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FGEN
RTRX AUPH
FGEN AKBA
FGEN AKBA
IONS ALNY
RNAi random comments:
Several years ago I think it was commonly thought (and I was no exception) that RNAi and related technologies would enable quick competition. I.e. someone finds a target, then multiple companies come in with me-toos. Quick trials, show knock-down, approved.
It has, however,become ever more apparent that it is, currently, nowhere near that easy, but I think the investment community hasn't yet fully grokked this. RNAi's are hard.
1) The delivery backbone/agent/technology is often dangerous. Especially when given at high doses. (E.g. I think there is a reasonable chance that a meaningful side effect shows up for SRPT in their confirmatory, high dose, etep trial)
2) Picking the exact sequence matters a lot from an AE perspective. I am not well read on it, but I know that, for instance, there is a lot of literature on potent immunogenicity of some sequences (and the lack thereof for other sequences). It was, for instance, one of the big changes that IONS did to lower their (very bad) injection site reactions. (I'd be very surprised if IONS didn't have by far the best database for this).
3) It is very very difficult to target anything outside the liver and a few other organs. (I suspect IONS is one of the furthest along in developing technology to target specific cell types - but haven't seen a good comparison).
BTW - Anyone interested in the technology has to follow @RNAiAnalyst.
FGEN and AKBA - Implications of an uneven event rate (if it exists), and other random notes (last for a while):
Uneven Event Rates:
There is a reasonable chance that for CV and/or renal events these drugs show excess early excess events in NDD before lowering the event rate substantially below the control arm. The level of evidence for CV and renal is different, but, of course, both are uncertain because the data is still fairly limited. Nonetheless, because it is interesting, and because I think it reasonably likely that at least one is true, I think it worth discussion.
CV Evidence: In the paper for the single arm Roxa NDD trial there was a statement about significant imbalance of CV events vs Hbg levels. And low Hbg (where the events occurred) was a small fraction of the time (and likely mostly at the beginning of the trial). And note that the event rate vs the total man-months at low Hbg was very very high - hence my hypothesis that there is an initial, short lived, detrimental effect. (note that the case for longer term benefit is much much weaker because smaller event rates take more man-months of data).
Renal Evidence: there is very likely to be an excess hyperkalemia incidence due to drug. Hyperkalemia, for other drugs (e.g. ACEs), is something that occurs much much more frequently early in dosing (i.e. early harms). But the AKBA RCT showed post hoc stat sig improvement in eGFR rate of decline (vs control arm). I.e. early detriment but late benefit.
If either of these, or both, are true then there are some interesting effects/ramifications:
a) The real benefits of the drug won't be strongly and 'officially' visible until they stop enrolling - because the recent enrollees' excess event rate will swamp the earlier enrollees' benefit. (because essentially all trials enroll more people/month every month).
b) Corollary 1: The DSMBs could see a dramatic benefit, be very confident of it, and yet be unable to stop the trial even if something similar shows up in overall survival - because the trial community (including the FDA) generally do not use terminal slopes, only absolute totals. This is related to my earlier post on how renal trials could be shortened.
c) Corollary 2: The shorter trials (like the FGEN Chinese trials) may not show a benefit at all. Perhaps even harms (it depends on the depth, and length of the bad event rate vs the good event rate). I think it unlikely we will see that for renal events, but for CV or OS... ?
Other notes on this topic:
1) The above is for Non-Dialysis Dependent nephropathy. We have, essentially, no useful data for Dialysis (incident or stable).
2) If either of the above are true, the sponsors could undoubtedly see it even in blinded data. And again, the reminder that AstraZeneca (Roxa partner) bought ZSPH late last year for its hyperkalemia drug. So I'd suggest this supports the theory for renal events.
3) I'd make a case that the early excess event rate in incident dialysis (and under SOC there is definitely excess event rates in the first month or so) is another indication of something similar.
Random other notes:
A) Per ClinicalTrials the Roxadustat trials just (9/20) added additional exclusion criteria for two of their on-going trials. Now all trials exclude liver disfunction and most exclude alcoholics.
B) Roxa is continuing to enroll all trials but one of the Dialysis trials. Many of these have 52 week endpoints (per clinicaltrials) so if they are enrolling now... . That said, this is the month that FGEN and partners decide what path to take forward for the trials.
AKBA FGEN
AKBA and FGEN - question: do you know the AKBA ph 3 protocols? Dose like the AKBA ph2 (only 50% made it to 11 Hgb) or like FGEN (almost everyone to 11)?
Reason it could be important: the over 11 group in Roxa NDD ph2 had no CV events. Between 10 and 11 not as good. (Note that this *could* be just a correlation to time on drug, not an Hgb causation. But it's a risk unless AKBA can see in their ph2b data)
AKBA
FGEN -
FGEN - Links to relevant papers and some key liver quotes:
Trial 017 (NDD):
https://www.researchgate.net/profile/Anatole_Besarab2/publication/285420191_Besarab_2015_NDT_Study_017_NDD_roxadustat/links/565e24d408ae4988a7bd3d0c.pdf
Key quotes:
FGEN (and AKBA) - Thanks for the feedback/dialog. Comments below (FWIW):
FGEN and AKBA – and the Non-Dialysis data published by each company in the last few months (FGEN’s, 041, had no placebo, AKBA’s was an RCT). Some of this was recently ‘discussed’ in brief on twitter (e.g. @biomaven and @JQ1234t), but it is interesting enough to merit more detailed commentary and questions. In no particular order or flow… :
Side effects - FGEN vs AKBA:
The side effects are remarkably similar between the two drugs (e.g. diarrhea being the most common side effect and at very similar rates). The most marked differences are liver related items. FGEN shows more SAE, including the dreaded bilirubin (although they take pains to emphasize not coincident in time with the ALT elevations to >3ULN). But AKBA too had one liver SAE (the poster for the trial seems to treat it more seriously than the subsequent paper). And only FGEN shows a cholesterol improvement.
Hyperkalemia – I’ve speculated before that hyperkalemia appears to be a likely side effect of this class of drug. It never hits stat sig in any one RCT, but the numbers are remarkably consistent where they are known or can be guessed at (in the FGEN 041 paper they don’t give hyperkalemia, only acute and chronic renal failure – but it is likely that much of that is, or comes with, hyperkalemia). In the AKBA RCT trial it was 5.1% vs 0%, in the FGEN 017 RCT it was 4.5% vs 0%, in the FGEN 047 RCT (in China) it was ~3% vs 0% (see S-1) and in the 041 trial (which is the primary focus of this post) there were 2.8% “Acute Renal Failures”.
FGEN Commentary:
First – the inconsistencies with regard to their liver story:
FGEN, in their paper for the Trial 041, a 16 to 20 week single arm trial in 145 non-dialysis patients, say
Overview of Byzantine drug pricing practices in the US. Best summary I've seen to date. Normally I find Gottlieb (the author) too partisan, but in this case his story seems less laden with politics.
Note that I know that some on this board know a lot about this, so I am hoping some will critique or add to it as the mood strikes. E.g. I believe that tax structures also impact this, but are not mentioned in the article. Anyone who can clarify?
http://www.forbes.com/sites/scottgottlieb/2016/09/12/how-congress-can-make-drug-pricing-more-rational/#110501d02f6b
RTRX
$rtrx
RTRX
RTRX - Meets primary endpoint (proteinurea):
September 7, 2016
Retrophin Announces Positive Top-Line Results from Phase 2 DUET Study of Sparsentan in Patients with Focal Segmental Glomerulosclerosis
Combined sparsentan treatment group experienced 44.8 percent reduction of proteinuria, more than double the reduction of irbesartan; achieves statistical significance in primary efficacy endpoint
Preliminary safety findings show sparsentan was generally safe and well-tolerated
Conference call scheduled for today at 8:30 a.m. ET
SAN DIEGO, Sept. 07, 2016 (GLOBE NEWSWIRE) -- Retrophin, Inc. (NASDAQ:RTRX) today announced positive top-line results from the Phase 2 DUET study of sparsentan for the treatment of focal segmental glomerulosclerosis (FSGS), a rare kidney disorder without an approved pharmacologic treatment that often leads to end-stage renal disease. The study achieved statistical significance in the primary efficacy endpoint for the overall sparsentan treatment group, demonstrating a greater than two-fold reduction of proteinuria compared to irbesartan after the eight-week, double-blind treatment period.
"We are very pleased with the robust top-line results from DUET, which suggest sparsentan could be a significant advancement in the treatment of FSGS," said Stephen Aselage, chief executive officer of Retrophin. "FSGS patients today face poor outcomes with limited medical options; we look forward to working with the FDA to find the most expeditious path forward that would deliver the first approved pharmacologic treatment to the FSGS community."
In the DUET study, the mean reduction of proteinuria from baseline after eight weeks of treatment for all patients treated with 200, 400, and 800 mg/day of sparsentan (n=64) was 44.8 percent, compared to a mean reduction of proteinuria for all patients receiving 300 mg/day of irbesartan (n=32) of 18.5 percent (p=0.006). Further, the mean reduction of proteinuria from baseline after eight weeks of treatment for all patients treated with 400 mg and 800 mg doses of sparsentan (n=51) was 47.4 percent, compared to a mean proteinuria reduction of 19.0 percent for patients receiving 300 mg of irbesartan (n=25) in these two dose cohorts (p=0.011). The comparison of individual sparsentan dose cohorts to irbesartan showed clear signals of relative improvement, but did not reach statistical significance.
"The results from DUET serve as proof of concept for sparsentan's novel approach of combining endothelin receptor type A blockade with angiotensin II inhibition for the treatment of FSGS," said Alvin Shih, M.D., executive vice president and head of research & development for Retrophin. "Significant reductions in proteinuria, along with a well-tolerated preliminary safety profile have us excited about being one step closer to providing a new treatment option for patients with FSGS."
Top-line results suggest sparsentan was generally safe and well-tolerated in the DUET study. One serious adverse event, anemia, classified as potentially related to treatment occurred in the sparsentan group but did not result in study discontinuation during the eight-week blinded treatment period. There were no withdrawals due to fluid retention during the eight-week blinded treatment period. All patients who completed the eight-week treatment period entered the ongoing open label extension study, and the vast majority of these patients continue to receive therapy.
The Company plans to present detailed study results, including data from the open label extension, at an upcoming medical meeting or in a peer-reviewed publication.
Conference Call Information
Retrophin will host a conference call and webcast today, Wednesday, September 7, 2016 at 8:30 a.m. ET to discuss the DUET study results. To participate in the conference call, dial +1-855-219-9219 (U.S.) or +1-315-625-6891 (International), confirmation code 76903331 shortly before 8:30 a.m. ET. The webcast can be accessed at www.retrophin.com, on the Events and Presentations page within the Investors section. A replay of the call will be available starting at 11:30 a.m. ET, September 7, 2016 until 11:59 p.m. ET, September 14, 2016. The replay number is +1-855-859-2056 (U.S.) or +1-404-537-3406 (International), confirmation code 76903331.
About the DUET Study
The DUET study is an international, randomized, double-blind, Phase 2 clinical trial assessing the safety and efficacy of sparsentan in 109 patients with focal segmental glomerulosclerosis (FSGS), of which 96 qualified for the evaluable database. The primary endpoint is the reduction of proteinuria, as compared to irbesartan, which is part of a class of drugs used to manage FSGS in the absence of an approved pharmacologic treatment. After a two-week washout period, patients were randomized to receive daily oral doses of 200 mg, 400 mg, and 800 mg of sparsentan or 300 mg of irbesartan. After completing the eight-week treatment period, all patients were eligible to receive sparsentan as part of the study's open-label extension.
About Focal Segmental Glomerulosclerosis (FSGS)
Focal segmental glomerulosclerosis, or FSGS, is a rare disorder without an approved pharmacologic treatment option that is estimated to affect up to 40,000 patients in the U.S. with similar prevalence in Europe. The disorder is defined by progressive scarring of the kidney and often leads to end-stage renal disease. FSGS is characterized by proteinuria, where protein is found in the urine due to a breakdown of the normal filtration mechanism in the kidney. Other common symptoms include swelling in parts of the body known as edema, as well as low blood albumin levels, abnormal lipid profiles, and hypertension.
Reduction in proteinuria is widely regarded to be beneficial in the treatment of FSGS, and may be associated with a decreased risk of progression to end-stage renal disease. In the absence of an approved pharmacologic treatment, FSGS patients are currently managed with angiotensin receptor blockers, angiotensin converting enzyme inhibitors, calcineurin inhibitors, and steroids.
About Sparsentan
Sparsentan could be the first approved pharmacologic treatment for focal segmental glomerulosclerosis, or FSGS, a rare kidney disorder that often leads to end-stage renal disease. Sparsentan's dual mechanism of action combines angiotensin receptor blockade with endothelin receptor type A blockade. In several forms of chronic kidney disease, endothelin receptor blockade has been shown to have an additive beneficial effect on proteinuria in combination with renin-angiotensin blockade via angiotensin receptor blockade or angiotensin converting enzyme inhibitors.
The Phase 2 DUET study of sparsentan met the primary efficacy endpoint for the overall treatment group, demonstrating a greater than two-fold reduction of proteinuria compared to irbesartan, after the eight-week, double-blind treatment period. The Company plans to engage the FDA to determine the most expeditious path forward to advance the development of sparsentan towards approval. In 2015, the U.S. Food and Drug Administration and European Commission each granted sparsentan orphan drug designation for the treatment of FSGS.
About Retrophin
Retrophin is a fully integrated biopharmaceutical company dedicated to delivering life-changing therapies to people living with rare diseases who have few, if any, treatment options. The Company's approach centers on its pipeline featuring clinical-stage assets targeting rare diseases with significant unmet medical needs, including sparsentan for focal segmental glomerulosclerosis (FSGS), a disorder characterized by progressive scarring of the kidney often leading to end-stage renal disease, and RE-024 for pantothenate kinase-associated neurodegeneration (PKAN), a life-threatening neurological disorder that typically begins in early childhood. Research exploring the potential of early-stage assets in several rare diseases is also underway. Retrophin's R&D efforts are supported by revenues from the Company's commercial products Thiola®, Cholbam® and Chenodal®.
Commentary:
Meeting the primary endpoint isn't a particular surprise since historically these drug classes are typically additive in proteinurea. But FWIW I'd suggest that there is substantial regulatory risk going forward.
1) Will the FDA provide Accelerated Approval based upon proteinurea? For other, bigger, indications, like Diabetic Nephropathy, I think it is a virtual certainty they would not (for good reason - combining drugs might look good for proteinurea, but actually end up harmful on more important endpoints like GFR etc)? Martin's argument that they would accept proteinurea for FSGS was that FSGS is a substantially more 'proteinuric' disease than most nephropathies (and, or course, that it is an orphan indication)
2) I would suggest that the likelihood of the FDA providing AA on this data will depend substantially on other parameters seen in the trial:
a) GFR change at the end of trial: There is a pretty good chance that the GFR change was substantively worse for the drug than for the SOC (typical with most nephropathy drugs over the first 2 to 4 months). That would (and probably should) make the FDA nervous given history of nephropathy drug combos. The mitigation would potentially be the extension data - e.g. if it flattens in the extension. (Interesting note - I know of only one drug class that seems to avoid this issue.)
b) SAE - particularly edema (the claim is that by being extremely specific to ETA (vs ETB) this won't be an issue - and the (sparse) data for Sparsentan does make this a plausible hypothesis), but the PR says no more than 'no withdrawls due to edema'.
FWIW - I'd suggest checking non-CV death. (I.e. Mortality minus MACE and stroke deaths). Both JELIS and Omega show meaningfully more such mortality in the treated arm (perhaps 'stat sig' in both, although I haven't run the numbers and it certainly is post hoc) - and, if memory serves, that isn't the first time that omega-3s/fish-oils have shown such hints. ?
PS sorry for stalking, but I like to follow interesting debates.
CARA - Summary of my (negative) view of CARA (link to a post on Biomaven's board in response to Bladerunner):
http://www.siliconinvestor.com/readmsg.aspx?msgid=30714416
SRPT
SRPT
SRPT
SRPT PTCT
IONS and hiding (or being blasé?) about AE.
Feuerstein had an interesting (truly, not being euphemistic) defense of his extreme skepticism about all things IONS. His mailbag this week is a worthwhile read. See https://www.thestreet.com/story/13665173/1/biotech-stock-mailbag-ionis-trust-issues-and-oops-don-t-look-at-that-slide-deck.html
My commentary:
1) I had neither seen nor heard of this oops chart before so it was useful both to understand IONS and to understand WS' view of them.
2) regardless, I don't think the fact that IONS underplays Adverse Events is news to anyone who has been paying attention to IONS over the last 2 or 3 years. Thus the only info added by the slide AF shows is that some of that is intentional on the part of IONS. Shame on them (although I sincerely doubt that they are alone among biotech wrt hiding unattractive trends or spinning them significantly).
3) My disagreement w AF (e.g. Referred to him an IONS hater in the post to which this post is a response) is multifold:
3a) he assumes that such hiding applies to all IONS data, even data outside of the AE. For instance, his first reaction the recent IONS announcement of the successful SMA1 interim strongly implies that they were hiding a lack of efficacy on survival, but in fact they were explicit about survival being only a trend in the recent trial, and they were also clear that the basis of their survival would be, in large part, in the ph2. He was also not thinking about the fact that survival should be less stat sig than the endpoint used in the interim.
3b) he (and others) seem to start with the position that they are more extreme in their ignoring AE than they probably really are. At least not now - e.g. they clearly have been working on the dosing of the their GCCR or GCGR (can't remember which and too hard to look up on this platform) after the ALT issues 2 years ago. Also it is clear that the ISRs of their current drugs are wildly better than their Kynamaro era drugs. Note that this is not to say that they are sufficiently clear yet - but neither is it ignored.
3c) IONS is, in many ways, much more transparent about their pipeline than others. E.g. They publish an amazing amount of their preclinical. And they generally get more data out (full chart packages) right after the trial results for ph2s. Rarely do they employ the common practice of 'just top line results' to preserve published capability, Very few others in the industry do these things. That said, yep, the AE in these releases is generally less than others release in their full (albeit much later) packages..
All told, I think Ionis is both a little too blasé (aka in self-denial) about their AE (e.g. In their R&D Day they simultaneously said no platelet class effect and then presented a lot of data that said it is a class effect, albeit a much milder one than initially thought). And they generally intentionally hide the very data that is of interest because they are too blasé and think the rest of the world is too sensitive to AE issues. But outside of SAE they are actually, IMO, generally more transparent than most biotech. (Note - this is NOT to say that they are always perfectly transparent - and I am not interested in trying to create ratings scales for IONS vs other companies for transparency outside of AE. But perfection isn't of interest to me anyway.)
As usual - comment/critique is welcome.
IONS BIIB