One thing regarding 358 coming out now that I was wondering. Does thing speak to anything regarding 214? I would have to think they would likely be seeing something one way or another by now (beyond simply seeing no signs of vascular leak syndrome), so would they open up a can of worms with a new IL-2 candidate if things were not looking at least promising. I completely understand it's a completely different candidate, but I would certainly keep it under wraps with 358 if I knew things were going poorly on the 214 front.
Honestly Hijacked I think 358 has been kept "under wraps" simply because it was too premature to talk about. Auto immune disease is a tough nut to crack in general. The historical options are general immunosuppression with corticosteroids and synthetic analogues. The systemic immunosupressants like tacrolimus, and sirolimus generally used in organ transplant type cases. Then more recently specifc immunotherapies for example the TNF targeting antibodies that have achieved efficacy in indications where TNF has a substantial role RA, Chron's , psoriasis... folate analogs have some utility here as well.
358 is really a different approach. That novelty demands a large amount of testing both to develop the molecule with the appropriate selectivity, and to test it's meaningfulness in vivo you probably want to go to primate models before saying much of anything (that's my guess anyway). Nobody has tried to tackle auto/hyper immune disorders with a 358 type candidate (to my knowledge), so the very novelty that makes it exciting, and a potential game changer makes it risker in that they are truly on unexplored real estate. While HR might want to pump candidates the scientist would definitely push back with a 358 candidate saying it's too premature. Remember the concept of 214 as a biased IL2 is not novel and not a NKTR discovery. NKTR's PEG conjugation technology just seems to have given them the best toolbox to develop a credible drug candidate. This plus the rodent models in IO are more meaningful than anything one could do to look at 358. To me 358 is still a coin flip in terms of what this likely means in humans, but if it pans out a novel strategy that POSSIBLY more closely mimics the bodies natural control of the system could be huge..
As for the 'risk' for a premature buyout IMO that risk is far greater while you have programs under wraps. Once in the public domain any buyout rumors grant credibility to the companies tech, and buyers must pay a premium.
I should clarify that I do think the 102 combo might be interesting in the longer term, but it's way down on the experimental agenda of things that can/should be done with NKTR-214. Some preclinical results in the relatively near term would not surprise me however. If HR is mentioning it it's likely a suggestion that they have run some proof of concept preclinical experiments, and there is literature to suggest topo I inhibitors do synergize somewhat with IO drugs. Perhaps damaging the tumor with cytotoxic sparks an immune response as the body cleans up damaged/dead tumor cells.
Hijacked I should have said anti PD-1 both/either drug would prove the point, and ultimately both will likely get a look. My point was the notion that 102 would be in the near term clinical plans for 214 because of a slide in an investor presentation is just silly.
No it wont! Since 102 is NOT approved here (or in EU for now), and it would add complication without good reason to try that combination out of the gate. They have been clear the logical combo would be checkpoint inhibitors, and I expect Keytruda will be the highest priority.
If 102 gets approved in EU physicians my try combo on their own. We might see results in scientific literature prior to anything NKTR might try in the clinic.
BTW funny how NKTR resolved our discussion about the reverse logic 214 candidate. I had thought about that too, but assumed it was probably wishful thinking. Well happy to hear I was wrong. A new way to approach autoimmune disorders could be a very big deal. I really don't know much about the preclinical models they might look at here, but it will be interesting to see what indications they settle on.
I have wondered the same is there a way to reverse the logic of 214. My hunch is that would be very difficult. I think the logic of the cartoon depicting 214 while simplistic is essentially correct. 214 works by adding PEG arms to the cytokine on one face to interfere with binding of one subunit of the receptor complex that's far simpler than trying to increase affinity for that complex (at least that would be my guess)
The past is prelude, at least until it isn't anymore.
A whole lot of failure on the road to success is normal, and in the case of immunotherapy it's a case of the technology being inadequate until recently. Of course of the earliest cases of IO success is/was IL-2, and people pressed on in spite of failures because there was recognition that once the technology hurdles were overcome the potential was tremendous.
You cite Provenge as a failure, and it was in most senses there was too little benefit for the cost. If however somebody were to come up with a candidate that was capable of magnifying the immune response a drug on the fringe of efficacy might become a candidate for re-examination of it's potential. But a drug that might selectively magnify the immune response by growth and differentiation of CD8+ Tcells well that's the stuff of science fiction/fantasy.
"What's in a name a rose by any other name would smell as sweet"
Nektar, Schmektar- PFE, AZN, MRK As long as well all benefit appropriately for enduring a long wait and enjoy a large premium I'm ok with a name change.
Plus there is the human side of wanting to see the IO platform develop as rapidly as possible. I make no pretense about being here for my own financial benefit, but I believe for almost all of us watching an important technology evolve out of this would be a very nice side benefit.
"NKTR will still need lots of cash to pay for the 181 and 214 trials through 2017."
If NKTR is scaling up 214 trials through 2017 cash to pay for it wont be an issue!
"and up to 14 infusions (one every eight hours) for NKTR-214 in an ICU setting. That's at least five days in the hospital per dosing. Taking Keytruda is a spit in the bucket compared to NKTR-214 treatment."
In an attempt to trash NKTR-214 you inadvertently pointed out a key advantage. What you describe is the parent IL-2 Adeluskin NOT NKTR-214!
NKTR-214 dosing is expected to be similar to the antibody therapies and the toxicity in preclinical work was dramatically improved (no signs of vascular leak syndrome the key toxicity of the IL-2 parent). The fact that people are still trying to incorporate IL-2 into IO therapy in spite of the tox. profile speaks volumes about the potential of a candidate with more convenient dosing and dramatically reduced tox. The hope is that 214 would be possible to dose on an outpatient basis.
Like I said it's nothing like the preclinical timing, but IO isn't like your typical drug. The activation of the immune system has more lasting effects (certainly we have seen this in the 214 preclinical). My point was that even with a month or more between checkpoint inhibitor and 214, I would still be looking for signs of something different in these patients.
Ultimately they need to figure out the optimal timing for combination of checkpoint inhibitor and 214 (assuming we see some activity). The most likely beneficial scenario intuitively would be in immediate succession where the effects of the first drug are still pronounced when the second drug is administered. You probably don't get access to best case patients until we see some promising effects. E.G. you typically don't get to try a combo in PI on a patients first run with established therapy where they are having a robust response, but this is where one would expect greatest benefit.
Having said all this I'm not holding my breath for any news until the 3rd quarter or so. If we get something sooner wonderful.
While I'm anxious to see combo results the real key results should come early. Are we seeing the sort of stimulation of T-cell production (w/o upregulation of t-reg cells) preclinical results predict? Plus we may get an early indication of combo potential from those who have relapsed after checkpoint inhibitor treatment. Remember the best results for 214 were NOT with co-dosing of checkpoint inhibitors, but rather with sequential treatment (it didn't seem clear which order was optimal). Of course the dosage timeframe here vs preclinical is completely different, but there is a chance there will be a real difference in these patients.
As for your earlier post a few days ago comparing the buyout price for the targeted lung cancer drug it's really apples to oranges in terms of valuation. IF (and it's still a very big IF) NKTR-214 pans out it could be a cornerstone/keystone compound in IO. The tongue in cheek article DCX mentioned about the future of cancer therapy is "PD-1/checkpoint inhibitor + insert your candidate here" might very will evolve into "NKTR-214+ your candidate". In simple terms 214 is strategically positioned in terms of its mode of action IF the science pans out. I can remember writing a paper in high school biology which I titled "Interferon the big IF" (I may have plagiarize the title I forger :). This was decades ago well before there as any sort of practical access to the parent molecules much less a polymer modified variant.