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>>Has anyone come up with a (credible) theory that Alzheimer's is more than one distinct disease or perhaps has multiple factors that lead to the later stage symptoms?
Maybe ALS is a good analogy. There are currently seven distinct genes that are currently known to cause familial ALS. The genes are mostly all quite different from each other, although you can kind of see how most (but not all) might have something to do with protein disposal. So basically familial ALS must be multiple diseases ending in a common pathway (as the eventual brain pathology is indistinguishable).
>>What proof is there that brain amyloidosis correlates to AD anyway?
Well there is certainly a strong correlation. But nobody knows if it is causal or an epiphenemenon, or even if it is causal, whether reducing it would help in an established case.
>>$AZN news -- FDA accepts application for PD-L1 durvalumab in bladder cancer
Very weird to halt a big pharma for news like that.
I really don't think you need anything more to explain the sector moves than the Trump statements plus the momentum traders.
The threat of drawing Trump's attention will certainly concentrate the minds of the industry - so expect high profile pricing increases to be a thing of the past. Trump would like nothing more than to have some company rescind a price increase after he tweeted about it.
REGN to date the best behaved by far on pricing of a high priced drug (Eylea).
>>That increases the FCF and value of those companies a lot. Money losing companies do not get that bump.
But still increases their NPV (assuming people think rates will stay low).
If your theory was correct, there should be a big discrepancy between the profitable biotechs with high tax rates (should be strong) and those with low rates and the unprofitable ones.
>>10b5-1 selling is rules-based
And you can make any crazy rule you want. So you could say sell when the volume on some day exceeds a minimum.
On twitter, some folks I follow have been complaining about BLUE CEO's sales, which they complain are irregular and seemingly well-timed.
Of course in theory a company could decide when to release (certain) news based in part on the timing of upcoming sales. But I really doubt that actually happens except very rarely indeed.
>>(ALK+) advanced non-small cell lung cancer (NSCLC) treated with first-line Zykadia (ceritinib) had a median progression-free survival (PFS) of 16.6 months
Worth pointing out that that PFS is about the same as for 2nd-line brigatinib (15.6 months) after first failing on crizotinib.
There are only two horses left in this race - Alectinib and the somewhat better Brigatinib. Alectinib of course has a lead to market of a year or more and more marketing muscle. But Briga is the better drug, particularly after criz failure (because of brain mets).
That's the article that puts Sprycel and Tasigna in the "no evidence for improved QOL" bucket. Can't take this methodology seriously.
>>From the MOA of anti-CD47 I am a bit surprised the strategy is monotherapy.
Well of course they have to start out in monotherapy. They are running a ritux combo that might be very interesting based on preclinical results.
For PD1 combo they would have to partner first.
They did get asked about occupancy. Said they weren't ready to disclose individual patient data yet. Right now they don't have tumor CD47 occupancy - they are using leukocyte occupancy as a surrogate. The next set of trials should allow actual tumor occupancy.
I think they might have implied that some of the variability in occupancy comes from differential levels of CD47 expression in different tumors. I'd have to re-listen to check that.
They also noted that some of the attenuation in platelets over time might simply be the bone marrow revving up. So unclear if the RBC story plays out on platelets too. (RBCs are much longer lived, so not necessarily a good analogy).
They did discuss half-life - pretty variable, but clearly increasing over time.
From a science perspective it would be much better if this was a big company that could do much more extensive dose ranging studies.
Peter
>>So is tril now the current leader in cd47?
Seems that way to me. They started about 1-2 years behind but have now clearly at least caught up, if not moved into a modest lead.
Maybe retail's expectations were too high here - they maybe expected the tumors to be all eaten by now. :)
(TRIL - Copy of my SI post):
TRIL CC was mostly color on ASH poster - (decent) questions from analysts mostly rehashed stuff that has been discussed here and on Ihub.
There was a question about the best responses coming at the lowest dose. Company was very much aware of that but basically said too little data to draw any conclusions. My take is it could be coincidence, but I suppose also possible that the drug at higher doses is adversely impacting leucocytes in some way.
Impact on platelets at the 2mg dose is clearly manageable - might be more of a challenge in AML though. But they will allow platelet transfusions.
Notable that the patient with prolonged stable disease at the lowest dose (first patient enrolled) exited the trial only because they were moving.
Good risk reward at these levels I think. There is clear activity and good safety and I suspect one of the PD1 players will come calling soon.
Peter
I made some further TRIL comments on SI, copied here:
Couple more comments:
1. Dose effectively increases over time, they claim because of target-mediated clearance. Maybe the older platelets are getting removed and so less drug clearance.
2. Even though the effective dose increases over time, the impact on platelets is actually lessening.
3. The 2mg dose is same ballpark as the 3mg human equivalent from highest tolerated non-human primate dose.
4. So at this point I really don't have a dosing concern.
5. With less sick patients, you could expect longer sustained dosing which might improve responses.
Note also that decent chance these TRIL patients had previously failed PD1 as well.
Basically as you get more and more treatments in some disease the severity of your Phase I oncology patient populations increase over time.
>>Why start in lymphoma if you expect best results in AML?
Because AML Phase I patients are all frail, elderly and already have all sorts of hematological issues (in particular anemia), so it's hard to tease out safety and dosing.
I had some preliminary thoughts here:
http://www.siliconinvestor.com/readmsg.aspx?msgid=30872810
>>So how would you reconcile that with the Ladenburg call
There is indeed clearly a tension between those two positions. But it's not unreasonable for them to want see what happens if you do flood the tumor. The current dose could likely be increased if need be with some supportive measures or using a higher dose with longer intervals.
It's a brand new modality - pretty much the only way to figure things out is to try all reasonable approaches.
Peter
>>Shock prostate cancer with Testosterone
This phenomenon has been known for a while.
Here's a short free full-text article discussing the concept:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577587/
>>Yes the company updated the ASCO GI data on the Q1 cc
The resectability endpoint is a composite of those other endpoints, so this is informative to some degree. I was wondering if we'd seen more data like that shown in the graphs I mentioned.
Likely we have to wait for next month for that data.
>>BPMC reports phase-1 BLU-285 data in GIST:
These results are phenomenal. Sutent was approved for 2nd-line GIST (after Gleevec failure) based on a 9% ORR and a median PFS of 24 weeks vs. 6 weeks with placebo and having poor tolerability to boot.
The alternative is to have some sort of subsidized high-risk pool. Kind of like some states do with drunk drivers for auto insurance (although I don't think that is directly subsidized - rather it is an indirect subsidy by requiring carriers to participate).
I still wonder who the most at-risk health-insurance companies are here. Might be worth buying some puts in case things disintegrate.
Oral thrombin inhibitor aggravates platelet adhesion and aggregation during arterial thrombosis
http://stm.sciencemag.org/content/8/367/367ra168
I posted some comments on FGEN pancreatic trial changes here:
http://www.siliconinvestor.com/readmsg.aspx?msgid=30867848
Back in February FGEN did publish some graphs relating to some of these endpoints - see slides 43/44 here:
https://www.sec.gov/Archives/edgar/data/921299/000119312516458401/d133008dex991.htm
Were there any update on those graphs subsequently? I seem to recall a bit more data than this being disclosed.
Peter
>>what type of fund is best suited to make a mid 8 figure investment in a private company
Some funds like Orbimed and Baker Bros. (and on a smaller scale RA Capital) make investments in non-public healthcare companies.
Couple of good articles on the difficulties of replacing Obamacare:
http://talkingpointsmemo.com/livewire/obamacare-repeal-and-delay-risks
http://talkingpointsmemo.com/dc/republicans-grapple-with-how-far-obamacare-repeal-should-reach
More details here:
https://www.niaid.nih.gov/news-events/first-new-hiv-vaccine-efficacy-study-seven-years-has-begun
A modestly effective vaccine might encourage more risky behavior, complicating the calculus of how useful it might ultimately be.
So someone (Miljenko) on SI suggested that the sudden and unexplained biotech downdraft on Tuesday might have been a smart short with advanced access to the bad LLY news.
Now I'm usually never one to posit conspiracy theories or hidden forces moving the market, but this is has at least some plausibility to my eyes. I think there has to be at least a reasonable chance that someone has penetrated the Lilly computer systems, or if not Lilly itself, then a Lilly associated entity such as a CRO or PR firm. If you take as a given (as I do) that state-level hackers can penetrate pretty much any commercial computer system, then the bad result could easily have been known ahead of time to a bunch of foreign entities.
People these days are mostly too smart to go short or long an individual stock based on leaked or hacked information, but this was news that likely would hit the whole sector. So a big HF or even foreign government allied entity (like a sovereign wealth fund or the like) could easily profit in this way.
Thoughts?
>>Regarding tachyphylaxis, this is an issue specific to Roxa. Not a class effect.
Well we don't know about the GSK drug - they've only published 4-week data (as far as I know).
They do have a nausea signal (mostly at higher doses but still some at the Phase III dose). Their published Phase II data was certainly messier than FGEN's - bunch more discontinuations (mostly at higher doses) and less clear of a dose-response curve - FGEN's was basically linear and very clean. Might be a signal of more variability depending on individual patient.
The GSK VEGF graph was weird:
http://www.ajkd.org/cms/attachment/2056135612/2061266308/mmc6.pdf
Big difference is GSK is once-daily vs three-times-a-week for FGEN.
For compliance, once a day is likely better.
FGEN believes more genes get activated with daily and so you get potentially more side effects and perhaps decreasing efficacy over time (tachyphylaxis).
Probably not:
That's a solitary thigh. :)
If you look at that paper you will see they cite 10ng/ml as the baseline for brain function. That's a very low level indeed - very much doubt if any of the participants here would have levels anywhere near that.
That said, I am fine with modest (say 2,000 IU/day) level supplements, which is about what I do myself in the winter. I am not OK with folks that believe megadoses are a good idea (had a problem on SI with just such an obsessed person). There is at least modest evidence of a U-shaped curve - too high might be as problematic as too low. (There was a very large Israeli observational study to this effect).
PTH (parathyroid) levels actually probably the best way to titrate D levels. People have different D-receptor polymorphisms which makes it hard to figure out the optimal level in any individual. African-Americans, for example, do fine with lower levels.
>>The bioavailability of Eligen B12 was more than double the OTC oral B12 supplement (5.09% vs. 2.16%)
Well at (I'm guessing) >100X the price, you can just take a bit more of the OTC lozenge. Something like Trader Joe's methylcobalamin - $10 for a year or more's supply. One a week is all one typically needs.
B12 supplementation particularly important for anyone on an acid blocker as absorption is reduced.
Used to be when people were mildly B12 deficient they developed some anemia. Now that food is supplemented with folate that signal has gone away.
Some currently thin old people are actually very sick fat people. So that distorts the numbers.
One of the best single body measures of 10-year longevity in middle-aged people is thigh size - everyone above a certain size (60cm circumference) does fine (even the people with huge thighs), and the ones with skinny thighs die much more quickly. Smokers with thin thighs have a mortality HR of around 3 or more.
>>Maybe the decline is related to people taking lots more supplements – vitamin D, vitamin B12, omega-3?
I'd personally believe B12, but not D - just doesn't fit with the epidemiology.
Low D levels are indeed present in all manner of ill health, but close to zero evidence of supplements helping despite numerous trials. So evidence mounting that low D is just a marker for ill health. That said, in northern climes moderate (2,000 IU/day) D supplements in winter make sense. Can't make D from sunlight unless your shadow is shorter than your height.
I'd hazard the decline in dementia mostly due to improved cardiovascular health - more control of hypertension, more exercise.
Peter
That's basically what Brownback tried in Kansas - net result was a very significant drop in tax revenue and not much at all in the way of business expansion - I believe Kansas did worse than neighboring states.
Health insurers may be at significant risk here:
http://talkingpointsmemo.com/dc/obamacare-repeal-trump-ryan-house-burwell-lawsuit
Anyone know which of the insurers is most vulnerable?