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CCXI
SAGE
PRTO:
PRTO
Another paper on inverse correlation of cholesterol and T2D via PCSK9 mutations.
http://www.thelancet.com/pdfs/journals/landia/PIIS2213-8587(16)30396-5.pdf
As I've noted before, APOC3 is the only target that I've seen that seems to benefit both T2D and cholesterol.
Note that I haven't checked the lancet paper to be sure it isn't a regurgitation of the datasets used in previous papers.
GSK vs AKBA vs FGEN
I'd suggest that there are a lot of points of contention about the differences of the different PH Inhibitors. I address many of the most common comparisons below, but my summary is that I would suggest that, other than effect on liver, the data we have is completely inadequate to differentiate them. If you believe you have additional data that I've missed, I'd love to be corrected. In any case, I think the below is a reasonable summary of what I've seen:
1) Liver effects:
Roxa does seem to act on the liver (multiple papers mention the lowering of total cholesterol). The Vada ph2 paper specifically mentions no effect on cholesterol levels.
SAE - database too small. Both Vada and Roxa has some liver events, although Roxa shows more - quite possibly just due to more patients in their ph2s.
GSK is silent on cholesterol. And I have found only one case of ALT SAE.
2) PH targets - PH1 vs PH2 vs PH3
I haven't seen any clean data on this for either Vada or Roxa (I haven't looked for GSK). Note that the liver data does indicate that there is probably a difference since there is a difference in pathways for the PHs in the liver - but the actual PH efficacy data I've seen so far doesn't elucidate this.
3) Blood pressure
FGEN's S-3 indicates "a modest decrease in BP" in the NDD RCT (017) (I presume this is an average BP across all 017 patients), but it doesn't show up in the published data for Roxa. ???
Vada OTOH says no change in BP over time in their NDD RCT - but they had meaningfully more incidences of hypertension (8% vs 3% - which is too small in number to be anywhere near conclusive).
GSK is silent (to my knowledge).
4) Tachyphalaxis (i.e. dosing daily or 3x per week)
I haven't seen any good data that would let me differentiate - even animal data. If anyone else has seen such... I'd love a pointer.
5) Random other Adverse Events and Differences
I've covered hyperkalemia elsewhere, so won't cover it again. But the most common additional AE are:
Nausea - all show this. It (and other GI problems) are the most frequent AE across all the reported data. But the numbers are definitely too small to say how the drugs differ.
Nasopharangitis (aka the common cold) shows up in two of the GSK RCTs (and I am pretty sure I've seen excess in someone else's data too - but can't refind it). There is a large excess number for those GSK trials - but not sure how to interpret general silence in the data for the other drugs.
GFR effects - AKBA has released data in NDD indicating a benefit. I've seen nothing to date from the other companies.
Target Hbg - AKBA is clearly targeting a lower Hbg than FGEN (presumably because they are worried that the recent reduction in EPO guidelines was because due to too high a target Hbg - but I personally don't see any strong reason to believe that the Hbg was the primary route of EPO's CV problems)
RTRX
FSGS: Dual ETAR/AT1R blockade in DUET study, design #KidneyWk pic.twitter.com/x8Xfv4gbzL
— D.Guerrot (@dguerrot) November 19, 2016
AUPH -
21st Century Cures:
Antibiotics - an approach that bears watching:
https://www.statnews.com/2015/12/03/antibiotics-bacteria-research/
@matthewherper think u'll find high %age long term inv mostly agree w ur positions. Science is an edge. Chaos is bad.
— Clark H (@Clarksterh) October 25, 2016
FGEN - Notes and commentary on end-of-quarter cc:
Focus of these notes will be on items not appearing elsewhere. Caveat that these were written more quickly than usual, so I have not captured precise numbers etc. Feel free to correct:
1) Trial enrollment: Stable dialysis is fully on track, but NDD is an issue because too many of the patients meeting the FDA criteria of <10 Hbg are eGFR<15 (i.e. eligible for dialysis even though they aren't currently on dialysis). They are having a meeting with the FDA at the end of November to discuss this and other issues (probably chief among the other issues is the fact that the incident dialysis trial is also having enrollment issues - and is also something being pushed by the FDA). Commentary:
a) It shouldn't really be too much of a surprise that by limiting enrollment to <10 Hbg you would get a lot of Stage 5 - e.g. see the baseline CKD stages for the Akebia trial (and presumably FGEN sees something similar in their NDD ph2s - although it wasn't broken out as cleanly in their ph2 papers)
b) Assuming that hyperkalemia is, in fact, a potential side effect of roxa, it is probably true that having an extremely low eGFR exacerbates this since it does with other hyperkalemia inducing drugs. And note that, because hyperkalemia normally happens early after initiation of dosing, the companies would be able to see this through the blind.
c) Just a brief note that the fact that it was the NDD trials, but not the dialysis trials, that were having enrollment issues was something apparent in the clinicaltrials.org data (I commented on this last weekend).
2) Completion dates for the various global trials - although Neff said that 'the date given on the Astrazeneca site is still accurate' (2H17 in August investor charts) he was using phraseology like 'still possible' ... . Commentary: I'll be reasonably surprised if the NDD trials finish in 2017 unless the FDA gives them relief. So the only question is how far apart do the different dates for dialysis and NDD have to diverge before the have to announce them separately, and, potentially, even submit them separately?
3) China - several notes:
a) Unlike US populations, the NDD and Dialysis patients are typically treated by the same docs - thus making it much easier to address both markets together.
b) One selling feature of roxa is that it more easily addresses the less sick patients because, unlike ESAs, it doesn't require hospital visits and doesn't require all sorts of difficult storage requirements.
4) MDS trials - trials in US will start earlier than in China (comment: despite fact that they actually started talks with regulatory in China earlier per previous cc). Plan is for ~20 single arm dosing, leading to RCT of >100. Trials are 52 week endpoints. Partners are paying for the trials.
5) IPF trials will finish in mid 2017.
FGEN - Doodling with numbers (I'm bored ---> I doodle):
At this point the dialysis Ph3s should have enough patients that:
a) If the epidemiological data is true about CV events being about 30% lower (or more) at altitude for dialysis patients
b) if those same numbers apply to HIF raising (big if, of course - but as I said, just doodling) - without some strange time varying curves.
c) if they are willing to stop the trials based purely on CV events (vs overall survival or ...)
Then they should soon pass the p value that would force a DSMB to halt if they were going to halt (i.e. p<0.00001 - which seems a reasonable p value to force a stop even with no pre-defined alpha spend). Even with very conservative assumptions about the CV benefit as seen in the epi data. So if they do not stop, the altitude benefit doesn't translate to the drug, they aren't willing to stop for anything other than OS, they are judging each trial separately or ... .
OTOH - for OS the epidemiological data generally seems to get a lower benefit from altitude (i.e. most of the benefit is CV). With the same assumptions as above it thus translates to a less-good p value. It might get to p<0.0001 before mid next year (see all the caveats above) if the OS benefit is as good as middle epi data. But it probably never gets below 0.00001 unless the best epi data is correct.
BTW - Random note that the NDD trials appear to be the one in which they have trouble getting events since it is primarily the NDD trials that have been adding sites over the last year.
BTW2 - Please, no one go all PPHM on me. Truly, this is random doodling and shouldn't be taken very seriously. More just providing context - and I posted because others might find it interesting.
AUPH From their press release on the topic of the new trial:
FGEN
FGEN AKBA severe hypoxia causes regrowth of mouse heart:
http://m.medicalxpress.com/news/2016-10-low-oxygen-environment-heart-regeneration-mice.html
In a quick look didn't find underlying paper. But still interesting - particularly the threshold effect.
AVXS IONS BIIB
TRVN - Notes from their American Society of Anesthesiologists R&D day (it wasn't officially an R&D day - but was 2 hours long and 3 different non-TRVN MDs) on oliceridine.
The 3 MDs were a P&T Committee Member, a surgeon and a anesthesiologist (i.e. a good representation).
Notes, in no particular order, on things that I hadn't heard on a TRVN cc before:
1) All 3 MDs noted that the lower rate of non-respiratory side effects was the most important from a cost perspective because respiratory depression that adds meaningful cost is an infrequent occurrence.
1a) Obviously the biggest well tested factor in the human data is the lower rates of nausea and vomitting.
1b) Two of the 3 MDs clearly wanted to assume that the mouse data, showing much better intestinal motility than morphine, was also true in humans (although both caveated it with - we don't actually have human data).
1c) They gave specific reasons why it is helpful - and, for instance, showed that in current SOC it is standard to use a drug that decreases morphine induced ileus. (Note that in response to a question, TRVN answered that the existing ph3s do have a standard set of AEs, and ileus is on it, but they don't expect to hit stat sig because the treatment duration is so short.)
1d) Respiratory Depression data - they quoted a statistic of only about 100 lawsuits due to Respiratory Depression adverse outcomes over a decade. And they further noted that Respiratory Depression is one of those things that produces a moderate number of close, scary calls, but generally doesn't have longer impacts (there was a quote from one of the MDs that said they track the use of the opioid blockers and in his institution they use about about 5 per year - out of presumably 1000s of surgeries). Finally note that one of the MDs made a passing mention of respiratory depression impacting him due to middle-of-the-night calls.
2) P&T Committee decisions - they noted that in theory the P&T Committee is supposed to make decisions that save overall cost, but in practice they have a "siloed" budget and thus it is difficult to get new drugs onto pharmacy. Two of the MDs independently noted that to get a new drug approved an MD within the institution generally has to ask and then is often approved only provisionally until they can, in fact, show the savings elsewhere.
AVXS IONS BIIB
FGEN
FGEN
PPHM
AKBA