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Northwest Biotherapeutics: Data Is Done, Just Wait For Approval
Nov. 23, 2022 7:20 AM ETNorthwest Biotherapeutics, Inc. (NWBO)109 Comments
15 Likes
Summary
NWBO published topline data on JAMA Oncology, resoundingly, I must say.
Data shows stat sig on all major primary and secondary endpoints.
DCVax-L is a winner, and so may NWBO be, soon.
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Last month, I was complaining about Northwest Bio (OTCQB:NWBO) not releasing data in a proper manner, which made it a confusing investment and a Hold for me. The company now is finally out with the topline data, published on November 17 on the peer-reviewed and well-regarded JAMA Oncology - here. The stock is up 70% and counting, one patient survived 8 years following DCVax-L treatment, a British patient survived 7 years, everything looks good, and all’s well with the world.
However, there’s talk about how the peer-reviewed article missed a few key points - the FDA’s partial clinical hold, the crossover design and the change in the endpoint - and how these things will make life difficult for NWBO. Well, they may or may not do so, but what these arguments miss is that I have never come across a peer-reviewed original investigation report that discusses anything but data and results. These other things are in the realm of the retail investing public - bears and bulls - and it is not the job of JAMA to figure that out. They only discuss data.
And the data was outstanding. Another thing I have hardly ever seen is a JAMA article with 67 named authors. Ms. Linda Powers has given this publication all she had, knowing full well that if there’s something that should shut the critics up for good, it would be from a publication like this with named authors who read like the who's who in glioblastoma expertise. [see appendix below for list of authors/affiliations.]
I wanted to put that out in order to show you that the scientific community seems to have given this all they could and have come together to support Dr Linda Liau’s discovery of DCVax-L.
Now let's review the data. Here it is, short and sweet and to the point:
A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (MOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03).
The active treatment here was DCVax-L plus standard of care temozolomide, which was approved nearly two decades ago. External control nGBM (newly diagnosed GBM) patients received temozolomide and placebo; while rGBM patients received “approved GBM therapies,” where there is no SOC. Results were statistically significant. I note that almost every endpoint measured except the methylated MGMT one achieved statistical significance. As the authors also note, “only 1 phase 3 trial in nGBM and no phase 3 trials in rGBM have demonstrated a survival benefit” since 2005. This successful phase 3 trial was with TTFields, a promising new therapeutic modality, plus temo. While PFS was the primary endpoint, OS was a secondary endpoint and the data was as follows:
Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone.
Note that for the nGBM population, DCVax-L also demonstrated 19.3 months of OS versus 20.9 months for the TTFields trial, however placebo had a 0.5 months higher survival in DCVax-L; of course, these cross trial comparisons do not really work. What should be noted is that both new therapies worked in nGBM; and DCVax-L also worked in rGBM patients, where nothing else works.
In the US, more than 13,000 people will be diagnosed with GBM in 2022 according to the National Brain Tumor Society. In the EU, there should be an equal number of patients; the UK alone has 2500 patients. Indeed, the EU number is actually quite a bit higher, at 22000 patients, according to this source. GBM occurs more in the developed countries than in the rest of the world; while this could be caused by underreporting, as one understands, the market is truly in the developed countries. There are some 1771 Japanese patients. From China, I had PBT (primary brain tumor) mortality data, which stood at 21,215. Assuming a 70% mortality and a 50% GBM among these PBT patients, I get a figure of 15,000 Chinese patients with GBM; which sounds a bit low given the population, and may or may not be caused by underreporting. Thus, there could be as many as 50,000-60,000 patients in the developed/relatively developed world for GBM. This is the target population for DCVax-L. Median treatment cost for GBM patients could well cross $100,000, and I wouldn’t be surprised if it goes beyond $200,000 per year. A treatment that extends OS significantly can be priced in the ballpark range - probably higher given how some very well-known people have succumbed to GBM. What that means is that a lot of people who could afford treatment did not survive due to a lack of it, so that could inform pricing. If we put it - quite randomly - at $200,000, then the total addressable market in the developed world comes to $12bn. TTFields treatment was approved for GBM patients by the FDA.
Coming back to the JAMA-Onc report, here’s something interesting - and to me, definitive- that it says about the crossover design:
Many trials, especially for incurable diseases, incorporate a crossover design for feasibility and/or ethical reasons. A crossover was considered necessary when our study began in 2007 to make patient enrollment and retention feasible when novel immunotherapies were not yet generally viewed as promising for cancer. The crossover was also important to justify the placebo group for patients undergoing a leukapheresis—an invasive procedure necessary for blinding and for manufacturing vaccine but offering no benefit to patients in the placebo group if they could not receive their autologous vaccine.
I think we can put that issue to rest.
Another issue that had vexed investors was pseudo-progression. The company explained why a change from a PFS endpoint to OS was necessary in order to avoid pseudo-progression:
The PFS end point became infeasible for this trial due to the challenges now well recognized in trying to distinguish true progression from pseudo-progression (including vaccine-induced immune cell infiltration).13 There were 494 imaging time points when possible progression was observed by the independent radiologists, and 256 of these (>50%) required adjudication due to discordant interpretations. Based on these assessments, the median PFS was 6.2 (95% CI, 5.7-7.4) months for patients receiving DCVax-L and 7.6 (95% CI, 5.6-10.9) months for the placebo group. This difference was not statistically significant (P = .47).
I have no particular comment here; I discussed pseudo-progression in another article.
A few other points to note:
DCVax-L did particularly well with patients with poor prognosis, like older patients, or those with substantial residual tumors, rGBM patients and so on, compared to ECP (external control population).
DCVax-L was well-tolerated. Of 2151 total doses of DCVax-L administered, only 5 serious adverse events were deemed at least possibly related to the investigational treatment. There were no immune rejection issues with the treatment.
DCVax-L could work well with other treatment modalities like checkpoint inhibitors for example.
About the trial, Linda Powers, CEO of NWBO, said:
We are excited to see the meaningful survival extensions in glioblastoma patients treated with DCVax-L in this trial – particularly in the long tail of the survival curve, where we see more than double the survival rates as with existing standard of care. With well over 400 clinical trials for glioblastoma having failed over the last 15 years, it is gratifying to be able to offer new hope to patients who face this devastating disease.
Here’s some commentary from a Guardian article.
Financials
NWBO has a market cap of $1.2bn and a cash balance of just $11.7mn (current assets). Now that they published TLD, they will have triggered a $15mn loan facility. Plus, like I said before, Ms. Powers, the CEO, had offered a loan to the company before when it was in a much weaker position than now; I am guessing she can do so again, now that it is looking stronger. Last quarter, the company spent $7.8mn in R&D and $8mn in G&A - here. If they continue at that rate, there's no cash; however, with the solid data that they have, they may be able to get cash, even through a market offering.
Risks
NWBO's primary risks are two - lack of cash, and lack of clarity. I just discussed the cash problem. As for clarity, my previous coverages have touched on that. Like I grumbled in October:
If the company behaved like a normal company, announced official data, published, filed for approval - sued its detractors
It has published data now, so there's a lot more clarity. The company now needs to sit down with analysts and be willing to take questions and so on - like it used to do earlier. They went into a dormant phase in the long years while their trial was running. Now that they have TLD, they need to come out of that phase and get vocal again.
Bottomline
NWBO went up over $2 in May when the company reported primary data at the New York Academy of Sciences. Now that they have their TLD in JAMA, the stock is just up to $1.15. This will be followed by an NDA, then PDUFA. Like all things NWBO, don’t expect a quick turnaround. However, things will start to move positively from here. Just a day before the publication, Sentinus, LLC took a large position in NWBO. Institutional interest is still quite low, at just .2%. I expect that to change as the company gains legitimacy. This would be a good time to buy the stock.
Appendix
Here’s the full list of authors:
Linda M. Liau, MD, PhD1; Keyoumars Ashkan, MD, FRCP, FRCS2; Steven Brem, MD3; Jian L. Campian, MD, PhD4; John E. Trusheim, MD5; Fabio M. Iwamoto, MD6,7; David D. Tran, MD, PhD8; George Ansstas, MD9; Charles S. Cobbs, MD10; Jason A. Heth, MD11; Michael E. Salacz, MD12; Stacy D’Andre, MD13; Robert D. Aiken, MD14; Yaron A. Moshel, MD, PhD14; Joo Y. Nam, MD15; Clement P. Pillainayagam, MD16; Stephanie A. Wagner, MD17; Kevin A. Walter, MD18; Rekha Chaudary, MD19; Samuel A. Goldlust, MD20; Ian Y. Lee, MD21; Daniela A. Bota, MD, PhD22; Heinrich Elinzano, MD23; Jai Grewal, MD24; Kevin Lillehei, MD25; Tom Mikkelsen, MD, FRCPC21; Tobias Walbert, MD21; Steven Abram, MD26; Andrew J. Brenner, MD, PhD27; Matthew G. Ewend, MD28; Simon Khagi, MD29; Darren S. Lovick, MD30; Jana Portnow, MD31; Lyndon Kim, MD32; William G. Loudon, MD33; Nina L. Martinez, MD34; Reid C. Thompson, MD35; David E. Avigan, MD36;Karen L. Fink, MD, PhD37; Francois J. Geoffroy, MD38; Pierre Giglio, MD39; Oleg Gligich, MD40; Dietmar Krex, MD41; Scott M. Lindhorst, MD42; Jose Lutzky, MD43; Hans-Jörg Meisel, MD, PhD44; Minou Nadji-Ohl, MD45; Lhagva Sanchin, MD44; Andrew Sloan, MD46; Lynne P. Taylor, MD47; Julian K. Wu, MD47; Erin M. Dunbar, MD48; Arnold B. Etame, MD, PhD49; Santosh Kesari, MD, PhD50; David Mathieu, MD51; David E. Piccioni, MD, PhD52; David S. Baskin, MD53; Michel Lacroix, MD54; Sven-Axel May, MD55; Pamela Z. New, MD56; Timothy J. Pluard, MD57; Steven A. Toms, MD58; Victor Tse, MD59; Scott Peak, MD59; John L. Villano, MD, PhD60; James D. Battiste, MD, PhD61; Paul J. Mulholland, MD62; Michael L. Pearlman, MD63; Kevin Petrecca, MD, PhD64; Michael Schulder, MD65; Robert M. Prins, PhD66; Alton L. Boynton, PhD67; Marnix L. Bosch, PhD67
And here are their affiliations:
1Department of Neurosurgery, University of California, Los Angeles
2King’s College Hospital, London, United Kingdom
3Department of Neurosurgery, Penn Brain Tumor Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia
4Division of Neurology, Washington University School of Medicine in St Louis, St Louis, Missouri
5Givens Brain Tumor Center, Abbott Northwestern Hospital, Minneapolis, Minnesota
6Columbia University Irving Medical Center, New York, New York
7New York-Presbyterian Hospital, New York, New York
8Preston A. Wells, Jr. Center for Brain Tumor Therapy, Division of Neuro-Oncology, Lillian S. Wells Department of Neurosurgery, University of Florida College of Medicine, Gainesville
9Department of Neurological Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri
10Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Medical Center, Seattle, Washington
11Taubman Medical Center, University of Michigan, Ann Arbor
12Neuro-Oncology Program, Rutgers Cancer Institute of New Jersey, New Brunswick
13Sutter Health, Sacramento, California
14Glasser Brain Tumor Center, Atlantic Healthcare, Summit, New Jersey
15Department of Neurological Sciences, Rush Medical College, Chicago, Illinois
16Department of Neurology, The Ohio State University, Columbus
17The Cancer Center of Columbus Regional Health, Columbus, Indiana
18University of Rochester, Rochester, New York
19University of Cincinnati, Cincinnati, Ohio
20John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey
21Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan
22Department of Neurology and Chao Family Comprehensive Cancer Center, University of California, Irvine
23Rhode Island Hospital, Providence
24Long Island Brain Tumor Center at NSPC, Lake Success, New York
25Department of Neurosurgery, University of Colorado Health Sciences Center, Boulder
26Ascension St Thomas Brain and Spine Tumor Center, Howell Allen Clinic, Nashville, Tennessee
27Mays Cancer Center at UT Health San Antonio, San Antonio, Texas
28Department of Neurosurgery, UNC School of Medicine and UNC Health, Chapel Hill, North Carolina
29The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
30Advent Health, Kansas City, Kansas
31Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, California
32Division of Neuro-Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
33Saint Joseph’s Hospital, Orange, California
34Jefferson Hospital for Neurosciences, Jefferson University, Philadelphia, Pennsylvania
35Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
36Beth Israel Deaconess Medical Center, Harvard Medical School, Cambridge, Massachusetts
37Baylor Scott & White Neuro-Oncology Associates, Dallas, Texas
38Illinois Cancer Care, Galesburg, Peoria
39Medical University of South Carolina Neurosciences, Charleston
40Mount Sinai Medical Center, Miami Beach, Florida
41Uniklinikum Dresden, Dresden, Germany
42Hollings Cancer Center, Medical University of South Carolina, Charleston
43Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
44BG Klinikum Bergmannstrost, Halle, Germany
45Neurochirurgie Katharinenhospital, Klinikum der Landeshauptstadt Stuttgart, Stuttgart, Germany
46Seidman Cancer Center, University Hospitals–Cleveland Medical Center, Cleveland, Ohio
47Department of Neurosurgery, Tufts Medical Center, Boston, Massachusetts
48Piedmont Physicians Neuro-Oncology, Piedmont Brain Tumor Center, Atlanta, Georgia
49Department of Neuro-Oncology, Moffitt Cancer Center
50Pacific Neurosciences Institute and Saint John’s Cancer Institute, Santa Monica, California
51Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, Quebec, Canada
52UC San Diego Moore’s Cancer Center, La Jolla, California
53Department of Neurosurgery, Houston Methodist Hospital, Houston, Texas
54Geisinger Neuroscience Institute, Danville, Pennsylvania
55Klinik für Neurochirurgie, Chemnitz, Germany
56Baptist Health System, San Antonio, Texas
57Saint Luke’s Cancer Institute, Kansas City, Missouri
58Departments of Neurosurgery and Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
59Kaiser Permanente, Redwood City, California
60University of Kentucky Markey Cancer Center, Department of Medicine, Neurosurgery, and Neurology, University of Kentucky, Lexington
61Oklahoma University Health Science Center, Oklahoma City
62University College London Hospitals, London, United Kingdom
63Blue Sky Neurology/Neuro-Oncology, Englewood, California
64Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
65Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Uniondale, New York
66University of California, Los Angeles
67Northwest Biotherapeutics, Inc, Bethesda, Maryland
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Hi Sojo. Hope your feeling better looks like its starting to turn a little ?
Hoff. gotta love having dry powder. buy buy buy la la la thanks for the gifts
Fireman. I agree. When it is getting close you tend to see big whips up and down with stock price. Kinda feels like FORESHOCKS before the Big Quake.
Hi Judge. what do you think if we pop through the $1.20 and is that what you are predicting ? ty
yes. ty.
two little spikes on volume
just hung up. they are aware of the problem. otc. issue
Something I notice. anyone else? level 2 time and sales has not been showing the orders for the last three days.for Nwbo only. im on with ameritrade and they can't expand why as of yet.
ty stonk
ty. hoff
u2 Sir Pump.
Hello Sojo, Happy to hear the good news.
Hi Judge. are still around? can you give a update.
hey judge/sojo . what can you tell us.
nite on the bid for 1.5 mil @.64
Judge/Sojo any thoughts on our chart?
Hey Judge. I know its going to be a mess after, no power trees down everywhere. Hopefully people are safe and the criminals stay away.
Hey Judge Thank you. stay safe
disregard Judge. I just saw. ty
Judge. not a bad close. be safe in Tampa I was there 2004. that was a busy season.
any take on the eod chart
Northwest Bio: Buy Again, Wait For Regulatory Process
May 21, 2022 8:37 AM ETNorthwest Biotherapeutics, Inc. (NWBO)478 Comments
23 Likes
Summary
Data is excellent.
I explain the bearish commentary here.
The stock may go up on NDA announcement and other regulatory steps.
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After 20 years of waiting, Northwest Biotherapeutics (OTCQB:NWBO) declared results last week. And to use a four-word opinion - those results were outstanding.
Yet the stock had a rollercoaster ride, going up 300% at one point and then subsiding to below its pre-data position.
The reason: a concerted bearish commentary against this small company. 77 million shares changed hands on the fateful day, May 10, when it finally announced results. Average historical volume of trading is less than a million. However, note the low short interest; either the market does not believe in the bearish commentary anymore, or the shorts have closed their positions at these low prices. I doubt that second conditional because the price may have gone up when shorts were trying to cover. So many would not have waited for the price to fall.
So how was such a commentary launched against a company with outstanding data? Let me explain.
First, the trial met both its pre-specified endpoints, which were:
Primary Outcome Measures:
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 newly diagnosed glioblastoma. [ Time Frame: Until death ]
Secondary Outcome Measures:
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 recurrent GBM. [ Time Frame: Until death ]
A few things to note here. First, OS is the absolute gold standard in cancer trials, and here OS was measured for two groups of patients. The first group consisted of those patients who were randomized to DCVax-L directly. The second group consisted of those patients who were randomized to placebo first, but then took DCVax-L anyway following disease recurrence.
Both groups met the clinical endpoint of OS with clean and absolute statistical significance.
The second point to note here is that there is no active control arm here. Bears have tried to make a big deal out of it but what they don't divulge to you is there is no control drug because there are none. Temodar is the only approved drug in GBM and its data is so poor as to make it effectively useless. In primary GBM, temodar gives a 4-month OS benefit and mOS of 12 months, while in recurrent GBM, 12 month OS was observed in 36% of patients. In many ways, it is better to look at historical records than a control drug - in my opinion, it produces a cleaner record.
There's a third point and at least one analyst who has been pretty vocally anti-NWBO has made a big deal about it after the trial data was published. In 2020, NWBO officially changed the study protocol to replace original endpoints to new ones. Here's the text from their March 2021 10-K:
The statistical analysis plan that we submitted to regulators for the Phase III trial embodies a different primary endpoint and secondary endpoint than did the original Protocol for the trial. Under the Protocol the primary endpoint was progression free survival, or PFS, and the secondary endpoint was overall survival, or OS. Both of these endpoints were confounded: the PFS endpoint by pseudo-progression, and the OS endpoint by the "crossover" provision in the trial design, which allowed all of the patients in the trial to cross over to DCVax-L treatment after tumor recurrence (while remaining blinded as to which treatment they received before tumor recurrence).
So what is pseudoprogression? It is an initial flare-up of the tumor after immunotherapy, which may change to a more favorable response. As this paper defines it:
Likewise, clinical experience with ICI has shown that it is common to observe early "tumor flare," described as pseudo-progression, which is considered an intratumoral inflammatory process that can last weeks to months before a favorable response is ultimately achieved.
ICI means immune checkpoint inhibitor. Pseudoprogression is a common enough phenomenon in immune therapies, and diagnostic techniques - see here - have been studied to try and distinguish a pseudoprogression from a real progression. Outside of diagnostic techniques, a good way, where possible, is to ignore progression altogether and go with an OS endpoint - exactly what NWBO has done.
In plainspeak, when you take an immunotherapy medicine, the drug activity itself may cause the tumor to get inflamed, basically acting as if disease has progressed. However, if the progression then subsides, a simple PFS endpoint is not going to be able to measure it. What is then needed is overall survival, which can tell us whether the progression was real - causing death, for instance - or it was fake, subsiding later to produce a complete or partial response, and ultimately improving overall survival.
This is exactly what happened with the DCVax-L trial. Before data was unblinded, they changed the PFS endpoint to a much more robust OS endpoint, and they saw success - so if bears are telling you otherwise, be sure you know what is happening.
Dr Linda Liau, the originator of the DCVax-L therapy, has consistently been aware of, and tried to avoid, pseudoprogression from the trial. As early as 2015, we see her adapting the design to avoid confounding it with pseudoprogression:
Progression needed to be determined by independent review on two consecutive scans for early progressor classification to avoid enrolling patients with pseudoprogression.
Even after a few years, the same problem crops up and protocol has to be developed to avoid it:
1. Screen-Fail for protocol 020221 due to either: - Radiographic evidence of disease progression or pseudoprogression at the Baseline visit under protocol 020221, as determined by central imaging review, OR - Insufficient vaccine manufactured for protocol 020221 (i.e. less than 5 doses).
And in 2018 as well:
Patients were excluded if they already had apparent early disease progression/recurrence or pseudo-progression at the baseline visit, similar to the inclusion/exclusion criteria of other recent trials in glioblastoma..
The study's primary endpoint is PFS, and the secondary endpoint is OS. PFS has not yet been evaluated for this publication and will be the subject of later analyses to allow for central, multi-factorial assessment by an expert panel, using criteria currently emerging as appropriate for immune therapy in this patient population where progression can be complex to determine and pseudo-progression is a known confounding phenomenon.
Progressive disease or pseudo-progression (which are indistinguishable at this point)..
These quotes tell me why the company finally changes the original protocol itself, from PFS to OS. There is nothing controversial here, and for shorts to say there is one (which involves prominent scientists like Dr Liau, as seen in the quotes above) may be overplaying their hands. NWBO can be a poor investment for many reasons - but not because of this one. Like Dr Paul Muholland says:
Original primary endpoint, when trial designed in 2007: Progression-Free Survival (PFS) While the trial was underway, Pseudo-progression (PsPD) became recognized as major issue -- difficulty distinguishing real vs. PsPD is an even bigger issue with immune cell therapies: vaccine-induced infiltration of immune cells PFS endpoint not feasible due to PsPD. So, SAP focused on OS, and specified OS as the primary endpoint before unblinding.
One more issue the bears which has confused investors is the crossover trial design and how that led to adding a crossover component to the endpoints. First, here's what Dr Paul Mulholland says about the need for crossover:
Crossover was necessary for feasibility and ethical reasons: Necessary for enrollment and retention of patients in era when immune therapies not yet generally viewed as promising for cancer Important to justify all patients undergoing invasive leukapheresis procedure. No benefit to placebo patients unless they could receive their autologous product made from the leukapheresis
In effect, 90% of patients went on to take DCVax-L over the years. There's a necessity to differentiate between crossover patients and originally DCVax-L randomized patients, which is why the new secondary endpoint was introduced. So again, I think this invalidates the bearish concerns.
Moreover, this also explains the following from the Paul Mulholland presentation:
OS endpoints could not be within-study comparisons of DCVax-L patients vs. placebo patients, because placebo patients received DCVax-L following crossover. So, the OS endpoints compared DCVax-L patients with external controls. This approach fits well with growing commentary in support of streamlined trial designs and use of external controls where classic within-study comparisons are not feasible.
This is why external controls were used; because internal controls, the actual patients, found DCVax-L so good that they went for it en masse.
These are the final data:
DCVax-L data
DCVax-L data (Company website)
The data speaks for itself. Look at those survival tail data. No other GBM trial has shown such improvements over historic controls in long-term survival curve tails.
Before I conclude, let's not forget the excellent safety data, which was comparable to placebo. Of nearly 3000 treatment injections, there were only 5 SAEs. Temodar has a terrible safety profile.
Financials
NWBO has a market cap of $707mn and a cash balance of $7mn. I mentioned a loan in my previous articles with an interesting angle:
Here's some detail on a new $15mn loan they received:
On November 22, 2021, Northwest Biotherapeutics, Inc. (the "Company") entered into a loan financing with Streeterville Capital, LLC (the "Lender") pursuant to which the Company received net proceeds of $15,000,000 (the "Loan"). The Loan has a maturity of 22 months. No payments are due for the first 8 months of the Loan term. …Upon announcement of the top line data ("TLD") from the Company's Phase III clinical trial of DCVax®-L for glioblastoma brain cancer, the Lender has a then springing right to exchange the outstanding balance of the loan for common shares priced at the price of the first private placement transaction following TLD less a 12% discount and to purchase another 50% of that number of shares at the same price. This then-springing right expires 14 days after the post-TLD private placement.
As it says here, the lender can transform the loan to equity if TLD is announced. I will wait to see if they do it because prices are back to where they were before. Since the company has now announced strong TLD, I am hoping they will get access to more funds to run this through the regulatory process.
However, longs must accept that NWBO's finances are in dire strait. They spent $13mn in the previous quarter, so they really don't have money to survive another. Expect fundraising on this data; we would be lucky if it is not dilutive.
Bottomline
NWBO is again a buy. These prices are low, and the stock, with excellent TLD, is now heavily derisked.
BSB. lol. Turtle Chicago correct?
Friday, September 09, 2022 11:03:30 AM
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Nice clip .. I wonder who ...
BSB
Hi ae Kusterer why not ask BSB? I think he was there.
BSB. yes. saw that. may be more during the day. 311.813 @.80. 10:53.
Sojo... I hope your travels are good ones. not college. Be well please keep a eye on us while you are away. Thank you for your help
Hi Sojo/Judge. Any thoughts here.
UNDERSTAND SERIES C FUNDING
Series C funding is the fourth stage of capital raising by a startup. Companies that go to this round of investments already have proof of their success and a high valuation. At the time, the businesses were “young mature” whose owners had already convinced venture capital firms or other institutional investors. Founders are considered to have a viable business, and the investors are generally encouraged about its long-term odds of success.
While previous rounds of funding use investment money to start making money and carve out their space in the market, it is assumed that Series C funding funnels large amounts of cash into profitable businesses to scale them up and get a quick return for the investors. Series C funding aims to prepare a company to be acquired, go public on the stock market, or undergo significant expansion.
HOW DOES SERIES C FUNDING WORK?
How does Series C funding work?
Preferential shares are used to raise funds in Series C funding, just as they were in the prior funding rounds. The shares are meant to be convertible. Holders will be able to convert them into shares in the company at a later date. To clarify, companies that are looking to raise money through a series C round are no longer startups. They are often well-established and profitable businesses in their last stages of development. A large customer base is drawn to their core products or services because of the high demand they generate.
Companies seek series C financing for further expansion to reinforce their existing success. Following a series C round, the company aims to scale its operations and grow. The proceeds from this financing round are most commonly used to enter new markets, research, development, or acquisitions of other companies.
WHO PROVIDES SERIES C FUNDING?
There are several firms that offer Series C Funding, most notable ones are venture capital investors, private equity firms and investment banks. Investors might be looking for a few key things when startups reach this stage in their business. We explain more about them below:
Venture Capital Investors – Venture Capital funds invest in early-stage startups that are at an embryonic stage through seed capital. Venture capitalists may battle with management during this round of fundraising. Many venture capital investors, however, are more than just financial backers. As a result, they have strategic directives that focus on things like enhancing a company’s market presence and increasing its financial and operational efficiency.
Private Equity Firms – Private equity firms are an alternate mode of private financing, composed of funds and investors that directly invest in startups. One of the most important things to keep an eye on is how much ownership a company might lose with private equity firms. It’s not uncommon for private equity firms to demand a considerably bigger percentage of a company’s equity in exchange for more money. Many of these companies demand majority ownership in the company, leaving you with an enormous profit loss.
Investment Banks – An investment bank advises the startup when it matures and sets to go public through an initial public offer (IPO). While a bank loan allows you to retain control of your firm, there are several factors to consider. Starting with high-interest bank loans. Given this and the fact that many banks don’t lend enough money to satisfy the company’s needs, meeting your expansion ambitions can be challenging. Another factor to consider with banks is qualification. Important to have a solid track record or at least respectable collateral. Companies may also be required to submit personal guarantees in order to obtain money. In the event of a business failure, your assets may be taken.
WHY IS SERIES C FUNDING IMPORTANT?
As evident from the discussion, series C funding is more strategic and operational where funds are raised to study a new market, develop a new product or service or analyze consumer behavior, a few more essential places for series C funding includes:
Long-term Growth – Although it is not the last stage, the Series C funding is the final missing puzzle piece. Successfully raising Series C funding means investors are convinced that the startup will continue to achieve long-term growth.
Radical and Large Expansion – Series C funding caters to startups that want to undergo significant expansion and growth. It involves acquiring one or more businesses and entering a new target market for expansion. The founder can launch a new product or service in the international market in terms of expansion. A higher level of expansion requires more consistent and extensive fundraising.
Established Status and Valuation – It is estimated that a startup needs a valuation of $118 million to enter this fundraising stage. But most firms that undergo Series C funding have three or four times higher valuation than $118 million. Essentially, this stage of the funding round turns into a less risky investment for investors. At this point, startups can get offers from hedge funds, banks, private equity firms, and other financial institutions.
WHICH COMPANIES PRIMARILY RECEIVE SERIES C FUNDING?
Because Series C companies are no longer considered startups, this round of capital is distinct from other funding rounds. As a result, the startup continues to grow at an accelerating pace. However, it is not uncommon for companies in their third round of funding to focus on expanding their workforce in order to keep up with demand.
For instance, a startup may need to expand its HR department, or the startup may find that the business requires new hires as the demand for new product development.
Startups that have reached this funding round are doing incredibly well and are ready to expand to new markets, develop new products, or acquire other businesses. Startups at this stage may also be interested in reaching international markets and increasing their valuation before an acquisition or Initial Public Offering.
Companies at the Series C funding stage of their business are thinking a lot more strategically and about their long-term goals.
HOW TO RAISE SERIES C FUNDING?
Series C capital is used to prepare a firm for sale, IPO, or significant expansion. It is usually the final step of a startup’s fundraising, though some companies do further rounds. The founding and the core team of the startup venture must consider the legal compliance and must also adhere to sovereign government rules and regulations in the jurisdiction the startup is based on to raise funding. Follow these steps to raise Series C funding for your startup.
Driver. I agree with you 100 pct. The 3 month hold to convert could be a message that we might be on the verge of good news. I feel they will make sure the shares are in safe hands . Angle investors. Seems like they also are preparing for the need of more shares and being ready if a squeeze occurs. This is all positive in my opinion.
Northwest Bio: Buy Again, Wait For Regulatory Process
May 21, 2022 8:37 AM ETNorthwest Biotherapeutics, Inc. (NWBO)376 Comments22 Likes
Summary
Data is excellent.
I explain the bearish commentary here.
The stock may go up on NDA announcement and other regulatory steps.
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After 20 years of waiting, Northwest Biotherapeutics (OTCQB:NWBO) declared results last week. And to use a four-word opinion - those results were outstanding.
Yet the stock had a rollercoaster ride, going up 300% at one point and then subsiding to below its pre-data position.
The reason: a concerted bearish commentary against this small company. 77 million shares changed hands on the fateful day, May 10, when it finally announced results. Average historical volume of trading is less than a million. However, note the low short interest; either the market does not believe in the bearish commentary anymore, or the shorts have closed their positions at these low prices. I doubt that second conditional because the price may have gone up when shorts were trying to cover. So many would not have waited for the price to fall.
So how was such a commentary launched against a company with outstanding data? Let me explain.
First, the trial met both its pre-specified endpoints, which were:
Primary Outcome Measures:
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 newly diagnosed glioblastoma. [ Time Frame: Until death ]
Secondary Outcome Measures:
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 recurrent GBM. [ Time Frame: Until death ]
A few things to note here. First, OS is the absolute gold standard in cancer trials, and here OS was measured for two groups of patients. The first group consisted of those patients who were randomized to DCVax-L directly. The second group consisted of those patients who were randomized to placebo first, but then took DCVax-L anyway following disease recurrence.
Both groups met the clinical endpoint of OS with clean and absolute statistical significance.
The second point to note here is that there is no active control arm here. Bears have tried to make a big deal out of it but what they don't divulge to you is there is no control drug because there are none. Temodar is the only approved drug in GBM and its data is so poor as to make it effectively useless. In primary GBM, temodar gives a 4-month OS benefit and mOS of 12 months, while in recurrent GBM, 12 month OS was observed in 36% of patients. In many ways, it is better to look at historical records than a control drug - in my opinion, it produces a cleaner record.
There's a third point and at least one analyst who has been pretty vocally anti-NWBO has made a big deal about it after the trial data was published. In 2020, NWBO officially changed the study protocol to replace original endpoints to new ones. Here's the text from their March 2021 10-K:
The statistical analysis plan that we submitted to regulators for the Phase III trial embodies a different primary endpoint and secondary endpoint than did the original Protocol for the trial. Under the Protocol the primary endpoint was progression free survival, or PFS, and the secondary endpoint was overall survival, or OS. Both of these endpoints were confounded: the PFS endpoint by pseudo-progression, and the OS endpoint by the "crossover" provision in the trial design, which allowed all of the patients in the trial to cross over to DCVax-L treatment after tumor recurrence (while remaining blinded as to which treatment they received before tumor recurrence).
So what is pseudoprogression? It is an initial flare-up of the tumor after immunotherapy, which may change to a more favorable response. As this paper defines it:
Likewise, clinical experience with ICI has shown that it is common to observe early "tumor flare," described as pseudo-progression, which is considered an intratumoral inflammatory process that can last weeks to months before a favorable response is ultimately achieved.
ICI means immune checkpoint inhibitor. Pseudoprogression is a common enough phenomenon in immune therapies, and diagnostic techniques - see here - have been studied to try and distinguish a pseudoprogression from a real progression. Outside of diagnostic techniques, a good way, where possible, is to ignore progression altogether and go with an OS endpoint - exactly what NWBO has done.
In plainspeak, when you take an immunotherapy medicine, the drug activity itself may cause the tumor to get inflamed, basically acting as if disease has progressed. However, if the progression then subsides, a simple PFS endpoint is not going to be able to measure it. What is then needed is overall survival, which can tell us whether the progression was real - causing death, for instance - or it was fake, subsiding later to produce a complete or partial response, and ultimately improving overall survival.
This is exactly what happened with the DCVax-L trial. Before data was unblinded, they changed the PFS endpoint to a much more robust OS endpoint, and they saw success - so if bears are telling you otherwise, be sure you know what is happening.
Dr Linda Liau, the originator of the DCVax-L therapy, has consistently been aware of, and tried to avoid, pseudoprogression from the trial. As early as 2015, we see her adapting the design to avoid confounding it with pseudoprogression:
Progression needed to be determined by independent review on two consecutive scans for early progressor classification to avoid enrolling patients with pseudoprogression.
Even after a few years, the same problem crops up and protocol has to be developed to avoid it:
1. Screen-Fail for protocol 020221 due to either: - Radiographic evidence of disease progression or pseudoprogression at the Baseline visit under protocol 020221, as determined by central imaging review, OR - Insufficient vaccine manufactured for protocol 020221 (i.e. less than 5 doses).
And in 2018 as well:
Patients were excluded if they already had apparent early disease progression/recurrence or pseudo-progression at the baseline visit, similar to the inclusion/exclusion criteria of other recent trials in glioblastoma..
The study's primary endpoint is PFS, and the secondary endpoint is OS. PFS has not yet been evaluated for this publication and will be the subject of later analyses to allow for central, multi-factorial assessment by an expert panel, using criteria currently emerging as appropriate for immune therapy in this patient population where progression can be complex to determine and pseudo-progression is a known confounding phenomenon.
Progressive disease or pseudo-progression (which are indistinguishable at this point)..
These quotes tell me why the company finally changes the original protocol itself, from PFS to OS. There is nothing controversial here, and for shorts to say there is one (which involves prominent scientists like Dr Liau, as seen in the quotes above) may be overplaying their hands. NWBO can be a poor investment for many reasons - but not because of this one. Like Dr Paul Muholland says:
Original primary endpoint, when trial designed in 2007: Progression-Free Survival (PFS) While the trial was underway, Pseudo-progression (PsPD) became recognized as major issue -- difficulty distinguishing real vs. PsPD is an even bigger issue with immune cell therapies: vaccine-induced infiltration of immune cells PFS endpoint not feasible due to PsPD. So, SAP focused on OS, and specified OS as the primary endpoint before unblinding.
One more issue the bears which has confused investors is the crossover trial design and how that led to adding a crossover component to the endpoints. First, here's what Dr Paul Mulholland says about the need for crossover:
Crossover was necessary for feasibility and ethical reasons: Necessary for enrollment and retention of patients in era when immune therapies not yet generally viewed as promising for cancer Important to justify all patients undergoing invasive leukapheresis procedure. No benefit to placebo patients unless they could receive their autologous product made from the leukapheresis
In effect, 90% of patients went on to take DCVax-L over the years. There's a necessity to differentiate between crossover patients and originally DCVax-L randomized patients, which is why the new secondary endpoint was introduced. So again, I think this invalidates the bearish concerns.
Moreover, this also explains the following from the Paul Mulholland presentation:
OS endpoints could not be within-study comparisons of DCVax-L patients vs. placebo patients, because placebo patients received DCVax-L following crossover. So, the OS endpoints compared DCVax-L patients with external controls. This approach fits well with growing commentary in support of streamlined trial designs and use of external controls where classic within-study comparisons are not feasible.
This is why external controls were used; because internal controls, the actual patients, found DCVax-L so good that they went for it en masse.
These are the final data:
DCVax-L data
DCVax-L data (Company website)
The data speaks for itself. Look at those survival tail data. No other GBM trial has shown such improvements over historic controls in long-term survival curve tails.
Before I conclude, let's not forget the excellent safety data, which was comparable to placebo. Of nearly 3000 treatment injections, there were only 5 SAEs. Temodar has a terrible safety profile.
Financials
NWBO has a market cap of $707mn and a cash balance of $7mn. I mentioned a loan in my previous articles with an interesting angle:
Here's some detail on a new $15mn loan they received:
On November 22, 2021, Northwest Biotherapeutics, Inc. (the "Company") entered into a loan financing with Streeterville Capital, LLC (the "Lender") pursuant to which the Company received net proceeds of $15,000,000 (the "Loan"). The Loan has a maturity of 22 months. No payments are due for the first 8 months of the Loan term. …Upon announcement of the top line data ("TLD") from the Company's Phase III clinical trial of DCVax®-L for glioblastoma brain cancer, the Lender has a then springing right to exchange the outstanding balance of the loan for common shares priced at the price of the first private placement transaction following TLD less a 12% discount and to purchase another 50% of that number of shares at the same price. This then-springing right expires 14 days after the post-TLD private placement.
As it says here, the lender can transform the loan to equity if TLD is announced. I will wait to see if they do it because prices are back to where they were before. Since the company has now announced strong TLD, I am hoping they will get access to more funds to run this through the regulatory process.
However, longs must accept that NWBO's finances are in dire strait. They spent $13mn in the previous quarter, so they really don't have money to survive another. Expect fundraising on this data; we would be lucky if it is not dilutive.
Bottomline
NWBO is again a buy. These prices are low, and the stock, with excellent TLD, is now heavily derisked.
Fe Mikey. Have a Snickers already
Scotty. what did you see at 9.40. buy or sell 100k + order.