Recent FDA Approval of Renvela (sevelamer carbonate): A New Agent for Hyperphosphatemia

Craig B. Langman, MD


December 13, 2007

Editor's Note:

On October 22, 2007, the US Food and Drug Administration (FDA) granted marketing approval to Genzyme for Renvela, a new treatment for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis. Renvela is a next-generation version of Renagel (sevelamer hydrochloride). Left untreated, studies have shown that elevated serum phosphorus levels, or uncontrolled hyperphosphatemia, leads to increased morbidity and mortality, the development of secondary hyperparathyroidism, renal bone disease, calcification of vascular and nonvascular tissues, and cardiovascular disease. Similar to Renagel, Renvela is a calcium-free, metal-free, nonabsorbed phosphate binder. In clinical studies, Renvela and Renagel controlled serum phosphorus equally, but patients on Renvela were more likely to maintain bicarbonate levels within the recommended ranges and had a lower incidence of gastrointestinal (GI) adverse events.

Given the well-known consequences of hyperphosphatemia, early recognition and therapeutic intervention -- even prior to the initiation of dialysis -- are essential to slowing disease progression and improving and maintaining quality of life. And, as such, at the FDA Cardiovascular and Renal Drugs Advisory Committee's meeting on October 16, 2007, the majority of committee members voted to recommend the use of phosphate binders in Stage 4 CKD patients with hyperphosphatemia.[1] Anne G. Le, PharmD, RPh, Editorial Director of Medscape Nephrology, talked with Craig Langman, the Isaac A. Abt, MD, Professor of Kidney Diseases, Feinberg School of Medicine, Northwestern University, Chicago, Illinois and Head of Pediatric Kidney Diseases, Children's Memorial Hospital, in Chicago, Illinois, to discuss the potential benefits and significance of Renvela for CKD patients with hyperphosphatemia.

Medscape: What is the significance of the recent approval of Renvela for dialysis patients?

Dr. Langman: I think that approval for Renvela really is the recognition that there are ways to improve upon an already improved product. The issue with the current product, Renagel, is that some patients complain of some GI side effects, and there may be an acidosis because of the hydrochloride moiety attached to the sevelamer; the new product, Renvela, takes care of that because the carbonate base, as opposed to the hydrochloride base, really takes care of the acidosis and tends to lessen the GI side effects, should they occur. Overall, to me it reflects a continuing commitment by Genzyme to the kidney community to improve upon a perfectly good product.

Medscape: What is the body of evidence that supports the use of Renvela in dialysis patients?

Dr. Langman: There is a recently accepted publication that looks at the cross-over, in a cross-over design, on the efficacy of sevelamer carbonate, Renvela, compared with sevelamer hydrochloride, Renagel. In this study, patients were randomly given first either the carbonate or the hydrochloride form of sevelamer and then, after a 4-week period, switched over; and at relevant time points, biochemistries were obtained. Not only was the efficacy of phosphate binding looked at, but the ability to control parathyroid hormone (PTH), to lower lipids, was also looked at between the 2 compounds. The good news, of course, is that Renvela had equal potency compared with Renagel at phosphate binding, control of calcium phosphorus product, control of PTH, and continued reduction of lipids, so that it appears to have high efficacy equivalent to that of Renagel. From the safety side, we actually saw that there was an improvement in the serum bicarbonate value, and the GI side effects were noticeably less with Renvela compared with the Renagel, so that's probably the major trial that supported the use of Renvela in dialysis patients.

Medscape: Are the data for Renagel transferable to Renvela because both are sevelamer-based phosphate binders?

Dr. Langman: I would have to say yes completely. The cross-over design to me clearly demonstrates that the ability to control hyperphosphatemia, hyperparathyroidism, maintain normal calcium phosphorus product, and the continued control of the lipid effect is the same we see with Renagel. That is, rather than control the lipid effect, to have the lipid effect with the lowering effect of Renagel, all translates to me that these are completely equivalent compounds, with the added benefit of the carbonate moiety in Renvela.

Medscape: Does Renvela improve upon Renagel, and what are the benefits for patients on dialysis?

Dr. Langman: I think the answer is yes, for several reasons. One is there will be multiple dose forms of Renvela, not only in tablet, but also in a powder that will be able to be mixed with a liquid and then have taken as an emulsion -- so, alternative dose forms. Second, the ability to lessen or eliminate acidosis with the carbonate moiety of Renvela compared with the hydrochloride moiety in Renagel is a big benefit and, if the clinical trial and cross-over design is held out in larger use, then it looks like the GI side effects won't even be an issue at all with Renvela.

Medscape: Which CKD patients derive the greatest benefit from Renvela?

Dr. Langman: It's very important in our CKD 3-4 population, or CKD 5 before dialysis, to have a phosphate binder that doesn't have the possibility of causing an acidosis; even if there is one from Renagel in a small number of patients, since dialysis patients get dialysis, the extra acid can be removed pretty easily, but the patients in CKD 3-4 and before dialysis 5 don't have that capacity for dialysis, so they're sort of stuck with the acidosis. And now, with Renvela, that actually is not present. There is a small unpublished study that looks at that and actually shows that even in these patients, serum bicarbonate values are increased compared with the use of Renagel, so it looks like that effect carries forth in this population. So, because of the alternative dose forms that will be available as well as the absence of acidosis and presumably any GI side effects, this is a great treatment for CKD 3-4 patients.

Medscape: How does the extent of phosphorus lowering seen with Renvela correlate with the recommendations put forth in the KDOQI guidelines?

Dr. Langman: The ability to control hyperphosphatemia is exactly the same with Renvela; clinical studies are designed to use current KDOQI guidelines recommendations, and it appears that Renvela is absolutely as efficacious as Renagel in achieving KDOQI target values for hyperphosphatemia.

Medscape: Is Renvela being studied in predialysis patients with earlier stages of CKD?

Dr. Langman: Yes, I mentioned that I know of one trial of approximately 42 patients with varying CKD -- late 3, through 4 and nondialytic 5 -- looking at, after a washout period, the ability in a cross-over design of either Renagel or sevelamer to control hyperphosphatemia, hyperparathyroidism, etc. The early results I have seen from that trial are completely encouraging for the use of Renvela in that population.

Medscape: How will the availability of Renvela impact clinical practice and binder selection among nephrologists?

Dr. Langman: I think that if there was any hesitation in the use of Renagel because of the possibility of that acidosis from the hydrochloride moiety and the possibility of having some GI upset with the use of Renagel, then there should now be no hesitation in prescribing Renvela because we now have a carbonate moiety that eliminates the acidosis, and it appears that there are less GI, really no GI side effects with Renvela compared with Renagel. So, I think as a practicing nephrologist, there should be really now no hesitation in its use as a phosphate binder.

Medscape: What value ultimately will alternative formulations of Renvela have for hemodialysis patients?

Dr. Langman: Dialysis patients often complain of that pill burden -- how many pills during a day and at various times during the day they have to swallow as a dialysis patient. Having an alternative formulation in the form of a powder that can be taken with liquid, to me, provides a distinct advantage for dietary phosphate binding because it can actually now become part of the meal conceptually, without having to think of it as an additional pill burden, so I think it has a very high patient appeal. That suggests there might be even enhanced compliance with all of our prescribed medication for this.

Medscape: How would you characterize the need for the development of new drugs to treat patients with CKD?

Dr. Langman: I think it's incredibly high. First of all, we have even newer data that were published last week in the Journal of the American Medical Association, revealing that now 13% to 15% of the entire US population has chronic kidney disease, and that figure is revised upward from previous levels. So the disease is not going away. In fact, it's occurring more frequently. And in addition, at least if you look at how we've been able to control kidney bone disease, which we now call chronic kidney disease/mineral bone disorder or CKD/MBD, over the last 20 to 25 years, we've really not made many advances in the control of what we used to call renal osteodystrophy and are now calling CKD/MBD. Patients still fracture, have musculoskeletal complaints, and calcify their vessels, so I would argue that this is an incredibly important area for drug development.

Medscape: What is your impression of Genzyme's efforts to find new solutions for patients with kidney disease?

Dr. Langman: Well, I have to view it as very high, because they are coming up with new forms of an already effective drug to actually better improve patient care within CKD/MBD, so I am actually kind of happy that this and other things in development that I'm not even aware of will be benefiting patients with CKD now and in the future.

Medscape: How do you perceive Genzyme's role in the renal community?

Dr. Langman: I've been thinking about this and I think that it really reflects a real continuum of care. They are now interested in moving control of CKD/MBD back into CKD 3-4 and nondialytic 5 stage. They are heavily invested, obviously, in the care of the dialysis patient, and they also are venturing into the care of the transplant patient. We don't often think about that, but Genzyme makes one of the most potent antirejection drugs, called ATG or antithymocyte globulin. It's used broadly in the transplant community, and I would guess that they are moving into that area because more and more patients are having kidney transplants. So I think that from the entire spectrum of kidney disease, before dialysis, during dialysis, and even after with transplant, this is a company that seems invested in the population.


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