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Thanks for the clarification.
But still means that the CGRP drugs pose a considerable threat to AGN here. AGN has some CGRP drugs of its own, but they look to be late to the party.
>> AMGN/NVS is about one month ahead of TEVA in the race for approval of the first CGRP compound for migraine.
Couple of comments from a CS report:
There are rumors that AMGN/NVS will offer the drug for free for the first administration. That would be pretty unprecedented in my recollection.
The Teva drug has the possibility of 3-month dosing. The report commented that their trial involved placebos every month, so maybe the FDA won't be persuaded.
Finally, the report suggests AGN Botox is much more at risk than you had previously suggested.
>>The proportion of worldwide Botox sales attributable to migraine is about 5%, as far as I can tell (the exact number is not disclosed). The proportion of Botox patients who use Botox for migraine is much less than 5%, but the labeled migraine dose of 155U* is about 4x the typical Botox dose for cosmetic indications. <<
The report claims that about 40% of US Botox sales are migraine-related - about $475m in the US based on 2016 sales.
The report does wonder if insurers will require people to try Botox first ahead of a CGRP - I can't imagine they will.
I was told by someone who understands these things better than I do that you will often see temporary spikes in cytokines after anything that tickles the immune system. Thus these spikes could have nothing to do with the tumor at all - they don't seem to persist.
Peter
>>TRIL
Just to be clear, Sezary Syndrome is what I was referring to when I said this was a small orphan market. The more general CTCL in its various forms (like MF) is very common.
https://www.nature.com/articles/2405044
Yes, very small (orphan) market. But the key is to get the drug on the market as soon as possible and try to expand indications later.
Side effects are very benign in general, so key will be finding right combinations. Unclear to me what the impact will be of increasing dosage - you seem to get about as many responses at low dose as at high dose. Might be very hard to figure out why some people respond and others don't. (compare PD-1).
It might be that the right combo will prove to be with something like IFN-gamma or IL-2 at the right time rather than the fancier IO drugs.
As I've said repeatedly, this drug needs to be in the hands of a big company.
My take on TRIL PR:
My take on $TRIL from today's PR (haven't yet seen the posters):
— Peter Suzman (@Biomaven) December 11, 2017
1/ They have an approvable drug in R/R mycosis fungoides or Sézary syndrome
2/ The OR's in R/R DLBCL were 5/18 - down from earlier numbers, which perhaps explains weakness. But 5/18 with little tox is still great.
>>They have some convertible preferred stock that's excluded from the new investors numbers even though it converts one for one
If I remember these arcane calculations correctly, if the investor also holds convertible preferred that could become Common at their discretion, then those are included in the nominator of the percentage calculation for some purposes only (like the Proxy but apparently not the 10% holding calculation). Logically these converted shares would also be included in the denominator, but converts held by others would not be included in the denominator. There are also various complex attribution rules where sometimes holdings by others (like spouses) are included.
So bottom line, don't expect the percentage ownership to always total to 100% and expect to see different percentages in different types of reporting.
>>also probably inhibits collagen PH
Might even be a good thing - that has been proposed as a target in fibrosis:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634087/
But again, intermittent inhibition is quite possibly different from continuous inhibition.
>FGEN
I'm not concerned by that article much at all - key is they dosed daily for six days at what seems to be a high dose (comparable to what has been used for ischemic injury, which is quite a bit higher than for anemia) and saw about a 50% reduction in C1q. I think with the intermittent dosing that FGEN uses this likely would be ameliorated, and certainly it will be with lower doses.
Also a moderate reduction in complement activation is likely a desireable thing for most CKD patients.
Peter
(OT)
Anyone here use a self-directed IRA that they can recommend? Want it for a private company investment.
Peter
>DCPH
That article is from over 5 years ago.
Strange company somehow - like they are living in some parallel world doing their own thing differently from everyone else in the kinase space and moving at their own pace. But their GIST drug does seem real, although hard to judge exactly where it will fit.
Peter
>>Ownership of a mixed-breed dog was associated with higher risk of CVD
Bingo.
Strongly suggests that there is a confounder here - likely wealth or socioeconomic status - that they haven't properly accounted for.
And of course the possibility of reverse causation that has been previously suggested here (if you are frail or perhaps very obese you are less likely to get a dog) is also lurking. And the multiplicity is of course another worry.
The twin part of the study was likely too underpowered to conclude much.
Peter
>>If you're dead or lazy, you don't report your habits?
Well they were trying to compare twins where one twin had a dog and the other did not. So lack of reporting cancels out here - they would only look at twins where both reported.
I'll give a hint - take a closer look at the reported characteristics of the dogs.
>>select antibodies with TREM2 agonist activity
Anyone know of any approved antibodies that are agonists?
>>Reverse causality? One needs to be in good enough health to decide to get a dog (esp. a hunting dog)?
On the right track - but there was one more result in that paper that made me wonder about their result.
Current consensus is targeted RIPK1 would be enough.
Of the targets you mention I know most about TDP43 - that's the major dysfunctional protein in ALS and also frontotemporal dementia. A misfolded form of TDP43 called pathologic TDP43 is the major observable brain pathology in ALS. But nobody really knows if the issue is loss of function of the protein (it is used in RNA processing) or whether it is a symptomatic response to something else.
>>Are RIP1 and RIPK1 one and the same?
Yes.
Necroptosis is an alternative cell death pathway different from the more familiar caspase-dependent apoptosis. It involves three kinases - RIPK1, MLKL and RIPK3 of which RIPK1 appears easiest to target. GSK has a RIPK1 compound in trials in IBD, so it has potential applications outside the CNS.
Peter
(OT quiz)
Here's an article claiming owning a dog is associated with a significant improvement in mortality:
Dog ownership and the risk of cardiovascular disease and death – a nationwide cohort study
https://www.nature.com/articles/s41598-017-16118-6
Quiz: What in the article might lead you to believe this is a non-causal relationship?
(You are disqualified from entering if you follow my twitter feed!)
I tried to interest some folks in RIPK1 as a target for ALS back in 2014, but never was able to get it off the ground.
Blocking RIPK1 likely prevent necroptosis of motor neurons.
Peter
For Baker Brothers, who I am assuming is the buyer here, $20m is a rounding error. But they are in general highly informed, long-term holders.
No, because these are only Common. The Preferred (which are really Common in disguise but with no vote) are likely held by Baker Brothers.
I posted some TRIL SITC observations starting here:
1/ Some comments on $TRIL SITC poster:
— Peter Suzman (@Biomaven) November 12, 2017
No platelet issue *at all* in combo w/ rituxan, even at increased 0.3 mg/kg dose w/ rapidly rising trough drug levelshttps://t.co/b6kM2Pbo3b
>>OMER
>>reimbursement change coming in 2018.
It's so weird that this came as a surprise to the market. I know rkrw mentioned it to me late last year if I recall correctly, and there has been warning language in their filings for a long time.
>>Both Trillium and Fibrogen are down sharply
Someone commented to me about it being a competitor of mine in the SI charity contest (where I ended last week in 2nd place) :)
Trillium I suspect just profit taking.
FGEN I think in response to Leerink pushing out timelines a bit and in response to Neff talking about potential delays in Chinese reimbursement. I personally think the Chinese government will want to treat roxa as a poster child and will be quick on reimbursement.
I personally don't fuss much about short term stock price moves. I'm a long term holder and in the end the price will reflect the quality of the underlying drugs.
Peter
>>difference between the smaller wild berry and the cultivated larger berry?
For all the berries there is a wide difference in phytochemical content for different cultivars. Thus for blackcurrants you often see a two-fold variation in the amount they contain, with varieties grown in Europe markedly lower. If I recall correctly, wild blueberries have higher levels than cultivated ones.
Teva yields on their bonds don't seem to be sky-high, so bond market is not yet freaked out, for whatever that is worth.
Peter
I didn't know that. So, assuming approval, will Teva be ahead of AMGN?
If so, that's a pretty big deal.
Peter
>>Acalabrutinib was approved this past week.
Thanks - I'd completely lost track of it.
So looking at their pipeline, roxa is certainly a very plausible candidate - and maybe FGEN could kick in a contribution. I suppose their severe asthma drug or their SLE drug might be alternatives - not that familiar with their late-stage pipeline which seems generally on the thin side.
Peter
Interesting that AZN has an unused PRV - wonder if there is any chance they use it for roxadustat? Or more likely it goes for one of their oncology drugs like acalabrutinib.
Peter
I figure I should explain why I settled on delphinidin as the phytochemical of interest and Akkermansia as the key:
In a couple of large observational studies, I noticed that blueberries popped out as one of the few foods where regular consumption was correlated with less obesity and less diabetes. Fruits like strawberries did not show up, suggesting this might be a real phenomenon rather than some correlate of generally healthy eating. So I checked what blueberries contained that other fruits and berries did not, and delphinidin showed up - that's what produces their purple color. There are a number rat studies suggesting delphinidin changes gut composition in a favorable manner (reduced blood sugar etc.) in obese mice, with Akkermansia popping up as one of the changes.
This stuff is incredibly hard to study properly. Each microbiome is different, and metabolism within the gut is very complex, with Akkermansia sitting at the end of the food chain. I did give some thought to a "citizen science" experiment with having people do a microbiome analysis before and after feeding them purified delphinidin, but eventually decided it was just too hard to orchestrate. With no patents to be had, there is likely no commercial money to be had either.
Peter
Unfortunately they didn't give an analysis of the phytochemical composition of the navy beans. Some beans like black beans do seem to contain delphinidin, but navy beans in the following analysis had no flavonoids at all - don't seem to contain much unique from beans in general.
The polyphenolic profiles of common bean (Phaseolus vulgaris L.)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276374/
Because there are so many different cultivars, it's hard to get a handle on beans and grains like purple corn. Thus I've seen different analyses that show quite different constituents.
It certainly is plausible that other natural products than delphinidin have the same (or even better) activity. The other complication here is that delphinidin comes in around a dozen chemical variants which potentially have different profiles.
TEVA's CGRP migraine drug is decent, but they screwed up by not acquiring a PVR for it. So I'm assuming they'll be second to market after AMGN - still should be a good drug for them.
The time to buy them might be after they cut their dividend.
Peter
The black/purple color in blackberries comes from a different phytochemical called cyanadin. The purple one I'm after is called delphinidin.
Now I'm not saying that cyanadin might not do something similar, but if it does, I don't know about it.
Peter
>>Akkermansia muciniphila
Coincidentally (or maybe not) this is an important bug in obesity that I've researched extensively - it's one of the ones that typically re-appears after bariatric surgery. It is my own belief that purple berries (blueberries, blackcurrants, concord grapes) likely increase Akkermansia - they certainly do so in obese rats.
It's an interesting bug - it feeds off the excreta from other bugs rather than the food you eat and lives mostly attached to the epithelium of the large colon - perhaps making a better barrier.
Peter
(OT) Some interesting posts about Monsanto's Dicamba:
https://news.ycombinator.com/item?id=15559428
Two natural compounds - quercetin and tocotrienols, an isoform of Vitamin E, are modest senolytics.
Peter
AMGN will likely have the first CGRP migraine drug - and often first-in-class gets a big chunk of the eventual market. So it should easily be a $1bn drug.
On the other hand, some chance their remaining Epo sales disappear if FGEN's drug works as I think it will.
Peter
Kyprolis revenues have been growing at over 20% a year. Q2 revenues were $211 million.
LGND gets a 3% royalty if I recall correctly.
Peter
Any concern that potential cut in top marginal rate might impact muni prices?
>>added substantially to my ACHN position
Curious as to what you see there.
Peter