Expert Financial Analysis and Reporting

Glossary of Key Acronyms Used in this Report

MHRA    Medicines and Healthcare products Regulatory Agency is the United Kingdom regulatory counterpart to FDA. The two agencies have a close, collegial working relationship. Approval of DCVax-L by MHRA would carry great weight in the FDA’s decision making.

MAA  Marketing Authorization Application is the document that must be submitted to the MHRA by companies seeking approval for a drug. The MIA is an integral part of this submission. Approval of the MAA allows commercialization.

MIA   Manufacturer's Importation Authorization is required by the MHRA before a company  can manufacture, import or export drugs. To qualify, a manufacturer needs to demonstrate to MHRA that it complies with good manufacturing practices and can pass regular GMP inspections of its manufacturing site.

GMP   Good Manufacturing Practice is a system required by regulatory agencies for ensuring that drugs are consistently manufactured according to carefully defined quality standards. Guidelines address issues such as process validation, quality assurance assays, record keeping, personnel qualifications, sanitation, cleanliness, equipment verification and others.

NICE  National Institute for Clinical Excellence plays a crucial role in determining reimbursement for new pharmaceutical products and treatments in the UK's National Health Service (NHS). It is considered to be the gatekeeper to reimbursement by the NHS. A positive recommendation from NICE typically obliges the NHS to make funding available for a product or treatment, usually within three months

Introduction

It has been over a year since CEO Linda Powers has spoken about her strategic vision for Northwest Biotherapeutics; during this time there has been some remarkable progress. At the annual shareholder meeting on June 29^th, 2024 CEO Powers provided a comprehensive, hour long overview of what has been accomplished over the last 18 months and her key priorities for the coming year. In this report I have largely reproduced a verbatim transcript of her talk which contains a wealth of information. I have summarized what I consider to be the key points, but I would urge you to read the whole report in order to understand the amazing job that NWBO has done with the development of DCVax-L in the face of an egregious stock manipulation scheme that has had an extremely negative impact on the stock price and blocked ready access to capital.

The transcript of her talk is over 18 pages. Speaking is not always as precise as writing which makes reading the transcript challenging. I have tried to edit and organize the subject matter to give a more user friendly format. My purpose is to organize and edit but not to inject my own thoughts. Her presentation focused on issues relating to:

• MAA submission for DCVax-L in the UK,
• Manufacturing accomplishments at Sawston with special emphasis on Flask Works,
• Broad, industry leading portfolio of intellectual property covering dendritic cell technology that has been assembled.
• Groundbreaking lawsuit against the market makers who have been manipulating the stock price and continue to do so,
• Key accomplishments in the past 18 months and
• Priorities for the coming year.

My Key Takeaways

 I would urge you to take the time to read this full report. However, if you just want a quick summary here are my key takeaways.

• The MHRA is actively reviewing the MAA for DCVax-L for the treatment of newly diagnosed and recurrent glioblastoma multiforme (GBM). The regulatory agency has not issued and will not issue guidance on when their review process will be completed. Most analysts who closely cover the company, me included, are estimating UK approval in the September-October of 2024 time frame.
• NWBO has done an awesome job in building a world class personal cell manufacturing capability at its Sawston, UK facility to support the commercial launch. MIA approval was obtained in March 2023.
• Before launching DCVax-L in the UK, NWBO will need to get a favorable reimbursement recommendation from NICE. Ms. Powers reported that there have been ongoing interactions with NICE over years that have been quite encouraging and there is reason to hope that a positive reimbursement recommendation will follow swiftly on the approval of the MAA.
• The manufacturing capacity at launch is expected to be 1,000+ patients per year using grade B clean labs. However, the implementation of the Flask Works grade C lab technology could expand capacity to 15,000 in the not too distant future.
• NWBO has assembled an industry leading, dominant package of intellectual property covering dendritic cell technology which was recently bolstered substantially by the acquisition of a very important IP package from Roswell  Park whose scientists have spent 24 years developing a cutting edge dendritic cell technologies and arguably are the leading group worldwide in this field.
• Along with the IP acquired from Roswell, NWBO also gained control of two phase 2 trials that are being conducted by independent investigators that are fully funded by grants. NWBO will not be required to fund these trials or to provide any support until a phase 3 begins (if warranted). This gives an immediate jump start to the medium term pipeline.
• NWBO has been the target of a long term stock manipulation scheme that has had a devastating impact on the stock price. The company filed a lawsuit against seven market makers in December 2022 to block this. I believe that the defendants motion to dismiss the lawsuit will be denied in a month or two and allow NWBO to go forward to discovery. This could lead to stopping the manipulation and ultimately the awarding of substantial damages, possibly meaningfully above $1 billion.
• Market makers through illegal naked shorting can create a limitless number of counterfeit shares. The exact number can only be known after discovery allows NWBO to subpoena trading records from market makers and DTCC. However, based on what I have seen with other companies that have been victimized by this scheme, I hypothsize that there may be more than 1 billion counterfeit shares circulating in the market alongside legally issued shares.
• Discussions are underway to begin combination trials of DCVax-L with other drugs such as checkpoint inhibitors, targeted therapies and chemotherapies. We may hear more by year end. Phase 2 trials of DCVax-L combined with checkpoint inhibitors and other drugs have produced very exciting results in GBM.
• The company is in a number of discussions involving partnering parts of its technology platform. We may hear more by year end.
• NWBO is in the process of restarting trials of DCVax Direct. This product takes a different approach from DCVax-L in that it addresses the treatment of metastatic cancers in which the tumor cannot be surgically removed. This is a huge unmet need. DCVax-L addresses cancers that are surgically resectable.
• The major weakness of NWBO is an extremely strained balance sheet. Approval of the MAA and denial of the motion to dismiss in the lawsuit could provide access to the substantial low cost capital needed to implement the Company’s plans. Ms. Powers did not directly address this in her remarks.
• The company chose to file for regulatory approval in the UK because the process is much faster than for other regulatory agencies and because it us highly respected will carry great weight in future decisions by other regulatory agencies. It is preparing to file for approval in the US, European Union and elsewhere following UK approval.

The MAA Submission to the MHRA

Prerequisites to Filing the MAA

The MAA was filed on December 20, 2023 seeking approval for both newly diagnosed and recurrent glioblastoma multiforme. In addition to the clinical trial results from the DCVax-L phase three trial, there were significant prerequisites that had to be completed before MHRA would accept the submission.

• On March 20, 2023 NWBO announced that an MIA license had been approved and issued by the MHRA for commercial manufacturing of cell therapy products at the GMP facility in Sawston, U.K. Under this license, cell therapy products manufactured in the Sawston facility may be exported globally. Products (e.g., immune cells) may also be imported into the U.K. for production or release of cell therapy products under the facility’s licenses. This license was obtained by Advent
• A human tissue authority license is a regulatory requirement for organizations that use and store human tissue. This was also obtained by Advent.
• A Pediatric Investigation Plan (PIP) for clinical trials of DCVax-L in children had to be submitted to and approved by the MHRA; beginning the trial is not a requirement for approval of the MAA for DCVax-L. This work was largely done by NWBO.

Ms. Powers said that the interactions with MHRA have so far been wonderful. They gave NWBO quicker than expected turnarounds on each of these prerequisites.

Trial Master File Submitted with the MAA Is an Enormous Document

This phase three trial was one of the largest clinical trials of a cell therapy product (particularly a personalized cell therapy product) that has ever been conducted. This resulted in an enormous Trial Master File (TMF) which is a comprehensive collection of documents that provide evidence of how a clinical trial was conducted and managed. It also contains essential documents that demonstrate compliance with regulatory requirements and Good Clinical Practice. It allows monitors, auditors, and regulators to evaluate the conduct of a trial and the quality of data produced.

Pulling together all of the contents of the TMF, was an enormous organizational exercise. The drafting in combination with medical writers began in the fall of 2022. If the digital file were reproduced on paper, it would create a stack of paper 200 feet tall. There cannot be any gaps in the file and all data must be easily accessible. For example, if inspectors want to see lab tests for patient X at clinical trial site Y, the regulator must be able to immediately access that data.

Preparing for MHRA Inspections as Part of the MAA Review

An enormous amount of work is required to prepare for MHRA field inspections. NWBO as the sponsor is going to be inspected as are the contract research organization that conducted the trial, the independent database company that held the database and certain hospital trial sites. Each organization has to have everything ship shape and NWBO has been working diligently with teams of consultants to prepare them. MHRA typically sends a team of inspectors who may stay for a week or more. NWBO hired people who previously worked as inspectors for regulatory agencies and now act as consultants, to conduct audits and mock inspections. They try to anticipate what kind of questions MHRA will ask and what kind of supporting information might be required.

Demonstrating Mechanism of Action

The MHRA will also have questions on the proposed mechanism of action of DCVax-L. Over the last 18 months, NWBO completed and then presented results from mechanism of action studies which studied the underlying biology of how DCVax-L is believed to work. Chief Technical Officer, Dr. Marnix Bosch, presented that information in a company presentation at ASCO last year. It is tremendously important because it strongly supports the underlying biology hypothesized for DCVax that results in its broad spectrum of activity.

It was shown that the dendritic cells on which DCVax-L is based are picking up a very broad range antigens from the tumor tissue sample (the lysate). Studies showed that over 600 different tumor antigen targets were displayed to T-cells. This is the basis for its broad spectrum of activity. Those studies were extremely important to add scientific underpinning that supports the clinical trial results that have been seen. Proteomics technologies that study the activity of proteins that have only recently been developed and were used in this study.

Data from the Compassionate Use Program Supplements the MAA

They continue to follow patients still alive from the phase 3 trial; the exact number wasn’t specified. With standard of care, the five year survival rate is about 5%. There are still a meaningful number of patients alive from the trial in which the last patient was enrolled in November of 2015. This means that each of these patients has survived at the very least about nine years. NWBO has gleaned important information about these long-term survivors.

There has been a long running, well over a decade, compassionate use program that has provided valuable, real world experience. In a clinical trial, the goal is to replicate in cookie cutter fashion the treatment of each patient. However, this is not how it works in the real world. For example, there are patients whose tumor tissue sample wasn't in the condition that it was supposed to be. It may not have been frozen quite the right way or was frozen several years ago or the patients were way outside the age range. They have had patients in their 80s. And so the compassionate use program has been valuable in gaining a tremendous amount of real world experience, basically practicing for what will happen when they go commercial. Recent activity has slowed because of the preoccupation with the MAA.

Activities At Sawston, Commercial  Preparation and Flask Works

Sawston Has Received a License for Commercial Production of DCVax-L

Another huge area of activity over the past 18 months has been in the development of the Sawston facility allowing for the MIA and TIA licenses. To put this in perspective, Ms. Powers provided some history. The very first manufacture of DC-VAX-L for a patient in Sawston was in February of 2022. GMP allowing for the MIA in Sawston was obtained less than two and a half years from the time this first product was made; there has been enormous progress. Phase 1 grade A and grade B lab build outs that will be used for initial commercial production which were the basis for the MIA approval. Specialized architects and engineers are at work to design the grade C labs under development with Flask Works technology that will be ultimately used in production. Advent is working on commercial readiness.

Grade B Labs Will Be the Basis for Initial Manufacturing, But Grade C Labs Based on Flask Works Are the Future

NWBO highlighted in a March 2024 press release progress made in the Flask Works system which ultimately will be used for all production at Sawston. Before discussing Flask Works, Ms. Powers addressed the traditional type of clean rooms involved in a GMP (good manufacturing practice), clinical grade manufacturing facility. The regulatory requirement is to have labs with no particulates in the air. Europeans call these grade B labs; in the US they are referred to as a class 10,000 lab. They are high level sterility facilities that perform a complete air change of the whole suite once every minute. They are manned by technicians wearing spacesuits. Facilities require special water and environmental systems.

The traditional Class B facilities must be perfectly sterile and are very expensive. The objective of Flask Works system is to enable NWBO to transition first to being a closed system for most  manufacturing steps and then to automate the process in a grade C lab which will ultimately be the basis for all commercial manufacturing at Sawston.

Manufacturing Capacity Will Be Significantly Increased in a Grade C Lab

In the most rigorous, sterile grade B labs, only one product for one patient can be produced at a time. Then the whole suite has to be cleaned before the next product can be produced because the procedure is partially open. In the grade C lab, everything is closed allowing for the manufacture of product for multiple patients at the same time in the same suite. This has been a huge focus for NWBO. It's not simple to change planning from grade B labs to grade C labs, because not only is the size and the configuration different, even the load on the building is different. There has been tremendous progress over the last 18 months.

In terms of initial capacity, the current anticipation for the class B lab is estimated to be about 1,000 or 1,100 DCVax-L patient treatments per year. Sawston is very large with close to 88,000 square feet on two floors. When the building is fully built out with C labs, it is anticipated that each of the grade C labs operating with two shifts should be able to provide product for 15,000 patients a year. That is an enormous amount, especially for personalized cell therapies. The big companies who brought the CAR T cell technologies to the market in their first years of commercial operations were only able to produce 50 patient treatments per year. Having the eventual capacity to make product for up to 15,000 patients would be an absolutely enormous manufacturing achievement.

Additional Nuts and Bolt Preparations for Commercialization

There have also have been a lot of preparations for the more nuts and bolts things that are needed for commercial operations beyond the physical aspects of building out the facility. One example is that NWBO has established controlled clinical-grade cryogenic storage for three million dosage vials. Also, readouts from the environmental monitoring system must be able to make sure that the number of particles in the air in the suite during the entire seven-day process stays below the maximum allowed.

An important focus is that after manufacturing is completed the product has to go through product release. This requires quality control tests using assays or tests or analyses that have been approved by the MHRA to test and assure the sterility, purity, potency and composition of the product. These are regulatory requirements.

The manual way of doing product release is for a certified quality person (QP) to manually review all records which can take up to 30 person hours. It’s one thing if a batch of product is made up a million tablets, but entirely different if a batch is a personalized therapy for one patient. The development of the manufacturing process was started five years ago by their Advent. It essentially automates the product release process and removes it as a bottleneck.

More on Flask Works

Before the acquisition by NWBO, Flask Works had developed only one approach for its system. It was a good approach and part of the reason why NWBO acquired it from Corning. Still, it wasn't as optimized as NWBO wanted. So over the last 18 months since the acquisition, Advent and NWBO have developed two additional, fundamentally different approaches to the automation and the closing of the manufacturing process. Extensive comparative testing between the two evaluated how cells did with one approach or another looking at parameters such as the yield and the stress on the cells.

They first developed an optimized non-GMP, non-clean room version of the machine and then adapted it for the clean room. This required the use of different materials and different mechanics. The adaptation work for GMP was recently finished. There are a couple of improvements that are being done to streamline the machine for which units are about to be ordered.

Advent’s Contributions Have Been Critical

Most of the work at Sawston has been carried out by Advent which provides a range of contract services to Northwest that are critical. Advent people on the ground in the UK do things like:

• Manage the operation and development of this Sawston facility,
• Draft all the manufacturing related sections of the MAA,
• Conduct on-site detailed science,
• Oversee the functionality and the actual work done on the Compassionate Treatment Program.

This is all done under contract and in collaboration with NWBO.

Advent is owned by the Toucan Investment Fund which is managed by Linda Powers and this makes it a related entity. Working with Advent is far less costly than would be the case if NWBO were using a third-party provider with whom it did not have a close relationship. It makes a lot of operational sense and has produced a great working relationship.

NWBO monitors Advent inputs and costs very carefully. A large chunk of what is paid to Advent is just pass-through for costs of the work that they're doing with their personnel and the various contractors that they bring in to work on Sawston. Advent is compensated with a pass-through of costs plus a 15% fee on top.  Payment is based on meeting contractual milestones, e.g. receiving the MAA or getting the facility going for the next phase of  designing the grade C lab.  Advent is extremely valuable to NWBO not only in its manufacturing capabilities, but also on experimentation and the work that has to be done on the science side.

NWBO Has Assembled an Industry Leading Portfolio of Intellectual Property

Dendritic Cell Technology Is in Its Early Stages of Development

Acquisition of dendritic cell technology intellectual property has been a significant area of activity and has been very productive. From a big picture standpoint, the  goal is to build the industry leading platform. The mainstream biopharma thundering herd are always a followers on innovative technologies such as monoclonal antibodies and CAR-T. The herd hasn't yet fully recognized the special capabilities of dendritic cells, but it's beginning. For example, when the federal government created a new agency modeled on DARPA (Defense Advanced Research Projects Agency) which is called ARPA-H (Advanced Research Projects Agency for Health). The very first grant that this elite “technologies of the future” agency awarded was a large $25 million grant for dendritic cell technologies to an academic setting. Increasingly people are beginning to recognize the special capabilities of dendritic cells. NWBO  has been aggressively building a dominant franchise before the thundering herd recognizes the promise of dendritic cell technologies.

In its regulatory filings, NWBO has been quietly reporting on the in-licensing of technologies that they believe will be valuable in building this franchise. NWBO just recently announced a consequential agreement that was the in-licensing of IP from Roswell Park Comprehensive Cancer Center. It covered the IP package developed by a world leading group of dendritic cell scientists based on seven years of work at Roswell. However, NWBO previously completed an  in-license of a package of the original, older foundational work which that group had spent 17 years developing at another institution.

Synergy of Acquired Intellectual Property and Technologies with the DCVax Platform

NWBO stayed in stealth mode while it was putting all the IP pieces together. The two packages just described have some wonderful things in them. They include enhanced versions of dendritic cells. They also include technologies that are complementary to use with dendritic cells such as immune system boosters for use in combination trials. This collection of new tools and technologies provides a wealth of growth opportunities that complement the existing DCVax platform of which there are two versions. DCVax-L is for operable tumors and DCVax Direct for inoperable tumors. NWBO hasn’t said much about DCVax Direct lately, but Advent is finishing up requirements that will allow a restart of the DCVax Direct program

The in-licensed IP also can be used with drugs of other companies. For example, there is a conditioning regimen meant to condition the patient to have a stronger response to immune therapies; this is referred to as reprograming the tumor microenvironment. This is synergistic with any type of agent and would allow NWBO to partner with companies who have biologics or targeted therapies or checkpoint inhibitors which might or might not be promising combinations with the DCVax platforms.

One of the really important aspects of the in-licensed package from Roswell is that NWBO gained two phase two trials currently underway. They are fully funded by grants and are being fully carried out by independent investigators. NWBO isn’t required to provide funding or any other type of support. If they produce encouraging results, NWBO will then have the right to take them into phase three. Roswell is a very prestigious, top tier cancer center. They have done a marvelous job of developing dendritic cell technologies at the research stage and at the early clinical trial stage and even now into the mid stage clinical trials. NWBO is really gratified that they were chosen to carry the baton to take these assets forward into late stage clinical trials and hopefully into commercialization.

These are some of the intellectual property, that NWBO has been quietly in-licensing. They provide quite a number of different pieces of technology that they feel will be useful building blocks. NWBO has also been putting some collaborations in place which haven’t yet been announced; those will be something that will be coming along.

Lawsuit Against Citadel, Virtu, Canaccord Genuity, G1 Execution, GTS, Instinet and Lime Trading-in the United States District Court, Southern District of New York. 

Status of the Lawsuit

NWBO filed a lawsuit in December 2022 that alleges that seven market makers illegally manipulated its stock price. Management and investors are unbelievably frustrated that the share price is not reflecting the value that has been and is being built because of this. NWBO believes this scheme has been going on for many years. Management was very anxious to try to take some action to do something about it, but had to bide its time and meticulously collect evidence as the bar for success in this type of lawsuit is extremely high. The degree of detail required to be put in a complaint is hard to even describe. NWBO did bide its time until it could put together a very strong case.

Since the lawsuit was filed, it has gone through a lot of back and forth skirmishes, all of them relating to the defendants’ effort to have the case dismissed by filing a motion to dismiss. NWBO is encouraged that the magistrate and the court have found that the pleadings in the complaint have been sufficient on all but one of the elements that they need to plead in order to deny the motion to dismiss and  proceed to discovery and then to trial or settlement.

NWBO Has Successfully Pled that the Market Makers Purposely Manipulated Its Stock

The magistrate and district court have found already that NWBO’s pleadings are sufficient to show that the defendants engaged in manipulation of the stock through spoofing and that they did so with scienter (intent to damage Northwest). This is at the pleading stage so the court has only said that they have adequately pled this; it has to be proven in a trial. However, this is a very, very big deal. This is a widespread scheme and there are many, many cases in which the companies who've been the victims or targets of this alleged criminal enterprise have not been able to get anywhere close to trying to seek redress.

This is because the plaintiff must articulate all the minute details of the transactions that are alleged in the manipulation before getting to discovery. However this data is controlled by the market makers and DTCC and not readily available. This is a catch 22 in which the data that is necessary to proceed to discovery isn’t available unless they get to discovery. Hence for years and years, victim companies have been unable to get over that bar. Ms. Powers encourages investors to read the complaint in which the result of a special investigative technique allowed them to get details for thousands of transactions down to the millisecond. NWBO is very proud of this and a lot of work thar went into it over the years that NWBO has been vigorously pursuing this case.

The Court found based on NWBO pleadings that the market maker defendants had spoofed the stock. Spoofing is a trading strategy where traders manipulate market prices by pretending to have interest in buying or selling assets without the intention to execute those trades.  In the U.S., spoofing was explicitly made illegal by the Dodd-Frank Wall Street Reform and Consumer Protection Act of 2010. In addition to spoofing, NWBO had to demonstrate three other acts in its pleading. Two of these were reliance which essentially means that the trading data used in the pleading is valid and scienter which means that the defendants knowingly spoofed the stock with the intent to damage NWBO. The magistrate ruled in NWBO’s favor on reliance and scienter as well as spoofing.

Successfully Pleading Loss Causation is Key to Having the Motion to Dismiss Denied

The fourth and final element of the case is loss causation. This must establish that the illegal spoofing did cause financial damage to NWBO. It needs to be shown that  that there is a connection between the defendants bad behavior and the damage it caused. The magistrate and the court said that NWBO hadn't pled sufficiently this element which is referred to as loss causation. The court was asking if they did manipulate the stock with the intention to harm, in what time frame and to what extent did this occur?  Was it the same day? Was it within 24 hours? Was there a lingering effect that lasts for much longer-weeks, months or years? Encouragingly, the court and the magistrate specifically gave NWBO permission to amend its complaint to strengthen the pleading claims on loss causation.

An amended filing that only deals with loss causation has been submitted. There is no need to reargue reliance, spoofing or scienter. The defendants made their objections to the filing as it pertains to loss causation and NWBO replied. The company is now waiting for the magistrate to evaluate this and give his report and recommendation, which the court will then act on. It has been a long time ( a year and a half) since the complaint was filed. They have tried to press the schedule as much as they can but defendants went to great lengths to slow the process. Still, this is a pretty good pace from what they understand. It's in line with other cases of this type and may actually be a little bit faster. It's just that the wheels of justice grind slowly.

Strong Reasons to Believe Defendants Motion to Dismiss Will Be Denied

There are no guarantees, but they are optimistic about what the ultimate decision will be about the motion to dismiss, namely, that the motion to dismiss will be denied and the case will be allowed to go forward to discovery. They believe the case is meritorious and strong and that there will be an opportunity to recoup damages and to get the manipulation to stop.

Looking Forward

To this point, the presentation focused on accomplishments reached in the last 18 months. The next part of the presentation dealt with potential milestones in the next 18 months or so. CEO Powers laid out priorities, grouping them into three categories: top priorities, second priorities and then feasible priorities.

Top Tier Priorities

MAA Approval for DCVax-L in the UK

Needless to say the top priority on which they are laser focused is to complete the process and hopefully obtain the first commercial approval of DCVax-L in the UK. NWBO believes that the MHRA is following the hundred and fifty day process that they have but do not have confirmation and don't have a way to be sure. They believe that the hundred and fifty day process involves approximately three stages and the time frame of each stage is approximate. The first stage is approximately 80 days of initial review of the application. The second is approximately a 60 day clock stop when the agency delivers a list of questions to the sponsoring company. It's not just that they deliver questions; they may also ask for supplementary information. After the 60 days or however long the clock stop turns out to be, there is a third stage of approximately 70 days in which MHRA may seek additional information. NWBO is trying to guess what they might ask and to prepare to provide all the answers and for additional information in the third stage.

In the US, the FDA gives a target date for reaching a decision. There is not an equivalent thing in the UK. The approximate timeframes of the three stages also depend also on MHRA's workload and backlog. CEO Powers also emphasized that during this approximate 150 day process there will be numerous inspections that will have to be completed before an MAA decision can be rendered. NWBO as is typical for biopharma companies will not provide information on interim steps or questions asked and answered. They will just release the result when the MAA reaches its decision.

Preparing for the Commercial Launch

Another top priority is preparation for commercial launch. They have been working on this for years, but there is still a lot to do. They anticipate  beginning commercialization using the existing grade B labs while pursuing . the buildout process for the grade C labs. As a part of this preparation for commercialization, they will be finishing the process previously described for the Flask Works machine to establish a  grade C lab. The design work has been done. Advent will need to conduct a large number of engineering or practice runs. They will need to collect all the data and compare it with the data from the DCVax-L products produced by the existing manual process.

NWBO will have to demonstrate to regulators that the Flask Works machine operates properly and doesn’t shed particles into the clean room air. They also have to show that it produces a product that's the same or acceptably close to the same. They will collect all the data and do equivalency studies and collect the data from that. These will be submitted to the regulator for approval.

These are all things going on in parallel as the MAA process and inspections are taking place. They also need to do some more mundane things like expanding operating arrangements. One example is expanding contractual arrangements for leukapheresis blood draw slots. They have to contract for those and they have to pay for them so it's such a little bit of chicken and egg calibration. They want to have enough slots but don't want to get too far ahead of needs and needlessly increase the burn rate. So they will  be calibrating contract arrangements for more of those slots. They will certainly need to expand the staff who will handle logistics. As part of the preparation for commercialization, they will need to determine what the pricing model is going to be for DCVax-L. That's something on which they are working with expert advisors and it will be important obviously and again all these tracks are going on in parallel.

Applying for Reimbursement

Following MAA approval, they will need to go through the process of applying for reimbursement. In the UK, the gatekeeper is NICE. CEO Powers says that NICE has been absolutely supportive in their dealings with NWBO and she cannot say enough wonderful things about the relationship so far. They have been reaching out to NWBO every couple of months to check on the status of things. She couldn't imagine a government agency that's been as supportive as they have been. NWBO will need to do a health economics model that justifies the cost benefits of the DCVax-L treatment. NWBO has engaged specialized consultants to develop that model. This is certainly one of top priorities over the coming 18 month period.

Filing for Approval in Other Countries

NWBO is planning to submit applications for approval in other countries. They are very happy to be going through the first approval process in the UK because they have a very fast process; probably the fastest in the world. In submissions to other counties, they have an important head start because one big components of the application anywhere is data comparable to the trial master file combined with the 20 years of efficacy and safety data from every program that's ever been done with DCVax-L This includes use with cancers other than GBM.

Expanding the Management Team

The management team needs to be substantially expanded. Core members of the senior team have been wearing multiple hats fulfilling multiple roles. In many cases these normally would require a separate senior management person. They need to ramp up, but want to be highly selective as they expand the management team.

Vigorously Pursuing the Lawsuit

The last item in the grouping of top priority is to continue to vigorously pursue the lawsuit in New York against the parties that they believe have been and are continuing to manipulate the stock.

Second Grouping of Priorities

Pediatric Trial of DCVax-L in the UK

NWBO is planning to initiate a pediatric glioma trial with DCVax-L in the UK as a requirement by MHRA. CEO Powers emphasized that  completing the trial itself is not a specific requirement for obtaining approval for the adult GBM indication. What was in fact a prerequisite in order to file the MAA was that they had an approved plan. This was a long process in the UK that involved a year and a half of discussions with pediatric neurosurgeons and oncologists before reaching conceptual agreement. NWBO is going to proceed with just one of the two planned pediatric trials first and the second one will be sequential rather than simultaneous. This is actually a good thing as it will reduce the bandwidth and resource requirement.

Restarting the DCVax Direct Program

NWBO has been eager to restart the DCVax Direct program. The first requirement is to restart manufacturing which requires a technology transfer to Sawston. This is necessary because the product was only produced in the US by parties who are no longer operational. This requires the drafting of a whole new set of standard operating procedure, regulatory documents.

Usually a technology transfer, especially for a cell therapy, is a minimum of at least six months of work. There have been two major challenges that have been faced and hopefully will soon be behind NWBO. One related to the machine that is used for the first stage of the process and the other to some key ingredients in the process. Restarting the manufacturing process is a significant priority. There will be a press release once manufacturing is restarted

Once manufacturing is restarted NWBO is very eager to get the clinical trials underway. The early stage trial was a phase one trial which was conducted at MD Anderson. It treated 13 different types of very diverse, inoperable  solid tumors-pancreatic, breast, lung colorectal, et al. There were very encouraging survival extensions in metastatic patients who had failed all other treatments. DCVax Direct was really encouraging in this extremely difficult to treat patient group. Today with all the billions that have been spent by the pharma and biotech industry on cancer development, there is not very much that can be done with patients who have inoperable, metastatic solid tumors.

DCVax Direct is a very promising technology because it is directly injected into the tumor. In many cases, the tumor can't be surgically removed  because there are too many metastases or because of where it is located. With image guidance physicians can reach almost any location in the body and inject DCVax directly  into the tumor. Ms. Powers said that she’s not aware of any treatment that has had the kind of encouraging results shown in phase one trial at MD Anderson.

Starting Combination Trials

In all of its public presentations about the trial results in the phase 3 trial, NWBO has emphasized the survival extensions with DCVax L when used as a monotherapy in combination with standard of care. This is version 1.0 of the DCVax L technology platform. They are eager to build on that by combining DCVax-L with drugs having different mechanisms of action. Its benign safety profile and broad spectrum lends itself to combination therapies. It is eminently combinable with treatments such as checkpoint inhibitors (Keytruda and Opdivo), targeted therapies, chemotherapies and indeed almost any variety of therapy. They have received considerable interest from various companies. NWBO has some collaboration discussions underway and one of their priorities is to do one or more of those combination trials in the not too distant future.

The DCVax-L phase 3 trial was one of the biggest and without question the longest trial ever done in glioblastoma. NWBO believes that it will be a major landmark study in the field. However, they now want to do future trials  more focused and using faster path tumor shrinkage endpoints. They want to focus particularly on clinical trials where tumor response (meaning tumor shrinkage) can be the endpoint as opposed to overall survival.  Tumor shrinkage can be seen in a matter of months while survival takes years. They have so many opportunities that the challenge is choosing the right one.

Partnering

NWBO has had questions from shareholders as to whether they are open to partnering. Ms. Powers cited a couple of examples of potential partnering deals especially now that they have this this tool chest of new technologies and intellectual property. They are looking for deals that have either strategic or financial value. This could be a regional partnering. They have emphasized filing and maintaining their IP in a wide range of countries. They would also consider partnering for a specific application.

Listing on a National Exchange

Shareholders have also asking about up listing to a national exchange from the OTC. The company realizes that some investors are experiencing difficulties with some brokers with share management and purchases. They will be looking to up list when the time is right.

Conclusion

Ms. Powers in her concluding comments said that she had tried in this presentation to give an overview of a lot of different areas without going into great detail.  She feels they have made tremendous progress in the last 18 months and are a different and much stronger company. While there are no guarantees, she believes they are well positioned to get their first product approval and begin commercialization with DCVax-L in the UK. They believe that the infrastructure and the systems that they have been working on for years are in order to build for the day that's now arriving. They have the physical facilities, operating systems and strategies that can facilitate  commercialization

She believes that through in-licensing they have built a tool chest that provides tremendous growth opportunities. She is painfully aware that the share price does not currently reflect the progress that has been made. She  believes that they can continue making progress in building intrinsic value if they can continue taking action against parties that they believe are artificially manipulating and holding the shares down. They also will work to attract institutional investors. Ms. Powers thinks that the combination of building intrinsic value and fighting back against manipulation will ultimately lead the market to recognize the value.

Categorized as Company Reports, LinkedIn