NorthWest Biotherapeutics Inc (NWBO)

[ae kusterer]

hyperopia
Transcript of 2023 ASM held June 29, 2024
https://nwbio.com/audio-of-nwbio-2023-annual-shareholders-meeting/


Having concluded the formal business, we have no other business that was properly brought before the annual meeting of stockholders. Within 4 business days, we will provide the final voting results in a form 8k filed with the SEC, Securities and Exchange Commission. I would now like to take this opportunity for an information discussion, informal information discussion, in regard to questions submitted by stockholders in advance of the meeting. We may have to make this point. We may make forward looking statements during this discussion, and our actual results may differ materially from those forward looking statements.

You should not rely upon forward looking statements, and you should read Northwest Biotherapeutics Inc. periodic filing with the US Securities and Exchange Commission for a nonexclusive list of risk factors related to our business and operations that could cause actual results to differ materially from any forward looking statements provided during this meeting, and discussion. And now without further ado, we'll transition into that discussion. So now it can be a little more informal. Right?

This is meant to be a discussion of questions, that we're aware of, that shareholders have submitted or shareholders have raised with us. First thing that, what? Before I dive into the discussion, I think all of us at Northwest, I speak for all of us, wanna really thank all the stockholders for the tremendous voter turnout, and the tremendous, number of shares voted for this annual meeting. We really appreciate it, and we really appreciate the positive votes.

And we, we're just tremendously thankful and appreciative for that. We got a lot to discuss today, and we hope you're gonna find it exciting. And you're gonna leave the meeting feeling as excited as we do about the progress we've been making, and what our plans look like going forward. We plan to spend up to about an hour in this discussion, and we will, I will go through kind of a lot of information, that we've collected and that we think covers most of the questions, that we're aware of, that have come from shareholders. So I'm gonna start by, I'm gonna talk about the MAA, about developments at the Sawston facility, about progress with FlaskWorks. Also, gonna talk about some of the new exciting IP that we've acquired, and an update on our groundbreaking lawsuit against the folks that we believe have been manipulating our stock price.

So that'll be a kind of recap of where have we come in the last 18 months since the last annual meeting of shareholders. It's been a a busy period. After reviewing, the recapping the past 18 months, we're gonna look forward. And I'll describe our planning and our priorities for the next approximately 18 months.

And we think we hope that you'll find that exciting at with, a lot of anticipated, growth areas and potential progress. So, I wanna just go through some of these particular subject areas, for the last 18 months. So recapping where we've come to, over the last 18 months. First of all, near and dear to all of our hearts, is the MAA, for the commercial approval, application for the commercial approval of our DCVax-L product for glioblastoma brain cancer in the UK. And during this past period, key things that have been accomplished relating to this.

First of all, as you may recall, there were quite a few very significant prerequisites, that we had to complete before we were even eligible to apply. And that was in addition to the clinical trial results from our phase 3 trial. So we had to get 3 licenses for the Sawston facility. We had to get the initial license. We had to get a human tissue authority license. And then, most importantly, we had to get the MIA commercial license.

And that license, which was obtained in March of last year, was one of the first that's been granted for cell therapies in the UK. All of those licenses, the work was done, and the license was obtained, by Advent Bioservices, that worked with us. Another key, prerequisite that we had to do before being eligible to apply with the MAA, related to pediatric, treatments. We had to have a pediatric investigation plan, a PIP, which seems like a very English term.

And, the PIP had to be submitted to the regulator, and approved by the regulator, MHRA. And, so that was accomplished, and in fact, was accomplished in, what we understand to be, approximately half the usual amount of time. MHRA has been wonderful. They have given us rapid turnarounds, more than we could have expected or hoped for, in the steps that we've had with them so far. That doesn't necessarily predict anything, but it's been it's been a really great experience so far.

So completing all of those prerequisites, there were a lot of preparations as well, that kind of our surrounding context of the application itself. Pulling together the enormous, I mean it’s, it's just an enormous paper exercise, the trial master file. I don't even, I mean, I'm told it's a couple hundred linear feet of paper. I've seen it. I haven't measured it.

It's ginormous, and you cannot have any gaps. And when the inspectors come and they say, I wanna see the lab tests for patient X at clinical trial site Y, you have to be on top of that, and go right to it, and pull that page right out, and be ready for them. And we're talking an enormous trial master file. This phase 3 trial was one of the largest clinical trials of any, of a cell therapy product, particularly a personalized cell therapy product, that anybody has conducted.

And the trial master file is correspondingly enormous. That's just an example to give you a flavor. There's just a such an enormous amount, particularly to prepare for inspections, and that's a common theme you're gonna hear. We have been working our tails off with teams of consultants, because everybody's going to be inspected. We, the sponsor, are gonna be inspected. The contract research organization, who conducted the trial, is gonna be inspected. The document, the trial master files, its own, its own inspection. The independent database company that held the database for the trial will be inspected, the hospital sites, selected ones that were trial sites, are gonna be inspected.

So what I just described as the glimpse, the example, of the trial master file, every one of these parties has to have everything shipshape. And when they come with inspectors, our understanding from our advisers, is they will send a team of inspectors. Two, three, four inspectors, and they'll stay for a week.

That is a big undertaking. So we've been spending enormous amounts of time with all our teams of consultants preparing for all of those things. And we have gone through, audits, mock inspections. We hire people who used to be inspectors for regulatory agents and are now consultants, and we've gone through mock inspections. And each cycle is several months, and we get a report and then fix those things.

And so, anyway, that gives you a bit of a flavor. The drafting of the MAA package itself was a year long process as everybody knows. It was our Christmas present last year (haha) to to ourselves and everybody. Got it submitted on December 20th this past year, and had been working with medical writers since the fall of the year before. It was a multi thousand page, submission.

And then in the period since the submission, of course, there's been post-filing support. One of the things we are trying to do, working with consultants, a little bit like the practice inspections. We're trying to guess. We're trying to predict, what kind of questions might MHRA ask us about the package we submitted? And what kind of supplementary information might they ask us for? So that, to the extent possible, to send, to whatever extent we've guessed right with the guidance from all our advisors, who are experts in this, that will enable us to do a faster turnaround time.

That's the whole idea. We wanna try to keep the momentum, and keep up with path, rapid turnaround time. So that's a big area. As I think you know, also during this past 18 months, we we conducted and carried out and then publicly presented, all the, the results of our mechanism of action studies. These were, studies about the underlying biology of how DCVax works.

And our our chief technical officer, doctor Bosch, presented all that information in a company presentation during ASCO last year, and it was tremendously important because it showed with the underlying biology that DCVAX is what we've always hypothesized, it is. That it gave support for the hypothesis that it's a broad spectrum treatment. We reported that, in the examples that were studied, in those mechanism of action studies, the dendritic cells were picking up, and from the tumors tissue sample, the lysate, and presenting to the T-cells over 600 different tumor targets. So when we say it's a broad spectrum treatment, you know, that gives you a flavor of it. And those mechanism of action studies were really important to add more scientific underpinning that supports the clinical trial results that we've seen in the patients, and help support our MAA.

And we, it was very important, you know, we use proteomics technologies that are relatively recently developed. You know, proteomics, the study of the proteins, active agents, are not as far along as genomic, tools. And so we were using quite recent technologies in doing these studies, and that was really important.

We . . . on another front, we do continue to follow our patients from the phase 3 trial. We do still have patients alive. I'll remind you that the last patient was enrolled in November of 2015.

We also have, continuing our ongoing compassionate use program, we have not had as much activity in that while we've been so occupied with the MAA. But that program continues to give us really valuable real-world experience. You know, in a clinical trial, you try to do everything as cookie cutter as possible, as homogeneous, the same as possible, but that's not the way the real world is. And so, the compassionate use program has been so valuable for us because we've gained a tremendous amount. And we still are gaining tremendous amount of real world experience, basically practicing for when we're able to be commercial.

So we have patients who their tumor tissue sample isn't in the condition that it's supposed to be, or it hasn't been frozen quite the right way, or it was frozen several years ago, or the patients are way outside the age range. We have patients in their eighties, and upper eighties. So lots of real-world circumstances that, that's really been valuable for us. And, I think it's been very valuable for the patients too, which is quite important, and we are learning lessons. We have some very nice long term survivors, 8, 9, 10 years. And, so we are learning lessons from the cases of long term survivors as well.

Okay, another huge area of activity over these past 18 months has been in the Sawston facility. The development of it, not just the licenses, which I've already touched on. But let me just let me just, for a moment of history here, remind everybody, the very first manufacture of a DCVax-L product for a patient in the Sawston facility, product number 1 ever, was manufactured in February of 2022.

Just two . . . and and there's a press release about it, you can find it on our on our website. . . just two and a half years later, look at where we are. We've completed the phase 1A build out, the phase 1B build out. We have worked with specialized architects and engineers to design the grade C labs, that I'll talk about in a minute, that will be, for the build out going forward. We've gotten, Advent has gotten, all 3 of those licenses, and we're working on commercial readiness, less than two and a half years from the first product ever made GMP in that facility. So that's been a huge area of work. We're very proud of that progress, and it's a, it's a valuable facility.

One of the things we've mentioned, that you may remember from our press release earlier this year, about the progress on the FlaskWorks system, which I'll come to in a second, is that the traditional, type of clean rooms in a GMP, (good manufacturing practice) clinical grade manufacturing facility, are what the Europeans call grade B labs, the letter B as in boy. We would call them class 10, 000 in the US. These are the high level sterility, an entire air change of the whole suite 60 times every hour, I.E. full air change every one minute. Technicians wearing spacesuits, special water, special environmental systems, no particulates, whatever, all of that. Those are the traditional ones. They're super expensive to build. They're super expensive to operate.

What we are transitioning to now, and we're able to do this because of the FlaskWorks system, is we're transitioning to grade C labs, which would roughly be more like class 100, 000 in the US. In other words, it's a lower level of rigor and sterility, and you can only do that when you have your whole manufacturing process is done in a closed way. The word closed is a magic word in the world of medical manufacturing. Right?

When your process is closed, that means it's all kept within a machine, or within a bag, or within a flask, or something that's not open to the air. Because once it's open to the air, it's no longer closed, and then the air has to be basically perfect. And that's very expensive. So the FlaskWorks system has enabled us to transition first to being a closed system for the manufacturing steps, and also to start the process of automation, which is a separate thing and an additional benefit. So we've ,we as we look towards the further development of the Sawston facility, we are, we're moving into to, all grade C labs from here on out.

And another huge difference, just to crystallize it for you . . . In this grade B labs, the more, the more rigorous sterile ones, you can only produce one patient's product at a time. You have to clean the whole suite in between each product. Imagine that. And that's on top of all the special air, and everything that I just said. Okay. And that's because, if you're doing a procedure in there that, at least partially, is open. That's why the word closed is such a magic word. So in the grade C lab, because everything is, magic word . . . closed, you can, the regulators allow you to manufacture product for multiple patients at the same time in the same suite. So you can begin to see the efficiencies. So important.

So that this whole area has been a big amount of focus for us, and work. There's a lot of aspects. It's not simple. Nothing is simple, but it's not simple to change your planning from grade B labs to grade C labs, because not only is the size and the configuration, and so forth, different, even the load on the building is different. And, oddly, some of the load is more problematic, more challenging structurally, for grade C labs, than for grade B labs, which I was surprised about. But, anyway, a lot of work, big area, tremendous progress over the last 18 months.

Just before we leave that subject, in terms of capacity, our current anticipation . . . and this is, you know, based on assessments, by the Advent folks, who are the experts, is that we anticipate that each of the grade C labs should be able to, with two shifts operating, produce about a 1, 000 or 1,100 patients products per year, per grade C lab. Okay? And we anticipate, you know, we're so fortunate this building, is very large, and it's about, close to 88, 000 square feet on 2 floors. We anticipate, ultimately, when the building is fully built out, if it's fully built out with C labs, with our current understanding, and if the engineers don't change things, we anticipate being able to manufacture up to, up to potentially 15,000 patients a year, with all grade C labs in the rest of the building.

So you can start to see, even if we get part of the way towards 15,000 a year, that is an enormous amount of patients, especially for personalized cell therapies. My understanding is, for example, big company, the big companies who bought the CAR T cell technologies, in their first years of commercial operations, made 50 patient products. Right? So, you know, having the eventual capacity to make up to 15,000 patients would be absolutely enormous.

We also have been doing a lot of preparations of the nuts and bolts of things that would be needed for commercial operations. I won't take time on that, but just to give you one glimpse of it, again, giving you flavor. We have established, and it’s existing today, we have controlled clinical grade cryo storage for 3 million vials of doses. So, 3 million is a pretty good amount to start with.

Part of all this is not just the physical aspects of building out the Sawston facility, but there's a step that have, that you have to go through for any medical product for a human patient. And that is, after you manufacture the product, it has to go through product release, and it it has to go through quality control tests, using quality control assays, or tests, or analyses, that have been approved by the regulator. You have to test the sterility, the purity, the potency, the composition, all of that, of your product. Okay?

But you also have to check that all during the manufacturing process, all of those regulatory requirements were met. So you have to check the readouts from the environmental monitoring system to make sure that the the number of particles in the air in the suite, during the entire 7-day process, stayed below the maximum allowed. I mean, it's enormous. And the manual way of doing product release, is for a certified person, they're called a QP, a qualified person, is to manually review all those records.

Well, that can take up to 30 person hours to do that, and that's one thing if a batch of product is like a million tablets. But a batch of product of a personalized therapy, is one patient. So that would have been a bottleneck if you manufacture the product and you can't release it to be used in a patient. So we started, close to 5 years ago now. Advent has worked with a company. They've developed a system, and the system, I won't bore you with the details. We'll have more to say about it, in the coming weeks, and months. But the system essentially automates the product release process, and removes that, as or hopefully, potentially, removes that as a bottleneck. Certainly, greatly improves over the manual process. So, again, huge area of work.

Yeah. I'm taking too much time, so I have to hurry up. Flaskworks . . . I'll just say, 18 months ago, we, they had only developed one approach for the system. It was a good approach. It was attractive. It's part of why we acquired them from Corning, but it wasn't necessarily, specifically as optimized as we would like it to be. So over these 18 months more, we developed two other fundamentally different approaches to the automation, the closing, magic word, and automation of the manufacturing.

Did extensive testing, comparatively evaluated: how did the cells do? Were the cells stressed with one approach or another? Was the yield better? All that kind of thing you would imagine. Selected the best approach, developed, optimized a non-GMP, non-cleanroom version of the machine, and then, went through and, just in this year to date, we've done the adaptation of that, to go into the clean room. Which you have to use different materials, and you have to use some different mechanics and so forth, that I won't go into. So that adaptation work for GMP was recently finished. There are a couple of improvements that we are doing to streamline, and then those units are about to be ordered shortly. So that's the that's the clinical grade machines.

Les is going to, I guess, make a couple comments about the, about the role. Most of this work that I've described has either been carried out, or driven by Advent. So we know that stockholders had some questions about Advent: How our arrangements with Advent are, how we pay them, what the structure is, and Les is gonna give you just a minute or two on that.

Thank you. Advent provides a range of contract services to Northwest that is very important and significant in terms of having people on the ground in the UK able to do things like: manage the complete development of the Sawston facility, prepare for, and draft all the sections of the MAA, from a from a scientific perspective, and the writing on-site, detailed science, oversee the functionality, and the actual work done on the compassionate treatment program, again, all under contract to Northwest. Substantial inputs, as Linda indicated, into development of the Flaskworks system. It involves a lot of collaboration, and a lot of testing and a lot of, it's been amazing how much work has been done, and how great the people there have done on that. And the way that Advent is finishing up ,even right now, things like the restart of DCVax-Direct, which will be coming up, and has done put a lot of work on that in the last 7, 8 months. And and let me take on, and and state how we compensate them under these contracts.

And that is, that the payment structure provides a pass through of all baseline costs, and, a fee, if you will, for the administration of it all, which is a 15% on top of that cost. But Advent doesn't really realize any gain on any of that until they meet the milestones, like getting the MAA in, or or getting the facility going for the next phase of the of the C, the C, services. And so, we find that that kind of an approach is very favorable to us, and to Advent because of the assemblage of all the capability, not only on manufacturing, but on the experimentation, and the work that has to be done on the science side. And so that kind of a compensation is something that allows us to get services that would be far less costly than if we had to go to a third party provider that we didn't have this close intimate relationship with. And and it makes a lot of sense, and it's been a great relationship.

And we monitor all of these inputs very carefully. And, I oversee that. And, we just wanna give you a flavor of how all that works. A large chunk of what we, pay to to Advent is just pass through costs of of the work that they're doing with their personnel and the various contractors that they bring in to do things like get the facility put together, or to do the C labs. Right. Thanks.

Thank you. So we have kind of two more large subjects, to finish up the recap of the last 18 months. Having gone over the MAA, and the facility, and the Flaskworks and all that, Now I like to turn to talking for a minute about intellectual property and collaboration. That's been a a significant area of activity for us.

We've reached completion on some things that we're quite excited about. So I'll talk for, just a minute, a couple minutes about that subject. And then I'll finish by talking briefly about our lawsuit, and the progress of our lawsuit against the parties who we believe are manipulating our stock, and we'd like that to stop. Yeah, so would you, right? Little understatement of the millennium. Right?

Okay. Intellectual property. Let me start with the big picture point. Our goal is to build a franchise in dendritic cell technologies. We want to build a leading, and preferably THE leading franchise in this area. The mainstream thundering herd hasn't yet fully recognized the special capabilities of dendritic cells, but it's starting to happen more and more. If you noticed, for example, when the the federal government created a new agency, modeled on DARPA, the Defense Advanced Research Projects Agency, which they call ARPA-H, for Health, Advanced Research Project.

The very first grant that this elite technologies of the future agency awarded, was a large $25 million grant for Dendritic Cells Technologies, in academic setting. And that's just one glimpse, but increasingly, people are beginning to recognize the special capabilities of dendritic cells. So we are working busily to build a dominant franchise in the meantime, before the thundering herd arrives, or while they're on their way. (haha) So we have quietly, and you may, or may not have noticed, but in our 10K and 10Q’s, we have been quietly reporting that we have been in-licensing technologies that we think will be valuable for the future in building this franchise.

Now just recently, we announced one that was particularly big. I mean, ginormous. And that's the arrangement, the in-licensing package that we did from Roswell Park. But if you noticed, even in that announcement, we explained that that package from Roswell covered 7 years of work by this leading research group on dendritic cell technologies. But we had also completed last year, an in-license of a package of the original older foundational work, that that group had spent 17 years developing, at another institution. And we have in-licensed both of those packages. And we purposely stayed in stealth mode while we put all the pieces together, because we believe, in our own analysis, that the whole, the sum is greater than the parts.

And those two packages together have some just wonderful things in them. They include enhanced versions of dendritic cells. They also include technologies that are complementary to, to use with dendritic cells. For example, a combination treatment regimen, in a trial, or agents to just be immune booster agents, that kind of thing. And if you think about it, interestingly, this collection of new tools or technologies, gives us a lot of growth opportunities, which we can use together with our existing DCVax platforms, which as you know, we have two versions of the platform, DCVax-L for operable tumors, DCVax-Direct that you haven't heard much about recently, but which will be coming up again, now I'm happy to say, for inoperable tumors. We can use these complementary technologies with our own DCVax platforms.

We can even use them with other kinds of agents. You can use a conditioning regimen, for example, that's meant to condition the patient to have more of a response to immune therapies, or is meant to, as people like to say, reprogram the tumor environment, the tumor microenvironment, to be more conducive to an immune response. You can use those with any type of agent. So we could, we could do partnering with other companies who have, biologics, or targeted therapies, or checkpoint inhibitors. That could either be with the dendritic cells included, or with just the other agents.

So we start to have a pipeline that has complementary things, but has many permutations and combinations that we can can do. And, obviously, one of the really nice things about the package, and I was, we were surprised because people, maybe it didn't quite register. But as we said in our announcement, there are two phase 2 trials currently underway with these technologies that we in licensed. Okay? And these two clinical trials are fully funded by grants, and they're being fully carried out by the investigators.

So we don't pay anything, and we don't do anything. But these are the results of technologies that we now have. So those will be going along in the background in parallel, while we're busily working on the MAA, and all of that. And if they produce positive encouraging results, we will then take them on into phase 3. And, we we think Roswell, which is an absolutely top tier. If you don't know, it's a very prestigious institution, very top tier cancer center. We think they've done a marvelous job of developing the technologies at the research stage ,and then the early clinical trial stage, and even now into the mid stage clinical trials.

And we're really gratified that they chose us to pass the baton to, to take it forward, for late stage clinical trial ,and hopefully, eventually, the commercialization. So, these are some of the, intellectual property, but we've been quietly in-licensing quite a number of different pieces of technology that we feel will be useful building blocks in building our, our franchise. And we've also, been putting some collaborations in place. So we haven't announced those yet, but, those will be, something that will be coming along. Okay.

The last section for the past . . . and we went way longer than we're supposed to here . . . is our lawsuit against the seven market makers. You know, all of us, I don't have, I mean I hardly have to say this, but all of us are unbelievably frustrated that the share price is not yet reflecting the value that we are working to build. And we believe that our stock has been manipulated, and we believe that was going on for many years, and we were very anxious to try to take some action to do something about it. But we had to bide our time, and meticulously collect evidence and so forth, because the bar is extremely high. You, the degree of detail that you have to put in a complaint, is, hard to even describe. It’s, I mean, in our, so we did bide our time until we had, what we believe, is a very strong case put together.

We filed that in December of 2022, so just before the last annual meeting, And it has gone through, a whole lot of back and forth skirmishes, all of them relating to the defendant's effort to have the case dismissed, and never go anywhere, by filing a motion to dismiss. And we are very gratified that the magistrate and the court have found that the pleadings in our complaint have been sufficient on all but one of the elements that we have to plead, and that's in process. I'll come back to that. So what they found already, is that our pleadings are sufficient, to pleading that the defendants engaged in manipulation of our stock, and that they did so with scienter, with the intent to damage Northwest. Now, again, we're at the pleading stage.

So the court has only said that we have adequately plead this, but that's a very, very big deal, because these cases that the companies who've been the victims or targets or, never have pretty much not been able to get anywhere trying to seek redress with this kind of case, because you have to be able to articulate all the minute details of the transactions that you allege involve the manipulation. And you have to do that first before you can get to the stage of discovery, but you can't get the information unless you get discovery. So it's kinda like when you get out of school and you can't get your first job until you have experience, but you can't get experience until you have your first job. And so, for years and years, decades, victim companies have have been, unable to get over that bar. And I encourage you guys to read the complaint.

I mean, read it when you wanna go to sleep, but,(haha) I mean, we did our complaint details thousands of transactions down to the millisecond. We're very proud of this, and it, a lot of work went into that. And so, and and we've been vigorously pursuing this case. The only element that the magistrate and the court said that we hadn't plead sufficiently, was one element, which is referred to as loss causation, saying, okay, well, if they did manipulate our stock, and they did have the intention to harm us, you know, what's the connection between their bad behavior, and what damage we say that we incurred.

You have to be able to connect the dots. And there's a time element to it. Like, was it the same day? Was it within 24 hours? Is there a lingering effect that lasts? You know, all of that complexity. So the court, and the magistrate specifically gave us permission to amend our complaint, to strengthen the pleading claims on that one element. We've done that. It's been submitted. The defendants made their objections. We did our reply. So now we're just waiting for the magistrate to evaluate all this, and give their report and recommendation, which then subsequently the court will act, unlike before.

So I know it feels like it's taking a long time, because, you know, it's been a year and a half since we filed a complaint. And we've been fighting, you know, we we try to press the schedule, as much as as we can. But, actually, this is a pretty good pace, from what we understand. It's in line with other cases of this type, and actually a little bit faster even, than some other cases of this type. It's just that the wheels of justice grind slowly, but we are pursuing this vigorously.

So you’ll see that, and there are no guarantees, but we are optimistic about what the ultimate decision will be, about the motion to dismiss. Namely, we are optimistic that it will be denied and the case will be allowed to go forward. We believe our case is meritorious and strong, and we believe that the case may be an opportunity to recoup damages, and to get, what we believe, is manipulation, to stop. So this is a big area of effort for us, and we just want you guys to know that, because we're as frustrated as you, are about the situation.

Okay. That was a really long recap of the last 18 months. The looking forward, I can buzz through faster. Well wanna do, like, a 7th inning, what is that? What inning is it? 7th inning stretch. Anybody wanna do a 7th inning stretch? Get a drink, or whatever, cookie? Just had to check which inning it was. 7th inning stretch. Okay. I know it's way too long . . . .

Was just only meant to be, like, a minute, but, okay. So now we're changing focus to forward looking. And let me remind you what I said at the end of the formal meeting, which is, these are forward looking statements. The actual results could vary materially for lots of different reasons. Please read the risk factors in our SEC filings, and please don't rely on forward looking statements.

So what I'd like to do, is just give you a sense of looking ahead now, for the going forward 18 months or so. What are our priorities that we're gonna be focusing on? And I'm grouping them into 3 groups; our top priorities, our second priorities, and then our, as we can, as feasible, priorities. So I'll give you the 3 groupings, and I'll just, describe. So, needless to say, our top priority, our laser focus, is to complete the process, and hopefully obtain our first commercial approval in the UK, hopefully, approval of the MAA.

We're well underway. We believe the MHRA is following the 150-day process that they have, but we don’t, we do not have confirmation of that. We don't have a way to be sure of that, to know it for sure, but we believe that. It, the “150 days,” quote, unquote, involves approximately 3 stages, and the time frame of each stage is approximate. So it's not, you know, on the button.

The first stage is approximately 80 days of initial review of the application. The second stage is approximately 60-day clock stop, when the agency is going to deliver a list of questions to us, as they do in all these processes. It's not just us. They'll deliver a list of questions. They'll ask for supplementary information, all of that. And, and we will try to respond as fast as we can, which is part of why we're trying to guess what they might might ask, and try to already kind of prepare.

The 3rd stage, which will come after the 60-day clock stop, or however long the clock stop turns out to be, to provide all the answers and info, additional information. The third stage is approximately 70 days of further review, and reaching a decision. Again, the the timelines are approximate. As as far as we've seen, there is not an equivalent thing in the UK that's similar to a PDUFA date in the US. You know, under the legislation in the US, you know, FDA can have a target date for giving you a decision.

We don't have a target date. It'll be what it'll be, okay? And those approximate time frames of those 3 stages that I described, of course, depend also on MHRA's workload, and what backlog they have, and so forth. So that's the approximate process, and the approximate timelines.

I mentioned, with a lot of emphasis, and a lot of discussion about the inspections, that they're gonna inspect everyone, and everything. Those are gonna be going on all during this MAA review process, and those will have to be completed before an MAA decision can be rendered. Right? So there's gonna be extensive inspections, and it's gonna be going on, during this period.

So we, the typical thing, we are gonna follow the typical practice of biotech and pharma companies, which is, we are not going to provide interim step blow by blow. They asked us this, we answered that. They asked us the next thing, we answer that. No, we’re not gonna do the interim steps. We're just going to tell the result when the process is finished. That's the typical approach, and that's the approach that we're gonna be taking. Okay. That's our big priority area, of course.

Another big priority, in this grouping of top priority, is preparations for commercial launch. There, we've been working on this for years, as I've described, but there's still a lot to do. We're very excited about working on this. First off is, we anticipate that we will be beginning commercialization using our existing grade B labs. So we're gonna be pursuing the build out process for the grade C labs as rapidly as we can, but we're not counting on that to get started with commercialization. We're able to get started with our existing B labs. We will, and likewise, we, a part of this preparation for commercialization, will be finishing the process that we described with the FlaskWorks machine.

So now that the adaptation for clinical grade GMP, that design work has been done. The remaining steps are; complete the the streamlining, or condensing some of the portions of it, get the units ordered, have the units delivered, and then Advent will need to conduct a large amount of, what are referred to as, engineering runs. They're practice runs. You have to run, do practice runs with the Flaskworks machine in the Sawston facility, collect all the data, compare the data with the data from the DCVax products produced by the existing manual process, because they have to show, they have to demonstrate to the regulator, not only that the Flaskworks machine operates properly, doesn't shed particles into the clean room air, things like that.

We have to show that it produces a product that's the same, or as close to the same, as a biologic product can be. So they'll be in addition, after they do all of these engineering runs, and they collect all the data, they'll do comparability studies, equivalency studies, and collect the data from that. And then all of that will be submitted to the regulator, and the regulator will give approval. And this will all be going on, these are all things, all going on in parallel. Right? So this will be going on over the coming months, at the same time that the MAA process is going on, and the same time that the inspections are going on, and so forth. So it's not stretching out, you know, to infinity. It's parallel. What else on this? I think that's enough.

We definitely, we need to do some mundane things like expand our operating arrangements. We need to expand our contractual arrangements for leukapheresis, blood draw slots. You have to contract for those, and you have to pay for those. So it's such a little bit of chicken and egg, or a calibration as, you know, you want to have enough slots, but you don't wanna get too far ahead of yourself, and have your burn rate get too high before you need it.

So, anyway, we'll be calibrating, making contract arrangements for more of those slots. We will certainly need to expand the staff who will handle logistics, you know, mundane things like that. There's just a lot of mundane things to do, but it’s, it needs to be done. Among other things is, as part of the preparation for commercialization, we will need to determine what our pricing model is gonna be. What's gonna be the pricing model for DCVAX? That's something on which we will work with expert advisors, and, but it will be important, obviously. And, again, all these tracks going in in parallel. Okay.

After the MAA, and the commercialization preparation, and those activities, we also need to go through the process of applying for approval for reimbursement. So in the UK, that's a process that is handled by NICE. And NICE has been absolutely wonderful to us. I cannot say enough things wonderful about NICE. They've been supportive. They've been flexible. They're standing by.

We talk to them. They reach out to us every couple of months to check on the status of things. I mean, I couldn't imagine a government agency, that's been so supportive as they've been. What we will need to do is, we'll need to engage specialized consultants to develop, what's referred to, as a health economics model. We have to make an economic model about the cost benefits of the DC vaccine treatment, and how it fits with their policies, and that sort of thing. So, that for sure will be, in our grouping of top priority activities, over the, as we look forward, over the coming 18 month period, 12 months, whatever.

Of course we are anxious to submit applications for approval in other countries. We're very happy to be going through our first process in the UK, because they have the fastest process of any that we know of. And it's been really great, but, of course, we want to get start, getting applications put together, and that'll be another thing that we'll be working on during this period, and getting those prepared and submitted. We have a partial head start on them because one big component of the application anywhere, is the clinical study report, which is a ginormous document that has the 20 years of efficacy and safety data from every program that's ever been done in DCVax, even programs other than brain cancer. So, we have a partial head start, but applications in other countries will be important.

And very dear to our hearts, we need to expand the management team. We need to expand the management team rather substantially. As you probably have guessed, and as we described in the proxy, each of the core members of the senior team has been wearing multiple hats, has been fulfilling multiple roles. And I mean, multiple roles that would each be normally a separate senior management person at other companies. And I'm really proud that we've been able to do that, but we need to we need to ramp up. We we've got tremendous opportunity, and we need to ramp up. So that is going to be a significant focus for us, as soon as we can achieve it. We wanna be highly selective, but we plan to substantially expand the management team.

Okay, the last item in our top grouping of top priority, is what I've already mentioned, which is continue to vigorously pursue the lawsuit in New York against the parties, that we believe have been, and are continuing, we believe, to manipulate our stock.

Okay, second grouping of priorities for this going forward period: we plan to initiate the pediatric glioma trial. Just so everybody understands, that conducting the trial itself, is not specifically a requirement connected to our obtaining approval for our adult medicine. What was a requirement, it was in fact a prerequisite, and it was a requirement in order to, for our application to be validated, which it has been as we publicly reported. We had to have an approved plan. We don't have to have completed the trial. So we're going to be pursuing that.

It's been a very long process in the UK. It's been a year and a half of discussions with pediatric neurosurgeons, or oncologists. We actually just recently, finally, after a year and a half of all this, reached conceptual agreement with them. We are gonna be proceeding with just one of the two pediatric trials first, and then the next one will be in sequentially, rather than simultaneous, which is actually a good thing. It'll kind of reduce the bandwidth, and resource requirement on us. So that'll be proceeding.

We, as you can imagine from what I've already discussed, we'll be pursuing build out and equipment of the first grade C lab, the one with the magic closed systems, in the Sawston facility. We will do, on FlaskWorks, what I've already said, which is finish the process. I've already described what that involves.

For the product release system that I described, to release a batch of product, just in terms of where we are with that . . so that was developed from scratch starting about 5 years ago. It was deployed in a pilot version in the small GMP lab in London several years ago. I believe, if I'm remembering correctly, it was about 3 years ago. And it went through a pilot testing period in the small GMP lab in the London facility. And then I believe about a year ago, if I'm remembering correctly, was, initially, it was installed on a pilot basis, in Sawston.

And now we have to go through all the usual steps. We have to go through the practice runs, it has to be optimized, we have to collect data, and so on. And we always have to show equivalency. Right? We have to show that the system produces an equivalent evaluation as the manual process by a QP, a qualified person. And again, this is another parallel track. This isn't, you know, off, you know, in the future, it'll be in parallel underway. Advent will be doing all of this, so fortunately, won't be us.

DCVax-Direct . . . very near and dear to our hearts. We have been eager to restart this program for a long time. And we, the first thing, of course, that we need to do, is restart the manufacturing. As it turns out . . . and this will be something that we'll make a public announcement when the time is right . . . anytime that you do a technology transfer process, because that product was only ever produced in the US, by parties who are no longer there, and so we had to do a technology transfer process to the Sawston facility.

Whenever you do a technology transfer process, you have to draft a whole new set of SOPs, (standard operating procedures), regulatory documents, all of that. And usually a technology transfer, especially for a cell therapy, is a minimum of at least 6 months of work. And then we've had two additional, challenges, which I think, we're on our way to having behind us. One that related to the machine that we use for the first stage of the process, and one which related to some key ingredients in the process. And when we come to that announcement, we'll we'll sort of explain all that.

But suffice it to say, restarting the manufacturing process, is a significant priority for us, in this going forward period, and you'll be hearing from us about that. And then once we've got the manufacturing restarted okay. Then we come to the last grouping of priorities. Once we have the manufacturing restarted, we are very eager to get the clinical trials underway to proceed. I guess, I don't know to what extent people remember, but the early stage trial that we did, was a phase 1 trial which, in which, it was conducted at MD Anderson.

We treated 13 different types of solid tumors, very diverse, pancreatic, breast, sarcoma, lung, colorectal. I mean, very diverse solid tumors, with very encouraging survival extensions in patients who were metastatic, and had failed every other treatment, and were pretty, pretty broken. DCVax-Direct. So that was really encouraging in the phase 1 trial. And even today, with all the billions that have been spent by the whole pharma and biotech industry on cancer treatments, when you have metastatic solid tumors today, there's not very much for you, as a patient.

And DCVax-Direct is a wonderful technology because it's directly injected into the tumor. The tumor that can't be surgically removed, either because there's too many of the tumors, or because it's located somewhere, where you might bleed out on the operating table, whatever, that are inoperable. But you, with image guidance, any form of image guidance, physician's choice, you can reach pretty much any location in the patient's body, to inject directly into the tumor. And even now, all these years later, we haven't seen, I'm not aware . . . maybe it's out there, but I'm not aware, we aren't aware . . . of any treatment like it, that's had the kind of encouraging results that the phase 1 trial did, and MD Anderson, in these patients. So we are very eager to get, get going again with that program. So that is, another priority.

We also, we have said, in all of our presentations about the results of our . . . now switching back to DCVax-L, lysate, for tumors that are operable . . . we have said, in all of our public presentations about the trial results, that this is very exciting to see the survival extensions with DCVax-L by itself, as a monotherapy, and version 1.0 of the DCVax-L technology, and that we are eager to build on that, with combinations of DCVAX L. And because DCVax-L has such a benign safety profile and because of what its mechanism of action, as a broad spectrum, we believe, that it will be eminently combinable with most other types of treatments.

You can imagine combining it with checkpoint inhibitor drugs, with targeted therapies, with chemotherapies, any variety of type of therapy. So we, we have some collaboration discussions underway, and at the appropriate time, because we only announce things when they're significant, and they're done. Right? We don't say, and that you know, giving our forward perspective, is quite unusual for us. But, anyway, again, these are forward looking statements. Everybody knows that. Right? Just reminding you again.

But we have said in every presentation, we are eager to combine DCVax-L with these other combinations. And so one of our many priorities, for the going forward period, is to do one or more of those combinations. And we've received considerable interest from various parties for that. So, we are looking forward to that. One thing I will say about our general approach, as we look forward on further clinical trials, is this: We want to focus particularly on clinical trials where tumor response, meaning tumor shrinkage, can be the endpoint as opposed to overall survival being the endpoint.

Why? Because, if you're going to see tumor shrinkage from a treatment, you can typically, potentially see it in a matter of months . . . and survival takes years and years. And we've just got done conducting one of the biggest, one of the longest, one of, you know, a real a major landmark in the field, in our opinion. But we would now like to do some more focused, faster path, tumor shrinkage endpoint trials. So we are, as we evaluate, I mean, we have so many opportunities in front of us now. Really, the challenge is choosing. Right? And so we we gotta steer ourselves, to the extent we can, towards that direction, to more shrinkage endpoints.

Two last points before we're done, done, done. Partnering. We've had some questions, various questions from shareholders. We're quite open to partnering. I've just I gave you a couple examples earlier of potential partnering, especially now that we have this tool chest of all these more technologies. But we're open to partnering. We'd like to be, where we see a partnering that could have either strategic value, or financial value, or both. And as we think about it, a partnering could be a regional partnering, geographic region. We have made a point of filing our IP and maintaining our IP in countries, wide range of countries. And we we try to build for the day when it would be, useful for that type of partnering, or it could be partnering for particular applications. So, we ,we will be open to that, and see what makes sense.

Last but not least, some folks have asked about uplisting. Certainly, everyone would love to be on a national exchange rather than the OTC, and we do realize, we do know that you guys are having difficulties, some of you, with the brokers, and they're making it difficult sometimes with our shares, while we're on the OTC. So we, we will be looking for when the strategic timing is right. We're not quite there yet, but we will be looking for that, so as we look at the going forward, period.

So let me close with just, a couple of concluding comments. First of all, I've I've tried to give you a flavor of a lot of different areas, without being here till next Tuesday. It's been longer than it was supposed to be. But all in all, I I have to say we've made, we feel, we've made tremendous progress in the last 18 months.

We're such a different company, further on company, than we were 18 months ago, and we're proud of that. And we hope that you are finding that exciting too. Second, comment is; there's no guarantees. I have to say this again, but we believe that we are well positioned to get a favorable result, and get our first approval, and begin commercialization. So that's all we can say is, we believe that we're well positioned, but, you know, and we'll all know, you know, reasonably soon.

We also believe that the infrastructure, and the systems that I've tried to give you a glimpse of without being too boring, that we've been working on these for years, in order to build for the day that's now arriving. Show that we have the physical facilities, and we also have the operating systems, and the strategies that can make this kind of a product, you know, can facilitate the commercialization. Also, we believe that at this point, with the careful in licensing, we've built a tool chest that has just tremendous growth opportunities to work with. I'll say again, we are painfully aware that the share price does not, at least currently, not yet, reflect this progress that we've made, that I'm describing. And I've said several times now repeatedly, we know how frustrating that is.

I will say, we believe, that if we can continue making progress in building actual value, intrinsic value, real value, and if we can continue taking action against parties, that we believe are artificially manipulating, and holding the shares down, and if we can work to attract some additional institutional investors, like our recent one, that we're very gratified, we think the combination of those things, building intrinsic value, fighting back against what we believe is manipulation, and attracting institutional investors, that ultimately the market will recognize the value. We know that we're not there yet.

And last of all, is what I get began with, which is we're so appreciative of all the votes that you guys cast. It was a phenomenal turnout, really impressive turnout, and we're so grateful for all the positive votes. And thank you. We're all done. I move that the meeting be adjourned.


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Expert Financial Analysis and Reporting
Northwest Biotherapeutics: CEO Linda Powers’ In-depth Company Overview at the Annual Meeting
POSTED by LARRY SMITH on JUL 8, 2024 • (0)

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 29th, 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.
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 a 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 potential milestones upcoming in the 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 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 in in parallel.

Applying for Reimbursement

Following MAA approval, they will need to go through the process of applying for reimbursement. In the UK, 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 of 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 we believe have been and are continuing to manipulate our 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 approved plan. This was a long process in the UK that involved a year and a half of discussions with pediatric neurosurgeons and oncologists passing 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 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.

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 major landmark in the field. However, they now want to do 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 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.

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.