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We are a diversified clinical-stage company developing therapeutics in areas of high unmet need.
−Removed: As a result of the Acquisition of VCN, described in more detail below, the began transitioning its 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, improve access of co-administered cancer therapies to the tumor, and promote a robust and sustained anti-tumor response by the patient’s immune system.
+Added: As a result of the Acquisition of Theriva Biologics, S.L.
+Added: (“VCN”, formerly named VCN Biosciences, S.L.), described in more detail below, we began transitioning 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, improve access of co-administered cancer therapies to the tumor, and promote a robust and sustained anti-tumor response by the patient’s immune system.
Prior to the Acquisition, our focus was on developing therapeutics designed to treat gastrointestinal (GI) diseases which included.
−Removed: our lead clinical development candidates:
−Removed: (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, Clostridioides difficile infection (CDI), overgrowth of pathogenic organisms, the emergence of antimicrobial resistance (AMR), and 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.
+Added: our clinical development candidates:
+Added: (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 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 around our SYN-004 and SYN-020 assets.
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Advancement of these products may be better achieved through out-licensing or partnering and we will explore opportunities for both SYN-004 and SYN-020 moving forward.
−Removed: Acquisition of VCN Biosciences, S.L
−Removed: On March 10, 2022, pursuant to the terms of the Share Purchase Agreement (“Purchase Agreement”) we entered into with VCN and the shareholders of VCN Biosciences S.L.
−Removed: (the “Sellers”), we completed our acquisition of all the outstanding shares of VCN (the “VCN Shares”) from the shareholders of VCN.
−Removed: Pursuant to the Purchase Agreement, as consideration for the purchase of the VCN Shares of capital stock, we paid $4,700,000 (the “Closing Cash Consideration”) to Grifols Innovation and New Technologies Limited (“Grifols”), the owner of approximately 86% of the equity of VCN, and issued to the remaining Sellers 2,639,530 shares of our common stock, $.001 par value (the “Closing Shares”), representing 19.99% of the outstanding shares of our common stock on December 14, 2021, the date of the Purchase Agreement.
−Removed: As additional consideration for the purchase of the VCN Shares held by Grifols, we also agreed to make certain milestone payments to Grifols.
−Removed: In September, 2022, we received approval from the FDA that it is safe to proceed with our phase 2 clinical trial of VCN-01.
−Removed: Due to this approval we will pay Grifols $3.0 million in Q4 2022.
−Removed: Pursuant to the terms of the Purchase Agreement we loaned VCN $417,000 to help finance the costs of certain of VCN’s research and development activities.
−Removed: In addition, at Closing VCN and Grifols entered into a sublease agreement for the sublease by VCN of the laboratory and office space as well as a transitional services agreement.
−Removed: We agreed as a post- Closing covenant to commit to fund VCN’s research and development programs, including but not limited to VCN-01 PDAC phase 2 trial, VCN-01 RB trial and necessary G&A within a budgetary plan of approximately $27.8 million.
−Removed: VCN is a clinical-stage biopharmaceutical company developing new oncolytic adenoviruses for the treatment of cancer.
−Removed: VCN’s lead product candidate, VCN-01, is being studied in clinical trials for pancreatic cancer and retinoblastoma with additional investigator sponsored trials in indications including head and neck squamous cell carcinoma (HNSCC)..
−Removed: VCN-01 is designed to be administered systemically, intratumorally or intravitreally, either as a monotherapy or in combination with standard of care, to treat a wide variety of cancer indications.
−Removed: VCN-01 is designed to replicate selectively and aggressively within tumor cells, and to degrade the tumor stroma barrier that serves as a significant physical and immunosuppressive barrier to cancer treatment, Degrading the tumor stroma has been shown to improve access to the tumor by the virus and additional therapies such as chemo- and immuno-therapies.
−Removed: Importantly, degrading the stroma exposes tumor antigens, turning “cold” tumors “hot” and enabling a sustained anti-tumor immune response.
−Removed: VCN has the rights to four exclusive patents for proprietary technologies, as well as technologies developed in collaboration with the Virotherapy Group of the Catalan Institute of Oncology (ICO-IDIBELL) and with Hospital Sant Joan de Deu (HSJD), with a number of additional patents pending.
−Removed: Recent Developments
−Removed: Effective October 12, 2022, we changed our name to Theriva Biologics, Inc.
−Removed: by filing a Certificate of Amendment to its Articles of Incorporation (the “Certificate of Amendment”) with the Secretary of State of the State of Nevada on October 11, 2022.
−Removed: In addition, effective October 12, 2022, the Company amended and restated its Amended and Restated Bylaws (the “Bylaws”) to reflect the Name Change (the “Amended and Restated Bylaws”).
−Removed: The Amended and Restated Bylaws contain no other changes.
−Removed: In connection with the Name Change, the Company’s Common Stock will began trading on the NYSE American LLC under the new ticker symbol “TOVX” effective as of the opening of trading hours on October 13, 2022
−Removed: Reverse Stock Split
−Removed: On July 15, 2022, we announced a reverse stock split (the “Reverse Stock Split”) of our issued and outstanding common stock, par value $0.001 per share (the “Common Stock”), at a ratio of one (1) share of Common Stock for every ten (10) shares of Common Stock, effective July 25, 2022 (the “Effective Date”).
−Removed: Our Common Stock began trading on a split-adjusted basis on the NYSE American when the market opened on July 25, 2022.
−Removed: The Reverse Stock Split was authorized by our Board of Directors on July 11, 2022.
−Removed: Private Placement Offering
−Removed: On July 29, 2022, we closed a private placement offering pursuant to the terms of a Securities Purchase Agreement (the “Purchase Agreement”) dated as of July 28, 2022 entered into with MSD Credit Opportunity Master Fund, L.P.
−Removed: (the “Investor”), pursuant to which we issued and sold (the “Offering”) 275,000 shares of the Company’s Series C Convertible Preferred Stock, par value $0.001 per share (the “Series C Preferred Stock”), and 100,000 shares of the Company’s Series D Convertible Preferred Stock, par value $0.001 per share (the “Series D Preferred Stock,” and together with the Series C Preferred Stock, the “Preferred Stock”), at an offering price of $8.00 per share, for gross proceeds of approximately $3.0 million in the aggregate, before the deduction of discounts, fees and offering expenses.
−Removed: The shares of Preferred Stock will be convertible, at a conversion price (the “Conversion Price”) of $1.22 per share (subject in certain circumstances to adjustments), into an aggregate of 2,459,016 shares of the Company’s common stock, par value $0.001 per share (the “Common Stock”), at the option of the holders of the Preferred Stock and, in certain circumstances, by the Company.
−Removed: The Purchase Agreement contains customary representations, warranties and agreements by the Company and customary conditions to closing.
−Removed: Recent Clinical Developments
−Removed: On July 8, 2022, we were notified of the clearance of the safety evaluation period by the first patient that had been dosed in the investigator sponsored Phase 1 clinical trial evaluating VCN-01 (NCT05057715), an intravenous oncolytic adenovirus, in combination with mesothelin-directed lentiviral transduced human chimeric antigen receptor modified T cells (huCART-meso) for patients with pancreatic and serious epithelial ovarian cancers.
−Removed: On September 5, 2022, we issued a press release announcing presentation of a poster entitled “A Phase I Study to Evaluate the Safety, Tolerability, and Efficacy of VCN-01 in Combination with Durvalumab (MEDI4736) in Subjects with Recurrent/ Metastatic Squamous Cell Carcinoma of the Head and Neck (R/M HNSCC)” at the European Society for Medical Oncology (ESMO) Congress of initial data from a Phase 1 investigator-sponsored study evaluating VCN-01 in combination with durvalumab for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M HNSCC).
−Removed: We also issued a press release on September 12, 2022,
−Removed: Key data and conclusions featured in the ESMO presentation include:
−Removed: Treatment with VCN-01 had an acceptable safety profile when administered with durvalumab in the sequential regimen (single dose of VCN-01 administered 14 days prior to the first dose of durvalumab;
−Removed: o The most common treatment-related adverse events (TRAEs) were pyrexia, flu-like symptoms and increases in liver transaminases.
−Removed: o TRAEs were dose-dependent, reversible and consistent with TRAEs previously described for other adenovirus-based products.
−Removed: ● Pharmacokinetics (PK) and pharmacodynamics (PD) :
−Removed: Based on toxicology and PK/PD analysis the recommended Phase 2 dose is 1x10 13 viral particles (vp)/patient.
−Removed: ● Biological activity :
−Removed: Sustained blood levels of VCN-01 viral genomes and increased serum hyaluronidase levels were maintained for over six weeks.
−Removed: o Observed an increase in CD8 T cells, a marker of tumor inflammation and an upregulation of PD-L1 in tumors.
−Removed: o Analysis of serial tumor biopsies revealed differential gene expression profiles and downregulation of matrix-related pathways after VCN-01 administration.
−Removed: On September 27, 2022, we issued a press release announcing positive outcome from the DSMC review of results from the first 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 (aGVHD).
−Removed: Key data and conclusions disclosed in the press release include:
−Removed: Cohort 1 enrolled 19 patients who received at least 1 dose of study drug (SYN-004 or Placebo randomized 2:1).
−Removed: Sixteen patients received at least one dose of intravenous (IV) meropenem and 12 of these patients completed sufficient doses of IV meropenem to be evaluable towards the study endpoints.
−Removed: The study is on-going and remains blinded;
−Removed: however, key findings from blinded data for Cohort 1 are included below:
−Removed: ● Adverse events (AEs) and serious adverse events (SAEs) observed in Cohort 1 were typical of those observed in allo-HCT patients and no AEs or SAEs were determined to be related to study drug treatment by the investigators.
−Removed: o A total of 13 SAEs were reported among 10 patients, with the most common SAE being infections and infestations including sepsis.
−Removed: o One patient died 14 days after the last dose of study drug (within the 30-day reporting period) due to sepsis that was not related to study drug.
−Removed: ● Consistent with previous studies of SYN-004 in healthy volunteers, SYN-004 was not observed in blood samples from the majority of the evaluable patients.
−Removed: o A total of 3 plasma samples (~2% of all analyzed samples) had low but quantifiable levels of SYN-004 using a sensitive ECL assay.
−Removed: o None of the 3 ECL positive plasma samples was found to contain active SYN-004 using a functional enzyme activity assay.
−Removed: ● Meropenem pharmacokinetics were as expected for this patient population.
−Removed: Based on a review of the safety and pharmacokinetic data, the DSMC has recommended that the study may proceed to enroll Cohort 2 in which study drug (SYN-004 or Placebo) will be administered in combination with the IV beta-lactam antibiotic piperacillin/tazobactam.
−Removed: On September 30, 2022, we issued a press release announcing an oral presentation entitled “Topotecan enhances oncolytic adenovirus infection, replication and antitumor activity in retinoblastoma,” featuring Dr.
−Removed: Victor Burgueño, Professor at Fundació Sant Joan de Déu at the SIOP 2022 Congress of the International Society of Pediatric Oncology, being held in Barcelona, Spain from September 28-October 1, 2022.
−Removed: The new data from the study for which Dr.
−Removed: Victor Burgueño is the lead investigator further support evaluation of VCN-01, an oncolytic adenovirus expressing hyaluronidase, and topotecan for the treatment of refractory retinoblastoma.
−Removed: Key data and conclusions showcased in the SIOP presentation include:
−Removed: ● VCN-01 treatment in combination with topotecan, but not with carboplatin or melphalan, significantly increased VCN-01 infection and replication in retinoblastoma cells (p=0.0007) in vitro.
−Removed: ● In athymic mice engrafted with human retinoblastomas, topotecan administered systemically after intratumoral VCN-01 increased viral genome replication and the number of VCN-01 infected cells when compared to administration of VCN-01 alone (p = 0.0002).
−Removed: ● Sequential administration of intratumoral VCN-01 followed by systemic topotecan significantly increased median ocular survival, compared to VCN-01 alone (p =0.0364).
Our Current Product Pipeline
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CPI immune checkpoint inhibitor.
−Removed: Gem/nab-P Gemcitabine + Abraxane® (nab-paclitaxel).
+Added: Gem/Nab Gemcitabine + Abraxane® (nab-paclitaxel).
HNSCC head and neck squamous cell carcinoma.
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OV oncolytic adenovirus engineered to selectively replicate in tumors and express hyaluronidase enzyme PH20.
−Removed: ¹Additional products with preclinical proof-of-concept include SYN-006 (carbapenemase) to prevent aGVHD and infection by carbapenem resistant Enterobacteriaceae and SYN-007 (ribaxamase) DR to prevent antibiotic associated diarrhea with oral β-lactam antibiotics.
+Added: ¹Additional products with preclinical proof-of-concept include SYN-006 (carbapenemase) to prevent aGVHD and infection by carbapenem resistant enterococci and SYN-007 (ribaxamase) DR to prevent antibiotic associated diarrhea with oral β-lactam antibiotics.
²Depending on funding/partnership.
−Removed: SYN-004 may enter an FDA-agreed Phase 3 clinical trial for the prevention of Clostridioides difficile infection.
+Added: SYN-004 may enter an FDA-agreed Phase 3 clinical trial for the treatment of CDI.
³We have an option-license agreement with Massachusetts General Hospital to develop SYN-020 in several potential indications related to inflammation and gut barrier dysfunction.
−Removed: Our Gastrointestinal (GI) and Microbiome-Focused Pipeline
−Removed: 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.
−Removed: When the natural balance or normal function of these microbial species is disrupted, a person’s health can be compromised.
−Removed: All of our programs are supported by our growing intellectual property portfolio.
−Removed: We are maintaining and building our patent portfolio through:
−Removed: filing new patent applications;
−Removed: prosecuting existing applications;
−Removed: and licensing and acquiring new patents and patent applications.
−Removed: Clinical and Pre-Clinical Update
−Removed: SYN-004 (ribaxamase) — Prevention of antibiotic-mediated microbiome damage, C.
−Removed: difficile infections (CDI), overgrowth of pathogenic organisms, the emergence of antimicrobial resistance (AMR) and acute graft-versus-host disease (aGVHD) in allogeneic HCT recipients
−Removed: Phase 1b/2a Clinical Study in Allogeneic HCT Recipients
−Removed: In August 2019, we entered into a Clinical Trial Agreement (CTA) with the Washington University School of Medicine (Washington University) to conduct a Phase 1b/2a clinical trial of SYN-004 (ribaxamase).
−Removed: Under the terms of this agreement, we serve as the sponsor of the study and supply SYN-004 (ribaxamase).
−Removed: Dubberke, Professor of Medicine and Clinical Director, Transplant Infectious Diseases at Washington University and a member of the SYN-004 (ribaxamase) steering committee serves as the principal investigator of the clinical trial in collaboration with his Washington University colleague Dr.
−Removed: Schroeder, Associate Professor of Medicine, Division of Oncology, Bone Marrow Transplantation and Leukemia.
−Removed: On January 7, 2020, we announced the receipt of official meeting minutes from the FDA following a Type-C meeting held on December 2, 2019 at our request to discuss the development of SYN-004 (ribaxamase) for treatment of allogeneic HCT recipients who are administered IV beta-lactam antibiotics in response to fever.
−Removed: Based on the final meeting minutes, the Phase 1b/2a clinical trial will comprise a single center, randomized, double-blinded, placebo-controlled clinical trial of oral SYN-004 (ribaxamase) in up to 36 evaluable adult allogeneic HCT recipients.
−Removed: 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;
−Removed: 150 mg four times daily) administered to allogeneic HCT recipients who receive an IV carbapenem or beta-lactam antibiotic to treat fever.
−Removed: Study participants will be enrolled into three sequential cohorts administered a different study-assigned IV antibiotic.
−Removed: Each cohort seeks to complete eight evaluable participants treated with SYN-004 (ribaxamase) and four evaluable participants treated with placebo.
−Removed: Safety and pharmacokinetic data for each cohort will be reviewed by an independent Data and Safety Monitoring Committee, which will make a recommendation on whether to proceed to the next IV antibiotic cohort.
−Removed: The study will also evaluate potential protective effects of SYN-004 on the gut microbiome as well as generate preliminary information on potential therapeutic benefits and patient outcomes of SYN-004 in allogeneic HCT recipients.
−Removed: On July 30, 2020, we received written notification from the FDA informing us that they determined the Phase 1b/2a clinical program in adult allogeneic HCT recipients may proceed per the submitted clinical study protocol.
−Removed: On December 22, 2020, we announced that we received approval from the Institutional Review Board (IRB) at Washington University to commence the Phase 1b/2a clinical trial of SYN-004.
−Removed: During the first quarter of 2021, Washington University began screening patients for enrollment of the first of three antibiotic cohorts in the Phase 1b/2a clinical trial of SYN-004 in allogeneic HCT recipients.
−Removed: On April 14, 2021, we announced that the first patient had been dosed in our Phase 1b/2a clinical trial of SYN-004 (ribaxamase) in allogeneic hematopoietic cell transplant (HCT) recipients for the prevention of acute graft-versus-host-disease (aGVHD.
−Removed: On September 27, 2022, we issued a press release announcing positive outcome from the Data and Safety Monitoring Committee (“DSMC”) review of results from the first Cohort of the Company’s 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 (aGVHD).
−Removed: To date, we have completed Cohort 1, which enrolled 19 patients who received at least 1 dose of study drug (SYN-004 or Placebo randomized 2:1).
−Removed: Sixteen patients received at least one dose of intravenous (IV) meropenem and 12 of these patients completed sufficient doses of IV meropenem to be evaluable towards the study endpoints.
−Removed: The study is on-going and remains blinded;
−Removed: however, key findings from blinded data for Cohort 1 are included below:
+Added: Recent Clinical Developments
+Added: On January 9, 2023, we issued a press release announcing that the first patient has been dosed in the Phase 1 investigator sponsored clinical trial of intravenous VCN-01 in patients with high-grade brain tumors who are scheduled for surgical resection.
+Added: On January 17, 2023, we issued a press release announcing the first patient has been dosed 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 (PDAC) (NCT05673811).
+Added: On February 16, 2023, we issued a press release announcing that the presentation of blinded safety and pharmacokinetic (PK) data from the ongoing 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 (aGVHD).
+Added: These data were featured in a poster presentation at 2023 Tandem Meetings:
+Added: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, being held in Orlando, Florida from February 15-19, 2023.
+Added: Cohort 1 of the study enrolled 19 patients who received at least 1 dose of study drug (SYN-004 or Placebo randomized 2:1).
+Added: Twelve of these patients completed two doses of IV MER to be evaluable towards the study endpoints.
+Added: While the study is on-going and remains blinded, key findings showcased in the poster presentation (#LBA6) titled “Interim Analysis of SYN-004 Phase 1b/2a Trial in Hematopoietic Cell Transplant (HCT) Recipients” include:
● Adverse events (AEs) and serious adverse events (SAEs) observed in Cohort 1 were typical of those observed in allo-HCT patients and no AEs or SAEs were determined to be related to study drug treatment by the investigators.
−Removed: o A total of 13 SAEs were reported among 10 patients, with the most common SAE being infections and infestations including sepsis.
−Removed: o One patient died 14 days after the last dose of study drug (within the 30-day reporting period) due to sepsis that was not related to study drug.
● Consistent with previous studies of SYN-004 in healthy volunteers, SYN-004 was not observed in blood samples from the majority of the evaluable patients.
−Removed: o A total of 3 plasma samples (~2% of all analyzed samples) had low but quantifiable levels of SYN-004 using a sensitive ECL assay.
−Removed: o None of the 3 ECL positive plasma samples were found to contain active SYN-004 using a functional enzyme activity assay.
● Meropenem pharmacokinetics were as expected for this patient population.
−Removed: Based on a review of the safety and pharmacokinetic data, the DSMC has recommended that the study may proceed to enroll Cohort 2 in which study drug (SYN-004 or Placebo) will be administered in combination with the IV beta-lactam antibiotic piperacillin/tazobactam.
−Removed: If enrollment proceeds on the current schedule, we may be positioned to announce data readouts for the second cohort during the second half of 2023 and the third cohort during the second half of 2024.
−Removed: Due to the unique challenges posed by the global COVID-19 pandemic, Washington University had previously halted the commencement of the Phase 1b/2a clinical trial and they continue to evaluate non-essential activities which may have a direct impact on the continuation of the ongoing clinical trial.
−Removed: Continuation of the Phase 1b/2a clinical trial including, but not limited to, the enrollment of new patients remains largely at the discretion of Washington University and is contingent upon their ability to conduct this clinical program free from the impact of COVID-19.
−Removed: We remain in close contact with Washington University and are actively monitoring the potential impact of COVID-19 on the clinical development plans of SYN-004 (ribaxamase) program.
−Removed: On November 3, 2022 we announced the first patient has been dosed in Cohort 2 of its 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 (aGVHD).
−Removed: SYN-020 — Oral Intestinal Alkaline Phosphatase
−Removed: SYN-020 is a quality-controlled, recombinant version of bovine Intestinal Alkaline Phosphatase (IAP) produced under cGMP conditions and formulated for oral delivery.
−Removed: The published literature indicates that IAP functions to diminish fat absorption, tighten the gut barrier to diminish “leaky gut,” promote a healthy microbiome, and diminish GI and systemic inflammation.
−Removed: Despite its broad therapeutic potential, a key hurdle to commercialization has been the high cost of IAP manufacture, which is commercially available for as much as $10,000 per gram.
−Removed: We believe we have developed technologies to traverse this hurdle and currently have the ability to produce more than 3 grams per liter of SYN-020.
−Removed: If the yields are successfully translated to a commercial scale, we could ultimately manufacture IAP for roughly a few hundred dollars per gram.
−Removed: Based on the known IAP mechanisms of action, 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.
−Removed: 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 begun planning for potential development of SYN-020 in indications that may offer a more accelerated or streamlined pathway to registration while also addressing significant unmet medical needs.
−Removed: Such indications include celiac disease, non-alcoholic fatty liver disease (“NAFLD”), and indications to treat and prevent metabolic and inflammatory disorders associated with aging, which are supported by our collaboration with Massachusetts General Hospital (“MGH”).
−Removed: Across the six major markets, the total prevalent cases of celiac disease are expected to increase from 5.8 million cases in 2013 to an expected 8.1 million cases in 2023, representing an annual growth rate of approximately 4%.
−Removed: During the same period, prevalent cases in the U.S.
−Removed: are expected to increase from 2.8 million in 2013 to an expected 4.3 million in 2023, representing a significant market opportunity.
−Removed: During the second quarter of 2020, we announced that we entered into an agreement with Massachusetts General Hospital 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.
−Removed: During the second quarter of 2021, we announced an amendment to our option for an exclusive license agreement with MGH to include intellectual property and technology related to the use of SYN-020 to inhibit liver fibrosis in select diseases, including NAFLD.
−Removed: Research published by a team of investigators led by Richard Hodin, MD, Chief of the Massachusetts General Hospital Division of General and Gastrointestinal Surgery and Professor of Surgery, Harvard Medical School, evaluated long-term oral supplementation of IAP, including SYN-020, in mice.
−Removed: Hodin’s research demonstrated that IAP administration, starting at 10 months of age, slowed the microbiome changes, gut-barrier dysfunction, and gastrointestinal and systemic inflammation that normally accompany aging.
−Removed: Additionally, the IAP administration resulted in improved metabolic profiles in the aged mice, diminished frailty, and extended lifespan.
−Removed: Under the terms of the agreement, we are granted exclusive rights to negotiate a worldwide license with MGH to commercially develop SYN-020 to treat and prevent metabolic and inflammatory diseases associated with aging.
−Removed: If executed, we would use this license in the advancement of an expanded clinical development program for SYN-020.
−Removed: 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.
−Removed: 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.
−Removed: On April 1, 2021, we announced that enrollment had commenced in the Phase 1 SAD clinical trial of SYN-020.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: No serious adverse events were reported.
−Removed: During the third quarter of 2021 we initiated a Phase 1 clinical study evaluating multiple ascending doses (“MAD”) of SYN-020.
−Removed: On October 21, 2021 we announced that patient enrollment, dosing and observation commenced in the Phase 1 MAD of SYN-020.
−Removed: This Phase 1, placebo-controlled MAD study was designed to evaluate the safety, tolerability and biodistribution of SYN-020 upon repeated dosing in 8 healthy adult volunteers in each of four cohorts (32 total study participants).
−Removed: SYN-020 was given orally twice daily for fourteen days as multiple ascending doses ranging from 5 mg to 75 mg.
−Removed: Safety reviews were conducted at the end of each cohort to approve progression into the next higher dose cohort.
−Removed: On May 10, 2022, we announced positive safety data from our Phase 1, placebo-controlled, double-blind multiple ascending dose (MAD) clinical trial of SYN-020 intestinal alkaline phosphatase (IAP).
−Removed: The Phase 1 MAD study enrolled 32 healthy adult volunteers into four cohorts with SYN-020 administered orally in doses ranging from 5 mg to 75 mg twice daily for 14 days with a follow-up evaluation at day 35.
−Removed: Each cohort included six subjects who received SYN-020 and two who received placebo.
−Removed: Analyses of preliminary data demonstrated that SYN-020 maintained a favorable safety profile and was well-tolerated across all dose levels.
−Removed: There were a few treatment-related adverse events, and all were mild (grade 1) and resolved without medical intervention.
−Removed: The most common adverse event, constipation, occurred in three out of 24 subjects in the treatment arm and in one out of eight subjects in the placebo arm.
−Removed: No adverse event led to discontinuation of the study drug and there were no serious adverse events.
−Removed: SYN-020 levels were below the limit of quantitation in all plasma samples at all timepoints during the study.
−Removed: The Phase 1 data from our SAD and MAD studies are intended to support the development of SYN-020 in multiple clinical indications targeting disorders stemming from gastrointestinal (GI) inflammation.
−Removed: We will continue to explore the therapeutic potential of SYN-020 across indications including celiac disease, NAFLD, age-related metabolic and inflammatory diseases.
−Removed: With our transition to an oncology focused Company, we are exploring strategic opportunities to enable advancement of this potentially valuable asset.
−Removed: Our Current Oncology-Focused Pipeline (through the acquisition of VCN)
+Added: Our Current Oncology-Focused Pipeline
Oncolytic Viruses
2 unchanged sentences
Oncolytic viruses exploit the fact that cancer cells contain mutations that cause them to lose growth control and form tumors.
−Removed: 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.
+Added: Once inside a tumor cell, oncolytic viruses are designed to 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 by OVs also alerts the immune system, which can then attack the virus infected cells and the tumor cells to help destroy the tumor in some instances.
−Removed: Our OV products are engineered to efficiently infect and selectively replicate to a high extent in tumor cells versus normal host cells, which enables intravenous delivery.
+Added: Our OV candidates products 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.
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.
−Removed: Our first product, VCN-01, is a clinical stage oncolytic human adenovirus that is modified to express an enzyme, hyaluronidase, that helps the virus and other molecules to penetrate the tumor.
+Added: Our first product candidate, VCN-01, is a clinical stage oncolytic human adenovirus that is modified to express an enzyme, hyaluronidase, that degrades 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, they will be further protected by data and/or market exclusivity in major markets.
−Removed: 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
−Removed: 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.
−Removed: These modifications have been shown in preclinical and clinical studies to confer tumor selective replication and antitumor activity.
−Removed: VCN-01 was engineered to replicate in and kill virtually all types of cancer cells, to expose tumor neoantigens of lysed tumors, to reduce liver tropism, and to express PH20 hyaluronidase to enhance the penetration of virus, chemotherapy and immune cells into the tumor.
−Removed: Malignant tumors are made up of tumor cells as well as significant supporting tissue known as tumor stroma.
−Removed: The tumor stroma supports the formation and growth of tumors and contains cells and other components that are required for robust tumor growth and metastasis.
−Removed: The stroma also forms an effective barrier to the entry of therapeutic agents such as chemotherapy and antibodies.
−Removed: VCN-01 is designed to overcome the stroma barrier problem by expressing the well-characterized stroma degrading enzyme PH20 hyaluronidase after it infects tumor cells.
−Removed: Expression of PH20 by VCN-01 degrades the hyaluronic acid within the tumor stroma and improves virus spread.
−Removed: Based upon the foregoing, we believe our oncolytic virus platform, exemplified by VCN-01, represents a new and potentially powerful form of therapy that combines tumor cell killing, anti-tumor immunity and stroma destruction after intravenous delivery.
−Removed: The VCN-01 product candidate is provided as a sterile liquid concentrate that is diluted for infusion or injection.
−Removed: The proposed therapeutic indication for VCN-01 is the treatment of solid tumors, as its selectivity mechanism relies on cellular properties shared by virtually all human tumor cells.
−Removed: 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.
−Removed: VCN-01 has been administered to 77 patients across four Phase 1 clinical trials, including patients with pancreatic cancer, head and neck squamous cell carcinoma, ovarian carcinoma, colorectal cancer, and retinoblastoma.
−Removed: Pancreatic Ductal Adenocarcinoma
−Removed: Cancer of the pancreas consists of two main histological types:
−Removed: 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.
−Removed: Pancreatic Ductal Adenocarcinoma (“PDAC”) accounts for more than 90% of all pancreatic tumors.
−Removed: It can be located either in the head of the gland or in the body-tail.
−Removed: Pancreatic cancer usually gives metastases to liver and peritoneum.
−Removed: Other less common sites are lungs, brain, kidney and bone.
−Removed: Since in early stages the pancreatic cancer does not give any characteristic symptoms, patients visit their physician late.
−Removed: In many instances, progressive abdominal pain is the first symptom.
−Removed: Therefore, for most cases, pancreatic cancer is diagnosed in its late stages (locally advanced non-metastatic or metastatic stage of the disease) when the radical resection and possibly curative treatment is not possible anymore.
−Removed: It’s generally assumed that only 10% of cases are resectable at presentation, whereas 30-40% of patients are diagnosed at local advanced/unresectable stage and 50-60% presents distant metastases.
−Removed: PDAC Clinical Unmet need and Market Opportunity
−Removed: PDAC is one of the most fatal cancers accounting for the 3 rd highest cause of cancer-associated deaths in US and 4 th in the European Union.
−Removed: Despite significant research efforts, minimal progress has been achieved to date.
−Removed: The five-year overall survival rate is < 10% and has not substantially improved over the last 30 years.
−Removed: Surgery is the only treatment that offers the prospect of long term-survival;
−Removed: however, the 5-year survival for the limited number of patients in whom resection is possible remains low (20 – 30 %).
−Removed: Patients with advanced disease are managed with chemotherapy.
−Removed: 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.
−Removed: However, the results are still very poor and new therapeutic interventions are needed.
−Removed: The increase is particularly evident in younger people and several studies anticipate that pancreatic cancer is expected to become the second leading cause of cancer-related death in the United States by 2030.
−Removed: The rising incidence of pancreatic cancer and its current economic burden place increased pressure to improve outcomes for patients.
−Removed: 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.
−Removed: Phase 1a/Proof of Concept Trial of VCN-01 by intratumoral administration in PDAC
−Removed: 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”).
−Removed: 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 (coincident 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).
−Removed: The treatment regimen was generally well-tolerated;
−Removed: however, one patient died from severe intraabdominal fluid collection that was considered to be related to VCN-01 treatment.
−Removed: Evaluation of virus pharmacokinetics and PH20 levels in serum were consistent with strong virus replication in the tumors.
−Removed: This was supported by the presence of viral particles in tumor cells as assessed in paired tumor biopsies collected before and after treatment.
−Removed: Tumor stiffness was reduced in all VCN-01-injected lesions as measured by elastography.
−Removed: Disease stabilization of injected lesions was observed in 5 out of 6 patients although subsequent tumor progression was observed in most of the patients due to the appearance of new lesions or growth of distant, non-injected, metastatic lesions.
−Removed: This study provided encouraging mechanism of action data for VCN-01;
−Removed: however, intratumoral injection did not appear to deliver sufficiently high VCN-01 levels for effective delivery to non-injected tumors.
−Removed: We believe these results supported the evaluation of the safety/tolerability and potential efficacy of VCN-01 via intravenous administration in combination with chemotherapy and/or immunotherapies for the treatment of advanced PDAC.
−Removed: The results of this study were, published in the Journal for ImmunoTherapy of Cancer.
−Removed: 2021 Nov;9(11):e003254.
−Removed: 10.1136/jitc-2021-003254.
+Added: VCN-01 has been administered to 82 patients across multiple Phase 1 clinical trials, including patients with pancreatic cancer, head and neck squamous cell carcinoma, ovarian carcinoma, colorectal cancer, and retinoblastoma.
+Added: Current clinical update
+Added: We are currently conducting a Phase 2 Trial of intravenous VCN-01 with or without nab-paclitaxel plus gemcitabine in patients with solid tumors and PDAC.
+Added: Additional Phase 1 investigator sponsored studies are evaluating intravitreal VCN-01 in patients with retinoblastoma, a Phase 1 Trial of intravenous VCN-01 in Combination with Durvalumab in Subjects with Recurrent/ Metastatic SCCHN and a Phase 1 Trial evaluating the intravenous administration of VCN-01 in patients prior to surgical resection of high-grade brain tumors
+Added: Phase 1 Clinical Trials in PDAC
+Added: The safety, tolerability, and potential dosing regimens for VCN-01 in patients with PDAC or colorectal cancer were evaluated in Phase 1 clinical trials evaluating intratumoral (n=8;
+Added: NCT02045589) and intravenous (n= 42;
+Added: NCT02045602) VCN-01 either alone or in combination with gemcitabine ± nab-paclitaxel (published in J.
+Added: Cancer 2021 Nov;9(11):e003254 and J.
+Added: Cancer 2022 Mar;10(3):e003255 respectively).
+Added: Intravenous VCN-01 was found to have an acceptable safety/tolerability profile in PDAC and colorectal cancer patients and demonstrated compelling biochemical and clinical outcomes that enabled the advancement of VCN-01 into Phase 2 clinical trials in patients with metastatic PDAC.
Phase 2 Trial of intravenous VCN-01 with or without nab-paclitaxel plus gemcitabine in patients with solid tumors and PDAC
−Removed: 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.
−Removed: The data, published in the Journal for ImmunoTherapy of Cancer, suggests that intravenous treatment with VCN-01 is feasible and has an acceptable safety profile, with encouraging biological and clinical activity.
−Removed: (Journal for Immunotherapy of Cancer 2022;10:e003255.
−Removed: doi:10.1136/jitc-2021-003255).
−Removed: Data from the recent publication had previously been presented, in part, in a poster at the ESMO 2019 annual meeting.
−Removed: The published study was a multicenter, open-label, dose-escalation phase I clinical trial of a single dose of intravenous VCN-01 alone (Part I, 16 patients with advanced refractory solid tumors) or in combination with nab-paclitaxel plus gemcitabine (Part II and III;
−Removed: patients with pancreatic adenocarcinoma).
−Removed: In Part II, 12 patients received VCN-01 dose concurrent with chemotherapy on day 1, whereas in Part III 14 additional patients received the dose of VCN-01seven days before chemotherapy.
−Removed: The recommended phase 2 doses (RP2D) were determined to be 1x10 13 viral particles (vp)/patient in Part I, 3.3x10 12 vp/patient in Part II and 1x10 13 vp/patient in Part III.
−Removed: Based on its apparent safety profile and the absence of dose-limiting toxicities, 1x10 13 vp/patient using sequential dosing schedule was selected for further clinical development.
−Removed: Pharmacokinetic data showed dose linearity, as well as relevant VCN-01 exposure.
−Removed: Analysis of VCN-01 clearance in patients enrolled in Part II did not show significant differences with respect to patients receiving VCN-01 as a single agent.
−Removed: VCN-01 viral genomes were detected in tumor tissue in 5 out of 6 biopsies.
−Removed: A second viral peak in plasma and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients.
−Removed: Increased levels of immune biomarkers (IFNγ, sLAG3, IL-6, IL-10) were found after VCN-01 administration.
−Removed: 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.
−Removed: Median progression free survival (PFS) for patients in Part III was 6.7 months, and median overall survival (OS) was 13.5 months.
−Removed: Eight patients (66.7%) survived more than 12 months.
−Removed: In addition, in April 2021, a subgroup analysis of patients at the RP2D (1.x10 13 vp/patient followed by nab-paclitaxel plus gemcitabine one week later, n=6) was conducted and showed an ORR of 83%, with a median PFS of 6.3 months and median OS of 20.8 months.
−Removed: Some VCN-01 treated patients appeared to benefit from late-onset responses.
−Removed: This form of delayed anti-tumor activity is not common with chemotherapy but is frequently observed with immunotherapies.
−Removed: We believe an immune mechanism of action associated with the oncolytic activity of VCN-01 may be the underlying explanation.
−Removed: 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.
−Removed: Future Planning and Potential Regulatory Strategy for development of VCN-01 in PDAC
−Removed: We are currently planning a Phase 2 clinical trial of systemically administered VCN-01 in PDAC patients and submitted of the protocol to the FDA and Spanish and German regulatory agencies in June of 2022.
−Removed: In September 2022 the trial received “safe to proceed” from FDA and it has been approved by Spanish National Authority (AEMPS) The proposed Phase 2 trial will be an open-label, randomized study to test the efficacy of VCN-01 in combination with gemcitabine and nab-paclitaxel in patients with newly diagnosed metastatic pancreatic cancer.
+Added: 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 expected to enroll 92 patients and be conducted at approximately 25 sites in the US and EU.
−Removed: Two doses of VCN-01 are planned in the treatment arm:
−Removed: the 1st dose will be administered on day 1, then one week later 3 cycles of gemcitabine and nab-paclitaxel as standard of care will be administered.
−Removed: The second VCN-01 dose will be 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.
−Removed: Manuel Hidalgo, chief of the Division of Hematology and Medical Oncology at Weill Cornell Medicine/New York-Presbyterian Hospital has been appointed as Principal Investigator.
−Removed: Initiation of recruitment is expected during Q4 2022.
+Added: Two doses of VCN-01 are included in the treatment arm:
+Added: 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.
+Added: 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.
Retinoblastoma
−Removed: Retinoblastoma is a tumor that originates in the retina and it is the most common type of eye cancer in children.
−Removed: It occurs in approximately 1 / 14,000-1 / 18,000 live newborns and accounts for 15% of the tumors in the pediatric population < 1 year old.
−Removed: The average age of pediatric patients at diagnosis is 2, and it rarely occurs in children older than 6.
−Removed: 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.
−Removed: Bilateral retinoblastoma (Rb1 germinal mutation) represents 25-35% of the cases while unilateral retinoblastoma (sporadic mutation) accounts for 65-75%.
−Removed: While retinoblastoma is a highly curable disease, 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.
−Removed: Current treatments are not without significant morbidity, which may include visual impairment and severe cosmetic deformity secondary to enucleation and/or irradiation of the orbital region.
−Removed: The use of intravenous chemotherapy and more recently intra-arterial and intravitreal chemotherapy have resulted in a significantly greater number of eyes preserved with fewer long-term effects compared to past treatments such as external radiation therapy.
−Removed: However, allowing patients with advanced intraocular disease to be treated conservatively, led to the appearance of a subgroup of patients with advanced intraocular disease who relapsed after an initial response.
−Removed: Most of these cases include those patients who present gross vitreous or subretinal seeding.
−Removed: Once the aforementioned treatments are exhausted, these patients rarely manage to preserve the eyes and vision and must be enucleated.
−Removed: The ocular preservation rate of these eyes with advanced disease is still less than 50%.
−Removed: 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
7 unchanged sentences
The investigator has reported that one patient treated with VCN-01 has had a complete regression lasting more than 30 months.
−Removed: This study is currently ongoing and anticipated to be completed in the first quarter of 2023.
−Removed: We anticipate the initiation of a Company-sponsored trial of VCN-01 as either an adjunct to chemotherapy in pediatric patients with advanced retinoblastoma in the second half of 2023.
−Removed: VCN-01 in combination with Immunomodulatory therapeutics
−Removed: 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.
−Removed: Biopsies from the Phase 1 trial of PDAC patients administered intravenous VCN-01 demonstrated lymphocyte (CD8+) infiltration and modulated levels of immune markers in tumors, including an induction of the PD1/PD-L1 expression in tumor tissue from some of the patients.
−Removed: Preclinical experiments demonstrated that VCN-01 significantly increased extravasation of an anti-PD-L1 antibody into subcutaneous xenograft tumors compared to non-treated (PBS) tumors and also that PH20 hyaluronidase improves the ingress of T-cells in animal models.
−Removed: Thus, we hypothesize that the administration of VCN-01 into the tumor will help to overcome the observed resistance to PD-L1 checkpoint inhibitors and to mesothelin-directed CAR-T cells.
+Added: Six (6) patients have been treated with VCN-01 to date.
+Added: This study is ongoing and the enrollment period has been extended to include additional patients.
+Added: We anticipate meeting with the FDA during the second half of 2023 to discuss the path forward for VCN-01 as an adjunct to chemotherapy in pediatric patients with advanced retinoblastoma.
+Added: On September 30, 2022, we issued a press release announcing an oral presentation entitled “Topotecan enhances oncolytic adenovirus infection, replication and antitumor activity in retinoblastoma,” featuring Dr.
+Added: Angel Montero-Carcaboso, Researcher at Fundació Sant Joan de Déu at the SIOP 2022 Congress of the International Society of Pediatric Oncology, being held in Barcelona, Spain from September 28-October 1, 2022.
+Added: The new data from the study for which Dr.
+Added: Angel Montero-Carcaboso is the lead investigator further support evaluation of VCN-01, an oncolytic adenovirus expressing hyaluronidase, and topotecan for the treatment of refractory retinoblastoma.
+Added: Key data and conclusions showcased in the SIOP presentation include:
+Added: ● VCN-01 treatment in combination with topotecan, but not with carboplatin or melphalan, significantly increased VCN-01 infection and replication in retinoblastoma cells (p=0.0007) in vitro.
+Added: ● In athymic mice engrafted with human retinoblastomas, topotecan administered systemically after intratumoral VCN-01 increased viral genome replication and the number of VCN-01 infected cells when compared to administration of VCN-01 alone (p = 0.0002).
+Added: ● Sequential administration of intratumoral VCN-01 followed by systemic topotecan significantly increased median ocular survival, compared to VCN-01 alone (p =0.0364).
Phase 1 Trial of intravenous VCN-01 in Combination with Durvalumab in Subjects with Recurrent/ Metastatic SCCHN
2 unchanged sentences
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.
−Removed: Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune, which supplies the product for its use in the clinical study.
+Added: Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that inhibits binding of PD-L1.
+Added: 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:
4 unchanged sentences
Patient recruitment into Arm I and Arm II was performed concurrently.
−Removed: Intravenous VCN-01 is administered to each patient only once during the trial at the VCN-01 dose level to which they are randomized.
−Removed: Durvalumab is administered Q4W until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion.
+Added: Intravenous VCN-01 was administered to each patient only once during the trial at the VCN-01 dose level to which they were randomized.
+Added: Durvalumab was administered Q4W until disease progression,
+Added: unacceptable toxicity, withdrawal of consent, or another discontinuation criterion.
Patient recruitment into the study was completed in February 2022 with a total of 18 patients enrolled.
−Removed: On September 05, 2022 we announced a presentation of initial data from a Phase 1 investigator-sponsored study evaluating VCN-01 in combination with durvalumab for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M HNSCC).
−Removed: Data will be featured in a poster presentation at the European Society for Medical Oncology (ESMO) Congress.
+Added: On September 05, 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.
2 unchanged sentences
and downregulation of matrix-related pathways after VCN-01 administration.
+Added: The last patients in this study are currently being followed for overall survival and patent samples are being analyzed to evaluate potential VCN-01 pharmacodynamic effects.
+Added: We expect to report additional results from this study in H2 2023 as data become available.
Phase 1 Trial evaluating the safety and feasibility of huCART-meso cells when given in combination with VCN-01
1 unchanged sentence
Carl June) in patients with histologically confirmed unresectable or metastatic pancreatic adenocarcinoma and serous epithelial ovarian cancer (NCT05057715).
−Removed: 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 will 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.
+Added: 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.
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.
2 unchanged sentences
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.
−Removed: On July 8, 2022, we were notified of the clearance of the safety evaluation period by the first patient that had been dosed in the investigator sponsored Phase 1 clinical trial evaluating VCN-01 (NCT05057715), an intravenous oncolytic adenovirus, in combination with mesothelin-directed lentiviral transduced human chimeric antigen receptor modified T cells (huCART-meso) for patients with pancreatic and serous epithelial ovarian cancers.
+Added: 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.
+Added: The study is on-going.
Phase 1 Trial evaluating the intravenous administration of VCN-01 in patients prior to surgical resection of high-grade brain tumors
4 unchanged sentences
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.
−Removed: This trial has already received approval from Medicines & Healthcare Products Regulatory Agency (MHRA) from UK Government and recruitment is on-going.
−Removed: Initiation of VCN-01 dosing is expected in Q4 2022.
+Added: This trial has already received approval from Medicines & Healthcare Products Regulatory Agency (MHRA) from UK Government.
+Added: On January 9, 2023, we issued a press release announcing that the first patient was dosed in this study and recruitment is on-going.
+Added: Our Current Gastrointestinal (GI) and Microbiome-Focused Pipeline
+Added: 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.
+Added: When the natural balance or normal function of these microbial species is disrupted, a person’s health can be compromised.
+Added: All of our programs are supported by our growing intellectual property portfolio.
+Added: We are maintaining and building our patent portfolio through:
+Added: filing new patent applications;
+Added: prosecuting existing applications;
+Added: and licensing and acquiring new patents and patent applications.
+Added: 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
+Added: SYN-004 (ribaxamase) is a proprietary oral capsule prophylactic therapy designed to degrade certain IV beta-lactam antibiotics excreted into the GI tract and thereby maintain the natural balance of the gut microbiome.
+Added: Preventing beta-lactam damage to the gut microbiome has a range of potential therapeutic outcomes, including prevention of CDI, suppression of the overgrowth of pathogenic species (particularly antimicrobial-resistant organisms) and potentially reducing the incidence and/or severity of aGVHD in allogeneic hematopoietic cell transplant (HCT) patients.
+Added: SYN-004 (ribaxamase) 75 mg capsules are intended to be administered orally while patients are administered certain IV beta-lactam antibiotics.
+Added: The capsule dosage form is designed to release the SYN-004 (ribaxamase) enzyme into proximal small intestine, where it has been shown to degrade beta-lactam antibiotics in the GI tract without altering systemic antibiotic levels.
+Added: Beta-lactam antibiotics are a mainstay in hospital infection management and include the commonly used penicillin and cephalosporin classes of antibiotics.
+Added: Clostridioides difficile Infection
+Added: Clostridioides difficile (formerly known as Clostridium difficile and often called C.
+Added: difficile or CDI) is a leading type of hospital acquired infection and is frequently associated with IV beta-lactam antibiotic treatment.
+Added: The Centers for Disease Control and Prevention (CDC) identified C.
+Added: difficile as an “urgent public health threat,” particularly given its resistance to many drugs used to treat other infections.
+Added: CDI is a major unintended risk associated with the prophylactic or therapeutic use of IV antibiotics, which may adversely alter the natural balance of microflora that normally protect the GI tract, leading to C.
+Added: difficile overgrowth and infection.
+Added: Other risk factors for CDI include hospitalization, prolonged length of stay (estimated at 7 days), underlying illness, and immune-compromising conditions including the administration of chemotherapy and advanced age.
+Added: According to a paper published in BMC Infectious Diseases (Desai K et al.
+Added: BMC Infect Dis.
+Added: 303) the economic cost of CDI was approximately $5.4 billion in 2016 ($4.7 billion in healthcare settings;
+Added: $725 million in the community) in the U.S., mostly due to hospitalizations.
+Added: Phase 1b/2a Clinical Study in Allogeneic HCT Recipients
+Added: In August 2019, we entered into a Clinical Trial Agreement (CTA) with the Washington University School of Medicine (Washington University) to conduct a Phase 1b/2a clinical trial of SYN-004 (ribaxamase).
+Added: Under the terms of this agreement, we serve as the sponsor of the study and supply SYN-004 (ribaxamase).
+Added: Dubberke, Professor of Medicine and Clinical Director, Transplant Infectious Diseases at Washington University and a member of the SYN-004 (ribaxamase) steering committee serves as the principal investigator of the clinical trial in collaboration with his Washington University colleague Dr.
+Added: Schroeder, Associate Professor of Medicine, Division of Oncology, Bone Marrow Transplantation and Leukemia.
+Added: 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 of the Company’s 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 (aGVHD).
+Added: To date, we have completed the first of 3 study cohorts (Cohort 1), which enrolled 19 patients who received at least 1 dose of study drug (SYN-004 or Placebo randomized 2:1).
+Added: Sixteen patients received at least one dose of intravenous (IV) meropenem and 12 of these patients completed sufficient doses of IV meropenem to be evaluable towards the study endpoints.
+Added: The study is on-going and remains blinded;
+Added: however, key findings from blinded data for Cohort 1 are included below:
+Added: ● Adverse events (AEs) and serious adverse events (SAEs) observed in Cohort 1 were typical of those observed in allo-HCT patients and no AEs or SAEs were determined to be related to study drug treatment by the investigators.
+Added: o A total of 13 SAEs were reported among 10 patients, with the most common SAE being infections and infestations including sepsis.
+Added: o One patient died 14 days after the last dose of study drug (within the 30-day reporting period) due to sepsis that was not related to study drug.
+Added: ● Consistent with previous studies of SYN-004 in healthy volunteers, SYN-004 was not observed in blood samples from the majority of the evaluable patients.
+Added: o A total of 3 plasma samples (~2% of all analyzed samples) had low but quantifiable levels of SYN-004 using a sensitive ECL assay.
+Added: o None of the 3 ECL positive plasma samples were found to contain active SYN-004 using a functional enzyme activity assay.
+Added: ● Meropenem pharmacokinetics were as expected for this patient population.
+Added: Based on a review of the safety and pharmacokinetic data, the DSMC recommended that the study may proceed to enroll Cohort 2 in which study drug (SYN-004 or Placebo) will be administered in combination with the IV beta-lactam antibiotic piperacillin/tazobactam.
+Added: If enrollment proceeds on the current schedule, we may be positioned to announce data readouts for the second cohort during the first half of 2024 and the third cohort during the first half of 2025.
+Added: On November 3, 2022 we announced the first patient has been dosed in Cohort 2 of its 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 (aGVHD, NCT04692181).
+Added: 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:
+Added: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR and at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) respectively.
+Added: SYN-020 — Oral Intestinal Alkaline Phosphatase (IAP)
+Added: SYN 020 is a quality-controlled, recombinant version of bovine Intestinal Alkaline Phosphatase (IAP) produced under cGMP conditions and formulated for oral delivery.
+Added: The published literature indicates that IAP functions to diminish GI and systemic inflammation, tighten the gut barrier to diminish “leaky gut,” and promote a healthy microbiome.
+Added: Despite its broad therapeutic potential, a key hurdle to commercialization has been the high cost of IAP manufacture which is commercially available for as much as $10,000 per gram.
+Added: 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 for roughly a few hundred dollars per gram at commercial scale.
+Added: 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.
+Added: 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.
+Added: Such indications include celiac disease, non-alcoholic fatty liver disease (“NAFLD”), and indications to treat and prevent metabolic and inflammatory disorders associated with aging which are supported by our collaboration with Massachusetts General Hospital (“MGH”).
+Added: Across the six major markets, the total prevalent cases of celiac disease are expected to increase from 5.8 million cases in 2013 to an expected 8.1 million cases in 2023, representing an annual growth rate of approximately 4%.
+Added: During the same period, prevalent cases in the U.S.
+Added: are expected to increase from 2.8 million in 2013 to an expected 4.3 million in 2023, representing a significant market opportunity.
+Added: 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.
+Added: 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).
+Added: On April 1, 2021, we announced that enrollment had commenced in the Phase 1 SAD clinical trial of SYN-020.
+Added: 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.
+Added: 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.
+Added: Analyses of preliminary 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.
+Added: No serious adverse events were reported.
+Added: During the third quarter of 2021 we initiated a Phase 1 clinical study evaluating multiple ascending doses (“MAD”) of SYN-020 (NCT05045833).
+Added: On October 21, 2021 we announced that patient enrollment, dosing, and observation commenced in the Phase 1 MAD of SYN-020.
+Added: The placebo-controlled, blinded study enrolled 32 healthy adult volunteers into four cohorts with SYN-020 administered orally in doses ranging from 5 mg to 75 mg twice daily for 14 days with a follow-up evaluation at day 35.
+Added: Each cohort included six subjects who received SYN-020 and two who received placebo.
+Added: On May 10, 2022, we announced positive safety data from the Phase 1 MAD study demonstrating that SYN-020 maintained a favorable safety profile and was well-tolerated across all dose levels.
+Added: There were a few treatment-related adverse events, and all were mild (grade 1) and resolved without medical intervention.
+Added: The most common adverse event, constipation, occurred in three out of 24 subjects in the treatment arm and in one out of eight subjects in the placebo arm.
+Added: No adverse event led to discontinuation of the study drug and there were no serious adverse events.
+Added: 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.
+Added: 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.
+Added: During the second quarter of 2021, we announced an amendment to our option for an exclusive license agreement with MGH to include intellectual property and technology related to the use of SYN-020 to inhibit liver fibrosis in select diseases, including NAFLD.
+Added: Research published by a team of investigators led by Richard Hodin, MD, Chief of the Massachusetts General Hospital Division of General and Gastrointestinal Surgery and Professor of Surgery, Harvard Medical School, evaluated long-term oral supplementation of IAP, including SYN-020, in mice.
+Added: Hodin’s research demonstrated that IAP administration, starting at 10 months of age, slowed the microbiome changes, gut-barrier dysfunction, and gastrointestinal and systemic inflammation that normally accompany aging.
+Added: Additionally, the IAP administration resulted in improved metabolic profiles in the aged mice, diminished frailty, and extended lifespan.
+Added: Under the terms of the agreement, we are granted exclusive rights to negotiate a worldwide license with MGH to commercially develop SYN-020 to treat and prevent metabolic and inflammatory diseases associated with aging.
+Added: If executed, we plan to use this license in the advancement of an expanded clinical development program for SYN-020.
+Added: 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 indications supported by our collaboration with Massachusetts General Hospital.
+Added: With our transition to an oncology focused Company, we are exploring strategic opportunities to enable advancement of this potentially valuable asset.
Research Programs
−Removed: SYN-006, SYN-007
−Removed: To date, our research programs have been primarily directed to the development of GI acting products that have generated preclinical proof-of-concept with two pipeline products (SYN-006 and SYN-007) that expand the potential utility of our beta-lactamase strategy.
−Removed: SYN-007 is a specially formulated version of SYN-004 (ribaxamase) designed to degrade orally administered beta-lactam antibiotics to protect the gut microbiome from antibiotic-mediated dysbiosis.
−Removed: SYN-006 is a carbapenemase designed to degrade intravenous (IV) carbapenem antibiotics within the GI tract to maintain the natural balance of the gut microbiome for the prevention of CDI, overgrowth of pathogenic organisms and the emergence of antimicrobial resistance (AMR).
−Removed: Our research programs may be expanded to include development of new oncolytic virus products and/or explore oncology applications of our existing products such as SYN-006 and SYN-020.
VCN-11 Albumin Shield™ Technology
9 unchanged sentences
In the second quarter of 2020, VCN had several interactions with Spanish regulatory authorities (AEMPS) to agree on the design of the non-clinical GLP toxicology and biodistribution studies that are required to support a first-in-human clinical trial for VCN-11.
−Removed: In March 2021, preclinical data obtained with VCN-11 was published, showing that VCN-11 induced 450 times more cytotoxicity in tumor cells than in normal cells.
+Added: In March 2021, preclinical data obtained with VCN-11 was published (J Control Release.
+Added: 2021 Apr 10;332:517-528), showing that VCN-11 induced 450 times more cytotoxicity in tumor cells than in normal cells.
VCN confirmed VCN-11 hyaluronidase production 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.
−Removed: VCN-11 evaded NAbs from different sources and tumor level were demonstrated in the presence of high levels of NAbs in vivo, whereas the control virus without ABD was neutralized.
−Removed: 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).
−Removed: VCN-11 increased
−Removed: ALT levels on day 3 within an acceptable range that returned to normal levels by day 9.
+Added: VCN-11 evaded NAbs from different sources and tumor levels of VCN-11 were demonstrated in the presence of high levels of NAbs in vivo, whereas the control virus without ABD was neutralized.
+Added: VCN-11 showed a low toxicity profile in
+Added: 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).
+Added: VCN-11 increased ALT levels on day 3 within an acceptable range that returned to normal levels by day 9.
Fractionated intravenous administration of VCN-11 (splitting the dose into two portions administered 4 h apart) appeared to improve VCN-11 circulation kinetics and increase tumor levels.
3 unchanged sentences
Our internal discovery programs are currently evaluating new oncolytic viruses derived from VCN-11 that may expand the potential efficacy of Albumin Shield viruses.
+Added: SYN-006, SYN-007
+Added: To date, our research programs have been primarily directed to the development of GI acting products that have generated preclinical proof-of-concept with two pipeline products (SYN-006 and SYN-007) that expand the potential utility of our beta-lactamase strategy.
+Added: SYN-007 is a specially formulated version of SYN-004 (ribaxamase) designed to be used with orally administered beta-lactam antibiotics to protect the gut microbiome from antibiotic-mediated dysbiosis.
+Added: SYN-006 is a carbapenemase designed to degrade intravenous (IV) carbapenem antibiotics within the GI tract to maintain the natural balance of the gut microbiome for the prevention of CDI, overgrowth of pathogenic organisms and the emergence of antimicrobial resistance (AMR).
+Added: Our research programs may be expanded to include development of new oncolytic virus products and/or explore oncology applications of our existing products such as SYN-006 and SYN-007.
Intellectual Property
3 unchanged sentences
and foreign patents pending.
−Removed: VCN Biosciences, through assignment or exclusive licenses, controls over 40 U.S.
+Added: VCN, through assignment or exclusive licenses, controls over 40 U.S.
and foreign patents and over 15 U.S.
1 unchanged sentence
The SYN-004 (ribaxamase) program is supported by IP that is assigned to Theriva Biologics, namely U.S.
−Removed: patents and foreign patents (in most major markets, e.g.
+Added: and foreign patents and patent application (in most major markets, e.g.
Europe (including Germany, Great Britain and France), Japan, China and Canada, among others) and U.S.
7 unchanged sentences
The SYN-020 (oral intestinal alkaline phosphatase (IAP)) program is supported by IP that is assigned to Theriva Biologics, namely U.S.
−Removed: and foreign patent applications (in many major markets, e.g.
+Added: and foreign patents and patent applications (in many major markets, e.g.
Europe, China, Japan, Korea, Canada, and Australia).
These patent applications, which cover various formulations, medical uses and manufacture of SYN-020, are expected to expire in 2038-2040, if granted, and without taking potential patent term extensions or patent term adjustment into account.
−Removed: The VCN-01 and VCN-11 programs are supported by patents and patent applications that are assigned to VCN Biosciences or exclusively licensed from Fundacio Privada Institut d’Investigacio Biomedica de Bellvitge (IDIBELL), Institut Catala d’Oncologia (ICO), and Hospital Sant Joan De Déu Barcelona.
+Added: The VCN-01 and VCN-11 programs are supported by U.S.
+Added: and foreign patents and patent applications that are assigned to VCN or exclusively licensed from Fundacio Privada Institut d’Investigacio Biomedica de Bellvitge (IDIBELL), Institut Catala d’Oncologia (ICO), and Hospital Sant Joan de Déu in Barcelona.
The patents and patent applications include U.S.
10 unchanged sentences
Critical Accounting Estimates
−Removed: The condensed consolidated financial statements are prepared in conformity with U.S.
+Added: The preparation of our consolidated financial statements in accordance with accounting principles generally accepted in the United States of America (U.S.
GAAP) which requires the use of estimates, judgments and assumptions that affect the reported amounts of assets and liabilities, the disclosure of contingent assets and liabilities at the date of the condensed consolidated financial statements, and the reported amounts of revenues and expenses in the periods presented.
1 unchanged sentence
however, due to inherent uncertainties in making estimates, actual results may differ from the original estimates, requiring adjustments to these balances in future periods.
−Removed: The critical accounting estimates that affect the condensed consolidated financial statements and the judgments and assumptions used are consistent with those described under Part II, Item 7 of our 2021 Form 10-K.
+Added: There are accounting policies, each of which requires significant judgments and estimates on the part of management, that we believe are significant to the presentation of our consolidated financial statements.
+Added: The most significant accounting estimates relate to research and development costs, business combinations, contingent consideration, and impairment of long-lived assets.
Business Combination
11 unchanged sentences
The Company tests the carrying amounts of goodwill for recoverability on an annual basis or when events or changes in circumstances indicate evidence a potential impairment exists, using a fair value-based test.
−Removed: Pursuant to ASU 2017-04, the Company must record a goodwill impairment charge if a reporting unit’s carrying value exceeds its fair value.
−Removed: In-process research and development, or IPR&D, assets are considered to be indefinite-lived until the completion or abandonment of the associated research and development projects.
+Added: If a reporting unit’s carrying value exceeds its fair value, then the Company will record a goodwill impairment charge for the excess amount.
+Added: In-process research and development (“ IPR&D”), assets are considered to be indefinite-lived until the completion or abandonment of the associated research and development projects.
IPR&D assets represent the fair value assigned to technologies that the Company acquires, which at the time of acquisition have not reached technological feasibility and have no alternative future use.
2 unchanged sentences
If development is terminated or abandoned, the Company may have a full or partial impairment charge related to the IPR&D assets, calculated as the excess of carrying value of the IPR&D assets over fair value.
+Added: Goodwill represents the excess of the purchase price paid when the Company acquired VCN in March 2022, over the fair values of the acquired tangible or intangible assets and assumed liabilities.
+Added: The Company will conduct an impairment test of goodwill on an annual basis as of October 1 of each year and will also conduct tests if events occur or circumstances change that would, more likely than not, reduce the Company’s fair value below its net equity value.
+Added: During the quarters ended September 30 and December 31, 2022, the Company experienced a sustained decline in the quoted market price of the Company’s common stock and the Company deemed this to be a triggering event.
+Added: The Company performed an impairment analysis at both September 30 and December 31, 2022 and concluded that the Goodwill and IPR&D was not impaired at both dates.
Contingent Consideration
6 unchanged sentences
Contingent consideration liabilities expected to be settled within 12 months after the balance sheet date are presented in current liabilities, with the non-current portion recorded under long term liabilities in the consolidated balance sheets.
−Removed: Impairment of Long-Lived Assets
+Added: Long-Lived Assets
Property and equipment is reviewed for impairment whenever events or changes in circumstances indicate that the carrying amount of an asset may not be recoverable.
3 unchanged sentences
Acquired In-Process Research & Development represents the fair value assigned to those research and development projects that were acquired in a business combination for which the related products have not received regulatory approval and have no alternative future use.
−Removed: IPR&D is capitalized at its fair value as an indefinite-lived intangible asset, and any development costs incurred after the acquisition
−Removed: are expensed as incurred.
+Added: IPR&D is capitalized at its fair value as an indefinite-lived intangible asset, and any development costs incurred after the acquisition are expensed as incurred.
Upon achieving regulatory approval or commercial viability for the related product, the indefinite-lived intangible asset is accounted for as a finite-lived asset and is amortized on a straight-line basis over the estimated useful life.
2 unchanged sentences
Impairment is calculated as the excess of the asset’s carrying value over its fair value.
−Removed: During the quarter ending September 30, 2022, the Company experienced a sustained decline in the quoted market price of the Company’s common stock and the Company deemed this to be a triggering event.
−Removed: The Company performed an interim impairment analysis and concluded that the Goodwill and IPRD was not impaired as of September 30,2022.
−Removed: Goodwill represents the excess of the purchase price paid when the Company acquired VCN in March 2022, over the fair values of the acquired tangible or intangible assets and assumed liabilities.
−Removed: The Company will conduct an impairment test of goodwill on an annual basis as of October 1 of each year and will also conduct tests if events occur or circumstances change that would, more likely than not, reduce the Company’s fair value below its net equity value.
+Added: Research and Development Costs
+Added: We expense research and development costs associated with developmental products not yet approved by the FDA to research and development expense as incurred.
+Added: Research and development costs consist primarily of license fees (including upfront payments), milestone payments, manufacturing costs, salaries, stock-based compensation and related employee costs, fees paid to consultants and outside service providers for laboratory development, legal expenses resulting from intellectual property prosecution and other expenses relating to the design, development, testing and enhancement of our product candidates.
+Added: Research and development expenses include external contract research organization (“CRO”) services.
+Added: We make payments to the CROs based on agreed upon terms and may include payments in advance of study services.
+Added: We review and accrue CRO expenses based on services performed and rely on estimates of those costs applicable to the stage of completion of study as provided by the CRO.
+Added: Accrued CRO costs are subject to revisions as such studies progress to completion.
+Added: At March 31, 2023 and 2022, we have accrued CRO expenses of $0.8 million and $1.0 million, respectively, that are included in accrued expenses.
+Added: As of March 31, 2023, and 2022, we have prepaid CRO costs of $2.5 million and $0.3 million, respectively, that are included in prepaid expenses.
Results of Operations
−Removed: Three Months Ended September 30, 2022 and 2021
−Removed: General and Administrative Expenses
−Removed: General and administrative expenses increased to $2.4 million for the three months ended September 30, 2022, from $1.3 million for the three months ended September 30, 2021.
−Removed: This increase of 88% was primarily comprised of increased consulting and legal costs related to the VCN acquisition, increase in the fair value of the contingent consideration, higher insurance costs, audit fees, and public relations expenses, and VCN administrative expenses not included the in prior year.
−Removed: The charge related to stock-based compensation expense was $93,000 for the three months ended September 30, 2022, compared to $83,000 for the three months ended September 30, 2021.
−Removed: Research and Development Expenses
−Removed: Research and development expenses increased to $2.6 million for the three months ended September 30, 2022, from approximately $2.0 million for the three months ended September 30, 2021.
−Removed: This increase of 30% is primarily the result of VCN research expenses related to VCN-01 not incurred in the prior year and, to a lesser extent, higher manufacturing expenses related to our Phase 1a clinical trial of SYN-020.
−Removed: We anticipate research and development expense to increase as we plan for and initiate enrollment for our VIRAGE phase 2 clinical trial for VCN-01 in PDAC, and our proposed clinical trial in retinoblastoma, expand GMP manufacturing activities for VCN-01, and continue supporting our VCN-11 and other preclinical and discovery initiatives.
−Removed: The charge related to stock-based compensation expense was $28,000 for the three months ended September 30, 2022, compared to $19,000 related to stock-based compensation expense for the three months ended September 30, 2021.
−Removed: The following table sets forth our research and development expenses directly related to our therapeutic areas for the three months ended September 30, 2022 and 2021.
−Removed: These direct expenses were external costs associated with preclinical studies and clinical trials.
−Removed: research and development expenses related to employee costs, facilities, stock-based compensation and research and development support services that are not directly allocated to specific product candidates.
−Removed: Three months ended
−Removed: September 30,
−Removed: September 30,
−Removed: Therapeutic Areas
−Removed: SYN-004 (ribaxamase)
−Removed: Other therapeutic areas
−Removed: Total direct costs
−Removed: Total indirect costs
−Removed: Total Research and Development
−Removed: Other Income/Expense
−Removed: Other income was $161,000 for the three months ended September 30, 2022 compared to other income of $2,000 for the three months ended September 30, 2021.
−Removed: Other income for the three months ended September 30, 2022 is primarily comprised of interest income of $170,000 offset by an exchange loss of $9,000.
−Removed: Other income for the three months ended September 30, 2021 was primarily comprised of interest income.
−Removed: Net Loss Attributable to Common Stockholders
−Removed: Our net loss attributable to common stockholders was approximately $5.2 million, or $0.33 per basic and dilutive common share for the three months ended September 30, 2022, compared to a net loss of approximately $3.3 million, or $0.25 per basic common share and dilutive common share for the three months ended September 30, 2021.
−Removed: Net loss attributable to common stockholders for the three months ended September 30, 2022 includes the effect of the warrant exercise price adjustment of $340,000.
−Removed: Nine Months Ended September 30, 2022 and 2021
+Added: Three Months Ended March 31, 2023 and 2022
General and Administrative Expenses
−Removed: General and administrative expenses increased to $5.6 million for the nine months ended September 30, 2022, from $4.0 million for the nine months ended September 30, 2021.
−Removed: This increase of 40% was primarily comprised of increased consulting and legal costs related to the VCN acquisition, higher insurance costs, and public relations expenses, and VCN administrative expenses not included in the prior year offset by a decrease in the fair value of the contingent consideration.
−Removed: The charge related to stock-based compensation expense was $264,000 for the nine months ended September 30, 2022, compared to $248,000 for the nine months ended September 30, 2021.
+Added: General and administrative expenses increased to $2.2 million for the three months ended March 31, 2023, from $1.7 million for the three months ended March 31, 2022.
+Added: This increase of 29% is primarily comprised of increased expense related to the fair value of the
+Added: contingent consideration, additional salary and benefits related to new headcount, audit fees, consulting fees, travel, and VCN administrative expenses not included in the prior year, offset by a decrease in consulting and legal costs related to the VCN acquisition.
+Added: The charge related to stock-based compensation expense was $87,000 for the three months ended March 31, 2023, compared to $85,000 for the three months ended March 31, 2022.
Research and Development Expenses
−Removed: Research and development expenses increased to $8.6 million for the nine months ended September 30, 2022, from approximately $5.0 million for the nine months ended September 30, 2021.
−Removed: This increase of 30% is primarily the result of VCN research expenses related to VCN-01 not incurred in the prior year and, to a lesser extent, higher manufacturing expenses related to our Phase 1a clinical trial of SYN-020 and expenses related to our Phase 1b/2a clinical trial of SYN-004 (ribaxamase) in allogeneic HCT recipients.
−Removed: We anticipate research and development expense to increase as we plan for and initiate enrollment for our VIRAGE phase 2 clinical trial for VCN-01 in PDAC, and our proposed clinical trial in retinoblastoma, expand GMP manufacturing activities for VCN-01, and continue supporting our VCN-11 and other preclinical and discovery initiatives.
−Removed: The charge related to stock-based compensation expense was $82,000 for the nine months ended September 30, 2022, compared to $57,000 related to stock-based compensation expense for the nine months ended September 30, 2021.
−Removed: The following table sets forth our research and development expenses directly related to our therapeutic areas for the nine months ended September 30, 2022 and 2021.
+Added: Research and development expenses increased to $3.0 million for the three months ended March 31, 2023, from approximately $2.6 million for the three months ended March 31, 2022.
+Added: This increase of 15% is primarily the result of increased clinical trial expenses related to VCN-01 not incurred in the prior year, offset by lower expenses related to our Phase 1b/2a clinical trial of SYN-004 (ribaxamase) in allogeneic HCT recipients and decreased manufacturing expenses related to our Phase 1a clinical trial of SYN-020.
+Added: We anticipate research and development expense to increase as we continue enrollment in our VIRAGE Phase 2 clinical trial of VCN-01 in PDAC, and our ongoing Phase 1 clinical trial in retinoblastoma, expand GMP manufacturing activities for VCN-01, and continue supporting our VCN-11 and other preclinical and discovery initiatives.
+Added: The charge related to stock-based compensation expense was $39,000 for the three months ended March 31, 2023, compared to $28,000 related to stock-based compensation expense for the three months ended March 31, 2022.
+Added: The following table sets forth our research and development expenses directly related to our therapeutic areas for the three months ended March 31, 2023 and 2022.
These direct expenses were external costs associated with preclinical studies and clinical trials.
−Removed: research and development expenses related to employee costs, facilities, stock-based compensation and research and development support services that are not directly allocated to specific product candidates.
−Removed: Nine months ended
−Removed: September 30,
−Removed: September 30,
+Added: Indirect research and development expenses related to employee costs, facilities, stock-based compensation and research and development support services that are not directly allocated to specific product candidates.
Therapeutic Areas
−Removed: SYN-004 (ribaxamase)
Other therapeutic areas
3 unchanged sentences
Other Income/Expense
−Removed: Other income was $157,000 for the nine months ended September 30, 2022 compared to other income of $4,000 for the nine months ended September 30, 2021.
−Removed: Other income for the nine months ended September 30, 2022 is primarily comprised of exchange loss of $40,000, offset by interest income of $197,000.
−Removed: Other income for the nine months ended September 30, 2021 was primarily comprised of interest income.
+Added: Other income was $370,000 for the three months ended March 31, 2023 compared to other expense of $21,000 for the three months ended March 31, 2022.
+Added: Other income for the three months ended March 31, 2023 is primarily comprised of interest income of $364,000 and exchange gain of $6,000.
+Added: Other expense the three months ended March 31, 2022 is primarily comprised of exchange loss of $23,000, offset by interest income of $2,000.
Net Loss Attributable to Common Stockholders
−Removed: Our net loss attributable to common stockholders was approximately $14.4 million, or $0.95 per basic and dilutive common share for the nine months ended September 30, 2022, compared to a net loss of approximately $17.9 million, or $1.51 per basic common share and dilutive common share for the nine months ended September 30, 2021.
−Removed: Net loss attributable to common stockholders for the nine months ended September 30, 2022 includes the effect of the warrant exercise price adjustment of $340,000.
−Removed: Net loss attributable to common stockholders for the nine months ended September 30, 2021 excludes net loss attributable to non-controlling interest of $1,000 and includes the accretion of the Series B preferred discount of $1.5 million on converted shares, Series A Preferred Stock accrued dividends of $24,000 and the deemed dividend for the effect of the Series A preferred shares price adjustment of $7.4 million.
+Added: Our net loss attributable to common stockholders was approximately $4.5 million, or $0.30 per basic and dilutive common share for the three months ended March 31, 2023, compared to a net loss of approximately $4.3 million, or $0.32 per basic common share and dilutive common share for the three months ended March 31, 2022.
Liquidity and Capital Resources
−Removed: As of September 30, 2022, the Company has a significant accumulated deficit, and with the exception of the three months ended June 30, 2010 and the three months ended December 31, 2017, the Company has experienced significant losses and incurred negative cash flows since inception.
+Added: As of March 31, 2023, the Company has a significant accumulated deficit, and with the exception of the three months ended June 30, 2010 and the three months ended December 31, 2017, the Company has experienced significant losses and incurred negative cash flows since inception.
The Company expects to continue incurring losses for the foreseeable future, with the recognition of revenue being contingent on successful phase 3 clinical trials and requisite approvals by the FDA or foreign equivalents.
−Removed: Historically, the Company has financed its operations primarily through public and private sales of its common stock and a private placement of its preferred stock, and it expects to continue to seek to obtain required capital in a similar manner.
−Removed: The Company has spent, and expects to continue to spend, a substantial amount of funds in connection with implementing its business strategy, including planned product development efforts, clinical trials and research and discovery efforts.
−Removed: Cash and cash equivalents totaled approximately $50.5 million as of September 30, 2022, which includes the net proceeds from sales of our Series C and D Convertible Preferred Stock issued during the three months ended September 30, 2022, Common Stock in “at-the-market” (ATM) equity offerings during 2021 and cash proceeds through the exercise of a portion of the October 2018 warrants.
−Removed: With these additional sources of liquidity, we believe we will be able to fund our operations into the first quarter of 2024.
+Added: Our cash and cash equivalents totaled $36.1 million as of March 31, 2023, a decrease of $5.7 million from December 31, 2022.
+Added: During the three months ended March 31, 2023, the primary use of cash was for working capital requirements and operating activities which resulted in a net loss of $4.5 million for three months ended March 31, 2023.
+Added: Cash and cash equivalents includes the net proceeds from sales of our Series C Preferred Stock and Series D Preferred Stock issued during the year ended December 31, 2022, proceeds from the sale of Common Stock in “at-the-market” (ATM) equity offerings during 2021 and cash proceeds through the exercise of a portion of the October 2018 warrants in 2021.
+Added: With these additional sources of liquidity, we believe we will be able to fund our operations through the second quarter and into the third quarter of 2024.
Management believes its plan, which includes the additional testing of SYN-004 (ribaxamase) and the advancement of VCN-01 will allow us to meet our financial obligations, further advance key products, and maintain our planned operations for at least one year from the issuance date of these consolidated financial statements.
−Removed: However, the amount of capital needed by us will also depend upon whether we develop SYN-004 and/or SYN-020 internally or we out-license or partner such development.
−Removed: If necessary, the Company may attempt to utilize the ATM or seek to raise additional capital on the open market, neither of which is guaranteed.
−Removed: Use of the ATM is limited by certain
−Removed: restrictions and management’s plan does not rely on additional capital from either of these sources.
−Removed: If the Company is not able to obtain additional capital (which is not assured at this time), our long-term business plan may not be accomplished and we may be forced to cease certain development activities.
+Added: However, the amount of additional capital needed by us will also depend upon the costs to advance our VCN-01 clinical programs and whether we continue to develop SYN-004 internally, or out-license or partner such development.
+Added: If necessary, we may attempt to utilize the ATM or seek to raise additional capital on the open market, neither of which is guaranteed.
+Added: Use of the ATM is limited by certain restrictions and management’s plan does not rely on additional capital from either of these sources.
+Added: If we are not able to obtain additional capital (which is not assured at this time), our long-term business plan may not be accomplished, and we may be forced to cease certain development activities.
More specifically, the completion of any later stage clinical trial will require significant financing or a significant partnership.
−Removed: The uncertain financial markets, disruptions in supply chains, mobility restraints, and changing priorities as well as volatile asset values could impact our business in the future.
−Removed: The outbreak and government measures taken in response to the pandemic have also had a significant impact, both direct and indirect, on businesses and commerce, as worker shortages have occurred;
−Removed: supply chains have been disrupted;
−Removed: facilities and production have been suspended;
−Removed: and demand for certain goods and services, such as medical services and supplies, have spiked, while demand for other goods and services, such as travel, have fallen.
−Removed: The future progression of the pandemic and its effects on our business and operations are uncertain.
−Removed: We may face difficulties recruiting or retaining patients in our ongoing and planned clinical trials if patients are affected by the virus or are fearful of traveling to our clinical trial sites because of the outbreak.
−Removed: We and our third-party contract manufacturers, contract research organizations, and clinical sites may also face disruptions in procuring items that are essential to our research and development activities, including, for example, medical and laboratory supplies used in our clinical trials or preclinical studies, in each case, that are sourced from abroad or for which there are shortages because of ongoing efforts to address the outbreak.
−Removed: Further, although we have not experienced any material adverse effects on our business due to increasing inflation, it has raised operating costs for many businesses and, in the future, could impact demand or pricing manufacturing of our drug candidates or services providers, foreign exchange rates or employee wages.
−Removed: We are actively monitoring the effects these disruptions and increasing inflation could have on our operations.
Historically, we have financed our operations primarily through public and private sales of our securities, and we expect to continue to seek and obtain additional capital in a similar manner.
−Removed: During the year ended December 31, 2021, our only source of cash was from the exercise of the 2018 Warrants and sales of our common stock through the Original ATM Sales Agreement and the Amended and Restated ATM Sales Agreement discussed above.
−Removed: There can be no assurance that we will be able to continue to raise funds through the sale of shares of common stock through the Amended and Restated ATM Sales Agreement.
+Added: During the year ended December 31, 2022, our only source of cash was from the sales of our Series C Preferred Stock and Series D Preferred Stock.
+Added: During the year ended December 31, 2021, our only source of cash was from the exercise of the 2018 Warrants and sales of our common stock through the Original ATM Sales Agreement and the Amended and Restated ATM Sales Agreement.
+Added: There can be no assurance that we will be able to continue to raise funds through the sale of shares of common stock through the Amended and Restated ATM Sales Agreement or other equity financings.
If we raise funds by selling additional shares of common stock or other securities convertible into common stock, the ownership interest of our existing stockholders will be diluted.
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We have committed, and expect to continue to commit, substantial capital in order to implement our business strategy, including our planned product development efforts, preparation for our planned clinical trials, and performance of clinical trials and our research and discovery efforts.
−Removed: We believe our cash position of $50.1 million as of November 1, 2022 is sufficient to fund our operations through at least the end of the fourth quarter of 2023, including continuation of our ongoing Phase 1b/2a clinical study of SYN-004 (ribaxamase) in allogeneic HCT recipients for the prevention of aGVHD, as well as our planned Phase 1 clinical programs for SYN-020 and to fund our committed obligations under the Purchase Agreement for the VCN Acquisition.
−Removed: Following the anticipated completion of our ongoing Phase 1b/2a clinical study of SYN-004 (ribaxamase) in allogeneic HCT recipients, the Phase 1 SAD and MAD clinical studies with SYN-020, and the proposed clinical trials with VCN-01, we will need to obtain additional funds for future clinical trials.
+Added: We believe our cash position of $35 million in early May 2023 is sufficient to fund our operations through at least the end of the second quarter of and into the third quarter 2024, including continuation of our ongoing Phase 1b/2a clinical study of SYN-004 (ribaxamase) in allogeneic HCT recipients for the prevention of aGVHD, our ongoing Phase 1 and Phase 2 clinical trials for VCN-01, preclinical studies of VCN-11 and related discovery initiatives, and to fund our committed obligations under the VCN Purchase Agreement for the VCN Acquisition.
+Added: Following the anticipated completion of our ongoing Phase 1b/2a clinical study of SYN-004 (ribaxamase) in allogeneic HCT recipients, our ongoing Phase 1 and Phase 2 clinical trials for VCN-01, and the preclinical studies of VCN-11, and related discovery initiatives, we will need to obtain additional funds for future clinical trials.
We anticipate that our future clinical trials will be much larger in size and require larger cash expenditures than the aforementioned clinical programs.
We do not have any committed sources of financing for future clinical trials at this time, and it is uncertain whether additional funding will be available when we need it on terms that will be acceptable to us, or at all.
−Removed: As the COVID-19 coronavirus has persisted around the globe and world governments have reacted to the on-going war in the Ukraine, we have experienced and may, in the future, experience disruptions that impact our business and clinical trials.
−Removed: These include postponement of clinical site initiation as was observed for the Phase 1b/2a clinical trial of SYN-004, increased costs of goods and services, supply chain constraints, and disruptions and changes in vendor personnel.
−Removed: The full impact of the COVID-19 and global economic downturn continues to evolve as of the date of this report.
−Removed: As such, it is uncertain as to the full magnitude that these factors will have on our financial condition, liquidity, and future results of operations.
−Removed: We are actively monitoring the global situation and its potential impact on our financial condition, liquidity, operations, suppliers, industry, and workforce.
−Removed: Given the daily evolution of persistent COVID-19 and the global economic downturn, we are not able to estimate the future effects of these factors on our results of operations, financial condition, or liquidity.
Off-Balance Sheet Arrangements
−Removed: During the three months ended September 30, 2022, we did not have, and we do not currently have, any off-balance sheet arrangements, as defined under SEC rules.
+Added: During the three months ended March 31, 2023, we did not have, and we do not currently have, any off-balance sheet arrangements, as defined under SEC rules.
Contractual Obligations
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ROU assets are included in other noncurrent assets and lease liabilities are included in other current and non-current liabilities in our condensed consolidated balance sheets.
−Removed: As of June 30, 2022, we did not have any material finance leases.
+Added: As of March 31, 2023, we did not have any material finance leases.
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.