8-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of Report (Date of earliest event reported): December 14, 2021

SYNTHETIC BIOLOGICS, INC.

(Exact name of registrant as specified in its charter)

Nevada	001-12584	13-3808303
(State or other jurisdiction of incorporation)	(Commission File No.)	(IRS Employer Identification No.)

9605 Medical Center Drive, Suite 270

Rockville, Maryland 20850

(Address of principal executive offices and zip code)

(301) 417-4364

Registrant’s telephone number, including area code

N/A

(Former name or former address, if changed since last report)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):

¨ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

¨ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

¨ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

¨ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

Title of each class	Trading Symbol(s)	Name of each exchange on which registered
Common stock, par value $0.001 per share	SYN	NYSE American

Indicate by check mark whether the registrant is an emerging growth company as defined in in Rule 405 of the Securities Act of 1933 (17 CFR §230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (17 CFR §240.12b-2 of this chapter).

Emerging growth company ¨

If an emerging growth company, indicate by checkmark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ¨

Item 8.01   Other Events.

Synthetic Biologics, Inc. (the “Company”) will be making corporate presentations over the next several weeks, including a planned webcast Business Update on Tuesday, December 14, 2021. In connection with the presentations, the Company intends to discuss the slide presentation attached as Exhibit 99.1 hereto, which is incorporated herein by reference.

The slide presentation attached as Exhibit 99.1 to this Current Report on Form 8-K includes “safe harbor” language pursuant to the Private Securities Litigation Reform Act of 1995, as amended, indicating that certain statements contained in the slide presentation or in the press release are “forward-looking” rather than historical.

The Company undertakes no duty or obligation to update or revise information included in this Current Report on Form 8-K or Exhibit 99.1 hereto.

Item 9.01. Financial Statements and Exhibits.

(d) Exhibits

Exhibit No.	Description
99.1	Synthetic Biologics, Inc. investor presentation dated December 14, 2021

SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

Dated: December 14, 2021	SYNTHETIC BIOLOGICS, INC.
	By:	/s/ Steven A. Shallcross
		Name:	Steven A. Shallcross
		Title:	Chief Executive Officer and Chief Financial Officer

EX-99.1

Exhibit 99.1

December 14, 2021 Business Update

Forward - Looking Statements This presentation includes forward - looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 , as amended, concerning Synthetic Biologics and VCN Biosciences (“VCN”) . In some cases forward - looking statements can be identified by terminology such as "may," "should," "potential," "continue," "expects," "anticipates," "intends," "plans," "believes,“ "estimates,” “indicates,” and similar expressions . These statements are based upon management’s current beliefs, expectations and assumptions and are subject to a number of risks and uncertainties, many of which are difficult to predict and include statements regarding the proposed acquisition of VCN by Synthetic Biologics, the timing of such acquisition and the various timelines for development of VCN’s product candidates . The forward - looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those set forth or implied by any forward - looking statements . Important factors that could cause actual results to differ materially from those reflected in Synthetic Biologics’ forward - looking statements include, among others, the risk a ssociated with Synthetic Biologics’ and VCN’s ability to satisfy the conditions to consummate the proposed acquisition, including obtaining necessary governmental approvals, the timing of the closing of the proposed acquisition, the occurrence of any event, change or other circumstance or condition that could give rise to the termination of the Stock Purchase Agreement between the shareholders of VCN and Synthetic Biologics, unanticipated difficulties or expenditures relating to the proposed acquisition or development of VCN’s drug candidates , the response of business partners and competitors to the announcement of the proposed acquisition, and/or potential difficulties in employee retention as a result of the announcement and pendency of the proposed acquisition, whether the combined business of Synthetic Biologics and VCN will be successful, Synthetic Biologics’ and VCN’s product candidates demonstrating safety and effectiveness, as well as results that are consistent with prior results, the ability to initiate clinical trials and if initiated, the ability to complete them on time and achieve the desired results and benefits continuing enrollment as expected, the ability to obtain regulatory approval for commercialization of product candidates or to comply with ongoing regulatory requirements, regulatory limitations relating to Synthetic Biologics’ and VCN’s ability to promote or commercialize their product candidates for the specific indications, acceptance of product candidates in the marketplace and the successful development, marketing or sale of Synthetic Biologics’ and VCN’s products, developments by competitors that render such products obsolete or non - competitive, Synthetic Biologics’ and VCN’s ability to maintain license agreements, the continued maintenance and growth of Synthetic Biologics’ and VCN’s patent estate, and other factors described in Synthetic Biologics’ annual report on Form 10 - K for the year ended December 31 , 2020 , subsequent quarterly reports on Form 10 - Qs and any other filings we make with the SEC . Synthetic Biologics can give no assurance that the conditions to the acquisition will be satisfied . The information in this presentation is provided only as of the date presented, and Synthetic Biologics undertakes no obligation to update any forward - looking statements contained in this presentation on account of new information, future events, or otherwise, except as required by law . 2

• Founded in Barcelona, Spain in 2009 by Drs. Ramon Alemany, Gabriel Capellà and Manel Cascalló • Developing unique oncolytic viruses ( OVs ) optimized for intravenous administration and maximum tumor destruction • Evaluating first product, VCN - 01, as monotherapy and combination therapy with 70 cancer patients across 4 clinical studies to date • Launching a Phase 2 clinical study in patients with newly - diagnosed metastatic pancreatic ductal adenocarcinoma ( PDAC ) and a Phase 2/3 study in retinoblastoma VCN has also developed a compelling platform of next - generation OVs for addressing additional cancers with high unmet need VCN Biosciences S.L. 3

VCN Experienced Management Team • Dr. Cascalló will assume the role of Managing Director in the Synthetic Biologics EU subsidiary • More than 12 years experience as CEO of biotech companies • Expert in clinical development of oncolytic adenovirus and author of many peer - reviewed scientific publications • Inventor on several patents for the use of adenovirus as antitumoral agents • Serves as an independent expert for the European Medicines Agencies (EMA) Manel Cascall ό PhD CEO & Founder, VCN Biosciences • Dr. Tufaro plans to assume the role of Chief Operating Officer for Synthetic Biologics • More than 25 years experience as founder and CEO of several biotech companies in the space • Former Professor of Microbiology and Immunology at the University of British Columbia with numerous patents and peer - reviewed scientific publications • Highly experienced in the development of oncolytic viruses based on herpes simplex and adenovirus • Board member and advisor for several companies in the biotechnology space Frank Tufaro PhD COO (planned) Synthetic Biologics / VCN Biosciences Ramon Alemany PhD VCN Founder & Scientific Committee Chairman 4 • Dr. Alemany will jointly lead Preclinical & Discovery activities of Synthetic Biologics • A world - wide recognized expert in oncolytic adenoviruses for cancer treatment • Published more than 100 peer - reviewed publications and numerous patents in the fields of Gene Therapy and Virotherapy • Acts as editor and reviewer for the main international journals in these fields • Consultant for several companies based on adenoviruses • Member of Executive Board of the Spanish Society of Gene and Cell Therapy

• Synthetic Biologics (NYSE American: SYN ) to acquire 100% outstanding equity of VCN • Total upfront consideration for the acquisition is $4.7M in cash • Shares of SYN common stock equal to 19.99% of the outstanding shares of common stock distributed to VCN • Up to $70.25M total cash milestone payments • Backend loaded predominantly based on future Phase 2/3 clinical and regulatory milestones • No royalties or commercial sales milestones to sellers • VCN to maintain current legal structure, operate as a wholly owned subsidiary of SYN • Closing subject to Foreign Direct Investment ( FDI ) approval by the Spanish government ( anticipated within 60 days from signing) SYN - VCN Transaction Summary 5

• Advanced Clinical Oncology Pipeline and Platform • Multiple SYN and VCN clinical assets • Lead orphan cancer indications with critical unmet medical need • Continued expansion of the pipeline with joint discovery programs • Synergies Between Teams • Complementary skill sets and experience in OVs, gene therapy, CMC, and product development • Immediate access to laboratory facilities and personnel for joint discovery and development • Shared international clinical trial expertise • Multinational Presence • Facilitates access to clinical study sites, patients, regulatory agencies • Establishes a footprint in key EU market for partnering and commercialization • Access to US financial markets SYN - VCN: Accelerating the Pathway to Value 6

VCN Technologies

• Oncolytic Viruses are a Promising Therapeutic Approach • Combines the natural ability of certain viruses to cause immunogenic cell death, induce inflammatory responses and trigger immune cell infiltration into treated tumors • Can be combined with other therapies to treat cancer more effectively (e.g. chemotherapy, checkpoint inhibitors and CAR - T cells) • OV companies have attracted a lot of pharma and investor interest at all stages of development • Current Challenges • Intravenous dosing is not as well advanced as intratumoral injection for OVs due to difficulties in producing virus at scale and off - target toxicities • Metastases are not effectively addressed by localized intratumoral injection • Virus replication and spread in the target tumor(s) may be restricted by dense stroma • Certain tumors are difficult to directly inject safely and repeatedly (e.g. lung, pancreatic) Oncolytic Virus Features and Challenges 8

Unique Mechanism of Action for VCN Platform 9

VCN - 01 Oncolytic Adenovirus • SYSTEMIC • Increased affinity for tumor cells • Reduced liver tropism • Highly replicating • SELECTIVE • Replication only in tumor cells with defects in the retinoblastoma Rb - E2F pathway ¹ • Transgenes only expressed after virus replication² • STROMA DEGRADING • Degrades hyaluronic acid in the stroma ( PH20 ) ³ • Increases virus dissemination in the tumor • Increases tumor immunogenicity • Increases tumor access of cancer therapeutics • Potential combination with multiple interventions 10 ¹Most if not all solid tumors; Giacinti (2006) Oncogene 25: 5220; Polager (2009) Nat Rev Cancer 9: 738. ²Transgene expression under control of virus major late promoter ( MLP ). ³PH20 is human testicular hyaluronidase enzyme. For additional details and references see Appendix. IMAGE CREDIT: https://microbewiki.kenyon.edu/index.php/Adenovirus - based_Gene_Therapy:_a_Promising_Novel_Cancer_Therapy E2F + E1a - Δ24 [MLP] PH20 Genetic modifications RGDK modification to fiber shaft AdV5 (Group C) RGD retained in penton base

Pancreatic Ductal Adenocarcinoma (PDAC) • PDAC accounts for 3 rd highest cause of cancer - associated deaths in US (4 th in EU) ¹ - ³ • North America ~63,000 new cases and 53,000 deaths each year • Western Europe ~46,000 new cases and 43,000 deaths each year • PDAC h as the lowest survival rate of all major organ cancers • Median survival 4 - 6 months from diagnosis , 1 - year survival 24% • Treatment options for metastatic PDAC are limited ³ • First - line therapies include (m)FOLFIRINOX, gemcitabine + nab - paclitaxel • Checkpoint inhibitors have been largely ineffective • PDAC stroma is a physical and immunosuppressive barrier to therapy • Stromal hyaluronan accumulation is associated with low immune response and poor prognosis ⁴ 11 ¹ Bengtsson (2020) Sci Rep 10: 16425. ² Carioli (2021) Ann Oncol 32: 478. ³For additional details and references see Appendix. ⁴ Tahkola (2021) Sci Rep 11: 12216. (m)FOLFIRINOX (modified) leucovorin + 5 - FU + irinotecan + oxaliplatin. nab - Paclitaxel nanoparticle albumin - bound paclitaxel. IMAGE CREDIT: Dragovich T. et al. “Pancreatic Cancer: Practice Essentials”. Medscape, 2021. https://emedicine.medscape.com/article/280605 - ove rview Pancreatic adenocarcinoma resected from the pancreas body and tail

VCN - 01 PDAC Clinical Data Encourage Phase 2 • Multicenter, open - label, dose escalation study of a single IV dose of VCN - 01 “ gemcitabine/Abraxane® ( G/A )¹ • 42 patients treated with different dosing regimens, including monotherapy; concomitant treatment; and sequential treatment ² • Outcomes • Safety/tolerability demonstrated • RP2D defined • Promising antitumor activity 12 ¹NCT02045602. ²Concomitant VCN - 01 administered same day as first dose of G/A, sequential VCN - 01 administered 7 - days prior to fir st dose of G/A. ³ Von Hoff (2013) NEJM 369: 1691. Abraxane ® nab - paclitaxel. OS overall survival. ORR overall response rate. PFS progression free survival. RP2D recommended phase 2 dose. vp virus particles. Favorable Survival with VCN - 01 vs Published Standard - of - Care VCN - 01 Sequential Regimen VCN - 01 + G/A Published G/A alone ³ Overall Survival, median months (n) 3.3x10¹² vp/patient (6) 13.1 1.0x10¹³ vp/patient (6) 20.8 Combined (both doses) (12) 13.5 8.5 Overall Response Rate (n) 3.3x10¹² vp/patient (6) 16.7% (1) 1.0x10¹³ vp/patient (6) 83.3% (5) Combined (both doses) (12) 50% (6) 23% Survival > 12 months 8 (75%) Survival > 27 months 3 (25%)

VCN - 01 Remodels the PDAC Tumor Matrix 13 Sustained hyaluronidase quantification in patient sera is linked to viral activity and can be used for tracking effective VCN - 01 replication Hepatic metastasis of PDAC patient a - CD8 a - IDO VCN - 01 remodels pancreatic tumor matrix and the immunological environment, favoring tumor inflammation

• Retinoblastoma ( Rb ) is an orphan indication that accounts for ~2 - 3% of all childhood cancers¹ • 200 - 300 cases each year in the USA, EU ² - ⁴ • VCN - 01 selectivity enables development as an intravitreal treatment for Rb patients • VCN - 01 can be used in combination with chemotherapy to potentially improve outcomes • VCN - 01 can be used as a rescue therapy for patients who fail standard therapy Retinoblastoma, a Rare Pediatric Malignancy 14 ¹https://www.cancer.org/cancer/retinoblastoma/about/key - statistics.html. ²Stacey (2021) Ophthalmology 128: 1369. ³One Retinoblastoma World Map https://map.1rbw.org/. ⁴For additional details and references see Appendix. IMAGE CREDIT: Courtesy of Hospital Sant Joan de Déu, Barcelona

VCN - 01 in Retinoblastoma • Single center, open - label dose escalation study of intravitreal ( IVT ) VCN - 01 ¹ , ² • Children aged 1 - 12 years • Rb that is recurrent or refractory to chemotherapy and for whom enucleation is the best treatment option • VCN - 01 (2.0x10 ⁹ or 2.0x10 ¹º vp per eye) on days 1 and 15 • Outcomes • Safety/tolerability demonstrated • RP2D defined • Promising antitumor activity 15 ¹EudraCT 2016 - 001060 - 11. NCT03284268. ²Pascual Pasto (2019) Sci Transl Med 11: eaat9321. VCN - 01 IVT 2.0x10¹º vp x 2 doses Pt 2 2 Pt 3 Reduced number and size of tumor vitreous seeds following VCN - 01 administration² Complete tumor regression D14 D28 D0 D64 M8 D0

Exploring Expanded indications for VCN - 01 Location Phase Indication Co - therapy Route (n) Status NCT or EudraCT Multicenter (ESP) 1 PDAC Gemcitabine + nab - Paclitaxel IT (8) Complete¹ NCT02045589 Institut Català d'Oncologia (ICO) 1 HNSCC Durvalumab IV (11) On - going NCT03799744 U. Leeds 1 Adult brain tumors .. IV (12) Safe to proceed 2020 - 003405 - 59 U. Pennsylvania 1 PDAC, Ovarian huCART - meso² IV (12) Safe to proceed NCT05057715 U. Navarra 1 Pediatric brain tumors .. IC (9 - 18) Pre - IND 2020 - 002860 - 30 16 ¹Bazan - Peregrino et al. (2021) J Immunother Cancer 9: e003254. ² huCART - meso are autologous T cells engineered to express an extracellular single chain variable fragment (scFv) with mesothelin specificity. HNSCC head and neck squamous cell carcinoma. IC intracranial. IV intravenous. IT intratumoral. IVT intravitreal VCN is collaborating with world - leading clinical research institutions

• PDAC Phase 2 Clinical Trial • Finalizing protocol for a multinational, multicenter, study evaluating IV VCN - 01 with gemcitabine/nab - paclitaxel compared to gemcitabine/nab - paclitaxel alone • Newly - diagnosed metastatic PDAC patients treated with gemcitabine/nab - paclitaxel first line therapy • Principal Investigator Dr. Manuel Hidalgo Medina, MD PhD ‒ Chief of the Division of Hematology and Medical Oncology at Weill Cornell Medicine/New York - Presbyterian Hospital ‒ Member of the Board of Directors, Bristol Myers Squibb • Rb Phase 2/3 Pivotal Trial • Developing a protocol for a multinational, multicenter, study evaluating intravitreal VCN - 01 • Principal Investigator: Dr. Guillermo Chantada, MD PhD ‒ Principal Researcher, Associate Physician, Hospital Sant Joan de Déu, Barcelona, Spain; National Council of Research in Argentina (CONICET); Scientific Director, Pediatric Hemato - Oncology Service of the Hospital Universitario Austral, Argentina and Hospital Pereira Rossell , Montevideo, Uruguay ‒ President, International Society of Paediatric Oncology VCN - 01 Next Steps 17

Albumin Shield Œ to Expand the VCN Platform • VCN has developed the Albumin Shield technology to protect OVs as they travel to the tumors¹ , ² • Albumin Shield modified OVs are coated by albumin and protected from circulating antibodies in cancer patients pre - exposed to adenovirus • Albumin Shield may enable multiple intravenous administrations for hard - to - treat patients • Albumin Shield first candidate VCN - 11 is being prepared for a Phase 1 clinical trial in ovarian cancer and other solid tumors 18 ¹Rojas (2016) J Control Rel 237:78; ABD binds mouse and human serum albumin, but not bovine; ²Mato - Berciano (2021) J Control Rel 332: 517. Albumin Shield modified OVs express an albumin binding domain (ABD) on the virus surface ( hexon ) that binds host serum albumin. The modification allows parent and the progeny to be albumin coated for continued protection Hexon

VCN Albumin Shield Platform Candidates 19 CLINICALLY - TESTED ADENOVIRUS EXPRESSING PH20 HYALURONIDASE TO DEGRADE STROMA + ALBUMIN SHIELD ΠTO PREVENT NEUTRALIZATION BY CIRCULATING ANTI - VIRAL ANTIBODIES TO FACILITATE IV MULTIDOSING + UNIQUE MULTIFUNCTIONAL PROTEINS TO TURN COLD TUMORS HOT VCN - 11: Hyaluronidase alone Hyaluronidase + Bispecific Engagers Hyaluronidase + Toxins Hyaluronidase + Immunomodulators COMMON FEATURES PRODUCT SPECIFIC FEATURES Albumin Shield platform invites potential licensing opportunities

• VCN OVs ARE OPTIMIZED FOR SYSTEMIC DELIVERY • Treatment of primary and metastatic lesions for multiple solid tumor types (Rb - E2F defective in most solid tumors) • Extremely selective with improved safety and pharmacokinetics (liver sequestration tumor penetration ) • VCN OVs ARE HIGHLY REPLICATIVE • Fulfilling systemic dosing requirements • Potent transgene expression is a built - in biomarker for tracking viral replication in the tumor • VCN OVs EXPRESS HYALURONIDASE to DEGRADE TUMOR STROMA • Increased tumor dissemination allowing co - administered chemotherapies and immunotherapies (CAR - T, CPI) • Improved infiltration of anti - tumor immune responders to improve efficacy • VCN OVs ENABLE MULTIDOSING in HARD - TO - TREAT TUMORS • Preclinically validated platform with decreased NAb susceptibility for systemic re - administration • Co - delivery of hyaluronidase and additional therapeutic transgenes VCN Potential Competitive Advantages 20 CAR - T chimeric antigen receptor T - cell. CPI checkpoint inhibitor. NAb neutralizing antibody. Rb - E2F pathway reviewed in Giacinti (2006) Oncogene 25: 5220 and Polager (2009) Nat Rev Cancer 9: 738.

Pipeline and Milestones

SYN and VCN Combined Pipeline IND - enabling Phase 3 Phase 2 Phase 1 β - lactamase SYN - 004 Hyaluronidase Technology (HT) VCN - 01 VCN - 01 VCN - 01 Prevention of aGVHD in allogeneic HCT recipients Pancreatic Cancer (IV) േ GEM/nab - paclitaxel Retinoblastoma (IVT) Combination Therapy with CPI bIAP SYN - 020 Radiation enteritis + other indications HT+Albumin Shield VCN - 11 Solid tumors Candidate aGVHD acute graft - vs - host disease; allogeneic HCT allogeneic hematopoietic cell transplant. bIAP bovine intestinal alkaline phosphatase. CPI immune checkpoint inhibitor. GEM/ nab+paclitaxel Gemcitabine + Abraxane ® . IT intratumoral. IV intravenous. IVT intravitreal. 22

Upcoming News and Potential Milestones H1 2023 Q4 2021 Q2 2022 Q3 2022 Q4 2022 • VCN - 01 U. Leeds ISS first patient dosed • SYN+VCN merger closing • VCN - 01 UPenn ISS first patient dosed • SYN - 004 Phase 1b/2a data 1 st antibiotic cohort • SYN - 020 Phase 1 MAD topline data • SYN - 004 Phase 1b/2a 2 nd cohort begins dosing • SYN - 020 Phase 2a initiation (indication TBD) • Initiation of VCN - 01 PDAC Phase 2 • SYN - 004 Phase 1b/2a data 2 nd antibiotic cohort • VCN - 01 RB proposed pivotal trial initiation • SYN - 020 Phase 2a data (indication TBD) • SYN - 004 Phase 1b/2a data 3 rd antibiotic cohort • VCN - 11 IND Filing • Initiation of VCN - 11 Phase 1 in solid tumors 23 Q1 2022

Appendix

• Oncolytic viruses ( OVs ) infect and lyse cancer cells without harming normal cells • Can be naturally occurring or genetically engineered to improve selectivity, safety and efficacy • Can be developed from multiple virus types, including adenovirus , herpes simplex (HSV), measles, parvovirus, reovirus, and vaccinia • OV tumor cell lysis can reverse immune tolerance to tumors • Exposes tumor - specific and tumor - associated antigens (turning “cold” tumors “hot”) • Retarget the adaptive immune system to induce a long - lasting anti - tumor response • OVs face multiple challenges to systemic delivery • Poorly penetrable, antiviral and immunosuppressive tumor stroma • Host anti - OV immune responses • Sequestration and destruction of OV in the liver and spleen Oncolytic Viruses 25 Reviewed in: Balachandran (2019) Gastroenterology 156: 2056. Gonzalez - Pastor (2021) Cancer Gene Ther 28: 375. Hemminki (2020) J Hematol Oncol 13: 84. Martinez - Quintanilla (2019) J Clin Invest 129: 1407. Ungerechts (2016) Mol Ther Methods Clin Dev 3: 16018.

Adenovirus Overview 26 ¹Charman (2019) FEBS Lett 593: 3531. ²Hemminki (2020) J Hematol Oncol 13: 84. ³Hajeri (2020) Cancers 12: 1504. ⁴Gonzalez - Pastor (2021) Cancer Gene Ther 28: 375 – 89. ⁵Recombinant Ad5 genomes can be up to 105% of the 36 kb genome of the native Ad5. IMAGE CREDIT: https://microbewiki.kenyon.edu/index.php/Adenovirus - based_Gene_Therapy:_a_Promising_Novel_Cancer_Therapy • Adenoviruses ( AdV ) are medium - sized (90 – 100 nm), non - enveloped viruses with icosahedral shaped capsids containing a double - stranded DNA ( dsDNA ) genome typically 30 - 36 kb in length¹ - ³ • There are at least 57 AdV serotypes classified into 7 subgroups (A to G)² • AdV2 and AdV5 (Group C) are the most commonly - used viruses for OV design ¹ - ⁴ • Large packaging capacity ⁵ • Infect both dividing and non - dividing cells • Lack of integration into the host genome • Mild nature of illness after infection

Structural features determining virus viability, tumor access and efficacy¹ - ⁴ Oncolytic Adenoviruses 27 ¹Hajeri (2020) Cancers 12: 1504. ²Gonzalez - Pastor (2021) Cancer Gene Ther 28: 375. ³Yamamoto (2017) Cancer Sci 108: 831. ⁴ Khare (2012) J Virol 86: 2293, as much as 95 - 98% of an IV dose of unmodified Ad5 is trafficked to the liver where ~90% of the dose is sequestered and destroyed by resident liver macrophages called Kupffer cells. IMAGE CREDIT: https://microbewiki.kenyon.edu/index.php/Adenovirus - based_Gene_Therapy:_a_Promising_Novel_Cancer_Therapy Virus attaches to target cell by interaction between the fiber knob and the host cell coxsackievirus and adenovirus receptor ( CAR ) Virus internalized into target cell by interaction between the penton base and target cell αvβ3 and αvβ5 integrins Genetic engineering can confer tumor selectivity and improve therapeutic efficacy² , ³ • Conditionally replicate only in tumor cells • Express therapeutic payloads that elicit or enhance anti - tumor effects • Avoid host and tumor defense mechanisms Hexon components can interact with host neutralizing antibodies, receptors, proteins, and cells and elicit an AdV - specific T - cell response Fiber shaft can bind to heparan sulphate proteoglycans ( HSPG ) and facilitate uptake into the liver ⁴

VCN Oncolytic Virus Genetic Modifications L5 L5 Fiber Shaft RGDK L3 Hexon ABD SA K pA PH20 2 8 ¹ Since this is a transgene and not a chemical/physical coating, progeny virus will also be albumin coated. ²MLP control means tra nsgenes will only be expressed after replication, which occurs selectively in tumor cells. Transgene expression (PH20 in blood) can be a biomarker for viral repli cat ion in the tumor. ³PH20 cassette inserted downstream of the fiber gene contains a splice acceptor ( SA ), a kozak sequence ( K ) and a polyadenylation stop sequence ( pA ) 28 VCN - 01 VCN - 11 Ad5 wild type | Reduces Liver Tropism Fiber Shaft KKTK Host albumin | Enables replication in normal cells | Facilitates liver sequestration | Replication restricted to tumor cells (Rb - E2F mutated) ABD albumin binding domain ( streptococcal protein G)¹ Ad5 Adenovirus type 5 E1a - Δ24 deletion of 24 base pairs within the E1a promoter; further modified by insertion of 8 extra E2F binding sites and one Sp1 - binding site at nucleotide site 415 ( 415p ) MLP major late promoter² PH20 soluble human testicular hyaluronidase³ KKTK Lys - Lys - Thr - Lys putative HSPG binding domain on fiber shaft RGDK Arg - Gly - Asp - Lys inserted in place of KKTK on fiber shaft VCN - 12 VCN - 11 armed with additional therapeutic transgene Degrades tumor stroma RGDK SA K pA PH20 | Binds host albumin to protect against neutralizing antibodies

Pancreatic Cancer Cases and Deaths 2020 ¹ REGION ALL Male Female New Cases Deaths New Cases No. per 100,000 Deaths New Cases No. per 100,000 Deaths Caribbean 2,746 2,668 1,479 5.1 1,440 1,267 3.6 1,228 Central America 6,576 6,244 3,232 3.8 3,111 3,344 3.2 3,133 South America 28,030 27,118 13,766 5.4 13,346 14,264 4.3 13,772 Northern America 62,643 53,277 32,938 9.3 27,888 29,705 6.9 25,389 Eastern Asia 181,450 173,212 98,421 7.0 93,135 83,029 4.8 80,077 South - Eastern Asia 16,485 16,167 9,458 2.9 9,309 7,027 1.8 6,858 South - Central Asia 21,954 21,144 13,634 1.5 13,089 8,320 0.9 8,055 Western Asia 13,812 13,511 7,975 7.1 7,804 5,837 4.4 5,707 Central & Eastern Europe 44,371 42,788 22,576 9.9 21,812 21,795 5.6 20,976 Western Europe 45,461 43,336 22,672 9.9 21,684 22,789 7.4 21,652 Southern Europe 30,836 28,517 15,250 8.4 14,409 15,586 6.2 14,108 Northern Europe 19,448 17,493 9,712 8.3 8,793 9,736 6.7 8,700 Australia and New Zealand 4,674 3,776 2,370 7.9 1,952 2,304 6.7 1,824 WORLD 495,773 466,003 262,865 5.7 246,840 232,908 4.1 219,163 29 ¹Data from The Global Cancer Observatory, GLOBOCAN International 2020 survey of persons 0 - 74 years. https://gco.iarc.fr/today/data/factsheets/cancers/13 - Pancreas - fact - sheet.pdf . For additional US specific data see da Costa (2020) JNCI Cancer Spectrum 4: pkaa033.

¹ PDAC pancreatic ductal adenocarcinoma. Cancers in the pancreas head (~70%) are diagnosed earlier than cancers in the body or tail (e ach ~15%), which have a worse prognosis, Sarantis (2020) World J Gastrointest Oncol 12: 173 - 181. ²Bengtsson (2020) Sci Rep 10: 16425. ³GLOBOCAN 2020 survey of persons 0 - 74 years. Ushio (2021) Diagnostics 11: 562. ⁴ Toesca (2018) Int J Radiation Oncol Biol Phys 100: 1155 - 1174. ⁵American Joint Committee on Cancer T umor size, N odal involvement, M etastasis. ⁶Yu (2015) Gut 64: 1783 - 9. Pancreatic Cancer Resectable Borderline Resectable Metastatic / Recurrent (unresectable) Stage I Stage II Stage III Stage IV PDAC >90% pancreatic cancer¹; median age 67 - 68 yr ; 51% male² 1 - year (5 - year) overall survival 24% (9%)³; median 4 - 6 months² Locally Advanced (unresectable) Differentiated by tumor involvement with vasculature⁴ AJCC Stage IA IB IIA IIB III IV T - N - M⁵ T1 N0 M0 T2 N0 M0 T3 N0 M0 T1 - 3 N1 M0 T1 - 3 N2 M0 T4 NX - 2 M0 TX - 4 NX - 2 M1 Median Age, yr (range) ⁶ 66 (30 - 88) 66 (31 - 89) 68 (31 - 93) 66 (30 - 95) 67 (31 - 94) 67 (30 - 95) Male (Female), %⁶ 51 (49) 48 (52) 50 (50) 51 (49) 50 (50) 54 (46) Proportion of PDAC, %² 1.3% 4.4% 11.5% 16.3% 10.6% 56.0% 5 - Year Survival, %² 31.7% 11.8% 9.0% 8.7% 1.9% 0.5% Pancreas Head, %⁶ 61% 58% 77% 85% 75% 55% Male (per 100,000)³ N. America 9.3; W. Europe 9.9; E. Asia 7.0 Female (per 100,000)³ N. America 6.9; W. Europe 7.4; E. Asia 4.8 30 Pancreatic Cancer Staging

¹Radiotherapy is used in <20% of PDAC cases as most present at a late stage. ²Neoadjuvant chemotherapy - if indicated - is ident ical to first - line chemotherapy. ³Patients with good performance status ECOG 0 - 1. ⁴Patients with good to moderate performance status ECOG 0 - 2.⁵Patients with poor performance status ECOG 3 - 4. ⁶Checkpoint inhibitor ( CPI e.g. pembrolizumab) added in some cases but CPIs have had very limited efficacy in PDAC to date. (m)FOLFIRINOX (modified) leucovorin + 5 - FU + irinotecan + oxaliplatin. nab - Paclitaxel nanoparticle albumin - bound paclitaxel. Tempero (2021) J Natl Compr Canc Netw 19: 439. Pancreatic Cancer Treatment 31 Resectable Borderline Resectable Metastatic / Recurrent (unresectable) Locally Advanced (unresectable) Differentiated by tumor involvement with vasculature⁴ (m)FOLFIRINOX³ Gemcitabine + nab - Paclitaxel⁴ OR FOLFIRI(NOX)³ Gemcitabine + nab - Paclitaxel⁴ 5 - FU + Leucovorin + Liposomal Irinotecan⁴ Radiotherapy if resection margins¹ Neoadjuvant² Gemcitabine ± erlotinib ; single agent capecitabine or 5 - FU; ± CPI⁶ Single agent g emcitabine , capecitabine or 5 - FU⁵ First - Line Progression or Recurrence 31 Stage I Stage II Stage III Stage IV Differentiated by tumor involvement with vasculature⁴ VCN - 01

Tumor Stroma Barriers to Therapy Pancreatic Ductal Cell Carcinoma (PDAC) 32 Graphic from ¹Balachandran (2019) Gastroenterology 156: 2056. ²Sarantis (2020) World J Gastrointest Oncol 12: 173. ³Orth (2019) Radiation Oncol 14: 141. ⁴Christenson (2020) Lancet Oncol 21 :e135. ⁵ Elsayed (2021) Biomedicines 9: 389. ⁶ Tahkola (2021) Sci Rep 11: 12216. • PDAC stroma can account for 50 - 70% of the total tumor mass¹ , ² (up to 90% of the tumor volume³ , ⁴) • PDAC stroma is characterized by dense immunosuppressive desmoplasia which stems from activated pancreatic stellate cells ( PSCs ) that produce collagens, laminin, and fibronectin¹ - ⁵ • Extracellular matrix components such as hyaluronic acid can creating a physical barrier to the delivery of chemotherapy and immunotherapeutics by elevating interstitial fluid pressures and collapsing intratumoral vasculature¹ - ⁵ • Malignant cells, fibroblasts, and myeloid cells secrete immunosuppressive cytokines and chemokines that prevent effective anti - tumor T cell responses • PDAC has remained almost completely resistant to immunotherapy (including checkpoint inhibitors)¹ , ³ • Stromal hyaluronan accumulation associated with low immune response and poor prognosis⁶ STROMA

• Retinoblastoma ( Rb ) is a rare pediatric malignancy accounting for ~2 - 3% of all childhood cancers¹ • Primarily diagnosed in children ≤2 years¹ • 200 - 300 cases each year in the USA, EU and >1,000 cases each in China and India² , ³ • Significant regional disparities in age/stage at diagnosis, treatment options, and mortality (40 - 70% mortality in low - income countries cf. 3 - 5% in high income countries)⁴ - ⁷ • Rb can be unilateral (60 - 70% of cases) or bilateral (30 - 40%)⁴ , ⁸ • Unilateral disease: 85% of cases have a somatic RB1 mutation, 15% have a germline (heritable) mutation • Bilateral disease: assumed that 100% have a germline mutation • Rb treatments vary with stage of disease⁴ • Prior to intraarterial chemotherapy ( IAC ), enucleation was the primary life - saving intervention for Rb patients • IAC, where available, has dramatically reduced enucleation rates (from >95% pre - IAC to <10%)⁹ • Multiple potential opportunities for VCN - 01 in Rb treatment • Improve outcomes of surgery and/or chemotherapy (potential reduction in intensity) • Rescue therapy to prevent enucleation Retinoblastoma 33 ¹https://www.cancer.org/cancer/retinoblastoma/about/key - statistics.html. ²Stacey (2021) Ophthalmology 128: 1369. ³One Retinoblastoma World Map https://map.1rbw.org/. ⁴For additional details and references see Appendix slides 34 - 36. ⁵ Tomar (2020) Ophthalmology 127: 1719. ⁶ Fabian (2020) JAMA Oncol 6: 685 . ⁷Canturk (2010) Br J Ophthalmol 94: 1432. ⁸https://eyewiki.org/Retinoblastoma. ⁹Abramson (2015) PLoS ONE 10: e0145436.

Rb Cases - One Retinoblastoma World Map ¹ 34 ¹Reported number of retinoblastoma cases from One Retinoblastoma World Map https://map.1rbw.org/.

¹ Fabian (2020) JAMA Oncol 6 :685; m edian [IQR] age; ²Fabian ID (2018) Community Eye Health 31: 11. ³ Tomar (2020) Ophthalmology 127: 1719. HIC high income countries; ICRB International Classification of Retinoblastoma. IIRC International Intraocular Retinoblastoma Staging System. IRSS International Retinoblastoma Staging System. LIC low - income countries. Subret subretinal. Retinoblastoma Staging EXTRAocular IRSS² IIRC/ICRB² Group A INTRAocular Group B Group C Group D Group E Stage I Stage 0 Stage II Stage III Stage IV Metastatic (a) No CNS (b) CNS 0.5% 18.7% Enucleated Tumor completely resected 40.8% 33.8% Enucleated Microscopic r esidual t umor 0.6% 11.5% Regional Extension Orbit, cervical lymph nodes 0.5% 20.1% Intraocular Patient treated conservatively HIC 56.8% cases LIC 8.7% cases Very Low Risk of losing eye Tumor ≤3 mm Only retina No vitreous seeding 6.1%, 6.5% Low Risk of losing eye Tumor >3 mm Only retina No vitreous seeding 16.5%, 20.9% Moderate Risk of losing eye Discrete tumor Any location Focal vitreous or subret seeds 7.3%, 1.4% High Risk of losing eye Non - discrete Disseminated Diffuse vitreous or subret seeds 38.8%, 9.7% Very High Risk of losing eye Eye is anatomically or functionally destroyed 31.3%, 61.5% HIC: LIC: HIC 1.5% cases LIC 49.1% cases¹ HIC 98.5% cases LIC 50.9% cases¹ HIC Age 14.0 [6.2 - 26.6] mos at diagnosis¹ LIC Age 30.5 [18.3 - 45.9] mos at diagnosis UNILATERAL HIC 69.2% LIC 68.3%¹ BILATERAL HIC 30.8% LIC 31.7% IIRC, ICRB³ 35 RETINOBLASTOMA

Retinoblastoma Treatment Bilateral or germline RB1 Group A Unilateral Group B Group C Group D Group E 36 Extraocular IAC Cryo or ITT GLOBE SALVAGE Consolidation Cryo or TTT; IAC; IvitC ; IcamC Plaque radiotherapy (brachytherapy; rare) ENUCLEATION ± High Dose IVC IVC, IAC Macula Involved Adapted from: Ancona - Lezama (2020) Indian J Ophthalmol. 68: 2356. Cryo cryotherapy. IAC intra arterial chemotherapy ( melphalan ± topotecan , carboplatin). IcamC intra cameral chemotherapy (melphalan, topotecan). IVC intra venous chemotherapy ( vincristine+etoposide+carboplatin ). IvitC intra vitreal chemotherapy (melphalan, topotecan). TTT transpupillary thermotherapy. FAIL GLOBE SALVAGE 1 st Line FAIL FAIL RETINOBLASTOMA FAIL

• Bayo - Puxan N et al. (2006) Role of the putative heparan sulfate glycosaminoglycan - binding site of the adenovirus type 5 fiber shaft on liver detargeting and knob - mediated retargeting. J Gen Virol 87:2487 – 2495 • Rojas J et al. (2012) Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG - binding domain with RGD. Gene Ther 19:453 – 457 • Rodríguez - García A et al. (2015) Safety and efficacy of VCN - 01, an oncolytic adenovirus combining fiber HSG - binding domain replacement with RGD and hyaluronidase expression. Clin Cancer Res 21:1406 - 18 • Pascual Pasto G et al. (2019) Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN - 01. Sci Transl Med 11:eaat9321 • Martínez - Vélez N et al. (2019) The oncolytic adenovirus VCN - 01 as therapeutic approach against pediatric osteosarcoma. Clin Cancer Res 22:2217 - 25 • Bazan - Peregrino M et al. (2021) VCN - 01 disrupts pancreatic cancer stroma and exerts antitumor effects. J ImmunoTher Cancer 9:e003254. • Rojas LA et al. (2016) Albumin - binding adenoviruses circumvent pre - existing neutralizing antibodies upon systemic delivery. J Control Rel 237:78 – 88 • Mato - Berciano A et al. (2021) Oncolytic adenovirus with hyaluronidase activity that evades neutralizing antibodies: VCN - 11. J Control Rel 332:517 - 528 VCN Biosciences Key Publications 37

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