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IONS ALNY TTR amyloidosis -
Random notes:
a) FWIW both ALNY and IONS/GSK are using biopsy confirmation of amyloidosis in their cardiomyopathy trials (interesting note that ALNY does not require cardiac biopsy per se - just some biopsy). E.g. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641994/pdf/1750-1172-10-S1-P8.pdf
b) It should be noted that although the IONS "Pipeline" charts, even fairly recent ones, look like there are 2 different ph3s in TTR amyloidosis cardiomyopathy I believe that will only really be one (a combo of mTTR and wt-TTR - see above link)? Also note that Pipeline chart is a little misleading in that it doesn't differentiate between awaiting start of ph3 (which the cardiomyopathy Ph3 trial is) and already started.
c) The IONS chart that discusses predicted data releases for 2016 shows a FAP Ph3 OLE data release in between Q2 and Q3 of 2016. My guesstimate is that at this point in time (i.e. today) the OLE data is probably about 1/4 the size of the overall dataset available in the blinded portion of the trial plus the OLE. Given the very varied sequelae of FAP and the 2:1 enrollment any AE have be very imbalanced or very obviously connected to the drug to be reliably observable. (FWIW my further guesstimate is that by the time of the planned OLE data release in about August(?) they will have twice as much exposure in OLE as they do now.)
d) Random note: ALNY has reported fairly benign AE from their phase 2.
IONS
IONS TTR-Rx cardiac amyloidosis
Orphan Drugs - History and categorization of FDA approvals
A find by @Sport234a2b. http://www.childneurologysociety.org/docs/default-source/handouts-2015/sasinowski-child-neurology-society-symposium-on-rare-diseases-october-9-2015-(00148338).pdf?Status=Temp&sfvrsn=2
FGEN -
FGEN – Notes on recent year end CC:
Below are some of the more interesting (IMO) pieces. And note that it is possible some of this may have been in other CCs, but I don’t listen to every one of the CC:
Roxadustat:
Chinese trials – 1 ND trial of 150 pts, 1 Dialysis trial of 300 pts. Both expected to finish enrollment about mid 2016. China requires at least 100 pts with at least one year on drug before approval and expect to hit enrollment for that by March this year. Expect to start filing for provisional approval by end of 2016. (Full approval will require 2000 patients and thus come later). Notes on data releases from Chinese trials: Chinese trials will not be very comparable to ROW trials since in non-dialysis the Chinese regulatory authorities require placebo switch to treated at 8 weeks and in dialysis the epo arm gets substantially different treatment (e.g. lower dose epo). Also not clear what the Chinese regulators will say about releasing trial results and Fibrogen does not want to rock the boat. Finally note that Fibrogen and partner are moving out to start Roxa trials in Myelodysplastic Syndrome and Chemo Induced Anemia (also starting to think about similar indications outside of China – but further behind)
ROW Trials – As has been well broadcast, of the 3 trials for which Fibrogen is responsible, they hit enrollment targets in one on in Sept/Oct 2015, they just hit (or very very shortly will hit) another, but the third has been pushed out to Q3 after the 3 companies agreed that they needed more US and Latin American pts, and fewer EE and Asia Pacific pts. (Note that Fibrogen still cannot comment on enrollment in trials being run by their partners – but did say going ok, and also noted that the trial being pushed out to Q3 didn’t affect the overall timelines (i.e. there are at least some other trials that will finish at about the same time)).
Other points:
1) In response to a question about projected end dates Neff commented that ‘the trials are event driven’ and for ND they need 480 events, and Dialysis 615 events (Note: Endpoint is MACE (Death, MI or Stroke)). (Lots of comments: only the Safety trials are likely to be event driven, and if they hit their enrollments by June 2016 with events by June 2017 that would imply about blended 25% events/year in dialysis, and about 10% events/year in ND. Both of these seem higher than I would expect to see in an RCT – so I expect that the trials will take longer, but I would also expect them to continue to enroll past their original targets. (Interesting note: all three Fibrogen trials still show ‘enrolling’ on ClinicalTrials.gov even though one hit enrollment targets 4 or 5 months ago, which is longer than most to show a change in enrollment status). My final comment on this is that it is possible that the event numbers listed above may include events in the non-event-driven trials – and this would bring the needed event rates down substantially especially if they keep enrolling past the planned patient counts.)
2) Neff noted that the 3 companies plan to optimize the trials in Q3 this year (he talked of scrubbing the events etc).
3) With regards to data releases based upon each of these trials hitting their endpoints (the non-event-driven trials generally have 52 week or shorter endpoints) he noted that the 3 companies have to reach ‘harmonization’ on release (note that in a discussion about 3019 Pancreatic Cancer release he was very clear that it was he that pushed to release the interim results). Finally note that he made explicit mention of the fact that they need to decide how they file (e.g. combining all NDD and all DD trials in some way).
3019 – IPF RCT in first line expected to finish enrollment in Q2 2016 (results 1 year later).
Finances – expect to get another non-contingent milestone of $62M in Q2 2016. There is also another $425M of contingent milestones having to do with Roxa filings and approvals.
Random comments: Neff has several times noted Pancreatic Cancer survival rates in operable vs non-operable as if the patients they can convert to operable will get the same survival rate as the patients that have historically been operable. I am dubious of this. That said, in this conference call they made it clear that they are also looking at other possible endpoints (obviously survival, but also ORR) and looking in other oncology approvals for examples (they were interested in anyone knowing of approvals in any cancer indication based upon conversion to resectable disease – and noted that Head and Neck has a history of pre-operative use).
Finally note: if anyone thinks I’ve captured any of the above incorrectly … feel free to correct it.
Innate and Lirilumab trial in elderly AML (Effikir) – going long?
Obviously, given my board history on “Going long” arguments (i.e. extremely skeptical), ordinarily I wouldn’t post on the topic, but in this case the “going long” argument is more complex (i.e. interesting) than typical and thus worthy of at least a little comment (but a warning that complex/interesting doesn’t mean either positive or negative).
Original Design:
1) Trial was 80% powered for HR=0.60 Leukemia Free Survival (LFS) for p=0.1
2) Originally that was about 100 events over 3 equal size arms (see poster linked below). I.e. the trial was designed to be event driven
3) Originally the followup was until relapse (see poster here: http://innate-pharma.com/sites/default/files/asco2013_tps3117_0.pdf )
Subsequent Events:
1) In early 2015 (after enrollment completed) one of the arms of trial was halted for futility. (Although I am unaware of any announcement about which arm was halted, subsequent to the halt the new trials with Lirilumab have all used the (much) higher dose or higher still – caveat: that is not a definitive argument if Innate themselves doesn’t know which arm halted.)
2) Up until recently Innate has predicted an end to the trial in 1H16, but now says 2H16 – hence the “going long” argument.
Additional note: corporate presentations subsequent to the above poster have said something different than the poster with regards to followup. E.g. the latest corporate presentation says “Maximum follow-up period: 24 months after last patient entry”.
Commentary:
In order to even reverse engineer the implications of Innate’s changed end date there are more questions than typical for a “going long” debate:
a) Is the new end-date just 24 months after the last patient enrolled – and not a predict in any way about the future event count?
b) When Innate was making a prediction based upon future event count (which they previously had to have been doing) was it counting the futile arm – or not? And against what number of required events?
Random FWIW notes:
1) The historical data for AML LFS/DFS in elderly patients is more consistent than in many cancers and the assumptions initially used by Innate to design the ph2 seem consistent with it. (median LFS/DFS around 12 months)
2) Conversely the observations that appeared in some Innate materials of several years ago (that the low doses of the IPH2101 trial had PFS of only 2 months vs high dose of 9 months) is suspect because the low dose median LFS is absurdly low.
PPHM
OT? - "Superforecaster" attributes:
(I put the "OT?" because, of course, this board is all about forecasting in biotech)
http://slatestarcodex.com/2016/02/04/book-review-superforecasting/
IONS SMA and other data readouts and status:
FDA and free speech concerns. Good summary article:
http://archinte.jamanetwork.com/article.aspx?articleid=2484907
Some particularly interesting pieces:
CLLS
FGEN AKBA - Morbidity and mortality in dialysis. Over the last few months I've spent some time trying to sort out the mess that is the metrics related to renal failure morbidity and mortality. Since some here might have an interest I thought I'd write it up. It gathers my thoughts and might spark some discussion.
First - the high level issues:
a) There is substantive disagreement about the primary cause of death for patients on dialysis. The two primary contenders are cardiovascular and infection and although on a count basis there are probably meaningfully more papers supporting CV there are plenty showing infections as the primary threat (e.g. http://home.smh.com/sections/services-procedures/medlib/Pandemic/Pan_Renal/PanRenal_Naqvi_050809.pdf see Figure 4).
b) There is substantive disagreement about the magnitude and duration of the increased death rate in incident dialysis.
c) Finally, a more traditional issue (for this board in any case) is that the expected death rates in dialysis are highly variable in the literature.
Discussion:
Causes of death? - With regard to the substantive disagreement about the primary cause of death for dialysis patients I would suggest that, as I have noted before, causes for death are often very noisy. What gets marked for the clinical trial or on the death certificate seems to vary from the proximate cause to the ultimate cause. My guess is that it varies substantively even from hospital to hospital or from region to region. And dialysis patients are probably particularly vulnerable since their major causes of death are all inter-related (e.g. infection often leads to either MI or CHF, AHF often leads to MI, … . Or for an example directly from Fibrogen’s paper on Study 053 – "The patient was hospitalized on day 72 for worsening heart failure and began receiving warfarin for atrial fibrillation. Last roxadustat dose was given on day 84 (end of treatment). On day 85, the patient’s Hb dropped from 9.9 to 5.5 g/dl from acute gastric ulcer bleeding, which led to two red blood cell transfusions. Despite these transfusions, acute myocardiac infarction occurred on day 89.") Not only is this true between classes of death (e.g. infection leads to MI), but even within classes (e.g. within infection UTIs are not as common as the listed cause of death as sepsis, but in dialysis a surprisingly large fraction of bacteremia is probably caused by UTIs).
Death rate in incident dialysis vs non-incident – although the published papers show general agreement that incident dialysis has higher mortality than later “Stable Dialysis” there is still substantial uncertainty on both the increased rate and the duration of the effect. For example one of the papers referenced in the Roxa paper from the Incident Dialysis trial ( Eckardt et al ) shows that the really large spike is gone within the first 5 or 6 weeks (reminder that the on-going Roxa trial is in patients who initiated dialysis within the last 2 weeks to 4 months). And there are other papers that show essentially no increased mortality within the first few months. See next section.
Statistics about dialysis death rate – there are good national-registry type statistics about aggregate death rates in dialysis (in excess of 20% per year), but there are also multiple papers which show much lower rates of death. The lowest I’ve seen to date is A Rondomized, Controlled Trial of Early versus Later Initiation of Dialysis(See Figure 2B which shows around 8-9 pct death per year.) But there are plenty of others that also show rates substantially lower than 20% - e.g. low teens to mid teens, which is well below the national registry data. But unlike the mess that is attempting to determine causes of death we know the primary factor in this much lower death rate – randomized trials. It is, in fact, hard to find randomized trials in dialysis which have 20% per death rates. Finally, tying this back to the incident dialysis statistics, note that the paper linked in this paragraph above actually shows no increase in mortality during the first few months (Figure 2B again – the slope in the first 6 months is no different than the later slopes). Again I suspect this has to do with whether the patient is in a randomized trial (better SOC and/or better patient selection). All told I don’t expect an RCT of Incident Dialysis to show more than, 20 or 30 percent (at most) higher mortality rate than an RCT in Stable Dialysis - and perhaps no meaningful difference at all.
BTW - there are a variety of things that are very difficult to assess from the literature that would probably help when trying to disentangle complex issues like the above: how does treatment differ in different regions - and not just nominal treatment, but treatment for the various potential morbidity concerns (e.g. hyperkalemia, UTI, ...).
SMMT -
SRPT
SRPT
SRPT
SRPT
SRPT
SRPT BMRN
OT? Hoax websites - good overview. I was debating whether this is relevant to this board, but I think there is enough posting of garbage on this board that it is useful to understand the context.
https://www.washingtonpost.com/news/the-intersect/wp/2015/12/18/what-was-fake-on-the-internet-this-week-why-this-is-the-final-column/
AFMD
PIRS