Therapeutic focus – Phosphate binders seeking safety in small numbers

One of the most promising new phosphate binders in development, Keryx Pharmaceuticals’ Zerenex, reported encouraging pivotal data last week. A treatment for high phosphate levels, or hyperphosphataemia, the agent appears to hold the potential to significantly shake up a $1bn market.

Almost all chronic renal failure patients have elevated phosphate levels and require therapy to keep levels under control. Existing medications, however, are far from perfect; safety and ease of use, as well as expense, are big problems. The market is currently dominated by Genzyme’s Renagel and Shire’s Fosrenol, medications that require some patients to take 11 pills a day. Keryx appears to be leading the pack in the drive to find better drugs (see tables below).

Life-threatening

Hyperphosphataemia can be a life-threatening condition for chronic renal failure patients on dialysis. Even in earlier stages of the disease, high phosphate levels can lead to bone problems and cardiovascular complications.

Parathyroid hormone (PTH) regulates the absorption of phosphates and calcium. In failing kidneys, PTH cannot effectively remove phosphate and concurrently leaves serum calcium levels low. This leads to secondary hyperparathyroidism, a cause of bone development disorders, breaks and tumours.

While dialysis and restricting phosphate in the diet are standard practise for controlling serum phosphorus levels, they are not sufficient alone. Nearly all chronic renal failure patients require oral phosphate binder therapy, usually taken with meals, though existing treatment options are considered far from optimal. Side effects and high pill requirement are major drawbacks for the compounds currently available, and it is thought that less than half of end-stage renal disease patients achieve target serum phosphorus levels because of non-compliance.

Early options

Aluminium hydroxide was classically used as a phosphate-lowering agent, but is very toxic with repeated use and high doses, associated with encephalopathy and bone mineralisation disorders. Calcium-based drugs and supplements available over the counter can bind dietary phosphorus before it is absorbed, whilst also raising serum calcium. But intake therefore must be strictly controlled as overuse can lead to hypercalcaemia and calcification which leaves damaging scarring, especially on cardiovascular tissues.

Magnesium-based compounds work similarly to calcium compounds but are not considered as effective. As a result of needing large doses for effect, the patient can develop hypermagnesaemia, diarrhoea, and hyperkalaemia.

Often, combinations of magnesium-based and calcium compounds are used to limit exposure to either type of metal, but this far from a perfect solution.

Market leaders

The launch of Renagel in 1998 brought the first non-metal phosphate binder to the market. Despite the high pill burden and probably aided by the high price, the current market leader generated $700m last year for Genzyme, accounting for half of phosphate binder prescriptions and three quarters of total sales. It is approved as a first-line treatment for stage 5 renal failure patients – those on dialysis.

Shire’s Fosrenol followed in 2005, and sold $184m last year. Late last year Shire received European approval for use of Fosrenol in earlier-stage renal disease patients not on dialysis; at the time, Shire was evaluating its options for the label extension in the US.

Both of these compounds, and other phosphate binders, are known for poor gastrointestinal tolerability; Fosrenol can also leave unwanted deposits on bone, liver and cerebral tissues. Some patients need to take 9–11 pills per day to get levels lower.

However despite these draw backs the market for these agents grew substantially in the last few years, forecast to peak at just over $1bn in 2012.

Zerenex and the next generation

These side effects and high pill burden mean many believe the market is ripe for improved medicines.

Keryx’s Zerenex is widely viewed as the most promising candidate in development. It works by forming non-absorbable complexes with phosphates in the gastrointestinal tract, which are then excreted.

The company is running a two-study pivotal programme – a short efficacy study and a long term safety study. The former reported encouraging data last week, whilst the latter will not complete until late 2011 or early 2012.

The efficacy trial showed that six-gram (six pills per day) and eight-gram (eight pills per day) regimens significantly reduced serum phosphates in 151 patients by 25% and 28.8%, respectively; a one-gram arm failed. A secondary endpoint of raising serum bicarbonate was also met whilst tolerance was encouraging with only a 6% drop-out rate.

Should a competitive safety profile also emerge later next year, Zerenex could represent an attractive new option for treating this condition. Analysts currently estimate sales of $135m in 2016, a figure which could creep up on the back of the first set of phase III data. Ultimately, however, the potential is much higher.

The one draw back commercially for Zerenex is a short patent life. Generically called ferric citrate, a widely-available compound, Zerenex may only win three years exclusivity.

Other options

Going from 10 pills to 8 pills a day is an improvement, but clearly the potential remains for much better convenience, and a number of other candidates are in development.

Similar to Zerenex is another ferric citrate derivative, PA21, being studied for kidney failure patients on hemodialysis by Vifor-Fresenius Medical Care Renal Pharma. This new specialty company was formed last week by Fresenius and Galenica.

PA21 demonstrated good tolerability in recently-released phase II data, with comparable efficacy to Renagel. Galenica says the therapy requires a very favourable regimen of three chewable pills per day. Preparation for phase III studies are underway in North America and Europe.

Several completely new molecular entities are on the horizon. Phase III trials are ongoing in Japan for Astellas’ ASP1585 (bixalomer), including a head-to-head trial with Renagel. The compound was licensed from Amgen, which abandoned its own development efforts early last year.

Phase III trials of Novartis’ Seboren (SBR759), also an iron-based binder, in dialysis patients are due to complete by year-end, while a phase II trial comparing Seboren with Renagel is expected to report data early in 2011.

Heading for change

The phosphate binder market is heading for change anyway, with the patent expiry of Renagel approaching. However, the need for safer and more convenient phosphate binders means a new agent could easily take market share.

A safe drug that can sustain efficacy at low doses is the winning formula and a medicine with these attributes may even be able to extend into the pre-dialysis market, pointing to greater potential.