MDCO
#Thanks, <UNK>.
These are both good results.
I'm going to see if <UNK> wants to talk about the Carbavance additional studies in just a moment.
He's very close to that business.
Let me just deal with the PCSK9 issue.
If you want to prove that this drug lowers LDL, we already have the data.
It does.
And it lowers it competitively, as mentioned.
The real value of a Phase 3 trial in these patients is essentially safety.
So you are going to want to see patients on study for 4 to 6 injections, something like that, for two years to give you a real sense.
And as I mentioned earlier, we would anticipate having about 1,000 patients with two years of data and about 2,000 patients with one year, which would imply 2 or 3 injections there.
I think that would cover it on the safety side.
As for the primary LDL endpoint, given that the antibodies were proved on 12-week endpoints, as you point out it's odd because injections aren't even given every 12 weeks.
So we'll have to probably have a thought about that.
But we will be able to show, as you saw in the Phase 1 data, that at 12-week LDL is robustly down.
And I can show you, based on our press release, that's also true in the Phase 2 study as well.
So the exact timing of the input, whether it be 12 weeks or 24 weeks, is a bit academic because we're going to follow the patients for up to two years anyway.
Thank you, <UNK>, thank you.
Yes.
As you know, Joe, early stopping rules using things like the O'BrienFleming boundaries and so on tend to be very high hurdles.
So that was the case for the first look at the data that [they] did and we did.
Didn't achieve that hurdle.
So the study continued.
In actual fact, a large number of the patients had already been enrolled so we wouldn't have stopped enrollment under any circumstances anyway, likely.
It didn't meet the hurdle.
So it couldn't stop.
We will have 126 patients that were enrolled.
Not quite sure how many of them have been fully treated with drug.
So don't know the actual end number that will be presented.
I think that final analysis will give us the right direction.
And that's what we're looking forward to.
Does that ---+ I'm not sure I've really covered your question.
But that's the best I can do right now.
Probably when the study is published, the statistical section would have those sorts of things.
It's obviously thinking about what the threshold for 40 patients was might be less important than what the results for 126 patients are, which would be interesting to see.
Sure.
Those methodologies are not usually not trade secrets.
You're welcome.
Thanks, <UNK>.
Great questions.
Yes, you're right.
Picking the right dose for 216 isn't just a question of plasma concentrations and the level and the amount of PD or efflux demonstrated.
It also is a question of, as you say, how frequently, how long a duration of treatment.
That's why the MILANO second dose ranging study may be needed.
And that's what <UNK> was talking about earlier.
This pilot is a pilot.
It's an attempt to nail the right dose with an efficient study.
But it won't answer the whole story of dosing, I agree.
Let's see what the data show, and then we'll take the next steps accordingly.
As to strategy, I can ask <UNK> to comment in just a moment.
We're not unfamiliar with the cardiovascular worldwide market.
We're certainly not unfamiliar with running very large cardiovascular clinical trials, substantially with efficiency, I think.
And our track record is that we have had eight major cardiovascular trials published in journals like the New England Journal of Medicine, and JAMA, and The Lancet.
We can do them.
They've all been the foundations for drug approvals for our acute care drugs with one-year follow-up.
We haven't done chronic dosing studies such as would be required for at least PCSK9 synthesis inhibitor.
But we're not phased by that.
We have people on the team who've done a great deal of clinical development and commercial preparation work in the space of dyslipidemia.
However, as you say, these are large trials.
They're global trials.
And there would be no reason at all not to consider partnering at the right moment, because ultimately these are also global markets.
And The Medicines Company is not in a position to operate ex-US with any great strength.
So clearly I'll hand this to <UNK> now.
We're going to look at all of our options as we see the data and see the reactions.
<UNK>.
Yes.
<UNK>, is that okay.
Any other follow-ups.
I guess <UNK> got a follow-up.
So you can have one.
We had a good time there.
We not only had several posters in ASA and also in the International Society of Anesthetic Pharmacology which precedes on Friday.
But we also had a very substantial advisory board meeting for six hours where we went through the entire experience to date.
We have accumulated experience in about 350 subjects now.
And how to crank up the Phase 2 program, which has already started.
I think the encouraging news is that our viewpoint that respiratory depression is a big deal for anesthesiologists was very much validated.
Our viewpoint that a fast on/fast off product could be very helpful was very much reinforced.
I think the cardiovascular stability of this particular drug relative to ---+ associated with this drug relative to perhaps [propofol] was also highly appreciated.
There are dosing issues.
We have to continue to work on in Phase 2.
There are issues related to involuntary muscle movements that we have to work through.
But we were very encouraged and looking forward to seeing a lot more data.
I did ---+ I want to be very clear.
I did indicate in the script here that our results for the Phase 2 induction study will be coming out in the first half of next year.
We had originally thought they may be available this year.
We made some protocol amendments based upon expert input and the requirements for institutional review board changes during the summer in Europe meant that we delayed enrollment.
So that's running a little bit behind where we had originally hoped for, but still very much scientifically on track.
Yes.
Thanks, <UNK>.
Thank you very much.
I think it was a bit of volume [down, wasn't it a little] bit.
Because we continued to see ---+ I'm looking at <UNK> <UNK> who is here, who might want to say some words.
But it's a dog-eat-dog generic world out there.
And there's no question, this is a very, very attractive generic product.
The generitization of this product has obviously destroyed our business.
And people are taking pieces of it.
So <UNK>, volume, price, a bit of both.
Yes.
Look, there's two big players in the market, I think, [fighting] over volume.
I think prices remained relatively stable throughout the back half of the year.
But fighting over volume.
Very important to state.
And I don't mean this in any kind of nod and wink kind of way.
I really mean it seriously.
We have no control whatsoever over Sandoz' pricing strategies, or indeed volume placement strategies.
The market is playing out in a competitive way.
And the result is what you're seeing.
Again, I'll hand that over to <UNK>.
Thanks, <UNK>.
Thank you.
Yes.
Thank you, <UNK>.
Indeed, I think we're very fortunate in a way to be able to witness and think about outcomes trials, (inaudible) outcomes trials, on the strength of Amgen's experience, and Sanofi Regeneron's, and possibly also Pfizer program which is called Spire 2 ---+ Spire 1 and 2.
So yes, we would like very much to know how those guys get on with their programs.
We're very optimistic about the likelihood of them bringing home good outcomes results.
And obviously we'll look at the data to see which patient groups make the most sense for an outcomes trial that we one day would expect to do.
So yes, we're looking forward very much to seeing their data, and very optimistic about their data, frankly.
With regard to ORION-2, that would be in homozygous familial hypercholesterolemia patients.
We've had some good dialogue with the FDA.
And they would like to see us do some patients compared to current standard of care, meaning not antibodies.
We've indicated to them we'd like to actually do some (technical difficulties) trials with antibodies.
As the program rolls out, and we will begin with [the pilot dose] finding, of course, in a half a dozen patients or so, we'll then make a comparative design with current therapy and also try to make some kind of comparison to the antibodies as we report.
That's the basis of (technical difficulties) project.
As you know, with homozygous FA, we're not likely to have a study population much more than 30 to 50 patients in total.
No.
We recently, as you may know, the familial hypercholesterolemia group meeting was held successfully.
We attended that.
And used that as something of a platform for making sure that the main players are onboard with that program.
And we expect to start enrolling patients before the end of the year.
In fact, we've already identified [a] size for the protocol written.
And it's a matter of days, weeks at most before we start treating patients.
Thanks, <UNK>.
Thanks, <UNK>.
We would like to thank everybody for joining us this morning, of course, and look forward to seeing you, as many as possible, at AHA.
And we're very excited to see those data presentations being made.
And in the meantime, get in touch with <UNK> if you have any additional questions.
Thanks so much, everybody.
