ZS-9 Follow Verify

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http://www.zspharma.com/clinical-development/zs9/
ZS-9
Indications and Usage	lower and maintain control of serum potassium levels
Dosage Forms and Strengths	Not defined
Contraindications	Not defined
Warnings and Precautions	Not defined
Adverse Reactions	Not defined
Drug Interactions	Not defined
Use in Specific Populations	Not defined
Recent Changes	Not defined

ZS-9 is an insoluble, nonabsorbed zirconium silicate designed to trap potassium ions preferentially in order to lower and maintain control of serum potassium levels. ZS-9 is passed through the digestive tract and eliminated in the stool.

HISTORY AND TIMELINE

The FDA approved the IND (Investigational New Drug) for ZS-9 in December 2010. 

March 2017

The FDA has rejected AstraZeneca’s hyperkalemia drug ZS-9 for the second time in 12 months. The news marks a further blow for a program AstraZeneca saw giving it a sizable share of a $6 billion (€5.5 billion) market when it acquired the asset in its $2.7 billion buyout of ZS Pharma.

Next to nothing has gone right for AstraZeneca and ZS-9 since then. The problems began in May when the FDA rejected the drug—which was already being reviewed at the time AstraZeneca bought ZS Pharma—on the basis of observations made by its inspectors during a preapproval assessment of the ZS-9 manufacturing facility. Ten months later, AstraZeneca is still being dogged by regulatory concerns about the production of ZS-9.

AstraZeneca revealed scant details in a release to disclose its latest FDA complete response letter (CRL). But in noting the rejection followed an FDA inspection of the ZS-9 production plant, AstraZeneca has again pointed to manufacturing problems as the source of its woes.

In between the two CRLs, AstraZeneca picked up regulatory approval for ZS-9 in the European Union. But it needs to access the U.S. market if it is to begin racking up the sort of sales required to justify the price it paid for ZS Pharma in 2015. At that time, the takeover looked like a direct route to blockbuster sales for AstraZeneca, and a blow to Relypsa’s attempts to corner the hyperkalemia market with its ZS-9 competitor Veltassa.

Today, 16 months after the ZS Pharma buyout, Relypsa has sold out to Vifor Pharma for $1.5 billion and AstraZeneca is still yet to get its drug on the market in the U.S.

Vifor, the specialty pharma unit of Galenica, is using Veltassa and the commercial footprint it acquired to spearhead its attempts to become a strong enough business to thrive after its parent company spins off its pharmacy business. And it is committing serious cash to the cause, with the 2017 budget for the launch and ramp up of Veltassa coming in at upward of $260 million. AstraZeneca’s missteps are helping Vifor’s efforts.

At the time of the last CRL, AstraZeneca thought recently-submitted manufacturing data not yet reviewed by the FDA could help its case but the problems at the plant persist. AstraZeneca said it is working with the FDA to fix the outstanding issues “as soon as possible.”

CLINICAL STUDIES

The Company has completed two phase 3 trials, ZS003 and ZS004, and the ZS002 phase 2 trial. These were all randomized, placebo-controlled, dose ranging trials that treated patients up to 30 days. These trials enrolled 1,101 patients with hyperkalemia due to all major causes, including patients with chronic kidney disease, heart failure, type 2 diabetes and those on renin-angiotensin-aldosterone system inhibitor (RAASi) therapy. Each of these three studies achieved its primary efficacy endpoint.

ZS003 was a two part double-blind, randomized, placebo-controlled, dose ranging pivotal trial. It enrolled 753 patients with hyperkalemia (indicated by potassium levels between 5.0 and 6.5 mEq/L). ZS004 was a double-blind, randomized, placebo-controlled, dose ranging phase 3 trial in 258 patients that had serum potassium levels of ≥5.0 mEq/L and also treated patients with potassium levels > 7.0 mEq/L.

In conjunction with ZS004, ZS Pharma also conducted ZS004E, an extension study that generated longer-term open-label safety, tolerability and efficacy data in patients who participated in ZS004. In ZS004E, patients received an additional 5 months of treatment, resulting in a combined potential of 6 months of treatment with ZS-9 over the course of ZS004 and ZS004E. The Company is also conducting and a 12-month safety study ZS005, which is still active.

Study name	Safety & Efficacy of Zirconium Silicate in Chronic Kidney Disease or Moderate Kidney Dysfunction With Mild Hyperkalemia
Phase	II
Study ID Number	ZS002
Study design	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Supportive Care
Patient population	N=90 Hyperkalemia, CKD 5.0 to 6.0 mEq/L
Publications	Ash SR, Singh B, Lavin PT, Stavros F, Rasmussen HS. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggest that the selective potassium trap ZS-9 is safe and efficient. Kidney Int 2015; 88:404–11.
Efficiency results	This study was the first-in-human, double-blind, randomized, placebo-controlled Phase 2 study of ZS-9 in patients with CKD (chronic kidney disease) and hyperkalemia, demonstrating achievement of normokalemia within 48 hours and similar safety profile to placebo.
Status	This study has been completed

Study name	Multicenter, Two-phase, Multi-dose, Prospective, Randomized, Double-blind, Placebo-Controlled Study of Safety and Efficacy of Microporous, Fractionated, Protonated Zirconium Silicate in Mild to Moderate Hyperkalemia
Phase	III
Study ID Number	ZS003
Study design	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Supportive Care
Patient population	N=753 Hyperkalemia, regardless of etiology, 5.0 to 6.5 mEq/L
Publications	Packham, D. K., Rasmussen, H. S., Lavin, P. T., El-Shahawy, M. A., Roger, S. D., Block, G., ... & Singh, B. (2015). Sodium zirconium cyclosilicate in hyperkalemia. New England Journal of Medicine, 372(3), 222-231.
Efficiency results	This 753-patient Phase 3 study showed that ZS-9 rapidly reduced serum potassium in hyperkalemic patients to normal levels within the 48-hour Acute Phase and then controlled potassium in the normal range throughout the 12-day Extended Treatment Phase. In addition, the study provided evidence suggesting that ZS-9 is well tolerated with an adverse event profile similar to placebo.
Status	This study has been completed

Study name	Multicenter, Two-phase, Multi-dose, Prospective, Randomized, Double-blind, Placebo-Controlled Study of Safety and Efficacy of Microporous, Fractionated, Protonated Zirconium Silicate in Mild to Moderate Hyperkalemia
Phase	III
Study ID Number	ZS004
Study design	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Supportive Care
Patient population	N=258 Hyperkalemia, regardless of etiology, >5.0 mEq/L
Publications	Kosiborod, M., Rasmussen, H. S., Lavin, P., Qunibi, W. Y., Spinowitz, B., Packham, D., ... & Singh, B. (2014). Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. Jama, 312(21), 2223-2233.
Efficiency results	The HARMONIZE (HyperkAlemia RandoMized interventiON multI-dose ZS-9 maintEnance) study was a global, prospective, randomized, double-blind, placebo-controlled trial that enrolled 258 patients with hyperkalemia with no upper limit on serum potassium (K+) at entry. Patients included are those with chronic kidney disease (CKD), heart failure (HF), diabetes and those on renin angiotensin aldosterone system (RAAS) inhibitor therapy. In the open-label induction phase of this study, patients received 10g of ZS-9 administered three times daily for 48 hours and were monitored to establish the speed and magnitude of serum potassium reduction. Patients who achieved normokalemia (K+ levels between 3.5 and 5 mEq/L) were randomized in a double-blind fashion to one of three doses of ZS-9 (5g, 10g or 15g) or placebo administered once-daily for 28 days (the randomized withdrawal period). The primary efficacy endpoint compared the mean serum K+ level of each ZS-9 treatment group to that of placebo over the interval between day 8 and day 28 of the randomized withdrawal period. Patients who completed the initial 28-day maintenance phase were eligible to enroll in an ongoing open-label extension study, ZS004E.
Status	This study has been completed

Study name	Open-label Extension to Study ZS-004 [Phase 3 Multicenter, Multi-phase, Multi-dose, Prospective, Randomized, Double-blind, Placebo-controlled Maintenance Study of Safety Efficacy of ZS (Sodium Zirconium Cycolsilicate) in Hyperkalemia.]
Phase	III
Study ID Number	ZS004E
Study design	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Supportive Care
Patient population	N=258 Hyperkalemia, regardless of etiology, >5.0 mEq/L
Publications
Efficiency results
Status	Completed/extension ongoing

Study name	Multicenter, Multi-Dose, Open-Label Maintenance of Long-Term Safety and Efficacy of Sodium Zirconium Cyclosilicate (ZS) in Hyperkalemia
Phase	III
Study ID Number	ZS005
Study design	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Supportive Care
Patient population	N=750 Hyperkalemia, regardless of etiology, >5.0 mEq/L
Publications
Efficiency results
Status	Completed/extension ongoing

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