CYTK
#Yes, so we won't be able to comment on specific discussions and interactions we're having with regulatory authorities.
Otherwise we can speak more in general tone, which is to say that when you engage with the FDA at the end of Phase 2 interactions you pose specific questions.
Those questions then prompt answers and a dialogue.
With regard to EMA, it's a slightly different process as you may know, where you seek protocol assistance and scientific advice.
With regard to our regulatory interactions, we have in this quarter interactions with FDA, EMA, and other regulatory authorities, and we are together with Amgen discussing a plan for a phase 3 program that contemplates a specific protocol, and we get an opportunity to discuss the inclusion and exclusion criteria, the end points, as well as other specifics regarding the protocol or protocols, as well as other issues around CMC and non-clinical activities.
So, it's different for FDA and EMA in terms of how those conversations go, and what I can reiterate is, those are all planned to occur this quarter.
Some have already occurred and as we and Amgen are going through these together we're encouraged by already what has transpired.
I don't think I can do much better than that.
With regard to breakthrough designation, that's something that we will contemplate.
It's not something that we have determined.
Hi, <UNK>.
We've already discussed publicly how we are looking at a potential Phase 3 program that would enroll thousands of patients, and which would be event-driven, and which would be pivoting around a primary end point that would include death and hospital readmission with secondary end points that would flow from there.
And, as such, while we can't speak specifically about our own plans together with Amgen.
What we have been able to do is share with you and others that we believe that studies like the PARADIGM-HF study, the other study are ones that create some markers or bookends around which we and Amgen are discussing with regulatory authorities possibilities that may be appropriate for omecamtiv mecarbil.
So I think that is still the best information I could provide.
Certainly we have our own feelings that we are discussing with regulatory authorities about where we may lie in that space and that's what in particular these meetings are set up to discuss.
Yes, I think that seems reasonable.
I expect that we will be making a decision by following the conclusion of these regulatory interactions.
That's something that we and Amgen would be making together and that we proceed the plan to still hopefully begin a Phase 3 program before the end of the year.
So I'll turn it to <UNK> to answer in part, but I'll start by saying it was partially a function of our ability to invest in the program and do so with more confidence.
That's something we always would've wanted to do.
Now we go from 80% power to 90% power and that's informed by other analyses.
But it's also informed by feedback we're receiving from the sites and in particular with regard to enrollment rate and the design of the study, the study design seemingly to meet expectations in terms of being able to hopefully elucidate and improve safety and tolerability profile.
Yes, I think there is no particular analysis that was done.
It would always have been better to have had 90% power for the primary end point of a Phase 3 study and, again, I think this may be the third time one of us has said it.
We always would've preferred that, but we didn't feel that we really could make the investments of those resources until more recently.
And while I wouldn't say it was necessarily part of our thinking, I do think that seeing far fewer post randomization premature terminations with this design than we have with BENEFIT is also encouraging and supports enlarging the trial without taking a risk of missing timelines.
Well, when we designed the trial we very conservatively assumed that the longer open label treatment period, the slower dose titration, and targeting three different dose levels, not trying to get everybody up to 500, would have no effect on the dropout rate.
That's not what we believed.
We thought it would and it proves to have had a good effect on the dropout rate.
But just in term of the assumptions we made we assume there would be no improvement because that was the most conservative thing we could do.
But, in fact as the trial has progressed we are seeing, I think, meaningfully fewer dropouts post randomization.
It's important to know, though, that with patients now supposed to be in the study for over a year, the length of the trial alone is going to probably cause dropouts to pick up a bit as we get further and further into the trial.
As a function of disease progression.
Not for that reason, but it's always possible without taking an alpha penalty to look at the aggregate standard deviation, and we generally do that.
So if we had found that we had seriously mis-underestimated the actual standard deviation, there is always an opportunity to address that.
I don't ---+ I'm optimistic that will not happen, however.
I'll also remind you that also in the interest of being conservative, we estimated an effect size at 24 weeks, which was no different than the one we observed in BENEFIT ALS at 12 weeks.
Six percentage points from the change from baseline in SVC, even though the effect size was growing from week 4 to week 8 to week 12 BENEFIT ALS.
So we may now have well over 90% power to detect that difference at 24 weeks if the standard deviation holds true to what we estimated.
Yes, much like the SMA study, this is hypothesis-generating.
And in fact there's quite a lot of detail available on the clinicaltrials.
gov website pertaining to CK-107.
Being that that study has not yet started, we have chosen not to elaborate on this earnings call, but that information is out there.
It's a good question, but unfortunately, <UNK>, it may be a bit premature for us to respond that.
I think that may have to wait until we have finalized the study design that we can then communicate publicly.
Yes.
So, recently Amgen, in collaboration with Cytokinetics, conducted another Phase 1 study of omecamtiv mecarbil in Japan in Japanese patients, and now we are moving swiftly to begin a Phase 2 study of omecamtiv again in Japan in Japanese patients, with the goal of having that completed in such a way that Japan could be included in the potential global Phase 3 program.
Correct.
It's similar in that it will be in heart failure patients, but not something of that magnitude, nor would it be expected to be rate-limiting to the potential start of the Phase 3 program.
Well, it's really hard to know when you go into a new population what you're going to find, but I will point out that this is a study of eight weeks' duration.
You may recall the first Phase 2 in ALS is actually a single-dose study, so there will be multiple evaluations of these very functional end points over time.
So I would hope that this study will yield reasonably robust results and inform whether or not we should further develop the drug for young adults and older children with SMA.
Another way to think about this, <UNK>, is this is a population of adolescents and adults with SMA who may not be progressing as rapidly as ALS patients do, and therefore it's conceivable that we may potentially identify end points that could even point to the potential to improve muscle function, as well as potentially slow the decline in muscle function, and that's things that we will be monitoring over the course of this two-month duration treatment.
Yes, I think that an extremely important point that <UNK> just made, the fact that we have a much more stable disease platform in SMA, because they just don't progress monthly as we saw.
And that alone makes it difficult to see drug effects in ALS because the best anybody's ever been able to do is to keep them from getting worse a little bit more slowly.
I didn't say that right, but you can only make them get worse more slowly.
No one's been able really turned them.
Whereas in SMA we actually might be able to see some improvements from baseline.
I first might add that we're talking about next generation cardiac sarcomere activators, but not necessarily operating by the same mechanism of option of cardiac myosin activation as does omecamtiv mecarbil.
And then, secondly, certainly as we have learned about omecamtiv mecarbil, there could be an opportunity to affect systolic ejection time in such a way that it may not impinge on diastolic filling to the same degree or with the same therapeutic window.
So those are the kinds of things that you always look for in a next generation compound, whether it's the same mechanism or not.
Thank you.
Hi, Vernon.
The COPD patients are a little older and more functional than SMA patients, and so we didn't feel it was necessary to study first a lower dose level and then a higher dose level, but could just go in with a single-dose level study.
The rationale is that the drug has acute effects on fast skeletal muscle performance.
We've seen this with tirasemtiv as well.
It doesn't take time for it to build up.
The effects happen immediately.
So, if there is improvement in the skeletal muscles of patients with COPD, and I'm going to come back to that in a second, it ought to be a discernible within a relatively short treatment period and then again they also have a very stable platform of disease.
So it's not likely that patients who receive placebo first and then drugs second are going to be very different when they get the drug and vice versa.
They are pretty stable over time.
So the other question you haven't asked, but I'll answer anyway because I anticipate someone may, is this is not about improving respiratory performance in these patients.
The disease is associated with significant limb muscle abnormalities, metabolic abnormalities and weakness, and also something that sort of fortunate for this particular compound, a switch from slow to fast fiber predominance.
And there's a lot of literature you can find that shows that exercise intolerance in COPD patients is at least as much if not more so related to their limb muscle dysfunction than it is to their respiratory insufficiency.
So that's the rationale for going into that population.
We don't comment on what the triggers are related to milestones.
We do anticipate milestones from both Amgen and Astellas in the coming year, but I can't tell you what the triggers are.
Hi, <UNK>.
We typically don't provide guidance with respect to specific costs of the trial.
We can tell you that this would be in the range of $5 million to $10 million from an (technical difficulty - distorted audio) standpoint of adding the additional patients.
I disagree with that.
I think the likelihood is that we just can't know until we have the data that those curves that we showed you so many times for the changes over time in slow vital capacity on tirasemtiv versus placebo are going to continue to diverge over time, and it was a very conservative assumption that the six percentage point difference that evolved over 12 weeks of treatment in benefit would not evolve further.
So, yes, we may be highly overpowered to see the primary end point, but that's not a bad thing.
I'm not sure that it would necessarily produce a synergistic effect, but those of the kinds of things that we have talked about and resource limitations being what they are that's not currently in the cards.
We did not have access to the DEX arm, but they were willing to share the placebo data with us, and I think that maybe is more relevant, anyway, because what we're really trying to do is obtain a natural history exercise, if you will, to confirm that on the extrapolations we made regarding our primary end point and other respiratory end points from the limited amount of treatment duration we had in BENEFIT ALS appeared to be consistent over time and similar across databases.
And I think I'll emphasize that first characteristic, because I mentioned during the call, but I didn't say too much about it, I think it's very reassuring to have data that goes out to 68 weeks on these patients and see that the decline in slow vital capacity is highly linear over that entire period of time.
It's not as though you get six months out or something like that and then they start to decline more rapidly.
Certainly there are patients that will do that and these are mean data based on 900 plus patients, but on average the decline is highly linear and predictable over time, so that really does really bode well for us being able to demonstrate what we hope to be able to demonstrate in VITALITY-ALS.
I can't comment on that yet.
Thank you very much.
Okay, well, thank you.
Thank you, Operator.
Thank you to all the participants on our teleconference today.
We're very pleased with how 2015 ended on a positive note leading into strong momentum as we now proceed in 2016.
We look forward to keeping you updated on our progress.
We appreciate your continued support and your interest in Cytokinetics.
Operator, with that we can conclude the call.
