Thomas Morrow, MD

Imagine our body as a symphony and our organs as the performers and instruments. Each instrument plays a key role in the entire musical experience as each individual sound from each instrument comes into play at precisely the right time and at the right frequency and beat. Each performer listens for the other instruments to queue their contribution.

The kidneys may not be the concertmasters of the physiological orchestra, but they are certainly major instruments. They do much more than simply filter blood. Healthy, well-functioning kidneys are inextricably connected with the parathyroid gland, bones, and cardiovascular system. The structure and function of the kidneys can be measured with simple imaging, blood, and urine tests. As the kidneys lose function, primarily due to hypertension and diabetes, the diagnosis of chronic kidney disease (CKD) can be made from these tests. If CKD worsens to the point that life is threatened, it becomes end stage renal disease (ESRD). Dialysis or kidney transplantation are the only treatments for ESRD. Currently, about 460,000 Americans with ESRD are receiving dialysis. As the prevalence of diabetes—especially type 2 diabetes—continues to rise, the number of Americans with CKD or ESRD needing dialysis is also expected to increase.

The rapid increase in the incidence and prevalence of diabetes, CKD, and ESRD has emerged as a large (and potentially lucrative) target for pharmaceutical companies. They are plowing millions of research-and-development dollars into elucidating the intricacies of the renal system and its pathology.

Step-by-step

CKD and ESRD also go hand in hand with a secondary condition called mineral and bone metabolism disorder, or CKD–MBD. CKD–MBD is a triad of biochemical, bone, and vascular abnormalities: abnormal serum levels of calcium, phosphorus, vitamin D, and parathyroid hormone (PTH); abnormal bone turnover and mineralization, which affect growth and strength; and calcification of soft tissue, especially blood vessels (particularly in the heart).

As CKD–MBD progresses, the severity and number of these abnormalities generally increase to the point that normal homeostatic processes cannot keep up and problems ensue.

The processes involved are so complex that the understanding of the sequence in which they occur is incomplete and the explanations often speculative.

But in broad brushstrokes, as the nephrons of the kidney lose function, calcium levels start to drop, in part because of a reduction in gastrointestinal absorption. Phosphate rises as the kidney decreases secretion, which, in turn, stimulates the parathyroid gland to produce more PTH to push the kidney into trying to rid the body of phosphate. That causes a cascade of events that winds up affecting vitamin D and bone metabolism. The overall condition causes a feedback loop that creates a condition called secondary hyperparathyroidism.

Historically, treatments followed a step-by-step approach. The first step is to reduce phosphate load by restricting dietary intake of phosphate, which is present in meat, beans, colas, beer, and nuts. Sometimes oral phosphate binders are prescribed to allow phosphate to pass through the intestine unabsorbed. The next step is calcium supplements and vitamin D to try to maintain normal calcium level.

But when these steps fail, it is time to try to reduce PTH directly. One way to do that is to surgically remove or ablate the parathyroid glands.

Another approach is to use a class of drugs called calcimimetics, which reduce PTH by binding to and modifying the calcium-sensing receptor in the parathyroid glands.

The first calcimimetic, cinacalcet tablets, sold in North America as Sensipar, was approved more than a decade ago and has remained the only drug in this category. It is taken in an escalating dose schedule until an acceptable level of PTH is reached. One challenge is relatively poor adherence. In some studies, half of all patients stop taking the drug over the long run.

Thomas Morrow, MD

In February, the FDA granted Amgen approval for etelcalcetide (Parsabiv). Parsabiv acts on the same receptor as cinacalcet and is indicated for secondary hyperparathyroidism in adult patients with CKD on dialysis.

Because it is given intravenously at the end of dialysis, Parsabiv could be the answer to the adherence problems posed by cinacalcet. Most patients are pretty adherent to dialysis. One study found that people missed only 7.1 episodes of dialysis per patient-year, which isn’t perfect but it’s certainly better than adherence to self-administered drugs.

The efficacy and safety of Parsabiv was studied in two 26-week, randomized, double-blind, placebo-controlled studies in 1,023 patients. The primary outcome measure was the proportion of patients with a greater than 30% reduction in PTH levels from baseline. The other outcome measures were the proportion of patients with a mean PTH of less than or equal to 300 pg/mL, percent change from baseline PTH, and calcium and phosphate levels. In both studies, a significantly higher proportion of patients treated with Parsabiv achieved reductions in PTH levels as well as calcium and phosphate.

Better adherence, better control of CKD–MBD caused by secondary hyperparathyroidism—who can argue with that? Assuming the cost of Parsabiv and cinacalcet is about the same, it is likely to be a wash—at least initially.

But the patents for cinacalcet end in mid-2018. The generic products will likely—if not right away, eventually—be much lower in cost than for Parsabiv.

Although CMS sets reimbursement for dialysis patients covered by Medicare, commercial plans pay a significant part of the total cost of dialysis. Dialysis centers have historically maintained enormous pricing power over health plans, often charging multiples of the average sales price (ASP) for dialysis drugs. Parsabiv, because it will be administered as part of dialysis, will probably be priced at a huge markup for commercial plans.

No head-to-head trials were done between these two Amgen products. What’s more, endpoints were tweaked to be just dissimilar enough to make direct comparison of the outcomes for cinacalcet and Parsabiv virtually impossible. My spidey sense analysis of the labels for both drugs suggests to me that the results are similar. But so far, my spidey sense does not constitute proof.

Major markup

Nephrologists will need to decide what is best. The calcimimetics are expensive. The standard dose of orally branded cinacalcet starts at about $900 per month retail. If the maximum dose is needed, the cost can triple, so the annual bill is often more than $30,000. Payers are hoping that the generics will be priced much lower. Meanwhile, facility-infused drugs are likely to be marked up by multiples of the ASP.

On the bright side, the approval of Parsabiv and the cinacalcet generics present opportunities for managing this category of drugs in a smart, cost-effective way.

But Parsabiv is also an example of how lack of head-to-head trials, site-of-care differences, and minor adjustments can help pharmaceutical companies maintain sale of high-priced drugs even with generic competition. Health plans are well advised to keep a diligent watch.

Thomas Morrow, MD, is a retired physician executive and part-time consultant. He has been the founding medical director of five HMOs and a disease management company, a medical director at Genentech, and president of the National Association of Managed Care Physicians. You can contact him at thomasmorrowmd@hotmail.com.