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Massimo Dr. Glenn 🧬🧠👽💪🏻📈 Here’s CNBC’s great piece which explains in layman’s terms what exactly is CRISPR-Cas9, interviews its co-inventor & Nobel prize winner Emmanuelle Charpentier, how $CRSP transformed this Gene Editing tool into the first ever FDA approved therapy - CASGEVY & its future plans $XBI
16,897 次观看 • 10 个月前 •via X (Twitter)
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![An interview by VERY DARK AND CORRUPT Wall Street Journal aired today [1] WSJ's terrible "journalists" (and I use that term lightly) made many false statements about Sarepta's worthless, dangerous drug and Vinay Prasad's firing [1,2] I explain how the FDA sausage is made in excruciating detail Buckle up To get readers up to speed -> In June, corrupt pharma company Sarepta Therapeutics paid $40,000 to lobbying group Michael Best Strategies (MBS) to deal with a problem [3] -> MBS had recently hired Chris LaCivita, who had close connections with "MAGA" influencer Laura Loomer [4] -> With stock down 88%, Sarepta needed to sell their very bad, very dangerous drug or the company would go bankrupt [5] -> After several deaths from the drug this year, FDA official Vinay Prasad said "no way" and kicked the drug to the curb [2,6] -> Sarepta panicked and paid MBS (we believe) to deal with Prasad [3,4] -> If this story is right, LaCivita recruited Laura Loomer to take down Prasad [4,7] -> Loomer said she was defending Trump, but she was lying [7] -> She was defending taxpayer-funded payouts to a worthless, corrupt company [7] -> Laura Loomer so brave A history of bad drugs and regulatory failure -> This is one of the worst pharma scandals in American history and corrupt mainstream media isn't covering it -> Sarepta has a very long, troubled history [8] -> For more than a decade, every major Sarepta FDA drug approval has required INTENSE political intervention [8,9] -> Scientists at FDA have been repeatedly overruled [8,9] -> Many scientists have resigned, very publicly, over these POLITICAL decisions, some writing scathing public criticisms of these terrible decisions [10,11] -> The most recent resignation by Vinay Prasad is not something new; it follows in a long tradition [2,10] -> In fact, standards have dramatically deteriorated since the first controversies about the company's drugs in the 2010s [8,9] -> Prasad was trying to hold the line in the face of rapidly deteriorating standards at the agency [2,6] -> For that, pharma launched a coup--a literal coup of a drug regulator [4,6] -> This is unprecedented -> Banana republic sht, unbelievably corrupt 2016: first Sarepta drug approval and the "highly unusual" decision -> The first Sarepta drug approved by FDA was called Exondys 51 [8] -> This drug was for patients with mutations in dystrophin, a muscle protein [8] -> This is a debilitating and fatal disease affecting children [8] -> Exondys 51 increased dystrophin by 0.2% of normal levels [8,12] -> Unsurprisingly, there was no good evidence the drug worked [8,12] -> Why would it? It increases the protein from zero to 1/500th of normal levels -> One reviewer wrote: "I can find no precedent of an accelerated approval for a marketing application where the effect size on the surrogate endpoint is as small as 0.3%." [12] -> The study submitted by the company included no proper control group [12] -> The techniques used were so bad not even a first-year PhD student would do a study that way -> This the level of work you would expect from a mediocre undergraduate with no guidance -> It's almost like it was so bad on purpose -> (Narrator: it was on purpose) -> Nerd time: -> One reviewer wrote: "The Western blots submitted by the applicant for Study 201 were oversaturated, unreliable, and uninterpretable." [12] -> Another wrote: "Because CDER also determined that the conditions under which the original IHC analysis was performed were inadequate, including that the reader was not masked to sequence and time, the Center requested a re-reading of the stored images by three masked pathologists under different conditions. The IHC results from the reread were not nearly as favorable, as compared to the initial IHC results reported by Sarepta." [12] -> "The lack of concordance between the IHC and the Western Blot results is 'striking'" [12] -> "Study 201/202 had fundamental flaws, including baseline biopsies from external controls who could differ in unknown ways from study subjects, Week 180 biopsies from different muscles than baseline, and potential protein degradation in stored baseline samples." [12] -> And on and on. -> FDA commissioner Robert Califf wrote at the time: the submitted study was "characterized by major flaws in the clinical study design" and "Blinded experts assembled by the FDA fundamentally debunked this study, which has yet to be retracted and continues to be cited" [9,12] -> That's right, the FDA commissioner expressed dismay that the study that the company used to gain approval hadn't yet been retracted, it was so bad [9] -> Senior FDA official Janet Woodcock decided to approve before scientific review team had even voted [9,12] -> Woodcock be like: yeah i'm going to decide before you guys can because i know what you're going to say lol -> Despite external intense pressure, FDA scientists voted against Exondys 51's efficacy [9,12] -> They then voted against its accelerated approval [9,12] -> The review team filed an appeal with FDA commissioner after "passionate" disagreement with Woodcock [9,12] -> One reviewer called Woodcock's decision "unprecedented" [12] -> In a 126-page report, FDA commissioner Califf called Woodcock's decision "highly unusual" [9] -> The FDA board wrote: "[Woodcock's] involvement here appears to have upended the typical review and decision-making process. ... Care should be taken to avoid the appearance of interfering with the integrity of scientific reviews at the lower levels of a Center." [9] -> Again, the data were unbelievably bad, literally every technique in the study was inappropriately used [12] -> I would fire an undergraduate student who did science like this, immediately -> FDA's chief scientist accused Sarepta of "serious irresponsibility" for selectively publishing only some of the data [9] -> Even Woodcock, who approved the drug, called the research "seriously deficient" [12] -> Yes, even the person who approved the drug over the heads of FDA's scientists said the research was horrible [12] -> Still, FDA tried to bury their heads in the sand and beg that, basically, Sarepta pretty please do a better job next time -> FDA commissioner: "The utmost attention should be paid to optimizing the methodological rigor of [future] trial[s]" [9] -> FDA also demanded a clinical trial "to verify the benefit" of the drug [8] -> Welp, this was in 2016 [8] -> The trial results are supposed to be available in 2026, maybe [13] -> Or maybe later, depending on how much money needs to be made first -> As an article published in Nature three years later despaired of the decision: "The approval was conditional on the company agreeing to conduct a two-year post-approval trial to show Exondys 51’s efficacy. But by August 2019, the company had yet to begin such a trial and in the meantime had profited from sales of $300 million in 2018." [13] -> If it sounds like Sarepta used political pressure to get its drug approved and then tried to avoid actually publishing the study showing it didn't work, it sounds that way because that's exactly what happened [13] -> FDA commissioner after deferring to Woodcock: "I am confident this unique situation will not set a general precedent for drug approvals under the accelerated approval pathway, as the statute and regulations are clear each situation must be evaluated on its own merits based on the totality of data and information." [9] -> This statement was profoundly naive, and the historical record bears this out [8,14] -> Three FDA scientists resigned, including the lead reviewer of the drug, understanding the grave implications of the collapse of scientific standards and where they would lead [10,11] -> One was John K. Jenkins, M.D. Director, Office of New Drugs Center for Drug Evaluation and Research/FDA [10] -> In a presentation given just before his resignation, he wrote: -> "Path taken by Sarepta NOT a good model for other development programs" [10] -> Crucially: -> "Upholding statutory standards for approval in face of hopes and desires of patients, families, sponsors, and investors is a very difficult job" [10] -> "Personal attacks on FDA reviewers creates an atmosphere of distrust and isolation rather than collaboration" [10] This brings us to WHY Sarepta's drug was approved Facebook FDA -> So why did the drug get approved? -> Basically, Sarepta propagandized extremely desperate patients [9,15] -> They used miraculous snake oil promises and patients believed them -> Remember that this is life or death for patients, and they are extremely vulnerable -> Sarepta also professionally trained some patients to give testimonials to FDA and congress [15] -> The patients then went to congressmen who don't have time to understand the science [15] -> They gave emotional stories to congressmen [15] -> The result: -> Letter from 109 House members [15] -> Letter from 24 Senate members [15] -> And a media circus documented in the New York Times [16] -> Patients screaming at scientists during meetings [9] -> 2,792 emails written to FDA urging approval [12] -> One of them: "Dear Dr. califf: How is it that everyone in and around DMD understands this simple Idea and the science geniuses at FDA don't? You stupid fckers are costing each and every DMD kids days of their lives with your Moronic Dystrophin dance. Time to get a fcking clue" [12] -> Upon approval, a journalist for Reuters wrote: "owing to pressure from patient advocates, the U.S. Food and Drug Administration on Monday approved a treatment for Duchenne muscular dystrophy even though an outside panel of experts and the agency's own reviewers questioned the drug's efficacy" [17] -> A commentary in Nature Medicine was also published called "Railroading at the FDA" [9] -> Its author wrote: "In the words of one FDA committee member, Exondys lowers the agency's evidentiary standard for drug effectiveness 'to an unprecedented nadir.'" [9] -> A highly critical commentary was also published in Science, titled "Sarepta gets an approval - Unfortunately" [18] -> The article's author pharma veteran Derek Lowe wrote: "The company... called up Duchenne-affected boys and their families to plead with the FDA, and won over Janet Woodcock, and that appears to be enough. Is this going to be the new way to get a drug approved? Run a trial in a dozen people, generate unconvincing data, and then lobby Janet Woodcock? I share the worries that this might open the floodgates, because after all, Sarepta got their drug through." [18] -> One FDA reviewer ended in an equally grim note: ". Approval of this NDA would send the signal that political pressure and even intimidation – not science – guides FDA decisions, with extremely negative consequences. The public is well aware of this development program: the meager size of the study population, the marginal (at best) effect size, the Division’s dim view of the efficacy data, and the robust activism of some members of the DMD community. Many would be amazed at an approval action, because other DMD drugs, recently turned down for approval, appeared to provide stronger evidence of efficacy. ...The ramifications here are profound. The public will perceive that it was their unprecedented lobbying efforts that made the difference and earned eteplirsen its accelerated approval. For the future, this will have the effect of strongly encouraging public activism and intimidation as a substitute for data, which is one of the worst possible consequences for communities with rare diseases. This type of activism is not what was envisioned for patient-focused drug development." [12] -> A new era was born -> Activism had replaced data -> Facebook had fried people's brains -> And now Facebook-fried brains had fried FDA too -> FDA's credibility as a regulatory agency would now be hollowed out -> FDA's Facebook age had begun -> But the worst was yet to come Sarepta approvals: 2016 to present -> Three more drugs were approved from Sarepta on the same shoddy basis, proving Califf's promises that Exondys 51 was an isolated case empty [8,14] -> But things would take a turn for the worse with Sarepta's newest drug Elevidys in 2024 [19] -> At last a rigorous clinical trial looking at actual clinical outcomes was published [19,20] -> All would be put to rest -> At long last the issue could be resolved with HARD CLINICAL DATA -> There was only one problem -> The trial failed to show any benefit according to the primary outcome [19,20] -> The surrogate biomarker of micro-dystrophin meant absolutely nothing; it wasn't actually helping patients [19,20] -> What did FDA scientists do? They voted against approval. Of course [19] -> How could they not? The drug didn't actually work in the clinical trial [19] -> It's the only thing that made sense, since FDA is a scientific agency -> AND THEY WERE OVERRULED AGAIN BY PETER MARKS [19] -> YES THAT'S RIGHT, OVERRULED YET AGAIN -> PHARMA WINS AGAIN -> HAHAHAHAHAHA PHARMA ALWAYS WINS YOU FOOLS -> What happened is that Marks crossed his eyes somewhat, trying to make the words on the page blurry -> He prayed really hard, "my god please give me a sign, something, anything, I need this for my career" -> lzzosolsolzzolzozlslzolosllslozllzlzl -> Marks was trying really hard to see SOMETHING, come on come on, give me SOMETHIGN he said -> And he said: wait, look, there are these secondary, exploratory endpoints and a two of them look pretty good, I'LL APPROVE [19,20] -> AHAHAHHAHAHA YES PHAMRA WINS AGAIN -> And Marks said, "Thank you pharma go- I mean god, not pharma god, why did I just say that, FCK" -> The trial was explicitly designed for what Marks did NOT to happen [20] -> Once the primary endpoint was not met, the secondary endpoints couldn't even be statistically tested [20] -> And the trial explicitly said that they could not be interpreted the way Marks interpreted them [20] -> They were not adjusted for multiplicity and they were, like expression of dystrophin, simply bad endpoints [20] -> These two secondary endpoints were time to rise from lying on the floor and the 10-meter walk/run tests [20] -> Subjects who received the Elevidys performed, on average, about 0.5 seconds better than placebo recipients on these tasks [20] -> However several facts must be borne in mind when interpreting these: -> 1. At the time of testing, patients receiving the drug were receiving more corticosteroids than placebo patients, biasing the results [20] -> 2. Blinding might have been broken because those receiving the drug experienced lots of nausea and vomiting from the drug (~70%) [20] -> 3. These differences were tiny and may be attributable to chance, since the natural course of the disease varies widely [20] -> Marks knows this but who cares? Pharma I mean Facebook needed to be placated Elevidys: the drug -> To understand why this is so messed up, one must understand a few things -> On a Bayesian basis, one must assume that Elevidys is harmful until proven otherwise, for two reasons: -> 1. All drugs are potentially "toxic", but some toxins heal: by default you must assume it is a toxin that does not heal because this is what is actually usually the case; you need evidence that it actually heals -> 2. Elevidys IN PARTICULAR must be assumed to be harmful until proven otherwise because of the very nature of the drug -> Let's do a breakdown of the basic science of Elevidys that supports this (Bayesian) hypothesis: -> Gene therapy that permanently integrates into human genome [21] -> Meant to replace dystrophin, the protein that these patients cannot produce themselves [21] -> Preferentially targets muscle but gets expressed everywhere [21] -> Killed three people this year [6,21] -> Costs $3.2 million per injection [21] -> Truncated version of the protein it is supposed to replace [21] -> 3X shorter than the real protein [21] -> Has to be truncated because the technology cannot create the full protein [21] -> Because it's an abnormal protein, it's foreign, so immune system attacks it [21] -> Patients injected with drug are basically given an autoimmune disease [21] -> Patients have to be given anti-inflammatories to fight the disease that the drug causes [21] -> Causes terrible muscle inflammation [21] -> Inflames the heart, heart walls thicken because of the inflammation [21] -> Blows up the liver, causes acute liver injury and death [21] Drug should actually be assumed harmful, not beneficial -> Given all of the above, since the drug failed to meet its primary endpoint, it should actually be considered harmful by default, not beneficial [19,20] -> In other words, what we would actually expect if we added more patients and did an even larger study... -> Is that the drug would do worse than placebo, i.e., patients taking the drug would do worse than those taking placebo -> Why isn't this the default interpretation? -> They are reading the study with an intervention bias -> An intervention bias is natural, which is why "do no harm" is such a central tenet of medicine -> If I may put forward a thesis: most of Vinay Prasad's 500+-paper body of work has been dedicated to demonstrating the "do no harm" principle empirically [22] -> Rose-colored glasses study interpreters are simply not applying this principle properly and are thus failing scientifically in the most fundamental way -> Incomprehensible -> Back in 2016, scientists were adamant that the approval of Sarepta's first drug indicated the profound deterioration of scientific standards [8,9] -> But this latest approval is even worse: actual clinical data is now being overruled -> No standards at all are being enforced anymore; anything can now be approved based on any evidence whatsoever -> What Vinay was trying to do was simply to stop the unrelenting downslide -> And his firing punctuated that downslide for what it was The WSJ segment -> When Elevidys was approved, former FDA chief scientist and one of the original reviewers of Sarepta's first drug Luciana Borio said: -> "I don’t know what to say. Peter Marks makes a mockery of scientific reasoning and approval standards that have served patients well over decades. This type of action also promotes the growing mistrust in scientific institutions like the FDA." [23] -> To return to this video, these two WSJ reporters show an incredible level of ignorance and arrogance -> Finley says that the drug is "clearly" beneficial by misreading the secondary endpoints, just like Marks did -> An FDA memo from last year says about these endpoints: "Under these circumstances, they are misleading and cannot guide any stakeholders—including patients, family members and caregivers, and prescribers—in making informed decisions about the potential benefit of treatment with ELEVIDYS." [20] -> It really doesn't get any clearer than that -> But these two journalists are overruling the actual scientists, just like Marks did -> One of the most incredible comments during this interview was the complaint that "90% of clinical trials fail", as if that's bad thing [1] -> It's actually a good thing; most drugs suck; failing in clinical trial actually allows us to use only the drugs that don't suck -> These people don't understand the most fundamental purpose of the clinical trial -> They think clinical trials failing is a bad thing, as if it means that patients now won't get to use a useful drug -> No, it's a good thing, because it means that patients won't be exposed unnecessarily to a useless drug that might harm them -> The level of ignorance really is unbelievable -> What's worse is that these "journalists" defend their decision -> But what they did is exploit social media hysteria caused by Laura Loomer [1,7] -> Following up on her heels with editorials, using her as pharma attack dog [1,4] -> This is a huge blow to WSJ's credibility, and they know it -> Unbelievably shameful Where do we go from here? -> The Vinay Prasad firing creates a serious crisis of credibility at FDA [2,6] -> Up to this point, we could call these approvals a difference of opinion, but as we've seen, that's a huge stretch -> But any illusion of that is now shattered: the firing shows that drug regulation is explicitly political -> Janet Woodcock: approve, keep job -> Peter Marks: approve, keep job -> Vinay Prasad: block, transparently fired -> Make a decision that is anti-pharma and lose your job: that's the message -> Who can trust any decision at FDA anymore? -> RFK Jr. and Marty Makary both stand behind Vinay Prasad [24] -> Trump went along with lockdowns, he went along with mask mandates, he went along with all of the Covid pseudoscience that he now decries -> He should reverse course and not go along with this -> Trump has created a profound crisis of credibility at FDA and needs to fix it](https://image.24vids.com/tw-1952294845248114806/amplify_video_thumb/1952292444621451264/img/SPXp7ZpvQZ3FQV7_.jpg)
!["We have sequencing from a colon [tumor] biopsy from a patient who was 4 times vaccinated...we can find [DNA] plasmids in there a hundred copies per cell. They're not exactly the same as Pfizer's, which is a real head-scratcher, but they're in there." Kevin McKernan (Kevin McKernan), Chief Scientific Officer and Founder of Medicinal Genomics, as well as former R&D lead of the Human Genome Project, describes for Nick Jikomes (Nick Jikomes) how he and his colleagues have sequenced a colon tumor biopsy from a person who took four COVID injections and have found DNA plasmids—almost certainly from Pfizer's COVID-injection manufacturing process—at a ratio of 100 per cell. McKernan notes that the plasmids, however, are "not exactly the same as Pfizer's," which "is a real head-scratcher." "We haven't published the work yet, but we have sequencing from a colon biopsy from a patient who was 4 times vaccinated. A year after vaccination, they had a colon cancer. They biopsied it that day, and then 30 days later, they died, and then they biopsied after, and we have sequencing on both the pre-mortem and post-mortem samples," McKernan says. The scientist and entrepreneur, often cited as the first person to find DNA contamination in the mRNA COVID injections, adds, "we can find plasmids in there a hundred copies per cell. They're not exactly the same as Pfizer's, which is a real head-scratcher, but they're in there." "There's two of them," McKernan says of the plasmids. "And one encodes spike and one encodes nucleocapsid. We don't know where the hell the nucleocapsid one's coming from." (For reference, a nucleocapsid of a virus is the protein shell or capsid that encloses the nucleic acid—DNA or RNA—content, providing protection and structure to the viral genome.) When asked why the plasmids wouldn't exactly match those used in Pfizer's mRNA-injection manufacturing process, McKernan speculates: "Do they have more than one [DNA plasmid] in circulation? Like, BioNTech got a different manufacturing plasmid than the manufacturing plant out here in the US because they're making these in two different locations? It's possible. Is there contamination in their laboratory, in the manufacturing of this, they get the wrong plasmid in their E. coli vat, and suddenly they've got a different background there?" "And we've gotta do everything on our end to make sure we didn't introduce it, which we're doing. We're running all types of experiments to show that there's spike expression going on. But there's any number of reasons that could explain this," McKernan adds. Note that DNA plasmids—small, circular, double-stranded DNA molecules capable of replicating independently within a bacterial cell—were understood to be used in the manufacturing of the mRNA injections, but should've been removed below a certain threshold established by regulatory authorities such as the FDA. (The DNA contamination may be present in vials at 1,000 times higher than allowable according to one article published by the Brownstone Institute covering this issue. Article title: "The Vax-Gene Files: An Accidental Discovery") "We've got a case now that we're zeroing in on that looked like the SV40 poly-A signal, which is a termination signal. It's a transcription termination signal. We've got a piece of that integrating into chromosome 21, and it's breaking a gene that's involved in cancer. So, that one looks really interesting," McKernan tells Jikomes. "That could be maybe the driver of this whole thing. But the program spits out a long list of potential integrations that we have to go through and verify which ones are real and which ones are artifacts and all that. So I don't wanna get ahead of ourselves on that. That hasn't been Sanger verified yet." (For reference, Sanger sequencing is a method used to determine the precise order of nucleotides in a DNA molecule; the SV40 promoter is a strong regulatory region from the Simian Virus 40 that drives high levels of gene expression in mammalian cells when used in genetic constructs; a poly-A signal is a sequence in DNA or RNA that signals the end of a gene, prompting the addition of a polyadenine tail to the mRNA during processing, which stabilizes the mRNA and aids in its export from the nucleus.) "But the copy number alone suggests that these things aren't fully fragmented. Right? These plasmids really shouldn't be replicating to a hundred copies per cell," McKernan adds. "They couldn't, they shouldn't be in there at that level, because if you just do the math on how much is in the vaccine, when you do an injection of this, this person has four vaccines...1.2 ml of Pfizer...went into about 87,000 mls [of] body volume. So you should have a massive dilution into your body. Yet when we're sequencing this and doing qPCR off the tumor, the CTs coming back off the tumor are almost as high as they are straight out of the vial." (For reference, qPCR—or quantitative Polymerase Chain Reaction—is a technique used to amplify and simultaneously quantify a targeted DNA molecule. "CTs" is a reference to cycle threshold; PCR cycle threshold is the number of cycles at which the fluorescence signal from the reaction exceeds the background level, indicating that the target DNA amplification has occurred.) McKernan goes on to say: "And even if it were an integration event [that is, the DNA plasmid integrated into the genome]...I think there could be two things going on here: There could be plasmids replicating episomally [in the cell] and there could be parts of them integrated. But if it were purely integrated and the plasmid was gone, we would not expect to see the copy number of what integrated to be higher than the copy number of the genome. Right? You'd get one integration into one chromosome probably. So it would be half the signal of what you get amplifying a human house gene like RNAP, which is what we use. You would get a similar CT if it integrated. Because if it were a driver mutation, the cells would take off, and it would maybe have one copy of that mutation with it. And as a tumor advanced, you would probably you expect to see a CT score in PCR for that region that was similar to the actual genome background. But we're not seeing that. We're seeing CTs that are that are way ahead. If it's a hundred fold up there, it's around six to seven CTs ahead of the RNAP gene, which is the human gene. And then when we do sequencing, we see the same thing. "The coverage of sequencing is like 100 to 200X in the plasmids [vs.] 1X of the human genome. So they're in this tumor at really high levels. And that tells us that it has to be replicating. And this was a formalin fixed tissue. So it's not like we could sprinkle plasmids on it from our laboratory to contaminate that and have them be translationally active. Formalin is like this process when you take a tissue and you Formalin fix it. It's like...carbon freezing Han Solo. Alright? So you can't add plasmids after the fact and get it to replicate on cells, and you can't add plasmids on the fact afterwards and get it to integrate. Like those things can only occur if the cells are live. So we're pretty certain we've ruled out that, alright, this isn't coming from us. The anti-vaxxers aren't pouring plasmids on this to create a story. "This has certain biological signals that show this was present in the patient when they were alive. We don't know the source of it. They were four times vaccinated, and one of the vaccines that they used was one of the earliest vaccines from December 30th 2020."](https://image.24vids.com/tw-1863041263756624246/ext_tw_video_thumb/1863040923929571328/pu/img/RqpWM1Dr-laLIXD0.jpg)
