Ardelyx (ARDX) Phase 3 PHREEDOM Study Evaluating Tenapanor in CKD Patients on Dialysis Meets Primary Endpoint

Ardelyx, Inc. (Nasdaq: ARDX), a specialized biopharmaceutical company focused on developing first-in-class medicines to improve treatment for people with cardiorenal diseases, today reported positive topline results from PHREEDOM, a long-term Phase 3 study evaluating the efficacy and safety of tenapanor as monotherapy for the treatment of hyperphosphatemia in patients with chronic kidney disease (CKD) on dialysis. In the study, patients randomized to the tenapanor arm were treated in a 26-week open-label treatment period and were then re-randomized to a 12-week double-blind, placebo-controlled randomized withdrawal period. The PHREEDOM study met its primary endpoint demonstrating a statistically significant difference in least square (LS) mean serum phosphorus change (-1.4 mg/dL, p<0.0001), as compared to placebo. During the 26-week treatment period, 77% of tenapanor-treated patients in the intent-to-treat population (n=408) had a decrease in serum phosphorus, with a mean reduction from baseline of 2.0 mg/dL. Tenapanor is an investigational, first-in-class, phosphate absorption inhibitor being developed to treat hyperphosphatemia in patients with CKD on dialysis. If approved, tenapanor will be the only non-binder treatment for the control of serum phosphorus in patients with CKD on dialysis.

"If approved, tenapanor is poised to change the way we manage hyperphosphatemia in patients on dialysis," said Myles Wolf, M.D., MMSc, Charles Johnson, M.D. professor of medicine and chief of Duke Nephrology. "Tenapanor would be a first-in-class therapy that targets the primary pathway of phosphate absorption to significantly lower serum phosphate while requiring patients to take just one small pill twice per day. This would make tenapanor an important innovation and potentially an ideal first-line therapy for patients receiving dialysis for whom new effective treatments are desperately needed."

"These results are very exciting and represent a capstone to our tenapanor clinical development program, which is focused on the development of a new and important therapy for patients with hyperphosphatemia," said Mike Raab, president and chief executive officer of Ardelyx. "Based on the PHREEDOM data that demonstrate tenapanor as an effective monotherapy, and the previously released AMPLIFY data that demonstrate the benefits of a dual mechanism approach with tenapanor plus binders in those who require more aggressive phosphate management, it is clear that tenapanor has a role to play in the management of all dialysis patients with hyperphosphatemia. With these results in hand, our focus will now turn to completing and submitting our NDA, which we expect in mid-2020."

PHREEDOM Key Topline Results

Primary Endpoint:

As compared to patients treated with placebo, patients in the efficacy analysis set treated with tenapanor had a statistically significant difference in LS mean serum phosphorus change from the end of the 26-week treatment period to the endpoint visit in the 12-week randomized withdrawal period (-1.4 mg/dL, p<0.0001).

Safety:

Tenapanor was generally well-tolerated. As anticipated due to the mechanism of action, the most common self-reported adverse event was loose stools/diarrhea at an incidence rate of 52.5%, with approximately 90% of these events judged by the investigator to be mild to moderate in nature. The majority of the events were reported within the first five days of treatment and were transient notwithstanding continued treatment with tenapanor. In the 26-week open-label treatment period, 16% of the tenapanor-treated patients discontinued treatment due to diarrhea. Additionally, during the randomized withdrawal period, only 0.8% of tenapanor-treated patients discontinued due to diarrhea.

In the safety analysis set of the 26-week open-label treatment period, which included tenapanor (n=419) and sevelamer (n=137), 17.2% of tenapanor-treated patients compared to 22.6% of sevelamer-treated patients experienced a serious adverse event. The median dose for tenapanor was 60 milligrams per day throughout the study and the median dose for sevelamer was 4.8 grams per day after randomization and increased to 7.2 grams per day by the end of the 26-week open-label treatment period.

NORMALIZE Initial Results

Patients completing the PHREEDOM trial from both the tenapanor arm and the sevelamer active safety control arm had the option to participate in NORMALIZE, an ongoing open-label 18-month extension study. The goal of this study is to obtain real-world evidence regarding the dual mechanism of tenapanor and sevelamer to reduce patients' serum phosphorus levels to normal (<4.6 mg/dL) while minimizing medication burden.

Patients entering the study from the tenapanor arm with serum phosphorus levels in the normal range are followed with no medication changes. Patients entering the study from the tenapanor arm with serum phosphorus ³4.6 mg/dL have sevelamer tablets added incrementally to achieve normal serum phosphorus levels. Patients entering the study from the sevelamer active safety control arm have tenapanor tablets added to their treatment regimen and have sevelamer tablets withdrawn based on their serum phosphorus value, to achieve normal serum phosphorus levels.

In this initial analysis, 96% of eligible patients have chosen to enroll into NORMALIZE. Of the 73 patients thus far treated for more than one month of treatment, 42% have achieved normal serum phosphorus of less than 4.6 mg/dL and of those, 58% have accomplished this with either tenapanor alone or with tenapanor in combination with only one to three sevelamer tablets per day. These data represent a 45% improvement compared to current treatment practice data reported in the June 2019 Dialysis Outcomes Practice Patterns Study (DOPPS) Practice Monitor.

PHREEDOM Study Design

PHREEDOM is a one-year study with a 26-week open-label treatment period and a 12-week double-blind, placebo-controlled randomized withdrawal period followed by a 14-week open-label safety extension period. The study randomized a total of 564 patients with CKD on dialysis who had a serum phosphorus level between 6.0 mg/dL and 10.0 mg/dL and had an increase in serum phosphorous of at least 1.5 mg/dL after an up to 3-week phosphate binder wash-out period. Patients were randomized 3:1 to either the tenapanor arm (n=423, n=408 intent to treat) or the active safety control arm (sevelamer n=141). Those patients randomized to the active safety control arm are treated with sevelamer for 52 weeks. Patients in the tenapanor arm received tenapanor twice daily at a starting dose of 30 mg with dose adjustments allowed based on serum phosphorus level and gastrointestinal tolerability. At the end of the 26-week treatment period, patients in the tenapanor arm were randomized 1:1 to enter the randomized withdrawal period and either remain on the tenapanor dose they were taking or receive placebo for up to an additional 12 weeks. After the randomized withdrawal period, patients then continued on the study for an additional three months as part of the long-term safety extension. Patients in the active safety control arm received sevelamer at an initial dose based on its package insert with dose changes allowed at the discretion of the principal investigator for up to one year.

The primary efficacy endpoint of the study was the difference in change in serum phosphorus between the pooled tenapanor-treated patients and placebo-treated patients in the efficacy analysis set from the end of the 26-week treatment period to the endpoint visit of the 12-week randomized withdrawal period. The efficacy analysis set (n=131), which was accepted by the U.S. Food and Drug Administration as the primary analysis set, included patients who completed the 26-week treatment period and achieved a 1.2 mg/dL decrease in serum phosphorus in the same period.

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