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Losses happen!
It's annoying but a fact of life.
RETA looks shaky to me. The drug has a background safety concern, and I would not trust the company to say that it has been addressed, etc...
PRTO:
Sorry, I missed this a long time ago.
Whereas vonapanitase did not meet its primary end point, there were several clinically meaningful indicators that vonapanitase may be an effective therapy in fistula creation.
Importantly, vonapanitase was associated with increases in secondary patency and use of the fistula for hemodialysis.
JNCE:
It's co-stimulatory for T cell proliferation and cytokine secretion, so I can't personally see how an ICOS antagonist would be desired. Would appreciate input on this angle.
DCPH:
The other point I would make here is that in the 4th line dataset, the majority of the censored points are well past the median PFS for 4th line placebo (~2 months).
Doesn't absolve the dataset from a lack of reliability, but if one is fairly comfortable with the placebo response in 4th line GIST then it looks decent imo.
JNCE:
From the reading I did, I *could* make a case for CTLA-4. However, it appears that CTLA-4 antagonism upregulates ICOS. So if a cell needs to be responsive to CTLA-4 blockade to upregulate ICOS, then what strong need is there for JNCE's drug? It becomes a small, incremental addition to the response rather than an independent driver for a response.
Meh.
Re: JNCE
The obvious caveat is that there was preclinical data to support the PD-1 combo, but they barely got a signal
NKTR / Phase 3:
Perhaps I could see BMY (even then I don't agree) but why would you say NKTR is rushing? Since their on-going costs are capped isn't it more value creating for their shareholders to be more aggressive even at the risk of fewer/partial (subgroups in indications) approvals?
Don’t underestimate inherent bias from companies and investigators especially when it comes to IO combination.
BMY / IDO:
Absent some misconduct in the INCY / MRK trial, I don't see any reason why BMY should have any hope in its similar plan.
There's some attempt for salvation on twitter by mentioning the BMY compound displaces the heme in IDO. I don't think that matters one bit. Obvious caveat is that no one has seen BMY's melanoma data for this compound. BMY had a close look at INCY's IDO through their collaborative program, and still moved ahead with their IDO.
One aspect that confused me prior to this phase 3 data release was the aggressive moves by multiple players to enter the IDO space, their willingness to start phase 3s on limited data, and the selective disclosure of P1/2 data in some indications while not disclosing others. I figured the possibilities were either that they see something, or that they're all moving forward as a competitive / don't-get-left-behind play. In hindsight it seems option 2 is the more likely answer.
INCY
Wonder what will happen with all the other ongoing Phase 3s that just started.
MYOK:
I'm not at ACC.
I've honestly not followed MYOK too much recently. I'll have to take some time to catch up on these results.
Has MYOK indicated whether or not they'll need an outcomes trial eventually?
RCC / PD-L1 +/-
Isn't it also very important to detail the number of patients that were PD-L1 negative?
RCC / epacadostat:
I don't think the currently running phase 3 in RCC will meet its primary PFS endpoint. And even if it does, I don't think the data will be clinically competitive. They're running against sunitinib / pazopanib but I think newer drugs like axitinib are the real competition. Axitinib has also had some very strong response rate data in the 80% range in combination with PD-1 inhibitors.
NKTR:
This is admittedly unscientific, but it seems intuitively unlikely that a small-molecule drug added to a checkpoint inhibitor is going to be the Holy Grail in the treatment of metastatic cancers. I think this is one reason NKTR-214 is generating more excitement than, say, Epacadostat.
NKTR:
Yeah I'm just assuming that their most recent update, and those going forward, are for the treatment naive cohort. Reasonable given the response in the second line.
I haven't heard the company specifically say but with the way some have gone from SD to a response may be possible for some that do not get SD (and go off therapy) might in time have had a response if treated longer (or treated at a higher dose).
NKTR:
Yeah I'm not exactly sure what's going on there but haven't had time to relisten to the JPM presentation to seek clarity. Perhaps the 21 include those with prior lines of therapy and are therefore excluded from the treatment naive population shown later.
NKTR:
In the CC, did they clarify how they got to 71%? At SITC they had 13 patients in the RCC so I couldn't make the math work. I assume some additional patients have been added to the denominator, but any hint as to how many?
RETA:
Funny thing about this is that it's a PAH trial. They used to report 6 MWD from this trial, albeit in a very opaque manner.
This company is... suspect.
PRTA:
I actually didn't think their light chain amyloidosis data were all that bad. This definitely changes that view.
NKTR:
Why the heck would their management consider selling the company now?!
Doesn't ring true to me.
RETA:
I'm following it very loosely now. My general impression of the management is not flattering. I think they're the typical, cynical management team that will try to draw everything out while collecting a paycheck... for years.
For that reason, I've stepped back a bit and have not been following too closely. The Lariat trial was such a mess that I don't think Catalyst will show anything. But the treatment period is short enough that they may escape a safety signal; on that we agree. As for cardinal, I do not know if it has any interim analyses. I've not dug in to try and find out the specifics.
Given the safety signal with bardoxolone (and their dud of a follow-on compound), I agree with you that RETA is a good long term short. I think timing it may be frustrating because management will try to pass things off as equivocally as possible. Probably the best way to play RETA is to short it tomorrow at the open and then not check it again until 5 years from now. Hopefully by then all the acetylcholine has been used up and the legs on the cockroach are no longer squirming.
NKTR:
Yeah, I don't think you can get overly broad use with intratumoral injection.
One thing that's a bit interesting is that nektar is heavily into the biased agonist approach. This is the general method that I generally thought / think is a bit too dependent on experimental conditions you can invoke in the lab. It's why I was negative about Trevena's CV program.
NKTR:
I thought 262 looked interesting. I wonder if they can solve the delivery issue?
MDGL:
One of the features of my rants is that I save them for areas I have some background / understanding in.
Sadly I don't have the breadth of many others on here. So I don't know anything about MDGL, sorry.
SYRS:
One day I'm going to figure out how to get paid for ranting about drugs on biotech values!
These data are actually a touch worse than I imagined them to be. That says a lot.
FGEN:
The part that shows roxadustat, in addition to its intended inhibition of HIF PH, also probably inhibits collagen PH
Re: FGEN
I'm a bit confused. What part of this paper do you think indicates an in vivo risk?
OT:
90% of my biotech wisdom strategy is to steal items from that list and tweet them every 6-8 months or so!
MYOK:
I have a rule never to be excited by new hires. I don't think they're a reliable signal of program success or failure.
For example, Dr. Semigran was involved in the RELAX study which used sildenafil to target PDE-5 in the heart for HFpEF. Only problem? Many researchers have shown PDE-5 protein is not really expressed in the heart, and the trial was predictably a giant flop. See here.
Also, Dr. Semigran is involved in another garbage HFpEF trial, INDIE-HFpEF delivering nitrite. Guess what the biological "rationale" is? The same as the RELAX trial. Scientific process much?
I think it's easier to work off the clinical data rather than pushing reputations.
MYOK:
The back taxes are going to be a worry. I'm proposing renaming this new code the Education Death Tax so that we can get people more interested. People get angry at death and taxes.
I initially found omecamtiv's mechanism analogous to giving HF patients dobutamine... temporary relief of symptoms followed by more rapid deterioration. Drugs that provide some benefit in HF patients tend to all reduce contraction (beta blockers, calcium channel antagonists), so it seemed bizarre to see CYTK swim counter to the data current. I've not followed CYTK much in years, so I'm unsure if they've found an appropriate niche. MYOK's strategy is a bit more in tune with strategies that work in the clinic, so it seemed a better initial approach.
Strangely, I actually thought the initial MYOK focus on genetically defined CM was garbage. Many of the mutations are in practically non-druggable proteins with unknown penetrance and dubious functional data, so I thought it fictional to be able to target those. They then backed off that approach, so I became more positive about the proposition.
MYOK:
how is reduced contractility and lower ejection fraction good for HCM patients?
SYRS:
I think this drug is a complete dud. It's a synthetic retinoid analog of ATRA that they're trying to use in AML while "enriching" the population. Problem is that ATRA basically has zero efficacy / use in AML, so there is no meaningful efficacy to enrich.
The other problem is that this is another case of computational strength being used to create biological stratifications without any hard functional data. I don't think the groupings they've identified will provide any meaningful advantage. In a way, it reminds me of GNMX.
All this is supported by the fact that they're already talking about combo studies without having revealed any single agent efficacy data.
Buyer beware.
MYOK:
I think their data to date looks reasonable. As I mentioned earlier, I like their approach of reducing force production.
The targeted hypertrophic cardiomyopathy angle did turn out to be bunk, since they don't seem to be focusing on a mutation-driven strategy. I actually think that's a good thing.
GTHX:
I don't know what has changed to bring up the EP response rate into the 60-70% range since the 52% reported in the Socinski trial that was cited in the presentation. I don't know if that's really something to be worried about or not.
GTHX:
88% ORR and 1 CR in 17 pts in 1st line SCLC is impressive.
GTHX:
Yes, I'm aware of the claim. But having combed over their posters for the last couple of years, I'm not convinced there is a meaningful clinical difference.
GTHX:
Been watching it for a while. Looked into it a while ago and decided I wasn't too impressed. But now we see what that opinion is worth!
On a fundamental basis, I'm really not sure why it's ramping up. The data aren't all that clear for its lead product.
NLNK / INCY:
I agree with you that the INCY cohort appears to be worse off at baseline. How much that can impact the PFS data is anyone's guess. Perhaps NLNK IR could share how their Stage IV cohort fared in the PFS measurement?
The other factor that would help the comparison is to know the PD-L1 +/- split. PD-L1 - patients do not appear to respond all that often (1 responder of 6 in INCY cohort), so if there is an imbalance there between the trials, it would have to be brought into consideration.
For the record, I'm not too focused on the ORR of these regimens. I think durability (DOR / PFS) are the key metrics.
A couple of things that strike me as curious about these studies:
- I find it a bit surprising the NLNK combo appear to have actually reduced many AEs versus pembro alone. Grade 3/4 hyperglycemia is down, anemia abrogated and lymphopenia not even on the AE table for the combo. That's good I guess, but surprising.
- I think INCY isn't being fully forthcoming with their PFS data. The cutoff they're using for these presentations is rather far from the date of presentation. They've generally been a trustworthy management team, but I have an uneasy feeling around these data slices they present.
- I'm not sure how NLNK got their 12.9 month PFS number. From looking at the change in tumour volume over time graph, only about 1/4 of the study participants seem to have made it to 52 weeks at this point. I assume it's an estimate of sorts, but I'd keep an eye on it.
RETA:
Actual difference in SAEs between bard and placebo in BEACON that caused the trial being terminated early occurred quite early (3-4 weeks on bard) so it wasn't really long term effect.
AF:
I'm just guessing here, but it would be the type of deviousness worthy of AF.
Since SRPT was controversially approved based on a surrogate outcome, there is a chance that the post-market trials the company is obligated to run end up failing. In the case of this MRK news, AF may be making a list of people / goading people into arguing that the pembro approval based on the surrogate should not be revoked based on this survival outcome.
If / when the time comes that SRPT's follow-on trials show little effect, AF may start calling people out for advocating eteplirsen withdrawal when they looked the other way for pembro in SCCHN.
I think it's very much apples and oranges, given the preponderance of data validating the activity of pembro as a drug. But it's a typical twitter-type long term argument.