NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

Here’s Adam’s article in it’s entirety, and next, I’m going to pick it apart.

Maryland-based company developing an experimental brain cancer treatment called DCVax, said that it had collected enough clinical trial data to determine whether its vaccine could delay the growth of tumors longer than standard of care.

In other words, the randomized, controlled study was ready to be analyzed.

NWBO never said that. Yes, they did state they had reached 248 PFS events - which was the “threshold” for the trial; however they also stated in their February 6, 2017 PR that they would continue to accumulate PFS events as the trial continued. That does not sound like it was ready to be analyzed, as much as some of us would like some analysis.

https://www.nwbio.com/nw-bio-announces-lifting-clinical-hold-dcvax-l-phase-iii-trial-fda-progression-free-survival-events-reached-overall-survival-events-not-yet-reached/

By the way, "threshold" is defined as: the magnitude or intensity that must be exceeded for a certain reaction, phenomenon, result, or condition to occur or be manifested.

One year later, Northwest Bio’s pivotal Phase 3 study remains open. The DCVax data have not been analyzed or disclosed. Institutional investors have largely abandoned the company. Its stock trades for pennies on an over-the-counter exchange. And development on its only other drug has been stalled for years due to lack of funding.

The company stated at the ASM (which Adam also cites in his article) that they have analyzed the data every spring. What he is only correct about is that they haven’t disclosed it.

Even by the most lenient standards, investigators involved in Northwest Bio’s trial and outside cancer experts say that its reporting delay has been extraordinary and casts doubt on the study’s outcome.

You’ll see later how no investigators involved in the trial state what he states here. And so who are these so-called experts stating this is extraordinary who ARE investigator’s in the trial? There are none. There are just two “outside cancer experts.”

“The total lack of transparency is really unique. We work with a lot of companies and have a big clinical trial program, but I have never seen anything like this,” said Dr. Don O’Rourke, a neurosurgeon and brain tumor expert at Penn Medicine in Philadelphia. O’Rourke’s hospital enrolled brain tumor patients into Northwest Bio’s study.

Guess what, Dr. Don O’Rourke is NOT an investigator. The hospital he is affiliated with did enroll patients, however. But Dr. Don O'Rourke is chasing a different treatment modality in GBM - he is the the lead investigator on a… drum roll please… CAR T trial for glioblastoma (ahhhh). In fact, he’s loading the CAR Ts with EGFRv3 (double ahhhh).

Let's see if that doesn’t color every quote for you that he makes thereafter.

Dr. Don and CAR-T:
https://www.pennmedicine.org/news/news-releases/2016/april/pennled-team-presents-results

Biotechs generally enjoy some latitude when it comes to the timing of closing trials and reading out the data. But delaying trial results by one year, as Northwest Bio has done, is highly unusual, experts say. Investors can sometimes be kept out in the cold for too long, and patients left wondering whether an experimental treatment may one day be deemed effective.

So no one can think of a trial that’s delayed their results by a year?

AstraZeneca did for it’s PD-L1 MYSTIC study. I don't know how long they delayed it for but I know they delayed it. But Adam probably forgot them.
https://www.fiercebiotech.com/biotech/astrazeneca-delays-pd-l1-data-rejig-late-phase-program

“It’s the only time I can recall this happening in my career,” O’Rourke said.

O’Rourke forgot them too.

A DCVax study investigator, Dr. Tobias Walbert of the Henry Ford Health System Hermelin Brain Tumor Center, is also frustrated by the lack of updates from Northwest Bio. “No one really knows what’s going on. The study appears to be in limbo,” he said.

Cue Adam to the phone, he calls Dr. Walbert (who actually is a PI for the trial), who states no one knows what’s going on. If he’s a co-author, then he knows what’s going on, he just ain’t telling Adam. If he’s not, well then too bad for him. Remember I did suspect Adam was calling these people.

Northwest Bio has long denied that any interim look at the Phase 3 returned a futility verdict on DCVax. The company did not respond to a series of questions submitted for this article.

lol, like they are going to tell Adam anything. By the way, the subject of a futility verdict on DCVax has been discussed forever here. If one thinks a futility recommendation was made, I’d consider looking at who would make such a futility recommendation. Then, like with Dr. O’Roarke, I’d look to see what they might stand to gain by making it. Just saying.

But executives, speaking at an annual shareholder meeting on Jan. 21, reportedly shifted their priorities away from a timely reporting of study results.

According to multiple accounts of that meeting, the company is now focused on writing a scientific paper that will describe blended survival data collected from all brain tumor patients in the study, regardless if they were treated initially with DCVax or the current standard of care. (The study allowed control arm patients to cross over and receive DCVax when their tumors started growing again.)

Okay, he reported something accurately.

“The total lack of transparency is really unique. We work with a lot of companies and have a big clinical trial program, but I have never seen anything like this.”

DR. DON O’ROURKE, ENROLLED BRAIN TUMOR PATIENTS INTO NORTHWEST BIO’S STUDY

Consider the source people. This is coming from a big CAR T fan here who is NOT a PI for this trial.

Not everyone agrees with the approach. Dr. Vinay Prasad, an oncologist and assistant professor of medicine at the Oregon Health and Science University, believes Northwest Bio is merely trying to misdirect people away from the fact that DCVax does not work. Prasad has no ties to Northwest Bio and did not participate in the DCVax study.

“As a general rule, when you see endpoint switching, when you see delays in reporting results, when you see a company declining to unblind a study after the sufficient progression-free survival events are reached, and when you hear talk of taking a randomized trial and making a historical comparison — it is hard not to reach the conclusion that a product is more than likely an abject failure, the data are negative, and these efforts are merely a desperate attempt to salvage something,” Prasad said.

I can’t find this quote attributed to Prasad elsewhere, so it would seem he said it directly to Adam. I had thought Adam and Prasad didn’t get along so I’d initially suspected he’d found this quote in another article and used it, because Prasad is pretty well known for endorsing this perspective.

But I will point out that Dr. Prasad also was interviewed back in October 2016, and that he stated that when a trial is based on the rate of death (OS), if it takes longer for people to die, guess what? It’ll take longer to generate the result.

Here's what the outside cancer expert Prasad said (it's actually pretty interesting),

I hear that point a lot. Does waiting for survival take a very long time? That’s built into this question. That’s actually, to some degree—I hate to say it—it’s kind of a fallacy. And I’ll tell you why. The time it takes to generate a statistically positive result is, in some way, contingent on the rate of the event, which is death in this case. And, it is contingent on the rate of death; the longer that takes to happen, the longer it takes to generate the result. But it is also contingent on the sample size, and many modern trials have huge sample sizes.

We’ve looked at many of the oncology trials, and these trials that are being run in oncology are huge trials. We’re running oncology trials that are so powerful, they can detect survival benefits in a very short period of time. They are often overpowered to detect trivial differences.

The other thing this is all contingent upon is which indications do you develop cancer drugs for first? I think it is a mistake to think the manufacturers’ intent is to bring the drug to market as fast as possible. Manufacturers’ incentive is to bring the drug to market with as large a market share as possible. And in doing so, they often make decisions to chase a surrogate, even if that takes a longer period of time for a large indication. We have some examples of drugs that could have been brought to market even faster if we went for second rather than first line in a particular cancer.

So where should we allow surrogate endpoints? I think we should allow them in cases that are dire, where without a drug approved on a surrogate, people will pass away in a short period of time. I’m okay with them when there are a few other treatment options, for people who have very few options, like melanoma maybe five, six years ago. That’s where you want an accelerated approval. There’s literally nothing else we have to give people with that condition.

https://www.managedcaremag.com/archives/2016/10/conversation-vinay-prasad-md-first-do-no-harm-you-must-start-good-evidence

So back to Adam’s recent hit piece.

DCVax is a bespoke vaccine made from immune system sentinels called dendritic cells that are harvested from the blood of patients. These immune cells are exposed to a sample of each patient’s brain tumor in a lab. When re-injected into the patient, the trained dendritic cells, now known as DCVax, are supposed to find and kill cancer cells.

Yawn.

The challenge with this approach is that cancer cells have developed myriad ways to hide from or fight off dendritic cells, even when exposed to tumor targets in a lab. Similar vaccines developed by other biotech companies have failed. Dendreon’s prostate cancer vaccine Provenge is the sole exception, but the company eventually went bankrupt because the product could never overcome complaints about its cost or skepticism from doctors about its efficacy.

Uh huh. Blah, blah. But wait, Adam thought Rindo was going to do fabulously targeting the same EGFRv3 that Dr. Don is targeting with his CAR T GBM treatment. And we all know how Rindo turned out. And I thought Provenge was still being used, or did I miss something?

“The notion of treating patients with an individualized dendritic cell vaccine is not something people are endorsing right now,” said Penn’s O’Rourke. “The cancer immunotherapy field has moved on to checkpoint inhibitors and engineering of T cells.”

No surprise there. Of course Dr. Don thinks that.
But I have to ask, since when did the industry back dendritic cells? I also want to remind you that phRMA did feature this ad in late 2017, so I’m kinda thinking they are thinking they may be moving on to dendritic cells. I'll just feature their ad again here in my post. :)

The company hopes these blended survival data, compared against historical survival data published in the medical literature, will show DCVax helps brain tumor patients live longer and provide clinical evidence that could support the product’s approval. Northwest Bio is seeking to have the paper published in a medical journal.

Finally, Adam gets it.

Northwest Bio has been working on its experimental DCVax therapy for almost two decades, or roughly twice as long as most drugs take to move from discovery to regulatory approval.

Unfortunately, it takes awhile, as Dr. Prasad forgot he said earlier, it takes longer when every one is living longer.

The current DCVax Phase 3 clinical trial is now in its 10th year. By comparison, Celldex Therapeutics finished a randomized, controlled Phase 3 study of its own brain tumor vaccine in a little more than four years. The Celldex study enrolled twice as many patients as Northwest Bio’s DCVax study. It also failed.

Well a lot of us here kinda predicted Celldex would eventually fail, right? Their vaccine killed off the EGFRv3 protein, but so what? The tumor just came right back without it.

In August 2015, drug regulators placed a clinical hold on the DCVax study, preventing Northwest Bio from enrolling new brain tumor patients. (Treatment was allowed to continue for patients already in the study.) Northwest Bio never disclosed the reason for the clinical hold — another sharp departure from the norm, particularly for a publicly traded biotech company. Material events involving clinical trials are usually disclosed with more transparency.

Material events that could effect biases in blinded clinical trials are not usually disclosed, of course, unless they are bad. So I’m going out on a limb here, but… it must not have been bad. Or rather, it probably turned out not to be bad. Though there may have been a few involved who were bad seeds maybe even receiving honoraria that really tried to push the concept that it was. I wonder if there were, were they taken out of the loop and no longer had access to the information? Just a WAG.

The Food and Drug Administration lifted the hold in February 2017 — 18 months later — but in exchange, Northwest Bio agreed not to recruit any additional patients, meaning the study fell short of its enrollment goal.

Wrong, wrong, wrong. Now please don’t tell me Adam used ex and Avii as his “outside cancer expert" sources? lol. Anyway, NWBO announced on December 8 that they believed the “potential benefits that could be obtained from enrolling the final 17 patients would not be worth the time it would take, as the process of re-starting and re-training the sites (including through Institutional Review Board renewals) for further enrollment would take months, followed by further months for the recruitment itself.” Then on Feb 6, 2018, almost two months later, they announced the halt was lifted. My guess is that the FDA saw the light, and whatever might have been promulgated by people who might have been receiving honoraria who may have had a conflict of interest, or two, was finally chewed up and spat out. IMO

And now another year has passed. Inexplicably, Northwest Bio has become less communicative.

Yes… although the ASM note did provide us with some new insights. Adam too, but he, as usual, misunderstood them when he reported them.

“I don’t know what happened to the clinical trial since it was halted,” said Dr. Jana Portnow of the City of Hope National Medical Center in Duarte, Calif.

Hahahahaha. Dr. Portnow is a PI for the P3 trial. Her answer could be true, or it could be what she felt was the appropriate answer to give Adam who was obviously calling the PIs in the trial.

For investigators like O’Rourke, the company’s reluctance to analyze the clinical trial has only one likely explanation.

“I don’t think DCVax will wind up being the answer.”

Of course, O’Rourke is not an investigator in the DCVax-L trial so how would he know?

I’ll instead take the opinions of the 65 co-authors on the upcoming article over his. I’m sure this outside cancer expert Dr. Don O'Rourke has absolutely no idea what is going on with the DCVax-L trial.

And that's it in all its not very exciting entirety. :)

https://www.statnews.com/2018/02/15/northwest-bio-clinical-trial/?utm_source=STAT+Newsletters&utm_campaign=42879d981d-Readout&utm_medium=email&utm_term=0_8cab1d7961-42879d981d-150144869