Video Transcript: Rationale for Raising Current Clinical Practice Guideline Targets for Serum 25D in CKD | RPA Satellite Symposium 2019

Charlie Bishop: Good afternoon everybody and thank you very much for coming to the lunch time symposium. I’m Charlie Bishop and I’m CEO of the OPKO Renal division. I’m very pleased to introduce Dr. Stuart Sprague today.

He is probably the most appropriate person to be talking about what is the target for serum total 25D in stage 3, 4 patients.

After all, Stuart has pretty much started the conversation that the target needs to be higher than what’s specified in many of the clinical practice guidelines. Dr. Sprague is going to be presenting a study that he participated in as principal investigator which shows for the first time with prospective data that the clinical practice target that all of us have seem to have adopted of 30 nanograms/mL for serum total 25D is actually too low. And he’s going to tell you where the target should be. I’m going to introduce right now, Dr. Sprague.

Dr. Stuart Sprague: Thank you, Charlie. Good afternoon everyone. Welcome to lovely Chicago. I hear we might get a little drifting of snow tomorrow, so don’t be too surprised.

Anyways, we kind of titled this presentation

“Rationale for Raising the Current Clinical Practice Guideline Target for Serum 25 Hydroxyvitamin D in Chronic Kidney Diseases.” Charlie mentioned and I think many of you may now appreciate, that with progressive kidney disease we probably do need to reevaluate what’s an appropriate Vitamin D, and remember that vitamin D and parathyroid hormone are really a hormonal axis. Very much like thyroid hormone and TSH. I think you have to kind of keep that in the back of your mind as you look at these patients.

So basically what we’re going to do is I’m going to give a quick review of vitamin D metabolism. A very quick review of different vitamin D therapies. Spend a little bit of time talking about Rayaldee or extended release calcifediol. And then we’ll summarize what we run over this afternoon.

So as you all know, we generate vitamin D initially from the sun. It raises the temperature of the skin by about a half a degree centigrade and it causes a conversion of 7DHC to our pre vitamin D3. That is then taken up into the circulation and binds very tightly with D binding protein.

In addition we can get vitamin D2, and I’m sure everyone in this room realizes that’s a plant source as opposed to the animal source of vitamin D, that we get in our diet. That also is taken up in the circulation and will also bind to the vitamin D binding protein and in fact both D2 and D3, once they’re taken up, are pretty much handled the same. As it goes through the circulation, it goes to the liver where we have 25-hydroxylase with CYP27A1 being the major one where we get the 25 Vitamin D which then circulates in circulation again with D binding protein. It goes predominantly to the kidney where you have your CYP27B, or what we used to call 1-Alpha-Hydroxylase, that then activates it to the active hormonal form of vitamin D or calcitriol.

We actually do have extra renal sites that have the CYP27B that will also activate it and it’s unclear how much that has to do with our normal circulating vitamin D. But we do know that these extra sites activate it for local action. So the tissues that have the CYP27 and form the calcitriol will actually have active vitamin D working there and doesn’t necessarily need the circulating 1,25 going around.

We also have within the kidney the CYP24, which is an inactivating enzyme for calcitriol. As I mentioned we have the 1,25 D2 or D3 that then has this biological action. Obviously, it goes through the GI tract where it promotes calcium predominantly but also helps phosphate absorption. It also goes to the bone where it helps maintain normal mineral metabolism and normal mineralization of the bone and we know that it circulates and goes to the parathyroid gland where we have the vitamin D receptor in addition to a calcium receptor and it also down regulates parathyroid hormone production and secretion.

So when we take in nutritional vitamin D for treating secondary hyperparathyroidism, nutritional vitamin D has to be absorbed, it’s gotta be converted in the liver to 25D. It then has to go into the kidney where it’s converted to 1,25D and then it leaves for secondary hyperparathyroidism and it goes around to the parathyroid gland and bind with the vitamin D receptor. Again, we also have a lot of storage of vitamin D within the adipose tissue.

When we do active vitamin D we’re giving an active compound so this automatically increases our calcitriol and 1,25D level as soon as it’s taken in. It also upregulates the 24- hydroxylase which causes de-activation of vitamin D and it inhibits the natural 1-Alpha- Hydroxylase or CYP27 so it eliminates the production of normal vitamin D through our normal mechanism. By activating the 24-hydroxylase it actually decreases our 25 vitamin D levels and one needs to wonder are these big surges in calcitriol physiologically appropriate for our normal hormonal access.

In addition, we know that 1,25 actually greatly stimulates FGF23 which we now identify as a toxic factor in our patients with ongoing chronic kidney disease. We also know that under normal circumstances, calcitriol has very little effect on phosphate absorption in the GI tract. However, at these high levels and in people with kidney disease, the calcitriol does facilitate more phosphate absorption, which creates a whole other problem that we’re trying to deal with in our patients. In addition, it facilitates calcium absorption and hypercalcemia.

So, in terms of looking at therapies for secondary hyperparathyroidism in stage 3 and 4, nutritional D vs. Active D. So nutritional D probably is more physiologic where active D is a pharmacologic approach. Nutritional D becomes less effective or ineffective as CKD advances, where we know that active D remains effective. We do know that nutritional D is relatively safe and it’s very difficult to create vitamin D toxicity in these patients, and in fact, you need levels well above 100 or 120 to actually see any signs of vitamin D toxicity. However, we do know that active D does put us at a significant increase risk of hypercalcemia and potentially other complications due to calcium overload such as calciphylaxis, which we’re now seeing with increasing frequency in our patient population.

In terms of KDIGO it says that the use of nutritional D is unproven and now KDIGO says at least in CKD stages 3 and 4 it’s not recommended as a primary or for routine use.

Just looking at some of the changes to KDIGO in terms of the 2017 guidelines, we now state in patients not on dialysis the optimal PTH level is not known and we suggest that we start treating patients with progressively increasing parathyroid hormone levels and our therapies should be looking for modifiable factors such as treating hyperphosphatemia, hypocalcemia, and vitamin D deficiency. They suggest that calcitriol and vitamin D analogs not be routinely used. It’s reasonable to reserve the use of these active vitamin D analogs when patients start developing progressive hyperparathyroidism or it’s trending upwards. And again, unlike end stage dialysis patients, we really don’t have what is the ideal thing. So really, it depends on our own clinical judgement.

Some of the rationale for the update was really based on two actually fairly nice and well done studies, one called PRIMO and the other called OPERA, where they actually treated patients with CKD with active vitamin D compounds and they were looking for second, for real hard endpoints, such as in the PRIMO study left ventricular mass. What we ended up seeing is that we really did not get a beneficial effect in left ventricular mass in the PRIMO study but we saw that hypercalcemia actually occurred in 23 or 22.6% of the patients compared to less than 1% of the patients receiving placebo.

Again, the OPERA study, again looking at active vitamin D also did not see much change in the primary endpoint but also saw an incidence of 43% of hypercalcemia compared to 3% in the placebo. So clearly, these studies in the CKD population have been shown to increase the risk of hypercalcemia and the potential complications.

In terms of the calcifediol extended release or Rayaldee it is mentioned by KDIGO as a novel vitamin D prohormone that increases 25 and 1,25 vitamin D levels and does lower PTH. However they note that we have no outcome data so therefore no recommendation has been made.

So just a little summary here about Rayaldee or extended release calcifediol, it appears to be physiologic. I’ll show you some data but it appears to be effective and it appears to be safe in patients that have vitamin D insufficiency, which has been identified as patients with levels less than 30.

So right here is our randomized phase 3 studies. We had 2 identical studies that went simultaneously that we randomized patients to either get the Rayaldee or placebo and the primary endpoint was after the first 26 weeks of the study and like every other primary endpoint for treating hyperparathyroidism, it was a decrease of Parathyroid hormone of 30%. I’m not sure if any of you know that that’s totally arbitrary. It was actually decided by a group of people and I was in the room sitting here in Chicago about 25 year ago when we were looking at studies and we just pulled it out of a hat; and that’s become the guideline that the FDA now holds the bar to. So I find that rather interesting but I think you should know that in the back of your mind that there is no real science or proof or rationale for this 30% was actually somewhat arbitrary. And then we were looking at the primary endpoint during the weeks of 20, through 20, 22, 24, and 26.

We had 83% of subjects complete the study through week 26, and again this is randomized 2 to 1. Two to get active drug and one for placebo.

We also had an open label extension study so after the 26 weeks those who were getting the Rayaldee or calcifediol continued on it and those that were getting placebo were then started on it. And again this had a single titration point starting at 30 and going up to 60 micrograms. Again here we see about 70% of the patients were entered the open label extension study and 60% of all the patients completed the study out to 1 year.

Shown here are the baseline data for the patients. As you can see the mean age is about 65 years. It was pretty equally distributed between men and women. About ⅔ were Caucasian and about ⅓ were African American. About 20% were Hispanic and as you can see it was fairly equally distributed in terms of stage 3 and 4 CKD with a mean eGFR of about 30. Parathyroid hormone levels again about what we see just under 150. Calcium phosphate normal and vitamin D was actually a little bit under 20 as patients were randomized into this study.

This is looking at the % of subjects who achieved vitamin D levels greater than 30 during the phase of the study and as you can see that greater than 80% of the patients received vitamin D levels greater than 30 during the course of the study compared to just a nominal couple in those who were receiving placebo.

This right here is looking at the changes of vitamin D levels during the course of the study. Again, this first part is the randomized placebo active therapy then again at week 12. You can see that vitamin D levels came up very nicely to about 70 at the end of 26 weeks and going out to a year they remained relatively stable once they achieved this level to just being under 80. And again obviously those who were on placebo had no real change in their vitamin D and they basically, after 26 weeks, got essentially to where the patients who were getting the drug for the full year.

This right here are the patients who achieved 30% reduction in PTH in the 2 trials. And as you can see greater than 30% of the patients did receive a 30% reduction in PTH compared to those who were getting just the placebo during the trial where it was much less than 10%.

This right here is looking at the time frame in terms of the decreases in PTH, again we started at just under 150 and there was a nice progressive decrease in Parathyroid hormone and not surprisingly those that were receiving the placebo had a tendency to have the PTH increase over the 6 months.

This is looking at the open label extension study where again PTH levels stayed fairly consistent maybe a little bit of a drop after a year but came down real nicely in the patients who were on placebo then given active drug for the second 6 months.

This right here is looking at serum calcium concentrations and as you can see compared to placebo there really is not much change either during the double blind study, maybe a slight increase here, but this level here is about 9.25 and it still stayed less than 9.5. And again through the extension study so getting it out to a year there was very little increase in the calcium concentration in these patients.

This right here is actually looking at the mean calcium change. In the Rayaldee it was 0.2 mg/dL compared to placebo 0.1. Again because of the number of patients that was statistically significant but really a pretty minor change. Basically, very few patients needed a dose reduction and the subjects who got calcium greater than 10.5 was also very small and interestingly it also occurred in a couple of patients getting placebo.

Looking at serum phosphate, again similar, there’s essentially no increase in the serum phosphate going out for a year.

Again, change in serum phosphate was 0.2 in the Rayaldee compared to 0.1 in the placebo. Again, very little effect on dose reduction and patients who got phosphates greater than 4.5 was exactly the same between the two groups. So essentially demonstrating no change in the serum phosphate concentration.

So this is just to summarize here that Rayaldee does seem to be physiological, it does require activation in vivo. Activation is controlled by the body so it is actually controlled by our CYP450 enzymes both for activation and inactivation of it. We have a gradual predictable increase or effect on the 25 and 1,25 levels. We get clinically meaningful reductions in Parathyroid hormone. Minimal effects on calcium phosphorus and actually also on FGF23.

This right here is just looking at the data during the study comparing the patients with CKD stage 3 and CKD stage 4 getting placebo or drug. And as you can see there’s essentially no difference in terms of changes in vitamin D concentrations whether patients had CKD stage 3 or 4.

This here is looking at 1,25 levels, this is not absolute levels this is percent increase. This was the baseline and we had about a 40% increase in the first 12 weeks and about a 50% increase in 1,25 levels at the end of 6 months. And again no difference between patients who had CKD stage 3 and 4 in terms of increasing 125 concentrations.

This right here is looking at Parathyroid hormone decrease during the course of the study and again as shown earlier we did have some increase of Parathyroid hormone especially in patients with CKD stage 4 at 12 and 26 weeks. Not as great of an increase in those with CKD stage 3 which again is not surprising considering the severity of their disease. But the decrease in Parathyroid hormone was pretty comparable whether the patients had CKD stage 3 or 4.

So basically PTH lowering as a percent of baseline was unaffected by CKD stage and it raises the 25 levels that are able to lower the parathyroid hormone concentration.

So right here is a sub analysis that we just published this last month it came out. Looking at stratifying patients based on their vitamin D concentrations and when we saw decreases in parathyroid hormone, and again you can see we needed higher 25 levels in order to get a decrease in our parathyroid hormone concentration.

This right here is again looking at this and help us kind of stratify where we are but it wasn’t until we had vitamin D levels of about 50 did we really see significant decreases, this is quintile 3 here, in the parathyroid hormone concentrations. So again it’s the comments Charlie made and I made earlier, we have to think, what is an appropriate 25 D level in these patients with chronic kidney disease.

Well this right here is from a study we published several years ago where we first suggested this concept and what we did here is we looked at some 30,000 patients that were being cared for in the primary care office that had nothing to do with nephrologist. If they were seeing a nephrologist, they were excluded from our analysis. And what we ended up finding is based on the stage of CKD there’s a relationship, and again we know, the truth is, the way we came out with normal vitamin D levels is when we got maximum suppression of PTH, in your normal individual that usually occurs with vitamin D levels around 30. So as we have progressive CKD we actually demonstrated that we needed higher vitamin D levels to have that normal physiological feedback mechanism between 25D and parathyroid hormone. We demonstrated this here in terms of these patients out in the real world.

And right here we actually looked at was there an effect on these vitamin D levels in terms of their calcium and phosphorus. So the incidence of hypercalcemia was actually consistent across all CKD rates and had nothing to do with the vitamin D level. So patients with higher vitamin D levels did not have a higher incidence of hypercalcemia. What we did see is that hyperphosphatemia was increased with worsening chronic kidney disease, which wasn’t surprising but again the vitamin D concentration had no impact on the serum phosphate concentration. So again, similar to the findings we got in our proactive study giving Rayaldee we also see in a population based community study looking at the relationship between vitamin D, parathyroid hormone, calcium, and phosphorus.

So in terms of Rayaldee and its mechanisms of action in people who have appropriate or adequate kidney function, what we do is we have the extended release calcifediol which is absorbed and it slowly increases the 25D concentration. It then goes to the kidney where it’s activated predominantly by CYP27B to get the 1,25. Now this activation is normally regulated so we have substances such as parathyroid hormone that upregulates the CYP27 and we have FGF23 that down-regulates the CYP27 as well as 125 down-regulates the CYP27.

So we’re actually maintaining this normal hormonal balance by giving this drug as opposed to giving calcitriol or paricalcitol where that balance and that physiology is totally over rowed. We also know that we have as I mentioned 1-Alpha- Hydroxylase available in other tissues, we don’t know what extent when we give Rayaldee do we have extra renal activation to the 1,25 vitamin D. So this gradual increase in 125 then goes to the parathyroid gland and causes our down regulation.

So in terms of dosage and administration, this is based on our phase 3 study, is that the recommended initial dose is 30 mcg. We recommend that the serum calcium be normal or be less than 9.8.

The recommendation is that we can monitor them in 3 months. In 3 months check calcium phosphorus, vitamin D, and parathyroid hormone before changing a dose. If the parathyroid hormone levels are still above where you want to achieve you can increase the dose to 60 mcg. I didn’t mention that the vitamin D had to be less than 30. Now, this is not part of the package insert but I think this is where we have our clinical judgement. We’re trying to treat the PTH. This is a hormonal axis the same way you get thyroid hormone and you look at TSH. We have to look at PTH as the hormonal counterpart or the pre hormone for 1,25 or calcitriol. But again we want the calcium to be less than 9.8, the phosphorus again is recommended less than 5.5 and we do want to avoid toxicity so we want the vitamin D level to be less than 100.

And then after 3 months you can continue monitoring them every 3, 6, or 12 months to achieve the vitamin D, calcium, PTH levels that you want and maintain your dose where you want it. Again we want to keep the calcium normal, the phosphorus less than 5.5 and the vitamin D level somewhere between 30 and 100. But again I think this level depends at where the parathyroid hormone is and where you want to keep the parathyroid hormone level at. Again there’s a warning and we can have a discussion about that because we don’t want the parathyroid hormone to be persistently, abnormally low because of the potential of what some people are concerned about: low turnover bone disease. The other thing is that we want to be careful about the risk of hypercalcemia or if the vitamin D level gets greater than 100.

So in terms of the clinical trials, what about adverse reactions? These are the adverse reactions that occurred in over 1.4% of the Rayaldee treated patients. Nothing here is overly surprising in terms of some of the problems our patients have. Again not much different than what we saw in the placebo patients. Again a very low incidence.

This is events that occurred in greater than 4% in all subjects. Again, pretty much what we expect to see in our patients and pretty much a mix. And in fact if you go down here, more of these occurred in the placebo patients than in the Rayaldee treated patients.

Again, being a pharmacy sponsored lecture here, I have to go over the important safety information. We have to be concerned about hypercalcemia. It can cause hypercalcemia, severe hypercalcemia may require emergency attention and we should be monitoring and inform the patients. We have to be careful obviously with digitalis toxicity with serum calcium. Again, we can have a discussion about adynamic bone disease in this patient population with too low levels of PTH or too high levels of calcium. The most common adverse reactions were anemia, nasopharyngitis, increased blood creatinine, dyspnea, cough, congestive heart failure, and constipation, but again those were in both groups. We have to be careful if we use other drugs that affect the cytochrome P450 pathway because that will affect the hydroxylation and activation of 25 to 1,25. Calcium should be less than 9.8. And again, we want to monitor 3 months after starting therapy and then at least every 6 to 12 months after that.

So in summary, the first point I want to make is that in chronic kidney disease stages 3 and 4 we do need to achieve levels greater than 50 to significantly decrease parathyroid hormone concentrations. We saw that in the patient database that we looked at in people who weren’t being treated and we saw that it took levels greater than 50 in this prospective study to actually get a significant decrease in parathyroid hormone concentration. That Rayaldee is the first and only FDA approved vitamin D therapy that significantly increases 25 D and decreases parathyroid hormone. That it’s indicated for the treatment of secondary hyperparathyroidism in patients with stage 3 or 4 CKD and vitamin D levels less than 30. It’s not indicated for patients on dialysis right now. The recommended initial dose is 30 mcg once daily. The calcium should be less than 9.8 and we want to monitor at least 3 months after starting therapy. Finally, clinical trials have demonstrated a safety profile of Rayaldee which is very similar to placebo.

So I thank you for your attention and I’ll be very happy to address any of your questions or comments.

Indication and Limitations of Use

Rayaldee^® (calcifediol) extended-release 30 mcg capsules is indicated for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease and serum total 25-hydroxy- vitamin D levels less than 30 ng/mL. Rayaldee is not indicated in patients with stage 5 chronic kidney disease or end-stage renal disease on dialysis.

Important Safety Information

• Hypercalcemia: Excessive administration of vitamin D compounds, including Rayaldee, can cause hypercalcemia and hypercalciuria. Severe hypercalcemia due to substantial overdosage of vitamin D and its metabolites may require emergency attention. Patients should be informed about the symptoms of elevated calcium.

• Digitalis toxicity: Potentiated by hypercalcemia of any cause. Monitor serum calcium and signs and symptoms of digitalis toxicity more frequently when initiating or adjusting the dose of Rayaldee.

• Adynamic Bone Disease: Monitor for abnormally low levels of intact parathyroid hormone (iPTH) levels when using Rayaldee, and adjust dose if needed.

• The most common adverse reactions (≥3% and more frequent than placebo) were anemia,

  nasopharyngitis, increased blood creatinine, dyspnea, cough, congestive heart failure and constipation.

• Care should be taken while dosing Rayaldee with cytochrome P450 inhibitors, thiazides, cholestyramine or drugs stimulating microsomal hydroxylation due to the potential for drug interactions.

• Serum calcium should be below 9.8 mg/dL before initiating treatment.

• Monitor serum calcium, phosphorus, 25-hydroxyvitamin D and iPTH 3 months after starting therapy or changing dose.

Please visit Rayaldee.com for full Prescribing Information and additional information about Rayaldee.

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