27, 2025, we announced the presentation of the final data from an investigator-sponsored Phase 1 study of VCN-01 (zabilugene almadenorepvec) in refractory retinoblastoma patients in a poster presented by Dr.

Jaume Català-Mora, Pediatric Ophthalmologist, Sant Joan de Déu-Barcelona Children’s Hospital at the 2025 ASCO annual meeting.

Based on the study results, it was concluded that VCN-01 was well tolerated, after 2 intravitreal administrations at 2E10 vp/eye.

The most frequently reported treatment-related adverse events were Grade 1 or 2-uveitis being the most common adverse event and one patient with Grade 3 uveitis who did not receive the second dose because of medical decision and also experienced glaucoma requiring treatment.

No systemic toxicities occurred.

There were no dose limiting toxicities and no ocular or systemic toxicities greater than Grade 3 during the evaluation period.

Final findings include the following:

● Some degree of ocular inflammation and associated turbidity was observed after VCN-01 injection.

Inflammation was managed, and vitreous haze improved in some cases, using pre-emptive oral and/or topical steroids.

● VCN-01 did not cause retinal toxicity, and selective VCN-01 replication in retinoblastoma cells was observed by immunohistochemical analysis.

VCN-01 caused reversible changes in electroretinograms associated to turbidity.

● Replication of VCN-01 was detected over time within retinoblastoma tumors but was not observed in healthy tissue.

● Intravitreal VCN-01 demonstrated promising antitumor activity:

o Five patients presented a partial response, three presented stable disease and one, progressive disease

o The eyes of 3 out of 5 patients with partial response were preserved with vision after receiving eye-conservative therapy (follow-up 12-49 months)

VCN-01 (zabilugene almadenorepvec) in combination with Immunomodulatory therapeutics

Based on the clinical and pre-clinical data described below, we believe that the administration of VCN-01, can elicit an anti-tumor immune response that could potentiate the effects of VCN-01 and co-administered therapeutics.

2 unchanged sentences

We believe that the administration of VCN-01 into the tumor may help to overcome the observed resistance to PD-L1 checkpoint inhibitors and to mesothelin-directed CAR-T cells.

Phase 1 Trial of intravenous VCN-01 in Combination with Durvalumab in Subjects with Recurrent/ Metastatic SCCHN

Phase 1 Trial of intravenous VCN-01 (zabilugene almadenorepvec) in Combination with Durvalumab in Subjects with Recurrent/ Metastatic SCCHN

In February 2019, VCN entered into a Clinical Trial Agreement with Catalan Institute of Oncology (ICO) (Spain) to conduct an investigator sponsored Phase 1 clinical study to evaluate the safety, tolerability and RP2D of a single intravenous injection of VCN-01 combined with durvalumab in two administration regimens:

VCN-01 concomitantly with durvalumab, or sequentially with durvalumab starting two weeks after VCN-01 administration (NCT03799744).

The study is also designed to evaluate whether VCN-01 treatment can re-sensitize PD-(l)-1 refractory tumors to subsequent anti-PD-L1 therapy.

The study was also designed to evaluate whether VCN-01 treatment can re-sensitize PD-(l)-1 refractory tumors to subsequent anti-PD-L1 therapy.

Durvalumab is a human monoclonal antibody (“mAb”) of the immunoglobulin G (IgG) 1 kappa subclass that inhibits binding of PD-L1.

It is marketed as IMFINZI® by AstraZeneca/MedImmune, who supplied the product for its use in the clinical study.

This Phase I trial is a multicenter, open label, dose escalation study in patients with histologically confirmed head and neck squamous cell carcinoma from specific sites:

This Phase I trial was a multicenter, open label, dose escalation study in patients with histologically confirmed head and neck squamous cell carcinoma from specific sites:

oral cavity, oropharynx, larynx or hypopharynx that is recurrent/metastatic (R/M) and not amenable to curative therapy by surgery or radiation.

In addition, all patients should have undergone prior exposure to anti-PD-(L) 1 and progressed.

Patients are entered at each dose level, according to a planned dose escalation schedule.

The treatment is a single intravenous VCN-01 dose combined with concomitant intravenous durvalumab (MEDI4736) 1500 mg Q4W (Arm I) or durvalumab starting two weeks after VCN-01 administration (“sequential schedule”;

Patients were entered at each dose level, according to a planned dose escalation schedule.

The treatment was a single intravenous VCN-01 dose combined with concomitant intravenous durvalumab (MEDI4736) 1500 mg Q4W (Arm I) or durvalumab starting two weeks after VCN-01 administration (“sequential schedule”;

Patient recruitment into Arm I and Arm II was performed concurrently.

2 unchanged sentences

Patient recruitment into the study was completed in February 2022 with a total of 18 patients enrolled.

On September 5, 2022 we announced a presentation of initial data from this study in a poster at the European Society for Medical Oncology (ESMO) Congress.

The poster reported that treatment with VCN-01 had an acceptable safety profile when administered with durvalumab in the sequential schedule and the most common treatment-related adverse events were dose-dependent and reversible pyrexia, flu-like symptoms and increases in liver transaminases.

On September 5, 2022 we announced a presentation of initial data from this study in a poster at the ESMO Congress.

The poster reported that treatment with VCN-01 was well tolerated when administered with durvalumab in the sequential schedule and the most common treatment-related adverse events were dose-dependent and reversible pyrexia, flu-like symptoms and increases in liver transaminases.

Sustained blood levels of VCN-01 viral genomes and increased serum hyaluronidase levels were maintained for over six weeks and analysis of tumor samples showed an increase in CD8 T cells (a marker of tumor inflammation);

1 unchanged sentence

and downregulation of matrix-related pathways after VCN-01 administration.

The study has been completed and the clinical study report is being prepared.

On October 16, 2023, we presented additional data from this study in a poster at the European Society for Medical Oncology (ESMO) 2023 Congress held virtually and in Madrid, Spain from October 20-24, 2023.

The trial has been completed and the clinical study report has been completed.

On October 16, 2023, we presented additional data from this study in a poster at the ESMO 2023 Congress held virtually and in Madrid, Spain from October 20-24, 2023.

Key data and conclusions featured in the ESMO presentation include:

● 20 patients were enrolled with a median of 4 prior lines of therapy, from which six in the concomitant (“CS”) (single dose of VCN-01 in combination with durvalumab on day 1) and 12 in the sequential (“SS”) (single dose of VCN-01 on day -14 and durvalumab on day 1) were evaluable for response.

● In the CS cohort at the 3.3×10 12 viral particles (vp) dose, overall survival (OS) was 10.4 months.

● In the CS cohort at the 3.3×10 12 viral particles (vp) dose, OS was 10.4 months.

● In the SS cohort at the 3.3×10 12 vp dose OS was 15.5 months, whereas in the SS cohort at the 1×10 13 vp dose OS was 17.3 months.

9 unchanged sentences

● There was a statistically significant correlation between OS observed in patients and CPS on day 8 (p=0.005).

Phase 1 Trial evaluating the safety and feasibility of huCART-meso cells when given in combination with VCN-01

Phase 1 Trial evaluating the safety and feasibility of huCART-meso cells when given in combination with VCN-01 (zabilugene almadenorepvec)

In July 2021, VCN entered into a Clinical Trial Agreement with the University of Pennsylvania (Philadelphia) to conduct an investigator sponsored Phase 1 clinical study to evaluate the safety, tolerability and feasibility of intravenous administration of VCN-01 in combination with lentiviral transduced huCART-meso cells (developed by the laboratory of Dr.

Carl June) in patients with histologically confirmed unresectable or metastatic pancreatic adenocarcinoma and serous epithelial ovarian cancer (NCT05057715).

This is a Phase I study evaluating the combination of VCN-01 when given in combination with huCART-meso cells in a dose-escalation design in two cohorts (N = 3-6), where patients receive VCN-01 as a single IV infusion (at 3.3x10 12 or 1x10 13 vp) on Day 0, followed by a single dose of 5x10 7 huCART-meso cells on Day 14 via IV infusion.

This is a Phase 1 study evaluating the combination of VCN-01 when given in combination with huCART-meso cells in a dose-escalation design in two cohorts (N = 3-6), where patients receive VCN-01 as a single IV infusion (at 3.3x10 12 or 1x10 13 vp) on Day 0, followed by a single dose of 5x10 7 huCART-meso cells on Day 14 via IV infusion.

huCART-meso cells are modified T-cells targeting the mesothelin antigen, which is frequently expressed in multiple tumor types, particularly in pancreatic and ovarian cancers.

1 unchanged sentence

Initial VCN-01 clinical data from the studies described above suggest that administration of VCN-01 may increase tumor immunogenicity and improve access of the huCART-meso cells to tumor cells.

This Phase I study will evaluate the safety and tolerability of the VCN-01 huCART-meso cell combination and test the hypothesis that administration of VCN-01 may enhance the potential antitumor effects of the co-administered huCART-meso cells.

This Phase 1 study will evaluate the safety and tolerability of the VCN-01 huCART-meso cell combination and test the hypothesis that administration of VCN-01 may enhance the potential antitumor effects of the co-administered huCART-meso cells.

On July 8, 2022, we were notified that the first patient to be dosed with VCN-01 had passed the safety evaluation period in this study.

2 unchanged sentences

The peak and duration of huCART-meso T cells in the peripheral blood as well as duration of stable disease in evaluable patients showed encouraging trends.

On October 16, 2024, at the 2024 Advancing Gene Therapy and Cell Therapies for Cancer conference by the American Society for Gene and Cell Therapy in Philadelphia, University of Pennsylvania investigators presented results from the Phase 1 trial of huCART-meso cells administered in combination with VCN-01 in patients with pancreatic and serous epithetlial ovarian cancer.

Safety was in line with expectations from monotherapy studies and 3.3x10 12 was defined as the dose for further development.

3 unchanged sentences

This new CAR-T could potentially be evaluated in combination with VCN-01 in a future clinical trial.

Phase 1 Trial evaluating the intravenous administration of VCN-01 in patients prior to surgical resection of high-grade brain tumors

The trial is active, although not recruiting as treated patients are still on survival follow - up.

Phase 1 Trial evaluating the intravenous administration of VCN-01 (zabilugene almadenorepvec) in patients prior to surgical resection of high-grade brain tumors

In the second quarter of 2021, VCN entered into a Clinical Trial Agreement with the University of Leeds (UK) to sponsor a proof-of-concept Phase 1 clinical study to evaluate whether intravenously administered VCN-01 can cross the blood-brain barrier and infect the target brain tumor.

2 unchanged sentences

This study aims to assess the presence of VCN-01 within the resected surgical specimen after systemic VCN-01 delivery and determine the safety of intravenous VCN-01 in patients with recurrent high-grade glioma or brain metastases.

By confirming the presence of VCN-01 in high grade brain tumors following intravenous delivery, this study may pave the way for larger trials to study VCN-01 efficacy, both as a monotherapy and in combination with PD-1/PD-L1 blockade.

By confirming the presence of VCN-01 in high grade brain tumors following intravenous delivery, we believe this study may pave the way for larger trials to study VCN-01 efficacy, both as a monotherapy and in combination with PD-1/PD-L1 blockade.

This trial has already received approval from Medicines & Healthcare Products Regulatory Agency (MHRA) from UK Government.

On January 9, 2023, we issued a press release announcing that the first patient was dosed in this study and recruitment is on-going.

Our Current Gastrointestinal (GI) and Microbiome-Focused Pipeline

Our SYN-004 (ribaxamase) and SYN-020 clinical programs are focused on the gastrointestinal tract (GI) and the gut microbiome, which is home to billions of microbial species and composed of a natural balance of both “good” beneficial species and potentially “bad” pathogenic species.

On January 9, 2023, we issued a press release announcing that the first patient was dosed in this study.

Recruitment is on-going but challenging.

On May 12, 2025, a protocol amendment was submitted for this trial to MHRA and on July 8, 2025 we were notified by the investigator that the protocol amendment had been approved.

VCN-01 (zabilugene almadenorepvec) + Topoisomerase Inhibitors

On May 10, 2024, we presented non-clinical data describing enhanced anti-tumor effects in human pancreatic cancer xenograft-bearing mice treated with lead product candidate VCN-01 and liposomal irinotecan in a poster at the 27 th American Society of Gene and Cell Therapy (ASGCT) 2024 Congress held in Baltimore (Maryland) from May 7-11, 2024.

These data support the potential synergy of VCN-01 and additional first-line pancreatic cancer chemotherapy regimens FOLFIRINOX and NALIRIFOX.

Key findings reported in the poster include:

● The combination of VCN-01 + topoisomerase I (topo1) inhibitors, such as liposomal irinotecan, has a tolerable toxicity profile and may improve efficacy in the treatment of human pancreatic cancer.

● Viral protein expression was increased in human pancreatic cancer cell lines when they were exposed to topo1 inhibiting chemotherapeutics, irinotecan, its active metabolite, SN-38, and topotecan.

● Synergy of VCN-01 plus liposomal irinotecan was observed in animals bearing subcutaneous human pancreatic tumors.

o In human pancreatic mouse xenograft models, treatment with VCN-01 at a dose of 4x1010 vp or liposomal irinotecan alone (at both the 10 mg/kg and 5 mg/kg doses) resulted in significant tumor growth inhibition compared to saline.

o Combination therapy with VCN-01 + liposomal irinotecan at either dose displayed significantly reduced tumor growth compared to each treatment alone.

o qPCR analyses performed on tumors collected at end of study confirmed the presence of viral genomes, indicating ongoing transcriptional activity of VCN-01, which is consistent with viral replication for several days after administration.

We believe that intravitreal coadministration of VCN - 01 with topotecan may provide a new treatment option for children with refractory retinoblastoma and vitreous seeds, which remains an unmet medical need in patients with this rare disease.

Discussions are on - going with clinicians and key opinion leaders to define a clinical protocol for the VCN - 01 + topotecan combination in this patient population.

VCN-X Next Generation OVs and Albumin Shield™ Technology

We have also conducted research and development activities for next-generation oncolytic adenoviruses (termed VCN-X) with novel therapeutic payloads and structural modifications designed to increase tumor cell killing and improve systemic virus pharmacokinetics.

Preclinical proof-of-concept has been established with VCN-11, which has been engineered to contain all the features of VCN-01 as well as an additional modification to include an albumin binding domain (ABD) in the virus capsid.

The virus capsid is the target for neutralizing NAbs that are generated by the host immune system to destroy circulating viruses.

The presence of an ABD, however, blocks the binding of most neutralizing antibodies, which allows the virus to reach the tumor following intravenous administration.

This “Albumin Shield” works because human blood contains a large amount of albumin to coat the ABD-containing virus.

Importantly, this coating of albumin appears to be displaced after the virus reaches tumor cells to infect them.

In pre-clinical mouse studies to test the functionality of the “Albumin Shield”, mice pre-immunized with virus are able to completely neutralize an unmodified OV because they have a large concentration of Nabs in their blood.

By contrast, viruses such as VCN-11 that contain the ABD are not neutralized and retain their ability to infect and destroy tumor cells.

We believe the results with VCN-11 support the application of the Albumin Shield technology in our VCN-X program to advance treatments for tumors in which rapid multi-dosing may be beneficial.

VCN-12 is currently the focus of our preclinical studies.

In March 2021, preclinical data obtained with VCN-11 was published (J Control Release.

2021 Apr 10;332:517-528), showing that the ABD-containing virus induced 450 times more cytotoxicity in tumor cells than in normal cells.

Hyaluronidase production was confirmed by measuring the activity of the PH20 enzyme with a hyaluronic acid-degradation assay, and by measuring PH20 activity in VCN-11 infected tumors in vivo.

The ABD-containing virus evaded NAbs from different sources and tumor levels of virus were demonstrated in the presence of high levels of NAbs in vivo, whereas the control virus without ABD was neutralized.

VCN-11 showed a low toxicity profile in athymic nude mice and Syrian hamsters, allowing treatments with high doses and fractionated administrations without major toxicities (up to 1.2x10 11 vp/mouse and 7.5x10 11 vp/hamster).

ALT levels were increased on day 3 within an acceptable range that returned to normal levels by day 9.

Fractionated intravenous administration of the ABD-containing virus (splitting the dose into two portions

administered 4 h apart) appeared to improve virus circulation kinetics and increase tumor levels.

Antitumor efficacy was observed in the presence of NAbs against Ad5 and the ABD-containing virus.

In May 2022, we presented data at the 25th Annual Meeting of the ASGCT.

The presentation included preclinical results showcasing the potential of the Albumin Shield Technology to effectively target tumors after intravenous re-administration, even in the presence of high level NAbs, with no major toxicities observed.

Our internal VCN-X discovery programs are currently evaluating new oncolytic viruses armed with alternative payloads that may increase antitumor efficacy.

In October 2025, Dr.

Ramón Alemany, co-founder of VCN (now Theriva Biologics S.L.) and Head of the Immunotherapy and Virotherapy Group at the ProCURE Program of the Catalan Institute of Oncology (ICO) and the Oncobell Program of the Biomedical Research Institute of Bellvitge (IDIBELL) in Barcelona, presented new mechanistic and preclinical data for VCN-12, a next generation oncolytic adenovirus selected from our VCN-X discovery program at the 32 nd Annual Congress of the European Society of Gene & Cell Therapy (ESGCT) in Seville, Spain.

VCN-12 is derived from lead clinical product VCN-01 (zabilugene almadenorepvec) and is armed with additional transgenes designed to improve tumor cell lysis, enhance stroma degradation, and augment the antitumor immune response.

VCN-12 uses the same virus capsid as our lead clinical candidate VCN-01 (zabilugene almadenorepvec), but includes modifications intended to (i) increase stroma degradation by replacing human hyaluronidase PH20 with the more active bee hyaluronidase;

and (ii) increase tumor cell lysis by expressing the pore forming protein parasporin-2 to enable both cytotoxic and immunogenic cell death.

Parasporin-2 expression is expected to destroy both infected and surrounding uninfected tumor cells and stimulate a strong overall antitumor immune response and reduce viral immunodominance.

Data presented by Dr.

Alemany support the proposed VCN-12 mechanisms of action.

VCN-12 showed increased cell killing compared to VCN-01 in a variety of cancer cell models in vitro.

VCN-12 also displayed higher levels of hyaluronidase activity.

In animal studies, intravenous VCN-12 had a similar toxicity profile to VCN-01 in immunodeficient mice bearing human tumor xenografts.

Intratumoral VCN-12 significantly reduced tumor growth compared to VCN-01 in immunocompetent hamsters bearing HP-1 pancreatic tumors.

The antitumor effect of VCN-12 was observed in both the injected tumors and second tumors-implanted 4-days later but not injected.

Complete tumor regression of the first tumor was observed in two of nine hamsters and the second implanted tumor did not grow in these animals.

VCN-12 appeared to stimulate a persistent immune response that prevented the establishment of tumors in these two complete responders when they were implanted with HP-1 cells 43 days after VCN-12 treatment.

Further preclinical studies are planned to elaborate these initial findings.

THERICEL suspension cell lines for viral manufacturing

The THERICEL program is advancing a proprietary A549 suspension cell line for use in the manufacture of viral therapeutics.

These cells are entering feasibility studies to support significant scale - up and potential Phase 3 GMP manufacture of VCN-01 (zabilugene almadenorepvec) for use in clinical trials.

The use of the THERICEL suspension cells is expected to increase the efficiency and significantly reduce the cost of manufacture for VCN - 01 and other viral therapies.

We also have a Spanish government funded collaboration with the Universitat Autònoma de Barcelona to adapt the THERICEL suspension cell platform for the clinical manufacture of adeno - associated virus (“AAV”) therapies.

If successful, adaptation of the THERICEL platform to AAV manufacture will provide an opportunity for potential commercial collaborations in the manufacture of a range of gene therapy products.

Our Current Gastrointestinal (GI) and Microbiome-Focused Product Candidates

SYN-004 (ribaxamase) and SYN-020 are focused on the GI tract and the gut microbiome, which is home to billions of microbial species and composed of a natural balance of both “good” beneficial species and potentially “bad” pathogenic species.

When the natural balance or normal function of these microbial species is disrupted, a person’s health can be compromised.

All of our programs are supported by our established intellectual property portfolio and prosecution of existing applications.

We are exploring value creation options for our SYN-004 and SYN-020 assets, including out-licensing or partnering.

All of our programs have been supported by a robust patent estate.

As part of our strategic transformation into an oncology focused company, we (i) entered into the Rasayana License Agreement with Rasayana in February 2026, pursuant to which we granted Rasayana an exclusive worldwide license to research, develop, manufacture and commercialize any product related to or deriving from our SYN-020 asset, and (ii) we are exploring value creation options for our SYN - 004 asset, including out - licensing or partnering as we do not intend to further develop SYN-004 without receipt of grant funding or funding through a partnership or other collaboration.

SYN-004 (ribaxamase) — Prevention of antibiotic-mediated microbiome damage, thereby preventing overgrowth and infection by pathogenic organisms such as Clostridioides difficile infection (CDI) and vancomycin resistant Enterococci (VRE), and reducing the incidence and severity of acute graft-versus-host disease (aGVHD) in allogeneic HCT recipients

22 unchanged sentences

According to the European Society of Clinical Microbiology and Infections Disease (ECCMID), failure to address AMR could lead to a potential “antibiotic Armageddon”, resulting in 10 million deaths worldwide by 2050 and may cost as much as $100 trillion in worldwide economic output.

The Centers for Disease Control estimates the crude overall incidence rate of CDI in the United states to be 121.2 cases per 100,000 persons (approximately 500,000 patients) with a higher rate of community associated compared to healthcare associated infection (CDC Emerging Infections Program Healthcare-Associated Infections–Community Interface Report Clostridioides difficile Infection Surveillance, 2022.

https://www.cdc.gov/healthcare-associated-infections/media/pdfs/2022-CDI-Report-508.pdf) The overall incidence of CDI has declined since 2015 as better infection prevention practices and antimicrobial stewardship have decreased the number of healthcare associated acquired infections (Guh et al.

N Engl J Med.

however, the economic and social burdens of CDI remain high.

CDI infections are estimated to cost $5 billion per annum in the United States, primarily due to increased hospitalization and hospital length of stay, while mortality rates as high as 39% have been reported for patients with multiple episods of recurrent CDI (Feuerstadt et al.

BMC Infect Dis 23:132;

Malone et al.

Antimicrob Steward Healthc Epidemiol 3:e17.).

If approved, SYN-004 (ribaxamase) would be the first therapeutic intervention indicated to prevent the onset of antibiotic-mediated primary CDI.

The latest CDC estimates found the crude overall incidence rate of CDI in the United States to be 117.2 cases per 100,000 persons (approximately 392,000 patients based on the estimated US population at the end of 2023) with a higher rate of community associated compared to healthcare associated infection (CDC Emerging Infections Program Healthcare-Associated Infections–Community Interface Report Clostridioides difficile Infection Surveillance, 2023.

https://www.cdc.gov/healthcare-associated-infections/media/pdfs/2023-CDI-Report-508.pdf).

Phase 1a and 1b Clinical Trial Pharmacokinetic Data

In March 2015, we reported supportive pharmacokinetic data from a Phase 1a clinical trial, which suggested that SYN-004 (ribaxamase) should have no effect on the IV antibiotic in the bloodstream, allowing the antibiotic to fight the primary infection.

In February 2015, we reported supportive topline results from a subsequent Phase 1b clinical trial of escalating doses of oral SYN-004 (ribaxamase), with no safety or tolerability issues reported at dose levels and dosing regimens that were equivalent to or exceeded those expected to be studied in subsequent clinical trials.

The Phase 1a (40 participants) and 1b (24 participants) clinical trials of SYN-004 (ribaxamase) were initiated in December 2014.

In March 2015, we reported supportive pharmacokinetic data from a Phase 1a clinical trial (40 participants), which suggested that SYN-004 (ribaxamase) should have no effect on the IV antibiotic in the bloodstream, allowing the antibiotic to fight the primary infection.

In February 2015, we reported supportive topline results from a subsequent Phase 1b clinical trial (24 participants) of escalating doses of oral SYN-004 (ribaxamase), with no safety or tolerability issues reported at dose levels and dosing regimens that were equivalent to or exceeded those expected to be studied in subsequent clinical trials.

Two Phase 2a Clinical Trials:

7 unchanged sentences

Phase 2b Proof of Concept Clinical Trial Design & Results

In September 2015, we initiated a multicenter, randomized, placebo-controlled Phase 2b proof-of-concept clinical study in 412 patients (206 per group;

NCT02563106).

On January 5, 2017, we announced positive topline data from our Phase 2b proof-of-concept clinical trial intended to evaluate the ability of SYN-004 (ribaxamase) to prevent CDI, CDAD ( C.

On January 5, 2017, we announced positive topline data from our Phase 2b proof-of-concept clinical trial (412 participants-206 per group;

NCT02563106) intended to evaluate the ability of SYN-004 (ribaxamase) to prevent CDI, CDAD ( C.

difficile -associated diarrhea) and AAD (antibiotic-associated diarrhea) in patients hospitalized for a lower respiratory tract infection and receiving IV ceftriaxone.

7 unchanged sentences

Serious adverse events (SAEs) in the treatment arm, including fatal AEs, which exceeded those in the placebo arm, were not considered drug-related by investigators at the clinical sites, or by an independent third-party, each of whom determined SAEs were attributable to disparities in the underlying health and comorbidities between the groups.

This information is an estimate derived from the use of information under license from the following IMS Health Incorporated information service:

IMS Health Analytics for the full year 2016.

IMS expressly reserves all rights, including rights of copying, distribution, and republication.

On October 6, 2016 we were awarded a government contract in the amount of $521,014 by the CDC’s Broad Agency Announcement (BAA) 2016-N-17812 to examine changes in the gut resistome of patients in our Phase 2b clinical study.

Data generated under this contract are consistent with SYN-004’s (ribaxamase) mode of action of preserving the normal gut flora by degrading ceftriaxone in the upper GI tract of study participants treated with SYN-004 (ribaxamase).

The data further demonstrated that SYN-004 (ribaxamase) significantly reduced the loss of microbial diversity, reduced overgrowth of opportunistically pathogenic species(such as VRE), and reduced the emergence of antimicrobial resistance (AMR) genes caused by ceftriaxone treatment in SYN-004 (ribaxamase) treated patients compared to placebo.

The data further demonstrated that SYN-004 (ribaxamase) significantly reduced the loss of microbial diversity, reduced overgrowth of opportunistically pathogenic species (such as VRE), and reduced the emergence of AMR genes caused by ceftriaxone treatment in SYN-004 (ribaxamase) treated patients compared to placebo.

Future Potential Regulatory Strategy for Prevention of Primary CDI

1 unchanged sentence

Pursuant to the meeting, the FDA proposed criteria for Phase 3 clinical efficacy and safety which, if achieved, may support submission for marketing approval of SYN-004 (ribaxamase) on the basis of a single Phase 3 clinical trial.

The proposed SYN-004 (ribaxamase) Phase 3 clinical program entails a single, global, event-driven clinical trial with a fixed maximum number of approximately 4,000 patients for total enrollment and evaluates the potential efficacy and safety of ribaxamase in a broad patient population by enrolling patients with a variety of underlying infections treated with a range of IV beta-lactam antibiotics.

proposed SYN-004 (ribaxamase) Phase 3 clinical program entails a single, global, event-driven clinical trial with a fixed maximum number of approximately 4,000 patients for total enrollment and evaluates the potential efficacy and safety of ribaxamase in a broad patient population by enrolling patients with a variety of underlying infections treated with a range of IV beta-lactam antibiotics.

The proposed Phase 3 clinical trial incorporates co-primary safety and efficacy endpoints (mortality and the reduction in the incidence of CDI at one month after the last drug dose in the SYN-004 (ribaxamase) treatment group versus placebo, respectively).

1 unchanged sentence

Acute Graft-Versus-Host-Disease in Allogeneic Hematopoietic Cell Transplant (allogeneic HCT) Recipients & SYN-004 (ribaxamase)

In parallel with our clinical and regulatory efforts, we completed a Health Economics Outcomes Research (HEOR) study, which was conducted to generate key insights on how we can expect Health Care Practitioners, or HCPs, to evaluate patient access for SYN-004 (ribaxamase) while also providing a framework for potential reimbursement strategies.

In parallel with our clinical and regulatory efforts, we completed a Health Economics Outcomes Research (“HEOR”) study, which was conducted to generate key insights on how we can expect Health Care Practitioners (“HCPs”), to evaluate patient access for SYN-004 (ribaxamase) while also providing a framework for potential reimbursement strategies.

After evaluating findings from the study, we believe that there is significant potential value in exploring the development of SYN-004 (ribaxamase) in a narrower patient population where the incidence of the disease endpoint is high and the clinical development may be less costly.

4 unchanged sentences

Antibiotic-mediated damage to the gut microbiome is strongly associated with GVHD, bloodstream infections, VRE bacteremia, transplant relapse, and increased mortality in HCT recipients, raising concern over the spectrum of antibiotics used during HCT.

CDI occurs in up to 31% of HCT patients and is associated with GVHD and increased mortality.

CDI occurs in up to 31% of HCT patients and is associated with aGVHD and increased mortality.

aGVHD occurs in 30-60% of allogeneic HCT recipients and is recognized as a primary contributor to morbidity and mortality in this patient population.

4 unchanged sentences

It has been reported that in-patient costs for allogeneic HCT in the USA range from $180,000-$300,000 depending on the disease severity.

In 2014, all-cause costs for allogeneic HCT in the USA were greater than $600,000 per patient (up to 12 months post-transplant).

VRE infection is a persistent problem in HCT patients and VRE colonization after HCT has been associated with decreased patient survival.

4 unchanged sentences

Schroeder, Associate Professor of Medicine, Division of Oncology, Bone Marrow Transplantation and Leukemia.

The Phase 1b/2a clinical trial was a single center, randomized, double-blinded, placebo-controlled clinical trial of oral SYN-004 (ribaxamase) in up to 36 evaluable adult allogeneic HCT recipients.

The Phase 1b/2a clinical trial is a single center, randomized, double-blinded, placebo-controlled clinical trial of oral SYN-004 (ribaxamase) in up to 36 evaluable adult allogeneic HCT recipients.

The goal of this study is to evaluate the safety, tolerability and potential absorption into the systemic circulation (if any) of oral SYN-004 (ribaxamase;

6 unchanged sentences

On September 27, 2022, we issued a press release announcing positive outcomes from the Data and Safety Monitoring Committee (“DSMC”) review of results from the first Cohort and their recommendation that the study may proceed to enroll Cohort 2 in which study drug (SYN-004 or Placebo) is administered in combination with the IV beta-lactam antibiotic piperacillin/tazobactam.

On February 16, 2023 and April 13, 2023, we announced the presentation of safety and pharmacokinetic data from Cohort 1 of the Phase 1b/2a Clinical Trial of SYN-004 (ribaxamase) in allogeneic hematopoietic cell transplant recipients at the 2023 Tandem Meetings:

Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR and at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), respectively.

On October 3, 2024, we announced a positive outcome from the DSMC review of results from the second Cohort of our Phase 1b/2a randomized, double-blinded, placebo-controlled clinical trial of SYN-004 (ribaxamase) in allogeneic hematopoietic cell transplant (“HCT”) recipients for the prevention of acute graft-versus-host-disease.

Initiation of the third cohort is dependent on potential grant funding.

On February 16, 2023 and April 13, 2023, we announced the presentation of safety and pharmacokinetic data from Cohort 1 and on October 3, 2024, we announced a positive outcome from the DSMC review of results from the second Cohort of our Phase 1b/2a randomized, double-blinded, placebo-controlled clinical trial of SYN-004 (ribaxamase) in allogeneic hematopoietic cell transplant (“HCT”) recipients for the prevention of acute graft-versus-host-disease.

Based on a review of the safety and pharmacokinetic data, the DSMC recommended that the study may proceed to enroll Cohort 3 in which study drug (SYN-004 or Placebo) will be administered in combination with the IV beta-lactam antibiotic cefepime.

Based upon our current available funding and our focus on our clinical development of VCN-01 we do not anticipate that enrollment for the third cohort will commence unless we obtain grant funding, or find a licensee or partner for the SYN-004 development program.

SYN-020 — Oral Intestinal Alkaline Phosphatase (IAP)

3 unchanged sentences

We believe we have developed technologies to traverse this hurdle and now have the ability to produce more than 3 grams per liter of SYN-020 and anticipate a cost of roughly a few hundred dollars per gram at commercial scale.

Based on the known mechanisms as well as our own supporting animal model data, we intended to initially develop SYN-020 to mitigate the intestinal damage caused by radiation therapy that is routinely used to treat pelvic cancers.

While we believe SYN-020 may play a pivotal role in addressing acute and long-term complications associated with radiation exposure to the GI tract, we have also begun planning for potential development of SYN-020 in large market indications with significant unmet medical needs.

Based on the known mechanisms as well as our own supporting animal model data, we initially intended to develop SYN-020 to mitigate the intestinal damage caused by radiation therapy that is routinely used to treat pelvic cancers.

While we believe SYN-020 may play a pivotal role in addressing acute and long-term complications associated with radiation exposure to the GI tract, we have also explored the potential development of SYN-020 in large market indications with significant unmet medical needs.

Such indications include celiac disease, non-alcoholic fatty liver disease (“NAFLD”), and indications to treat and prevent metabolic and inflammatory disorders associated with aging.

On June 30, 2020, we submitted an IND application to the FDA in support of an initial indication for the treatment of radiation enteropathy secondary to pelvic cancer therapy.

On July 30, 2020, we announced that we received a study-may-proceed letter from the FDA to conduct a Phase 1a single-ascending-dose (“SAD”) study in healthy volunteers designed to evaluate SYN-020 for safety, tolerability and pharmacokinetic parameters (NCT04815993).

On June 29, 2021, we announced that enrollment, patient dosing and observation had been completed in the Phase 1, open-label, SAD study of SYN-020.

On June 29, 2021, we announced that enrollment, patient dosing and observation had been completed in the Phase 1, open-label, single ascending dose (“ SAD”) study of SYN-020.

The SAD study enrolled 6 healthy adult volunteers into each of four cohorts with SYN-020 given orally as single doses ranging from 5 mg to 150 mg.

The data demonstrated that SYN-020 maintained a favorable safety profile, was well tolerated at all dose levels, and no adverse events were attributed to the study drug.

No serious adverse events were reported.

No SAEs were reported.

Phase 1 Clinical Multiple-Ascending-Dose Study

During the third quarter of 2021 we initiated a Phase 1 clinical study evaluating multiple ascending doses (“MAD”) of SYN-020 (NCT05045833).

6 unchanged sentences

Additionally, fecal SYN-020 analyses verified intestinal bioavailability while plasma levels of SYN-020 were below the limit of quantitation in all samples at all timepoints verifying that SYN-020 was not absorbed into the systemic circulation.

During the second quarter of 2020, we announced that we entered into an agreement with Massachusetts General Hospital (“MGH”) granting us an option for an exclusive license to intellectual property and technology related to the use of IAP to maintain GI and microbiome health, diminish systemic inflammation, and treat age-related diseases, which option was later amended liver fibrosis in select diseases, including NAFLD.

The option expired unexercised on July 1, 2024.

The Phase 1 data from our SAD and MAD studies are intended to support the development of SYN-020 in multiple clinical indications including radiation enteritis, NAFLD, celiac disease, and diseases associated with aging.

With our transition to an oncology focused Company, we are exploring strategic opportunities to enable advancement of this potentially valuable asset.

Future Potential Regulatory Strategy for Prevention of Primary CDI

As part of our strategic transformation into an oncology focused company, we are exploring value creation options for our SYN-004 and SYN-020 assets, including out-licensing or partnering.

VCN-01 + Topoisomerase Inhibitors

On May 10, 2024, we presented non-clinical describing enhanced anti-tumor effects in human pancreatic cancer xenograft-bearing mice treated with lead product candidate VCN-01 and liposomal irinotecan in a poster at the 27 th American Society of Gene and Cell Therapy (ASGCT) 2024 Congress held in Baltimore (Maryland) from May 7-11, 2024.

These data support the potential synergy of VCN-01 and additional first-line pancreatic cancer chemotherapy regimens FOLFIRINOX and NALIRIFOX.

Key finding reported in the poster include:

● Viral protein expression was increased in human pancreatic cancer cell lines when they were exposed to topo1 inhibiting chemotherapeutics, irinotecan, its active metabolite, SN-38, and topotecan.

● Synergy of VCN-01 plus liposomal irinotecan was observed in animals bearing subcutaneous human pancreatic tumors.

In human pancreatic mouse xenograft models, treatment with VCN-01 at a dose of 4x1010 vp or liposomal irinotecan alone (at both the 10 mg/kg and 5 mg/kg doses) resulted in significant tumor growth inhibition compared to saline.

Combination therapy with VCN-01 + liposomal irinotecan at either dose displayed significantly reduced tumor growth compared to each treatment alone.

qPCR analyses performed on tumors collected at end of study confirmed the presence of viral genomes, indicating ongoing transcriptional activity of VCN-01, which is consistent with viral replication for several days after administration.

VCN-X Next Generation OVs and Albumin Shield™ Technology

In parallel with VCN-01 clinical development, we are developing next-generation oncolytic adenoviruses (termed VCN-X) with novel therapeutic payloads and structural modifications to increase tumor cell killing and improve systemic virus pharmacokinetics.

Preclinical proof-of-concept has been established with VCN-11, which has been engineered to contain all of the features of VCN-01 as well as an additional modification to include an albumin binding domain (ABD) in the virus capsid.

The virus capsid is the target for neutralizing antibodies (NAbs) that are generated by the host immune system to destroy circulating viruses.