| CLINICAL TRIALS JUSTIFYING THE USE OF A CALCIMIMETIC AGENT |
| J. Frazão,
Porto, Portugal |
| Chair:
W.G. Goodman, Los Angeles, USA |
J. Cannata-Andía,
Oviedo, Spain |
| |
|
Dr
J. Frazao |
Slide 1
Dr Frazao: What I want to try and do in this talk is to summarise the clinical data, the most up-to-date clinical data on these new compounds, the calcimimetics, specifically the cinacalcets.
Slide 2
Just a few words to set out a few initial concepts. Secondary hyperparathyroidism is really characterised by elevated levels of hormone, parathormone and disturbance in the mineral metabolism. Bone disease was really the most recognised consequence of secondary hyperparathyroidism but I think in the last few years, we have really been more focused on alterations in the calcium and phosphorous metabolism, resulting from either the secondary hyperparathyroidism or the therapy because these alterations really contribute to soft tissue and vascular calcification and have an impact in cardiovascular morbidity and mortality.
Slide 3
The problem with the vitamin D compounds that we have been using for the last 20 years or more, is that, actually the therapeutic window is very narrow, they're associated with significant toxicity and we all know the problems that we have with induction of hypercalcemia, hyperphosphatemia, soft tissue and vascular calcifications and the risk of low bone turnover, these are very well known consequences or complications of treatment with vitamin D, so there was actually a major interest in developing a new strategy for controlling these situations.
Slide 4
This is the calcium receptor shown very elegantly, some data with Doctor Nemeth just to say that you know this is the area, the agonist area probably of the receptor where it recognises ionised calcium controlling in this way PTH secretion.
Slide 5
Now this receptor obviously became a very attractive target for the development of compounds that act on it and therefore the calcimimetic compounds act on these receptors so the mechanism of action differs, it's completely different from vitamin D sterols, what it does is it increases the sensitivity of the calcium-sensing receptor to extra-cellular calcium, inhibiting the release of PTH and actually, the action is very acute as I will show you and happens within a few hours after oral administration.
Slide 6
So I'll try now to show you very early data just for us to understand what we are talking about and what we see when see all these phase 3 data. The initial data, this was a study presented actually by Doctor Coburn, a few years ago, where they administered, it was a double-blind placebo-controlled study where these dosages of cinacalcets were administered up from 5 to 100 mg single dose study in adults undergoing hemodialysis with secondary hyperparathyroidism.
Slide 7
The important thing about this data is that what you actually have is a dose-dependent suppression of PTH secretion and the lowest level is of 10 probably between 2 and 4 hours after oral administration, these are patients and then you have a slow recovery along the 24 hours and this is the pattern that repeats and that you always get whenever you administer these compounds.
Slide 8
Even more important than this is what you get with the calcium level that is actually a different profile. You have a much slower decrease along the 24 hours of the calcium, you're talking about a 5% change in the calcium levels and also dose-dependent and this actually favours the efficacy of these compounds because you get a suppression of PTH despite the increase in the calcium levels.
Slide 9
From this very old data, I will try to summarise the most recent data just published a few weeks ago in the New England Journal of Medicine. This was really data resulting from the combination of two similar randomised double-blind placebo-controlled 26 weeks studies. Basically there was a 12-week titration phase which was followed by 40 weeks of efficacy assessment where the doses were tried to be kept very stable. We're talking about 741 patients that were eligible for this study. 371 patients on cinacalcet and 370 on placebo and they actually were able to be stratified according to the severity of baseline values for calcium-phosphorous product. I'll show you some data on that.
Slide 10
The dosing was from 30 mg to 180 mg, the adjustments were done every 3 weeks according to the efficacy of the compound, actually the criteria for increasing or decreasing doses here obviously if PTH remained above 200 the dose was increased, while if PTH was below 100 for three consecutive visits the dose would be decreased.
Slide 11
Some characteristics, and I think that this slide is very important because it shows you that 66% of the patients in the cinacalcet group and 67% of patients in the placebo group were actually on vitamin D, on standard therapy, so what we're comparing here is actually the placebo group which is really a control group, we're comparing to standard therapy because the patients remain on their therapy and the other issue regarding this data is that mostly these were patients that were actually not controlled with standard therapy because most of them were actually on vitamin D and calcium phosphate binders.
Slide 12
This is the reduction on absolute values of intact PTH and we see in the placebo group, PTH levels remains very much constant, while you get a decrease to levels between 3 and 4 of the group treated with cinacalcet. I'm talking really about the number of patients at baseline and the number of patients at 26 weeks.
Slide 13
The same if you look at percent changes of PTH, intact PTH, you actually get a reduction of intact PTH when you treat patients with cinacalcet of around 43% below baseline level, between 40-45%, while in the control group you don't get any effect as you would expect.
Slide 14
If you measure full-length PTH you actually get basically the same consistent result showing a decrease in the levels of full-length PTH compared to non-change in the placebo group.
Slide 15
This shows that this is the percentage of patients with intact PTH below 250, in this column when you compare you've got 43% of the patients with PTH below 250 in the treated group with cinacalcet and you just get 5% in the control group and obviously this difference is significant. Again, if you get patients who've got more than 30% reduction in PTH you're looking at 64% of patients treated against 11% of the control group and I should mention that this actually greatly favours the efficacy of this compound because what you're measuring here, the data that you're looking at, it's 24 hours post-dose data. So this is really at the point where the PTH levels are recovering, so this is 24 hours post-dose PTH levels.
Slide 16
A number of patients where intact PTH gets below 250 increases at each time point compared to placebo.
Slide 17
But maybe even more important is that if you look at the different degrees of severity when you look at patients with more severe, severe secondary hyperparathyroidism, with intact PTH above 800 and you compare the effect of cinacalcet on those patients compared to the patients with mild secondary hyperparathyroidism, you actually don't see a difference, so the percentage of patients that you are able to get more than 30% reduction of intact PTH. This is basically the same when you compare different states of severity.
Slide 18
This slide shows the change does, very important data, a change in the calcium phosphorous product, you have a decrease, these are the absolute values of calcium phosphorous product, baseline and you see a nice decrease of calcium phosphorous product. We treated patients compared to placebo group.
Slide 19
It's important to say in this study that average doses of phosphate binding or vitamin D sterols did not differ significantly between groups and patients who received vitamin D sterols in this study were basically similar between the 2 groups and cinacalcet HCl reduced PTH levels regardless the changes in vitamin D dose and the percent reductions in calcium-phosphorous product were greater in the cinacalcet group regardless of changes in vitamin D dose.
Slide 20
Safety data, always very important, just to show you 2 points about this. The incidence of hypercalcemia is actually higher compared to placebo but there were no more withdrawals from the study for hypercalemia. Usually these events were asymptomatic, typically asymptomatic and easy to solve with changing the dose of calcium containing phosphate binders and vitamin D. There was a higher incidence of nausea and vomiting compared to the placebo group and actually also these transitory and relatively mild adverse events.
Slide 21
So to try to summarise all these phase 3 data, actually the mean intact PTH values increased 43% in cinacalcet group but increased 9% in the control group. The serum calcium phosphorus was declined by 15% in the cinacalcet group and remained unchanged in the control group and cinacalcet effectively reduced PTH levels independent of disease severity and were well-tolerated compounds.
Slide 22
Now if you look at the phase 3 important studies and US-Australian, European Union and US-Canada, the results that you get are very consistent in terms of suppression of PTH, decrease in calcium phosphorous product, decrease in phosporus and calcium. If you compare these numbers in all three studies they are actually very, very consistent and very similar, so basically you get around 40% of reduction of intact PTH with a decrease a little bit above 10% of calcium phosphorous product and a marginal decrease in the phosphorous levels.
Slide 23
So when you look at new K/DOQI targets and you compare the percentage of patients that get into those targets compared to the control group because you only look at PTH you have 56% getting in to target PTH compared with 10% if you get a calcium phosphorous product, you get 65% of patients treated with cinacalcet compared to 36% and if you look at both the PTH levels and the guidelines for calcium phosphorous product, if you actually treated patients with cinacalcet you get 41% of patients within both targets compared to 6% in the control group that again is a group treated with conventional therapy, with vitamin D and phosphate binders.
Slide 24
Just to finalise my talk I'd just like to show this long-term data because it's very important, actually this is a two year data, it was already presented last year at three year data a follow up of this three year data. I'll just show you the two-year data because it's very similar to what was presented. These were patients that entered an extension study. They were in two other studies and after one year from both these studies, they were eligible to enrol into an extension study in which all patients received cinacalcet. The daily doses were again between 30 mg and 180 and dose was increased based on the intact PTH response and safety.
Slide 25
This is very interesting data because we are talking about two years data against three years data and it's very similar you get here during the control placebo phase.
Slide 26
You get a nice reduction of intact PTH compared with control and then when you start treating all patients you maintain this PTH suppression at least for the two years of the observation.
Slide 27
And again the calcium phosphorous product is pretty much the same as also you would expect just to show you that this marginal suppression of calcium and phosphorus is maintained along the 2 years.
Slide 28
So to conclude my talk I think we have cinacalcet that represents a novel and very exciting approach for controlling secondary hyperparathyroidism in dialysis patients. It significantly reduces PTH in a dose-dependent manner up to 180 mg and significantly reduces calcium phosphorous product and again low serum calcium levels during cinacalcet treatment were asymtomatic and managed by adjustments in calcium-containing phosphate binders vitamin D sterols or reductions in cinacalcet dose.
Slide 29
Cinacalcet HCI is well tolerated and it helps to bring more patients within the new guidelines targets for iPTH, calcum and phosphorus. This should lead to an improvement in clinical outcomes. Outcomes trials will determine the efficacy of cinacalcet HCI in this regard.
Thank you!
