Pfizer, Embrel, and Alzheimer’s
I’m getting my medical news from the front page of The Washington Post where Christopher Rowland discusses the possiblity that embrel, an anti arthritis drug, reduces the risk of Alzheimer’s dementia.
The issue is clearly incredibly important. The article raises interesting ethical, economic, statistical, and biological questions.
Better to click the link, but I will attempt a quick summary. There is evidence from anonymized insurance claims records that people who take Embrel for arthritis are less likely to develop Alzheimer’s. This hypothesis could be tested against the null of no effect with a huge long lasting extremely costly clinical trial. The patent on Embrel is about to expire. Obviously the Pfizer executives decided not to fund the trial. They also didn’t publish the retrospective study (it seems someone leaked it to Rowland).
I am most interested in the biology. Pfizer claims that they decided this, because of scientific evidence that Embrel wouldn’t work. In particular it does not cross the blood brain barrier. The argument is that it can’t help the brain without entering the brain. This is nonsense.
Embrel binds the appealingly named but nasty protein hormone tumor necrosis factor alpha (TNF-alpha). TNF-alpha promotes inflamation. It has a role in fighting tumors. It also causes cachexia wasting away of cancer patients and tuberculosis patients. It was discovered two ways. One group was purifying the wonderful TNF, the other the evil cause of cachexia which they called Cachexin. Both were surprised to discover they had purified the exact same molecule.
embrel binds and blocks TNF-alpha. It is a soluble form of the TNF-alpha receptor which competes with actual receptors which send a signal to cells when they bind TNF-alpha. It is a very important treatment for rheumatoid arthritis.
I say it doesn’t matter than embrel doesn’t enter the brain, because TNF-alpha does. If embrel binds TNF-alpha the dimer doesn’t enter the brain. If TNF-alpha in the brain causes Alzheimer’s then Embrel can reduce the risk by inactivating TNF-alpha which would enter the brain (also keeping it out of the brain but that doesn’t matter).
Pfizer’s argument is like saying that strangling someone can’t cause brain damage, because the strangler’s hands don’t enter the brain. They block oxygenation of hemoglobin which does enter the brain. The argument is silly (and effectively refuted by Rowland and scientists he interviewed).
I mean it’s obvious that inflammation spreads. That’s why cold viruses in your nose make you feel aches and pains all over (that one is interferon not TNF-alpha but the logic is the same).
There is fairly extensive evidence that inflammation has a key role in Alzheimer’s.
Of course the economics is also very clear. A huge investment in finding a new use for a molecule whose patent is about to expire is absolutely inconsistent with any duty to shareholders. This is clearly a case in which the government should fund the trial.
The statistical or methodological issue is that doctors will not trust non experimental evidence. The FDA has very strict rules for approval of a new pharmaceutical and for advertizing a new use of a pharmaceutical. They do not have to be applied to the decision of whether to prescribe a pharmaceutical off label (not for the use for which it was approved) but they are. The idea is that prescribing something with known and very minor side effects without knowing it will work is irresponsible. The logic is completely different from maximizing the expected welfare of the patient (in this case the healthy adult).
The idea that non experimental evidence is highly suspect and to be used only to propose experiments is alien to me. The rules which are called medical ethics seem to me to have very little relationship with the actions which are, in fact, morally right and morally wrong.
I think everyone should take Embrel (as soon as it is off patent and affordable). I also think there really should be a publicly funded clinical trial (which will be possible because no one will take the advice I gave in the past paragraph).
update: pulled back from comments. My knowledge of US pharmaceutical regulation is out of date (30 months out of date, but that’s out of date). I said non experimental data should be considered. So did Congress and Barack Obama and their signed act is law.
Run75441
June 5, 2019 6:59 am
It became far easier to bring things to market under the recent passage of the 21st Century Cures Act.“The 21st Century Cures Act modified the FDA Drug Approval process. It was intended to expedite the process by which new drugs and devices are approved by easing the requirements put on drug companies looking for FDA approval on new products or new indications on existing drugs. For instance, under certain conditions, the act allows companies to provide “data summaries” and “real world evidence” such as observational studies, insurance claims data, patient input, and anecdotal data rather than full clinical trial results.”
Pharma R&D is given the normal tax break also.
Someone is lying.
Pfizer might have decided not to publish the data back before December 13 2916. In any case, they don’t need FDA approval to publish data (1st amendment and all that). They need approval to advertise a new use of Embrel, but they can publish the data.
It seems clear that their problem is that Embrel is going off patent and will soon just be competition for their newer still on patent drugs. The news is out (as of yesterday on the front page of the Washington Post).
It became far easier to bring things to market under the recent passage of the 21st Century Cures Act.
“The 21st Century Cures Act modified the FDA Drug Approval process. It was intended to expedite the process by which new drugs and devices are approved by easing the requirements put on drug companies looking for FDA approval on new products or new indications on existing drugs. For instance, under certain conditions, the act allows companies to provide “data summaries” and “real world evidence” such as observational studies, insurance claims data, patient input, and anecdotal data rather than full clinical trial results.”
Pharma R&D is given the normal tax break also.
Someone is lying.
Mylan (EpiPen) has filed patents from 2005 and onward to keep Teva out of the market with their version and has used patents to block a Teva generic version (based on EpiPen procedural usage being followed for a Teva generic product) their name brand version. It can not be a generic version if it can not be applied in the same manner.
There is something else going on with this. I would bet if the Enbrel is validated, it will cause other remedies in place or coming through the process of validation to be less applicable causing them to lose money in R&D. Somebody knows . . .
Reducing the risk of Alzheimer by 64% is a big deal.
Enbrel is Etanercept. Here is one study on 12 people done back in 2008. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease
T Tests: Two-tailed, paired t-tests were conducted comparing baseline performance to 6-month performance on all neuropsychological measures. T-tests were conducted comparing baseline assessment scores to 6-month assessment scores. Standard T scores were used in the CVLT-II 1–5, TMT, and Verbal Fluency analyses, and standard z-scores were used for WMSa, and secondary CVLT-II measures analyses, while raw values were used for the Boston Naming Test. As can be seen from the figure (Figure 1), all measures revealed a significant effect except for the Boston Naming Test and the TMT-4, with WMS-LM-II being marginally significant at p = .05. The FAS test for letter fluency [40, 41, 42] was most highly significant with a p < 0.0007. The chart is there so you can read and look yourself. Something else is going on here. I am sure you will have no problem interpreting the stats yourself and far better than I can.
This story is so unbelievable. 64% reduction in Alzheimer possible and nobody benefits. Reminds me of a new medical device I read about in Medical News Today five years ago. A pumping assist device for heart failure that works outside the heart and blood vessels, so there’s no concern for clotting or infection and that for the first time ever actually brought improvement in some patients and stopped progression in most.
Last I heard they wanted to move to third stage testing with 200 patients but could only get 100 subjects together, for lack of $30 million more dollars. That’s about $6 per American heart failure sufferer. They claim to have switched off to something else but nobody’s heard much from them since I believe. Meantime, half a million Americans a year die from heart failure. Nothing like making scientific progress a pawn of speculators.
https://www.medicalnewstoday.com/articles/283566.php
Lately, a drug I used to take for Type 2 diabetes (I’m now in remission probably thanks to the drug), Bydureon has been shown to stop Parkinson’s progression in it’s tracks in mice trials in 2010, in open label trial in 2015, in double blind trial in 2017 and maybe some day someone will get around to third stage, large double blind trials.
Astrazeneca couldn’t be bothered to do second stage trial because its patent was running out. Michael J. Fox Foundation had to pay for the second stage. Great scientific research system we’ve go going here.
Meantime we continue to pay Gilead and other big pharmaceutical firms $200-300 billion over 20 years NOT to cure Hepatitis-C nationwide in one year for one billion dollars. Maybe India has wiped the virus out at $999 a treatment — but there is so much deep poverty over there that access may be limited just by ignorance. Meantime, over 20 years a half a million may die and many times that be seriously harmed — as the disease continues to spread.
First class research system.
The problem is that Pfizer, and every other drug company, runs into situations like this repeatedly. They are constantly getting what seem to be good leads, but when they expand the trial and design a proper controlled experiment with real endpoints, the effect simply vanishes. This happens again and again. Proper trials are expensive and can take years. Every company has its own internal politics and voodoo for screening. I’m guessing that Pfizer and the others bury dozens of similar leads every year. I know they follow up dozens, and only rarely do they wind up with a useful drug.
My usual source for stuff in the drug business is In The Pipeline blog over at the AAAS. It’s popular with pharmaceutical chemists in particular. The author is one and the comments, often drug development war stories, are most informative. I’m guessing the author will have a post on this latest in the next week or two. (The blog author worked at Pfizer at one point.)
A large percentage of research is tax deductible. The prices charged more than covers the failures and costs at a rate of $14.50 to every $1 invested (recent WHO study https://apps.who.int/iris/bitstream/handle/10665/277190/9789241515115-eng.pdf?sequence=1&isAllowed=y).
EpiPens do not cost (mfg) $600 per pack, Vimovo (Naproxen and Esomeprazole) does not cost (mfg) $2600 for 60 tabs, and the same with many other drugs on the market today such as the decades old Humalog for diabetes at a ridiculous price.
Novartis CEO applied the “value-based” analysis to justify pricing for Kymriah used to treat unresponsive b-cell acute lymphoblastic leukemia when there are no other options for them or their families. It is a one-time treatment with follow-up treatments far less frequent than traditional therapies. Here is what they believe should be charged for this treatment.
Using an independent expert body assessing cost effectiveness of medical treatments, it was said Novartis could charge a price covering the cost effectiveness value of up to $1,688,000 for Kymriah for its use in children. The value the treatment considered the four key measures to set the Kymriah list price for pediatric use at $475,000, which is well below the cost effectiveness value set by this body, and $373,000 for rapidly progressing adult cancers. Those 4 key measures I pointed out in a recent post?
The improvements they offer to patients both clinically and in terms of their quality of life, and the benefits they offer to the health-care system and society more generally. Novartis CEO Vas Narasimhan. I am sure Novartis could offer coupons to mitigate much of the cost and shuffling it off to insurance to pay for through Pharmacy Benefit Managers.
What will you pay for a glass of water in the desert if you are days away from it?
Like I said earlier, this is not an argument over costs. It is a discussion of whether it works or not. If you go to a LINK I provided Robert, it will take you to one particular study performed in 2008 with 15 people. Attached to this study are other studies performed earlier. Briefly, the end result of these studies was an improvement in cognitive abilities.
The WaPo article, I believe is hinting at something more recent. I also wonder why Pfizer (or whoever owned Enbrel at the time) did not move forward with the findings.
“Of course the economics is also very clear. A huge investment in finding a new use for a molecule whose patent is about to expire is absolutely inconsistent with any duty to shareholders. This is clearly a case in which the government should fund the trial. ”
For profit science is FUNDAMENTALLY wrong. The problem is that when we decide what is important solely on the basis of how much money it can bring a particularly actor, we are not doing science anymore because the goal of science is to find OBJECTIVE truth (so are pre-filtering what we look at, some of which is the truth we are supposed to be seeking). I wish I could get people to understand this. Maybe I’m saying it wrong somehow.