Saturday, April 12, 2014 12:49:42 AM
NWBO Investment Thesis
I have outlined below a thorough basis for investment in Northwest Biotherapeutics based on extensive research from a multitude of sources.
Technology
Northwest Biotherapeutics' two main treatments currently in clinical trials are DCVax-L (Ph III, with looming possibility of a halt for efficacy) and DCVax-Direct (in Ph I/II, currently undisclosed regarding progress, but by all signs appearing to be well under way and possibly demonstrating efficacy).
From NWBO's site regarding DCVax-L:
For DCVax-L, the monocytes are differentiated into dendritic cells, and matured, activated and loaded with biomarkers (“antigens”) from the patient’s own tumor tissue (which is collected in a simple kit at the time of surgery to remove the tumor). The loading of biomarkers into the dendritic cells “educates” them about what the immune system needs to attack. The activated, educated dendritic cells are then isolated with very high purity and comprise the DCVax-L personalized vaccine. DCVax -L is administered to the patient through a simple intra-dermal injection in the upper arm, similar to a flu shot. The dendritic cells then convey the tumor biomarker information to the rest of the immune system agents (T cells, B cells and others), as “marching orders,” and the immune system agents then fan out through the body searching for anything with these biomarkers and attacking it.
From NWBO's site regarding DCVax-Direct:
For DCVax-Direct, the monocytes are differentiated into dendritic cells and partially matured. DCVax-Direct is administered by injection directly into inoperable tumors. These injections can reach tumors located virtually anywhere in the body, with ultrasound image guidance. After injection into the tumors, the DCVax-Direct dendritic cells pick up the tumor biomarkers (“antigens”) in situ in the tumor. Then, like the DCVax-L product, the dendritic cells in the DCVax-Direct product then convey the tumor biomarker information to the rest of the immune system agents (T cells, B cells and others), who then act upon it throughout the body.
DCVax-L Group Breakdown
-Ph III double blind placebo controlled trial. 312 patients in main group, which breaks down into 160 in main treatment arm, 80 in main placebo arm; 48 in cohort (unspecified patient category) treatment arm, and 24 in cohort placebo arm (this is the most probable breakdown of the cohort--this group is undefined, however, including their possible break-up into treatment/ placebo arms). There are various theories on who this 'cohort' might be, which will be touched upon later.
-An estimated 75-100 additional patients (not included in the 312) in the 'early progression group,' who are crossed over to treatment, but whose results will not affect the outcome of the trial. Early progressives are those who show signs of tumor recurrence very early on. Of these it is further estimated that 25-35 of them are what is called "pseudo-progressive" (henceforth labeled as "psPD"). These are those who show signs of early progression (both by MRI and physical symptoms), but it is later revealed that they are not in fact experiencing tumor recurrence (more on this discussed ahead).
-It should be noted that any patient in a placebo group experiencing progression (tumor recurrence) has the option to immediately be crossed over to the treatment arm (and almost certainly will).
DCVax-Direct Group Breakdown
-Ph I/II(a) unblinded trial for patients with inoperable tumors (obviously beyond DCVax-L's reach), comprised of 60 patients. These break down into two stages. The first stage involves 36 patients with inoperable tumors, 6 from each of the following six cancer categories: colon (#2 killer, quick metastasis), breast cancer with brain metastasis (not many treatments for this type of breast carcinoma), lung cancer (#1 killer), pancreatic cancer (small market, fast regulatory pathway), melanoma, and 'miscellaneous' (unspecified--could be as few as one other cancer type, could be as many as six). The second stage involves 24, comprised of patients with inoperable tumors of one specific cancer type (for example, 'colon').
-Ph II(b) has not yet been enumerated by official document or PR, but described by the CEO at a recent important immunology conference, as including 144 patients, comprised of 24 from each of the aforementioned six cancer groups (colon, breast w/ brain met., lung, pancreas, melanoma, and misc.).
-Total patient enrollment: 204.
-It should be noted here that moving from one stage of the trial to the next will occur "seamlessly," according to the CEO, by not requiring additional clearance from the FDA:
Once we complete that stage [stage I: safety, feasibility and dose finding] we will go seamlessly into stage II [efficacy]. We do not have to go back to the agency, we just keep going. And if we see glimpses of efficacy in multiple cancers, we can go right into phase II in parallel and multiple cancers, two dozen patients per cancer." --Linda Powers
[brackets mine]
In Summary:
-Stage I is essentially Phase I, and includes 36 patients, 6 from each of the six cancer categories, testing for safety, feasibility and dose finding ("with an eye for efficacy," according to the CEO).
-Stage II has 24 additional patients from one specific cancer (for example, 'colon') in its Phase IIa leg, to determine efficacy. This will also be the lead-in for the larger part of the stage II section, its Phase IIb leg ("parallel and multiple cancers"), which will involve 144 patients, comprised of 24 from each of the 6 cancer categories (not including the 24 from the Ph IIa leg--hence the 'parallel').
-Therefore we have 60 in Ph I/IIa, and 144 in Ph IIb, for a total of 204 patients.
*Of note also is the fact that one chosen cancer designation (from Ph IIa) will have the statistical advantage of demonstrating efficacy data from 54 treated patients.
DCVax-L Prior Ph I Trial Results
Much has been made of these stellar results, though the critics mention the trial was too small to be sufficiently powered, and thereby should not be taken too seriously. The contention of those who rather give it weight primarily state two reasons for doing so:
-p-value
and
-unbiased, statistical matching
On p-value, Larry Smith from "Smith on Stocks" states:
The Kaplan Meier curves for progression free survival and overall survival show strong statistical significance, although it must be understood that this is comparing data from different trials. The p value for median progression free survival was 0.00001 and the p value for overall survival was 0.0003. A p value of 0.0003 means that there is only a 3 in 10,000 probability that the results were obtained by chance. The “p” value is a measure of statistical significance: it is the probability that a set of results were due to chance. So, the smaller the p value, the smaller the chances are that the results were due to chance and were not “real.” The FDA generally requires a p value of 0.05 or less (i.e., a 5 in 100 or less possibility that the results of clinical trials were due to chance) for approval.
On non-biased, statistical matching, proponents state that the Company (NWBO) used every measure available to them to avoid type I error, citing (from their Ph I DCVax-L study):
*"Treated patients [were] matched for age, gender, Karnofsky score, extent of surgical resection, and same standard of care treatment, at same hospital, in same time period."
This, they would assert, is going above and beyond what is necessary to ensure against type I error. And further cannot be seen as "cherry picking patients," as some critics suggest.
The results of their Ph I/II trial were spectacular (to any objective observer), especially when considering the disease in question, glioblastoma multiforme, which has a very grim diagnosis, and has had seen no real benefit from scientific advancement in over a decade. These results are given here (as compared with standard of care (SoC) alone--resection and chemoradiation):
DC Vax-L showed an improvement in median progression free survival of 25.0 months versus 6.9 months for SOC and an improvement in median overall survival of 36.4 months versus 14.6. At the end of three years, the data suggests that 55 of every 100 patients treated with DC Vax-L would be alive versus 16 of every 100 treated with SOC.
Recent Hospital Exemption Approval by the PEI of Germany
From the official PR:
BETHESDA, Md., March 10, 2014 – Northwest Biotherapeutics (NASDAQ: NWBO) (NW Bio), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, announced today that it has received approval from the Paul Ehrlich Institute (“PEI”- the FDA of Germany) of a “Hospital Exemption” early access program under Section 4b of the German Drug Law. Under this Hospital Exemption, NW Bio may provide DCVax-L to patients for the treatment of any glioma brain cancers (both Glioblastoma multiforme and lower grade gliomas), both newly diagnosed and recurrent, outside of the Company’s clinical trial and charge full price. The patients may be from Germany or elsewhere. This approval has a term of five years, and can be re-applied for and re-issued at the end of that period.
NW Bio also announced today that the German reimbursement authority (Institut Für Das Entgeltsystem Im Krankenhaus, or InEK) has determined that DCVax-L treatments for glioma brain cancers are eligible to obtain reimbursement from the Sickness Funds (health insurers) of the German healthcare system. Applications for such reimbursement eligibility may only be submitted to InEK by German hospitals, not by a company. Six major hospital centers across Germany applied for such reimbursement eligibility for DCVax-L for glioma brain cancers. The amount and terms for such reimbursement will now be negotiated by NW Bio, the hospitals and the Sickness Funds over the coming months, and will be applied to patients case by case. In the meantime, patients may self-pay for DCVax-L.
It is important to note how different this is from compassionate use. Compassionate use allows for only one patient to be treated at a time, with long processes of paperwork for each patient. Hospital exemption however, allows the treatment of any number of patients and without lengthy paperwork. Also, hospital exemption allows the Company to charge full price for each treatment. However, companies cannot charge the patient or hospital at all, nor can they receive reimbursement under compassionate use
Points made from the 3/27/14 conference:
-1st German validation: Germany Hospital exemption: “major validation” for DCVax-L. Any grade of glioma, newly diagnosed and recurrent, for all stages, I-IV (proponents would note that this is a stunning extension of the therapy, considering the trial's focus was only on the most lethal form of glioma--stage IV, glioblastoma multiforme).
For 2.5 years the PEI of Germany rejected many applications from many companies and only approved three, including DCVax L--yet in this regard, with many firsts:
-first new product approved that was not already on market and grandfathered
-first immune therapy
-first product with drug-like activity in body
-first cell therapy, first non German co.
And it is open to anyone "elsewhere" in the world (outside of Germany) who can afford to travel there and pay for the treatment.
-2nd German validation: German Central Reimbursement Authority--six major medical centers applied (thus far) to the Reimbursement Authority. This is a kind of “double validation” in that the company cannot apply for this--only medical centers can. The technology and company had to be fully vetted first. Centers have applied for eligibility for reimbursement now while treatment is still in clinical trials. Such a precedent has never happened before. They can apply for reimbursement now, as opposed to having to wait years. Usually even an FDA approved drug will have to be on the market for 1-2 years to be eligible for reimbursement, and yet NWBO’s DCVax-L is eligible now, and it will remain thus for the next 5 years (and then can be reapplied for). The Company will receive full payment for every treatment administered.
*It is estimated nearly 14,000 newly diagnosed and recurrent patients fall under this category in Germany, and at $30,000 (minimal) per patient per year, that would equate to $420mm in sales potential, conservatively figured (price of vaccine likely to be higher, and relegated to German citizens alone). However, it is also open to anyone with the means from around the world.
Recently (4/10/14), the Company released a PR about receiving financing of "up to $32 million dollars," ($15mm upfront) stating:
With this financing, we are particularly focused on accelerating the expansion of our manufacturing in Europe, especially following the recent favorable decisions in Germany...
It seems clear they will be using the monies in large part for a much increased manufacturing of DCVax-L, a demand for which has almost certainly arisen out of the vaccine's recent approval and immediate availability (to anyone capable of paying for it) in Germany. It is probable, then, that it will not be long before an announcement that reimbursement negotiations with the German Central Reimbursement Authority have been finalized, and that subsidized treatments may begin promptly.
The German authorities have actually gone so far as to supply the manufacturing space to NWBO at no cost to them (and have said they will enlarge this space as needed)--and it must be admitted, that is quite a validation in and of itself. However, in that the Company will receive "reimbursement" for the vaccine, they must shoulder the upfront cost of manufacturing--hence the immediate need for financing.
DCVax-L Current Ph III Trial Implications
(from Guidance for Clinical Trial Sponsors)
3.2. When there is a steering committee, the sponsor may elect to have the DMC communicate with this committee rather than directly with the sponsor.
This is where we have been since the first interim look, which occurred in early Dec. 2013. The steering committee, appointed by the Company (or possibly firewalled employees--but that is less likely), has been in extensive talks with the DMC (as of 4/10/14). The original estimate for the time it would take to receive a recommendation was "6-8 weeks." This came with the predication that the recommendation to simply "continue" the trial had a 90% probability, while that to halt the trial for efficacy or futility/safety reasons was given a split 5% each.
The estimate on time to receive the recommendation was then further amended once the 8-week mark had passed to be "2-3 more weeks." Finally, once this threshold was likewise surpassed, any further estimation of time to receive the DMC recommendation based on efficacy data has been given up by the Company, and they now simply reiterate "the DMC recommendation based on efficacy data is still outstanding."
We are now (if not considering the holidays) almost 18 weeks into the first interim look (as of 4/10/14). Since initially, the Company was expecting the trial to continue after look, giving that a 90% probability, while giving a halt a 10% probability, we might assume that these estimations have also evolved over time, although they have not expressed such.
However, the longer the DMC takes, the more likely that the reason for the delay is in their consideration of a halt for efficacy. The reason being is that a halt for safety is off the table as per the Company's 3/7/14 PR, and a halt for futility would (typically speaking) have already occurred by now.
In addition, IMUC ran a similar dendritic cell vaccine Ph II trial, using what many consider an inferior technology to DCVax-L, in that their lead product, ICT-107, utilized just six synthetic antigen biomarkers expressed in only a minority of the GBM population (whereas DCVax-L expresses the full array of organic antigens from the patients actual resected tumor, representing scores or possibly even hundreds of antigens--and can be used on the entire GBM population). By the end of the trial it was shown that, although their secondary endpoint of PFS had reached statistical significance, showing a (perhaps "meager") 2 month increase over placebo, their primary endpoint of overall survival (OS) was not statistically significant (although it did show a numeric advantage of 2-3 months over placebo--in time their p-value may come down enough to become stat. sig.). And although an interim look for a trial with a primary endpoint of PFS and one with a p.e. of OS would differ in protocol, it would not differ enough to explain the incongruency as to why IMUC received a quick "continue" recommendation, while the status of NWBO's trial is still, after some 18 weeks, "outstanding." If ICT-107 showed low efficacy and received a quick continue (and by their interim look most likely showed little efficacy considering the meager outcome), then DCVax-L, if the efficacy data was little to none, should have likewise gotten a quick continue. In this we have precedent. Therefore, through the process of elimination, consideration for a halt for efficacy due to substantial benefit is the most likely reason for this delay.
Let us examine then the following sections of Guidance for Clinical Trial Sponsors:
Interactions between the steering committee and the DMC consist primarily of discussions during "open sessions" (see Section 4.3) of DMC meetings and the communication of recommendations following each DMC review of the trial. More extensive interactions might occur when early termination is being considered.
The specifics of such extensive talks are enumerated in another section:
7.2.1. DMC Recommendations to Terminate the Study
In almost all cases, a DMC is advisory to the sponsor; the sponsor decides whether to accept recommendations to discontinue a trial. FDA will rarely, if ever, tell a sponsor which decision to make. For trials that may be terminated early because a substantial benefit has been observed, however, consideration may still need to be given to the adequacy of data with regard to other issues such as safety, duration of benefit, outcomes in important subgroups and important secondary endpoints.
Safety has already been put to rest. The safety monitoring board already recommended the trial continue on a safety basis (3/7/14 PR). The treatment is regraded as highly safe, as the Company notes:
Nearly as important in clinical trials to date, there has been no toxicity (no serious adverse events) related to DCVax. In ten years of clinical experience, there have been only been a couple of “serious adverse events” and we believe these were due to the patient’s underlying brain cancer, rather than the DCVax treatment. The broad and rapidly growing body of scientific literature about dendritic cells is consistent with the DCVax clinical experience.
However, "duration of benefit, outcomes in important subgroups, and important secondary endpoints (i.e. overall survival)" are very much on the table.
"Duration of benefit" is directly speaking of this trial's primary endpoint (progression-free survival) and its secondary endpoint (overall survival). The discussion could be ongoing as to the extent these benefits are currently being seen. This also applies to "important secondary endpoints," which in this case is OS (overall survival) as well as others unnamed (more on this later). Given that the patients in the placebo group who show progression of the disease will be placed in the "crossover arm" and given treatment with DCVax-L, the true determination of an OS benefit will have to rely on historical mortality rates as opposed to an objective comparison with an in-trial placebo group. This is one of a handful of reasons why OS was chosen as the secondary and not primary endpoint. Having a crossover arm is an ethical decision when dealing with such an aggressive terminal illness as GBM.
"Outcomes in important subgroups" is an open topic for this trial. Some have opined that the additional cohort is comprised of the psPD patients mentioned previously. Specifically, the Company released a PR at the time when this trial was upgraded to a Ph III including the addition of another cohort:
The Company also announced that the FDA has accepted an amendment of the clinical trial, which does not make any change in the treatment regimen, which leaves all data collected to date intact for use in the trial’s overall results, and which includes the following:
-Designation as a Phase III trial
-Expanded and enhanced statistical endpoint analyses
-Addition of another cohort of patients which can potentially expand the application of DCVax®-L, and which increases the trial to up to 300 patients
-Addition of interim analyses for efficacy
Later, they adjusted this further to include a total of 312 patients, and added one interim look for potential trial re-sizing (which will be expounded upon forthcoming).
In any event, the mention of "another cohort of patients which can potentially expand the application of DCVax®-L" has caused much speculation as to just who this cohort might be. One educated guess, elaborated by the blogger DocLogic, runs as follows:
After the phase l trial with DCVax-L Dr. Linda Liau at UCLA and her team did a micro array analysis of the resected tumors from the patients. She was able to discover various genetic differences in tumor types and was able to identify 3 subtypes. She identified them as mesenchymal, proliferative and proneural.
Since that time they have been reclassified into neural, proneural, classical and mesenchymal. What Dr. Liau discovered was that mesenchymal GBM genotype responded extremely well to DCVax-L immunotherapy. She also noted that ~33% of all GBM patients bore the mesenchymal genotype and that the proneural genotype responded the least. Along with this she noted that after treatment, there are genetic changes that occur that transforms many or most of the non mesenchymal genotypes into mesenchymal phenotypes (characterization) since she measured an ~85% phenotype characterization after recurrence.
If you look at a microarray analysis you will immediately note that there are variances within subgroups since no genetic marker groups are exactly identical. With this in mind it becomes clear that the extent to which a mesenchymal footprint is stamped into a given tumor, and perhaps methylation of MGMT is involved, will probably impact the level of benefit provided by an immunotherapy like DCVax-L.
If indeed the numbers provided correlate to proneural non-responders, which would be consistent with scientific observation to this point, the remainder from the 8% pseudo progressors plus 74% non-early progressing patients would be the responder group that Linda has indicated exists. Within this new total then would lie the 33% mesenchymal genotype group (strongest mesenchymal expression) and 41% additional patients that have become mesenchymal phenotype (lesser and more varied mesenchymal expression) [to clarify, so far we have 8% psPD, 33% mesenchymal, 41% non-mesenchymal, and 18% early progressives. Note that this is also the order of best responders to DCVax-L to worst].
Now taking the various results from IMUC, NWBO and others using immunotherapy in clinical trials, there appears to be the potential for a 50% 3 year MOS [median overall survival] in early stage trials. In IMUC's case this potential came from patients that had tumors expressing most or all of the targeted antigens. Since DCVax-L has all of these key cancer stem cells included and more, their phase lll trial should, at a minimum, approximate the phase l results of ICT-107 or be even better since the early progressors have been removed from the phase lll trial that were counted in their phase l trial.
If NWBO has accounted for mesenchymal genotype only, mesenchymal genotype with methylated MGMT, mesenchymal phenotype only, mesenchymal phenotype with methylated MGMT, proneural genotype only and proneural genotype with methylated MGMT, then the amount and type of information gathered and combinations of high responding subgroups could and would be linked to determine efficacy.
And so, it becomes complicated. It is possible that this cohort (subgroup) consists of patients pre-screened for methylated tumors. It is opined that these would respond better to DCVax-L, and of course are not limited to those with GBM (glioblastoma multiforme). Another subgroup could be those with the mesenchymal phenotype, who also seem to respond better to DCVax-L. Again, the potential here would be to show effect across multiple cancers by showing DCVax-L has superb effect in those with these designations (and so could be used to treat anyone, with any tumor, of any cancer type, that could be categorized thus).
One group it is most likely not to be are the psPD. For one, they include just 8% of all patients (Sanghera, Perry, Sahgal et al.). Finding and recruiting 72 of these would be highly difficult, and they cannot easily be screened for (in fact, it is only after they are labeled as early progressives, and given enough time without any treatment, that it becomes evident they are pseudo-progressives--not an exact science). Besides this, they are already designated to be part of the crossover group (like all early progressives and usual progressives alike) who receive treatment and whose results are tabulated, but will not affect the main trial's results.
In any event, the cohort is specifically mentioned to "potentially expand the application of DCVax-L." One obvious and immediate way it could be expanded is to treat all gliomas. The PEI's recent hospital exemption for DCVax-L (a first of its kind, landmark achievement) made this somewhat stunning extension of L already. However, it is evident from the CEO's remarks that she sees the function of L as even farther reaching. She stated:
[All operable tumors can be treated with DCVax-L across multiple cancer types without the need for further trials. It will eventually be used in all cancer types with same technology--no need to start over with various trials]"After that [current ph. III trial], we will then take it [DCVax-L] into other types of solid tumor cancers, and a real advantage will be that it’s the same product made in the same way, just using biomarkers from tumor tissue from a different location in the body, and that means that each of the further cancers is just a label extension. It’s not starting all over again with phase one trials and so forth."
[brackets mine]
And so, just who this cohort might be comprised of and how exactly it will "potentially expand the application of DCVax-L" is as yet unknown. Likewise, the ways in which it may be lending to the trial's delay are unknown. It is possible that certain stopping boundaries relative to this group have yet to be crossed, and which crossing has also been predicted to occur before the second interim look, and therefore a recommendation to "continue" until the second interim look (88 events) would waste time and money, and thus the committees are simply waiting for the stopping boundaries relative to this cohort to be crossed before issuing a recommendation to halt for efficacy (assuming they already have all stopping boundaries crossed in the main group). This brings up the next topic.
On Stopping Boundaries
4.3.2. Statistical Methods
One of the major responsibilities of a DMC is to evaluate the relative treatment effects based on protocol-specified endpoints to determine if the trial is meeting its objectives. A major concern when data on group differences are assessed repeatedly as they accumulate is that the Type I error (false positive) rate may be inflated if adjustment is not made for the multiple looks at the data. Typically, the monitoring plan will specify a statistical approach that permits multiple interim reviews while maintaining the Type I error rate at the desired level. These approaches usually generate boundaries for interim estimates of benefit that indicate the magnitude of benefit needed to support stopping the trial at interim points prior to its planned completion, while maintaining the desired overall probability of Type I error. Such boundaries can serve as useful guidelines to the DMC in making recommendations regarding continued accrual to and conduct of the trial. The DMC will usually recommend termination when these thresholds are crossed, but it is not obligated to do so, since other aspects of the interim data may complicate the issue. For example, the data on effectiveness may be very strong, with a stopping boundary having been crossed, but emerging safety concerns may make the benefit-to-risk assessment non-definitive at that interim review. FDA expects the sponsor to direct the DMC to exercise its own judgment in such circumstances; the DMC can be flexible in assessing the data relative to the stopping boundaries. If the DMC recommends early termination for efficacy before a boundary is crossed, however, and this recommendation is implemented, the Type I error cannot be preserved and the study results may be difficult to interpret.
In the literature it says that prior to beginning a trial the Sponsor meets with the FDA to determine a set of "stopping boundaries" for the trial. Should these boundaries be crossed before the end of the trial, the DMC will commonly recommend an early termination due to efficacy (which is why they were put in place to begin with), and the FDA will most likely approve the treatment in due course.
However, if they are not all crossed, but most are, the DMC can still recommend it, and the Sponsor accept it, but they are warned by the FDA that such action would increase the probability of type I error. The FDA may reject such a request by requiring yet another Ph III trial (untenable). It is far better to wait until all are crossed. However, and for the sake of argument, let's suppose 7 of the 10 have been crossed, and they surmise the other three will take another 12-16 weeks (from some 6 weeks into the review). Should the DMC simply advise a "continue" until the 88th event (possibly another 6-7 months away), or should they wait it out? If they simply recommend it "continue," there is an ethical dilemma in that because they deduce the total number of stopping boundaries would be crossed before the next interim look, they would be depriving the placebo group (and likewise the broader population) months of treatment.
Of course, they cannot tell management of this (hence the Company's response to the public that the efficacy data is "pending," or "outstanding"). The steering committee/ firewalled employees are briefed by the DMC and make the call for NW management until they are able to unblind them to the data.
But how might the FDA be brought into talks?
We recommend that sponsors of trials that could potentially be terminated early for efficacy reasons discuss these issues with FDA prior to implementing the trial, when the statistical monitoring plan and early stopping boundaries are being developed. In these settings, consultation with FDA may provide the sponsor with important information regarding the regulatory and scientific implications of a decision and may lead to better decisions.
This is prior to the trial. But then:
Sponsors are encouraged to revisit these issues with FDA when considering DMC recommendations for early termination if new issues have arisen and/or if the regulatory implications of early termination were not adequately clarified at the outset of the trial.
And in this case, that refers to the steering committee, not the Company. Thus, Linda Powers and management are and have been blinded to any and all of these discussions.
The PEI-FDA Connection
Now, we know that the FDA can be brought into these discussions between the DMC and steering committee for reasons as simple as "something new" occurring, unanticipated at the outset of the trial, or merely needing "clarification" on some point or other. It is likely the FDA has been unblinded to the data before now. Then consider (from fda.gov):
The United States Food and Drug Administration (USFDA), a part of the United States Department of Health and Human Services, is authorized under 21 C.F.R. § 20.89 ("Communications with Foreign Government Officials") to disclose non-public information to the Paul-Ehrlich-Institut (PEI) reporting to the German Federal Ministry of Health (BMG) regarding USFDA regulated products as part of cooperative law enforcement or cooperative regulatory activities.
The PEI understands that some of the information it receives from the USFDA may include non-public information exempt from public disclosure under the laws and, regulations of the United States of America, such as confidential commercial information; trade secret information; personal privacy information; law enforcement information; or internal, pre-decisional information. The PEI understands that this non- public information is shared in confidence, and that USFDA considers it critical that the PEI maintains the confidentiality of the information. Public disclosure of this information by the PEI could seriously jeopardize any further scientific and regulatory interactions between USFDA and the PEI. USFDA will advise the PEI of the non-public status of the information at the time that the information is shared.
It makes logical sense to deduce that the steering committee was presented with the dilemma, they in turn approached the FDA seeking "clarification" (from FDA guidelines), the FDA unblinded the PEI according to the obligations of their arrangement, the PEI approved the vacc., and we may be waiting on an outcome that could potentially prolong the lives of many more patients than halting now and risking the FDA finding problems with the maturity of the data (type I error) that would cause them to recommend another Ph III trial, or making the unethical choice of recommending it to continue when there aren't many stopping boundaries left to be crossed. Otherwise, why did the PEI not just wait until the DMC made their recommendation based on efficacy data (which is still "outstanding")? Or why not wait until the second interim look? Or tabulated results at the end of the year? Then they would have more to back their first-of-its-kind hospital exemption approval. Unless, of course, they already were unblinded to the data.
Trial Powering
The CEO expounded upon this Ph III trial's powering recently at an Immunotherapy conference (3/27/14). She stated:
One of the concerns investors express most often about biotech companies, and understandably so, is that they chronically underpower their trials. They chronically underestimate the size and power that they’ll need in their trial.
This 312 patient, placebo controlled double blind trial is powered to achieve a p-value (probability results are due to chance) of 0.02 (as mentioned, the FDA requires 0.05 or less). Thereby the likelihood the results will be deemed statistically significant are much increased.
It is also powered to achieve progression free survival of 6 months over SoC. That bar is set quite low when compared to their Ph I results of 18 months PFS over SoC. It is evident they are taking every measure possible to ensure success. It should be noted that even the bare minimum of 6 months PFS with a p-value of 0.05 would make this vaccine a blockbuster, revolutionizing how GBM is treated.
The primary endpoint is progression free survival (PFS), which has been accepted many times as the basis for approval from the FDA, and which has unique advantages relevant to this trial. Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics states:
3.Time to Progression and Progression-Free Survival
TTP and PFS have served as primary endpoints for drug approval. TTP is defined as the time from randomization until objective tumor progression; TTP does not include deaths. PFS is defined as the time from randomization until objective tumor progression or death. The precise definition of tumor progression is important and should be carefully detailed in the protocol.
a. TTP vs. PFS
Compared with TTP, PFS is the preferred regulatory endpoint. PFS includes deaths and thus can be a better correlate to overall survival. In TTP analysis, deaths are censored, either at the time of death or at an earlier vis it representing informative censoring (nonrandom pattern of loss from the study). PFS assumes patient deaths are randomly related to tumor progression. However, in situations where the majority of deaths are unrelated to cancer, TTP can be an acceptable endpoint.
b. PFS as an endpoint to support drug approval
Table 1 provides advantages and disadvantages of using PFS as an endpoint. PFS can reflect tumor growth and be assessed before the determination of a survival benefit. Its determination is not confounded by subsequent therapy. For a given sample size, the magnitude of effect on PFS can be larger than the effect on overall survival.
Likewise, their secondary endpoint, overall survival (OS) has certain disadvantages to it being used as a primary endpoint as it relates to this trial. These are enumerated as follows:
Advantages of PFS:
•Smaller sample size and shorter follow-up necessary compared with survival studies
•Measurement of stable disease included
•Not affected by crossover or subsequent therapies
•Generally based on objective and quantitative assessment
Disadvantages of OS:
•May involve larger studies
•May be affected by crossover therapy and sequential therapy
•Includes non-cancer deaths
It is important to note that this was all seen by and discussed with the FDA beforehand:
When possible, studies should be blinded. Blinding is particularly important when patient or investigator assessments are included as components of the progression endpoint. At a minimum, the assessments should be subjected to a blinded independent adjudication team, generally consisting of radiologists and clinicians. The FDA and the applicant should agree prospectively on the following items:
•The study design
•The definition of progression
•The data to be recorded on the case report form (CRF)
•The SAP
•The methodology for handling missing data and censoring methods
•The operating procedures of an independent endpoint review committee (IRC), if applicable
They further have written into the trial design the possibility to re-size it, to achieve even further powering. From one of the Company's powerpoints:
• 312 patient, randomized (2:1), double blind, placebo controlled Phase III trial: the “gold standard” in clinical trial design
– Primary endpoint: PFS (progression free survival)
– Secondary endpoints include OS (overall survival)
– 2 interim analyses for efficacy & 1 interim analysis for sample size
– 3 DCVax-L treatments upfront (Day 0, 10, 20), then 3 boosters (months 2, 4, 8) then 4 treatments twice/year for maintenance phase (months 12, 18, 24, 30)
This is of course done while management is completely blinded, and a decision to re-size the trial (in this case, most likely by enlarging it) cannot therefore be made on the basis of the Company having viewed any data, or knowing whether or not achieving the primary endpoint (6 months PFS) is in doubt. It is a sophisticated process, whereby statisticians use complex algorithms to preserve alpha and still discover whether or not certain variances or rates are beyond what was expected. It means only that the results are leaning away from what was expected. It does not infer that this is good or bad for the trial's outcome. It only makes the trial more efficient. However, it should be noted that enlarging the trial would de facto lower the necessary PFS required while still maintaining a 0.05 or less p-value. It could go from 6 months necessary, to 5, or even 4 months. Since the endgame (approval of treatment) of a trial is of the utmost importance, the Company should take every measure at its disposal to ensure it is successful. This would be one. Also, it should be noted that variance (one of the indicators used to determine sample re-sizing) is more likely to represent an increase in expected PFS and OS than a decrease, based on the very low bar set by the Company relative to what was seen in previous trial experiences (DCVax-L, DCVax-Prostate, and DCVax-Ovarian--all utilizing the same basic technology, and all showing consistent, efficacious results).
Another interesting mention from that power point is the following:
–Secondary endpoints include OS (overall survival)
Apparently there is more than one secondary endpoint. In addition to OS, these may include:
-Symptom Endpoints(patient-reported outcomes)
-Disease-Free Survival
-Objective Response Rate
-Complete Response
-Time to Progression (deaths before progression censored)
You can read about them in more detail in Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.
One final note on powering is the decision by management to drop the early progression group from the trial (however, enabling them to receive treatment in the crossover arm). Given that, statistically, this group is comprised of approximately 67% true early responders (who unfortunately will not survive very long), and 33% (or about 8% of the total population) psPD patients (who are genetically blessed to fight GBM), it empowers the trial further to sideline the entire group. The majority of this group will lower the PFS and OS of the trial. In this regard, the results of this Ph III trial could theoretically outperform their Ph I trial, as in the former trial they were all included.
DCVax Direct for Inoperable Tumors and ASCO
The abstract, which is not designated as a trial in progress (TIP), but rather a late breaking abstract (LBA), will be presented at ASCO on May 30, 2014. They likewise have reserved a significant amount of booth space (approx. 4,000 sq.ft.). It is evident they have much to say and are anticipating a very high level of foot traffic.
Unlike with most Ph I trials, the Company not only has a highly effective animal study to go on, but also a related pilot study conducted by Triozzi in which multiple patients with melanoma and breast carcinoma had their tumors injected with a similar DC (dendritic cell) vaccine. These ten individuals showed great response to treatment, not just in the directly injected tumor, but also in the localized vicinity of injection. The study can be found here:
http://www.ncbi.nlm.nih.gov/pubmed/11135227
DCVax Direct is an improvement over the vaccine used by Triozzi. It utilizes precisely matured DCs that are more capable of taking up tumor antigens and also better able to travel to the lymph nodes. This has also been applied to DCVax-L and Prostate as well (essentially DCVax-L made to focus on particulars of prostate cancer):
3/18/2013 PR NW Bio Receives U.S. Patent On Broad Processes For Producing More Potent Dendritic Cells
Next Generation Technology Already In DCVax®-Direct Will Be Applicable To All DCVax® Products
Going forward, NW Bio’s now patented methods of producing more potent dendritic cells will also enable development of the next generation of NW Bio’s other two product lines: DCVax-L and DCVax-Prostate. The current DCVax-L and DCVax-Prostate products have already delivered striking results in clinical trials to date, extending the time to tumor recurrence and the patients’ survival time by 1-1/2 to 2 years or more, with a substantial portion of patients going far beyond that. Incorporating NW Bio’s patented methods for more potent dendritic cells will enable production of enhanced versions of these DCVax-L and DCVax-Prostate products.
(DCVax-Prostate is awaiting partnership, and i therefore outside the scope of this paper, except to demonstrate the consistency of trial results using the same basic technology)
Since NWBO has improved upon the technology used by Triozzi, it is anticipated that the results will exceed Triozzi's in efficacy.
Most everything else about DCVax-Direct has been kept under wraps. Embargoed, specifically, and as per the plan set in motion when the Company envisaged the unveiling of results at ASCO. Given that the first patient was treated in the summer of 2013, and given the fact that possible efficacy can be measured in mere months, and given the fact that enrollment has been speedy according to the Company, and given the fact that they have incurred a large expense to reserve massive floor space at ASCO, it is expected by many that the results unveiled there will be groundbreaking.
Anecdotal Support for DCVax-Direct
It is evident the CEO is excited and in her words "Quite encouraged" by what she has seen first hand (given the trial is not blinded). There have been a number of mentions on cancer treatment boards and in other places online of patients giving testimonials (both for L and Direct), and in such a way as to appear quite genuine, stating their success story out of the apparent motivation to help others who have terminal disease. One such mention very recently was the following:
Ever since going to Orlando Health I feel much better. My tumor in colon has begun to shrink in size and is no longer attached to abdominal wall. It is also beginning to move away from my bladder. The thickness of tumor in colon has also been reduced. Colon surgery will now be successful and it looks like I may be able to keep most of my urinary bladder and not have to worry about cancer in bladder reoccurring.
It certainly sounds genuine, and makes sense from a medical perspective. It also sounds a bit like something someone who was treated and told what had occurred would say without having a medical background. Although this is not a documented result from a regulated clinical trial, and should not be given the same weight, it is a possible validation. And it seems logical that patients being treated and seeing their tumors dissolve to the point where surgery becomes possible (life saving) would come online to share their testimony.
Ramping Up
Northwest Biotherapeutics has been aggressively pursuing manufacturing capacity in the US and in Europe. They are very close to meeting their goal of full capacity. This effort has been aided (one might say, "subsidized") by Germany and the UK:
In Europe, as part of our partnering arrangements, the Fraunhofer Institute in Germany and Kings College in the U.K. have dedicated their own “cGMP” (clean room) state-of-the-art manufacturing facilities to our programs. We thereby obtained these manufacturing facilities without capital cost to us, and without the 18-month or more lead time usually required to develop the facilities.
That alone provides quite the validation for their DCVax platform. The Company continues:
In addition, Fraunhofer, Cognate, we and Kings College began the 7-month processes for regulatory approvals and institutional approvals in both the U.K. and Germany to enable the manufacturing in Germany to supply DCVax-L for the clinical trial in the U.K. as well. This German supply arrangement is in addition to the manufacturing under development in the U.K.
In addition, our partner, Fraunhofer IZI Institute in Germany, has received approval and certification from the regional and national regulatory agencies in Germany for the manufacture of DCVax for GBM. We anticipate that the manufacturing facilities in the U.K. will eventually obtain the necessary approvals, and that the German and U.K. facilities’ will be able to supply DCVax products for anywhere in Europe.
An update (as of 4/11/12) regarding the current state of trial affairs from the Company ran as follows:
As of February 28, 2014, our Phase III clinical trial of DCVax-L in GBM is being conducted at approximately 50 sites across the United States and at one site in the United Kingdom. We are also in the process of adding further U.S. sites and up to 30 European sites. We have accelerated and strengthened our programs in Europe by partnering with large, prominent institutions, including the Fraunhofer IZI Institute in Germany and King’s College Hospital in the U.K.
In the U.K., we previously received approval from the Medicines and Healthcare Products Regulatory Authority, or MHRA, to proceed with our Phase III clinical trial of DCVax-L for GBM, which we initiated in May 2013. The lead site is Kings College Hospital in London. Half a dozen other major medical centers in the U.K. are preparing to proceed with the trial. In April 2013, we announced that the National Institute of Health Research, or NIHR (a branch of the National Health System) in the U.K. had completed a multi-stage evaluation of our DCVax-L technology and our Phase III clinical trial of DCVax-L for GBM, and the NIHR had “adopted” our trial as a nationwide priority trial in the U.K.
We have also been working on preparations for the clinical trial in Germany. On July 25, 2012, we announced that manufacturing certification has been received from the German regulatory authorities for the clinical trial in Germany, which is the first step towards implementation of the Phase III trial in Germany. We submitted the application to the German regulatory authority (the Paul Ehrlich Institute, or PEI) for approval of the Phase III trial, which we received on September 16, 2013. As of February 28, 2014, an initial dozen clinical centers are in varying stages of preparations as trial sites in Germany, with further sites to follow.
A matter of clarification on what they mean by implementing the Ph III trial in Germany (wasn't it already approved there via Hospital Exemption?). It is actually akin to what is called a "confirmatory" or Ph IV trial here in the US. The vaccine will receive full reimbursement from the German Central Reimbursement Authority, however they cannot market the product (much like in the US) until the "confirmatory trial" phase has past. As DocLogic and Larry Smith have collaboratively expressed, the differences in regulations of the FDA and PEI run as follows:
FDA: 30 day review of safety. Trial can begin after 30 days without FDA response.
PEI: Precise wording for all trial procedures and inclusions/exclusions defined and approved. Entire commercial production process and facilities must be put in place, fully functioning and approved. Total time required for reviews and approvals is 2 years or more. Newer technologies generally take longer. Once approval is granted then individual hospitals can petition to be included and reimbursed by the hospital funds or private insurance. Approval for reimbursement is rare and depends much on early evidence of benefit. If not approved, cost is born entirely by trial sponsor. This request is approvable for 1-5 years (NWBO was given 5 years and is reconsidered for renewal after this). Clinical trials can begin immediately after approval but generally hospitals will wait for a reimbursement decision and or hospital exemption if applicable.
Hospital exemption allows for changes to some clinical trial protocols and allows use of the treatment on an open basis with restrictions placed on advertising and sometimes other aspects of use. With DCVax-L, the use was expanded to all gliomas in both newly diagnosed and recurrent patients. This expansion decision is essentially like the ignition of rocket motors before launch. Increasing the manufacturing capacity is like powering up the engines to full throttle before launch.
Product approval process:
PEI: Gathers all data from trials with or without hospital exemption status or reimbursement to be assessed for final approval or termination for lack of efficacy or safety concerns not previously noted.
FDA: Phase l safety and tolerability generally no basis for approval.
Phase ll open label (generally non approvable) or double blind (approvable) study. Safety and efficacy.
Phase lll, if needed, for efficacy and possible approval for registration. Final approval requires approved commercial manufacturing site or sites and agreed upon labeling for use.
Conclusions
FDA: Front end of trial takes less time to start and lower costs allowing more small innovative companies to participate in the process. Back end costs increase which can jeopardize the process or be seen as commercial vetting of potential and waiting for long term results can delay time to general use in patient populations with limited options.
PEI: Up front costs high and time to start delayed. Back end potential for quicker product reimbursement or sale and hospital exemption that gets product into general use more quickly. Products demonstrating good initial safety and potential for efficacy are more likely to benefit for the sake of those patients who want to try it and have limited options for treatment. This process offers patients treatments that have been fairly well vetted for safety and potential efficacy while the PEI continues to gather data to make a final determination for full commercialization approval or termination due to lack of efficacy or whatever safety concerns might be revealed in a larger patient population.
Marketability
The potential in DCVax-L and DCVax-Direct is difficult to quantify. With such open ended applications using label extension for L to treat "all solid tumor cancers," and the very broad classification of "all inoperable tumors" for Direct, it is easy to see how the numbers can run wild. The defining feature behind these two front line treatments, however, lies in their exclusivity. There is no treatment for inoperable tumors. They are given palliative care, and sent home (or to hospice) to die. GBM patients, in short order, likewise. These are concrete realities, and a potential future valuation of NWBO can be tabulated based on them. It is the further potential in treating "all gliomas," as the PEI has approved, the inclusion of all worldwide regulatory bodies (Japan, Aus, NZ, China, India, Russia, etc.) and the use of label extension for L, that requires a daunting and highly speculative task. Here are some conservative estimations, going low in particular on the potential treatment costs, that are as yet to be enumerated (although around $40,000 per patient per year has been mentioned):
-DCVax-L used to treat GBM worldwide, new and existing cases, with 80% penetration in all major markets (excluding 90% of cases in Asia, Africa, Central and South America, which account for 60% of the world's cancer rates, but unfortunately have depressed economies), but not considering any lesser gliomas, estimated at an average of $30,000-$50,000 per patient per year ==> $4.8B - $8B in sales
-DCVax-L used to treat all lesser gliomas (stages I-III), new and existing, on a case by case basis, 80% market penetration worldwide (with the same exclusions as above), estimated at an average of $15,000 per patient per year ==> $6B in sales
-DCVax-L used by label extension to treat all operable, late stage cancers worldwide (with the same exclusions as above) with 20% penetration and $30,000 per patient per year ==> $8B+ in sales
-DCVax-Direct used to treat all inoperable tumors worldwide (with the same exclusions as above), with 80% penetration and $15,000 per patient per year ==> $36B+ in sales
Based on these figures, the immense potential and long awaited realization of the dendritic cell vaccine platform, multiple validations in Europe (especially Hospital Exemption Approval in Germany) and the United States centers of excellence, the evidence that a halt for efficacy is currently in talks, and latent pressure building in the mega-blockbuster potential magnitude of DCVax Direct--an immediate price target of $24.00 (rounded up) appears highly reasonable, even in pre-approval (US and EU) status.
Should results at ASCO appear as groundbreaking as they are hinted at being, showing marked reduction in tumor size, making inoperable malignant masses suddenly operable, thus saving the lives of potentially millions (yes, millions), then even with the status of their Ph III DCVax-L trial pending, a price target of $53.00 (rounded up) would then appear reasonable.
Should DCVax-Direct results prove stellar, and DCVax-L results meet their primary endpoint (or be halted for efficacy), then a price target of $287.00 (rounded up) appears reasonable.
There has been a misunderstanding regarding the potential and current state of affairs regarding NWBO. Due in part to the amount of misinformation currently circulating, and to attaching too much significance to the failings of other dendritic cell vaccines that use an inferior technology. It is my hope that this paper proved useful in clearing up much of that.
*My sincere thanks to DocLogic and Larry Smith for their direct and indirect contributions to this article.
I have outlined below a thorough basis for investment in Northwest Biotherapeutics based on extensive research from a multitude of sources.
Technology
Northwest Biotherapeutics' two main treatments currently in clinical trials are DCVax-L (Ph III, with looming possibility of a halt for efficacy) and DCVax-Direct (in Ph I/II, currently undisclosed regarding progress, but by all signs appearing to be well under way and possibly demonstrating efficacy).
From NWBO's site regarding DCVax-L:
For DCVax-L, the monocytes are differentiated into dendritic cells, and matured, activated and loaded with biomarkers (“antigens”) from the patient’s own tumor tissue (which is collected in a simple kit at the time of surgery to remove the tumor). The loading of biomarkers into the dendritic cells “educates” them about what the immune system needs to attack. The activated, educated dendritic cells are then isolated with very high purity and comprise the DCVax-L personalized vaccine. DCVax -L is administered to the patient through a simple intra-dermal injection in the upper arm, similar to a flu shot. The dendritic cells then convey the tumor biomarker information to the rest of the immune system agents (T cells, B cells and others), as “marching orders,” and the immune system agents then fan out through the body searching for anything with these biomarkers and attacking it.
From NWBO's site regarding DCVax-Direct:
For DCVax-Direct, the monocytes are differentiated into dendritic cells and partially matured. DCVax-Direct is administered by injection directly into inoperable tumors. These injections can reach tumors located virtually anywhere in the body, with ultrasound image guidance. After injection into the tumors, the DCVax-Direct dendritic cells pick up the tumor biomarkers (“antigens”) in situ in the tumor. Then, like the DCVax-L product, the dendritic cells in the DCVax-Direct product then convey the tumor biomarker information to the rest of the immune system agents (T cells, B cells and others), who then act upon it throughout the body.
DCVax-L Group Breakdown
-Ph III double blind placebo controlled trial. 312 patients in main group, which breaks down into 160 in main treatment arm, 80 in main placebo arm; 48 in cohort (unspecified patient category) treatment arm, and 24 in cohort placebo arm (this is the most probable breakdown of the cohort--this group is undefined, however, including their possible break-up into treatment/ placebo arms). There are various theories on who this 'cohort' might be, which will be touched upon later.
-An estimated 75-100 additional patients (not included in the 312) in the 'early progression group,' who are crossed over to treatment, but whose results will not affect the outcome of the trial. Early progressives are those who show signs of tumor recurrence very early on. Of these it is further estimated that 25-35 of them are what is called "pseudo-progressive" (henceforth labeled as "psPD"). These are those who show signs of early progression (both by MRI and physical symptoms), but it is later revealed that they are not in fact experiencing tumor recurrence (more on this discussed ahead).
-It should be noted that any patient in a placebo group experiencing progression (tumor recurrence) has the option to immediately be crossed over to the treatment arm (and almost certainly will).
DCVax-Direct Group Breakdown
-Ph I/II(a) unblinded trial for patients with inoperable tumors (obviously beyond DCVax-L's reach), comprised of 60 patients. These break down into two stages. The first stage involves 36 patients with inoperable tumors, 6 from each of the following six cancer categories: colon (#2 killer, quick metastasis), breast cancer with brain metastasis (not many treatments for this type of breast carcinoma), lung cancer (#1 killer), pancreatic cancer (small market, fast regulatory pathway), melanoma, and 'miscellaneous' (unspecified--could be as few as one other cancer type, could be as many as six). The second stage involves 24, comprised of patients with inoperable tumors of one specific cancer type (for example, 'colon').
-Ph II(b) has not yet been enumerated by official document or PR, but described by the CEO at a recent important immunology conference, as including 144 patients, comprised of 24 from each of the aforementioned six cancer groups (colon, breast w/ brain met., lung, pancreas, melanoma, and misc.).
-Total patient enrollment: 204.
-It should be noted here that moving from one stage of the trial to the next will occur "seamlessly," according to the CEO, by not requiring additional clearance from the FDA:
Once we complete that stage [stage I: safety, feasibility and dose finding] we will go seamlessly into stage II [efficacy]. We do not have to go back to the agency, we just keep going. And if we see glimpses of efficacy in multiple cancers, we can go right into phase II in parallel and multiple cancers, two dozen patients per cancer." --Linda Powers
[brackets mine]
In Summary:
-Stage I is essentially Phase I, and includes 36 patients, 6 from each of the six cancer categories, testing for safety, feasibility and dose finding ("with an eye for efficacy," according to the CEO).
-Stage II has 24 additional patients from one specific cancer (for example, 'colon') in its Phase IIa leg, to determine efficacy. This will also be the lead-in for the larger part of the stage II section, its Phase IIb leg ("parallel and multiple cancers"), which will involve 144 patients, comprised of 24 from each of the 6 cancer categories (not including the 24 from the Ph IIa leg--hence the 'parallel').
-Therefore we have 60 in Ph I/IIa, and 144 in Ph IIb, for a total of 204 patients.
*Of note also is the fact that one chosen cancer designation (from Ph IIa) will have the statistical advantage of demonstrating efficacy data from 54 treated patients.
DCVax-L Prior Ph I Trial Results
Much has been made of these stellar results, though the critics mention the trial was too small to be sufficiently powered, and thereby should not be taken too seriously. The contention of those who rather give it weight primarily state two reasons for doing so:
-p-value
and
-unbiased, statistical matching
On p-value, Larry Smith from "Smith on Stocks" states:
The Kaplan Meier curves for progression free survival and overall survival show strong statistical significance, although it must be understood that this is comparing data from different trials. The p value for median progression free survival was 0.00001 and the p value for overall survival was 0.0003. A p value of 0.0003 means that there is only a 3 in 10,000 probability that the results were obtained by chance. The “p” value is a measure of statistical significance: it is the probability that a set of results were due to chance. So, the smaller the p value, the smaller the chances are that the results were due to chance and were not “real.” The FDA generally requires a p value of 0.05 or less (i.e., a 5 in 100 or less possibility that the results of clinical trials were due to chance) for approval.
On non-biased, statistical matching, proponents state that the Company (NWBO) used every measure available to them to avoid type I error, citing (from their Ph I DCVax-L study):
*"Treated patients [were] matched for age, gender, Karnofsky score, extent of surgical resection, and same standard of care treatment, at same hospital, in same time period."
This, they would assert, is going above and beyond what is necessary to ensure against type I error. And further cannot be seen as "cherry picking patients," as some critics suggest.
The results of their Ph I/II trial were spectacular (to any objective observer), especially when considering the disease in question, glioblastoma multiforme, which has a very grim diagnosis, and has had seen no real benefit from scientific advancement in over a decade. These results are given here (as compared with standard of care (SoC) alone--resection and chemoradiation):
DC Vax-L showed an improvement in median progression free survival of 25.0 months versus 6.9 months for SOC and an improvement in median overall survival of 36.4 months versus 14.6. At the end of three years, the data suggests that 55 of every 100 patients treated with DC Vax-L would be alive versus 16 of every 100 treated with SOC.
Recent Hospital Exemption Approval by the PEI of Germany
From the official PR:
BETHESDA, Md., March 10, 2014 – Northwest Biotherapeutics (NASDAQ: NWBO) (NW Bio), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, announced today that it has received approval from the Paul Ehrlich Institute (“PEI”- the FDA of Germany) of a “Hospital Exemption” early access program under Section 4b of the German Drug Law. Under this Hospital Exemption, NW Bio may provide DCVax-L to patients for the treatment of any glioma brain cancers (both Glioblastoma multiforme and lower grade gliomas), both newly diagnosed and recurrent, outside of the Company’s clinical trial and charge full price. The patients may be from Germany or elsewhere. This approval has a term of five years, and can be re-applied for and re-issued at the end of that period.
NW Bio also announced today that the German reimbursement authority (Institut Für Das Entgeltsystem Im Krankenhaus, or InEK) has determined that DCVax-L treatments for glioma brain cancers are eligible to obtain reimbursement from the Sickness Funds (health insurers) of the German healthcare system. Applications for such reimbursement eligibility may only be submitted to InEK by German hospitals, not by a company. Six major hospital centers across Germany applied for such reimbursement eligibility for DCVax-L for glioma brain cancers. The amount and terms for such reimbursement will now be negotiated by NW Bio, the hospitals and the Sickness Funds over the coming months, and will be applied to patients case by case. In the meantime, patients may self-pay for DCVax-L.
It is important to note how different this is from compassionate use. Compassionate use allows for only one patient to be treated at a time, with long processes of paperwork for each patient. Hospital exemption however, allows the treatment of any number of patients and without lengthy paperwork. Also, hospital exemption allows the Company to charge full price for each treatment. However, companies cannot charge the patient or hospital at all, nor can they receive reimbursement under compassionate use
Points made from the 3/27/14 conference:
-1st German validation: Germany Hospital exemption: “major validation” for DCVax-L. Any grade of glioma, newly diagnosed and recurrent, for all stages, I-IV (proponents would note that this is a stunning extension of the therapy, considering the trial's focus was only on the most lethal form of glioma--stage IV, glioblastoma multiforme).
For 2.5 years the PEI of Germany rejected many applications from many companies and only approved three, including DCVax L--yet in this regard, with many firsts:
-first new product approved that was not already on market and grandfathered
-first immune therapy
-first product with drug-like activity in body
-first cell therapy, first non German co.
And it is open to anyone "elsewhere" in the world (outside of Germany) who can afford to travel there and pay for the treatment.
-2nd German validation: German Central Reimbursement Authority--six major medical centers applied (thus far) to the Reimbursement Authority. This is a kind of “double validation” in that the company cannot apply for this--only medical centers can. The technology and company had to be fully vetted first. Centers have applied for eligibility for reimbursement now while treatment is still in clinical trials. Such a precedent has never happened before. They can apply for reimbursement now, as opposed to having to wait years. Usually even an FDA approved drug will have to be on the market for 1-2 years to be eligible for reimbursement, and yet NWBO’s DCVax-L is eligible now, and it will remain thus for the next 5 years (and then can be reapplied for). The Company will receive full payment for every treatment administered.
*It is estimated nearly 14,000 newly diagnosed and recurrent patients fall under this category in Germany, and at $30,000 (minimal) per patient per year, that would equate to $420mm in sales potential, conservatively figured (price of vaccine likely to be higher, and relegated to German citizens alone). However, it is also open to anyone with the means from around the world.
Recently (4/10/14), the Company released a PR about receiving financing of "up to $32 million dollars," ($15mm upfront) stating:
With this financing, we are particularly focused on accelerating the expansion of our manufacturing in Europe, especially following the recent favorable decisions in Germany...
It seems clear they will be using the monies in large part for a much increased manufacturing of DCVax-L, a demand for which has almost certainly arisen out of the vaccine's recent approval and immediate availability (to anyone capable of paying for it) in Germany. It is probable, then, that it will not be long before an announcement that reimbursement negotiations with the German Central Reimbursement Authority have been finalized, and that subsidized treatments may begin promptly.
The German authorities have actually gone so far as to supply the manufacturing space to NWBO at no cost to them (and have said they will enlarge this space as needed)--and it must be admitted, that is quite a validation in and of itself. However, in that the Company will receive "reimbursement" for the vaccine, they must shoulder the upfront cost of manufacturing--hence the immediate need for financing.
DCVax-L Current Ph III Trial Implications
(from Guidance for Clinical Trial Sponsors)
3.2. When there is a steering committee, the sponsor may elect to have the DMC communicate with this committee rather than directly with the sponsor.
This is where we have been since the first interim look, which occurred in early Dec. 2013. The steering committee, appointed by the Company (or possibly firewalled employees--but that is less likely), has been in extensive talks with the DMC (as of 4/10/14). The original estimate for the time it would take to receive a recommendation was "6-8 weeks." This came with the predication that the recommendation to simply "continue" the trial had a 90% probability, while that to halt the trial for efficacy or futility/safety reasons was given a split 5% each.
The estimate on time to receive the recommendation was then further amended once the 8-week mark had passed to be "2-3 more weeks." Finally, once this threshold was likewise surpassed, any further estimation of time to receive the DMC recommendation based on efficacy data has been given up by the Company, and they now simply reiterate "the DMC recommendation based on efficacy data is still outstanding."
We are now (if not considering the holidays) almost 18 weeks into the first interim look (as of 4/10/14). Since initially, the Company was expecting the trial to continue after look, giving that a 90% probability, while giving a halt a 10% probability, we might assume that these estimations have also evolved over time, although they have not expressed such.
However, the longer the DMC takes, the more likely that the reason for the delay is in their consideration of a halt for efficacy. The reason being is that a halt for safety is off the table as per the Company's 3/7/14 PR, and a halt for futility would (typically speaking) have already occurred by now.
In addition, IMUC ran a similar dendritic cell vaccine Ph II trial, using what many consider an inferior technology to DCVax-L, in that their lead product, ICT-107, utilized just six synthetic antigen biomarkers expressed in only a minority of the GBM population (whereas DCVax-L expresses the full array of organic antigens from the patients actual resected tumor, representing scores or possibly even hundreds of antigens--and can be used on the entire GBM population). By the end of the trial it was shown that, although their secondary endpoint of PFS had reached statistical significance, showing a (perhaps "meager") 2 month increase over placebo, their primary endpoint of overall survival (OS) was not statistically significant (although it did show a numeric advantage of 2-3 months over placebo--in time their p-value may come down enough to become stat. sig.). And although an interim look for a trial with a primary endpoint of PFS and one with a p.e. of OS would differ in protocol, it would not differ enough to explain the incongruency as to why IMUC received a quick "continue" recommendation, while the status of NWBO's trial is still, after some 18 weeks, "outstanding." If ICT-107 showed low efficacy and received a quick continue (and by their interim look most likely showed little efficacy considering the meager outcome), then DCVax-L, if the efficacy data was little to none, should have likewise gotten a quick continue. In this we have precedent. Therefore, through the process of elimination, consideration for a halt for efficacy due to substantial benefit is the most likely reason for this delay.
Let us examine then the following sections of Guidance for Clinical Trial Sponsors:
Interactions between the steering committee and the DMC consist primarily of discussions during "open sessions" (see Section 4.3) of DMC meetings and the communication of recommendations following each DMC review of the trial. More extensive interactions might occur when early termination is being considered.
The specifics of such extensive talks are enumerated in another section:
7.2.1. DMC Recommendations to Terminate the Study
In almost all cases, a DMC is advisory to the sponsor; the sponsor decides whether to accept recommendations to discontinue a trial. FDA will rarely, if ever, tell a sponsor which decision to make. For trials that may be terminated early because a substantial benefit has been observed, however, consideration may still need to be given to the adequacy of data with regard to other issues such as safety, duration of benefit, outcomes in important subgroups and important secondary endpoints.
Safety has already been put to rest. The safety monitoring board already recommended the trial continue on a safety basis (3/7/14 PR). The treatment is regraded as highly safe, as the Company notes:
Nearly as important in clinical trials to date, there has been no toxicity (no serious adverse events) related to DCVax. In ten years of clinical experience, there have been only been a couple of “serious adverse events” and we believe these were due to the patient’s underlying brain cancer, rather than the DCVax treatment. The broad and rapidly growing body of scientific literature about dendritic cells is consistent with the DCVax clinical experience.
However, "duration of benefit, outcomes in important subgroups, and important secondary endpoints (i.e. overall survival)" are very much on the table.
"Duration of benefit" is directly speaking of this trial's primary endpoint (progression-free survival) and its secondary endpoint (overall survival). The discussion could be ongoing as to the extent these benefits are currently being seen. This also applies to "important secondary endpoints," which in this case is OS (overall survival) as well as others unnamed (more on this later). Given that the patients in the placebo group who show progression of the disease will be placed in the "crossover arm" and given treatment with DCVax-L, the true determination of an OS benefit will have to rely on historical mortality rates as opposed to an objective comparison with an in-trial placebo group. This is one of a handful of reasons why OS was chosen as the secondary and not primary endpoint. Having a crossover arm is an ethical decision when dealing with such an aggressive terminal illness as GBM.
"Outcomes in important subgroups" is an open topic for this trial. Some have opined that the additional cohort is comprised of the psPD patients mentioned previously. Specifically, the Company released a PR at the time when this trial was upgraded to a Ph III including the addition of another cohort:
The Company also announced that the FDA has accepted an amendment of the clinical trial, which does not make any change in the treatment regimen, which leaves all data collected to date intact for use in the trial’s overall results, and which includes the following:
-Designation as a Phase III trial
-Expanded and enhanced statistical endpoint analyses
-Addition of another cohort of patients which can potentially expand the application of DCVax®-L, and which increases the trial to up to 300 patients
-Addition of interim analyses for efficacy
Later, they adjusted this further to include a total of 312 patients, and added one interim look for potential trial re-sizing (which will be expounded upon forthcoming).
In any event, the mention of "another cohort of patients which can potentially expand the application of DCVax®-L" has caused much speculation as to just who this cohort might be. One educated guess, elaborated by the blogger DocLogic, runs as follows:
After the phase l trial with DCVax-L Dr. Linda Liau at UCLA and her team did a micro array analysis of the resected tumors from the patients. She was able to discover various genetic differences in tumor types and was able to identify 3 subtypes. She identified them as mesenchymal, proliferative and proneural.
Since that time they have been reclassified into neural, proneural, classical and mesenchymal. What Dr. Liau discovered was that mesenchymal GBM genotype responded extremely well to DCVax-L immunotherapy. She also noted that ~33% of all GBM patients bore the mesenchymal genotype and that the proneural genotype responded the least. Along with this she noted that after treatment, there are genetic changes that occur that transforms many or most of the non mesenchymal genotypes into mesenchymal phenotypes (characterization) since she measured an ~85% phenotype characterization after recurrence.
If you look at a microarray analysis you will immediately note that there are variances within subgroups since no genetic marker groups are exactly identical. With this in mind it becomes clear that the extent to which a mesenchymal footprint is stamped into a given tumor, and perhaps methylation of MGMT is involved, will probably impact the level of benefit provided by an immunotherapy like DCVax-L.
If indeed the numbers provided correlate to proneural non-responders, which would be consistent with scientific observation to this point, the remainder from the 8% pseudo progressors plus 74% non-early progressing patients would be the responder group that Linda has indicated exists. Within this new total then would lie the 33% mesenchymal genotype group (strongest mesenchymal expression) and 41% additional patients that have become mesenchymal phenotype (lesser and more varied mesenchymal expression) [to clarify, so far we have 8% psPD, 33% mesenchymal, 41% non-mesenchymal, and 18% early progressives. Note that this is also the order of best responders to DCVax-L to worst].
Now taking the various results from IMUC, NWBO and others using immunotherapy in clinical trials, there appears to be the potential for a 50% 3 year MOS [median overall survival] in early stage trials. In IMUC's case this potential came from patients that had tumors expressing most or all of the targeted antigens. Since DCVax-L has all of these key cancer stem cells included and more, their phase lll trial should, at a minimum, approximate the phase l results of ICT-107 or be even better since the early progressors have been removed from the phase lll trial that were counted in their phase l trial.
If NWBO has accounted for mesenchymal genotype only, mesenchymal genotype with methylated MGMT, mesenchymal phenotype only, mesenchymal phenotype with methylated MGMT, proneural genotype only and proneural genotype with methylated MGMT, then the amount and type of information gathered and combinations of high responding subgroups could and would be linked to determine efficacy.
And so, it becomes complicated. It is possible that this cohort (subgroup) consists of patients pre-screened for methylated tumors. It is opined that these would respond better to DCVax-L, and of course are not limited to those with GBM (glioblastoma multiforme). Another subgroup could be those with the mesenchymal phenotype, who also seem to respond better to DCVax-L. Again, the potential here would be to show effect across multiple cancers by showing DCVax-L has superb effect in those with these designations (and so could be used to treat anyone, with any tumor, of any cancer type, that could be categorized thus).
One group it is most likely not to be are the psPD. For one, they include just 8% of all patients (Sanghera, Perry, Sahgal et al.). Finding and recruiting 72 of these would be highly difficult, and they cannot easily be screened for (in fact, it is only after they are labeled as early progressives, and given enough time without any treatment, that it becomes evident they are pseudo-progressives--not an exact science). Besides this, they are already designated to be part of the crossover group (like all early progressives and usual progressives alike) who receive treatment and whose results are tabulated, but will not affect the main trial's results.
In any event, the cohort is specifically mentioned to "potentially expand the application of DCVax-L." One obvious and immediate way it could be expanded is to treat all gliomas. The PEI's recent hospital exemption for DCVax-L (a first of its kind, landmark achievement) made this somewhat stunning extension of L already. However, it is evident from the CEO's remarks that she sees the function of L as even farther reaching. She stated:
[All operable tumors can be treated with DCVax-L across multiple cancer types without the need for further trials. It will eventually be used in all cancer types with same technology--no need to start over with various trials]"After that [current ph. III trial], we will then take it [DCVax-L] into other types of solid tumor cancers, and a real advantage will be that it’s the same product made in the same way, just using biomarkers from tumor tissue from a different location in the body, and that means that each of the further cancers is just a label extension. It’s not starting all over again with phase one trials and so forth."
[brackets mine]
And so, just who this cohort might be comprised of and how exactly it will "potentially expand the application of DCVax-L" is as yet unknown. Likewise, the ways in which it may be lending to the trial's delay are unknown. It is possible that certain stopping boundaries relative to this group have yet to be crossed, and which crossing has also been predicted to occur before the second interim look, and therefore a recommendation to "continue" until the second interim look (88 events) would waste time and money, and thus the committees are simply waiting for the stopping boundaries relative to this cohort to be crossed before issuing a recommendation to halt for efficacy (assuming they already have all stopping boundaries crossed in the main group). This brings up the next topic.
On Stopping Boundaries
4.3.2. Statistical Methods
One of the major responsibilities of a DMC is to evaluate the relative treatment effects based on protocol-specified endpoints to determine if the trial is meeting its objectives. A major concern when data on group differences are assessed repeatedly as they accumulate is that the Type I error (false positive) rate may be inflated if adjustment is not made for the multiple looks at the data. Typically, the monitoring plan will specify a statistical approach that permits multiple interim reviews while maintaining the Type I error rate at the desired level. These approaches usually generate boundaries for interim estimates of benefit that indicate the magnitude of benefit needed to support stopping the trial at interim points prior to its planned completion, while maintaining the desired overall probability of Type I error. Such boundaries can serve as useful guidelines to the DMC in making recommendations regarding continued accrual to and conduct of the trial. The DMC will usually recommend termination when these thresholds are crossed, but it is not obligated to do so, since other aspects of the interim data may complicate the issue. For example, the data on effectiveness may be very strong, with a stopping boundary having been crossed, but emerging safety concerns may make the benefit-to-risk assessment non-definitive at that interim review. FDA expects the sponsor to direct the DMC to exercise its own judgment in such circumstances; the DMC can be flexible in assessing the data relative to the stopping boundaries. If the DMC recommends early termination for efficacy before a boundary is crossed, however, and this recommendation is implemented, the Type I error cannot be preserved and the study results may be difficult to interpret.
In the literature it says that prior to beginning a trial the Sponsor meets with the FDA to determine a set of "stopping boundaries" for the trial. Should these boundaries be crossed before the end of the trial, the DMC will commonly recommend an early termination due to efficacy (which is why they were put in place to begin with), and the FDA will most likely approve the treatment in due course.
However, if they are not all crossed, but most are, the DMC can still recommend it, and the Sponsor accept it, but they are warned by the FDA that such action would increase the probability of type I error. The FDA may reject such a request by requiring yet another Ph III trial (untenable). It is far better to wait until all are crossed. However, and for the sake of argument, let's suppose 7 of the 10 have been crossed, and they surmise the other three will take another 12-16 weeks (from some 6 weeks into the review). Should the DMC simply advise a "continue" until the 88th event (possibly another 6-7 months away), or should they wait it out? If they simply recommend it "continue," there is an ethical dilemma in that because they deduce the total number of stopping boundaries would be crossed before the next interim look, they would be depriving the placebo group (and likewise the broader population) months of treatment.
Of course, they cannot tell management of this (hence the Company's response to the public that the efficacy data is "pending," or "outstanding"). The steering committee/ firewalled employees are briefed by the DMC and make the call for NW management until they are able to unblind them to the data.
But how might the FDA be brought into talks?
We recommend that sponsors of trials that could potentially be terminated early for efficacy reasons discuss these issues with FDA prior to implementing the trial, when the statistical monitoring plan and early stopping boundaries are being developed. In these settings, consultation with FDA may provide the sponsor with important information regarding the regulatory and scientific implications of a decision and may lead to better decisions.
This is prior to the trial. But then:
Sponsors are encouraged to revisit these issues with FDA when considering DMC recommendations for early termination if new issues have arisen and/or if the regulatory implications of early termination were not adequately clarified at the outset of the trial.
And in this case, that refers to the steering committee, not the Company. Thus, Linda Powers and management are and have been blinded to any and all of these discussions.
The PEI-FDA Connection
Now, we know that the FDA can be brought into these discussions between the DMC and steering committee for reasons as simple as "something new" occurring, unanticipated at the outset of the trial, or merely needing "clarification" on some point or other. It is likely the FDA has been unblinded to the data before now. Then consider (from fda.gov):
The United States Food and Drug Administration (USFDA), a part of the United States Department of Health and Human Services, is authorized under 21 C.F.R. § 20.89 ("Communications with Foreign Government Officials") to disclose non-public information to the Paul-Ehrlich-Institut (PEI) reporting to the German Federal Ministry of Health (BMG) regarding USFDA regulated products as part of cooperative law enforcement or cooperative regulatory activities.
The PEI understands that some of the information it receives from the USFDA may include non-public information exempt from public disclosure under the laws and, regulations of the United States of America, such as confidential commercial information; trade secret information; personal privacy information; law enforcement information; or internal, pre-decisional information. The PEI understands that this non- public information is shared in confidence, and that USFDA considers it critical that the PEI maintains the confidentiality of the information. Public disclosure of this information by the PEI could seriously jeopardize any further scientific and regulatory interactions between USFDA and the PEI. USFDA will advise the PEI of the non-public status of the information at the time that the information is shared.
It makes logical sense to deduce that the steering committee was presented with the dilemma, they in turn approached the FDA seeking "clarification" (from FDA guidelines), the FDA unblinded the PEI according to the obligations of their arrangement, the PEI approved the vacc., and we may be waiting on an outcome that could potentially prolong the lives of many more patients than halting now and risking the FDA finding problems with the maturity of the data (type I error) that would cause them to recommend another Ph III trial, or making the unethical choice of recommending it to continue when there aren't many stopping boundaries left to be crossed. Otherwise, why did the PEI not just wait until the DMC made their recommendation based on efficacy data (which is still "outstanding")? Or why not wait until the second interim look? Or tabulated results at the end of the year? Then they would have more to back their first-of-its-kind hospital exemption approval. Unless, of course, they already were unblinded to the data.
Trial Powering
The CEO expounded upon this Ph III trial's powering recently at an Immunotherapy conference (3/27/14). She stated:
One of the concerns investors express most often about biotech companies, and understandably so, is that they chronically underpower their trials. They chronically underestimate the size and power that they’ll need in their trial.
This 312 patient, placebo controlled double blind trial is powered to achieve a p-value (probability results are due to chance) of 0.02 (as mentioned, the FDA requires 0.05 or less). Thereby the likelihood the results will be deemed statistically significant are much increased.
It is also powered to achieve progression free survival of 6 months over SoC. That bar is set quite low when compared to their Ph I results of 18 months PFS over SoC. It is evident they are taking every measure possible to ensure success. It should be noted that even the bare minimum of 6 months PFS with a p-value of 0.05 would make this vaccine a blockbuster, revolutionizing how GBM is treated.
The primary endpoint is progression free survival (PFS), which has been accepted many times as the basis for approval from the FDA, and which has unique advantages relevant to this trial. Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics states:
3.Time to Progression and Progression-Free Survival
TTP and PFS have served as primary endpoints for drug approval. TTP is defined as the time from randomization until objective tumor progression; TTP does not include deaths. PFS is defined as the time from randomization until objective tumor progression or death. The precise definition of tumor progression is important and should be carefully detailed in the protocol.
a. TTP vs. PFS
Compared with TTP, PFS is the preferred regulatory endpoint. PFS includes deaths and thus can be a better correlate to overall survival. In TTP analysis, deaths are censored, either at the time of death or at an earlier vis it representing informative censoring (nonrandom pattern of loss from the study). PFS assumes patient deaths are randomly related to tumor progression. However, in situations where the majority of deaths are unrelated to cancer, TTP can be an acceptable endpoint.
b. PFS as an endpoint to support drug approval
Table 1 provides advantages and disadvantages of using PFS as an endpoint. PFS can reflect tumor growth and be assessed before the determination of a survival benefit. Its determination is not confounded by subsequent therapy. For a given sample size, the magnitude of effect on PFS can be larger than the effect on overall survival.
Likewise, their secondary endpoint, overall survival (OS) has certain disadvantages to it being used as a primary endpoint as it relates to this trial. These are enumerated as follows:
Advantages of PFS:
•Smaller sample size and shorter follow-up necessary compared with survival studies
•Measurement of stable disease included
•Not affected by crossover or subsequent therapies
•Generally based on objective and quantitative assessment
Disadvantages of OS:
•May involve larger studies
•May be affected by crossover therapy and sequential therapy
•Includes non-cancer deaths
It is important to note that this was all seen by and discussed with the FDA beforehand:
When possible, studies should be blinded. Blinding is particularly important when patient or investigator assessments are included as components of the progression endpoint. At a minimum, the assessments should be subjected to a blinded independent adjudication team, generally consisting of radiologists and clinicians. The FDA and the applicant should agree prospectively on the following items:
•The study design
•The definition of progression
•The data to be recorded on the case report form (CRF)
•The SAP
•The methodology for handling missing data and censoring methods
•The operating procedures of an independent endpoint review committee (IRC), if applicable
They further have written into the trial design the possibility to re-size it, to achieve even further powering. From one of the Company's powerpoints:
• 312 patient, randomized (2:1), double blind, placebo controlled Phase III trial: the “gold standard” in clinical trial design
– Primary endpoint: PFS (progression free survival)
– Secondary endpoints include OS (overall survival)
– 2 interim analyses for efficacy & 1 interim analysis for sample size
– 3 DCVax-L treatments upfront (Day 0, 10, 20), then 3 boosters (months 2, 4, 8) then 4 treatments twice/year for maintenance phase (months 12, 18, 24, 30)
This is of course done while management is completely blinded, and a decision to re-size the trial (in this case, most likely by enlarging it) cannot therefore be made on the basis of the Company having viewed any data, or knowing whether or not achieving the primary endpoint (6 months PFS) is in doubt. It is a sophisticated process, whereby statisticians use complex algorithms to preserve alpha and still discover whether or not certain variances or rates are beyond what was expected. It means only that the results are leaning away from what was expected. It does not infer that this is good or bad for the trial's outcome. It only makes the trial more efficient. However, it should be noted that enlarging the trial would de facto lower the necessary PFS required while still maintaining a 0.05 or less p-value. It could go from 6 months necessary, to 5, or even 4 months. Since the endgame (approval of treatment) of a trial is of the utmost importance, the Company should take every measure at its disposal to ensure it is successful. This would be one. Also, it should be noted that variance (one of the indicators used to determine sample re-sizing) is more likely to represent an increase in expected PFS and OS than a decrease, based on the very low bar set by the Company relative to what was seen in previous trial experiences (DCVax-L, DCVax-Prostate, and DCVax-Ovarian--all utilizing the same basic technology, and all showing consistent, efficacious results).
Another interesting mention from that power point is the following:
–Secondary endpoints include OS (overall survival)
Apparently there is more than one secondary endpoint. In addition to OS, these may include:
-Symptom Endpoints(patient-reported outcomes)
-Disease-Free Survival
-Objective Response Rate
-Complete Response
-Time to Progression (deaths before progression censored)
You can read about them in more detail in Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.
One final note on powering is the decision by management to drop the early progression group from the trial (however, enabling them to receive treatment in the crossover arm). Given that, statistically, this group is comprised of approximately 67% true early responders (who unfortunately will not survive very long), and 33% (or about 8% of the total population) psPD patients (who are genetically blessed to fight GBM), it empowers the trial further to sideline the entire group. The majority of this group will lower the PFS and OS of the trial. In this regard, the results of this Ph III trial could theoretically outperform their Ph I trial, as in the former trial they were all included.
DCVax Direct for Inoperable Tumors and ASCO
The abstract, which is not designated as a trial in progress (TIP), but rather a late breaking abstract (LBA), will be presented at ASCO on May 30, 2014. They likewise have reserved a significant amount of booth space (approx. 4,000 sq.ft.). It is evident they have much to say and are anticipating a very high level of foot traffic.
Unlike with most Ph I trials, the Company not only has a highly effective animal study to go on, but also a related pilot study conducted by Triozzi in which multiple patients with melanoma and breast carcinoma had their tumors injected with a similar DC (dendritic cell) vaccine. These ten individuals showed great response to treatment, not just in the directly injected tumor, but also in the localized vicinity of injection. The study can be found here:
http://www.ncbi.nlm.nih.gov/pubmed/11135227
DCVax Direct is an improvement over the vaccine used by Triozzi. It utilizes precisely matured DCs that are more capable of taking up tumor antigens and also better able to travel to the lymph nodes. This has also been applied to DCVax-L and Prostate as well (essentially DCVax-L made to focus on particulars of prostate cancer):
3/18/2013 PR NW Bio Receives U.S. Patent On Broad Processes For Producing More Potent Dendritic Cells
Next Generation Technology Already In DCVax®-Direct Will Be Applicable To All DCVax® Products
Going forward, NW Bio’s now patented methods of producing more potent dendritic cells will also enable development of the next generation of NW Bio’s other two product lines: DCVax-L and DCVax-Prostate. The current DCVax-L and DCVax-Prostate products have already delivered striking results in clinical trials to date, extending the time to tumor recurrence and the patients’ survival time by 1-1/2 to 2 years or more, with a substantial portion of patients going far beyond that. Incorporating NW Bio’s patented methods for more potent dendritic cells will enable production of enhanced versions of these DCVax-L and DCVax-Prostate products.
(DCVax-Prostate is awaiting partnership, and i therefore outside the scope of this paper, except to demonstrate the consistency of trial results using the same basic technology)
Since NWBO has improved upon the technology used by Triozzi, it is anticipated that the results will exceed Triozzi's in efficacy.
Most everything else about DCVax-Direct has been kept under wraps. Embargoed, specifically, and as per the plan set in motion when the Company envisaged the unveiling of results at ASCO. Given that the first patient was treated in the summer of 2013, and given the fact that possible efficacy can be measured in mere months, and given the fact that enrollment has been speedy according to the Company, and given the fact that they have incurred a large expense to reserve massive floor space at ASCO, it is expected by many that the results unveiled there will be groundbreaking.
Anecdotal Support for DCVax-Direct
It is evident the CEO is excited and in her words "Quite encouraged" by what she has seen first hand (given the trial is not blinded). There have been a number of mentions on cancer treatment boards and in other places online of patients giving testimonials (both for L and Direct), and in such a way as to appear quite genuine, stating their success story out of the apparent motivation to help others who have terminal disease. One such mention very recently was the following:
Ever since going to Orlando Health I feel much better. My tumor in colon has begun to shrink in size and is no longer attached to abdominal wall. It is also beginning to move away from my bladder. The thickness of tumor in colon has also been reduced. Colon surgery will now be successful and it looks like I may be able to keep most of my urinary bladder and not have to worry about cancer in bladder reoccurring.
It certainly sounds genuine, and makes sense from a medical perspective. It also sounds a bit like something someone who was treated and told what had occurred would say without having a medical background. Although this is not a documented result from a regulated clinical trial, and should not be given the same weight, it is a possible validation. And it seems logical that patients being treated and seeing their tumors dissolve to the point where surgery becomes possible (life saving) would come online to share their testimony.
Ramping Up
Northwest Biotherapeutics has been aggressively pursuing manufacturing capacity in the US and in Europe. They are very close to meeting their goal of full capacity. This effort has been aided (one might say, "subsidized") by Germany and the UK:
In Europe, as part of our partnering arrangements, the Fraunhofer Institute in Germany and Kings College in the U.K. have dedicated their own “cGMP” (clean room) state-of-the-art manufacturing facilities to our programs. We thereby obtained these manufacturing facilities without capital cost to us, and without the 18-month or more lead time usually required to develop the facilities.
That alone provides quite the validation for their DCVax platform. The Company continues:
In addition, Fraunhofer, Cognate, we and Kings College began the 7-month processes for regulatory approvals and institutional approvals in both the U.K. and Germany to enable the manufacturing in Germany to supply DCVax-L for the clinical trial in the U.K. as well. This German supply arrangement is in addition to the manufacturing under development in the U.K.
In addition, our partner, Fraunhofer IZI Institute in Germany, has received approval and certification from the regional and national regulatory agencies in Germany for the manufacture of DCVax for GBM. We anticipate that the manufacturing facilities in the U.K. will eventually obtain the necessary approvals, and that the German and U.K. facilities’ will be able to supply DCVax products for anywhere in Europe.
An update (as of 4/11/12) regarding the current state of trial affairs from the Company ran as follows:
As of February 28, 2014, our Phase III clinical trial of DCVax-L in GBM is being conducted at approximately 50 sites across the United States and at one site in the United Kingdom. We are also in the process of adding further U.S. sites and up to 30 European sites. We have accelerated and strengthened our programs in Europe by partnering with large, prominent institutions, including the Fraunhofer IZI Institute in Germany and King’s College Hospital in the U.K.
In the U.K., we previously received approval from the Medicines and Healthcare Products Regulatory Authority, or MHRA, to proceed with our Phase III clinical trial of DCVax-L for GBM, which we initiated in May 2013. The lead site is Kings College Hospital in London. Half a dozen other major medical centers in the U.K. are preparing to proceed with the trial. In April 2013, we announced that the National Institute of Health Research, or NIHR (a branch of the National Health System) in the U.K. had completed a multi-stage evaluation of our DCVax-L technology and our Phase III clinical trial of DCVax-L for GBM, and the NIHR had “adopted” our trial as a nationwide priority trial in the U.K.
We have also been working on preparations for the clinical trial in Germany. On July 25, 2012, we announced that manufacturing certification has been received from the German regulatory authorities for the clinical trial in Germany, which is the first step towards implementation of the Phase III trial in Germany. We submitted the application to the German regulatory authority (the Paul Ehrlich Institute, or PEI) for approval of the Phase III trial, which we received on September 16, 2013. As of February 28, 2014, an initial dozen clinical centers are in varying stages of preparations as trial sites in Germany, with further sites to follow.
A matter of clarification on what they mean by implementing the Ph III trial in Germany (wasn't it already approved there via Hospital Exemption?). It is actually akin to what is called a "confirmatory" or Ph IV trial here in the US. The vaccine will receive full reimbursement from the German Central Reimbursement Authority, however they cannot market the product (much like in the US) until the "confirmatory trial" phase has past. As DocLogic and Larry Smith have collaboratively expressed, the differences in regulations of the FDA and PEI run as follows:
FDA: 30 day review of safety. Trial can begin after 30 days without FDA response.
PEI: Precise wording for all trial procedures and inclusions/exclusions defined and approved. Entire commercial production process and facilities must be put in place, fully functioning and approved. Total time required for reviews and approvals is 2 years or more. Newer technologies generally take longer. Once approval is granted then individual hospitals can petition to be included and reimbursed by the hospital funds or private insurance. Approval for reimbursement is rare and depends much on early evidence of benefit. If not approved, cost is born entirely by trial sponsor. This request is approvable for 1-5 years (NWBO was given 5 years and is reconsidered for renewal after this). Clinical trials can begin immediately after approval but generally hospitals will wait for a reimbursement decision and or hospital exemption if applicable.
Hospital exemption allows for changes to some clinical trial protocols and allows use of the treatment on an open basis with restrictions placed on advertising and sometimes other aspects of use. With DCVax-L, the use was expanded to all gliomas in both newly diagnosed and recurrent patients. This expansion decision is essentially like the ignition of rocket motors before launch. Increasing the manufacturing capacity is like powering up the engines to full throttle before launch.
Product approval process:
PEI: Gathers all data from trials with or without hospital exemption status or reimbursement to be assessed for final approval or termination for lack of efficacy or safety concerns not previously noted.
FDA: Phase l safety and tolerability generally no basis for approval.
Phase ll open label (generally non approvable) or double blind (approvable) study. Safety and efficacy.
Phase lll, if needed, for efficacy and possible approval for registration. Final approval requires approved commercial manufacturing site or sites and agreed upon labeling for use.
Conclusions
FDA: Front end of trial takes less time to start and lower costs allowing more small innovative companies to participate in the process. Back end costs increase which can jeopardize the process or be seen as commercial vetting of potential and waiting for long term results can delay time to general use in patient populations with limited options.
PEI: Up front costs high and time to start delayed. Back end potential for quicker product reimbursement or sale and hospital exemption that gets product into general use more quickly. Products demonstrating good initial safety and potential for efficacy are more likely to benefit for the sake of those patients who want to try it and have limited options for treatment. This process offers patients treatments that have been fairly well vetted for safety and potential efficacy while the PEI continues to gather data to make a final determination for full commercialization approval or termination due to lack of efficacy or whatever safety concerns might be revealed in a larger patient population.
Marketability
The potential in DCVax-L and DCVax-Direct is difficult to quantify. With such open ended applications using label extension for L to treat "all solid tumor cancers," and the very broad classification of "all inoperable tumors" for Direct, it is easy to see how the numbers can run wild. The defining feature behind these two front line treatments, however, lies in their exclusivity. There is no treatment for inoperable tumors. They are given palliative care, and sent home (or to hospice) to die. GBM patients, in short order, likewise. These are concrete realities, and a potential future valuation of NWBO can be tabulated based on them. It is the further potential in treating "all gliomas," as the PEI has approved, the inclusion of all worldwide regulatory bodies (Japan, Aus, NZ, China, India, Russia, etc.) and the use of label extension for L, that requires a daunting and highly speculative task. Here are some conservative estimations, going low in particular on the potential treatment costs, that are as yet to be enumerated (although around $40,000 per patient per year has been mentioned):
-DCVax-L used to treat GBM worldwide, new and existing cases, with 80% penetration in all major markets (excluding 90% of cases in Asia, Africa, Central and South America, which account for 60% of the world's cancer rates, but unfortunately have depressed economies), but not considering any lesser gliomas, estimated at an average of $30,000-$50,000 per patient per year ==> $4.8B - $8B in sales
-DCVax-L used to treat all lesser gliomas (stages I-III), new and existing, on a case by case basis, 80% market penetration worldwide (with the same exclusions as above), estimated at an average of $15,000 per patient per year ==> $6B in sales
-DCVax-L used by label extension to treat all operable, late stage cancers worldwide (with the same exclusions as above) with 20% penetration and $30,000 per patient per year ==> $8B+ in sales
-DCVax-Direct used to treat all inoperable tumors worldwide (with the same exclusions as above), with 80% penetration and $15,000 per patient per year ==> $36B+ in sales
Based on these figures, the immense potential and long awaited realization of the dendritic cell vaccine platform, multiple validations in Europe (especially Hospital Exemption Approval in Germany) and the United States centers of excellence, the evidence that a halt for efficacy is currently in talks, and latent pressure building in the mega-blockbuster potential magnitude of DCVax Direct--an immediate price target of $24.00 (rounded up) appears highly reasonable, even in pre-approval (US and EU) status.
Should results at ASCO appear as groundbreaking as they are hinted at being, showing marked reduction in tumor size, making inoperable malignant masses suddenly operable, thus saving the lives of potentially millions (yes, millions), then even with the status of their Ph III DCVax-L trial pending, a price target of $53.00 (rounded up) would then appear reasonable.
Should DCVax-Direct results prove stellar, and DCVax-L results meet their primary endpoint (or be halted for efficacy), then a price target of $287.00 (rounded up) appears reasonable.
There has been a misunderstanding regarding the potential and current state of affairs regarding NWBO. Due in part to the amount of misinformation currently circulating, and to attaching too much significance to the failings of other dendritic cell vaccines that use an inferior technology. It is my hope that this paper proved useful in clearing up much of that.
*My sincere thanks to DocLogic and Larry Smith for their direct and indirect contributions to this article.
Recent NWBO News
- Biophma Announces Exclusive In License for Dendritic Cell Technology, Sending Shares Higher • AllPennyStocks.com • 06/17/2024 04:40:00 PM
- Form 8-K - Current report • Edgar (US Regulatory) • 06/04/2024 09:11:16 PM
- Form DEF 14A - Other definitive proxy statements • Edgar (US Regulatory) • 06/03/2024 09:22:55 PM
- Form PRE 14A - Other preliminary proxy statements • Edgar (US Regulatory) • 05/22/2024 08:13:36 PM
- Form 10-Q - Quarterly report [Sections 13 or 15(d)] • Edgar (US Regulatory) • 05/10/2024 09:04:57 PM
- Form NT 10-K - Notification of inability to timely file Form 10-K 405, 10-K, 10-KSB 405, 10-KSB, 10-KT, or 10-KT405 • Edgar (US Regulatory) • 03/01/2024 10:04:38 PM
- Form 4 - Statement of changes in beneficial ownership of securities • Edgar (US Regulatory) • 12/02/2023 01:31:35 AM
- Form 8-K - Current report • Edgar (US Regulatory) • 11/16/2023 10:11:54 PM
- Epazz, Inc. (OTC Pink: EPAZ) ZenaDrone Demonstration to Defense Departments of UAE and Saudi Arabia • InvestorsHub NewsWire • 11/15/2023 12:19:31 PM
- Form 10-Q - Quarterly report [Sections 13 or 15(d)] • Edgar (US Regulatory) • 11/09/2023 09:30:39 PM
- Epazz, Inc. (OTC Pink: EPAZ) US Navy Collaboration ZenaDrone 1000 • InvestorsHub NewsWire • 11/09/2023 01:00:34 PM
- Epazz, Inc. (OTC Pink: EPAZ) US Navy Collaboration ZenaDrone 1000 Extreme Weather Demo • InvestorsHub NewsWire • 11/07/2023 12:29:43 PM
- Form 10-Q - Quarterly report [Sections 13 or 15(d)] • Edgar (US Regulatory) • 08/09/2023 08:36:14 PM
Last Shot Hydration Drink Announced as Official Sponsor of Red River Athletic Conference • EQLB • Jun 20, 2024 2:38 PM
ATWEC Announces Major Acquisition and Lays Out Strategic Growth Plans • ATWT • Jun 20, 2024 7:09 AM
North Bay Resources Announces Composite Assays of 0.53 and 0.44 Troy Ounces per Ton Gold in Trenches B + C at Fran Gold, British Columbia • NBRI • Jun 18, 2024 9:18 AM
VAYK Assembling New Management Team for $64 Billion Domestic Market • VAYK • Jun 18, 2024 9:00 AM
Fifty 1 Labs, Inc Announces Acquisition of Drago Knives, LLC • CAFI • Jun 18, 2024 8:45 AM
Hydromer Announces Attainment of ISO 13485 Certification • HYDI • Jun 17, 2024 9:22 AM
Start posting your company's news
Only $200 per official company press release!
