patience_and_focus

I want to start off by saying that my response below is not meant to be personal. There is a lot of half baked articles out there not doing justice to the complexity of the situation and significant fiscal and other ramifications of this decision on the society. It is also going to poison the well, politically speaking, for genuinely good drugs that work and come with a high list price tag but eventually are cost effective over long term. Hence the passion. Lots (literally tens to hundreds) of significant physiological/neuronal changes happen in the brain of a person with alzheimers that is different from a healthy brain. One of them is growth of amyloid plaque. It was theorized that growth of this kind of plaque is the cause of alzheimers (and not just a side effect of something else that causes alzheimers and as well as plaque). So theory was tested - slowing/stopping growth of plaques should slow/stop alzheimers. Well, the drug does slow the growth of plaque but does not slow the disease. So what is the result - (a) theory is wrong and drug is useless or (b) drug is doing a great job as it slows plaque growth? Actually it is quite clear now that slowing plaque does not improve outcomes after 20 failed potential drug candidates going after the plaque theory. https://www.biopharmadive.com/news/biogen-aducanumab-alzheimers-fda-drug-review/600897/ "Over the past two decades, drugmakers have advanced more than 20 drugs aimed, in various fashion, at these "amyloid" plaques, only for every one to fail in clinical trials." 1. 40% patients (out of a ~1100) got brain swelling (35% soldiered on in clinical trial and 5% dropped out). Nearly 20% then got micro-hemorrhage. See table 3 on page 6 of the drug's official label information here - https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s000lbl.pdf. Biogen in 2019 halted the trial for futility of continuation (literally that was the reason given - I am not kidding). My take - they did not want to find out if they had actually decreased survival time of patients as alzheimers complications pile up over time resulting in death. 2. Its a 56,000/year drug that (a) will be administered for years in potentially millions of patients ($$). (b) has to be administered in an out-patient hospital facility every time as it is an infusion ($$) (c) followed up with very frequent MRI's and other tests to monitor side effects ($$) There are currently 6 million patients in US. If 1/3 ask for this in the next 2 years that is minimum 112 billion / year just from the drug. All this extra expense will be first absorbed by private insurance and medicare and eventually by the society for non-existent benefit and a whole bunch of side-effects. I have no problems with the price tag if the drug actually works. But it just doesn't (in contrast see Harvoni from Gilead - cure rate of ~ 90% , list price $84000 for 12-week treatment). 1. It is not a live clinical trial. Patients will not be screened / selected as carefully and there will be no placebo control arm (which by the way was as effective as this drug with hardly any side effects). 2. What we have learned from the 20 different drug failures in 20 years is that plaque theory (and its treatments), at least in its current form, are useless.

This assumes that there is a central body (govt or non-govt) with power to approve or reject a medicine. The other proposed alternative is the libertarian utopia where drug companies are free to peddle any drug for a disease and its up to consumers / patients to make sense of the data and go for one drug vs another. No central authority needed. Food for thought.

It should not have been approved in the first place. It failed 2 clinical trials. It works not much better than the placebo control arm (essentially like comparing to sugar pill / infusion). Biogen abandoned the trial midway. Then sensing the desperation in the community to find treatments (any crap new treatment for that matter in 20-30 years) pushed the drug through. https://www.biopharmadive.com/news/biogen-aducanumab-alzheimers-fda-drug-review/600897/ "The announcement came as a shock. Late in 2019, Biogen revealed it would ask the Food and Drug Administration to approve an experimental Alzheimer's disease drug that, just seven months earlier, the biotech had said was unlikely to work." "Strikingly, the regulator played a direct role in encouraging Biogen's reassessment of its negative clinical trial results — support that has little, if any, precedent." "Over the past two decades, drugmakers have advanced more than 20 drugs aimed, in various fashion, at these "amyloid" plaques, only for every one to fail in clinical trials." I think insurance companies should resist paying for it but will have no choice but to pay for this crap. Why should I pay more as my health insurance will go up over time because millions of people will be prescribed this medication for 56K/year that does not really work. Private insurance companies will have to foot the bill only to recoup that cost from others by raising premiums. At the end since it doesn't work, insurers will anyway have to pay for hospital care of these patients. If patients want the drug, they should pay the entire bill out of pocket.

Bumping up this thread. Aptevo is a biotech company which currently has one candidate in clinical trial and a couple about to enter clinical trials. Its bi-specific platform "ADAPTIR" has been around for quite some time (history goes back to Trubion acquired by Emergent which then spun-off as Aptevo and subsequently one of earlier lead candidate failed). Operates in the currently hot field of cancer therapies. One of their main candidates is APVO436 is in AML/MDS and has shown some activity and just released press indicates clean toxicity profile. On the corporate side, seems like an activist hedge fund already tried to take it private for $50 / share last year but was rebuffed. Currently the share price sits at around $25 / share. Given the new information on APVO436 in the Phase I and potential for buyout, would love to get input from others on the merit of this as an investment. I do not consider it a high probability winner but the risk / reward seems to be certainly skewed towards potential upside. Disclosure: Had bought some stocks with a small allocation in 2019 but sold out at the end of 2020 for decent gains. Desire to get into this again given the new developments and current stock price.

+10 I think most of the sovereigns (Uncle Sam and all other Uncles out there) like control over something as fundamental as currency. Even if say US govt allows for broader adoption of any crypto (pick your favorite here) it will want to control the generation and distribution of that specific one (just like the dollar) and make all others as irrelavant as possible. At that point, its just another govt backed currency. It so happens that it is driven by crypto tech and has some other nice properties including, if its even possible, "green tech crypto". But (pseudo) anonymous will not be one of them.

ok - let me rephrase. If there was a simplified 2x2 matrix with rows as "ease of use" and columns as "non-traceability and anonymity" for large money transfers / laundering here is what is it will look - Cash: ease of use - low (particularly with large sums and trans national transfers) non-traceability and anonymity - mid to high (you could in theory trace using serial numbers) Traditional bank / wire transfer ease of use - mid to high non-traceability and anonymity - low to non-existent Crypto ease of use - mid to high (depends on acceptance by various organizations and is dynamically changing and increasing) non-traceability and anonymity - mid to high (less anonymous than cash in theory but in practice requires equal or more resources to catch bad actors due to ease of use) There is already govt movement towards cash less society prior to crypto arriving on the scene in a big way. The combination of high ease of use + non-traceability and anonymity will make it prime target of govt regulators/law enforcement. I am not making philosophical point and right or wrong at this time. This is just the way it is.

I think people are underestimating the risk posed by non-traceability of crypto. Its not just financial mania and stability. The ability of sovereign (countries) to respond to things like ransomware and other cyber crimes for money transfers is compromised. It will become untenable when it will start to be seen from the lens of national security (not just from regulation standpoint). At that point hammer will come down hard on crypto - https://fortune.com/2021/05/13/colonial-pipeline-paid-hackers-5-million-ransom-cryptocurrency-ransomware-attack/ https://www.bloomberg.com/news/articles/2021-05-12/crypto-s-anonymity-has-regulators-circling-after-colonial-ransomware-hack

Why not? Can you elaborate a bit. I know very little about them at this point.

As much as I like this for shareholders, it seems to me that it is a gigantic waste of taxpayers money. Unless I am missing something big and obvious.

I'm using Azure and it is horrible, I'm using it only because of free credits. Maybe I'm too much dum-dum, but I never were able to wrap my head around how to use GCP and I do not know anybody who use it. I've used AWS 10+ years ago, GCP maybe 3-4 years ago, Azure now. I don't see much difference or any issues. There are always magic commands all over the place. You just learn them and you're fine. ./shrug. It depends on what you run too. For someone who just launches couple VMs and then works inside VM, there's not much to know about Azure/AWS/GCP/etc. For someone who needs to run cloud-specific workloads with a lot of cloud-specific tools/scripts/magic, yeah, you need to know the specifics quite a lot. 8) FWIW, we dumped DigitalOcean for Kamatera because for our user case it is sufficient to be hosting our services on VMs and most other cloud providers (AWS/Azure/DigitalOcean) are too expensive for our user case. Then there is serverless compute on demand that we need for our service. For that we use google cloud functions (FaaS) launched from the VMs.

Related to this, the FT commentary is a good high level read. The take at the end is that Intel's chance of success are rather low. Taiwanese chipmaker TSMC: the most important company few people have heard of https://www.ft.com/content/05206915-fd73-4a3a-92a5-6760ce965bd9 Some industry experts are sceptical. “I would say this is difficult because Intel tried this before a few years ago, and they could not make it work even though they still had the best process technology at the time,” says Sebastian Hou, head of technology research at CLSA, a brokerage. TSMC will not yield easily. With its huge capital investment plans for this year, the company has already signaled that it is determined to hold on to its lead. A “significant portion” of TSMC’s projected capital expenditure will go into extreme ultraviolet (EUV) lithography machines, equipment that is indispensable in cutting-edge fabrication units, says an executive at a semiconductor tool vendor. ASML, the Dutch company which dominates the EUV market, said on its most recent earnings call that its capacity falls short of demand. Industry insiders therefore believe that every order placed now by TSMC will help it keep any potential competitor at arm’s length. “For sure, the longer Intel takes to tackle their difficulties, the wider the gap will open,” says the semiconductor equipment company executive. “TSMC will remain unassailable for the time being.”

I am somewhat concerned at this point but not enough to fundamentally change my thesis. I also think I have a bit of cushion in cost basis in the event some new information around this comes out to be super negative. My mental model on these departures (there are at least 2 high level) is as follows - (a) Insiders know something negative about the overall corporate picture that we don't and are leaving; hence it is a negative. But I am not seeing that in the scientific data coming out right now post discovery of the AML/MDS cases (either in Sickle cell or CALD). Unless they are hiding something or outright fabricating I am putting this as low probability event. It is a really bad idea to hide data or other information in this field from FDA. Just look at Astrazeneca and their COVID vaccine approval status in the US. (b) The other possibility is that due to corporate changes people leave. This happens when there is a change of guard at highest level (see Amazon and Merck for recent departures after succession of new CEO) or in the case of bluebird a split. My current bet is that since the gene therapy part of bluebird is getting a new CEO, egos are hurt and/or there was friction between certain individuals. Clearly CMO was passed on for the role of CEO in gene therapy part of bluebird post split. Its not too hard to imagine that under these circumstances along with all the negative events on their gene therapy, people will leave. It could also be that the chief medical officer is taking the fall for recent events. © There is one scenario I can think of where it may be bad for bluebird. If infact bluebird revealed certain information to press first before they let FDA know about it and CMO thinks that this move has definitely irritated the FDA and will make them delay a decision on Lenti based therapy for Sickle and Thalassemia. I think the probability is again low in this case because bluebird was already being closely watched by FDA on their manufacturing troubles before they fixed it. It would be utterly foolish of them to not have taken FDA and/or other regulators/medical practitioners into confidence before releasing some of what we heard in the press. Plus, FDA has to keep in mind patient's well being. By acting in just pure vendetta and not based on scientific evidence, they could hurt patients. Of-course I could be wrong here but right now my mental model is not raising red flags on ©.

This is good outcome for their LentiD platform in CALD - https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-presents-long-term-data-elivaldogene-autotemcel-eli Effectiveness (Efficacy): 2 year MFD-free survival of 90%. "90% of evaluable patients (27/30) alive and free of major functional disabilities (MFDs) at two years follow-up in Phase 2/3 Starbeam study (ALD-102). Patients in long-term follow-up study (LTF-304) continue to remain alive and MFD-free through up to nearly seven years of follow-up, suggesting eli-cel stabilizes the progression of disease" Adverse Effects: "No events of acute or chronic GvHD have been reported post-eli-cel treatment. There have been no reports of graft failure or graft rejection. In addition, there have been no cases of replication competent lentivirus or insertional oncogenesis to date." The alternative treatment of HSCT does not seems to have either a better efficacy or a better safety profile - https://pubmed.ncbi.nlm.nih.gov/30292747/ Effectiveness (Efficacy): 2 year MFD-free survival of 84%. "For patients who underwent HSCT with GdE+ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%)." Adverse Effects: "Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT." Disclosure: long BLUE. Significant holding at this point.

I think that statement is hopefully correct but not necessarily correct though that is the mainstream media opinion. https://www.timesofisrael.com/transmission-rate-nears-1-as-officials-warn-purim-parties-could-halt-reopening/ Israel’s virus transmission rate has continued to rise and is extremely close to showing expanded spread, data released by a military taskforce showed on Sunday. "In its latest report, the Military Intelligence taskforce said Israel’s coronavirus transmission rate was once again nearing 1, standing at 0.99. The rate had dipped to a low of 0.8 earlier this month." https://ourworldindata.org/grapher/weekly-hospital-admissions-covid-per-million?tab=chart&stackMode=absolute&time=2020-11-22..latest&country=USA~ISR The Israeli new hospitalizations are still very high...133 per million for Israel vs 42 for US as of February 21st. Unfortunately country to country comparisons are not a good metric to show effect of vaccination on respiratory illness unless we take into account many other factors such as population density (400 / sq km for Israel vs 36 for US), mobility in a given timeframe, cultural practices etc. In-fact I would posit that country to country comparison is fairly useless. It is much better for example to compare regions within each country with similar characteristics to draw any meaningful conclusions. That is why researchers from Israel used pre vaccination vs post vaccination data within the same regions in Israel and within a specific time frame as one of the comparisons to get a handle on effect of vaccination on spread. This also allowed them to control for other factors. One has to slice and dice this complex data in many ways to come to meaningful conclusion. This data may not be perfect but is far better than arbitrary but broad country based comparison. https://www.medrxiv.org/content/10.1101/2021.02.08.21251325v1 Please read methods section. Here is a snippet - "Third, we used data with a higher geographical-resolution termed geographical statistical areas(GSAs). The GSAs are small, relatively homogeneous intra-city units defined by the Israeli Bureau of Statistics, with an average of 3,000 residents, within cities with more than 10,000 inhabitants." Their conclusion (which I agree with) is that vaccination is effective in reducing hospitalizations / deaths in places where vaccination percentages are very high and is still following other covid guidelines.

Thank you much for posting. This is very informative. Agree that there is positive undertone (spin if you will) from the CEO Nick Leschly. But if we keep that aside and just hear the new information revealed by the CSO Philip Gregory, it is more matter of fact (for first 10 mins at least) and is indeed positive. For the first patient with AML and vector in the leukemic cell, they also found 11q abberation, monosomy 7 and other mutations. It will be very hard to prove that somehow the vector is root cause (driver) of these abberations in one patient (N=1) when they look at other subjects with equal disease severity in this and other arms of the clinical study and don't see any evidence of leukemia. Here is the original paper published last year on one patient who developed MDS following LentiGlobin a couple of years back - https://ashpublications.org/bloodadvances/article/4/9/2058/455054/Myelodysplastic-syndrome-unrelated-to-lentiviral. For example monosomy 7 is known to be a risk related to busufan treatment and was alluded to in this paper- "The finding of monosomy 7 in this patient is expected in secondary myeloid neoplasia, including following exposure to alkylating agents such as the busulfan." Also if these 2 subjects are not treatment naive for Hydroxyurea (they switched therapies when getting on clinical trials for lentiviral therapy) then there is one more important potential driver of AML. I don't know if these subjects were on previous therapy. The CSO hints (starting at 7:40 min) they may do a genome wide RNASeq. I have worked with this kind of data. It very hard to figure out if there is a causal link between changes in transcription patterns and phenotypic findings. So the finding can be open to interpretation which may bode well for bluebird given all the other information. I do think there is a risk of slow adoption of gene therapy in the clinic given the current life expectancy of sickle cell patients (and even for thalassamia) plus factors tied to gene therapy (cost, conditioning agent requirement, perceived risk of cancer etc).