The Changing Clinical Landscape of Anemia Management in Patients With CKD: An Update From San Diego Presentation 1

Transcription

1 Presentation 1 The following is a transcript from a web-based CME-certified multimedia activity. Interactivity applies only when viewing the activity online. This activity is supported by educational grants from Amgen Inc. and Affymax, Inc. and Takeda Pharmaceuticals International, Inc. Slide 1 Dr. Germain: Hello, this is Dr. Michael Germain from Tufts University School of Medicine. Welcome to this educational activity on recent and late-breaking data related to the management of anemia in patients with chronic kidney disease. This activity comprises two separate presentations. 1

2 Presentation 1 Slide 2 Dr. Germain: The slides, transcript, audio, Practice Aids, and other activity features are available for download for easy access anytime, anywhere. To share your thoughts, ask questions, or start a conversation with your peers, click the discussion tab below. After completing the activity, access the post-test and evaluation forms by clicking on the red Credit button to the right. 2

3 Presentation 1 Slide 3 Dr. Germain: Since the bundle payment system was implemented with CMS for Medicare patients in dialysis units, and the changes in the label for the ESAs, we ve seen a significant decline in hemoglobin levels in the dialysis population. Along with that, there s been a decrease in erythropoietin ESA doses and an increase in iron utilization and levels of iron markers, such as ferritin and percent saturation. There s also been a troubling significant increase in transfusion rates. 3

4 Presentation 1 Slide 4 4

5 Presentation 1 Slide 5 DOPPS: Dialysis Outcomes and Practice Patterns Study; ESA: erythropoiesis-stimulating agent; HD: hemodialysis. 1. Fuller DS et al. ASN Kidney Week Abstract SA-OR016. Dr. Germain: The DOPPS data, which collects data prospectively from dialysis units around the world, in this particular study look at the United States dialysis units that they follow, and they show between September 2010 and September 2011 there s been a decline in hemoglobin levels in this population. Even hemoglobin levels between 9 and 10 have increased. Associated with that is a steady decline in erythropoietin dosing, as well as an increase in iron dosing and utilization. 5

6 Presentation 1 Slide 6 The best answer is: e. a., b., and c. 6

7 Presentation 1 Slide 7 REF: reference. 1. Sibbel S et al. ASN Kidney Week Abstract FR-PO228. Dr. Germain: The USRDS [shows] that the transfusions rates in 2011 increased as much as between 20[%] and 30%. That s been associated with a decline in the ESA doses and hemoglobin levels. Since there s always a bell-shaped curve, and there s a lot of hemoglobin variability and cycling in this population, there are going to be people with hemoglobins of less than 8 even that would end up triggering transfusions. And, in fact, this data confirms that. Now, the factors that are associated with transfusion rates are lower hemoglobin levels, higher serum ferritin levels, greater IV iron utilizations. And so this calls into question whether high doses of iron alone are effective at preventing transfusions in the absence of effective doses of ESAs. And also, of course, the risk of iron overload is a major concern. 7

8 Presentation 1 Slide 8 TSAT: transferrin saturation. 1. Robinson BM et al. ASN Kidney Week Abstract TH-OR094. Dr. Germain: Since the changes in the bundle payment system, the use of IV iron rose by 20%, and the serum ferritin levels rose to a mean of almost 700. More iron [is] being given on a yearly basis to these patients than you would predict they d be able to utilize in terms of red cell production. There s also recent data showing that there s evidence of increased iron in the liver and spleen from MRI and other sorts of studies. And the concern is this will lead to actual toxicity in the patients. And the DOPPS data here suggests that even though people are targeting percent saturations of over 30%, up to 50%, increasing iron doses do not seem to have that much of an impact on TSATs once they re above 30. 8

9 Presentation 1 But the ferritin levels do continue to increase, again, suggesting perhaps the iron is not going to be used for red cell production, but instead gets deposited in tissue. 9

10 Presentation 1 Slide 9 EPO: epoetin alfa; ESRD: end-stage renal disease; USRDS: United States Renal Data System. 1. Bond TC et al. ASN Kidney Week Abstract TH-PO822. Dr. Germain: The USRDS data really does support what s being found in the DOPPS data, that over this time period there s been a decline in erythropoietin dosing. With that, a significant decline in hemoglobin, but an increase in amounts of iron given, and increased serum ferritins and percent saturation levels. 10

11 Presentation 1 Slide 10 PPS: prospective payment plan. 1. Burkart JM et al. ASN Kidney Week Abstract TH-PO795. Dr. Germain: The STEPPS study is very similar to the DOPPS study, except in small dialysis units in the United States. Prospective data gives us some reassurance that this is going to be accurate information that we re receiving. These dialysis units already markedly decreased their ESA use prior to implementation of the bundled system. And this has resulted in a decline in hemoglobin even before the bundle payment system was going into effect. And this resulted in increased transfusions, as we saw in the USRDS data. So really, all these studies the DOPPS, USRDS, and now this STEPPS study are really confirming the same findings. 11

12 Presentation 1 Slide 11 The best answer is: b. Use of the SAM algorithm resulted in a significantly higher proportion of patients achieving target Hb levels compared with control protocols. 12

13 Presentation 1 Slide 12 MCAMS: Mayo Clinic Anemia Management System. 1. McCarthy JT et al. ASN Kidney Week Abstract FR-PO234. Dr. Germain: What we ve seen over the past few years is the development of some very innovative algorithms for management of ESAs. And before this time, the algorithms were what we call expert systems. So it was basically the doctor and the package insert guiding how to dose erythropoietin. And it was more or less an intuitive approach; if the hemoglobin was low, you would increase the erythropoietin dose by a certain percentage. If it was too high, you would decrease the erythropoietin dose by a certain percentage. And so these newer algorithms take the approach of developing a biologic model of erythropoiesis and an engineering approach to control. And these are very robust systems that achieve very good control, but they may be counterintuitive to the usual way that doctors think about managing drug dosing. 13

14 Presentation 1 The Mayo Clinic study here looked at pre-implementation of their new protocol and then after. So this is not a randomized controlled trial, but they do show that the hemoglobins were more stable. There was less hemoglobin variability. 14

15 Presentation 1 Slide 13 SAM: Smart Anemia Manager. 1. Gaweda AE et al. ASN Kidney Week Abstract FR-PO233. Dr. Germain: The Smart Anemia Management system was developed with an engineering approach. And here they ve actually done a controlled trial, comparing the standard approach to their SAM protocol. There was a statistically significant better achievement of target hemoglobin in the SAM protocol with less people out of range. So again, this is a very promising approach in a randomized controlled trial of 62 patients. 15

16 Presentation 1 Slide 14 AMP: anemia management protocol. 1. Germain M et al. ASN Kidney Week Abstract FR-PO235. Dr. Germain: The approach we ve taken in Springfield, together with the engineering department at the University of Massachusetts, is, again, an engineering approach. And what we had done is look at data we had from a prior study in 44 patients who we prospectively collected data on over close to 2 years. And we were measuring the hemoglobin three times a week in those people, and so we had very robust data to develop our model on. And what we found was, one, that there are a number of different models of responsiveness that patients have, and that we can then plug patients into their EPO responsiveness and use that to better design an algorithm for managing their anemia. 16

17 Presentation 1 And what you see here is gain, and gain is how rapidly the hemoglobin will go up when they get a dose of erythropoietin. And gain generally does correlate with responsiveness, so the people who have the highest gain tended to have the lowest doses of erythropoietin, and the people who required high doses of erythropoietin generally had a slow gain. But it s not always the case. So if you look at the high-gain people, you can see there s a pretty wide range of responsiveness in terms of the dose of erythropoietin needed. So really, you need both the responsiveness and the gain to design a robust system for anemia control in dialysis patients. 17

18 Presentation 1 Slide 15 Dr. Germain: The prospective payment system, in addition to the changes in the package insert and the safety concerns, have dramatically changed anemia management in dialysis patients. The serum ferritin levels have dramatically increased, that raise a concern of iron overload and toxicity in our patients. Some newer engineering control models hold promise for better management of our patients and erythropoiesis dosing that can avoid hemoglobin cycling and maintain patients in target range more of the time. This will allow perhaps more efficient ESA dosing and iron dosing, and perhaps lead to decreased transfusion rates. 18

19 Slide 1 Narrator: In the second presentation, Dr. Michael Germain continues his discussion of anemia management in patients with chronic kidney disease by reviewing late-breaking data on current and emerging therapies. 19

20 Slide 2 EPO: epoetin alfa; hscrp: high-sensitivity C-reactive protein. 1. Levin NW et al. ASN Kidney Week Abstract TH-PO823. Dr. Germain: Peginesatide is a new ESA that has been approved for use in dialysis patients. And it is a long-acting ESA, a small molecule that hits that erythropoietin receptor, so it s different than erythropoietin. The phase 3 EMERALD 1 and EMERALD 2 trials compared using peginesatide monthly to erythropoietin, generally three times a week. This showed that the efficacy and safety is very consistent and similar between the current ESAs or erythropoietin and peginesatide. And this was true when you did a subanalysis of different patient groups based on age and race and other factors, including the CRP and presence or absence of congestive heart failure. 20

21 Slide 3 The best answer is: a. Patients treated with peginesatide required significantly lower iron doses to maintain iron stores compared with those who were treated with epoetin alfa. 21

22 Slide 4 HD: hemodialysis; Q4W: every 4 weeks; TSAT: transferrin saturation. 1. Provenzano R et al. ASN Kidney Week Abstract TH-OR097. Narrator: In addition, a post-hoc analysis of iron utilization from data pooled from the EMERALD 1 and EMERALD 2 trials was also recently presented. Dr. Germain: EMERALD 1 and EMERALD 2 looked at the iron dosing in the two groups of patients. There was [a] significantly lower dose of iron required in the peginesatide group versus the erythropoietin group. These are pretty modest differences. We re seeing 168 mg per month versus 148 [mg per month] in the peginesatide group. But it was statistically significant. The iron saturation results showed that although both groups started at the same level, there was a greater increase in the percent saturation in the peginesatide group compared to the erythropoietin group. 22

23 It perhaps suggests that there s more efficient utilization of iron in peginesatide versus erythropoietin, and this bears further study. 23

24 Slide 5 PRCA: pure red cell aplasia. 1. Schiller-Moran B et al. ASN Kidney Week Abstract FR-PO Locatelli F et al. ASN Kidney Week Abstract SA-PO Schatz PJ et al. ASN Kidney Week Abstract FR-PO262. Dr. Germain: It took only about 1 or 2 months to really get to stable dosing with peginesatide. In people with high CRPs or a chronic inflammatory state, we know this was associated with worse cardiovascular outcomes from other studies. But there was no difference between the two groups in terms of the subgroup of C-reactive protein they were in. Antibodies against peginesatide is uncommon, 1.2%, and was not associated with allergic reactions. And the antibodies against peginesatide did not cross-react with erythropoietin, so it s unlikely that it would lead to a pure red cell aplasia situation that can occur rarely with erythropoietin. 24

25 Slide 6 The best answer is: b. AKB-6548 significantly increased hemoglobin levels and enhanced iron mobilization. 25

26 Slide 7 CKD: chronic kidney disease. 1. Shalwitz R et al. ASN Kidney Week Abstract FR-OR116. Narrator: Dr. Michael Germain now shifts his attention to recently presented data on emerging therapies for the management of anemia in patients with CKD. Although these agents appear to be promising treatments for the management of anemia in this population, it is important to note that the efficacy, safety, and tolerability of these therapies compared with placebo and/or established ESAs have not yet been confirmed in large (phase 3) randomized, controlled trials. Dr. Germain: There are now two compounds that are being studied actively in humans with chronic kidney disease for management of anemia with the HIF or hypoxia inducible factor stabilizing drugs. And one is AKB And this was a randomized controlled trial that was blinded, and it was 93 patients with stage 3 through 5 CKD not on dialysis randomized to receive placebo or this HIFstabilizing drug. 26

27 There was a very significant increase in hemoglobin in this group, and there were no drug-related serious adverse effects reported, and the drug was generally well tolerated. The HIF stabilizers work through the normal way that the body produces erythropoietin. It responds to hypoxemia and then stimulates production of erythropoietin in the body. It seems to be more efficient with less iron requirements and a decrease in hepcidin, which is an inhibitor of iron mobilization, and hepcidin levels are often very high in people with chronic kidney disease. So these drugs are very promising in that regard. 27

28 Slide 8 BL: baseline. 1. Besarab A et al. ASN Kidney Week Abstract TH-OR096. Dr. Germain: This drug is a different HIF stabilizer. It shows very similar results to the other investigational drug we talked about. And in dialysis patients we are stimulating their native erythropoietin, even though they have very poor kidney function. And they also looked at it in peritoneal dialysis patients receiving oral iron. And in the dialysis patients, they randomized them to receive the drug with either oral iron, IV iron, or no iron. There is a good hemoglobin response in all the groups, and perhaps intravenous iron is not even necessary, or even oral iron, since the patients had a good response and seem to utilize their existing iron stores effectively. 28

29 Slide 9 MOA: mechanism of action; TC: total cholesterol; TIW: three times a week. 1. Jones J et al. ASN Kidney Week Abstract FR-PO257. Dr. Germain: In this study, again, the HIF-stabilizing drug FG-4952 was used in a study of 159 dialysis patients randomized to continuing erythropoietin in those patients versus FG And it looked at both the hemoglobin and the cholesterol in these patients. They found that these were people on stable dosing of erythropoietin with hemoglobins of around 11 in both groups. And the change from baseline was not significant between the two groups. So over this 6- to 19-week period, the hemoglobins remained stable when they were switched to the FG In addition, there was a reduction in cholesterol levels, and there [were] lower plasma erythropoietin levels in the study drug compared to the high doses that occur from the exogenous use of erythropoietin. 29

30 It was also well tolerated and there was no real difference in the adverse event profile compared to the control group. 30

31 Slide 10 PK: pharmacokinetics. 1. Brigandi RA et al. ASN Kidney Week Abstract SA-PO117. Dr. Germain: So this was another HIF stabilizer that was studied in patients with chronic kidney disease. And they studied these people for a month with two different doses of the HIF stabilizer. There was a dose-dependent increase in hemoglobin and iron metabolism biomarkers with increased erythropoietin levels, reticulocyte count, and hemoglobin that was dose dependent with the dose of the study drug given. 31

32 Slide 11 The best answer is: c g/dl. 32

33 Slide 12 ESA: erythropoiesis-stimulating agent; ND: nondialysis; 1. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Dr. Germain: The new KDIGO guidelines mirror the safety concerns that are in the package insert and that have been expressed by the FDA based on the CHOIR and TREAT studies, and also from the studies of the ESAs used in cancer patients, the concern of increase in cancer, especially in people with active cancer and increase in recurrence of cancer. So there are comments on safety concerns in the new KDIGO guidelines, using it with caution, people with malignancy, history of stroke, history of malignancies, and also concerns about targeting too high a hemoglobin level, but also the concern of too low a hemoglobin level in terms of impacting on quality of life and the concern that it may result in increased transfusion rates. 33

34 So I think we just see a reflection here of the concern of the community with both safety and efficacy of the ESAs, both targeting too low or too high a hemoglobin and how we could best individualize for patients the right hemoglobin level to target and to minimize the safety concerns with these agents. 34

35 Slide KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Dr. Germain: I think KDIGO guidelines do reflect the concern over the increased use of iron and the concern that we may be giving our patients too much iron. So they take a more conservative approach, saying to keep the ferritin less than 500, the percent saturation less than 30. All these guidelines suggest aiming for a lower target for iron utilization and assessing if the patient is responding to iron in terms of the hemoglobin. And if not, avoiding continued IV iron use if the person is not responding. 35

36 Slide 14 Dr. Germain: Peginesatide stimulates the erythropoietin receptor and is now available. It allows for monthly dosing and may allow for a modest decrease in iron utilization based on the pivotal phase 3 trials. HIF stabilizers are being studied in CKD patients, and they work by stimulating native erythropoiesis production, even in dialysis patients. This new mechanism of action appears to decrease hepcidin, which allows for more efficient iron utilization. So often the patients need no iron or small doses of oral iron and still get good responses in terms of their hemoglobin and can utilize their existing iron stores. The recently updated KDIGO guidelines for anemia reflect the safety concerns with the ESAs and the concern over excessive use of IV iron and transfusions. 36

37 Slide 15 Narrator: This activity has been jointly sponsored by Penn State College of Medicine and PVI, PeerView Institute for Medical Education. To share your thoughts, ask questions, or start a conversation with your peers, please visit the Discussion Forum by clicking on the "Discussion" tab. 37