About 15% of adults in the United States (US) have chronic kidney disease (CKD), and 1 in 3 US adults are at risk for CKD. Nearly 560,000 US adults are on dialysis. Minorities are disproportionately affected by CKD and end-stage renal disease (ESRD); in comparison to White Americans, Black Americans are 4 times more likely to develop kidney failure and Hispanic Americans are 1.3 times more likely to require dialysis.
As CKD progresses, phosphate excretion decreases, and phosphate retention occurs. Phosphate binders, which reduce the quantity of absorbable phosphate by binding to dietary phosphate to create insoluble compounds, are currently the only FDA-approved treatment for hyperphosphatemia and are prescribed to ~80% of U.S. patients on dialysis. Although phosphate binders are widely used, a large proportion of patients are unable to consistently achieve and maintain phosphate levels ?5.5mg/dL. 77% of dialysis patients on binders are unable to maintain levels ?5.5mg/dL over a 6-month period. An even greater proportion of patients on dialysis are unable to achieve more normal phosphate levels. Modern diets are high in phosphate, primarily from phosphate food additives, which makes it challenging for patients to take a sufficient amount of binders to consistently maintain target phosphate levels.
Current phosphorus management strategies are insufficient to achieve and maintain phosphate levels ?5.5mg/dL (or more normal levels) for the majority of patients. Phosphate binders have an inefficient mechanism of action that potentially explains the continuing clinical challenge of consistently achieving and maintaining target serum phosphorus concentrations. Instead of directly acting on phosphate absorption pathways, either the secondary transcellular pathway or the primary paracellular pathway, phosphate binders ‘scavenge’ particles of dietary phosphate in the gastrointestinal (GI) tract. To ‘scavenge’ and bind the phosphorus before it is absorbed, the binders must be in the gut at the same time as the dietary phosphorus. Thus, most patients are instructed to take phosphate binders with every meal and snack, resulting in a high dosing frequency. Moreover, in vivo, each pill can only bind a discrete amount of phosphorus. Thus, patients typically require many large pills every time they eat in an effort to bind a meaningful amount of dietary phosphate. Studies have shown that, on average, patients on dialysis are prescribed 10.8 phosphate binder pills/day, accounting for approximately 50% of their total daily pill burden.
Furthermore, as a class, phosphate binders have been associated with clinically significant GI tolerability issues, including abdominal pain, constipation, diarrhea, nausea, and vomiting. In clinical trials with phosphate binders, between 14% and 27% of patients discontinued treatment due to adverse reactions, with GI events being the most common reason. Furthermore, rarely, serious cases of GI obstruction, some requiring surgery or hospitalization, were identified in post-marketing reports of patients taking lanthanum carbonate. Calcium-based phosphate binders can lead to calcium loading and contribute to vascular calcification, potentially exacerbating negative clinical outcomes. These factors likely contribute to the inability of the majority of dialysis patients to achieve and maintain serum phosphorus concentrations of ?5.5mg/dL, indicating an opportunity for therapeutic innovations.
Why new treatments are desperately needed
Systemic phosphate homeostasis is maintained primarily via urinary excretion. As chronic kidney disease (CKD) progresses, renal function declines, leading to phosphate retention. Elevated serum phosphorus concentrations, or hyperphosphatemia, are seen in most patients with advanced CKD and those on dialysis. The goal of hyperphosphatemia treatment should be to reduce serum phosphorus to ?5.5mg/dL (or closer to normal levels) and alleviate negative clinical outcomes for patients with CKD, including associated CV mortality, and reduce negative impact on patient quality of life (QoL).
Elevated phosphate is associated with increased risk of CV events. Phosphate retention is also the trigger for increases in fibroblast growth factor 23 and parathyroid hormone levels, both of which have been suggested to have direct pathogenic CV effects. Elevated FGF23 levels promote left ventricular hypertrophy and congestive heart failure. Elevated PTH levels are associated with a proinflammatory effect, increased interleukin 6, impaired myocardial energy production, and cardiac fibrosis. Thus, improved phosphate management would is a logical approach to potentially improve CV health.
Current phosphate management options, including dietary restrictions and phosphate binders, decrease overall QoL for dialysis patients. The difficulty of maintaining a low phosphate diet is exacerbated by the large amounts of “hidden” phosphate additives in modern processed foods (e.g., frozen food, dry food mixes, packaged meat, cheese, and soft drinks) that are not required to be listed on labels.
Consuming a separate diet may also create social, physical, and timing distance between patients and their family members. Patients may not be able to participate in social activities, which may result in a feeling of isolation at home and/or with friends. Phosphate binders are difficult to incorporate into patients’ daily lives and can negatively impact and/or limit social interactions. Stringent dietary restrictions limit food choices and increase stress and anxiety. Multiple phosphate binder pills must be taken with each meal and snack. If patients do not have phosphate binders with them, they cannot eat anything. As a result, patients may feel stressed or burdened by always having to carry phosphate binders or be unable to have impromptu meals/snacks. New, more effective phosphate management options may reduce the negative impact of dietary restrictions and binders on patient quality of life.
Absorption of dietary phosphate occurs in the gastrointestinal (GI) tract via 2 distinct pathways: paracellular absorption and transcellular transport. The paracellular pathway is not limited by a saturation point and has been shown to be responsible for the vast majority of intestinal phosphate absorption, particularly when luminal phosphate concentrations are high. The transcellular pathway is responsible for phosphate absorption in the presence of low amounts of dietary phosphate, but this pathway saturates at low luminal phosphate concentrations. Available evidence indicates that the paracellular pathway is the primary mechanism of phosphate absorption under typical conditions of phosphate availability in individuals consuming standard Western diets.
To reflect the latest understanding of phosphate absorption, clinicians could consider implementing new hyperphosphatemia treatment paradigms to achieve phosphate goals, incorporating targeted phosphate absorption inhibitors. Tenapanor is an investigational, first-in-class non-binder phosphate absorption inhibitor with a unique mechanism of action that targets the primary paracellular absorption pathway, providing a novel approach to treating hyperphosphatemia.
Tenapanor effectively reduced phosphate levels in multiple clinical trials with a dosing regimen of one pill BID and was generally well-tolerated. Tenapanor has been evaluated for efficacy as monotherapy (vs. placebo) in separate 12- and 52-week trials. At 12 weeks, tenapanor administration lowered serum phosphorus in subjects from baseline concentrations of 8.1mg/dL to 5.5mg/dL in the efficacy analysis set. In the long-term phase 3 study, at 26 weeks, tenapanor administration lowered serum phosphorus in subjects from baseline concentrations of 7.7mg/dL to 5.1mg/dL in the efficacy analysis set. A recent trial comparing the combination of tenapanor and binder vs. placebo and binder found tenapanor plus binder resulted in a 0.65mg/dL larger mean serum phosphate reduction from baseline compared to placebo plus binder. Additionally, almost twice as many patients treated with tenapanor and binder achieved phosphate <5.5mg/dL compared to patients treated with placebo and binder (37-50% vs. 18-24%, p<0.05). This dual-mechanism approach may be particularly relevant for patients with persistent hyperphosphatemia. [Editor’s Note: The author has a consulting contract with Ardelyx, the maker of Tenapor]
Paracellular phosphate absorption inhibitors may also improve patients’ quality of life by reducing the total number of pills needed each day. Patients who were taking 2 or more than 2 phosphate binder pills three times/day received treatment with 30mg tenapanor twice daily, and 71.6% of patients achieved a 30% decrease in the total number of phosphate binder and tenapanor pills (p<0.001). Of those, 52.2% achieved a 50% decrease in total pill burden, and 26.9% no longer required any phosphate binders at week 26.
How the FDA decision may impact an underserved and disproportionately minority patient population)
Recently, Ardelyx announced that the FDA issued a complete response letter for tenapanor, a drug with an anticipated new mechanism of action to add to our options for managing hyperphosphatemia in the ESRD population. Given the suboptimal outcomes with existing therapies, there is a substantial unmet need that additional treatment options could potentially address. Beyond the overall general clinical health reasons why additional treatment options like tenapanor are needed, any decision on kidney medications disproportionately impacts a growing and particularly underserved minority population. Common conditions like high blood pressure, diabetes, and cardiovascular diseases are overrepresented in minority populations and are predisposing factors to CKD and eventual ESRD. Lower socioeconomic groups are also heavily represented in the ESRD population, with ~10x more prevalence in the population with the lowest socioeconomic status compared to that with the highest.
Photo: Edwin Tan, Getty Images