About Northwest Biotherapeutics

Northwest Biotherapeutics, Inc. operates as a biotechnology company. The company focuses on developing personalized immune therapies for cancer. The company has developed a platform technology, DCVax, which uses activated dendritic cells to mobilize a patient’s own immune system to attack their cancer. The company’s lead product, DCVax-L, is designed to treat solid tumor cancers in which the tumor can be surgically removed. The company has completed a 331-patient international Phase III trial of DCVax-L for Glioblastoma multiforme brain cancer (GBM). The company plans to conduct clinical trials of DCVax-L for other solid tumor cancers in the future, when resources permit. The company’s second product, DCVax-Direct, is designed to treat inoperable solid tumors. A 40-patient Phase I trial has been completed, and included treatment of a diverse range of more than a dozen types of cancers. The company plans to work on preparations for Phase II trials of DCVax-Direct as resources permit. On May 10, 2022, top line data from the Phase III trial of DCVax-L were presented in a scientific conference at the New York Academy of Sciences by one of the investigators in the trial. The presentation was made available publicly on a third-party site. On November 17, 2022, the Phase III trial results were reported in a peer reviewed publication in JAMA Oncology, a top scientific and medical journal. The company is now working on preparations for an application for regulatory approval of DCVax-L. The company is working with teams of specialized consultants on pre-requisites for the application, and on portions of the application package itself. One of the pre-requisites — obtaining regulatory approval of a Pediatric Investigation Plan (PIP) — was completed during 2022 on an accelerated basis, including regulatory approval to use the same trial design with external controls as was used in the company’s Phase 3 trial. Additionally, substantial progress was made with the contract research organization (CRO) and specialized consultants on preparing the Trial Master File to be inspection-ready for regulators. The DCVax Technology The company’s platform technology, DCVax, is a personalized immune therapy that uses a patient’s own dendritic cells, or DCs, the master cells of the immune system, as the therapeutic agent. The patient’s DCs are obtained through a blood draw, or leukapheresis. The DCs are then activated and loaded with biomarkers (‘antigens’) from the patient’s own tumor. For DCVax-L, the antigen loading process takes place during the manufacturing of the product. For DCVax-Direct, the antigen loading process takes place in situ in the tumor after the product is directly injected into the patient’s inoperable tumor. The loading of antigens into the DCs ‘educates’ the DCs about what the immune system needs to target. Manufacturing of DCVax The company uses a batch manufacturing technology for its DCVax products, and this manufacturing approach is a key part of the practicality of the company’s product and its economic feasibility. Generally, the company is able to produce enough doses for the patient’s treatment regimen through just one manufacturing process. When a batch of DCVax product has been made, the company then cryopreserves it. Both of these technologies -- the personalized batch manufacturing for each patient and the cryopreservation -- are essential elements of the company’s manufacturing model and product economics. Together, they enable the company to usually incur the high costs of manufacturing just one time for each patient, and then store the multi-year or multi-dose quantity of product, frozen, in single doses. This makes DCVax effectively an ‘off the shelf’ product for the patient after the initial manufacturing, even though it is personalized, and the company anticipates that this will enable the pricing of DCVax to be in line with other new cancer drugs. As previously reported, the company has been developing a manufacturing facility in Sawston, the U.K. Prior to 2022, the company’s production of dendritic cell vaccine products in the U.K. was taking place in a GMP (clean room) facility in London, with a capacity of about four to six patients per month. The Sawston facility contains a total of 88,345 square feet on two floors. The initial production capacity comprises two manufacturing suites, occupying approximately 4,400 square feet on the ground floor. These two suites, together with substantial support space for process development, Quality Control testing, quarantined storage, cryostorage and other functions are anticipated to have potential capacity to produce dendritic cell vaccines for up to 40 to 45 patients per month, or approximately 450 to 500 patients annually. The buildout of Phase 1A of the Sawston facility was previously completed, and the buildout of Phase 1B has been under way in 2022 and Q1 of 2023. The company’s buildout of the Sawston facility is designed to proceed in phases, as modules, both for efficiency in the timing of capital costs and to allow flexibility in operations and usage. During 2021, initial licenses were obtained for operations in the Sawston facility, after technology transfer from the London facility, recruitment of technical personnel, development of some 1,000 regulatory documents, and buildout of Phase 1A of the facility. The initial licenses included a license from the Human Tissue Authority (HTA) for collection and processing of human cells and tissues, and licenses from the Medicines and Healthcare Products Regulatory Agency (MHRA) for manufacturing for clinical trials and compassionate use. GMP production of DCVax-L products for compassionate use began in the Sawston facility in February 2022, after the licenses were obtained in Q4 2021, and continued throughout 2022. In parallel, extensive activities were conducted throughout 2022 to further develop the operations, personnel, regulatory documents and data necessary to apply for a commercial manufacturing license for the Sawston facility. The application package was submitted at the end of June, and reviewed by the regulatory authorities over the following months. An initial onsite inspection by regulatory authorities took place in October for the commercial license application, and also served as the annual review/renewal inspection for the prior licenses for compassionate use and clinical trial manufacturing. Further submissions and interactions with the regulator took place between October and February, and a follow-up inspection took place in early February 2023. The company is now awaiting any further requirements or communications from regulators. In parallel, production of DCVax-L products for compassionate use continued in the London facility. In the U.S., the company entered into contract discussions for resumption of manufacturing capacity there. The company also continued process and infrastructure improvements that will be needed for scale-up. These include work towards development of a system designed to avoid or reduce bottlenecks in quality control testing and product ‘release,’ and equipping the facility to establish capacity for controlled cryostorage of millions of doses. The initial production capacity in the Sawston facility occupies only a small fraction of the total space there. In light of this, and in light of the company’s obligation in connection with the buildout loan from the Cambridge development authority to make the Sawston facility benefit the regional business ecosystem and not just the company, as previously reported the company entered into a sublease on December 31, 2021 for a small portion of the space to the company’s contract manufacturer, Advent BioServices. It is anticipated that, as and when feasible, the subleased space may enable some production of third party cell therapy products. Such production of other products will fulfill the loan-related commitment to the Cambridge authority, will help support the capital-intensive Sawston facility costs and, in light of the growing demand for cell therapy manufacturing capacity, could substantially increase the asset value of the Sawston facility. All of the development activities for the Sawston facility, and the manufacturing at the Sawston facility, have been carried out or managed by Advent BioServices, who is the contract operator of the facility. In parallel with the company’s activities in the Sawston facility, development work on the Flaskworks system continued throughout 2022. The Flaskworks system is designed to close and automate the manufacturing of cell therapy products, such as DCVax. The Flaskworks company was previously owned by its technical founders and Corning Inc, and following the company’s acquisition in 2020 it became a wholly owned subsidiary of the company. The company anticipates that the Flaskworks system will enable substantial scale-up of production volumes of DCVax products and potentially substantial reduction of production costs (including potential reduction of indirect costs related to capital-intensive facility costs). The company anticipates that implementation of the Flaskworks system will enable certain phases of the Sawston buildout to be simplified and streamlined. For further details on the financial aspects of the Flaskworks acquisition, please see Item 8 Note 5 below. Intellectual Property and Orphan Drug Designation As of December 31, 2022, the company had 103 issued patents and 64 pending patent applications worldwide, grouped into 9 patent families. Of these, 98 issued patents and 43 pending patent applications directly relate to the company’s DCVax products. In the United States and Europe, some of the company’s patents and applications relate to compositions and the use of products, while other patents and applications relate to other aspects, such as manufacturing. For example, in the United States, the company has six issued patents and four pending patent applications that relate to the composition and/or use of the company’s DCVax products. The company also has other U.S. patents and applications that cover, among other things, a potential method for determining the immunopotency of the company’s dendritic cells produced by the company’s manufacturing processes and an automated system which will help enable the scale-up of production for large numbers of patients on a cost-effective basis. Similarly, in Europe, the company has five patents, validated as 59 national patents, issued by and four pending patent applications with the European Patent Office (‘EPO’) that cover the company’s DCVax products, and other patents and applications that cover aspects such as manufacturing, a potential method for determining immunopotency of the company’s manufactured products, and the automated system. In Japan, the company has seven issued patents and four pending patent applications relating to the company’s DCVax products, as well as manufacturing related patents. Patents have been granted or are pending in other foreign jurisdictions which may be potential future markets for the company’s DCVax products. During 2022, four new patents were issued to the company as part of the company’s worldwide patent portfolio. The European patent was validated as 16 national patents. The newly issued patents cover methods for manufacturing dendritic cells related to the company’s DCVax products, as well as encompassing certain methods of use and compositions that may be potential future markets for related DCVax products and a potential method for determining the immunopotency of dendritic cells produced by the company’s manufacturing processes. Additionally, with the acquisition of Flaskworks, the company gained ownership of a portfolio of patents and patent applications, which include those held by Flaskworks, as well as patents and patent applications exclusively licensed by Flaskworks from Northeastern University. The portfolio includes a total of thirteen patent families, with issued patents and pending applications worldwide. Collectively these patents and patent applications cover key aspects of the design and function of automated cell culture systems. During 2020, three new patents were issued to the company as part of its worldwide patent portfolio. The newly issued patents cover methods for manufacturing dendritic cells related to the company’s DCVax products, as well as encompassing certain methods of use and compositions that may be potential future markets for related DCVax products. The expiration dates of the issued U.S. patents involved in the company’s current business range from 2023 to 2036, and pending applications may involve longer time periods. The expiration dates of the issued European patents involved in the company’s business range from 2023 to 2036, and pending applications may involve longer time periods. In addition to the company’s patent portfolio, the company has obtained Orphan Drug designation for the company’s lead product, DCVax-L for glioma brain cancers. Such designation brings with it a variety of benefits, including potential market exclusivity for seven years in the U.S. and ten years in Europe if the company’s product is the first of its type to reach the market. Research and Development For the year ended December 31, 2022, the company’s research and development expense was $35.5 million. Competition Many other third parties compete with the company in developing alternative therapies to treat cancer, including: NovoCure and MagForce Nano Technologies AG. History Northwest Biotherapeutics, Inc. was founded in 1996. The company was incorporated in Delaware in 1998.