Bethesda, MD, January 24, 2011 – Northwest Biotherapeutics (OTC Bulletin Board: NWBO) announced today that the Company is resuming enrollment of additional new patients into its ongoing 240-patient, double blind, randomized, placebo controlled Phase II clinical trial of DCVax® for Glioblastoma multiforme (“GBM”) brain cancer.
To date, this trial has been conducted at 13 clinical sites across the U.S., with 33 patients already having been enrolled. These patients have continued to be treated with the DCVax® regimen and follow-up during the last two years. The only aspect of the trial that stopped for a period of time was the enrollment of additional new patients beyond the 33 patients who were already enrolled and receiving ongoing treatment. The Company is now resuming the process of accepting additional new patients to complete the trial.
GBM is a highly lethal cancer with at least 12,000 new cases per year in the US, and at least 40,000 new cases per year worldwide. With standard of care treatment (including surgery, radiation and chemotherapy), the median time to recurrence of the patient’s tumor is only about 6.9 months, and the median survival of the patient is only about 14.6 months. Less than 5% of such patients are still alive at 5 years. These clinical timelines for recurrence and survival have not changed significantly in decades.
DCVax® mobilizes the powerful immune system as a whole, in a natural way, without toxicity. DCVax® is a personalized therapy made from a fresh set of the patient’s own master immune cells (“dendritic cells” or “DCs”) and biomarkers from the patient’s own tumor. Prior clinical trials of DCVax® for GBM brain cancer have shown striking results. In the patients who received DCVax®, the median time to recurrence of the tumor was more than 2 years (vs. 6.9 months with standard of care), and the median survival was 3 years (vs. 14.6 months with standard of care). In addition, according to the latest longterm follow-up data as of July 2010, 33% of the patients had reached or exceeded 4-year survival; 27% of the patients had reached or exceeded 6-year survival, and the longest surviving patient to date had exceeded 10 years.
According to Bob Gibbs, a 6-year survivor of brain cancer who has been treated with DCVax®: “There is no question in my mind that I am alive today because of this vaccine. We need to finish this trial, and hopefully be able to make DCVax available to as many brain cancer patients as possible, as soon as possible, so that others can have the benefits that I have experienced. Any patients who would like to obtain more information about DCVax, the clinical trial or patients’ experiences are welcome to contact our organization, Miles for Hope (727-781-4673), and speak with Executive Director Barbara Gibbs or me.”
Dr. Linda Liau, Principal Investigator in the 240-patient Phase II clinical trial of DCVax® for GBM brain cancer, Professor and Vice Chair of Neurosurgery and Director of the UCLA Brain Tumor Program, commented that “after more than 10 years of development, DCVax is poised to make a real difference in the future treatment of brain cancer. DCVax is at the forefront of personalized therapy, which offers great potential for improving patients’ outcomes. DCVax is also non-toxic and allows our patients to carry on with their lives in a normal fashion. I’m excited to see the large Phase II trial moving towards completion.”
“Primary brain tumors are a major problem with an urgent need for new and better treatments,” said Dr. Michael Gruber, Clinical Professor of Neurology and Neurosurgery at the NYU Langone Medical Center. “Despite the significant advances in neurosurgery, radiation medicine, and new chemotherapy agents, such as Temodar, and targeted agents, such as Avastin, median survival of newly diagnosed patients with GBM remains at approximately 15 months. Phase I studies on DCVax have shown promise, with a number of patients living more than 3 years. We are hopeful that by completing a larger study these results will be confirmed as statistically significant and lead to better outcomes.”
“The very promising results to date, coupled with the excellent safety profile, make DCVax a strong candidate for future standard of care for brain cancer patients,” commented Dr. John Trusheim, Medical Director of Neuro-Oncology at the Virginia Piper Cancer Institute at Abbott Northwestern Hospital in Minneapolis. “Resumption of enrollment in this important trial will bring that goal one step closer.”
There are a lot of statements in this PR that create a perception that just isn't true. I'm not sure about you, but when I initially read it, it created the perception that 33 patients were enrolled in the Double-Blinded portion. That we know isn't true, and they combined both Open nGBM and Double-Blinded nGBM (and any rapid-progressor) in that 33 patient number to give the impression that enrollment at the restart of the Phase II trial was further along than it was at the time.
NWBO May 2011 Enrollment PR: To date, 33 patients have already been enrolled in this ongoing 240-patient GBM brain cancer trial and its information arm, and have been proceeding through the treatment regimen and follow-up.”
In May 2011, they reveal that the 33 patients are a mix of enrollment, and with it is "information arm" patients. If you're like most shareholders, you may perceive that to be a few "compassionate" information arm patients, or misconstrue it to be the disclosure of that new arm. But nope, that arm existed at the start of 2008. And, it's also clear that majority of those 33 patients belong in the "open" nGBM portion of the study.
NWBO SEC FORM 10K YEAR 2007 (April 8, 2008): In December 2006, we commenced recruiting patients with newly diagnosed GBM in a 141 patient Phase II DCVax®-Brain clinical trial. We planned to carry out the study at 12 to 15 clinical sites. The study was designed as a randomized study in which patients received either DCVax®-Brain in addition to standard of care or standard of care alone. To date, almost 50 patients have been screened at 4 clinical sites. However, patients have been reluctant to enroll in the study when faced with a 33% chance of being randomized into the control arm of the study under which they will receive standard of care alone. In order to address this issue we redesigned the study as a randomized, placebo controlled, double blinded study with a cross-over arm allowing control patients to be treated with DCVax®-Brain in the event that their cancer progresses. The study size has been increased from 141 to 240 patients and is designed to enable us to petition the FDA for accelerated approval if the study generates results similar to those achieved in earlier Phase I studies. In order to enable rapid enrollment, we are in the process of enrolling 45 to 50 additional clinical sites for this trial. As of April 9, 2008, seven sites are active and a further 31 sites are at various stages of the start-up process. We are engaged in discussions with the FDA concerning the study design and end points. Depending on trial results, we plan to seek product approval in both the U.S. and the European Union.
A) because they're SEC statements tell us where enrollment stands near the end of 2008, which was shortly before the study stopped:
NWBO SEC FORM 10-Q the quarterly period ending Sept 30, 2008 (Dated: November 19, 2008). We plan to rely on our current DCVax®-Brain Phase II clinical trial as a single study in support of regulatory approval. However, to date, only eleven patients have enrolled in the clinical trial, which is designed to include 240 patients. Given our current lack of funding, it is unclear how quickly we will be able to increase enrollment, if at all.
B) The Start Ledger quoted, Dr. Gruber as stating:
“Overlook is running the the trial in conjunction with NYU and so far has enrolled 20 patients."
Dr. Gruber must have been combining "Open" and "Blinded" enrollment in his figure as because NWBO confirmed enrollment at 6 patients on August 19, 2008; and Overlook count went down to 3 patients in Sept 2008:
NWBO SEC FORM 10-Q the quarterly period ended June 30, 2008 (Dated: August 19, 2008): We plan to rely on our current DCVax®-Brain Phase II clinical trial as a single study in support of regulatory approval. However, to date, only six patients have enrolled in the clinical trial, which is designed to include 240 patients. Given our current lack of funding, it is unclear how quickly we will be able to increase enrollment, if at all.
On Sept 4 2008, a Nurse Blog is written about Kathy Montag’s GBM story, with the Nurse’s Connection: Overlook’s enrollment count specifically in the Phase II is at 3 patients.
SEC 10Q March 2008: Research and development expense increased from $1.3 million for the three months ended March 31 to $3.1 million for the three months ended March 31, 2008. This increase was primarily due to:
- increased support cost related to the DEVELOPMENT of a clinical trial program and potential compassionate use/named patient programs in Switzerland and elsewhere of approximately $266,000
-initiation of additional clinical sites and screen and enrollment of patients in our Phase II DCVax®-Brain clinical trail of approximately $222,000.
Development cost at the end of March 2008, as it relates to the trial can only be Phase II Double-Blinded, which had yet to start.
Screening and enrollment of patients in their Phase II clinical trial can only relate to the OPEN portion, as the Blinded portion had not started.
NWBO SEC FORM10K 2008 (filed April 2009) Statement: We obtained a new FDA clearance and re-approvals by all the clinical sites, and commenced the new Phase II trial in early 2008. Unfortunately, we had only been underway for a short period when the economic crisis hit. We were able to keep the trial open, and continue treating the patients already enrolled in the trial, but we had to suspend new enrollment of additional patients into the trial.
So there you have it a total of 28 patients of the 33 accounted for, enrolled into the Phase II DCVax-L study; to which at least 17 would have been randomized to the Open 141-patient study without a placebo; and 11 patients would have been randomized to the Double-blinded 240 patient study with a placebo; and a total of 5 are unaccounted for, though in my view, likely belong to the last 2 of the 4 sites in the OPEN study. MY assumption given the state of finances: 22 OPEN RANDOMIZED PATIENTS and 11 DOUBLE-BLINDED PATIENTS (compassionate + main trial) = 33 ENROLLMENT.
Moving on, there is also a “it’s true" and the "whole truth" discrepancy between their press releases, promotion materials and the SEC statements which extends beyond Direct. Let’s explore a few of their statements, as follows:
NWBO Enrollment Resumed PR Jan 24, 2011 (entire PR pasted above): According to Bob Gibbs, a 6-year survivor of brain cancer who has been treated with DCVax.”There is no question in my mind that I’m alive today because of this vaccine. We need to finish this trial, and hopefully be able to make DCVax available to as many brain cancer patients, as soon as possible, so that others can have benefits that I have experienced.”
Bob’s statement is true. He enrolled into a DCVax-L study, but most likely in the prior open Phase I/II, as his diagnosis was a stage III and his surgery was conducted at UCLA in May 2008 (I believe UCLA did not join this double-blinded study again until 2011 as they were busy enrolling their own Ph I/II study). But, I bring up this example as NW Bio's 6-year statement is misleading as gives the impression at first glance that Bob enrolled into the earlier portion of the study and that his lengthy progression free survival was a direct result of DCVax-L and neither is the case. Sadly Bob passed in December 2011, 2.5 years after enrolling into the study. I don’t know the survival rates for stage III brain cancer patients, but again, NW Bio’s statement creates a correlation between years and months (Dr. Gruber's statement) that is not accurate, yet their entire statement and PR is true.
NWBO CUA PR August 2014: During 2011 and 2012, in addition to conducting the trial, The Company also treated 55 GBM patients with DCVax-L on a compassionate basis in an “information arm” outside the Phase III trial.
It's a true statement, but it's not the whole truth.
NWBO SEC FORM 10K 2014: “Information Arm” Outside the Phase III Trial. In parallel with the Phase III trial of DCVax-L for GBM, we accepted a total of 55 patients into an “Information Arm” outside of the trial, who failed to meet the eligibility requirements for the trial. Most of these patients (51 of the 55) were actual or potential “rapid progressors” (patients in whom the brain cancer is already appearing to re-grow by the time the patient finishes the 6 weeks of daily radiotherapy and daily chemotherapy following surgical removal of the tumor). At least 19 of the 51 patients were confirmed as being clear rapid progressors, with such aggressive cancer that the brain tumors were already re-growing within weeks after the original surgery, and during the daily radiotherapy and chemotherapy. The rest of the 51 patients could not be classified as clearly, with today’s imaging and other technology. All of the 51 patients were treated with the same DCVax-L product as in the Phase III trial, on the same treatment schedule as in the trial, at the same medical centers as in the trial, in the same time period as the trial, and the data were collected and maintained by the same Contract Research Organization (CRO) as is managing the trial.
The SEC statement is the whole truth.
On iVillage, it has been pointed out that NW Bio's SEC 10K 2014 statement did not actually confirm these 55 patients to be from the years of 2011 and 2012; and, therefore, concluded the 55 patient “information arm” enrolled between 2008 - 2012. I agree with these two points. Why? There is both SEC 10Q (March 2008) proof that the “compassionate” information arm was in development and Clinical Site enrollment solicitation proof that arm existed at the start of the double-blinded 240-patient Phase II trial (April 2008 likely). Considering this Phase II and its "compassionate" information arm enrollment eligibility ran in parallel, the Company in their SEC statement would need to disclose if they omitted any of the enrollment years. Their SEC statements caps the end date data as “accepted a total of 55 patients” and it also specifies the start date with: “in parallel” and “at the same time period of the trial”. Because the SEC did not mention any specific years of this “compassionate” information arm data, the only way to interpret it and have it be accurate is to use the start date of the double-blinded trial. As for the end date of this particular “compassionate” information arm cap, naturally would be once the “accepted total of 55 patients” was reached. You may be wondering, if that’s true how can the PR tell us the specific years and also be true? Explaining it is tricky, but please try and follow. The PR, only tells us that during 2011and 2012 they “treated” 55 GBM patients on a compassionate basis in an "information arm” outside of the Phase II trial. It is a general statement with regards to how many patients they treated within their “compassionate” information arm, and during those two years. It gives one who reads the statement the impression that these are the very same patients that are enrolled into the “information arm” abstract. However, while the statement may be accurate, the impression is misleading, as some of the patients within that 2012 timeframe are not included with the “55 Compassionate Information Arm’ data. In my view, they took the compassionate” enrollment period of 2011 and 2012, and then tallied those number of patients. Determined it to be 55 GBM compassionate patients it total, and then asked the CRO to collect a total of 55 patient “compassionate” Information arm data for the “in parallel” to the Phase II trial and to determine overall survival for those 55 GBM patients. The CRO naturally starts pulling data from 2008 and stops once the “accepted total of 55 patient” cap is reached. However, the “cap” excludes a few patients from the end of 2012 calendar year into the analysis. So maybe a total of 60-62 patients were treated in the overall “compassionate” information arm, but only a total of 55 patients made it into the “AACR abstract. And therein lies how both statements can be the true, but with the SEC statement gives us the whole truth.
Why would NW Bio continue with an inaccurate impression? The Company started and stopped their Phase II trial several times. I suppose they may have felt the need to build investor confidence in their Phase II double-blinded study could complete enrollment. Their investor base had already funded a part of the clinical trial and it may have been a strategic move to share where enrollment stood at the restart in 2011. Unfortunately given the economic downturn, the Company double-blinde Phase II trial enrollment period was brief and lack luster. As such, they created a false impression that the study was further along by using the entire study enrollment and presented it as one enrollment count in their announcement to resume the trial. Once May 2011 official enrollment re-start, they were legally obligated to disclose that the enrollment was not exactly all “main trial” enrolled patients and that some of the 33 “events” would not contribute to the endpoint data. That’s when they disclosed “information arm”, and of course, the investor base misunderstood this to mean a new disclosure of the “compassionate” information arm, verses “open randomized study” information arm. Given they did enroll some “compassionate” rapid progressor patients and most “open” nGBM patients, the use of “information arm” was accurate, though yet again misleading.
NWBO Website 2014, 2015 (may have been earlier): The trial is under way at 50+ sites (medical centers) across the US. The sites and the eligibility criteria are listed in the profile of the trial at ClinicalTrials.gov. The trial is also under way in Europe. The lead site is Kings College Hospital in London. Approximately 30 trial sites are also in varying stages of preparation in the U.K. and Germany.
NWBO FORM SEC 10K statement 2012: During 2012, the Phase III brain cancer trial was expanded to 42 sites in the US, and nearly 30 additional sites were identified and in varying stages in the UK and Germany.
Yes, their website statement must be true, but does it not paint a picture, in a few months many of these sites will join the trial? Meanwhile, I debated these exact same comments with Iclight, I believe November of last year. In going through old SEC statements I stumbled across NW Bio's statement and it immediately reminded me of our debates; and how easily he could have gotten me to concede if he only presented their statement. it occurred to me that NW Bio may define “identifying” a site to target as potentially qualifying it to be termed as in “varying stages”. I, however, do not. How many Germany sites are they up to 2.5 years later? I don’t know, but the Company is still no where near 30 sites in Europe, I can tell you that. It makes me wonder, if NW Bio is going to be so loose with their statements, does it also mean that having one phone call with a big Pharma also qualifies as a collaboration discussions? Answer: Maybe.
NWBO Direct June 11, 2014 PR: “ All 9 Out Of 9 Patients Who Have Reached 4 Injections Are Showing Tumor Cell Death, Tumor Shrinkage And/Or Stabilization Of Disease.”
It’s true. But it’s now clear, to me anyway, that the NW Bio, with the crafty wording, presented their data in the best light. The Company left us with the impression that most of the patients had not reached their 4th injection, with statements such as: “The Company plans to report more details when patients are further along in the treatment regimen. The first 3 injections are given in the first 2 weeks of the 32-week treatment regimen (at Day 0, Day 7 and Day 14).” And, then in their follow-up statements: "So far, 9 of the patients have received 4 of 6 planned injections” and “As of the 3rd injection in week 2 of the treatment, we know have 65 % of the patients (13 of 20) showing some positive effects, and as of the 4th injection in week 8 of the treatment, we now have 100% of patients (9 of 9) showing some positive effects.” I completely fell for these statements and purchased more shares. I couldn’t find holes in them back then, but I certainly can with data hindsight. Sure, again all their statements made about Direct at the time were true. But, what they failed to share and disclose in this nicely written press release is that they must have known at that point that many of these 3rd injection patients would not graduate to receive their 4th vaccine. After all, if we use Bosch’s data, we know that 1/2 of the overall Direct patients did not receive their 4th vaccine. And that’s the whole truth.
NWBO SEC FORM 10K 2014 (filed in April 2015): We have experienced recurring losses from operations. During the year ended December 31, 2014, net cash outflows from operations were $54.6 million for all of the Company’s ongoing programs (348-patient Phase III trial of DCVax-L at over 60 sites in the US and Europe, 41-patient Phase I stage of the Phase I/II DCVax-Direct trial, early access programs in both Germany and the UK) as well as substantial one-time expenditures, including for initiation payments related to the clinical trials and to development of large new manufacturing capacity in Europe.
Why that's interesting, did you catch it? The SEC documents state Direct as 41 patients! Yet, I only remember NW Bio ever mentioning 4 additional patients, beyond the initial 36 patients. I checked Linda Powers’ Oppenheimer speech, and she did not tell us how many patients they over enrolled into the study at that time. Some of her comments regarding Direct in December included: “We were mobbed. We were flooded with patients” and then, sometime later in her speech: “ We actually over enrolled the trial. The trial exceeded it’s maximum.”. I see now that she didn’t actually make any statement about over enrollment being a good thing, but I certainly walked away with that impression. When I read that 10K in April, this over enrollment concerned me, as within the filing, their auditors suggested that the Company business continuing is a “going concern”; and there exist an entire section of the 10K related to these “going concern" additional risks. Yet NW Bio’s spends the money to add 5 additional patients last year. Not a smart financial move for a cash strapped company. If I go by the SEC statement alone, the whole truth tells me there’s much more to this “over enrolled” patients than meets the eye. Luckily since then they’ve been able to raise a fair amount of capital, but clearly in December 2014, their finances were an issue. So I ask who over enrolls a trial with no money in their coffers unless they’re trying to continue to test to fix something? Hopefully you see why I hesitated on Direct. Getting back to the 41 patients, when did they add an extra patient into the study? AACR poster, states “To date, 40 patients were enrolled”, and I believe that abstract submission deadline was December 3, 2014. So does that mean they added a patient between December 2014 and April 2015 or does it mean they added an additional patient in December alone, and we may find that they added a few more this year in Phase I? What are they up to now - is this related to method B testing? Are they trying to get a more robust response from a new patients or a few more patients? Answer: I don’t know, they’re not transparent.
It’s SEC stuff like that that I read that upset me. We should be told these things. We shouldn’t stumble upon new information this way. We should be told that they may be testing additional Phase I patients, if that’s what they’re doing. Not 6 months later, which is their track record; we should be told at or near the time it occurs, they press release on everything positive after all. How about they disclose some of these potential negatives. About the only thing I liked that reading within the 10K these passed two days was about their intention to apply for Fast Track on DCVax-L. That was new information to me. Maybe that’s a indication that the long-term “open" data is trending positively or it could relate to the “compassionate” arm data. I don’t know. Maybe they plan to surprise us with that and pull it out of a hat one Monday morning. If it is related to the “compassionate” arm data, my view is NW Bio should have revealed that intention a the AACR conference. Let us know, particularly as this option exist as of April 2015. To my knowledge they haven’t but maybe I missed hearing something. In any event, I have no intention to add to my holdings in advance of some possible designation or at least not at this time. Instead due to earlier due diligence I reduce my position to diversified my investments. I also stopped giving “buy” recommendations on the stock, changing it to a “reduce” and “hold” and haven’t regretting it since. I’d rather be long and light, then worry about their financial state or how the Direct data is trending, particularly as I have no doubts that it will lead to revenue. I remain on the fence with Direct’s potential. I realize this particular study is in its infancy stage. I realize Direct is helping some patients and I realize the responses will improve. But that doesn’t mean I need to “blindly" invest in it. I’d rather pay more for shares down the road, upon seeing the Phase II efficacy data. I remain long on DCVax-L. At the time I reduced my position I still believed DCVax-L could reach their primary endpoint. (I still do now.) But because I was concerned of the Company behavior, about not being upfront in their press releases, I began to look back on all the earlier data. Obviously that survival data looks really good at first glance. Yet upon review the prior Ph I/II data that contained two agonist, which at the time I thought started from the first vaccine (it starts at booster stage). Beyond the agonist, the Phase I/II also contains a mix of stage III & IV patients and I became concerned that the efficacy data might be confounded. And, as such, I did reduce my position some more, decided to hold enough shares to call it a day. I reasoned with myself that the only thing that would get me to sell the rest of my shares is if something changed on the science; or if someone provides new evidence that the trial is doomed to fail and so far I’ve seen nothing eye opening or believable. And I’m not speaking about modeling, as I do not believe that is information that any poster could figure out on their own without inside knowledge. But trust that I do understand that there is always a chance that the trial may fail to reach significance. That to me is unlikely, though I believe the PFS data will trend a lot closer than most of us think - beating GBM is tough! I feel comfortable that the Company changed the statistical analysis portion such that the data will include many more overall survival event. If they did enroll some patients with depressed white blood cell counts, counting 248 events will certainly help to fix this. I also feel confident that the data the CRO presented on the “compassionate” information arm is the whole truth.
I’m not suggesting the Company is trying to mislead us into investing into a bad thing. I’m simply sharing my views. I want to believe that they themselves feel NWBO is a good investment. They have yet to sell one share. I’m suggesting they’re trying not to scare us from the risk associated in investing in the Company’s stock. It’s risky, it’s volatile. Only now, when I read the press releases, I see what they shared as being true statements, sometime misleading, but I then look to find what they didn’t tell share, I look to uncover the whole truth. And I’m at a point that I do want to continue to unravel riddles. I rather not have to guess what they mean by this or that. I rather spend my time looking into new investments, then picking up every rock to find yet another discrepancy with their statements. I’d rather be long and light, and so that’s why this iHub doesn’t see me posting much. I don’t watch the stock to see if it goes up, down or sideways. I don’t check daily for news of any press release. I care about the end of the study. I don’t read or check out this iHub as I once did. If it weren’t for my connection to the study, I probably wouldn’t continue to post at all. But, I do feel that some things are not being interpreted accurately by some really smart minds and so on that I post. I also point these things out as many on this iHub are not seeing the risk associated with their investment.
Which brings me right back to enrollment, but in order to address further, German protocol safety data needs to be addressed:
Germany protocol translated: The data on the safety of the drug.
In two completed Phase I/II clinical trials and and on-going Phase III study with a total of 103 patients with glioblastoma total of 70 adverse events have been reported in association with treatment of DCVax-L (in 12 patients in Phase I/II study no. 8434, 18 in patients in the Phase I/II study no. 11053, in.; see Table 1). Of these adverse events were not serious. The majority of the adverse reactions associated with DCVax-L were mild to moderate in severity, only two cases of headache were severe. There were no serious adverse events (AEs) with possible causal relationship to DCVax-L-therapy
SEC 10K: DCVax-Brain uses our DCVax platform in combination with the patient’s own glioblastoma tumor cell lysate antigens. Our clinical collaborators at UCLA conducted two Phase I clinical trials to assess the safety and efficacy of DC-based immunotherapy for Glioblastoma multiforme (“GBM”). In the first Phase I clinical trial, DCVax-Brain was administered to 12 patients and in the second Phase I clinical trial it was administered to 17 patients. The patients in both trials were treated with DCVax-Brain being administered as an adjuvant to the standard of care. Standard of care is defined as surgery followed by 6 weeks of radiation and temodar chemotherapy combination and a further 6 months of temodar chemotherapy
Only the data for DCVax -Brain has been discussed with European regulators. On an informal basis, a number of European national regulators have indicated that additional pre-clinical and clinical data could be required before the DCVax -Brain product would be approved. However, it is not clear whether such data will be required until formal scientific advice is sought from the EMEA, which is the regulator that will ultimately review any application for approval of this product. Unless the EMEA grants a deferral or a waiver, we may also be obliged to generate clinical data in pediatric populations.
NW Bio presented Germany with safety data on all the GBM patients, from all the studies, and by mid 2012, that number was 103 patients. A total of 30 GBM patients were in the prior first two studies conducted by UCLA; leaving safety data on 73 GBM patients . (The discrepancy with SEC 17 verses 18 patients in study #11053, could be the SEC year I pulled, as that study continued to enroll). That 73 patients with GBM data by mid-2012 would have all come from this on-going Phase III study. Some of the data before the trial was suspended, and most of the data after the restart. But how much? We know there is 33 patients both open GBM and blinded GBM portion of the study. And so one might naturally then assume that the remaining 40 patients would be at the restart cohort. That would be wrong. Why? Well because of the Open “randomization”. As a reminder, those 33 patients were enrolled into both the Open and the Double-blinded study (22 OPEN RANDOMIZED PATIENTS and 11 DOUBLE-BLINDED PATIENTS (compassionate + main trial) = 33 ENROLLMENT). While the double-blinded study, it would be clear that some placebo patient would be in the mix of safety data; after all, 30 patients of the total of 103 had no reaction to anything. However, in the case of the Open randomized study, that study was conducted with no placebo arm, randomized 2:1. NW Bio would not have given Germany data on a 1/3 of patients who would have been in the control arm of that open study, it makes no sense. Also, most of these control patients would have dropped out at the very start of enrollment, so no data to monitor anyway. So from the 22 Open enrolled patients, only data on 14 to 15 patients would have been given to Germany. The SEC statement which immediately follows the discussion on the earlier Phase Is, suggest that it is only GBM data that was discussed with Germany. The Company needed to apply for the HE separately, so I suspect that safety data was not included in that German protocol numbers. The other thing to note on the safety data for the 73 patients is that it only includes GBM data, so that would leave 58 -60 patients within that number that would only be GBM enrolled patients:
Phase I data on 12 Phase I/II data on 18 Phase II data on 14 Open patients- randomized to DCVax-L only Phase II data on 59 patients in the Double Blinded portion of the study. = 103 Safety patients
These points bring us back to enrollment. December 2013, the Phase III trial hit it's first interim at 66 "events". Of the 33 patients, only a fraction of them could have come from the period prior to Phase II suspension. Only 11 is confirmed to be from the Double-Blinded Ph II study, The rest of the "events" would come after the enrollment restart period, 2011 - 2013. If one believes the company enrollment continued to be slow, of course, they'll see it as the "event" data trending badly. It's impossible to know how many patients were enrolled month to month, but it is clear that they would have needed to enroll a decent amount of patients into the double-blinded portion of the study early on given so few from the 33 patients "events" will have counted.
NWBO May 2011 Enrollment PR: To date, 33 patients have already been enrolled in this ongoing 240-patient GBM brain cancer trial and its information arm, and have been proceeding through the treatment regimen and follow-up.
To date, 33 patient have already been enrolled [020221 study] into this ongoing 240-patient GBM brain cancer trial [double-blinded portion] and its information arm [141-patient open nGBM randomized arm] and have been proceeding through the treatment regimen and follow-up. - my interpretation
17 Open nGBM information patients (2 of 4 sites) + 11 Double-Blinded patients (11 sites) = 28 patients + 5 unaccounted for patients * The 5 patients unaccounted as to which arm they go in (Open or Blinded). And from those 11 double-blinded patients, a couple will likely fall into the "compassionate" rapid information arm. Therefore, most of the 66 events will be from the restart of enrollment, May 2011 onward. However, that said, I am of the opinion that the company SEC statements clearly show that enrollment speed improved at the Phase II trial restart.
NW Bio may have been concerned about how enrollment was going to be perceived, as in the Spring of 2013, they issued a press release to allude to 25+ patients a quarter. Of course, that was assuming finances were on-track, and assuming no other riddles. (Interesting enough that full press release article is gone from their own web-site, but exist on internet, though not their official copy.) However, finances only went off-track in 2014 (give or take a month or two other times (grant money used instead)). At the end of the day, no investor can tell you where enrollment stands. No one can tell you if the data is trending positively. However, modeling that begins with 5 per quarter, well that's not just damning, it's impossible. Why? Finances, spending, and SEC statements point to a speedy enrollment.
The speed of enrollment upon the restart in April 2011 is not the same as enrollment prior to the Phase II Double Blinded suspension (April 2008 - early 2009). One should not take the speed of their enrollment in 2008 period and assume that to pace of enrollment in their 2011 period. The company had no cash in 2008 - 2009. Yes, they were light on cash in March 2011, but they were moving debt around and they certainly had money They were able to raise money, exchange debt to shares, and issuing warrants. And they were enrolling at a much quicker speed. Enrollment would be a changing number in 2011 - 2013, defending on finances, as in early 2013, they planned to use grant money; Other than that, they had money.
SEC 10Q June 2011: Financing Activities: During the three and six months ended June 30, 2011, financing activities consisted of net proceeds from notes payable amounting to $4.2 and $6.2 million, respectively and proceeds from the issuance of common stock amounting to $5.1 and $5.3 million respectively.
SEC 10Q Sept 2011: On June 2, 2011, the Company entered into an agreement with Toucan Partners to establish an equity facility pursuant to which the Company will issue registered, tradable shares of its common stock (the “Common Stock”) for future financings of up to $25 million over a 30-month period in aggregate. The Company expects the shares involved in this equity facility will be registered in several tranches through a series of registration statements over the 30-month term. The 30-month period will begin on the effective date of the first registration statement. Any use of this equity facility will be entirely in the Company’s discretion.
SEC 10Q March 2012: During the three months ended March 31, 2012, our financing activities consisted of net proceeds from notes payable amounting to $3.5 million and proceeds from the issuance of common stock amounting to $0.1 million. The increase in the Company's debt financing activities was largely due to the need to raise funding for costs associated with the ongoing Phase II clinical trials in the United States.
SEC 10Q March 2013: During the three months ended March 31, 2013, our financing activities consisted of proceeds from notes payable from related parties amounting to $0.4 million offset by the repayment of $0.3 million of notes payable.
In April 2013, we entered into an agreement with one healthcare-dedicated institutional investor for a registered direct placement of $10.0 million of common stock at the closing market price of $3.90 per share. We issued to the investor warrants exercisable for 1,025,641 shares of common stock. The warrants have an exercise price of $4.29 per share and are exercisable beginning six months after closing, with a term of five years.
Research and Development Expense. Research and development expense increased from $1.2 million for the three months ended June 30, 2010 to $3.5 million for the three months ended June 30, 2011. The increase was primarily attributable to costs associated with the ramp up of enrollment in the ongoing Phase II brain cancer clinical trial.
Research and Development Expense. Research and development expense was $10.6 million for the six months ended June 30, 2012 compared to $7.9 million for the six months ended June 30, 2011. The increase was primarily attributable to increased number of clinical trial sites open and recruiting across the United States in our ongoing Phase III clinical trial of DCVax®-L immune therapy for Glioblastoma multiforme (GBM) brain cancer.
Research and Development Expense. Research and development expense was $9.9 million for the three months ended September 30, 2012 compared to $3.6 million for the three months ended September 30, 2011. The increase was primarily attributable to increased clinical development expenses incurred during the 3rd quarter of 2012 due to increased number of clinical trial sites open and recruiting across the United States in our ongoing Phase III clinical trial of DCVax®-L immune therapy for GBM, as well as expansion of the trial into Europe.
Research and Development Expense. Research and development expense was a combined (cash and non-cash) total of $28.9 million for the twelve months ended December 31, 2012 compared to $13.5 million for the twelve months ended December 31, 2011. The increase was primarily attributable to increased number of clinical trial sites open and recruiting across the United States in our ongoing Phase III clinical trial of DCVax®-L immune therapy for GBM, as well as expansion of the trial into Europe.
As of December 31, 2012 we had 42 clinical trial sites in operation in the U.S., compared to 25 clinical trial sites at December 31, 2011. We also had established a wholly owned subsidiary in Germany and substantially expanded both our manufacturing operations and our clinical trial related activities in both the U.K. and Germany, compared to December 31, 2011.
Research and Development Expense. Research and development expense was a combined (cash and non-cash) total of $11.6 million for the three months ended March 31, 2013 compared to $3.6 million for the three months ended March 31,2012. The increase was primarily attributable to the DCVax-Direct manufacturing and product development work described above, and the preparation costs for the launch of two clinical trial programs, in the US and UK, as described above, as well as expansion of the ongoing Phase III trial in the US, and increased manufacturing of DCVax®-L for the Phase III trial.
Okay, my take on NW Bio's press releases overall and on enrollment is complete. I’m not like most people, if there’s a potential bad side of the data, I do want to know about it and I feel compelled to share it. Feel free to discount and discard it. I appreciate all the posting on all boards, even if some of it is such a dark view, it does make me look for facts. Upon continued review of these things, I do see many of their points, though not all. I also see that the Company has brought much of the doubt over the science onto themselves. If I had found that they had been forthright from the beginning and not riddled their press releases or their statements I’d probably trust their words more than I do. Now anything they state is subject to SEC interpretation, for me anyway. And yet, I don’t doubt the merits of the science. No trial can guarantee success, so as far as my investment is concerned, my risk are appropriate.
Okay, need to get to work, please excuse any typos.
