Actually, I'm going to enter a new theory to add to the list of possible "certain information for regulatory review". I think they may have stopped screening so they can save some recruitment space for another regulatory body. Their SEC documents allude toJAPAN. Their most recent 10K states: "In 2014, the trial was approved by the Canadian regulatory authority to proceed". It took them until Feb 2015 to make that official regulatory body announcement. It's late in the trial, if another regulatory body is added, they will want some of their citizens in the study.
Our Current Phase III Clinical Trial
Our DCVax-L product is currently in a 348-patient Phase III trial. As of February 28, 2015, there are more than 60 clinical sites open and operating for the trial across the U.S. and in the U.K., Germany and Canada, with more sites expected to become operational during 2015, particularly in Europe. The trial was originally getting under way when the financial crisis began in 2008, enrolled a limited number of patients at that time, and then suspended new enrollment into the ongoing trial until the summer of 2011. The trial initially resumed enrollment in 2011 at about 10 sites, all in the US, then gradually expanded to a growing number of sites over the course of 2012 through 2014. In 2012, the trial was approved by the U.K. regulatory authority to proceed in the U.K. In the fall of 2013, the trial was approved by the German regulatory authority to proceed there. In 2014, the trial was approved by the Canadian regulatory authority to proceed there as well. We plan to continue adding sites to the trial, because the same institutional approvals, contract negotiations, personnel training and logistics arrangements that are needed for the trial also serve to prepare the sites for commercialization.
The trial is a double-blind, randomized, placebo controlled trial with two treatment arms. Patients in one arm receive standard of care plus DCVax-L; patients in the other arm receive standard of care plus a placebo. Patients are assigned randomly between the two arms: two-thirds of the patients into the DCVax-L arm and one-third into the placebo arm. Standard of care includes surgical removal of the brain tumor, followed by 6 weeks of daily radiotherapy and chemotherapy, followed by monthly chemotherapy. The standard of care chemotherapy is Temodar (temozolamide). The primary endpoint of the trial is median Progression Free Survival. Secondary endpoints include median Overall Survival. The trial includes a crossover arm, in which patients who originally receive the standard of care plus a placebo have an opportunity, when their disease progresses, to cross over and start receiving DCVax-L. However, there is still no un-blinding at the time of crossover.
We anticipate that the Phase III trial will reach its first interim analysis for efficacy during 2015. Various factors may affect the timing of completion of the trial, including the pace of adding more sites in Europe during 2015, and the pace of enrollment in Europe. We anticipate that the Phase III trial will reach its primary endpoint next year, potentially in the spring or summer.
In the meantime, while the Phase III trial is moving toward completion, during 2015 we plan to be developing and growing our early access programs for providing DCVax-L to brain cancer patients, such as the Hospital Exemption program in Germany, as described below.
“Information Arm” Outside the Phase III Trial
In parallel with the Phase III trial of DCVax-L for GBM, we accepted a total of 55 patients into an “Information Arm” outside of the trial, who failed to meet the eligibility requirements for the trial. Most of these patients (51 of the 55) were actual or potential “rapid progressors” (patients in whom the brain cancer is already appearing to re-grow by the time the patient finishes the 6 weeks of daily radiotherapy and daily chemotherapy following surgical removal of the tumor). At least 19 of the 51 patients were confirmed as being clear rapid progressors, with such aggressive cancer that the brain tumors were already re-growing within weeks after the original surgery, and during the daily radiotherapy and chemotherapy. The rest of the 51 patients could not be classified as clearly, with today’s imaging and other technology. All of the 51 patients were treated with the same DCVax-L product as in the Phase III trial, on the same treatment schedule as in the trial, at the same medical centers as in the trial, in the same time period as the trial, and the data were collected and maintained by the same Contract Research Organization (CRO) as is managing the trial.
As we have reported, a significant extension of survival compared with expected survival times has been seen to date in these Information Arm patients, including the 19 confirmed rapid progressors. Such patients usually do not respond much to any treatments. We plan to continue following these patients during this year, and plan to report on further results.
DCVax-L Early Access Programs
In March 2014, we received approval from the German regulatory authority of a “Hospital Exemption” for DCVax-L for glioma brain cancers under Section 4b of the German Drug Law. This approval for DCVax-L was the first of its kind in a number of key ways, although the law had been in place for several years. Under this Hospital Exemption, we may provide DCVax-L to patients for the treatment of any glioma brain cancers (both Glioblastoma multiforme, the most severe grade, and lower grade, less-malignant gliomas), and both newly diagnosed and recurrent stages of disease, outside of our Phase III clinical trial, and charge full price for the product. The patients may be from Germany or elsewhere. This approval has a term of five years, and can be re-applied for and re-issued at the end of that period.
During 2014, we undertook preparations for this Hospital Exemption early access program (for which the parties would not engage until we had received regulatory approval) including numerous contract negotiations with medical centers, separate arrangements for international patients at the medical centers, development of a registry and system for data collection, obtaining local licenses, development of patient contracts and consent and release forms, logistics arrangements, and other steps. During 2015, we plan to continue these program development activities, undertake outreach activities, and gradually grow the program.
Also in early 2014, we received a determination from the German central reimbursement authority that DCVax-L is eligible for reimbursement on an extraordinary basis, even though it is still in clinical trials. The reimbursement must be negotiated with the German Sickness Funds (health insurance companies). One aspect of the process involves negotiations with hospitals to seek inclusion in overall budgets which the hospitals negotiate with the Sickness Funds. Another aspect of the process involves negotiation of individual patient cases, one by one.
During 2014, we undertook considerable work on pricing models, and began the process of hospital budget discussions and case by case discussions. We expect to continue these processes in 2015. Although these are labor intensive and lengthy processes, we believe it is highly valuable to have an opportunity to undertake these processes now, while DCVax-L is still finishing its clinical trials and prior to commercialization, as normally these processes can only be begun after full product approval has been received and commercialization has begun.
In the U.K., we also undertook early access program activities in 2014. In April, 2014, the U.K. government launched a new program for early access to innovative new treatments for serious unmet medical needs: the Early Access to Medicines Scheme (EAMS). The EAMS involves a 2-step process. First is a scientific evaluation by the U.K. regulatory authority of the new treatment and whether it is likely to offer a major advantage over existing treatments for a serious disease with high unmet medical need. If the evaluation is positive, it results in a “PIM” (Promising Innovative Medicine) designation. Our DCVax-L for brain cancer went through this evaluation and, as we reported in September, 2014, DCVax-L became the first product to receive a PIM designation under the new EAMS program. The second (and final) stage of the EAMS involves a further Scientific Opinion and an evaluation of the manufacturing. Our activities for 2015 include pursuit of the second (and final) stage of EAMS. Recently, the first EAMS approval was granted to a big pharma’s checkpoint inhibitor drug, which is designed to “take the brakes off” a patient’s immune response to cancer. We consider this a helpful precedent.
As we have consistently said in our public presentations, we believe the most important value of early access programs such as the above lies in the regulatory validation involved, and the invaluable opportunity to practice for commercialization outside of clinical trials and before actual commercialization. The opportunity for some early revenues is also encouraging, but in our view is secondary.
Intellectual Property and Orphan Drug Designation
We have an integrated strategy for protection of our technology through both patents and other mechanisms, such as Orphan Drug status. As of December 31, 2014, we have over 136 issued patents and 47 pending patent applications worldwide, grouped into 12 patent families. Of these, 100 issued patents and 47 pending patent applications relate to our DCVax products. In the United States and Europe, some of our patents and applications relate to the composition and use of products, while other patents and applications related to other aspects such as manufacturing and quality control. For example, in the United States, we have three issued and five pending patent applications that relate to the composition and/or use of our DCVax products. We also have other U.S patents and applications that cover, among other things, quality control for DCVax, as well as an automated system which we believe will play a major role in the scale-up of production for large numbers of patients on a cost-effective basis. Similarly, in Europe, we have four patents issued by and six pending patent applications with the European Patent Office ("EPO") that cover our DCVax products, and other patents and applications that cover aspects such as manufacturing and quality control, and the automated system. In Japan, we have three issued patents and five pending patent applications relating to our DCVax products, as well as manufacturing related patents. Patents have been granted and are pending in other foreign jurisdictions we consider important potential future markets for our DCVax products.
During 2012, a dozen new patents, including one European and twelve other foreign patents, were issued to us as part of our worldwide patent portfolio. The newly issued patents covered a variety of subject matter, such as the proprietary partial maturation for DCVax-Direct, the machines and systems to manufacture DCVax-Direct, certain processes for enhancing the potency of dendritic cells in general, certain measures of product quality, and other matters.
During 2013, eight new patents, including three U.S. and five other foreign patents, were issued to us as part of our worldwide patent portfolio. The newly issued patents cover a variety of subject matter, such as the proprietary partial maturation for DC-Vax-Direct, the machine and systems to manufacture DCVax-Direct, and certain processes for enhancing the potency of dendritic cells in general, and other matters.
In September 2013, we announced that we had been issued U.S. patent #8,518,636, covering a next-generation process for manufacturing lower cost human dendritic cells of both a higher quality and higher reliability. This next generation system has already been cleared by the FDA for use in the manufacturing of dendritic cells for our clinical trials. These systems are now in use producing the vaccines which have already been injected into the tumors of DCVax-Direct patients.
During 2014, seven new patents (including one European patent validated into 26 patents in various European countries and seven other foreign patents) were issued to us as part of our worldwide patent portfolio. The newly issued patents cover a variety of subject matter, such as the machine and system to manufacture DCVax-Direct and certain processes for enhancing the potency of dendritic cells.
The expiration dates of the issued U.S. patents involved in our current business range from 2022 to 2028. The expiration dates of the issued European patents involved in our current business range from 2022 to 2028. For some of the earlier dates, we plan to seek extensions of the patent life, and believe we have reasonable grounds for doing so.
In addition to our patent portfolio, we have obtained Orphan Drug designation for our 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 our product is the first of its type to reach the market.
This market exclusivity applies regardless of patents, (i.e., even if the company that developed it has no patent coverage on the product). In addition, the time period for such market exclusivity does not begin to run until product sales begin. In contrast, the time period of a patent begins when the patent is filed and runs down during the years while the product is going through development and clinical trials.
Under patents, a couple of interesting things:
One, several patents in Japan. Why apply for manufacturing patents in Japan if they are not expecting them to be in this trial? Leads me to believe they will be announced their entry into Phase III soon.
Two, proof of use in current DCVax-L product and manufacturing methods. The date of file is when application counts. Clearly pasted below, they stopped using IL4 many years ago, they use IL15. They were using BCG and INFy. Also, they already had a patent for Tangential flow filtration devices and methods for leukocyte enrichment. Their 2013 patent, was an improvement on a 2003 file submission, "Generation of dendritic cells from monocytic dendritic precursor cells with GM-CSF", so yes, it's used in DCVax-L current trial. And their new submission and receipt last week could mean, a new jurisdiction, like say, Japan. :)
Generation of dendritic cells from monocytic dendritic precursor cells with GM-CSF in the absence of additional cytokines: Patent number: 8389278 Abstract: The present invention it was determined that dendritic cells could be derived from various sources including peripheral blood monocytes in the presence of only GM-CSF without other cytokines if the monocytes were not activated. By preventing activation, such as by preventing binding of the cells to the surface of the culture vessel, the monocytes do not require the presence of additional cytokines, such as IL-4 or IL-13, to prevent differentiation into a non-dendritic cell lineage. The immature DCs generated and maintained in this manner were CD14? and expressed high levels of CD1a. Upon maturation by contact with an agent such as, for example, BCG and IFN?, the cells were determined to express surface molecules typical of mature dendritic cells purified by prior methods and cultured in the presence of GM-CSF and IL-4.
Type: Grant Patent number: 8389278 Filed: February 27, 2004 Issued: March 5, 2013 Assignee: Northwest Biotherapeutics, Inc. Inventors: Benjamin Tjoa, Marnix L. Bosch
Generation of dendritic cells from monocytic dendritic precursor cells with GM-CSF in the absence of additional cytokines Patent number: 9102917 Type: Grant Filed: Mar 05, 2013 Issued: Aug 11, 2015 Patent Application Number: 20130273654 Assignee: Northwest Biotherapeutics, Inc. (Bethesda, MD) Inventors: Benjamin A. Tjoa (Seattle, WA), Marnix L. Bosch (Clyde Hill, WA) Primary Examiner: Amy Juedes Application Serial: 13/786,208
Method for induction of proliferation of natural killer cells by dendritic cells cultured with GM-CSF and IL-15 Application number: 20040197903 Abstract: The present invention provides a dendritic cell that can induce the proliferation and activation of natural killer cells. The dendritic cells, designated NK dendritic cells, are characterized by the expression of increased levels of CD80, CD1a, and CD86 as compared to a mature dendritic cell cultured in the presence of granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 4 (IL-4). Further, the dendritic cells are characterized by the expression of interleukin 12 (IL-12), tumor necrosis factor &agr; (TNF&agr;), and GM-CSF. The NK dendritic cells are produced by providing a cell population comprising low-adherence monocytic dendritic precursor cells that have been cultured in the presence of granulocyte-monocyte colony stimulating factor (GM-CSF) and interleukin 15 (IL-15) and by contacting the cells with an effective amount of a dendritic cell maturation agent. Type: Application Filed: February 2, 2004 Issued: October 7, 2004 Assignee: Northwest Biotherapeutics, Inc. Inventor: Linda Pestano
Method to increase class I presentation of exogenous antigens by human dendritic cells Application number: 20030175247 Abstract: Methods and compositions for use of human dendritic cells to activate T cells for immunotherapeutic responses against primary and metastatic cancer are disclosed. In one embodiment, human dendritic cells exposed to a tumor associated antigen, or an antigenic fragment thereof in combination with bacillus Calmette-Guerin (BCG), are administered to a cancer patient to activate a predominantly CD8+ T cell response in vivo. In an alternate embodiment, human dendritic cells are exposed to a tumor associated antigen or a specific antigenic peptide in combination with BCG in vitro and incubated or cultured with primed or unprimed T cells to activate a predominantly CD8+ T cell response in vitro. The activated T cells are then administered to a cancer patient. Antigen in combination with BCG is processed by dendritic cells through the MHC-CLASS I compartment which provides for a predominantly CD8+ T cell response. Type: Application Filed: May 11, 2001 Issued: September 18, 2003 Inventors: Michael Salgaller, Alton Boynton
METHOD TO INCREASE CLASS I PRESENTATION OF EXOGENOUS ANTIGENS BY HUMAN DENDRITIC CELLS Application number: 20080171023 Abstract: Methods and compositions for use of human dendritic cells to activate T cells for immunotherapeutic responses against primary and metastatic cancer are disclosed. In one embodiment, human dendritic cells exposed to a tumor associated antigen, or an antigenic fragment thereof in combination with bacillus Calmette-Guerin (BCG), are administered to a cancer patient to activate a predominantly CD8+T cell response in vivo. In an alternate embodiment, human dendritic cells are exposed to a tumor associated antigen or a specific antigenic peptide in combination with BCG in vitro and incubated or cultured with primed or unprimed T cells to activate a predominantly CD8+T cell response in vitro. The activated T cells are then administered to a cancer patient. Antigen in combination with BCG is processed by dendritic cells through the MHC-CLASS I compartment which provides for a predominantly CD8+T cell response.
Type: Application Filed: January 10, 2008 Issued: July 17, 2008 Assignee: NORTHWEST BIOTHERAPEUTICS, INC. Inventors: Michael Salgaller, Alton Boynton
Tangential flow filtration devices and methods for leukocyte enrichment Patent number: 7695627 Abstract: The present invention provides tangential flow filtration devices and methods for enriching a heterogeneous mixture of blood constituents for leukocytes by removal of non-leukocyte blood constituents. In one particular embodiment the device can provide a composition enriched in monocytes. One embodiment includes a remover unit (1) having a crossflow chamber (3) separated by a microporous filter (5) from a filtrate chamber (4), the remover unit (1) also having a tangential flow inlet (6), a fluid outlet (7) for a fluid enriched in leukocytes and a filtrate outlet (8). Type: Grant Filed: June 19, 2003 Issued: April 13, 2010 Assignee: Northwest Biotherapeutics, Inc. Inventors: Marnix L. Bosch, Paul C. Harris, Steven J. Monahan, Allen Turner, Alton L. Boynton, Patricia A. Lodge
Tangential flow filtration devices and methods for leukocyte enrichment Patent number: 8518636 Abstract: The present invention provides tangential flow filtration devices and methods for enriching a heterogenous mixture of blood constituents for leukocytes by removal of non-leukocyte blood constituents. In one particular embodiment the device can provide a composition enriched in monocytes. Type: Grant Filed: April 13, 2010 Issued: August 27, 2013 Assignee: Northwest Biotherapeutics, Inc. Inventors: Marnix L. Bosch, Paul C. Harris, Steven J. Monahan, Allen Turner, Alton L. Boynton, Patricia A. Lodge
Tangential flow filtration devices and methods for stem cell enrichment Patent number: 7790039 Abstract: The present invention provides methods for enriching a heterogenous mixture of bone marrow or blood constituents for stem cells by removal of non-stem cell constituents comprising separation of the non-stem cell constituents using a tangential flow filtration device. Type: Grant Filed: November 18, 2004 Issued: September 7, 2010 Assignee: Northwest Biotherapeutics, Inc. Inventors: Marnix L. Bosch, Patricia A. Lodge, Julie Anna McEarchern, Alton L. Boynton, Paul G. Hugenholtz
Compositions and Methods for Inducing the Activation of Immature Monocytic Dendritic Cells Application number: 20080254537 Abstract: The present invention provides methods for inducing the maturation of immature dendritic cells (DC) and for activating those cells without the use of a dendritic cell maturation agent. The activated DC can be used for inducing an antigen specific T cell response. Methods of the invention can also comprise the addition of a directional maturation agent, such as interferon gamma, to induce a Th-I and/or Th-2 bias in the response obtained. The present invention also provides dendritic cell populations useful for activating and for inducing antigen specific T cells. Similarly, activated antigen specific T cell populations, and methods of making the same are provided. Type: Application Filed: December 8, 2006 Issued: October 16, 2008 Assignee: Northwest Biotherapeutics, Inc. Inventors: Alton L. Boynton, Marnix L. Bosch
AI
