Toxicity knocks Ardelyx's hyperkalemia hopes back to preclinic

Mike Raab - Ardelyx
CEO Mike Raab says elevated bicarbonate will make chronic use of drug a problem.

Unexpected side effects have spelled the end for Ardelyx’s drug candidate to treat elevated potassium levels in the blood, which was in phase 3 testing.

The biotech says RDX7675 worked as expected, reducing levels of serum potassium at all doses tested, but this was accompanied by a decline in serum bicarbonate—a rise in the acidity of the blood that can cause complications and can be life-threatening.

As patients with hyperkalemia tend to require long-term treatment, the bicarbonate issue is too big a challenge to overcome and makes the drug commercially limited, says the company. So it has opted to shelve the polymer-based potassium binder—saving it about $40 million—and turn its attentions to small-molecule follow-up RDX013, which is back in preclinical development.

Hyperkalemia has been treated with sodium polystyrene sulfonate (SPS) for decades, but has unpleasant gastrointestinal side effects and can also result in low blood levels of magnesium and calcium, and is, frankly, not pleasant to take.

Sensing a commercial opening, the drug industry has expended quite a bit of effort trying to come up with alternatives, and a couple of years ago those efforts were rewarded when Relypsa (now part of Vifor Pharma) got FDA approval for Veltassa (patiromer) as the first alternative to SPS.

Sales haven’t quite been as Vifor hoped, however, at $16 million last year, but that swelled to about $24 million in the first half of the year and should get a further boost from approval in the European Union, which came in July, as well as label changes in the U.S.

Other efforts to develop alternatives to SPS have also struggled. AstraZeneca’s ZS-9 candidate was rejected by the FDA for the second time in 12 months in March, although it got a green light for the drug in Europe, where it is known as Lokelma.

“The goal for RDX7675 was to develop a palatable product that could be taken chronically to address an important medical need for patients with hyperkalemia,” said Ardelyx CEO Mike Raab. “We are pleased by the activity observed; however, the unanticipated bicarbonate side effect creates a barrier for RDX7675, which we believe could limit its chronic use.”

The demise of Ardelyx’s hyperkalemia front-runner comes after a choppy patch for the biotech in the last couple of years.

Positive efficacy readouts for lead candidate tenapanor for high blood phosphate levels (hyperphosphatemia) in end-stage renal disease patients on hemodialysis have been undermined by safety concerns, especially diarrhea, as well as a failed trial in diabetics with chronic kidney disease and the loss of AstraZeneca as a development partner.

The company now says it is ready to start enrolling patients in a second phase 3 tenapanor trial which, after discussion with the FDA, will include an active phosphate binder control arm as a safety comparator. If approved, tenapanor would be the first alternative to phosphate binders—which, according to Ardelyx’s chief development officer David Rosenbaum, Ph.D., are “highly burdensome” and difficult to take—for ESRD patients on dialysis.

The drug is also being tested for irritable bowel syndrome with constipation (IBS-c), and according to Raab remains on course for filing in that indication in the second half of 2018 after new data reported last month.

Earlier results for that program failed to impress investors, drawing out unfavorable comparisons with rival IBS-c therapies such as Ironwood Pharma’s already-approved Linzess (linaclotide) and Synergy’s Trulance (plecanatide), which is in late-stage testing.