ALXN
#If we look at the $320 million, $165 million came in in 2015.
We are absorbing around $120 million this year, so approximately $40 million, $50 million will be left, which will get felt in 2017 if the currency stays where it is.
Thanks, <UNK>.
<UNK>.
Just to say ---+ <UNK>, thank you for your question and really we will be focused on the heparin sulfate levels.
As you know, <UNK>, this is the bad player in this disease, and while it's a biochemical marker, it's directly related to the pathophysiology of disease.
So we will be concentrating on that and no intention to produce more natural history data at this stage.
<UNK>.
<UNK>, thanks a lot.
So what we're looking at it is ---+ let's address the R&D expenses first because that'll actually ---+ relates very closely with the 48%, 49%.
So you can look at second half of last year where we integrated Synageva, so average run rate per quarter in the second half is $150 million of R&D expenses.
So when we look at annualizing that for 2016, it's approximately starting from a $600 million base.
So, what we have looked at here is a very financially disciplined growth of literally 10% to 12%, much, much lower than what the topline growth is going to be, and we've continued this process as we go forward in 2017 and 2018.
So we take that 22% of sales down below 20% by the time we get to 2018.
Similarly in SG&A, we came down from 28% in the second half of last year to 26% this year, and as the sales move forward and we have topline growth coming over in 2017, 2018 and lesser FX impact, we will start seeing the improvement in those rates also from 26% further down by a few percentage, taking us down to 48.9%.
Can I pass it on to <UNK>.
Yes, <UNK>.
In terms of the second part of your question, thank you, <UNK>.
Obviously, we will be presenting those data at the meeting, so we can't discuss them now.
But if you remember, the three-months data that we did present, we were really very excited by.
And just as a reminder, if you think about the 3 milligrams per kilogram dose where we saw an 11% reduction, really showing that we were able to cross the blood-brain barrier, this has two impacts for me, really.
One is to look at the six-month data to see what we see in this disease.
But it also speaks to the expression platform that we're using here and that notion of being able to use the platform for other diseases where we need to get large molecules across the blood-brain barrier.
So in both levels, we're really excited by these three-month results and look forward to presenting the six-month data at that new time.
Thanks, <UNK>.
Next question.
Yes, <UNK>, before I turn it over to <UNK>, as a reminder, right, that one thing that was really nice that we showed back on investor day was the consistency of what we saw in the patients compared to what we saw in our preclinical models, which <UNK> indicated.
And there is a prescribed ---+ as you might imagine, taking a sample of the CSF, it is not something that is done so frequently.
So <UNK> can talk you through that, but the reason why I mention the preclinical data, remember, we also showed the preclinical data at the 5 and the 10 milligram per kilogram dose showing more reduction in the preclinical models of heparin sulfate in the brain, and so that's the intention of the program moving forward.
But <UNK> can provide more color on the frequency of the CSF and the next steps.
I think you (multiple speakers) articulated it very well, <UNK>, and thank you, <UNK>, for those three questions buried nicely into one question, very admirable.
Really, as we alluded to, this was a six-month study, which is the data that we will present at the world symposium, but we did have a 12 week ---+ we didn't look at our dates before that, so that answers the first part of your question.
In terms of the second, we won't present any higher doses at that six months.
This will be the six-month data for the 0.31 and 3 milligrams per kilogram.
But as you alluded to and <UNK> mentioned, our ability to now ---+ to go to higher doses makes complete sense in this devastating disorder.
And then, your third one is really a basic pharmacology question about how high can you go up with dose escalation.
And this applies to any program, as you know better than I do.
Given the devastating nature of the disease, the encouraging results that we see, particularly in the 3 milligram per kilogram dose, our ability to go higher than that is clear and it's something that we want to do.
We'll also, as always, be very careful.
We'll be looking at safety along the way such that we do proper dose escalation studies, and these will unfold over the next period.
Sure.
So why don't I start, then I'll go to <UNK>, and then over to <UNK>.
Remember in the myasthenia trial, the patients that we enrolled were failing multiple immunosuppressive therapies.
And so despite the use of aggressive standard of care, they were progressing with refractory disease and progressing the MGADL of at least six or even more.
And, of course, we leveraged our Phase II proof-of-concept data to help us design the trial and agree with regulators on what we thought the right endpoint would be, which is a change in MGADL at 26 weeks from baseline.
In terms of magnitude, <UNK>, do you just want to talk through what we saw in the proof-of-concept study and then as we bring that through the registration trial.
Absolutely, <UNK>.
Again, you highlighted the fact that MGADL, we agreed with the regulators that this would be the most meaningful clinical endpoint for the patients, and to answer a kind of sub-part of your question clearly, we'll be measuring exactly the same things in the placebo arm, and as we also said, we will aim to report data from the study in mid-2016.
In terms of the ---+ what we saw in the investigator studies that were the Phase II data, you may recall that we showed an 85% difference in the MGADL between eculizumab and placebo.
The trial has gone very well in terms of the mechanics of it.
We exceeded our enrollment and we believe we've got a really good clinically meaningful endpoint that we are really looking forward for the data to read out, as mentioned, midyear this year.
And <UNK>, on the European pricing discount side, we normally don't break it out by region.
But on an average, we've seen 2% to 3% decline in the prices over the past and that's what we've factored into our forecast going forward.
However, we will see that in 10-Q ---+ 10-K that will be submitted soon, but it was less than 2% in 2015.
<UNK>, I'll get started.
As you know, what we laid out was the patients are going to carry through on their original dose through the six-month period, right.
Then those patients are all going to move for a period of time to the highest of the initial three doses, the 3 milligrams per kilogram.
We are then, as we indicated at investor day, going to re-randomize the 11 patients to the five or the 10.
But yes, there will be a period of time in which ---+ I wonder if this is what you are asking.
There will be a period of time in which all 11 patients will move up to eventually the 3 milligram per kilogram dose for a short period of time on their way to what we have now amended the protocol to do is test even higher doses.
Is that your question.
No, you won't see anything from that, <UNK>.
In answer to, if I heard you correctly at the start, we've really gone beyond that and that's why we haven't discussed it.
Based on the data we saw in the 0.3, 1, and 3, and as <UNK> alluded to the move to the higher dosage with 5 milligrams and 10 milligrams, we believe we've gone over that.
As I said, we'll show the six-month data at the world symposium, and then clearly the 5-milligram and 10-milligram doses will come out in due course.
Which in a way, <UNK>, right, is we've got a couple of shots at looking at this, right.
The first is, what was the dose-dependent response at 12 weeks.
Hold the patients at that very same dose, see what the impact was in terms of additional time through an additional 12 weeks to get to six months, and then we'll dose escalate from there.
No.
I'll just say that I think we've laid out our plans for 103 and I think it's just too early at this point to sort of speculate on what the registration plan will be.
Clearly, we have liked what we've seen so far through 12 weeks.
We look forward to taking a look at the six-month data, and all of this will inform with some other secondary endpoints in the Phase I/II what our plan is moving forward.
It is a devastating disease, so we look forward to ultimately reaching patients as fast as we possibly can.
In terms of 1210, <UNK>.
Just as we've said before, what we are looking for here with 1210 is rapid, sustained, and complete inhibition.
As you know, 1210 is an antibody.
It's behaving very well in the study so far, and as you know, we've had a single ascending dose study, multiple ascending dose in volunteers, two studies in patients, one of them where we've completed enrollment, and clearly we are following the data along the way now and expect to be able to continue to see the data that we showed at investor day, showed that this antibody continues to be well behaved.
I would just add that ---+ so that's precisely why we are running two trials in PNH patients, one of which, as <UNK> indicated today, is completely enrolled.
We are looking at a variety of induction and maintenance doses and looking at intervals of once monthly and longer.
We will be evaluating those different dose levels and looking at troughs over time, and as <UNK> said, we look forward to presenting a more fulsome look at the data for 1210 for the first time near midyear in PNH patients.
So there will be more to certainly discuss then.
Maybe I'll just start and then <UNK> can jump in.
So, our view on 1210 PNH in 2018 is that certainly these two trials will be supportive, but not necessarily the rollover trials, for registration.
But all of it will be informative, both to our registration trial plan and design and the dose and the interval that we ultimately select.
I just sort of leave it at that, and we do feel comfortable that the way that we've laid it out that these timelines certainly fit nicely with what our plans are.
<UNK>, maybe I'll just say that ---+ and I know you would say the same thing.
<UNK>, it's too early to really talk about the plan for the registration trials at this time, whether or not it's naive or switch or a combination of the two.
I think we are assessing that as we speak and I think that as we develop Soliris and eculizumab in PNH, regarding your question about subtleties, I think we'd be looking like we normally do to develop a global program that would be ideally suited for all of the regions and territories in countries in which we operate.
I think you've really cracked it there, <UNK>, in terms of the two volunteer studies and two patient studies will really help us inform the pharmacokinetic and pharmacodynamic profile of 1210, which will allow us exactly to decide on the Phase III program.
We're very confident in the timelines that we've laid out, based on everything that we've seen to date, and then, secondly, just to really reinforce <UNK>'s point, we are clearly in discussions with regulators.
These will be global studies as we did with eculizumab and no expectations, really, of any nuances over and above what you regularly see talking with different regulators.
I think, <UNK>, the other thing I would just comment on is when we think about our timelines and such, obviously we have an extremely strong vantage point as it relates to the global PNH arena, the investigators, the physicians, the patients, which all enable us, obviously, to do outstanding development work in this area.
I'll start, <UNK>, and then Carson will come in.
I think that Q4 was certainly supported by ---+ you know, the program's been in our hands for a while.
We've been applying our PNH and aHUS know-how to HPP for some time.
And as a result of that, right, as we indicated that in any single country because the trials were generally small and global in nature, not any one country is necessarily disproportionately impacted by clinical transitioning patients.
But at the same time, with our introduction in the US in Q4, we did benefit from some clinical-trial patients moving over, and then through our efforts, some patients that we had identified along the way commencing treatment.
So as I think <UNK> and <UNK> indicated earlier in the call, an initial group of patients, but <UNK> can fill you in a little bit more on the types of patients that ---+ beyond whether or not they are clinical trial or not, sort of the dynamics in what we are seeing as the types of patients commencing treatment.
Yes.
Thank you, <UNK>.
So with our focus on the pediatric patient population and our disease education efforts on that population, certainly what we have seen so far is a lot of newly diagnosed patients in the pediatric onset HPP setting.
<UNK>, maybe ---+ so I'll just say this.
One thing we mentioned on HPP is it's ---+ unlike PNH and even LAL-D, where there are publications on prevalence, there really in both aHUS and HPP, it's been a little lighter.
There's been some indications of what the incidents might be in the youngest population of patients, a range of one in 100,000 to one in 300,000 live births being impacted by HPP.
There haven't been, and <UNK> and the team, working with <UNK>'s team, are trying to better understand some of the mutations that identified in the HPP space to try to give us a better understanding of what the prevalence might be.
But at this point, we don't really have much more to work on.
Even some of these incidence numbers I'm sharing with you are from as long ago as the 1950s with the Fraser publication and more recently a French publication.
Regarding MG.
Just to say briefly, <UNK>, I think, as you know, the patients that we have are refractory patients for myasthenia gravis that failed treatment with at least two treatments.
So they are the most severe.
In terms of the estimate, we do ---+ we estimate the subset is a small proportion of the broader MG population, maybe a few thousand patients in the US, as you may imagine.
So it's very much in the area where we work, these ultra-rare patient populations, the most devastating and the most severely affected by the disease.
Yes, and where these patients have really no other hope because they have been worked through the system and the standard of care.
Thank you.
