Few CDMOs are capable of supporting biopharma companies advancing oncolytic virus (OV) therapies toward late-stage clinical trials. Vibalogics, however, is investing in new large-scale capacity and will be positioned to provide process development through late-stage and commercial manufacturing services from state-of-the-art facilities in both the United States and Germany.
Benefits of Oncolytic Virus Therapies
OVs preferentially infect, replicate in, and kill cancer cells, leading to the presentation of both viral and tumor antigens and the induction of innate and adaptive immune responses. They are an ideal weapon against tumors, because cancer cells have minimal antiviral defenses. In addition to selectively targeting cancer cells, OVs can be engineered to deliver payloads, such as immunomodulating cytokines. OVs have been shown to trigger a lasting immune response. The actual mechanisms of action for any given OV depend on the type of virus, how the virus is engineered, and the tumor itself.
Once inside a cancer cell, an OV replicates until the cell lyses (immunogenic cell death). Tumor antigens and other materials released by the lysed cancer cells often provoke an immune response (local and/or systemic) by activating dendritic cells. The combination of the direct lysis and the activation of the immune system contribute to the oncolytic efficacy of OVs.
The challenge with OVs is to design the viruses to replicate and spread within a tumor as quickly as possible before they are recognized and destroyed by the immune system. Virus design and production methodologies have been developed to enable most OVs to evade the immune system for hours with systemic injection that enables them to reach their target. Direct intratumoral injection for solid tumors can be employed to maximize the infectivity potential before clearance, while studies have also found that systemic treatment of cancer patients with OV therapies via intravenous injection (rather than direct injection into the tumor) before surgery can boost their response to checkpoint inhibitors following surgery. Virus design, combination therapy regime, and delivery route all play important roles in the effectiveness of OVs in the greater oncology treatment design.
While OVs need to initially evade the immune system, their efficacy is also tied to triggering an immune response to the cancer after infection. The objective is to turn the “cold” tumor microenvironment lacking T cells into one that is “hot,” inflamed, and immunogenic. Recent evidence shows the antitumor immune attack is synergistically enhanced when combining OV therapy with immune checkpoint inhibitors targeting mainly PD-1 and CTLA-4 pathways. OVs can also be loaded with other immunomodulators, such as cytokines and/or tumor-(neo)-antigens, all designed to optimize patients’ local and distant (metastases) antitumor long-lasting immune response. In several clinical studies, patients receiving a combination therapy had a much higher response rate than those that only received a checkpoint inhibitor.
Amgen’s Imlygic (talimogene laherparepvec) for the treatment of advanced melanoma, based on herpes simplex virus (HSV-1), is the first FDA-approved (2015) OV therapy and remains the only such therapy to have received FDA approval. There are, however, a wide range of other OV platforms being investigated in clinical trials, among them adenovirus, vaccinia virus, measles, coxsackie virus, vesicular stomatitis virus (VSV), reovirus, picornavirus (polio), Newcastle Disease Virus (NDV), and arenavirus.
Expanding Market Opportunities
OV approaches have been gaining traction since the FDA’s approval of Amgen’s Imlygic for the treatment of advanced melanoma in 2015. Numerous recombinant and non-recombinant viruses are under clinical development, with 80% of these candidates in early stages of development, and even more candidates in preclinical stages. We estimate that the number of OV clinical trials has been growing at a rate of 20% p.a. Today, there are over 150 OV clinical trials active with the FDA that are being sponsored by more than 100 biopharma companies operating in the OV space.
Furthermore, as excitement in the clinical community builds over the potential of Imlygic — and other oncolytic HSVs, adenoviruses, measles viruses, NDVs, and reoviruses — there has been an acceleration in large cap pharma acquiring and investing in the most promising OV assets. In 2018, three major pharmaceutical companies acquired biotechs developing OVs: Merck & Co. acquired Viralytics for $394 million in February of 2018, J&J acquired BeneVir Biopharm for over $1 billion in May 2018, and Boehringer Ingelheim acquired ViraTherapeutics for $245 million in September 2018.
OVs preferentially infect, replicate in, and kill cancer cells, leading to the presentation of both viral and tumor antigens and the induction of innate and adaptive immune responses.
Vibalogics: Focused on Oncolytic Viruses
Vibalogics is a privately owned CDMO focused primarily on process development, manufacturing, testing, and fill-finish of OV products in full compliance with international GMP standards in a GMO BSL-2 classified facility in Germany.
The company places the greatest value on being a reliable partner and offering high-quality services to biopharmaceutical industry partners in Europe, the United States, and Asia-Pacific. Vibalogics distinguishes itself by being highly flexible, establishing and maintaining open communication lines, and delivering the best science to solve the complex production issues associated with OVs. The company’s team of around 60 scientists and project managers has experience from the early stages of process design and development through production of clinical material for use in OV trials around the world.
Furthermore, the company has plans underway to establish commercial-scale manufacturing capabilities in the United States, with designs complete, engineering in progress, and recruitment of a team of scientific experts and experienced management well underway. The suite of services provided by Vibalogics is supported by the company’s flexible multiproduct facility, an international customer base, and the long and deep experience of the scientific team, who are adept at all production platforms.
Both Cell- and Egg-Based Virus Manufacturing
Unlike most other CDMOs producing viral products, Vibalogics’ experienced personnel have established expertise in the development of both cell-based (suspension and adherent) and egg-based virus production methods to provide clients with a full suite of aseptic manufacturing capabilities, from drug substance process development to the fill-finish of drug product.
Most projects at Vibalogics involve the development of cell-based virus production processes for manufacturing OVs, viral gene therapy vectors, and viral vector vaccines. The company has deep expertise and a considerable track record in the production of HSV, adenovirus, pox-like-viruses (such as fowlpox and modified vaccinia virus Ankara (MVA)), VSV, influenza, and other viruses in various culture vessels, including single-use suspension bioreactors, disposable iCELLis fixed-bed bioreactors, roller bottles, and CellSTACKs. With a focus on aseptic processing, the company’s established downstream operations include dead-end, cross-flow micro-diafiltration and sterile filtration, ÄKTA-ready chromatography systems, and ultra-centrifugation for drug substance purification. Furthermore, while most competitors stop at the drug substance stage, Vibalogics has in-house manual and automatic fill-finish capabilities for the release of liquid (up to 30,000 glass vials DIN 2R formats) and lyophilized drug product.
Egg-based virus manufacturing is a tried and true methodology for the cost-effective production of certain OVs, such as Newcastle disease virus (NDV). Vibalogics uses specific-pathogen-free (SPF) eggs sourced from qualified suppliers. Batch sizes range from 1,000 eggs for chicken embryonic fibroblast (CEF) preparations to 5,000 eggs for allantoamnionic fluid (AAF) harvests. All batches are accompanied by relevant certificates to support use in a GMP environment. CEF cultivation can be performed in various culture vessels, including roller bottles, CellSTACKs, and iCELLis fixed-bed bioreactors. Downstream operations include diverse filtration steps. The team is highly experienced in aseptic process management for egg-based manufacture of non-sterilizable large viruses.
The continuous cell-based manufacturing process starts with an established, GMP-certified master cell bank and a characterized master virus seed. Vibalogics offers cell-based and egg-based virus seed banking services, providing clients with high-quality, robust, and fully traceable starting materials to use in manufacturing. All characterization work and release testing can be performed and managed by Vibalogics.
Feasibility Studies and Process Development
Virus feasibility studies enable Vibalogics to assess the possibilities for client technologies and product candidates. Vibalogics has the flexibility to assess and determine the optimal substrate and conditions for a virus candidate. The company combines years of virus process development expertise with cutting-edge analytical tools and “outside the box” thinking to translate customers’ ideas into clinical candidates.
Process development work is performed using a consultative approach with continuous and transparent communication. Following client consultation, Vibalogics proposes a scope of development work that provides a functional, scalable, and (most importantly) transferable process based on established GMP manufacturing principles. The company can provide advice for projects at any stage in the development cycle, comprising, for example, adaptation of adherent cells to suspension, optimization of production parameters, optimization of virus recovery from bulk harvest, purification strategy, and analytical tool usage and development. Vibalogics’ approach is to keep future requirements top of mind and design processes that can be directly scaled to larger equipment under GMP-compliant standards.
Virus design and production methodologies have been developed to enable most OVs to evade the immune system for hours with systemic injection that enables them to reach their target.
Assay Development and Stability Studies
Vibalogics has extensive expertise in the transfer, establishment, and validation of product-specific non-compendial analytical methods aligned with EP and USP needs. The company’s full analytical method development and analysis package is tailored to virus-based products and includes a comprehensive virus assay development service covering product development and manufacturing, in-process, bulk intermediate, and final product release analysis. In addition, Vibalogics provides a comprehensive set of representative virus stability studies and indicating tests, including identity, purity, physicochemical, and cell-based potency assays, performed according to ICH guidelines to support clients’ clinical product development. The company works closely with its clients to ensure that these virus stability studies meet their requirements and the expectations of the regulatory authorities.
GMP Manufacturing and Batch Release
GMP virus manufacturing for OVs, viral vectors, and viral vector vaccines at Vibalogics is performed in areas designed specifically for the production of viral drug substance and drug product within ISO 5/7 (class A/B Europe) BSL-2 clean room environments. By avoiding the need for internal process technology transfer, the company saves time and ensures the seamless transition between process development and GMP activities. Vibalogics has the capacity to manufacture for phase I/II clinical trials and the flexibility to expand as required. The planned facility in the United States will be able to provide late phase and commercial production scale.
Every GMP product that Vibalogics manufactures is subject to a stringent review and approval process resulting in Qualified Person (QP) batch release according to GMP guidelines. The company considers the specific needs of live viral products and follows Advanced Therapy Medicinal Product (ATMP) guidelines, if applicable. All processes are thoroughly characterized to ensure the identification of critical quality attributes that correlate with efficacy and safety and the development of controlled processes that consistently meet quality specifications. All aspects of the process are considered, including the starting materials (qualified cell banks and virus seed stocks), drug substance and drug product manufacturing, all characterization needs, and product release, storage, and distribution.
Batches are released by a Vibalogics’ QP confirming the pharmaceutical (cGMP) compliance, greatly facilitating the process. Our QPs have extensive experience and training with respect to European Union QP requirements and an in-depth understanding of all of the aspects associated with pharmaceutical manufacturing of such complex products. Vibalogics offers regulatory support, accompanies regulatory authority visits, and can help in preparing the CMC section of investigational new drug applications (INDs) and investigational medicinal product dossiers (IMPDs).
Flexible State-of-the-Art Virus Manufacturing Facility
Vibalogics’ 30,000 sq. ft. multiproduct facility in northern Germany features state-of-the-art modular design for increased flexibility. Five independent GMP suites are housed across three buildings totaling over 15,000 sq. ft., with BSL-2 laboratories for process development. The facility is well-equipped with an automated facility monitoring system and required utilities (AP, WFI, cooling water). Recently, the company increased its single-use bioreactor and purification capacity with a new manufacturing line to meet increasing demand for OVs and viral vectors. The new manufacturing line features 50 L and 200 L single-use bioreactors and a Siemens process control system. Vibalogics also invested in Äkta-Ready chromatography systems for downstream processing and liquid handling equipment to manage the increased volumes involved in this scale of operation. Furthermore, design plans are underway to build a handful of additional clean rooms that can fulfill increased demand for OV and viral vector manufacturing.
Plans for Late-Phase and Commercial Manufacturing
In May 2019, Vibalogics was acquired by Ampersand Capital Partners, a private equity firm specializing in growth equity investments in the healthcare sector. Ampersand has deep expertise in the development of specialized CDMOs, having been investors in companies such as Arranta Bio, Brammer Bio, MedPharm, Talecris, and TriPharm. The investment by Ampersand in Vibalogics is being used to expand the company’s capabilities to meet rapidly growing industry demand for the development and manufacture of complex oncolytic viral therapies.
Vibalogics will invest in additional process development and manufacturing capabilities to strengthen and expand its position in the United States and Europe. In response to requests from customers, a majority of which are located in the United States, the company plans to expand beyond early-phase activities into late-phase and commercial delivery of OV and viral vector. The new late-stage and commercial manufacturing facility, which will be located in the United States, is expected to be completed in 2021 and operational by 2022.