DEDUCED RECKONING: Northwest Biotherapeutics is finally ready for prime time [医药生物投资]

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Again mini-gap up in price before Topline data is announced:

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Now it looks more like a wrestling, up and pulling down, and up and pulling down absent of new positive news, let alone Topline data announcement. Nonetheless the trend is definitely still in favor of continued share price appreciation.

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Most likely share price will gap up again today, helped at least partly by this article:

Promising New Cancer Treatments Advancing Through The Pipeline In Over $200 Billion Dollar Drug Market
Financialnewsmedia.com News Commentary


News provided by
Financialnewsmedia.com
Oct 21, 2020, 08:30 ET

PALM BEACH, Fla., Oct. 21, 2020 /PRNewswire/ -- Cancer immunotherapy has emerged as a new avenue for revenue generation for pharmaceutical companies. Adverse effects, such as recurrence of cancer and organ failure, associated with conventional chemotherapies and rising demand for technologically advanced healthcare solutions are boosting the demand for immunotherapies. Moreover, introduction of newer drug classes, such as target receptors for multiple myeloma and checkpoint inhibitors, is poised to make way for advanced therapeutics in the market. Monoclonal antibodies are the most widely used immunotherapeutic drugs globally. Development of monoclonal antibodies as effective immunotherapeutic options are resulting in discovery of new therapeutic options for cancer treatment. A recent industry report from MarketsAndMarkets projected that the global immunotherapy drugs market is projected to reach USD 274.6 billion by 2025 from USD 163.0 billion in 2020, at a CAGR of 11.0 % during the forecast period. The growth of this market is majorly attributed to the rising prevalence of target diseases, increasing demand for monoclonal antibodies and biosimilars, increasing adoption of immunotherapy drugs over conventional treatments, and a favorable approval scenario. However, timeline issues, side-effects, and manufacturing complexities and a high attrition rate in the product development cycle are expected to challenge market growth. Active biotech and pharma companies in the markets this week include Actinium Pharmaceuticals, Inc. (NYSE: ATNM), AstraZeneca PLC (NASDAQ: AZN), Bristol Myers Squibb (NYSE: BMY), Northwest Biotherapeutics (OTCQB: NWBO), Merck (NYSE: MRK).
The report said that: "Based on type, the immunotherapy drugs market is segmented into monoclonal antibodies, checkpoint inhibitors, interferons & interleukins, and other immunotherapies. The monoclonal antibodies segment accounted for the largest share of the global immunotherapy drugs market in 2019. This large share can be attributed to their high specificity and fewer side-effects, increasing focus on personalized medicines, initiatives by industry players, and the rising target disease incidence and patient pool… On the basis of therapeutic area, this market is segmented into cancer, autoimmune & inflammatory diseases, infectious diseases, and other therapeutic areas. Cancer accounted for the largest share of the global immunotherapy drugs market, by therapeutic area, in 2019. The large share of this segment can be attributed to the growing prevalence of cancer, rising research activity in this area, and reimbursement coverage for immunotherapies for oncology."
Actinium Pharmaceuticals, Inc. (NYSE American: ATNM) BREAKING NEWS: Actinium Pharmaceuticals, Inc. Awarded Grant by National Institutes of Health to Study Novel Iomab-ACT Targeted Conditioning with a CD19 CAR T-Cell Therapy - Actinium Pharmaceuticals, Inc. ("Actinium" or the "Company") today announced that the National Institutes of Health has awarded Actinium a Small Business Technology Transfer grant to support a clinical collaboration with Memorial Sloan Kettering Cancer Center ("MSK") to study Iomab-ACT, Actinium's CD45-targeting Antibody Radio-Conjugate, for targeted conditioning to achieve lymphodepletion prior to administration of a CD19-targeted CAR T-cell therapy developed at MSK. The CD19 CAR-T has been previously studied by MSK in a Phase 2 trial with chemotherapy conditioning in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) or diffuse large B-cell lymphoma (DLBCL). MSK will lead this first of its kind study to utilize targeted radiopharmaceutical ARC-based lymphodepletion to replace chemotherapy-based conditioning prior to CAR T-cell therapy. The study will assess the feasibility of using Iomab-ACT targeted lymphodepletion prior to MSK's 19-28z CAR-T and assess safety and efficacy outcomes relative to results with MSK's CAR-T 19-28z in patients who had received chemotherapy-based lymphodepletion prior to CAR-T administration.
Results published in the New England Journal of Medicine with MSK's 19-28z CD19 CAR-T in 53 patients with R/R B-ALL reported complete remissions in 83% (44/53) of patients. Median event-free survival (EFS) was 6.1 months and median overall survival (OS) was 12.9 months at a median follow up period of 29 months (range 1 – 65 months) for all patients. Patients with low disease burden, defined as less than 5% blasts in the bone marrow, had markedly enhanced outcomes with increased median EFS of 10.6 months and median OS of 20.1 months. There was a 26% (14/53) rate of Grade 3 of greater cytokine release syndrome (CRS), with 1 patient death as a result, and 42% of patients experienced Grade 3-4 immune effector cell-associated neurotoxicity syndrome (ICANS). In addition to improved duration of response and survival, patients with low disease burden prior to receiving CAR T-cell therapy had lower rates of CRS and neurotoxicity.
"We are excited to be collaborating with MSK on this trial as they are a leader in the field of cellular therapies. We selected MSK's 19-28z CAR T-cell therapy for this NIH grant funded collaboration because it has produced high response rates in patients with relapsed or refractory B-ALL who have previously undergone several lines of standard therapy. However, toxicities such as cytokine release syndrome and neurologic toxicity, as well as durability of response, remain a challenge as is the case with many other CAR T-cell therapies" commented Dr. Mark Berger, Actinium's Chief Medical Officer. "Iomab-ACT enables the delivery of targeted radiation that selectively and specifically targets immune cells, including those implicated in the CAR-T-associated toxicities of cytokine release syndrome and neurotoxicity. We are hopeful that this study will demonstrate improvements in safety and outcomes with MSK's CAR 19-28z as a result of Iomab-ACT targeted lymphodepletion and that this will allow clinicians to make important improvements in patients' ability to receive CAR T-cell therapies."
CAR-T is a type of cellular therapy in which a patient's own (autologous) T-cells are genetically engineered outside of the body to target the patient's cancer cells and which are then reinfused back into the patient to seek out and kill cancer cells. Currently there are 2 approved CD19 targeted CAR-T therapies, which both require chemotherapy-based conditioning to deplete the patient's lymphocytes, known as lymphodepletion, and many other CAR-T constructs in development that also use chemotherapy conditioning for lymphodepletion.
Iomab-ACT targets cells that express CD45, an antigen found on immune cells such as lymphocytes and macrophages as well as leukemia and lymphoma cancer cells and delivers the radioisotope warhead iodine-131 to achieve cell depletion. Iomab-ACT is intended to deplete CD45+ immune cells such as macrophages that are implicated in CAR-T related toxicities and may also have an anti-tumor effect on chemo-refractory cancers. Iomab-ACT is a low dose extension of Actinium's lead program, Iomab-B, which is being studied in a pivotal Phase 3 trial for targeted conditioning prior to a bone marrow transplant. Preclinical data supporting Iomab-ACT's application in targeted lymphodepletion prior to ACT such as CAR-T was recently published in the journal Oncotarget (Volume 11, Issue 39 | Oncotarget). In addition, clinical data with trace doses of Iomab-B has shown transient, reversible lymphodepletion in patients and drug clearance pharmacokinetics that fit within the vein to vein time of CAR-T manufacturing and administration.
Sandesh Seth, Actinium's Chairman and CEO, said, "This clinical trial collaboration with MSK is a strong step forward for Actinium and our targeted conditioning program. The 19-28z CAR-T has already produced promising data and we look forward to working with MSK to explore Iomab-ACT's potential to reduce toxicities and improve patient outcomes. As we advance towards the SIERRA interim analysis in the fourth quarter, we are focused on the continued expansion of our ARC-based targeted conditioning program for bone marrow transplant and cell and gene therapies with the goal of providing targeted conditioning regimens that are less toxic and more effective than current chemotherapy-based conditioning. With these therapies being administered in a select number of concentrated centers, we see a large and growing market opportunity where our ARC-based targeted conditioning can improve outcomes and increase access to these important curative treatment options." Read this full release and more news for ATNM at: Financial News Media | ATNM News

Other recent developments in the biotech industry include:

AstraZeneca PLC (NASDAQ: AZN) AstraZeneca's TAGRISSO® (osimertinib) recently announced it has received acceptance for its supplemental New Drug Application (sNDA) and has also been granted Priority Review in the US for the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumor resection with curative intent.
While up to 30% of all patients with NSCLC may be diagnosed early enough to have potentially curative surgery, disease recurrence is still common in early-stage disease and nearly half of patients diagnosed in Stage IB, and over three quarters of patients diagnosed in Stage IIIA, experience recurrence within five years.
Bristol Myers Squibb (NYSE:BMY) recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of Opdivo (nivolumab) for the treatment of adults with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based combination chemotherapy. The European Commission (EC), which is authorized to approve medicines for the European Union (EU), will now review the CHMP recommendation.
"This positive CHMP opinion underscores the potential of Opdivo in the EU treatment landscape for esophageal squamous cell carcinoma, with the ATTRACTION-3 trial showing clinically meaningful survival coupled with a favorable safety profile," said Ian M. Waxman, M.D., development lead, gastrointestinal cancers, Bristol Myers Squibb. "We look forward to the EC's final decision, which could mark the first time an immunotherapy is approved for any upper gastrointestinal cancer in the EU. We remain committed to continuing to explore the potential benefits of Opdivo in earlier settings of esophageal cancer."
Merck (NYSE: MRK), known as MSD outside the United States and Canada, recently announced findings from two additional Phase 3 studies evaluating the safety, tolerability and immunogenicity of V114, the company's investigational 15-valent pneumococcal conjugate vaccine. In the PNEU-PATH (V114-016) study, healthy adults 50 years of age or older received V114 or PCV13 followed by PNEUMOVAX® 23 one year later. Immune responses following vaccination with PNEUMOVAX 23 (month 13) were comparable in both vaccination groups for the 15 serotypes in V114. Results also showed that at 30 days post vaccination with either V114 or PCV13 (day 30), immune responses were comparable for both groups across the 13 serotypes shared by the conjugate vaccines and higher in the V114 group for serotypes 22F and 33F, the two serotypes not included in PCV13. In PNEU-DAY (V114-017), a Phase 3 study in immunocompetent adults 18 to 49 years of age with underlying medical conditions associated with increased risk for pneumococcal disease, V114 generated immune responses generally comparable to PCV13 for the 13 shared serotypes and higher immune responses for serotypes 22F and 33F at 30 days post-vaccination. Results from both studies are based on opsonophagocytic activity (OPA) responses – a measure of vaccine-induced functional antibodies. V114 was generally well tolerated in both studies, with a safety profile consistent with that observed for V114 in previously reported studies.
Northwest Biotherapeutics (OTCQB: NWBO), a biotechnology company developing DCVax®personalized immune therapies for solid tumor cancers, recently announced that the database for the Phase III trial of DCVax®-L for Gliobastoma has been locked. With the database now locked, the independent service firms managing the Clinical Trial are arranging for the independent statisticians to have access to the unblinded raw data from the Trial. Neither the Company nor any party other than the independent statisticians will have access to any unblinded data at this stage.
The statisticians will proceed as quickly as possible with analyses of the raw data and prepare summaries of the Trial results for review by the Company, the Principal Investigator, the Steering Committee of the Trial, the Scientific Advisory Board, and a panel of independent brain cancer experts, who will analyze the data with the statisticians in preparation for public announcement and scientific publication.
DISCLAIMER: FN Media Group LLC (FNM), which owns and operates FinancialNewsMedia.com and MarketNewsUpdates.com, is a third party publisher and news dissemination service provider, which disseminates electronic information through multiple online media channels. FNM is NOT affiliated in any manner with any company mentioned herein. FNM and its affiliated companies are a news dissemination solutions provider and are NOT a registered broker/dealer/analyst/adviser, holds no investment licenses and may NOT sell, offer to sell or offer to buy any security. FNM's market updates, news alerts and corporate profiles are NOT a solicitation or recommendation to buy, sell or hold securities. The material in this release is intended to be strictly informational and is NEVER to be construed or interpreted as research material. All readers are strongly urged to perform research and due diligence on their own and consult a licensed financial professional before considering any level of investing in stocks. All material included herein is republished content and details which were previously disseminated by the companies mentioned in this release. FNM is not liable for any investment decisions by its readers or subscribers. Investors are cautioned that they may lose all or a portion of their investment when investing in stocks. For current services performed FNM has been compensated forty five hundred dollars for news coverage of the current press releases issued by Actinium Pharmaceuticals, Inc. by a non-affiliated third party. FNM HOLDS NO SHARES OF ANY COMPANY NAMED IN THIS RELEASE.

This release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E the Securities Exchange Act of 1934, as amended and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. "Forward-looking statements" describe future expectations, plans, results, or strategies and are generally preceded by words such as "may", "future", "plan" or "planned", "will" or "should", "expected," "anticipates", "draft", "eventually" or "projected". You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events, or results to differ materially from those projected in the forward-looking statements, including the risks that actual results may differ materially from those projected in the forward-looking statements as a result of various factors, and other risks identified in a company's annual report on Form 10-K or 10-KSB and other filings made by such company with the Securities and Exchange Commission. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this release are made as of the date hereof and FNM undertakes no obligation to update such statements.

Contact Information:
Media Contact email: editor@financialnewsmedia.com - +1(561)325-8757
SOURCE Financialnewsmedia.com
 

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Rising to fast, or a few steps forward, one step back? Plus a few million shares added to the float today, probably from warrant exercising and selling.

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For those who are not familiar with the now at least partially confirmed endpoint changes of DCVax-L trial and FDA's new guidelines and their implications, a post in ihub by sentiment-stocks explains them beautifully:




sentiment_stocks
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Re: sentiment_stocks post# 237034
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Post # of 322028


This is a post examining the new DCVax-L endpoints, likely alpha allocation, and the consideration of historical controls (same as external controls) new FDA Biological Products Guideline. The post that I’m replying to is one where I’d listed multiple pathways for DCVax-L to be successful and to get to market, and I think those may now be obsolete.

With the change in the endpoints listed on the EU GB site (https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-001977-13/GB), we can now see the changes that were made to the DCVax-L trial that were set forth by the phone book-sized SAP that took about a year to write. And those endpoint changes establish new pathways forward that make most of the possible pathways I’d presented in this earlier post of mine basically irrelevant now.

So let’s look at these new DCVAx-L endpoints, and what they might mean when we receive our long-awaited top line PR, and how they might predict regulatory approval to a filed BLA (Biological License Application).

As many of us know, the previous PFS primary endpoint was to be measured applying an alpha of .02. This linked PR indicated this to be the case (NW Bio Obtains Approvals For Enhancements Of Phase III Trial of DCVax®-L For GBM Brain Cancer - Northwest Biotherapeutics). Typically, most trials will use .05 alpha, and so it was my thought that the company had split the alpha allocating .02 to PFS and .03 to OS. It’s very possible the company went with the low .02 because if PFS been proven efficacious on that low .02 alpha, the FDA would have likely granted them AA (accelerated approval), and OS would have been the confirmatory trial to prove the AA was fairly granted.

Under the old protocol, had PFS been stat sig, the .02 would have then carried over to OS and OS would have been measured with the full alpha of .05. This concept of carrying over the alpha comes from the 2013 protocol for the trial which indicated that the endpoints were to be measured within the context of what’s known as a “Closed Testing Procedure”.

From 2013 and 2014 DCVax-L protocols:
Quote:The primary, and secondary, and tertiary
endpoints efficacy endpoints will be reviewed. They should be considered
within the context of a closed testing procedure, and in the order of the
stated efficacy hypotheses, specifically the primary endpoint
(progression-free survival) first, followed by the secondary endpoint
(all-cause mortality) followed by the tertiary endpoint.).

Defining Closed Testing Procedure
This concept means that each endpoint is evaluated in the order they are stated, followed by the next endpoint, and so on. So if the first endpoint in a trial fails (under a closed testing procedure), and that endpoint had all the assigned alpha allocated first to it, then there would be no more alpha left to measure the next in line endpoint. In fact, this is exactly what happened to Dendreon in that 2007 BLA filing. Their primary of PFS failed (for whatever reason - psPD?) while the secondary OS was showing promise and I believe was indicating a few to several months difference in OS between arms. But there was no alpha left to measure that OS endpoint. I believe that is what that now infamous 2007 DNDN AdCom was set to argue… that in spite of the fact that there was no more alpha to measure OS, that DNDN’s Provenge should still be given marketing approval. And in that 2007 instance, the company lost that battle.

Now to be clear, so some people here don’t think I sound super smart with all this use of acronyms and alpha allocations, I wouldn’t know how to apply the alpha to the statistical formula, even if it could save my life (well, maybe then I could figure it out, lol). However… I do understand the concept of how alpha is applied.

So what exactly is alpha? In fancy words, alpha represents the probability of rejecting the null hypothesis (the opposite of the hypothesis) when it is true. Therefore, if a hypothesis looks to be supported by the data, and one used and alpha of .05 to determine the efficacy, that would mean that there is a 5% chance there is no difference between the data, and a 95% chance that the data indicates that there is a difference.

So what does the recently discovered change to the endpoints mean for the DCVax trial?

First, instead of measuring the previous primary endpoint of PFS at an alpha of .02, the trial will measure OS in the first position… but what is the alpha to be applied?

My thinking, and a logical assumption is, that the alpha will equal.05. So what does that extra .03 difference between the possible new .05 and previous .02 mean? If I’m correct and this is the case, it means that there is more power to successfully prove the trial’s hypothesis. The company likely had originally chosen an alpha of .02 to measure the primary endpoint (PFS at the time) for two reasons: first) to save .03 for OS in case PFS failed; and two) because the thought was likely that by using such a low alpha - .02 - and still achieving a stat sig PFS endpoint (which they thought they could do - had pseudo progression caused by DCVax not entered the picture), then the FDA granting accelerated approval (AA) would have been very likely.

Now let’s take this discussion of alpha further and apply it as it would likely be applied to the newly discovered endpoints for this trial. The primary endpoint is:

Quote:The primary objective of this study is to compare overall survival (OS) between patients randomized to DCVax-L and control patients from comparable, contemporaneous trials who received standard of care therapy only, in patients with newly diagnosed glioblastoma. This endpoint will be assessed using 3 different analyses

As stated, it’s logical to think that they’ve applied the full .05 to the primary as I can’t see any reason to just use half of it - like .02 or .03, especially given that they’ve picked an easy, IMO, to achieve endpoint so better to use the whole .05.

It’s also important to note that it’s the DCVax-L treatment arm which will be measured against the control arms of the three historical trials. I stress this because in the past, some stat people here have compared the blended trial data to the treatment arms of other GBM trials to see how DCVax compared - like to like. Some have hypothesized what the treatment arm data for DCVax-L might look like, but these comparisons were hypothetical, and not based on any actual data.

So it’s difficult to see where the DCVax-L treatment arm doesn’t compare extremely well against other comparable GBM trial control arms. To that point, the UCLA Phase 1 trial in newly diagnosed GBM using DCVax had a mOS of 35 months. The current DCVax-L trial’s protocol had assumed a mOS of at least 25.3 (from randomization, so about 3 months from surgery) therefore, that’s about a 28.3 mOS from surgery.

By the way, I’m only using the mOS measurement of survival as it’s an easier metric to discuss comparisons. I’m not suggesting that this trial will use mOS as the final measurement of efficacy, as medians are not what the trial measures.

Moving on, if this trial is still using the same “closed testing procedure” that the trial used in the earlier protocol, then should the primary end point be stat sig, then the full alpha (I’m suggesting .05) carries down to the following end point - the secondary endpoint:

Quote:The first secondary objective is to compare overall survival (OS) between patients randomized to placebo who received DCVax-L treatment following disease recurrence and control patients from comparable, contemporaneous clinical trials, in patients with recurrent GBM.


Frankly, the company can project that this endpoint has a strong likelihood to be proven stat sig simply by looking at the blended data. I’m not going to go into great detail on that point at this time because I don’t want to wade into the weeds on that for now.

But I’d like to again point out a few things.

With the former endpoints, had PFS been stat sig using an established alpha of .02, it was my theory that this alpha (under the rules of the “closed testing procedure”) would have then passed on to measure OS. The alpha of .02 that had measured PFS would have been added to the missing .03 alpha to equal .05 to measure OS. The problem, as I saw it, was that if PFS had not been stat sig, then OS would have only had .03 left to measure the secondary endpoint. This concept is somewhat detailed in the post that I’ve responded to (which has been up in the yellow sticky section for some time now).

The beauty of this endpoint change is that this secondary endpoint will now, likely (remember, I am guessing here, but this seems logical, to me anyway), be able to access the full .05 alpha to measure this recurrent GBM OS endpoint. This endpoint is really similar to the earlier secondary endpoint from the original trial, EXCEPT, that the control arm will be historical arms, and not the control arm for this trial. And my bigger point is that this endpoint will likely be measured by the full .05 alpha.

I love that part.

Now, should this secondary endpoint be stat sig (which is likely), then the full alpha of .05, theoretically, would move down to the endpoint that follows:

Quote:The second secondary endpoint, confirmed progression-free survival (cPFS), is confirmed disease progression (cPD) compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.


This endpoint is very much like the original primary endpoint, except that now, all of the patients have had their progression adjudicated by a team of radiology experts that have (it’s already done) closely determined, on a blinded basis, when the patient actually progressed, and this endpoint will use that date. That’s why they’re calling it “confirmed progression-free survival”. This endpoint is hoping to remove the pseudo-progression problem, and to look at the real progression events for the trial patients.

Now… this may likely be very clear to some, and may be becoming clear now to others, this particular endpoint would now also be measured, not with that puny .02 alpha, but with the full .05 alpha. And to note, this is the alpha almost every trial uses to measure their endpoints.

And if this third in the line up of endpoints is also stat sig… and to my thinking, it would now have been measured using the additional .03 alpha to help ensure a better outcome - and that was not going to be used previously. So again, if I’m correct, then full .05 alpha would then move on to the next endpoint… and please note that this endpoint represents the original (let us call it the problem primary endpoint) primary endpoint measuring the trial’s actual arms from the previous trial protocol.

Quote:The third secondary endpoint, PFS, is progression-free survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.


And to drive home the point I’m trying to make here, if I’m correct, then instead of measuring the old primary with the originally intended .02 alpha, the old primary endpoint of PFS will now be measured with the full .05 alpha. See how that works?

Now I really love that part.

And finally, if this new endpoint (which was the former primary endpoint) is stat sig, and it would now also be measured using the full .05 alpha (and not the .03 I believe would have been used). In other words, the original OS endpoint will have now have more alpha to measure it now. then the full .05 alpha moves on to the next endpoint… which is exactly the former secondary endpoint of OS - comparing the actual arms in the trial. More alpha means it’ll be much easier to reach a stat sig reading.

Quote:The fourth secondary objective, OS, is overall survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.

Then there’s the final endpoint, the 5th secondary endpoint, which, under my theory, would be also be measured with the full .05 alpha if the 4th secondary endpoint of OS just discussed is stat sig.

Quote:The fifth secondary objective is tumor response compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.

To wrap up on the topic of these new endpoints, alpha, and closed testing procedures, I’d think most of us realize that these new endpoints are much more achievable, which takes away a great deal of risk from the trial. The former endpoints were a much greater hurtle to achieve a stat sig reading, meaning that on a fail, the company may have had a bigger mountain to climb to convince the regulatory agencies to approve DCVax-L.

That mountain has been trimmed down, IMO, more to like a little mole hill now.

Of course, this is all again, my own opinion. I haven’t seen the latest protocol… I doubt anyone outside has… and the only reason I had the others is that they were… conveniently (to the naysayers)… publicly leaked. So I don’t know that the alpha now being used to measure the primary is .05.

Now I’d like to make a quick examination at the recent December 2019 guidance that points to why these changes to the endpoints are likely to be acceptable to the FDA.

The guidance is entitled, “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products Guidance for Industry.”
https://www.fda.gov/media/133660/download

I’d like to do this because I know that there have been some naysayers, especially on Twitter, that seem to think that using a historical comparison in this trial will never work.

Let’s look first look at the FDA’s recent guidance pertaining to the concept of using “historical comparisons” in a trial that one hopes to use in order to obtain a marketing approval for a treatment.

The new guidance first addresses the risk versus benefit used in making an approval determination.
beginning at line 86:

Quote:The finding of substantial evidence of effectiveness is necessary but not sufficient for FDA approval. The approval decision also requires a determination that the drug is safe for the intended use. As all drugs have adverse effects, evaluating whether a drug is “safe” involves weighing whether the benefits of the drug outweigh its risks under the conditions of use defined in labeling.Uncertainties regarding benefits and risks are considered when making an approval determination; a drug with greater risks may require a greater magnitude and certainty of benefit to support approval.


We can pretty much count on DCVax-L passing this “safety” criteria with flying colors. What that means, IMO, is that when the FDA looks at the evidence of efficacy, risk to safety will not weigh against any efficacy because there basically is no risk to safety.

Next, let’s look at how the FDA’s guidance approaches the concept of using a historical control as a basis for determining the effectiveness of a treatment.

In the guidance, the FDA points out that historical controls (also called “external controls”) have been included in the earliest descriptions of adequate and well-controlled trials (AWC).
beginning at line 179:

Quote:Although randomized double-blinded, concurrently controlled superiority trials are usually regarded as the most rigorous design, as discussed further below, five types of controls are described in section 314.126:10 placebo concurrent control, dose-comparison concurrent control, no treatment concurrent control, active treatment concurrent control, and historical control (a type of external control).11 Of note, when the first version of the rule was published in 1970, historical controls and active treatment controls were included.12 Thus, from its earliest description of adequate and well-controlled trials, FDA included trial designs (as discussed below) that may be more difficult to interpret, which reflected FDA’s recognition that different trial designs (including choice of control) may be appropriate in different disease settings.

And here’s the footnote providing more extensive detail as to what is a historical or external control arm:
Quote:11 The regulation uses the term “historical control,” which is a subset of “external control.” FDA also accepts other types of external controls. An externally controlled trial compares a group of subjects receiving the test treatment with a group of patients external to the trial, rather than to an internal control group consisting of patients from the same trial population assigned to a different treatment. The external control can be a group of patients, treated or untreated, at an earlier time (historical control) or a group, treated or untreated, during the same time period but in another setting. An important subset of externally controlled trials are “baseline controlled trials,” where there is not a specific external control group but assurance, based on experience, that no change could occur (e.g., tumors are known not to shrink spontaneously or patients not given general anesthetic remain awake). See International Conference on Harmonisation E10 guidance on Choice of Control Group and Related Issues in Clinical Trials (ICH E10). This guidance uses the term “external control,” except when referring to section 314.126.

This guidance then addresses using “external controls” - which, as noted above, historical controls are a subset of.

at line 221
Quote:Externally controlled trials differ in several important ways from the other trial designs identified in 21 CFR 314.126. Most notably, random assignment is not a feature of external control designs. As a result, there may be differences in patient characteristics or concomitant treatments in the trial population compared to the external control population that lead to differences in outcomes that are unrelated to the investigational treatment. In addition, the lack of blinding could introduce bias. For these reasons, external control designs are usually reserved for specific circumstances, such as trials of diseases with high and predictable mortality or progressive morbidity (e.g., certain malignancies or certain rare diseases) and trials in which the effect of the drug is self-evident(e.g., general anesthetics).


In this passage the guidance states that problems with using external controls are that these types of trials usually don’t use “random assignment” (however, we know that the DCVax trial did use random assignment), and lack of blinding (and we know that the DCVax trial was quadruple blinded - quite literally). However, one will note that when these two stated problems (which this trial DOES NOT HAVE), these types of externally controlled designs are reserved for diseases with “high and predictable mortality… in which the effect of the drug is self-evident” (which one will also note, describes the GBM disease very accurately).

To that point, this guidance goes on to state,
beginning at line 231
Quote:Despite the limitations of externally controlled trials compared with concurrently controlled trials, strong support for effectiveness can emerge from externally controlled trials, especially when
(1) the natural history of a disease is well defined,
(2) the external control population is very similar to that of the treatment group,
(3) concomitant treatments that affect the primary endpoint are not substantially different between the external control population and the trial population, and
(4) the results provide compelling evidence of a change in the established progression of disease.


Such results could include partial or complete response in a disease where spontaneous regression is not observed, or stabilization or improvement in function in a disease where progressive functional decline is well documented to occur over the duration of the treatment period in the trial. Another example of where there is strong evidence of drug effectiveness is reversal of clinical signs and symptoms following a toxic exposure or overdose after administration of a drug antidote. In all such circumstances, a detailed understanding of the full range of possible clinical outcomes, with a well-documented natural history of the disease in the absence of treatment, is essential to interpreting trial results and, therefore, drawing a conclusion about the effectiveness of the drug.


We should note that the guidance is quite literally stating that “strong support for effectiveness can come from these types of externally controlled (using historical controls) trials, especially when:

(1) The history of the disease is well defined - as is absolutely the case with GBM

(2) The external control group is similar to the treatment group - most historical arms will be similar, although some of them will have included pseudo-progressors from chemo/radiation (these are the typical longer livers in GBM) in their trial, whereas the DCVax-L trial did their level best to screen these types of pseudo-progression longer livers out of the trial.

(3) Concomitant treatments used are not substantially different between the treatment group and the external control groups - most GBM trials used the same SOC treatment (radiation and temozolmide; and some crossovers may have used Avastin ) that DCVax used.

(4) The results provide compelling evidence of a change in the established progression of the disease - even the blended data (including using even 30 or so non-crossed over controls) still shows compelling evidence that adding DCVax to the treatment mix has increased the life span by a greater percentage for many of the trial participants. The top 100 were showing a mOS of almost 5 years, for goodness sakes!

And the last part that I highlighted about evidence of drug effectiveness is when they see a reversal of clinical signs and symptoms following a toxic (toxicity is not a concern - but definitely after a dosing of DCVax, this trial may see a some possible clinical outcomes that can only be attributed to the effectiveness off the drug - e.g. pseudo-progression).

beginning line 247
Quote:For example, compelling results may overcome challenges associated with less rigorous trial designs, such as those with an external control. As discussed above, a small externally controlled trial with an outcome markedly superior to the well-established natural history of a disease may provide a compelling case for drug effectiveness.


And in making the above stated point, the FDA guidance is signaling that compelling results - such as what we expect to evidenced in the DCVax-L results - should be enough to overcome any challenges to having used external controls to measure against the treatment arm in their new endpoints.

So anyone that is emphatically stating otherwise, must not be aware, or does not understand specifically what this new approach to historical or external controls that the new FDA guidance on Biologic Products is now signaling they're willing to accept.
 

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Today may pose as a day to start and/or add in a position (I personally bought more shares today but please do your own DD):

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GlobeCitizen

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Nothing has changed fundamentally. The company locked data on 5 Otc 2020. It seems the company has had report from statisticians for top line data and is now in a self-imposed quiet period (if you send an email to the company, you will get a reply indicating so).

So top line data can be announced any time now, and yet we have seen price drops in recent days. BTW, high volatility is quite normal in trading small biotech companies, particularly on the eve of some significant announcement.

Again please do your own DDs.
 

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Again I bought four batches of shares this morning ranging from $0.958 -$1.02.



Dan88 Wednesday, 10/28/20 12:08:22 PM
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A Summary of Anything NWBO Today:

There is a concerted force composed of probably some warrant holders and short hedges who has determined to bring down the price, probably to as low as about $0.80s to fill the last unfilled gap, and in doing so to make a market capitulation;

As a result, price has been brought down from about $2.3 to today's $1 range from probably selling of tens to twenties of million shares from warrant exercising, exacerbated by some short selling, and fear mongering in social media;

But, nothing has changed fundamentally. Instead, EU and UK are fully confirmed today to accommodate company's endpoint adaptations via confirmation of German clinical registry, and it seems it's only a matter of time FDA will be confirmed as well;

The most vicious NWBO attacker, aka grapefruit juice guy, now has nothing to say about the company but expression of his worry for the common retail investors over possible further warrant excursing and selling after 1 Nov;

The market as of now at 12:08pm has answered: I will buy any share which is for sale at this price range.

And what's the big difference to have a future price movement from $0.80s to $10 or from $1 to $10, considering one may miss out.

This is my last post for today, Good Luck!
 

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8-k dated 2 Nov:

On May 20, 2020, Northwest Biotherapeutics, Inc. (the “Company”) reported in a Form 8-K that 233 million warrants and options to purchase shares of the Company’s common stock had expired, would expire, or had been suspended through November 1, 2020. The Company has recently received questions concerning the status of those 233 million warrants and options and so provides the following updates:

Of the 233 million total, 62 million were warrants that had expired in May 2020 or were due to expire in June 2020. Approximately all 62 million such warrants have expired as of November 2020.

The remaining 171 million were warrants and options held by a group of significant long-term shareholders and the Company’s CEO, Linda Powers. The exercise of these 171 million warrants and options was previously suspended through November 1, 2020 as reported by the Company in May 2020. Approximately 157 million of those 171 million warrants and options have now been suspended through December 15, 2020.

Furthermore, the holders have agreed to suspend the exercise of approximately 21 million additional warrants through December 15, 2020 for a total of approximately 178 million new suspensions.

Consequently, approximately 274 million warrants and options are now suspended through December 15, 2020: the 178 million warrants and options as reported here plus approximately 96 million warrants suspended earlier in connection with new share purchases.

In consideration for the forgoing suspensions, the Company has agreed to extend the term of each suspended warrant by 45 days and issue approximately 5 million warrants to the holders of the 178 million suspended warrants and options.
 

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On way up supported by news concentrated weeks ahead:

1604414103313.png
 
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