NATIONAL KIDNEY FOUNDATION

NKF 2017 Spring Clinical Meetings

800: Calcimimetics for Secondary

Hyperparathyroidism: Something Old, Something
New
 Contents

Introduction and Overview .......................... 1

Pathophysiology of Secondary Hyperparathyroidism ..... 6

Optimizing Biochemical Control in Secondary

Hyperparathyroidism .............................. 17

Questions ....................................... 27

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 Introduction and Overview

[START RECORDING]

MYLES WOLF, MD, MMSC: [Slide 1] [0:00:00] I’m Myles Wolf, I’m
Professor of Medicine and Chief of the Division of
Nephrology at [Slide 2] [0:00:05] Duke University School of
Medicine and I’m going to moderate what I think is going to
be a really outstanding and timely session for you this
morning.

I want to make sure to acknowledge that this session is

being supported by an educational grant from Amgen. Let me
introduce all of our speakers now so that we don’t have to
take time during the session one-by-one. I introduced
myself. I’m going to give you the introduction and the
overview. This is going to be followed by Dr. Csaba
Kovesdy who is the Fred Hatch Professor of Medicine, the
Director of Clinical Outcomes and clinical Trials in the
Division of Nephrology at the University of Tennessee
Health Science Center where he is also the Section Chief of
Nephrology in the VA in Memphis.

Dr. Kovesdy is going to speak about the pathophysiology of

secondary hyperparathyroidism, a topic that has been
evolving for many years and has been the subject matter of
sessions like this for as long as I can remember, at least
15 years, and probably much longer.

After that, our third speaker is Dr. James Wetmore, who is

Associate Professor of Medicine from the University of
Minnesota School of Medicine. He’s primarily based in the
Division of Nephrology at the Hennepin County Medical
Center in Minneapolis. Dr. Wetmore is going to speak to us
about optimizing biochemical control in secondary
hyperparathyroidism and he’s going to talk about the
effects of calcimimetic-based regimens on biomedical and
clinical outcomes.

The other thing, while you’re finishing up hopefully the

pretest, is that we are going to have audience response
questions peppered throughout today’s talks. I’m going to
have a few and my colleagues that follow are going to have
their own.

[Slide 3] [0:01:56] Here are my personal disclosures.

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[Slide 4] [0:02:01] Just to get us started I introduced our
speakers, I’ve talked to you about the CME and I’ll just
briefly go over the objectives. We’re going to start by
reviewing the pathophysiology of secondary
hyperparathyroidism, the more expansive syndrome of chronic
kidney disease, mineral bone disorder, and talk about some
of the latest advances that are reshaping our understanding
of the pathogenesis of these syndromes including the role
of fibroblast growth factor 23.

We’re then going to talk about different therapeutic

approaches to managing secondary hyperparathyroidism
including calcimimetics, vitamin D, phosphate binders, the
things that all of you use in your day-to-day management of
patients undergoing dialysis. We’re going to describe some
of the newest things, apropos of our title, a new agent
that was just recently FDA approved for controlling
secondary hyperparathyroidism in patients undergoing
dialysis and I think that will be very exciting to hear
about these new [Slide 5] [0:03:08] advances.

I want to set the stage with a real case that I saw a

number of years ago and this is going to have some audience
participatory questions, so get ready.

This is a 35-year old African American man who I was taking

care of when he was undergoing dialysis. He had previously
had developed focal segmental glomerulosclerosis and
despite therapy, advanced to end-stage renal disease and by
the time of the case, the one I’m presenting now, he had
been undergoing dialysis for two years.

Other than having hypertension he had no prior major

comorbidities before starting end-stage renal disease, and
he was quite functional. He was working as a security
guard at night, had excellent appetite, was really
thriving. Excellent, left upper extremity AV fistula that
was providing perfect flow. His Kt/V was greater than 1.4,
you can see his prescription at the time, he was doing four
hours three times weekly, a 3K dialysate with a 2.5
calcium. His dry weight was 75 kilos, his Kt/V was well in
range of where we wanted it to be.

His medications included calcium acetate and sevelamer, he

was intermittently receiving intravenous vitamin D. I
should disclose a few years ago when there wasn’t

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calcimimetics at the time, he was taking an ACE inhibitor,
a beta blocker and he was receiving erythropoietin and iron
as needed. His hemoglobin was over 11, his albumin was
over 4, consistent with his good nutrition, his good
functional status and so [Slide 6] [0:04:52] on.

Here’s the first question and it’ll take you a few minutes
to whittle through all these to find the right one. What
set of laboratory tests for disorder of mineral metabolism
would you expect that this patient would most likely have
manifested given what I’ve told you so far. I’m going to
pause there instead of reading them to you and let you
vote.

[Slide 7] [0:05:13] The answer that I was looking for was C

and this is what the patient had. He actually had quite a
high PTH, he was not in the 300 to 600 range, which I think
is one of the distinguishing features of two versus three
and his serum phosphate was quite high. The tipoff here is
that when young people who are doing well on dialysis even
when they’re dialyzing well, if they eat extremely well
they often will have a high serum phosphate. He had
calcium in the normal range and as you all correctly
predicted for choice three he had a very high FGF23 level.

There were two tipoffs that this wasn’t going to be choice

two, the lower-ish phosphate and the low-ish FGF23. Almost
every dialysis patient whose been on for almost any period
of time whatsoever let alone two years, will have a very
high FGF23 level.

Let’s continue on. [Slide 8] [0:06:10] His calcium was

right in range. As I said, his phosphate was 7.6, his PTH
was off the wall, it was greater than 1,000. It was very
difficult to control his serum phosphate and his PTH
remained poorly controlled and it gradually rose to over
3,000. He repeatedly refused our recommendations to
consider parathyroidectomy, surgical treatment of the
severe secondary hyperparathyroidism and so we were left
trying to give him intermittent slams of very high-dose
vitamin D, which for those of you who are relatively new to
nephrology this was the state of the art about 15 years
ago, astronomical doses of vitamin D to try to suppress
vitamin D receptor in the parathyroid gland and see if we
can sneak it by the gastrointestinal tract so it wouldn’t

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cause hypercalcemia. Alas, this patient whenever we tried
it would develop episodes of hypercalcemia.

Nevertheless, he felt great and so he couldn’t understand

why we were recommending that he undergo surgery for
something that clearly wasn’t bothering him; he kept
working.

[Slide 9] [0:07:16] Based on the data, here’s question two,

epidemiological data, what complications is the patient at
increased risk for compared to a similarly aged dialysis
patient with a similar dialysis access, a similar serum
albumin and other clinical factors but with well-controlled
PTH, phosphate, calcium, and FGF23. In other words, what’s
he at risk for because all his numbers are out of whack
versus somebody who is under control. Is it death,
vascular calcification, fractures, and other
musculoskeletal complications or all of the above. These
are all some of the major complications of disordered
mineral metabolism.

[Slide 10] [0:08:02] How would you manage the patient?

Would you press him for parathyroidectomy? Would you get
into your time machine and come to today and initiate a
calcimimetic? Would you switch him to a non-calcium-based
binder because if his hypercalcemia? Would you refer him
to ethanol ablation of his parathyroid glands, a
nonsurgical approach to parathyroidectomy? [Slide 11]
[0:08:27] This is correct. If we were in Japan we probably
would refer him for ethanol ablation. It’s a common
practice there, it’s not widely used in the United States.
Non-calcium-based binders you recall he was already on and
I think we are beyond the time when a binder alone is going
to make a difference here. I think short of
parathyroidectomy initiating calcimimetic would make a lot
of sense [Slide 12] [0:08:53] and that was the correct
answer.

Let me give you a postscript of what happened to this

patient and one of the reasons why we care so much about
mineral metabolism. Here’s what happened to him. This was
in Boston. He slipped on the ice while he was working one
night. He was just standing up. He didn’t fall from a
height. It was just from standing. He spontaneously
ruptured both of his patellar tendons. What happens is the
calcification and the phosphate deposition in the fibrous

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tissue makes tendons brittle and this is a not frequent but
pretty typical classic complication that you can see. He
underwent bilateral patella repairs and now he understood
the significance of his underlying secondary
hyperparathyroidism. He had a parathyroidectomy. No
surprise given the degree of hyperparathyroidism and its
duration he had severe hungry bone syndrome but made it
through okay. This required a long hospitalization [Slide
13] [0:09:58] but ultimately worked out.

I’m just going to close with two slides to set the stage
for our speakers. I’m way over time. The first is what’s
become increasingly clear over a number of years of
research is that the kidney is very adaptable and the whole
body is very adaptable to changes in kidney function in
order to maintain in the center normal serum calcium and
phosphate levels and the way the body does that is by
increasing production of FGF23 which helps the kidney get
rid of phosphate. Increases levels of parathyroid hormone
which helps the kidney protect he serum calcium and also
get rid of phosphate. Finally, it suppresses 1,25 D
production which helps prevent overload of calcium and
phosphate in the setting of reduced GFR.

Unfortunately, what happens is these short-term things that

would be otherwise adaptive responses to kidney disease
when you consider that somebody has kidney disease from
months to years what is initially adaptive becomes
ultimately maladaptive and contributes to cardiovascular
disease, kidney disease progression perhaps, and skeletal
complications like the patient I just described.

[Slide 14] [0:11:14] What we’ve been in search of for many,

many years are therapies to prevent these adverse outcomes
and to prove by clinical trial that we can improve the
quality of life of our patients and reduce their risk of
these complications. We’ve had some observational studies
of many different therapeutic approaches like vitamin D in
the top left, and we’ve had some false starts with some
trials that we were all optimistic about but ultimately
yielded inconsistent results or not definitive results, for
example, with non-calcium-based binders in the top right,
and with cinacalcet in the lower panel.

The quest continues but I think as you’ll hear today where

there’s a new agent coming down that I think is generating

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 a lot of enthusiasm that hopefully can be something that we
can use as a tool to try to improve clinical outcomes in
patients [Slide 15] [0:12:07] with end-stage renal disease
and disordered mineral metabolism.

Pathophysiology of Secondary Hyperparathyroidism

DR. CSABA KOVESDY: Good morning. Thank you, Dr. Wolf.

[Slide 16] [0:12:28] Here are my disclosures. [Slide 17]

[0:12:32] The objectives of my talk would be to describe
epidemiology and outcomes of SHPT, review the physiologic
actions of PTH and examine pathophysiology. It’s a pretty
broad topic especially when we branch out into the
ancillary [Slide 18] [0:12:48] issues like FGF23.

Just to set the stage, we have to understand that chronic

kidney disease is a progressive entity so we move from
normal kidney function, normal physiology to end-stage
renal disease. It’s really the beauty of how things evolve
and change during the course of this process that makes
CKD-MBD, and SHPT such an intriguing field to study.

[Slide 19] [0:13:11] CKD-MBD as you all know is a systemic

disorder of minerals, bones, and vascular disease so it
entails biochemical abnormalities in calcium, phosphorus,
PTH, vitamin D, and FGF23, and also actual organ
abnormalities in bone; bone turnover problems,
mineralization disorders, and the fractures. Last but not
least, it also contains problems of vascular and soft
tissue calcifications. These together form the so-called
CKD mineral and bone disorder spectrum.

[Slide 20] [0:13:47] Let’s start with a question to segue

us into the rest of the talk. What would you guess? The
first CKD-MBD-related adaptive change in early chronic
kidney disease, so this is early CKD , A) an increase in
PTH; B) an increase in FGF23; C) a decrease in FGF23; D) a
decrease in PTH; or E) an increase in serum phosphorus.

[Slide 21] [0:14:12] It’s interesting that phosphorus which

is in many ways the target of many of these regulatory
actions that Dr. Wolf was mentioning stays normal and that
just speaks to the ability of the kidneys to maintain this
normal serum phosphorus for a very long time. What you see

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in front of you is a cross-sectional study where patients
with different levels of kidney function had their
phosphorus levels measured and this was ten years ago,
showing that both serum phosphorus and calcium levels
remained normal until very, very late in the course of
kidney disease.

[Slide 22] [0:14:44] If we follow longitudinally the same

patients, that is, we measure serially their phosphorus
levels as they advance, as we did in a large cohort of
veterans who initiated dialysis and this in their pre-
dialysis period, what you see indeed, that serum phosphorus
up to three years prior to starting dialysis was normal at
4 and then you started seeing very small increases in the
level about two years before starting dialysis, but really,
they stayed within normal range. It wasn’t until the last
few months before dialysis when you climbed into the
hyperphosphatemia range.

[Slide 23] [0:15:18] What changes though is the adaptive

mechanisms, the various humoral factors that are
responsible for maintaining normalcy. This is again from
the same Levine study showing that your 25-hydroxy vitamin
D levels decrease slightly but your 1,25 levels decrease
more remarkably from normal kidney function to near ESRD
and in parallel PTH also rises quite early. Bear in mind
that back ten years ago when this study was done, FGF23 was
really in its infancy and not really on the radar of most
investigators.

[Slide 24] [0:15:52] PTH, going back to our main molecule

today, is in fact, something that rises very early and to
the extent that in patients that have advanced CKD it is
rather the rule to have elevated PTH and we consider a
“normal” PTH unusual and probably abnormal at this stage.

[Slide 25] [0:16:13] When we compare FGF23 and PTH, and

this goes back to the question that we posed a minute ago,
it turns out that FGF23 probably even precedes the rise in
PTH in a quest to normalize CKD-MBD’S biochemical
parameters early in the course of kidney disease.

What you see here is a study by Dr. Wolf’s group comparing

the rise in PTH and the rise in FGF23 you may point out
that both of them were rising from very, very early stages
in kidney disease but the inflection point started to go up

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more sharply happened sooner with FGF23 and because of this
study, we currently think that FGF23 is probably the first
regulatory step that is enhanced in order to maintain
normal phosphatemia.

[Slide 26] [0:17:00] The reason that PTH is important

besides we don’t like abnormal numbers is that abnormal PTH
elevations have been associated with adverse outcomes as
again was pointed out in the introduction, higher mortality
has been associated with secondary hyperparathyroidism.
This was a small study of ours in a veteran’s hospitals
looking at the SHPT in patients with non-dialysis dependent
chronic kidney disease. You see a fairly linear increase
in the association with mortality with the typical PTH
ranges that we see in CKD patients.

[Slide 27] [0:17:36] The matter is a little more

complicated in ESRD and this is a study done in the DaVita
database showing this U-shaped or J-shaped association
between all-cause mortality and PTH levels. This just
speaks to the complexity of parathyroid hormone physiology
in end-stage renal disease patients. We’ll go in a little
more detail in the next few slides.

As you all know, the KDIGO recommended range in the

targetable PTH levels is quite broad ranging from around
130 to 580 depending on your assay, of course. As you can
see there is a lot of controversy about this recommendation
because if you just take this one study it encompasses many
of these levels that at least in an observational study
have been associated with mortality, but there's still a
lot of uncertainty about the clinical benefit of correcting
beyond these numbers.

[Slide 28] [0:18:31] Just to illustrate this point again,

this slide summarizes the various cutoffs above where below
which mortality has increased in various observational
studies for calcium, phosphate, and PTH. Specifically, for
PTH, you see that some studies have not found any
association. In fact, others have found this U-shape where
you see a lower and a higher level being associated.
Others have used various cutoffs to find an association,
but in general there is no overall consensus as to what
would constitute a uniform threshold for mortality.

[Slide 29] [0:19:10] How can we reconcile this? Probably

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by understanding physiology and it is a pretty complex
physiology sometimes, difficult to understand. [Slide 30]
[0:19:20] Parathyroid hormone is produced in the chief
cells of the parathyroid gland and after its production
intracellularly even intracellularly it gets degraded into
fragments and both the PTH fragments and the intact PTH
molecule can be secreted from the chief cells. Calcium is
the main factor that determines how these are secreted in
that when calcium goes up that blocks PTH intact molecule
secretion and favors fragment secretions and vice versa.

[Slide 31] [0:19:55] After these molecules are secreted

they can act on the bone which is the main target of PTH
and interestingly both the fragments. It appears that the
fragments have their own receptor, the so-called CPTH
receptor and the main receptor being PTH1 receptor for the
intact molecule. [Slide 32] [0:20:17] The degradation of
them happens in the liver and in the kidney and the kidney
is also a target of PTH physiologically.

[Slide 33] [0:20:29] Calcium is the most important

regulator of PTH production and secretion and calcium being
an essential element that has to be maintained within a
very, very narrow range physiologically. Not surprisingly
the set point for PTH regulation shows this typical curve
where even small deviations from ionized calcium levels
normal levels can either completely suppress or maximally
stimulate PTH level.

As you can see calcium, interestingly you would think it’s

an ion but it really works as a hormone. It acts on its
own receptor, the so-called calcium sensing receptor.

[Slide 34] [0:21:10] This is a G protein coupled receptor

which is highly expressed in the parathyroid tissue and
also abundantly expressed in the kidneys. It’s also
present in other cells at low levels such as pancreatic
beta cells or thyroid cells and in the central nervous
system. The receptor itself responds to very small
deviations from normal levels in ionized calcium level and
as a result it increases cytoplasmic calcium levels and the
result is a decrease in PTH secretion, a diminished PTH
mRNA level and also interestingly it retards parathyroid
gland hyperplasia so it works at different levels to
inhibit PTH secretion and production.

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[Slide 35] [0:12:55] Another factor that we need to mention
when we discuss regulation of CKD-MBD and parathyroid
hormone metabolism is vitamin D. You all probably know
that we can obtain vitamin D both from food and by being
exposed to UV radiation at one of the Disney parks. Once
vitamin D gets in circulation it has to pass through the
liver to undergo 25-hydroxylation and hence produce
25-hydroxy vitamin D which is the circulating vitamin D
that is measurable. This one has a long half-life so
that’s why we use it to describe vitamin D status as
opposed to 1,25 vitamin D which has a very short half-life
and is very difficult to measure properly.

The interesting physiology of vitamin D really happens

below the 25-hydroxy level where 25-hydroxy undergoes 1-
alpha hydroxylation in the kidneys and as you can see,
there is a host of various regulators that make sure that
the balance of vitamin D is maintained properly and these
include PTH, which stimulates 1-alpha hydroxylase, FGF23,
which inhibits 1-alpha hydroxylase and calcitonin which
stimulates it. Interestingly on the right side of this
graph, unfortunately I don’t have a pointer, you have
24-hydroxylase, 24, 25-hydroxy vitamin D. These also seem
to play a role in balancing the production of breakdown
products as a shunting away mechanism of lowering vitamin D
levels.

[Slide 36] [0:23:27] Vitamin D, again a misnomer. We’re

talking about a vitamin yet it is really a hormone. It has
its own receptor, the so-called vitamin D receptor which is
a nuclear receptor expressed primarily in the gut, in the
bone, the kidney, and the parathyroid but also, it’s
expresses in essentially all human tissues and it has a
host of various interesting effects at stimulation.

Expression regulated by 1,25 vitamin D calcium PTH and the

receptor itself binds 1,25-hydroxy vitamin D which will
lead to it exerting its physiologic effects which for the
purpose of CKD-MBD would primarily the enhancement of
gastrointestinal calcium and phosphorus absorption lowering
the suppression of PTH and the modification of bone cell
activities.

[Slide 37] [0:24:19] This slide shows you a summary of how

calcium and vitamin D would exert their effects on PTH
production and what it means is that both of them will act

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intracellularly in the nucleus to inhibit, you see the
negative signs, the production of PTH. Both have their own
receptors and both act on the parathyroid cells.

[Slide 38] [0:24:46] This graph shows you the summary of

how this happens and also illustrates the various levels
where PTH production can be affected. On the right side,
you see transcription and transcription is the process
whereby new PTH molecules are produced. Both vitamin D and
calcium can inhibit this process. If you have
hypercalcemia, if you have high vitamin D you will inhibit
a transcription of PTH. Interestingly transcription
happens in once cell so you can produce more PTH by one
cell but you can also influence the amount of PTH produced
in the entire parathyroid gland by influencing how many
cells you have. Hence, if you enhance the number of cells
you cause hyperplasia that will in itself boost the amount
of PTH. Interestingly activation of the calcium-sensing
receptor that you see on the left side can inhibit gland
hyperplasia. Another factor that does it is phosphorus.

Once PTH is produced it is stored in these granules and it

can be released. The release process in itself is also
influenced by factors and calcium also plays a major role
there in that it assures that PTH can be released very
quickly into the circulation and when you think about it
this is very important because when you have an acute
changing calcium you need to act rapidly to correct it.
This is an essential factor and you don’t have time to tell
the cell produce more hormone. You need the hormone
readily available to be released into the circulation.
Hence, calcium’s effects to the calcium-sensing receptor
can inhibit or stimulate the release of PTH from the
storage depending on hypo or hypercalcemia being present.

Naturally medications that can modulate these effects with

the calcium-sensing receptor and that will be the second
part of the talk that calcimimetics can influence all these
steps.

[Slide 39] [0:26:39] A summary of these effects, the acute

and chronic regulations of PTH production are on this
slide. On the one hand, you have PTH secretion which
happens within minutes and is primarily affected by calcium
levels and stimulation of calcium-sensing receptor. You
have the gene expression, the transcription and the mRNA

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stability that affects production of new PTH molecules in
individual cells. This typically can happen within hours
or days and the factors that affect it are vitamin D,
calcium, and phosphorus and then you have tissue
hyperplasia which determines the number of cells, the
amount of cells, and this is something that affects PTH
production over weeks and months and years and is also the
factor that’s probably most difficult to reverse once your
patient has developed it on dialysis and this is something
that’s affected by calcium, calcium-sensing receptor, and
phosphorus.

[Slide 40] [0:27:39] Let’s have a summary of how PTH

regulates calcium and phosphorus homeostasis. Let’s say if
serum calcium decreases this will result in an increase in
PTH release. We reviewed the steps whereby a calcium
through calcium-sensing receptor will do that. A high PTH
will act on a number of sites, number one on the kidneys it
will increase directly reabsorption of calcium, it will
enhance production of 1,25-vitamin D through increasing 1-
alpha hydroxylation and that will block phosphorus
reabsorption. That is not a primary effect calcium-wise
but it acts on other sites too so the gut will be a
secondary site, not directly affected by PTH but indirectly
through enhancing vitamin D synthesis, vitamin D then in
turn will enhance calcium absorption and phosphorus
absorption in the intestine. Then PTH also has the bone as
its main site enhancing calcium resorption and phosphorus
resorption. Calcium-wise at least the net effect is an
increase in the serum calcium so it’s a nice feedback
mechanism whereby hypocalcemia elicits these physiologic
responses to correct the low calcium and to make more
calcium available and not allow hypocalcemia to occur.

[Slide 41] [0:29:03] This slide is a little bit complicated

just illustrating the physiologic actions of PTH on the
bone and what you see there are three types of cells;
osteocyte on the right lower corner and there this
complicated cell. Then you have the osteoclasts on the
left and above it the osteoblasts. I’m not going to go
into detail. This is for a cell biologist primarily to
understand what the different molecules are but the bottom
line is PTH has receptors in the osteocyte and in the
osteoblast. These are its direct sites and indirectly
affects the osteoclasts through this osteoprotegerin rankl

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system affecting the ratio of these molecules. The net
effect, as you know, PTH releases calcium, releases
phosphorus from the bone but this is a very interesting and
very complicated, complex regulatory system where the type
of release and the duration of action of PTH can have very
different responses from the bone. For example, PTH if
released in bursts intermittently has primarily an anabolic
effect on the bone whereas PTH when it’s increased
constantly and remains high pathologically then it has a
catabolic effect, it leads to bone mass loss and just a
release of minerals from the bone. This is important to
understand because if you don’t have enough PTH that’s
probably just as bad as if you have too much and you all
know that there’s actually a drug that is synthetic PTH
that you can use under certain circumstances to treat
osteoporosis. It goes back to this complex physiology
where PTH is in fact, an essential element that’s important
to maintain the integrity and the structure of the bone and
too little or too much can both be bad. This is perhaps
one of the explanations out of several that explains the U-
shaped associations with outcomes for example.

[Slide 42] [0:30:58] The summary of physiology, this is

just very quickly going over what calcium and what vitamin
D do and showing that calcium has an effect on all three
levels of PTH secretion whereas vitamin D affects primarily
the production of vitamin D.

[Slide 43] [0:31:21] In some ways this is showing similarly

what we just showed a minute ago and I just want to
illustrate one point, not go over all the steps again with
hypocalcemia, PTH production and its actions on the gut,
the bone, and the kidneys. One thing to illustrate here is
that this is calcium-centric. You have primarily a
physiologic mechanism geared towards raising calcium in the
face of hypocalcemia but you may notice that PTH’s actions
primary and secondary will also affect phosphorus levels
and those are not going in the same direction; it could
either raise or lower phosphorus. For many years, we
thought that PTH may be the primary phosphorus regulators
but it just doesn’t make sense because you can end up with
high phosphorus or low phosphorus under different
circumstances.

[Slide 44] [0:32:10] Enter FGF23. For many years people

thought that there exist so-called phosphatonins, other

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humoral factors that enhance phosphorus excretion to
counterbalance the phosphorus raising effects of PTH in
this CKD-MBD context. FGF23 turned out to be a very
intriguing molecule for many reasons that we don’t have to
discuss in detail today. But what it does; in effect its
primarily a phosphorus-centric molecule in this biochemical
context in that it counterbalances vitamin D’s effects, it
counterbalances PTH’s effects on the bone and on the kidney
and it primarily results in the lowering of serum
phosphorus through phosphaturia.

[Slide 45] [0:32:55] Just a few words about where the name
comes. I find this very intriguing that we call it FGF23
so you might wonder what about the other 22. The mammalian
FGF family comprises 22 different polypeptides and they are
grouped into 7 subfamilies. On the bottom, you see the so-
called FGF19 subfamily which contains FGF19, 21, and 23.
These are really sort of the odd group in this family.
They may be just halfway related because all the other
hormones are really acting in a paracrine manner. They are
secreted and they are captured immediately at the site of
secretion and they exert their effect whereas these three
hormones are released into the circulation so they are true
hormones and they have endocrine actions. They can do this
because they have a certain structure that does not allow
their capturing locally and as they are released and they
act on other receptors throughout the body.

[Slide 46] [0:33:54] FGF23 the molecule main interest to us

contains 251 amino acids and has phosphaturic activity in
vivo. [Slide 47] [0:34:07] How we learned about its
existence is by discovering various disease states that
were characterized later as hereditary acquired FGF23
excess or deficiency and one of them was hypophosphatemic
rickets where you had FGF23 excess, the other one was
hereditary tumoral calcinosis with some malignancies you
had too much FGF23 being produced.

The phenotypes on the bottom tell you how patients

presented with these conditions. If you have FGF23 excess,
this is typically with normal kidney function the patient
would present with a low serum phosphorus, aberrant vitamin
D metabolism, low vitamin levels, and typically bone
disease, rickets and osteomalacia. The opposite end of the
spectrum is the FGF23 deficiency where you develop
hyperphosphatemia, elevated vitamin D levels, soft tissue

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calcifications and hyperostosis.

[Slide 48] [0:35:09] This is the scary slide. I just show

it to scare people because I don’t understand any of it.
For molecular biologists, this is probably heaven on earth,
but it’s supposed to illustrate the regulation of PTH
production and it just shows you how complicated things can
get and what I would point out is maybe you’ll notice 1,25-
vitamin D on the left side and then above it PTH and then
bone-derived factor. Those are really main regulators of
PTH production [Slide 49] [0:35:43] but I prefer this one
much better. What it shows is that the top three factors
are probably the primary stimulators or inhibitors of FGF23
production and mostly in the context of CKD-MBD milieu so
1,25 vitamin D is the main stimulator of FGF23 production.
PTH also is believed to stimulate production although under
certain circumstances for example if you give it in short
bursts it might actually inhibit FGF23 and then there are
all these nebulous bone metabolism factors that are related
to mineralization and bone health that are supposedly
modulating FGF23 production presumably because it’s
important to maintain phosphorus balance and adequate
mineralization of the bone.

On the bottom, you see the physiologic actions of FGF23 for

the sake of CKD-MBD primarily blocking of renal phosphorus
reabsorption, it’s a phosphatonin, phosphaturic hormone.
It inhibits klotho expression, it inhibits PTH secretion
even though later in the course of CKD you develop a
resistance to this effect, that’s why the question mark,
and also one main effect is to inhibit 1,25-hydroxy vitamin
D production. As you can see, most of these are feedback
loops where you have this factor that keeps everything in
balance so if something goes up it inhibits the next one
then everything is maintained in a nice balance as long as
you don’t overdo it.

[Slide 50] [0:37:15] As people have dug into FGF23 we’ve

learned that really the physiology is a lot more
complicated so that nice simple graph really doesn’t even
start to scratch the surface when you talk about additional
regulators which include calcium, corticosteroids, leptin,
estrogen, iron metabolism, inflammation, and a bunch of
local regulators at the bone cellular level. We don’t have
time to go into this.

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[Slide 51] [0:37:42] How about pathophysiology of SHPT and
CKD? This is now we’re arriving at that downslope of
kidney function so what happens when the kidney poops out
and you don’t have the tissue and you don’t have [Slide 52]
[0:37:57] the molecules that are produced. As you can see,
this is the original physiology of low calcium kicking into
motion all these physiologic responses. Now imagine that
your kidney is gone. You don’t have the outlet, you cannot
excrete phosphorus, you cannot reabsorb calcium anymore and
also you will have a problem secreting vitamin D because
your kidney tissue is low and also you have more FGF23 now
because it’s increased early in the course of CKD. As a
result, you will have lesser effects of vitamin D, you have
no effects on the kidneys, you will develop a slight
decrease in calcium, hypocalcemia, and also
hyperphosphatemia.

[Slide 53] [0:38:34] PTH in this context, because of the

hypocalcemia that’s caused will be stimulated. The
hyperphosphatemia, hypercalcemia, low vitamin D, all of
these if you remember the initial physiologic regulatory
steps will stimulate PTH. It would make for a nice
feedback loop where it quickly corrects these
abnormalities. The problem is your kidneys aren’t getting
better. They’re getting worse. If anything, this whole
situation, step-by-step is gradually getting worse and
worse and you end up with this adaptive turned maladaptive
that Dr. Wolf also showed in his initial slide where it’s a
self-perpetuating cycle. What makes this even more
complicated is that CKD in itself has complex effects on
both PTH metabolism and signaling.

This is where we get into this maybe uncharted or less well

understood territory. It would be so easy to postulate
that it’s all just going haywire because there are no
kidneys but in effect what [Slide 54] [0:39:32] happens is
quite complex. The gland itself is affected by the milieu
by CKD. PTH becomes, parathyroid gland becomes refractory
and not responsive to these signals perhaps in response of
the refractoriness of the underlying problem. You will
have increased parathyroid cell proliferation, and then a
downregulation of all the signaling mechanisms that assure
that you can block PTH in a physiologic manner.

Not only that, but we mentioned at the beginning the

presence of these C terminal fragments. It looks like they

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 also take on a life of their own. Their production is
enhanced or their ratio to the normal PTH molecule
increases under uremic conditions and they also have their
own receptors. They exert their own effects which are
believed to be antagonistic to PTH’s effects. This is also
not very clearly defined but it may be why you see some
patients who have very high measured PTH levels yet they
seem to be perfectly normal. On the face of it they have
normal calcium, normal phosphorus, and normal bone
sometimes. Almost done.

There also is this function at the receptor level in the

sense that PTH resistance is one of the key factors that
will be present in patients with CKD so that’s one of the
explanations why the range of PTH that’s acceptable has
really shifted to the right and we learned to accept this
new normal in CKD and ESRD where higher PTH is really what
we want not the “normal” physiologic PTH.

[Slide 55] [0:41:10] Why lower PTH? Besides the CKD-MBD

there is also this host of other systemic effects that are
postulated to be present and that could explain why for
example cardiovascular events may be worse in patients with
secondary hyperparathyroidism and we mentioned earlier that
PTH receptors are present in smaller amounts in other
organs, in the vasculature, in the bone marrow, in the
pancreas, and hence, there could be various cardiovascular
and metabolic effects that are a result of secondary
hyperparathyroidism.

[Slide 56] [0:41:44] In summary, PTH is a crucial regulator

of mineral and bone metabolism with SHPT developing early
in the course of CKD along with a host of other metabolic
abnormalities, calcium, phosphorus, vitamin D, FGF clonal
metabolism are all dysregulated leading to adverse outcomes
in patients with CKD and ESRD.

Thank you very much.

DR. WOLF: [Slide 57] [0:42:11] Thank you Dr. Kovesdy.

Optimizing Biochemical Control in Secondary

Hyperparathyroidism

DR. JAMES WETMORE: [Slide 58] [0:42:18] …some conflicts of

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interest here. I’m going to go quickly in the interest of
time. We won’t be talking about off-label use of any drug
here.

[Slide 59] [0:42:24] We’ll talk about early trials of

cinacalcet’s control of PTH. We’ll talk about hard or
primary outcomes from RCTs which is pretty much evolved.
We’ll talk about other outcomes of relevance in secondary
hyperparathyroidism from across the literature, things like
cardiovascular outcomes, vascular calcification,
parathyroidectomy, and calciphylaxis, and we’ll talk about
some new horizons, IV calcimimetics.

[Slide 60] [0:42:47] This is the study that put cinacalcet

on the map. Hard to believe it was 2004 with Geoff Bloch
and his team there. Cinacalcet was tested versus placebo
in patients who had uncontrolled secondary
hyperparathyroidism and receiving standard of care therapy.
Our definition of uncontrolled hyperparathyroidism has
changed because the PTH was only about 640 or so in each
arm. If you look there in the upper right, what you see is
the dark blue bars are the patients treated with cinacalcet
and the placebo is the light blue, and in the upper right
the percentage of patients achieving a more than 30%
reduction in PTH was much higher in the cinacalcet-based
arm. If we look in the middle graph right there, we see
that most of the effect of cinacalcet versus placebo in
terms of PTH suppression was really in the first 12 weeks
or so. The drugs acts over several months to effectively
suppress PTH.

[Slide 61] [0:43:47] Now let’s talk about cinacalcet versus

non-cinacalcet based therapies for control of SHPT. A
follow-on to the original trial that was published in NEJN
was the ACHIEVE trial. It was designed to test whether a
therapeutic strategy of using 1,25 vitamin D, how that
differed from a therapeutic strategy that involved
primarily use of cinacalcet with low-dose vitamin D used in
sort of augmentative fashion. For example, 2 micrograms of
paricalcitol, something like that. It was an RCT, modest
in size, 85 patients per arm. The outcomes were PTH
reduction but also changes in other mineral metabolism
analytes.

[Slide 62] [0:44:31] On the left here, what we see is that

the outcomes were the PTH level or a PTH level less than

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300 and a calcium phosphorus product of less than 55 or a
more than 30% reduction of PTH that cinacalcet was superior
to so-called Flex-D, Flex-D being the 1,25 vitamin D arm.
The dark bar, cinacalcet plus D exceed the light-colored
bars there. We won’t go into all the figures here but we
can see that the main PTH in the upper left there of the
four-panel figure demonstrates the time course whereby the
PTH is suppressed relative to the Flex-D arm which is the
open circles. We also see that the median calcium
phosphorus product was lower again in the upper right
there. The median calcium, not unexpectedly, dropped quite
a bit in the cinacalcet-based arm compared to the Flex-D
arm.

[Slide 63] [0:45:34] What about cinacalcet and 1,25 D

head-to-head? It’s very rare that such trials have been
conducted. I actually only know of one that was the
PARADIGM trial. PARADIGM was designed to test whether
cinacalcet versus 1,25 D in head-to-head fashion had any
differential effects on levels of PTH. About 300 patients
in this study. The median PTH was 700 or so in the two
arms reflecting more recent or contemporary practices for
secondary hyperparathyroidism.

[Slide 64] [0:46:09] The results of this trial were

somewhat surprising, at least to me, which is that when you
test cinacalcet versus 1,25 D head-to-head, there really
wasn’t very much of a difference in terms of PTH control
when you look at the top panel of the figure there, about
halfway through the year is the maintenance phase and at
the very end there, to the right, there’s the efficacy
assessment phase. Really what you see is that the dark
solid line and the dotted line overlap. This would have
suggested that cinacalcet and 1,25 vitamin D didn’t really
have any inherent differences in terms of ability to
suppress PTH.

There was a little bit of a twist to this trial which is

that the outcome really depended on the dialysate calcium
bath and so that what this truncated table at the bottom of
this slide is supposed to demonstrate. When the dialysate
calcium was greater than 2.5, which is the top half of that
table, the cinacalcet resulted in a reduction of PTH of
about 19%, -18.9. The vitamin D analog resulted in a
decrease of about 6%. In this post hoc analysis in
patients who had dialysate calcium greater than 2.5, the

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treatment difference was about 12.9% and that was nominally
statistically significant. That’s that P value of 0.04.
For the patients with a dialysate calcium less than 2.5
there really wasn’t a difference in the lower right, that’s
that P value of 0.20.

This is what biostatisticians would call statistical

interaction. The relative of efficacy of cinacalcet versus
vitamin D in terms of suppressing PTH really depends on the
calcium bath that dialysis patients are on and this came
about when the investigators of this trial looked at U.S.
sites versus non-U.S. sites and what they realized was the
in the U.S. for the past ten years or so the dialysate
calcium baths were falling quite a bit, probably due to
fears about vascular calcification which was not a
phenomenon that happened in Europe and Russia and other
places. When they looked at this they then took a look at
the calcium dialysate baths and found this effect. Just as
an aside, calcium baths now seem to be rising in the U.S.
and more and more units are going to 2.25 and 2.5 and
higher. There will probably be more of a concordance
between U.S. and non-U.S. practices in the future.

[Slide 65] [0:48:52] Cinacalcet therapy and mortality and

cardiovascular events. EVOLVE is the only RCT in
nephrology to really ever test the effects of secondary
hyperparathyroidism therapies on hard outcomes. The
primary outcome was time to a combination of death and
first nonfatal cardiovascular event. A nonfatal event was
an MI, unstable angina, heart failure, peripheral vascular
disease. Secondary outcomes were times to each individual
component, time to death from these various cardiovascular
events, time to stroke, fracture, and parathyroidectomy.

[Slide 66] [0:49:19] This is a slide that probably most of

us have seen and perhaps rued about or mused about. For
the primary composite endpoint, these two curves are
superimposable. There was no difference between cinacalcet
and placebo. The P value was 0.11. You can see the
confidence intervals span unity, there was a slight sign
there with a hazard ratio of 0.93 but unable to really call
this trial a positive trial. [Slide 67] [0:49:49] If you
look just at the death component of the primary composite
outcome again, the two curves are superimposable so no
mortality benefit associated with use of cinacalcet.

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[Slide 68] [0:50:00] I’m calling EVOLVE the most
controversial nephrology trial of recent times. I’d be
very interested in my colleagues, my fellow speakers,
whether they would agree with that and by agreed upon
convention this trial could not be called positive because
the prespecified endpoint was not met. The confidence
interval spanned unity and the P value was not significant
using traditional thresholds. There’s a lot of nuance to
the interpretation of this trial. There was a lot of
dropout. It was drop-in which is people not assigned to
cinacalcet getting commercial cinacalcet. There was a lot
of crossover. The aim for 90% power and power can only be
calculated prior to a trial’s initiation but you can
calculate post hoc power and post hoc power was only 54% in
this trial. They didn’t reach the power that they thought.
The age differed by a year. The people that got cinacalcet
were nearly a year older which would have favored the non-
cinacalcet arm.

When you do multivariable adjustment for the trial

population which is something that all trialists think that
all RCTs should undergo, it turns out that the HR was 0.88
for cinacalcet suggesting a benefit and then the
investigators embarked on a variety of very complex and
local techniques, things known as lag-censored analyses,
censoring for treatment crossover, sort of an as-treated
type analysis and when you do those types of analyses you
start to see suggestions of a signal the cinacalcet might
actually have provided a benefit. You get hazard ratios of
0.83 or 0.84 with less than 1 being a putative benefit
associated with cinacalcet. But because the primary
prespecified endpoint with the analytic strategy was not
met couldn’t really call it a positive trial.

[Slide 69] [0:51:46] Was EVOLVE a negative trial? The

prespecified endpoint using intention to treat approach was
nonsignificant. Could you argue that EVOLVE was a positive
trial? A variety of other adjusted analyses lag-censored,
censored weighted analyses, as-treated analyses these
favored cinacalcet and when you look at the supplementary
figures what you see is that the point estimates for all
the secondary endpoints for cinacalcet were almost always 1
or better. Cinacalcet was almost always exceeding the
benefits of the non-cinacalcet arm.

Was EVOLVE an inconclusive trial? You could take this

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position as well. The trial was contaminated by the need
to extend recruitment. Randomization failed despite having
nearly 4,000 patients. For example, the age difference was
quite skewed with cinacalcet patients being older.
Crossover was huge because of the availability of
commercial cinacalcet and the use in patients not
randomized to cinacalcet was high. The power was woefully
low.

For those of you who are interested in this or more broadly

interested in clinical trial design and issues involving
that I highly recommend a piece that came out about a year
ago or less from the investigators of EVOLVE. Patrick
Parfrey was the first author, it’s the reference there at
the bottom. It’s sort of a lessons learned, sort of a
requiem for this trial and really would encourage you all
to read it. it’s a very thought-provoking piece. They
argue for some things that might be a little bit
controversial like for example, saying that multivariable
analysis should be the way that all RCTs are analyzed but
it really makes for a good read for those of you interested
in this issue or in clinical trial design in general.

[Slide 70] [0:53:25] Let’s talk about vascular

calcification with - - the ADVANCE trial that tested 360
patients with PTH greater than 300 or controlled PTH and a
calc/phos product greater than 50. Treatment was 1,25 D
versus cinacalcet plus low-dose D. They looked at things
like coronary artery calcification, CAC scores, aortic
calcification, cardiac valve calcification and they looked
at the Agatston scoring and volume scoring, a number of
different ways of imaging calcium burden.

[Slide 71] [0:53:52] What you see in this figure right here
is that in most cases the solid line and the dotted line
representing the two different arms were superimposed but
there were some cases such as in the lower left where the
therapies differed. Basically, the Agatston coronary
artery calcification score increased by 24% in the
cinacalcet arm, 31 in the 1,25 D arm that was not
statistically significant. When they looked at it in some
other ways, for example, volume CAC scores 22% in the
cinacalcet arm versus 30 in the non-cinacalcet arm that was
statistically significant.

There’s a mixed picture came out of this study about

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whether cinacalcet was associated with less vascular
calcification. The people who believe that this is a
mechanism that’s operative would take some solace from
this. Others would say that the benefits of cinacalcet for
vascular calcification are anything but unanimous.

[Slide 72] [0:54:50] What about fracture? Fracture was

actually studied in EVOLVE and the same statistical issues
that we talked about for the overall trial, the primary
endpoint for death, arise when fracture was examined. When
vertebral and nonvertebral fractures are examined happened
in 13% of the patients on the placebo arm and 12.2% in the
cinacalcet arm. If you use your classic intent-to-treat
analytic strategy cinacalcet was not associated with a
decrease in fractures. The point estimate was 0.89 but the
confidence interval spanned 1.

You really couldn’t say that it was significant, but when

you start to do things like adjustment for baseline
characteristics or do things like lag-censored analyses you
start to see these point estimates being less than 1, 0.83,
0.72 suggesting that perhaps cinacalcet is associated with
decreased fracture risk. Again, there seemed to be a
statistical interaction, there seemed to be an effect. For
example, patients who are [Slide 73] [0:55:50] greater than
65 appeared to do better than people who were less than 65.
When you look at the top right panel for patients who are
less than 65 the two lines representing the treatment arms
are essentially superimposable, really no difference. When
you look at the individuals who were more than 65 you see
there starts to be a little bit of a separation in these
two lines with cinacalcet being the darker line below,
again, suggesting that if you look at different subgroups
perhaps cinacalcet is associated with decreased fracture
risk. If so, more prominently in older individuals.

[Slide 74] [0:56:26] What about parathyroidectomy. Here is

a figure right from the Cardinal publication right there.
Seven percent of cinacalcet treated patients underwent
parathyroidectomy. Twice as many had a parathyroidectomy
in the control arm. The hazard ratio was 0.44 and this was
probably the strongest evidence that cinacalcet based
therapies have a significant beneficial effect.
Parathyroidectomy was much less common in the patients
randomized to cinacalcet.

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[Slide 75] [0:56:56] What about calciphylaxis or CUA? The
numbers were small, about 18 patients were diagnosed with
CUA in the placebo arm in EVOLVE, about 6 in the
cinacalcet. The unadjusted hazard ratio was 0.3. If you
look at those confidence intervals, 0.13 to 0.79, those are
very wide because the number of events were small, the P
value was significant. Some suggestion that perhaps use of
cinacalcet could forestall or prevent development of
calciphylaxis in some way.

[Slide 76] [0:57:27] Here’s a Cochrane meta-analysis and

the Cochrane people do what the Cochrane people do, which
is to do large well-conducted meta-analyses. This is what
I call a gestalt slide. We’re obviously not going to go
through the results of every single point here but if you
look in the top panel this is the summary of effects for
mortality and you can see at those point estimates all line
up on the vertical line essentially 1 suggesting that the
Cochrane meta-analysis people couldn’t really discern a
mortality benefit associated with use of cinacalcet when
all those studies were analyzed.

Parathyroidectomy is the next band there, the narrower band

and there's where the evidence is probably most convincing
from the literature when its studied collectively. Using
cinacalcet appears to have a benefit with reducing the risk
of parathyroidectomy.

The third group down there is hypocalcemia and that’s way

out to the right there and that’s not unexpected.
Cinacalcet has been repeatedly shown to be associated with
hypocalcemia. Then there at the bottom is the symptom of
nausea and most of the point estimates there are to the
right suggesting that as most of us probably know
anecdotally cinacalcet is associated with nausea compared
to non-cinacalcet-based therapies. Their overall
conclusions that there was no difference in mortality. Use
of cinacalcet was associated with less parathyroidectomies
but more hypocalcemia and more GI symptoms.

[Slide 77] [0:58:54] The future. Let’s talk about

etelcalcetide. Several RCTs were recently published there
by Geoff Bloch and Glenn Chertow and others in that group.
They were published in the same issue of JAMA, Dr. Wolf
wrote the editorial for both of those studies.

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The first study I want to talk about is etelcalcetide
versus placebo or standard of care. They were in two
trials, about 500 participants each, 6 months in duration.
This is part of an FDA requirement to get a drug approved.
You have to test the drug against placebo or standard of
care and you have to really do it in two trials, they can
be identical in design but they have to be independent.
These involved hundreds of sites or nearly 200 sites
worldwide with many different continents. The endpoint the
classic 30% reduction in PTH.

[Slide 78] [0:59:43] Here’s etelcalcetide versus placebo.

The mean PTH at baseline about 850 or so. On the left we
have one trial, on the right we have another trial and in
terms of the primary endpoint of 30% reduction in PTH you
had 74% reaching that in trial one in cinacalcet, 8% in the
patients who received standard of care, in other words, no
cinacalcet. The numbers were very similar for the second
trial, 75 versus 10% and we see that when we look at the
Panel A and at Panel B we can see how the yellow arm which
is the etelcalcetide was associated with a substantial
decrement in PTH, again, about three months out you’re
getting most of your effect. Note that there was a drop in
calcium with partial recovery in the etelcalcetide arm.
Those are Panels C and D, you can see how cinacalcet fell.
Recovery is probably not exactly the right term because the
recovery wasn’t spontaneous. Providers were allowed to do
cointerventions; change dialysate calcium bath or provide
calcium supplementation or more vitamin D and so as you see
the calcium levels in the yellow, or cinacalcet tracings
right there start to go up it was probably because
providers were actually doing something to ameliorate the
effect of hypocalcemia.

Phosphorus also decreased by about 0.8 milligrams per

deciliter in the etelcalcetide arm initially but it tended
to converge up to about 0.2 to 0.5 at the end, so a modest
benefit in phosphorus control.

[Slide 79] [1:01:13] In terms of use of vitamin D not

unexpectedly 1,25 vitamin D compounds activated by vitamin
D tended to be used more in general as the trial
progressed. The top is Trial A, the bottom is Trial B, and
in the etelcalcetide arm which is in the red, what you see
is that the proportion of patients using vitamin D tend to
go up over time. In Trial B, you see the same general

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pattern; providers were reacting probably to the
hypocalcemia by increasing the use of 1,25 D compounds.
The median dose of etelcalcetide in the first trial was 7
milligrams in the second it was 5. In terms of adverse
events hypocalcemia was 7.2 in etelcalcetide treated
patients versus 0.4 in the placebo treated patients in
Trial 1. Similar numbers in Trial 2, 6.7 versus 0% in the
placebo arm. Not unexpected that etelcalcetide treated
patients would experience hypocalcemia. FGF decreased more
than 50% in the etelcalcetide arms at both trials and not
really an effect in the placebo.

[Slide 80] [1:02:19] Here’s the other major study right

here; etelcalcetide versus cinacalcet. This is more of a
real-world way to thinking about things. Six hundred
eighty-three patients from many countries randomized when
the PTH was more than 500. Endpoint was that 30% reduction
in PTH. The trial was very cleverly conducted because it
was primarily designed as a noninferiority trial. If you
could show that the reductions were similar you could say
that etelcalcetide was no worse than cinacalcet but if the
performance of etelcalcetide was much better, for example,
more patients were reaching a 50% reduction of PTH, you
could call etelcalcetide not only non-inferior but
superior. The primary finding was that the P value for
noninferiority was less than 0.01 suggesting that
etelcalcetide is not inferior to cinacalcet when it comes
to reducing PTH 30%. When it’s repowered for the issue of
superiority the P value for superiority of etelcalcetide
was 0.04. We see the tracings again, etelcalcetide is in
the yellow or the golden color and the PTH there is on the
left and we see that the PTH levels were reduced on average
quite a bit more and in terms of the calcium
concentrations, that’s in Panel B. We see that
etelcalcetide did have a greater effect in lowering serum
calcium. Hypocalcemia was present in 5% of the patients
randomized to etelcalcetide, 2.3% in the patients
randomized to cinacalcet.

Perhaps one of the most interesting things about this trial

was that nausea, which was collected by both this visual
analog scale where patients would put their degree of
nausea and score it and also an electronic recording device
where patients recorded their symptoms. Nausea was no
different in the IV administered compound etelcalcetide

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 versus cinacalcet; somewhat unexpected since reduction of
nausea was the potential rationale for the development of
IV calcimimetics.

[Slide 81] [1:04:22] In conclusion, cinacalcet has not been

shown to demonstrate survival in cardiovascular endpoint
benefits in the classic intention-to-treat framework.
Clinical trials have generally demonstrated superior SHPT
control with cinacalcet plus 1,25 vitamin D regimens in
which 1,25 is used as an augmentative therapy compared to
use of 1,25 D compounds alone. Hasn’t been shown to be
superior to 1,25 D when tested head-to-head, and
etelcalcetide at this level appears to be non-inferior and
I would argue is superior to cinacalcet in reducing PTH
levels but appears to be associated with more hypocalcemia
and not really a change in nausea.

Questions

DR. WOLF: I want to thank both our speakers for really

fantastic talks bringing clarity to what are very complex
topics and also for clearly going through the data from
patients on the different therapeutic choices that are out
there.

[Slide 82] [1:05:19] Total calcium versus corrected

calcium. That’s a good question. Anybody want to jump in
on that one? Csaba you want to give us your opinion on all
this stuff that we just discussed? What should we be
paying attention to?

DR. KOVESDY: Very good question and very complex too. As you
know, ionized calcium is what matters. That’s the
physiologic target there and the total calcium changes
according to ionized calcium changes. If your albumin is
low, if your bicarbonate is low then you can have a
decrease in total calcium without a change ionized calcium,
so my answer would be ionized calcium if I had to pick one.

My second choice would be corrected calcium. The problem

there is that the correction formulas that were developed
in patients with normal kidney function don’t perform well
in ESRD and that’s been proven over and over again. There
was a recent study by Dr. Obi who compared the so-called
correction formulas used in normal kidney function showed

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 that there’s actually a significant proportion of patients
who will have this hidden hypo and hypercalcemia if you use
them.

The short answer is if you have the opportunity then use

ionized calcium as your target.

DR. WOLF: Somebody asked about niacin and what is the role of
niacin as a therapeutic agent in this space. It was
directed to Dr. Wetmore. You’re welcome to jump in.

DR. WETMORE: This very question is being tested in clinical

trials that are ongoing under the auspices of the NIH.
Myles can add if he knows something different than I know,
but my understanding is that these are going to be tested
in UO1-funded studies.

DR. WOLF: Niacin or nicotinamide even better because niacin

causes a lot of flushing and almost nobody can handle it
for any period of time. Nicotinamide is one of the
catabolic byproducts of niacin and it seems to have less
flushing. What it does is it blocks NaPi2b which is the
phosphate transporter responsible for active transport of
phosphate in the GI tract. It’s not really that clear how
important that pathway is in general but it might become
very important the active phosphate reabsorption when
patients are taking phosphate binders. One of the thoughts
out there is why phosphate binders are not as effective as
perhaps we think they should be is because when patient
take phosphate binders and there’s a threat to absorbing
dietary phosphate they activate the NaPi2b dependent
mechanism to transport more phosphate and absorb more in
gut. We are testing a hypothesis as James said, that if we
simultaneously add nicotinamide on top of phosphate binders
that we will synergistically lower serum phosphate and
FGF23. We’re doing that in a pre-dialysis population but
there was recently a paper, I think a year or two ago out
of Europe using nicotinamide in dialysis patients so it
might have a secondary ancillary role but it is still being
worked out.

Let me go back to Dr. Kovesdy. PTH tests are high variable

and some nephrologists are focusing more on bone-specific
alkaline phosphatase, calcium, and phosphate. How do you
integrate the variability of the PTH test into your
approach?

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DR. KOVESDY: I completely agree. Biochemical testing of PTH is
quite frankly a mess. The second generation assays we
don’t have a calibration process so they’re all over the
map. The differ as much as 30 to 50% from each other so
using single thresholds is really impossible because it
depends on what test you have. That’s an additional reason
why we have this wide range of PTH target because it’s just
impossible to target this very precisely. Third generation
assays haven’t caught on and hence, it’s probably a good
practice to use a holistic approach where you assess your
patient from as many angles as possible, look at the other
biochemical parameters that characterize CKD-MBD and put
them in that context with your knowledge of physiology.
Alk phos is quite ubiquitously available. If bone-specific
alk phos is available to you that’s even better and it
really gives you a more direct measure of bone remodeling
than PTH which is more of an indirect measure.

DR. WOLF: Alright, I have two more questions and then we’re
going to close because we’re running out of time. Dr.
Wetmore, we were asked can you use or would you use
cinacalcet in recurrent hyperparathyroidism in patients
after parathyroidectomy?

DR. WETMORE: In principle I don’t see any reason why that could
not be done with the typical cautions that you have for
risk of hypocalcemia in any situation. You’d probably
start a very low dose but in principle that could be used.

DR. WOLF: Great. Then the last one to wind it up, back to our
first card which has multiple questions. Many
nephrologists instruct their dietitians not to increase
vitamin D therapy on patients with hyperparathyroidism and
simultaneously hyperphosphatemia. What would be the
approach there that you would recommend?

DR. KOVESDY: Of course, you shouldn’t be increasing vitamin D

because it will make your hyperphosphatemia worse. The
complexity of CKD-MBD is that you have to consider all
parameters simultaneously and you have to be aware of what
your effects and side effects of the various therapeutic
agents are. You have to combine use of phosphate binders,
vitamin D, calcimimetic agents, and so on and so forth, to
achieve your desired ideal biochemical milieu. Sometimes
that’s not possible so you have to throw in things like
parathyroidectomy but it really comes down to an

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 individualized approach based on the combination of
biochemical factors.

DR. WOLF: I’ll just close. I’ll weigh in on that one by saying
that that really does seem like an opportunity for the
future for etelcalcetide to be a treatment where you might
have a subtle reduction or a moderate reduction in serum
phosphate while simultaneously having a significant effect
on PTH.

I want to thank your speakers for fabulous presentations.

I want to thank the NKF for inviting us and you for
attending, and I want to thank Amgen for making this
meeting possible.

Thanks very much and enjoy the rest of the meeting.

[END RECORDING]

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