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As I've commented before, this for me is the key patent claim:
>>A method for treating anemia in a subject in need thereof, the method comprising administering to the subject an effective amount of a heterocyclic carboxamide compound that stabilizes the alpha subunit of hypoxia-inducible factor (HIFa), thereby increasing the percent transferrin saturation in the subject, wherein the subject is a subject having a percent transferrin saturation level below 20% prior to said administering. <<
This doesn't specifically mention hepcidin, and it broadly covers anemia treatment with these drugs for any patient with transferrin below 20%.
it's always been boom or bust, and starting to look much more like bust. Too bad, as they had one of the few potential drugs post Xtandi. Likely drug just isn't sufficiently potent.
As to whether the drug is doing anything, it would be nice to see individual PSA graphs. if prior to the drug the PSA levels were shooting up, then even a moderate decline might mean something.
>>Pfizer's $14B Medivation deal's now a cautionary M&A tale, thanks to ASCO
I'm fairly sure if PFE had run the same trial as JNJ they would have shown even better results. I haven't kept track of what Xtandi trials they are in fact running.
I'm focused more on the epo hyporesponders and patients with anemia of inflammation - for them low epo is clearly not the primary issue, because even with dramatically more than physiologic levels of epo they still don't make sufficient RBCs. For them, it turns out that lowering hepcidin is actually the key move given that more epo actually serves to lower hepcidin still further.
I've always been interested in this compound - indeed (misguidedly) had this stock in my charity portfolio last year because of this program. But the company itself is pretty flaky - worth noting that LGND didn't keep this compound when they spun Viking out and also didn't participate in funding when they desperately needed money.
I also wondered whether sick euthyroid syndrome might not be the right application for this drug - but when I had someone ask, the company had never heard of it, which didn't inspire confidence.
Peter
>>My hunch is that AKBA stands a good chance arguing that it is epo depletion that they are targeting primarily and the improvement in iron homeostasis is a side benefit, and that they are not intending to use their drug for traditional iron deficiency anemia that you see so commonly in the real world
But consider the following granted US patent claim:
A method for treating anemia in a subject in need thereof, the method comprising administering to the subject an effective amount of a heterocyclic carboxamide compound that stabilizes the alpha subunit of hypoxia-inducible factor (HIF.alpha.), thereby increasing the percent transferrin saturation in the subject, wherein the subject is a subject having a percent transferrin saturation level below 20% prior to said administering.
But the issue for me is that I don't trust what AKBA says here because they also claim freedom to operate in the US where four iron-related patents survived GSK's IPR challenge.
Here are some of the claims from the US patents;
1. A method for treating iron deficiency in a subject in need thereof, the method comprising administering to the subject an effective amount of a heterocyclic carboxamide compound that stabilizes the alpha subunit of hypoxia-inducible factor (HIF.alpha.), thereby treating iron deficiency in the subject.
2. The method of claim 1, wherein the iron deficiency is associated with anemia.
A method for increasing iron absorption in a subject in need thereof, the method comprising administering to the subject an effective amount of a heterocyclic carboxamide compound that stabilizes the alpha subunit of hypoxia-inducible factor (HIF.alpha.), thereby increasing iron absorption in the subject.
A method for treating anemia in a subject in need thereof, the method comprising administering to the subject an effective amount of a heterocyclic carboxamide compound that stabilizes the alpha subunit of hypoxia-inducible factor (HIF.alpha.), thereby increasing the percent transferrin saturation in the subject, wherein the subject is a subject having a percent transferrin saturation level below 20% prior to said administering.
A method for increasing serum iron in a subject in need thereof, the method comprising administering to the subject an effective amount of a heterocyclic carboxamide compound that stabilizes the alpha subunit of hypoxia-inducible factor (HIF.alpha.), thereby increasing serum iron in the subject. The compound of claim 1 for the use of that claim, wherein the iron deficiency is associated with a disorder selected from the group consisting of anemia, iron deficiency anemia, microcytic anemia, inflammation, infection, immunodeficiency disorder and neoplastic disorder.
The compound of claim 1 for the use of that claim, wherein the compound is for use in increasing iron absorption.
A compound that inhibits hypoxia inducible factor (HIF) hydroxylase activity for use in treating or preventing iron deficiency in a subject, wherein the compound is a structural mimetic of 2-oxoglutarate.
The compound of claim 1 for the use of that claim, wherein the compound is for use in increasing iron availability for erythropoiesis or red blood cell production.
---------
I assume the AKBA will want a label saying their drug can be used without IV iron - absent that claim they can't be competitive. So how does that not infringe, even though they can try to pretend their drug is just to treat anemia and somehow has little or nothing to do with iron.
I guess we might have to wait and see what the narrowed claims look like.
Here is the main claim as it presently stands:
A compound that inhibits hypoxia inducible factor (HIF) hydroxylase activity for use in treating or preventing iron deficiency in a subject, wherein the compound is a structural mimetic of 2-oxoglutarate.
also:
The compound of claim 1 for the use of that claim, wherein the iron deficiency is associated with a disorder selected from the group consisting of anemia, iron deficiency anemia, microcytic anemia, inflammation, infection, immunodeficiency disorder and neoplastic disorder.
The compound of claim 1 for the use of that claim, wherein the compound is for use in increasing iron absorption.
Akebia might argue that treating anemia without IV iron using their drug is not covered by those claims - I would beg to differ (as those claims presently stand).
FGEN/AKBA
See my tweets starting here:
1/ Here is $FGEN upheld patent vs $AKBA A compound that inhibits HIF hydroxylase activity for use in treating or preventing iron deficiency https://t.co/dxfab1J3nW
— Peter Suzman (@Biomaven) June 5, 2017
>> I could accept that certain individual ta practitioners could have detected some signals beforehand and be set up for the ride.
Of course, but how about all those other times that they detected a very similar signal and were proved wrong?
I repeat my premise - to the extent there is some reproducible pattern that can be exploited, it gets exploited by the quants until such time as it goes away - which is surely will do.
>>but definitely better than a coin flip
If it was definitely better than a coin flip do you seriously believe the high-powered quant funds wouldn't already have extracted every last drop of value from it?
People love to find patterns even when they are none, so they forget or excuse the false signals and recall the valid ones.
>> subtle incentive to misreport a lack of efficacy
I think this may reflect the policy of the publishing journals as much as anything.
Yes - I agree you could readily get a near-optimal solution. And near-optimal is all that matters here.
>>If the pairing is random, how can it also be one that minimizes cumulative M?
I should have been more precise. My assumption is that there are many possible sets of pairings that will produce around about the same cumulative M and it is likely computationally impractical to find the one that minimizes cumulative M. So instead randomly choose a subject, match that subject with the closest possible pair, and then randomly choose another subject and match with the closest possible remaining pair. If two possible matches are close enough you can choose randomly between them.
It might seem like cheating, but I suspect you can repeat this process several times and mash all the results together, thus reducing the chances that you got some fluke matching.
Peter
Thanks - appreciate the informed commentary.
I was thinking about these issues some, and wonder if you'd ever seen something along these lines:
Assume you have a 1-1 randomized trial of size 2n, with the members of the control group being C1...Cn and the intervention group I1...In.
You have some primary endpoint measurement you are considering, E. Now create a pre-specified similarity metric M that measures how similar any two subjects are. The baseline measure of E will be the dominant element of this metric, but you can also consider other parameters such as age, sex and the like.
Now randomly pair members of the control group with members of the intervention group in such a way as to minimize total M. You can potentially do this multiple times as there won't be a unique matching. Assume one such pair is (C2 I3). Now it is simple to compare their respective changes in E - you are comparing like with like and so don't have issues like regression to mean and ceiling and floor effects.
So the only secret sauce here is the pre-specified similarity metric M, so no p-hacking issues that I can think of. I guess it is basically similar to a case-control study, albeit in the context of a randomized trial.
Comments?
Peter
Interesting analysis from a biostatistician. His main complaint here seems to be comparing change from baseline of some measure in intervention vs. control groups. One issue is that degree of change is related to initial baseline as well as any impact from the intervention. Thus, for example, if you are measuring on say a 5-point scale, then someone that starts out at 5 can only go down, and vice versa from someone starting at zero. So, among other things, regression to the mean distorts your outcomes.
http://www.fharrell.com/2017/04/statistical-errors-in-medical-literature.html#glucpct
Note discussion of recent NBIX/Abbvie elagolix trial.
Instead he proposes some sort of ANCOVA analysis - but I can't say I recall seeing that used much at all in practice.
Comments from our resident stats gurus?
Peter
Really interesting and remarkably prescient.
That appears to be a 6-! stock - haven't seen one of those here in quite a while:
today!
below!
below!
$1.26!
gem!
day!
This might actually be a rarer sight than the more common umpteen-! stocks we sometimes encounter - but of course those cheat by using multiple !!!! in a row.
>>So this is just the opposite of what you see with chemo.
It's what you'd expect if you were impacting cancer stem cells and/or metastasis rather than simply bulk tumor.
>>Non-responders died quickly.
Right. Just to expand on that, OS is looking at the drug arm as a whole; duration of response is looking only at the subgroup where there was a CR or PR.
So what these results are saying is that usually the drug does not work, but when it does work it works fairly decently.
I've always worried that blocking MET is potentially double-edged - in some circumstances it might actually be bad.
Peter
>>AKBA has no patent issue. I prefer not to characterize as an 'issue' until there is one.
FGEN has seven issued US patents, six of which just survived an IPR challenge from GSK that has a significantly lower bar for success on the challenge than does a traditional patent case. (GSK didn't challenge the seventh screening patent that had previously blocked AMGN from this space).
The claims of those issued patents potentially mean that AKBA does not have freedom to operate in this space. So for me that means they have a patent problem even if they do not presently acknowledge one. This has nothing to do with their own patent - it's all about whether their drug infringes on these FGEN patents or not.
FGEN also has some even broader patent applications on file where the patent has not yet been issued. So those also pose a potential problem down the road should they ever issue.
Also see:
http://www.medkoo.com/products/7360
According to Miljenko, who is a medicinal chemist, that is a carboxamide
See FGEN patent 8,466,172
A method for treating a hypoxic or ischemic disorder or condition in a subject, the method comprising administering to the subject an effective amount of a heterocyclic carboxamide compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF.alpha.).
There were a number of comments from AKBA and AKBA IR that lead many investors to believe that this would give AKBA a lock on supplying Fresenius US. Nowhere did they state that it was quite unclear whether the drug would be included in the bundle - again only a very few sophisticated investors with detailed knowledge of FGEN understood the implications of their assumption.
So yes, the PR itself may have been correct on its face - but the way they presented this deal was still misleading in my judgement.
Peter
Confirmation that AKBA PR was pretty misleading - Fresenius in US not bound to use AKBA drug in any way:
$FGEN BL: $AKBA did not sign an exclusive deal with Fresenius as they cannot with a hospital. 100% of market will go to $FGEN as they r FTM. pic.twitter.com/XjTFsNn0xA
— c (@coho23) May 17, 2017
There is a pretty close analogy with the Vifor Micerva deal:
http://www.roche.com/investors/updates/inv-update-2015-05-28.htm
I am informed that only a minority of the Fresenius patients in fact use Micerva rather than other EPOs.
Based on my understanding, the AKBA PR does indeed seem pretty misleading.
Peter
AKBA patent issues.
So what are people's thoughts about this FGEN screening patent that was enough to stop AMGN in its tracks:
http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=1983455
https://www.google.com/patents/US6855510
So obviously we don't know if there was infringement in the design of the AKBA drug, but let's for a moment assume there was. So my question is what happens once this patent expires?
(This is obviously separate from the 6 FGEN patents GSK unsuccessfully challenged and also the several pending applications from FGEN that have not yet been granted).
Peter
>> the phenomenon has not been systematically studied.
I think that is an exaggeration. Certainly this issue is something that is systematically studied during the biologics approval process, and something that was even more closely studied in the old days before properly humanized mabs.
Maybe they mean not studied much once a particular drug is approved.
Peter
>>I think it's fair to say that efficacy data are going to be on par between the 2 drugs, but we don't know about safety yet
We don't really know this yet - AKBA drug is much less potent and (at least for daily dosing) may be near the top of their dose response curve.
Note that Vifor can terminate this agreement completely within 12 months after the topline vada data is disclosed.
Note also that this is not a deal with Fresenius US - it is a deal with an associated distributor.
Peter
AZN/Vifor
It may or may not be relevant that AZN and Vifor are serious competitors on ZS-9/Relypsa.
If the HIF drugs are outside the bundle, then there would be no negotiation needed on price - it would be a pass-through for the dialysis providers.
FGEN management has been pretty clear that they expect their drug to be outside the bundle because it is not the oral equivalent of an ESA. To my knowledge, that's the standard based on the way the regulations are written right now.
That said, obviously Fresenius in any event now has an incentive to prefer the AKBA drug once it is approved.
>>I would assume he knows the blackjack player competes only with the casino.
You are misunderstanding his analogy I think.
Here the casino is the stand-in for mother nature, the other players are the stand-in for competitor pharmas. You will do better than most other blackjack players if you use basic strategy (and they don't); you will do better than most other pharma if you use his checklist (and they don't).
>>Using basic strategy alone, at any casino I'm aware of, does not give one an incremental statistical advantage over time.
I think he meant you would do better than other players, not better than the casino.
This is good:
http://oncologydiscovery.com/2017/05/07/luck-and-skill-in-biopharma/
You can use the same checklist as an investor.
>>First ALS Drug In 22 Years Is Approved
Surprised the FDA approved this with marginal open-label trial.
Tough drug for patients because of all the infusions - 20 1-hour infusions each month. Don't know if they plan a port and home administration or not.
>>TRIL
Platelets subvert T cell immunity against cancer via GARP-TGFß axis <<
The dose-limiting AE isn't a bug, it's a feature. :)
>>Twitter's platform in general is plagued by bots and trolls
Yes, that's why you have to be smart about using it - basically pick out the good stuff automatically, which I believe is possible.
If there are any programmers/developers around, I have an interesting idea for a twitter-curated newsfeed. Could easily have commercial possibilities if done right.
Peter
So what are you now using for news? I do miss the old Yahoo biotech feed.
Some of the other sites I've tried are ridiculously cluttered with robot-generated news ("stock x is doing better than stock y over the last n days")
Yes, and the same issue (rebate structure) hinders price competition between similar drugs in say the RA space.
I believe these results were somewhat delayed compared to expectations and when the trial ended- that is often a warning sign in small biotechs as they try to spin results.