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>>ENTA
What do you think a reasonable revenue and earnings trajectory will be for them over the next few years (excluding milestones)?
>>I would hope it can still be combined w a PD-1
I'm sure these preclinical experiments must have already been done by now, which means the fact we haven't heard anything is either bad news (combo doesn't work straightforwardly as of now) or good news (want to keep it under wraps).
Certainly been radio silence on the issue from all the CD47 companies.
Thus, if ex-US profits were brought back to the US at a tax rate lower than what is specified in the current tax code, there would be a partial reversal of the corresponding deferred-tax liability, causing a one-time bump in GAAP income.
>>negative effects on WBCs including macrophages in the primate study given these cells are the effectors for the MOA of the drug itself?
This is obviously a concern, in particular as it might impact combinations with other IO therapies. But I'm guessing that the same phenomenon happens with these cells as with RBCs - it's the older ones that are more subject to phagocytosis. The EC50 binding to these cells is also about a factor of 3 weaker than for platelets which is reassuring. Likely worst case scenario is they have to stretch out dosing some to give them more time to recover.
>>If I were running a multi-national, I would not bring the cash home even at a 10% one-time tax.
I think a lot will. Who knows if they will ever get the chance again.
Have these profits already been tax-effected on the books? If so, bringing them back at a lower rate would boost EPS, and no CEO will be able to resist that.
Peter
I made some TRIL comments here:
http://www.siliconinvestor.com/readmsg.aspx?msgid=30855094
I think it mostly comes down to the foreign stuff. Can't see a Trump administration cutting some of the subsidies for oil-and-gas development or real estate, which is where the big bucks mostly are. Maybe some of the alternative energy stuff goes, but that's not a material amount.
Repatriation is obviously the big-ticket item here, albeit only as a one-time thing. But that will raise some significant revenue that can be used as an apparent offset to a lower rate (I say apparent because of the one-time vs ongoing discrepancy).
>>the lower corporate tax rates will be substantial and could add $20 to S&P eps
I assume the lower rates will be offset by the removal of some loopholes, particularly those involving foreign tax dodges. So for many companies might end up close to a wash.
Munis (and companies with big defined benefit plans) might yet be stressed by the upcoming state and local pension apocalypse.
Peter
>>I do not understand your position re IP; kindly explain your position.
Lack of COM patent.
>>What do you think of Amarin as a potential acquisition for GILD?
Very unlikely IMO. IP situation not that good, no synergy with existing sales force, too small to move the needle.
Peter
Well it's another Japanese trial, but unless I missed it I don't see any requirement for retinal monitoring. But there is an exclusion for active retinal disease.
All trial results are surrogates for how the drug will do in the "real world." Have to leave it to doctors to decide whether to use some of these marginal drugs with poor side-effect profiles (Sutent is even worse on that measure) on a particular patient.
OS is superficially appealing because it is a "hard" and undisputable endpoint. But even in a trial context it can get greatly muddled by post-trial treatments.
The paper goes on to suggest that the FDA force the trial population to be more "representative" - that's an untenable suggestion that would simply make drug development even slower and more costly than it is now.
Yes, the IRC data being better than the investigator data is the unusual result.
But the big discrepancy is not in the ORR - it is in the topline median PFS in the crucial dosing arm:
RC-assessed median PFS was 15.6 months
Investigator-assessed median PFS was 12.9 months
Those are remarkable results by brigatinib after crizotinib failure, remembering crizotinib front line only had a PFS of 10.9 months.
Quiz: What's unusual about the results?
>>So my " non medical lay mans " question is ....wouldn't patients prefer the oral Lasmiditan ( CLCD ) for the 8.3 migraine days then a sub Q injection , monthly to reduce those days from 8 days to 3-4 days ...especially since Lasmiditan has a fast on set of action ?
If you take that much of a triptan (and very likely this drug too) you will probably end up with so-called medication overuse headache. Basically you become more susceptible to headaches if you take too much acute medication.
There is zero evidence that the CLCD drug is more effective than generic triptans like Maxalt. So it's only use would be for people where triptans are contraindicated and doctors won't prescribe them. Not a big population in my view.
Since the author of the article you posted was presumably talking about genuinely new drugs
10% sounds about right, IMO; it may even be on the high side if “efficacy” is defined as clinically significant efficacy.
P-values <0.001 are not at all uncommon in a wide array of indications.
>>Main issue is 5% of 99,900 was calculated wrong.
Yes, but my big complaint is their example with only 10% of Phase II drugs having efficacy. And somehow they let a physicist into the room instead of a physician:
>>Once your findings reach ‘triple sigma’ levels (that is, p<0.001) you are more or less invulnerable to false discoveries, at least in clinical trials.<<
If you require .001 there will only be very limited indications where trials are feasible.
(FGEN)
>>The retinal stuff may possibly be a Japanese regulatory thing.
I can confirm my supposition was correct. According to the company, this was the same request made to GSK and viewed as simply routine.
False-discovery rates and Ph III failures:
http://www.forbes.com/sites/davidgrainger/2015/01/29/why-too-many-clinical-trials-fail-and-a-simple-solution-that-could-increase-returns-on-pharma-rd/#4d3e4235f67b
(Of course his basic presumption here is that the a priori chance of success in a Phase II is low).
Coincidentally, just talked to a friend with a mid-60's relative who was on a RA biologic (not sure which one) and who developed some sort of apparently mild infection and was dead from septic shock within hours.
There's a darker side to some of these best-selling drugs that isn't talked about much.
Peter
The celebrex long-term safety data published in the NEJM show it's a better drug than ibuprofen - clearly better on kidney and GI and very likely better on cardiac.
All the press you see will be very hedged because this was a non-inferiority trial and technically didn't allow proper superiority comparisons. But I would ignore the statisticians on this one - the HR's are clear.
Peter
>>Have you researched the IP for SAGE-547?
Nope.
>>I was surprised at how low of doses they were using.
I assume you mean Nektar? Yes - that is about as low a dose (0.003 mg/kg) as I ever recall seeing. (Except for botox of course - not sure what the botox dose is in terms of mg/kg other than it would have a whole bunch of zeroes after the decimal point before you ever saw a different numeral!).
I wasn't seriously suggesting that TRIL try a PD1/CTLA4 combo anytime soon, just commenting that when you give something like CTLA4 that revs up the immune system greatly then if your combo drug is indeed immunogenic you might end up in trouble.
There are so many possible IO combos out there now that I think only the big pharma are going to be able to figure out the best ones to try.
>>I'm not saying TRIL shareholders should be biting their fingernails on this point.
Antigenicity far down my list of potential concerns for TRIL. I'd guess neutralizing antibodies even if they developed (for which there is zero evidence) wouldn't prove insuperable - I would think you could just increase the dose some. That's the great thing about an on-target DLT - any loss in potency can be overcome by increased dosing.
Of course if you start combining with CTLA4 drugs or the like who knows what might happen.
The main concern here (as with all the CD47 drugs) is pretty much all efficacy - we still lack robust proof of that.
My key point on the TRIL DLT is that they are apparently dealing with an on-target effect - macrophages eating platelets. That makes the absolute dosing level close to irrelevant - if the drug was less potent, then the max dose would be higher, but there would be no gain in efficacy or therapeutic index.
The fact that they didn't first try a priming dose (like the other CD47 players) before expanding the trial suggests to me that they believe they have a potentially efficacious dose.
The company has certainly claimed roxa does not significantly upregulate VEGF, particularly given intermittent dosing. But haven't seen anything published to this effect yet.
The retinal stuff may possibly be a Japanese regulatory thing. There are some Japanese studies of EPO and retinal issues:
https://www.ncbi.nlm.nih.gov/pubmed/18051819
Sounds to me like this is a different mechanism than via HIF:
>>regulated by aerobic respiration-mediated oxidative DNA damage
Might fix the heart and screw the brain...
>>would be great to see a sell and hold in someone's 10b5-1 plan in december
By definition, 10b5-1 plans have no employee discretion other than you can (perhaps) terminate the Plan if you know good stuff coming.
I can't believe you can get much by comparing US and Europe - just too many different variables - different weather, soils, bugs, approved insecticides and herbicides, farming methods, costs of inputs.
Right now consumers see zero benefits from GMO crops. I'm still waiting for a GMO tomato that puts the taste back in ...
NY Times article questioning the benefits of GMO crops:
Doubts About the Promised Bounty of Genetically Modified Crops
http://www.nytimes.com/2016/10/30/business/gmo-promise-falls-short.html
There's an old South African joke that's on point with some of these below-cash companies. The protagonist, van der Merwe, is a stereotypical rural redneck character:
So van der Merwe won the South African lottery - a significant sum. When asked what he would do with his newfound wealth, he replied: "I don't know man. Maybe just keep farming until it's all gone."
>>CMX157 and TAF have the same active ingredient (tenofovir), and both requires a much lower dose than Viread to generate Viread-equivalent efficacy.
From what I know (which admittedly isn't much) the CMX drug concentrates in the liver. So they have at least a shot at a better therapeutic ratio for HBV.
>>The study protocol pre-specified the collection of thousands of patient samples for exploratory analyses over a wide range of possible biomarkers, including pre-treatment levels of beta-2 glycoprotein-1 (ß2GP1)
That means only that this was one of the pre-defined biomarkers. It is quite different from picking an arbitrary range and saying that that range is key. That's virtually the definition of data mining. At best it creates a testable hypothesis.
>>This is also the case with Bavituximab and B2GP1 as far as I can tell.
That you need some magic middle range? Not too low and not too high? I don't know of a single efficacy-related biomarker that works like that. Now there certainly are U-shaped curves out there in the world, but they are typically a caution flag in any retrospective analysis of a drug.
>>Why is one data-mining (PPHM) and one not so(BMY)??
Both biomarkers were indeed pre-defined. But for PPHM, they pulled a range out after seeing the results - their range was not pre-defined.
In the BMY case too, the biomarker was directly linked to the activity of their drug, so there is a sound scientific reason for low expression being different from moderate or high. Once you start claiming moderate (but not low or high) is what you need for efficacy, eyebrows are going to be raised.
>>FDA mandate wrt antibiotics for livestock and animal feed applies only to those used in human health
FDA has been under pressure for years by agricultural interests (and the GOP) to do nothing at all in this area. So I'm guessing they did what they could.
I know an expert (perhaps the expert on this issue) who tried to testify about this a few years back to a House Committee. It was a horror story - the GOP members basically wouldn't let him speak on the issue.
>>only a small portion of the antibiotics ZTS (and other animal-health companies) sells are ones that are relevant to human health
It is a mistake to assume that using antibiotics that are not used by humans will solve the problem. Many of the antibiotic resistance traits - efflux pumps and the like - are not specific to one antibiotic at all and can be spread to other bacteria.
https://en.wikipedia.org/wiki/Plasmid-mediated_resistance
>>FDA grants BTD for Roche’s Alecensa (alectinib) in first-line ALK+ NSCLC
Appropriately so.
Alectinib and brigatinib are the best of the bunch and should be used first-line ASAP.