hyperkalemia/zs-9 discussant - professional heart...

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Hyperkalemia/ZS-9 Discussant Bertram Pitt, M.D.* University of Michigan School of Medicine Consultant: Relypsa, Pfizer, Bayer, Eli Lilly, Astra Zeneca, SC Pharmaceuticals, Tricida, DaVinci therapeutics, Stealth Peptides, Aura sense, Sarfez Stock options: Relypsa, SC Pharmaceuticals, Tricida, Aurasense Patent pending: site specific delivery of eplerenone to the myocardium

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Page 1: Hyperkalemia/ZS-9 Discussant - Professional Heart …professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/... · Hyperkalemia/ZS-9 Discussant. Bertram Pitt, M.D.* University

Hyperkalemia/ZS-9

Discussant

Bertram Pitt, M.D.*University of Michigan School of

Medicine

• Consultant: Relypsa, Pfizer, Bayer, Eli Lilly, Astra Zeneca, SC Pharmaceuticals, Tricida, DaVinci therapeutics, Stealth Peptides, Aura sense, Sarfez

• Stock options: Relypsa, SC Pharmaceuticals, Tricida, Aurasense• Patent pending: site specific delivery of eplerenone to the myocardium

Page 2: Hyperkalemia/ZS-9 Discussant - Professional Heart …professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/... · Hyperkalemia/ZS-9 Discussant. Bertram Pitt, M.D.* University

Hyperkalemia

• What level of serum potassium is associated with an increased risk of mortality?

• What therapies are currently available or being developed for the chronic treatment of patients with hyperkalemia?

• What have we learned from the ZS-9 study?• What would we like to know about ZS-9?

Page 3: Hyperkalemia/ZS-9 Discussant - Professional Heart …professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/... · Hyperkalemia/ZS-9 Discussant. Bertram Pitt, M.D.* University

3

Normal Range

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0

Pred

icte

d Pr

obab

ility

of M

orta

lity

Levels of Serum Potassium (mEq/L)

Adjusted Mortality* by Serum K+ Level, Patients 45–64 Yr and ≥65 Yr With and Without Comorbid Illness

*Evaluated through de-identified medical records (2007-2012) of individuals with ≥2 serum K+ readings (Humedica, Cambridge MA). Spline analyses were performed to assess mortality at 0.1 mEq/L increments of serum K+ after adjusting for covariates and interactions . Comorbid patients are those diabetes, heart failure , chronic kidney disease stages 3-5, cardiovascular disease, or hypertension.

Comorbid ≥65 yr95% Conf Limits

Comorbid 45-64 yr95% Conf Limits

Control ≥65 yr 95% Conf Limits

Control 45-64 yr95% Conf Limits

Pitt B. et ak AHA 2014

Page 4: Hyperkalemia/ZS-9 Discussant - Professional Heart …professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/... · Hyperkalemia/ZS-9 Discussant. Bertram Pitt, M.D.* University

What Therapies are Available or being Developed for the Chronic Therapy of Hyperkalemia

Sodium polystyrene sulfonate (kayexalate)

ZS-9 Patiromer

Structure Cation exchange polymer-Crystal lattice

Zironium silicate-3 dimensionalcrystalline lattice

Metal free polymer

Exchange Ion Na+ Na+ and H+ Ca+

Primary site of Action Large intestine throughout the GI tract Throughout the GI tract, predominately colon

Safety • Sodium Retention• Intestinal necrosis

and GI perforation• Hypokalemia• Hypocalcemia• Hypomagnesemia

• Mild-moderate GI AEs

• UTIs• Hypokalemia

• Mild moderate GI AEs

• Hypokalemia

ApprovalS

1958 NDA submission:2015 NDA submission: O b 2014

Page 5: Hyperkalemia/ZS-9 Discussant - Professional Heart …professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/... · Hyperkalemia/ZS-9 Discussant. Bertram Pitt, M.D.* University

HyperkalemiaWhat Have we Learned from the Efficacy and Safety Study of

ZS-9 in Patients with Hyperkalemia?

• Doses of 5, 10, and 15 g QD appear to be effective in lowering serum potassium into the normal range

• 84% of patients were normokalemic by 48 hrs.• Normokalemia (K+ <5.1 m Eq/L) was

maintained over the 28 day study period• The overall safety profile appeared to be

comparable to placebo except for hypokalemia and edema .

Page 6: Hyperkalemia/ZS-9 Discussant - Professional Heart …professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/... · Hyperkalemia/ZS-9 Discussant. Bertram Pitt, M.D.* University

HyperkalemiaWhat Would We Like to Know About ZS-9 for

the Treatment of Hyperkalemia

• What is the long term (> 1 year) safety and tolerability of ZS-9 ( Zirconium ? )

• What is the explanation for the increase in edema, which appears to be dose related? ( Na+ exchanger ?)

• What type of long term monitoring of serum potassium and renal function will be required?

• What are the risk/benefit and cost/benefit implications of the long term administration ZS-9 vs. reducing the dose or discontinuing RAAS-inhibitors?

Page 7: Hyperkalemia/ZS-9 Discussant - Professional Heart …professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/... · Hyperkalemia/ZS-9 Discussant. Bertram Pitt, M.D.* University

HyperkalemiaConclusions:• The risk of death in patients with CKD, HF, and or

DM, especially those >/=65 years, is increased at serum potassium values above and below 4.5 meq/L

• ZS-9 provides a potential opportunity to treat and possibly prevent hyperkalemia in high risk patients such as those with CKD, HF, DM and or those on a RAAS-inhibitor

• Further data is however needed in regard to its long term safety and tolerability as well as its cost/benefit and health economic implications