Method for treating hyperkalemia with poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt

Abstract

The present invention relates to a method for preventing or treating hyperkalemia in a subject. The method comprises a first-stage dosing regimen in which poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt is orally administered to the subject 3 times a day, 3 g to 48 g each time, for 2 consecutive days. Optionally, the method comprises a second-stage dosing regimen in which 3 g to 48 g of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt is orally administered to the subject once a day or once every other day.

Description

Methods of treating hyperkalemia with poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt

[0001] This application claims the benefit of PCT Application No. PCT / CN2024 / 118865, filed September 13, 2024, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] The present application relates to the field of disease treatment. More specifically, the present application relates to methods of treating hyperkalemia using poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt. BACKGROUND

[0003] Potassium ion (K + ) is one of the most abundant cations in the human body, and plays an important role in maintaining cell metabolism, maintaining cell resting membrane potential, regulating osmotic pressure inside and outside the cell, and regulating acid-base balance. Under physiological conditions, the body maintains potassium homeostasis by balancing potassium intake and excretion, and regulating the distribution of potassium inside and outside the cell. 98% of potassium is distributed inside the cell, and 2% is distributed outside the cell. The main source of potassium in the body is the intake of potassium from food. Adults need to intake about 3-4 g of potassium per day. The kidney is the main organ for potassium excretion, about 90-95% is excreted by the kidney, and the remaining is mainly excreted by the colon. When the kidney function is not good, the amount of potassium excreted by the colon increases, and in patients with end-stage renal disease, the amount of potassium excreted by the stool is three times that of people with normal kidney function.

[0004] The normal concentration of serum potassium ions is 3.5-5.0 mmol / L. Serum potassium concentration > 5.0 mmol / L is diagnosed as hyperkalemia. Serum potassium levels in the range of 5.0 mmol / L to 6.0 mmol / L is mild hyperkalemia, which is usually not life-threatening. However, moderate to severe hyperkalemia (serum potassium greater than about 6.1 mmol / L) can lead to serious consequences, and arrhythmia and ECG waveform abnormalities are both characteristics of hyperkalemia. When serum potassium levels rise to about 9 mmol / L or higher, symptoms such as atrioventricular dissociation, ventricular tachycardia or ventricular fibrillation can occur. Hyperkalemia can also be divided into acute hyperkalemia and chronic hyperkalemia. A large-scale epidemiological study in China showed that among nearly 3 million outpatients with blood potassium examination records, the prevalence of hyperkalemia was 3.86%, among which the prevalence of hyperkalemia in patients with chronic kidney disease (CKD) was as high as 22.89%, and the proportion of hyperkalemia patients in the outpatient population of heart failure and diabetes was as high as 12.54% and 7.11% respectively (Bian JM et al. “Epidemiological study on the distribution and diagnosis of hyperkalemia in outpatients in China”, Chin J Blood Purif, 2020, 19(11):726-729,746). A meta-analysis showed that the prevalence of hyperkalemia in the general outpatient population was 1.3%, but in non-dialysis CKD and dialysis-dependent CKD patients, it was as high as 7.5% and 35% respectively (Humphrey T et.al. “How common is hyperkalaemia?A systematic review and meta-analysis of the prevalence and incidence of hyperkalaemia reported in observational studies”. Clin Kidney J. 2022, 15(4):727-737). A real-world study in Japan showed that the prevalence of hyperkalemia in CKD 3a, 3b, 4, and 5 was 13.22%, 24.56%, 43.65%, and 51.19% respectively (Kashihara N et.al. “Hyperkalemia in Real-World Patients Under Continuous Medical Care in Japan”, Kidney Int Rep. 2019 May 30;4(9):1248-1260).

[0005] The treatment methods for hyperkalemia include calcium agents, insulin, glucose, sodium bicarbonate, beta-adrenergic, diuretics, dialysis, cation exchange resin, new ion exchange polymer, low potassium diet, etc. The treatment methods commonly used in clinic for hyperkalemia have three different mechanisms of action: (1) promoting potassium ions into cells: the treatment methods with this mechanism of action include intravenous infusion of insulin and glucose, intravenous injection of sodium bicarbonate, intravenous injection or inhalation of beta2-adrenergic receptor agonists; (2) stabilizing myocardium: the treatment method with this mechanism of action includes intravenous injection of calcium agents; (3) promoting potassium ions to be excreted out of the body: for example, promoting potassium excretion by the kidney through loop diuretics or sodium bicarbonate alkalizing urine, rapidly reducing potassium through hemodialysis, and increasing fecal potassium excretion through potassium-binding agents. Among these treatment methods, the only drug that can effectively promote potassium ions to be excreted out of the body is potassium-binding agent. Although intravenous drugs can quickly reduce blood potassium levels by shifting potassium ions to cells, it does not change the total amount of potassium in the body, and the maintenance time is short, which is easy to rebound. The low-potassium diet recommended by the guidelines has low compliance, is difficult to implement, and may increase the risk of cardiovascular event-related death. Diuretics that promote the kidney to excrete potassium ions have no ion selectivity, and long-term use can cause patients to have reduced kidney function and worsen hyperkalemia. Potassium-lowering resin that excretes potassium ions through the gastrointestinal tract is a less harmful treatment method, especially non-absorptive polymer drugs, which are only excreted through the gastrointestinal tract and have more advantages in safety. However, there are very limited existing drugs of this type, and there are great limitations in treatment effect and onset time, and there is a problem of low selectivity for potassium ions.

[0006] The product of Concordia Pharmaceutical Inc. under the trademark was approved by the US FDA in 1958 for the treatment of hyperkalemia, and is administered orally or rectally. is the earliest potassium-lowering resin approved for the treatment of hyperkalemia. The oral administration regimen of the product is: the average total daily dose of an adult is 15-60 g, 15 g each time, 1-4 times a day. The rectal administration regimen of the product is: the average dose of an adult is 30-50 g, once every 6 hours. The active ingredient of is sodium polystyrene sulfonate (SPS), which is a cation exchange resin containing sodium counterions. The use dose is large and the administration frequency is high, resulting in poor patient compliance, which is not suitable for outpatients or long-term treatment. The onset of action is slow, and it takes several hours or even days to effectively reduce serum potassium levels. In addition, the product has severe gastrointestinal side effects, and there is a risk of intestinal obstruction and perforation. Moreover, the product can introduce excess sodium, leading to hypernatremia, fluid retention, and hypertension. To overcome the side effects of diuretics such as spironolactone are often required for patients, but in the case of patients with kidney disease, the efficacy of diuretics is limited, and diuretics are prohibited for patients in whom a decrease in blood pressure and blood volume is not beneficial.

[0007] The product of Vifor Pharma, Inc. under the trademark was approved by the US FDA in 2015 for the treatment of hyperkalemia, and is administered orally. The treatment regimen for the product is: the initial dose is 8.4 g, and it is administered once a day; the dose can be adjusted by 8.4 g per day at one-week intervals. For example, the serum potassium concentration is measured every week during treatment, and if the serum potassium has not returned to normal after one week, the dose is adjusted to 16.8 g or 25.2 g, but the maximum is 25.2 g per day. The active ingredient of the product is partiromer, which is a cation exchange polymer containing calcium-sorbitol counterions. Like , the onset of action is also slow, and a decrease in serum potassium levels is observed about 7 hours after the first administration. Moreover, causes gastrointestinal adverse reactions such as constipation, diarrhea, nausea, and vomiting, and it not only binds potassium ions in the body, but also binds magnesium ions, so it also has adverse reactions of hypomagnesemia. Patients using need to monitor serum magnesium levels, and often need to supplement magnesium.

[0008] The product of AstraZeneca under the trademark was approved by the US FDA in 2018 for the treatment of hyperkalemia in adults, and is administered orally. The current clinical treatment regimen for the product is: the initial dose is 10 g per time, and it is administered 3 times a day for 48 hours; the dose for maintenance treatment is 10 g per time, and it is administered once a day; the dose can be adjusted by 5 g per day at one-week intervals (i.e., up to 15 g per day or down to 5 g per day) to obtain the desired range of serum potassium concentrations. The active ingredient of the product is sodium zirconium cyclosilicate, and each 5 g contains about 400 mg of sodium, which preferentially captures potassium in the body while exchanging hydrogen and sodium. This mechanism of action leads to the use of edema in patients, and even heart failure or nephropathy in patients who should limit sodium intake or are prone to fluid overload. The package insert of the drug clearly lists edema as the most common adverse effect under the items of "Warnings and Precautions" and "Adverse Reactions". Therefore, patients are not suitable for long-term use

[0009] Therefore, there is a significant medical need for an effective and safer drug for the treatment of acute and chronic hyperkalemia. SUMMARY

[0010] The present application meets the above needs by providing a dosing regimen for treating hyperkalemia with poly(2-fluoroacrylate-Pentaerythritol triallyl ether) Calcium Ferric Sodium salt.

[0011] The dosing regimen of the present application can quickly control hyperkalemia in patients and control blood potassium within the normal range, avoiding adverse clinical problems caused by hyperkalemia, such as severe arrhythmia and even sudden cardiac death. Moreover, poly(2-fluoroacrylate-Pentaerythritol triallyl ether) Calcium Ferric Sodium salt has a rapid onset of action, and can effectively reduce serum potassium levels 1 hour after the first administration. Compared with , in the case of achieving the same efficacy, the dosing regimen of the present application has no adverse reactions of edema. Moreover, the dosing regimen of the present application also has no adverse reactions of hypomagnesemia.

[0012] The terms used herein have the meanings defined below, and the terms not defined herein have the usual meanings in the art.

[0013] The term "about", "approximately" when used in association with a numerical value means ± 5% of the numerical value used in association therewith, i.e. the numerical value used in association therewith is extended to a range having a lower limit of 95% of the numerical value and an upper limit of 105% of the numerical value.

[0014] The terms "comprise", "comprising", "include", "including" used herein mean including the recited elements, numerical values or steps, but do not exclude any other elements, numerical values or steps. In this document, when the terms "comprise", "comprising", "include", "including" are used, unless otherwise specified, the case of consisting of the recited elements, numerical values or steps is also covered, i.e. the terms "comprise", "comprising", "include", "including" also cover "consisting of".

[0015] The term "poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) calcium ferric sodium salt" as used herein refers to the cross-linked polymer of Calcium Ferric Sodium 2-fluoroacrylate with Pentaerythritol triallyl ether prepared in Example 3 of PCT application WO2023 / 088111A1, the simplified structure of which is as follows:

[0016] wherein m = 0.95, and n = 0.05,

[0017] Also referred to in this application as "polymer salt of the invention" or "MFA-APE-Na-Ca-Fe".

[0018] In Example 3 of PCT application WO2023 / 088111A1, the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) calcium ferric sodium salt was prepared using the following method:

[0019] Purified water (550 mL), NaCl (11.0 g), and polyvinyl alcohol (3.4 g) were added to a reaction flask and stirred at 20-30 °C until completely dissolved to give a clear solution. A 2-fluoroacrylate (MFA) solution was prepared by stirring and completely dissolving 104.0 g MFA (1.0 mol), 12.8 g pentaerythritol triallyl ether (APE) (0.05 mol), and 0.73 g benzoyl peroxide (0.003 mol) to give a clear solution, ready for use. The prepared MFA solution was added to the solution in the reaction flask. The temperature of the contents of the reaction flask was gradually increased to 70-80 °C, after which the temperature was maintained and stirring was continued for 15 hours. Gas chromatography monitoring showed that the reaction was complete. After the temperature was reduced to 20-30 °C, suction filtration was performed. The filter cake was slurried and washed with water and ethanol. The resulting wet product was dried at 50 °C under vacuum to give 97.3 g of a white solid, which was the MFA-APE ester polymer.

[0020] 400 mL water, 130 mL EtOH, and 48.0 g sodium hydroxide were added to a reaction flask, followed by the above MFA-APE ester polymer with stirring. The temperature was increased to 50-60 °C, then stirring was continued and the temperature was maintained for 15 hours. The temperature was reduced to 20-30 °C, then filtration was performed, and the filter cake was slurried and washed with water and ethanol, then filtered to give the wet MFA-APE sodium salt polymer (MFA-APE-Na).

[0021] Add 500 mL of water and 100 mL of concentrated hydrochloric acid to a reaction flask, then add the above wet MFA-APE sodium salt polymer, and stir at 20℃-30℃ for 15 hours. After filtration, wash the filter cake repeatedly with 4 L of water, and filter again to obtain the wet MFA-APE acid polymer (MFA-APE-H).

[0022] Add 240 mL of water to the above acid polymer and stir at 10-30 °C. Slowly add FeCl3 (0.7 g), Ca(OH)2 (18.0 g), and NaOH (9.6 g) to the mixture, controlling the internal temperature at 10-30 °C. Stir the mixture for 2-5 hours, then filter the mixture to obtain a wet solid. Slurry the wet solid with 2 L of water. After filtration, vacuum dry the resulting wet filter cake at 50 °C for 8 hours to obtain 99.0 g of yellow dry product. Crush the product and sieve it through a 120 mesh sieve to obtain the MFA-APE Na-Ca-Fe composite salt polymer (m = 0.95, n = 0.05) (MFA-APE-Na-Ca-Fe).

[0023] Poly(2-fluoroacrylate-pentaerythritol triallyl ether) iron calcium sodium salt is a non-absorbable, orally administered polymer with highly selective potassium... + Binding action, can bind K in the gastrointestinal tract + It is excreted in feces, thereby lowering blood potassium levels. In in vitro experiments simulating a human body environment, the amount of potassium ions bound by the polymer salt of this invention is... The polymer salt of this invention significantly reduced serum potassium levels and increased fecal potassium excretion in a rat model of hyperkalemia, effectively treating hyperkalemia in rats. Pharmacokinetic studies showed that a single oral administration of 300 mg / kg C to rats... 14The total drug-related substances concentration in the plasma of the labeled polymer salt of the present application at different time points within 24 hours after administration is lower than the lower limit of quantification, indicating that the polymer salt of the present application is not absorbed into the blood. There is no tissue distribution outside the gastrointestinal tract, no metabolite, only excretion through the feces, and basically all excretion within 48 hours after administration, with no gender difference. Safety pharmacology studies show that single oral gavage administration of 2000, 4000 and 6000 mg / kg / day doses of the polymer salt of the present application has no significant effect on the central nervous system and respiratory system, gastrointestinal propulsive movement, gastric juice volume and gastric juice pH value of rats, and single oral gavage administration of 500, 1500 and 3000 mg / kg / day doses of the polymer salt of the present application has no significant effect on the cardiovascular system and respiratory system of Beagle dogs. Single-dose toxicology studies show that in rats, the maximal tolerance dose (MTD) of the polymer salt of the present application is 9000 mg / kg / day; in Beagle dogs, the MTD of the polymer salt of the present application is ≥6000 mg / kg / day. Repeated-dose toxicity studies in animals also show that the no observed adverse effect level (NOAEL) of the polymer salt of the present application can be as high as 6000 mg / kg / day. Genetic toxicity studies show that the results of in vitro Ames test, mammalian cell chromosome aberration test and in vivo mouse micronucleus test are all negative, indicating that the polymer salt of the present application has no mutagenic and teratogenic effects.

[0024] The polymer salt of the present application has a low content of sodium ions in its structure, thus avoiding excessive sodium ions in the body due to sodium-potassium exchange and water sodium retention caused thereby, and reducing or avoiding the adverse reaction of edema.

[0025] The term "individual" as used herein refers to an animal. Preferably, the individual is a mammal, such as a primate (e.g., a human, a monkey, a chimpanzee), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, etc. More preferably, the individual is a human.

[0026] The terms "serum potassium" and "potassium" as used herein can be used interchangeably and both refer to serum potassium level.

[0027] The term "treatment" as used herein refers to a significant reduction in serum potassium level of an individual.

[0028] The term "adverse event" (AE) as used herein refers to any untoward medical occurrence in a subject administered a trial drug or placebo, and does not necessarily mean the event was caused by an investigational product. An adverse event can be an exacerbation of a pre-existing symptom, sign, laboratory abnormality, newly diagnosed illness, laboratory abnormality value, etc. The severity of adverse events is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V5.0) developed by the U.S. Department of Health and Human Services, National Institutes of Health during the trial. If the AE cannot be graded according to the CTCAE, the investigator can grade it as 1-5 according to the clinical situation. According to the causality assessment criteria for adverse events, the relationship between adverse events and trial drugs is judged as "definitely related, very likely related, likely related, possibly unrelated, and unrelated" in five levels.

[0029] The term "adverse reaction" as used herein refers to adverse events related to the trial drug, and adverse events of "definitely related, very likely related, likely related" are included in the calculation of the incidence of adverse reactions.

[0030] The term "qd" as used herein refers to once daily administration.

[0031] The term "tid" as used herein refers to three times daily administration.

[0032] The term "hyperkalemia" as used herein refers to a condition in which serum potassium ion concentration is too high (i.e., serum potassium ion concentration > 5.0 mmol / L) due to various causes, including mild hyperkalemia (i.e., serum potassium ion concentration in the range of 5.0 mEq / L to 6.0 mEq / L), moderate to severe hyperkalemia (serum potassium greater than about 6.1 mEq / L). The term "hyperkalemia" as used herein can also be classified as acute hyperkalemia or chronic hyperkalemia.

[0033] The term "acute hyperkalemia" as used herein refers to a type of hyperkalemia in which the blood potassium concentration rapidly increases above the upper limit of the normal value in a short period of time, particularly a type of hyperkalemia in which the blood potassium concentration acutely increases, and the intracellular concentration does not decrease. The causes are mainly excessive intake or input of potassium, decreased excretion of potassium by the kidney (increased body potassium content), and tissue destruction (normal body potassium content).

[0034] The term "chronic hyperkalemia" as used herein refers to a type of hyperkalemia in which the blood potassium concentration gradually increases above the upper limit of the normal value over a long period of time, particularly a type of hyperkalemia in which the blood potassium concentration gradually increases, and the intracellular concentration does not decrease. The causes are mainly excessive intake or input of potassium, decreased excretion of potassium by the kidney (increased body potassium content), and tissue destruction (normal body potassium content).

[0035] The term "pharmaceutically acceptable" as used herein refers to those substances suitable for use with human and animal tissues without substantial toxicity, irritation, allergic response, commensurate with a reasonable benefit / risk ratio.

[0036] The term "unit dosage form" as used herein refers to a physically discrete unit suitable for administration to a human or other animal, comprising a predetermined quantity of active ingredient and optionally excipients. Non-limiting examples of unit dosage forms include vials, tablets, capsules, suspensions, powders packets, and the like. The unit dosage form of the present application is preferably a dry suspension.

[0037] The term "dry suspension" as used herein refers to a powder mixture packaged in a sachet which is suspended in a suitable liquid, such as warm water, prior to use for oral administration. The dry suspension of the present application contains 3 g or 6 g of the polymeric salt of the present application and an appropriate amount of pharmaceutically acceptable excipients.

[0038] In a first aspect, the present application provides a dosing regimen of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt for administration to an individual in need of treatment for hyperkalemia, said dosing regimen comprising a first phase (i.e., an acute treatment phase or a correction treatment phase) dosing regimen, said first phase dosing regimen being oral administration of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt to said individual, 3 times daily, each administration being between 3 g and 48 g, such as 3 g, 6 g, 9 g, 12 g, 15 g, 18 g, 21 g, 24 g, 27 g, 30 g, 33 g, 36 g, 39 g, 42 g, 45 g, 48 g, for 2 consecutive days.

[0039] In one embodiment of the first aspect, said first phase dosing regimen is oral administration of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt to said individual, 3 times daily, each administration being between 6 g and 48 g, for 2 consecutive days.

[0040] In another embodiment of the first aspect, said first phase dosing regimen is oral administration of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt to said individual, 3 times daily, each administration being between 6 g and 36 g, for 2 consecutive days.

[0041] In another embodiment of the first aspect, said first phase dosing regimen is oral administration of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt to said individual, 3 times daily, each administration being between 6 g and 24 g, for 2 consecutive days.

[0042] In another embodiment of the first aspect, the dosing regimen of the first phase is that the individual is orally administered poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt 3 times daily, 6-18 g, such as 6 g, 9 g, 12 g, 15 g, or 18 g per administration, for 2 consecutive days.

[0043] In another embodiment of the first aspect, the dosing regimen of the first phase is that the individual is orally administered poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt 3 times daily, 12 g per administration, for 2 consecutive days.

[0044] In a second aspect, the present application provides a dosing regimen of administering poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt to an individual in need of treatment of hyperkalemia, the dosing regimen comprising the dosing regimen of the first phase as described above, and further comprising a dosing regimen of a second phase (i.e., a maintenance treatment phase) following the dosing regimen of the first phase, the dosing regimen of the second phase being that the individual is orally administered poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt 3-48 g (such as 3 g, 4 g, 5 g, 6 g, 9 g, 12 g, 15 g, 18 g, 21 g, 24 g, 27 g, 30 g, 33 g, 36 g, 39 g, 42 g, 45 g, 48 g), preferably 4-48 g, 5-48 g, or 6-48 g, once daily or once every other day.

[0045] In an embodiment of the second aspect, the dosing regimen of the second phase is that the individual is orally administered poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt 6-24 g, once daily or once every other day.

[0046] In another embodiment of the second aspect, the dosing regimen of the second phase is that the individual is orally administered poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt 6-18 g, such as 6 g, 9 g, 12 g, 15 g, or 18 g, once daily or once every other day.

[0047] In another embodiment of the second aspect, a dosing regimen of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt for administering to an individual in need of treatment of hyperkalemia is provided, the dosing regimen comprising a first stage dosing regimen and a second stage dosing regimen, the first stage dosing regimen being oral administration of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt to the individual 3 times a day at 12 g each administration for 2 consecutive days, and the second stage dosing regimen being oral administration of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt to the individual once a day at 6-18 g, e.g., 6 g, 12 g, or 18 g each administration.

[0048] In the second stage dosing regimen, poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt can be administered to the individual for any desired period of time. In one embodiment, in the second stage dosing regimen, poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt can be administered to the individual for, e.g., about 1 month to about 12 months.

[0049] The specific dosing amount of the polymeric salt of the present application in the first stage and second stage dosing regimen and the duration of administration in the second stage dosing regimen can be determined by a clinician as appropriate according to the age, gender, body weight, serum potassium level, concomitant medication, etc. of the individual. For example, in the second stage dosing regimen, the dosing amount of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt can be increased or decreased as appropriate in increments of 3 g or 6 g as appropriate according to the serum potassium concentration of the patient, and the patient can be administered poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt for one month or more. For example, in the second stage treatment, if the patient's blood potassium concentration is in the range of 3.5-5.5 mmol / L (including the boundary values), the patient can be given 12 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt once a day; in the second stage treatment, if the patient's blood potassium concentration is in the range of 3.5-4.0 mmol / L (including the boundary values) after treatment, the patient can be given 6 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt once a day; in the second stage treatment, if the patient's blood potassium concentration is greater than 5.5 mmol / L after treatment, the patient can be given 18 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt once a day. If the patient's blood potassium is continuously between 3.5-4.0 mmol / L (including the boundary values), the patient can be given 6 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt once every other day.

[0050] In a third aspect, the present application provides a method of treating hyperkalemia in an individual, the method comprising administering poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt to the individual according to the dosage regimen of the first aspect or the second aspect.

[0051] In a fourth aspect, the present application provides use of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in the manufacture of a medicament for treating hyperkalemia in an individual, wherein the poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt is administered to the individual according to the dosage regimen of the first aspect or the second aspect.

[0052] In a fifth aspect, the present application provides a dry suspension for oral administration comprising 3 g or 6 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt, and optionally a pharmaceutically acceptable excipient, for use in the treatment of hyperkalemia.

[0053] In an embodiment of the fifth aspect, the present application provides a dry suspension for oral administration comprising 1 g, 3 g or 6 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt, and comprising xanthan gum and silicon dioxide or a solid powder flavour comprising silicon dioxide, wherein the xanthan gum comprises > 0.5% (e.g. 0.5% to 20%, 0.5% to 15%, 0.5% to 10%, 0.5% to 5%, 0.5% to 2%) of the poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt by weight and the silicon dioxide comprises > 0.05% to < 3%, e.g. > 0.05% to < 3%, e.g. > 0.05% to 2.5%, 0.06% to 2.4%, 0.07% to 2.3%, 0.08% to 2.2%, 0.09% to 2.1%, or 0.1 to 2% of the poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt.

[0054] The dry suspensions described herein are for administering poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt to an individual having hyperkalemia according to the dosage regimen of the first aspect or the second aspect. EXAMPLE

[0055] Example 1. Preparation of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt

[0056] Poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt was prepared according to Example 3 of PCT application WO2023 / 088111A1.

[0057] Example 2. Preparation of test drug and placebo

[0058] Preparation of test drug:

[0059] Poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt dry suspension was prepared as follows:

[0060] (1) The lime powder essence was crushed and passed through a 100 mesh sieve to obtain a powder;

[0061] (2) The required amount of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, xanthan gum and the powder obtained in step (1) were weighed and added to a three-dimensional mixer, mixed at 10 rpm for 5 min to obtain a mixture;

[0062] (3) The mixture obtained in step (2) was passed through a 100 mesh sieve and then mixed at 10 rpm for 5 min to obtain a final mixture;

[0063] (4) The final mixture obtained in step (3) was filled into small bags with aluminum foil lining at 3.06 g or 6.12 g per bag to obtain a dry suspension containing 3 g of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt per bag, sealed and stored in cold storage (2-8°C).

[0064] The dry suspension prepared above is used for oral administration with warm boiled water (water temperature does not exceed 60°C).

[0065] Preparation of placebo:

[0066] The placebo was prepared as follows: the microcrystalline cellulose pill core, xanthan gum, lime powder essence, colorant were mixed to obtain a yellow to brown powder, which was filled into packages, 3.06 g / bag or 6.12 g / bag, sealed and stored in cold storage (2-8°C). It is used for oral administration with warm boiled water.

[0067] The test drug and placebo are basically consistent in appearance, odor, and properties.

[0068] Example 3. Phase I clinical trial of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt

[0069] 3.1 Test name

[0070] First human, single-center, randomized, double-blind, placebo-controlled evaluation of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt in Chinese healthy people for single and multiple dosing safety, tolerability study.

[0071] 3.2 Experimental purpose

[0072] Primary objective: To evaluate the tolerability and safety of single-dose escalation and multiple-dose escalation of oral poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt in healthy subjects.

[0073] Secondary objectives: To study the pharmacodynamic (PD) characteristics of single ascending and multiple ascending doses of oral poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in healthy subjects, to evaluate the changes in serum potassium, urinary and fecal potassium concentrations from baseline, and to provide the basis for the dosing regimen of the phase II clinical trial.

[0074] Exploratory objectives: To explore the effects of oral poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt on blood electrolytes (sodium, magnesium, calcium) in healthy subjects.

[0075] 3.3 Subjects

[0076] A total of 64 healthy volunteers, including males and females, were enrolled.

[0077] Inclusion criteria:

[0078] (1) The subject fully understands the purpose, nature, method of the trial and possible adverse reactions, voluntarily agrees to be a subject, and signs the informed consent form before any study procedure begins, and the informed consent process complies with GCP (Good Clinical Practice);

[0079] (2) Chinese healthy male or female volunteers aged 18-45 years (including the boundary value);

[0080] (3) Body weight ≥ 50 kg for males and ≥ 45 kg for females, and body mass index (BMI): 19.0-26.0 kg / m 2 , [including the boundary value, body mass index = weight (kg) / height 2 (m 2 )];

[0081] (4) The subject understands and complies with the study procedures, can communicate well with the investigator, voluntarily participates in the trial, and signs the informed consent form.

[0082] Any subject who does not meet the above conditions is not eligible to be enrolled as a subject.

[0083] Exclusion criteria:

[0084] If a subject meets any of the following criteria before screening or dosing, he / she cannot enter the study:

[0085] (1) Has a specific history of allergies (asthma, urticaria, eczema, etc.) or is allergic (e.g., known to be allergic to two or more substances), or has a known history of allergy to poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt and related excipients;

[0086] (2) have a history of chronic or serious diseases of liver, kidney, digestive tract, endocrine system, cardiovascular and cerebrovascular system, nervous system, metabolic system, blood system, respiratory system and autoimmune system, etc. or existing diseases of the above systems, and those who are judged by the investigator to be unsuitable for inclusion;

[0087] (3) have received surgery within 3 months before screening, or plan to undergo surgery during the study, and those who have received surgery that will affect drug absorption, distribution, metabolism, excretion;

[0088] (4) have difficulty swallowing or any gastrointestinal disease / symptoms that the investigator judges to affect drug absorption;

[0089] (5) are known to be unable to tolerate intravenous catheters or venous blood sampling and / or have difficulty with blood sampling, have a history of needle phobia or blood phobia;

[0090] (6) have smoked ≥5 cigarettes per day on average within 3 months before screening, or cannot stop using any tobacco products during the trial;

[0091] (7) have received blood transfusion or used blood products ≥400 mL or 2 units within 3 months before screening, or have lost blood ≥400 mL within 6 months, or have donated blood within 3 months;

[0092] (8) have participated in other clinical trials within 3 months before screening (the time of the last visit of the last trial is the start time) or have participated in clinical trials other than this one;

[0093] (9) have used any prescription drugs (including vaccines), non-prescription drugs within 4 weeks before screening;

[0094] (10) have used traditional Chinese medicine or health products for the treatment and / or prevention of their own diseases within 2 weeks before screening;

[0095] (11) have special requirements for diet, cannot comply with the unified diet (such as intolerance to standard food, intolerance to lactose, etc.), or cannot avoid eating foods or drinks rich in caffeine (coffee, tea, chocolate, etc.) within 72 hours before administration until the end of the study;

[0096] (12) women in pregnancy or lactation period, or those with positive results of pregnancy test before the trial; male subjects (or their partners) or female subjects who have plans for pregnancy, sperm donation or egg donation from the signing of the informed consent form to 6 months after the end of administration, and those who are unwilling to use a medically recognized non-drug contraceptive method (such as intrauterine device or condom) during the trial;

[0097] (13) have abnormal results of physical examination, vital sign examination, electrocardiogram examination, laboratory examination (including blood routine, urine routine, blood biochemistry, coagulation function), abdominal B-ultrasound examination, chest X-ray examination, which are judged by the investigator to be clinically significant;

[0098] (14) Positive for viral screening (hepatitis B surface antigen (HBsAg), HCV quantification, HIV quantification, Treponema pallidum antibody);

[0099] (15) Subjects with a history of drug abuse within 12 months prior to screening, or who have used drugs of abuse within 3 months prior to screening, or who have a positive urine drug screen;

[0100] (16) Subjects with a positive alcohol breath test, or who regularly drink alcohol, i.e., more than 14 units of alcohol per week (1 unit = 200 mL of beer or 25 mL of spirits or 85 mL of wine) on average, within 3 months prior to screening, or who are unable to abstain from alcohol during the trial;

[0101] (17) Subjects who have suffered from a disease or who have used a drug that, in the opinion of the investigator, precludes their inclusion in the study from screening to -3 days prior to admission to the hospital;

[0102] (18) Subjects who, in the opinion of the investigator, are not suitable for inclusion in the study.

[0103] 3.4 Trial design

[0104] The trial comprises two parts.

[0105] The first part of the trial is a simple ascending dose (SAD) study with a total of 40 subjects, who are randomly assigned to 5 groups of 8 subjects each (male and female) to receive the polymer salt of the present application or placebo in order to assess safety, tolerability and PD characteristics. Of the 8 subjects in each group, 6 subjects receive the polymer salt of the present application and 2 subjects receive placebo. The 5 groups are dosed at 6 g, 12 g, 24 g, 36 g and 48 g, respectively, once daily for 1 day. The polymer salt of the present application and placebo are taken in the fasted state.

[0106] The second part of the trial is a multiple ascending dose (MAD) study with a total of 24 subjects, who are randomly assigned to 3 groups of 8 subjects each (male and female) to receive the polymer salt of the present application or placebo. Of the 8 subjects in each group, 6 subjects receive the polymer salt of the present application and 2 subjects receive placebo. The 3 groups are dosed at 12 g, 24 g and 48 g, respectively, once daily for 7 days. The polymer salt of the present application and placebo are taken in the fasted state.

[0107] 3.5 Evaluation criteria

[0108] The evaluation criteria comprise three categories.

[0109] Safety endpoints:

[0110] (1) Adverse events (TEAEs) occurring during the treatment period, etc.

[0111] (2) Changes in clinical safety indicators: physical examination, vital signs (blood pressure, body temperature, pulse), clinical laboratory tests (blood routine, blood biochemistry, blood glucose, blood coagulation function, urine routine, fecal routine), 12-lead electrocardiogram;

[0112] Pharmacodynamic endpoints:

[0113] (1) Serum potassium (K + ) levels;

[0114] (2) Urinary potassium (K + ) excretion;

[0115] (3) Fecal potassium (K + ) excretion.

[0116] Exploratory endpoints: electrolytes (sodium, magnesium, calcium)

[0117] 3.6 Trial results

[0118] (1) SAD study results

[0119] Among the 40 subjects, a total of 25 subjects (62.5%) reported adverse events (AEs). The composition of the 25 subjects who reported AEs was 21 subjects (accounting for 70.0% of the subjects who received poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt) who received poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt and 4 subjects (accounting for 40.0% of the subjects who received placebo) who received placebo. No subjects had serious adverse events (SAEs), serious adverse reactions, AEs leading to early withdrawal, adverse reactions leading to early withdrawal, and AEs leading to death during the study. Except for 1 subject in the placebo group who reported a grade 2 decrease in white blood cell count, all other AEs were grade 1.

[0120] After a single oral administration of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt 6 g to 48 g, there was a trend of decreasing blood potassium concentration with increasing dose. The relative baseline change value and the relative baseline percentage of blood potassium concentration after administration were higher than those in the placebo group, indicating a hypokalemic effect. In addition, there was a trend of daily decrease in the daily urinary potassium excretion of subjects in the administration group on the 1st, 2nd, and 3rd days after administration compared with baseline.

[0121] (2) MAD study results

[0122] Among the 24 subjects, a total of 21 subjects (87.5%) reported AEs. The composition of the 21 subjects who reported AEs was 16 subjects (accounting for 88.9% of the subjects who received poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt) who received poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt and 5 subjects (accounting for 83.3% of the subjects who received placebo) who received placebo. No SAEs, serious adverse events, AEs leading to early withdrawal, adverse events leading to early withdrawal, and AEs leading to death occurred in the subjects during the study. Except for 1 subject who reported grade 2 hypertriglyceridemia in the subject who received 24 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt, all other AEs were grade 1.

[0123] After the healthy subjects were orally administered with poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt 12 g-48 g once a day for 7 consecutive days, the blood potassium concentration showed a tendency to decrease with the increase of the dose, and the relative baseline change value and the relative baseline change percentage of the blood potassium concentration after administration were higher than those of the placebo group, indicating that there was a hypokalemic effect. The percentage of fecal potassium excretion showed a dose-dependent increase. Compared with the baseline, the daily average excretion of fecal potassium showed a certain increasing trend (at each time point after administration at each dose, the P value was greater than 0.05). The percentage of urinary potassium excretion showed a dose-dependent decrease. Compared with the baseline, the daily average excretion of urinary potassium showed a decreasing trend.

[0124] The results of the above-mentioned phase I clinical trial proved that whether it was single administration or multiple administration, at a daily dose of up to 48 g, the oral administration of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt was safe and well tolerated. After the subjects were orally administered with poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt, the fecal potassium excretion gradually increased, and the corresponding urinary potassium excretion gradually decreased, indicating that poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt showed a hypokalemic effect.

[0125] Example 4. Phase II clinical trial of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt

[0126] 4.1 Test name

[0127] A multicenter, randomized, double-blind, placebo parallel control, dose exploration phase II clinical study on the effectiveness and safety of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt dry suspension in the treatment of hyperkalemia.

[0128] 4.2 Experimental purpose

[0129] To preliminarily evaluate the effectiveness and safety of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt dry suspension in the treatment of hyperkalemia.

[0130] 4.3 Subjects

[0131] A total of 140 subjects were enrolled in this study.

[0132] Inclusion Criteria

[0133] Subjects must meet all of the following criteria to be eligible for enrollment:

[0134] (1) Age ≥ 18 years, both male and female;

[0135] (2) Mean serum potassium value > 5.0 mmol / L and < 6.5 mmol / L at two consecutive screening visits (60 ± 10 minutes apart);

[0136] (3) Must be informed about the trial and voluntarily sign a written informed consent form, be able to communicate with the investigator and comply with the requirements of the clinical trial (scheduled visits, laboratory tests, and other trial procedures).

[0137] Exclusion Criteria

[0138] Subjects with any of the following conditions were not eligible for enrollment in the trial:

[0139] (1) Pseudohyperkalemia due to improper blood collection (e.g., tight tourniquet, excessive local rubbing, repeated fist-clenching and unclenching), difficulty or trauma in venipuncture leading to hemolysis of the blood sample, or severe leukocytosis (> 50 x 10^9 / L) or thrombocytosis (> 500 x 10^9 / L);

[0140] (2) Hyperkalemia requiring urgent intervention as assessed by the investigator: e.g., presence of marked ECG abnormalities (e.g., flattened or absent P waves, widened QRS complex), or presence of neuromuscular symptoms;

[0141] (3) Presence of uncontrolled or hemodynamically unstable arrhythmia with cardiac arrest or syncope, or other arrhythmia requiring immediate treatment;

[0142] (4) Presence of symptomatic or uncontrolled post-treatment atrial fibrillation, or asymptomatic persistent ventricular tachycardia (patients with controlled post-treatment atrial fibrillation were allowed to enter the study after assessment by the investigator);

[0143] (5) Presence of a disease requiring immunosuppressive therapy and predicted inability to discontinue immunosuppressive therapy during the treatment period, or use of immunosuppressive therapy that, in the investigator's opinion, affects serum potassium levels;

[0144] (6) Patients with congenital long QT syndrome, or with a history of drug-related QT interval prolongation that required discontinuation of the drug, or with a QTcF > 550 ms on screening ECG;

[0145] (7) Patients with type 1 diabetes mellitus, or with diabetic ketoacidosis within 1 month prior to screening;

[0146] (8) Patients who have been hospitalized for acute worsening of heart failure within 3 months prior to screening;

[0147] (9) Patients with a prior or current diagnosis of severe swallowing disorders, moderate to severe gastrointestinal dysfunction, or major gastrointestinal surgery (e.g., bariatric surgery or colectomy);

[0148] (10) Patients who are currently on maintenance hemodialysis or peritoneal dialysis;

[0149] (11) Patients known or suspected to be hypersensitive to poly(2-fluoropropenyl acid-pentaerythritol triallyl ether) iron calcium sodium salt dry suspension or any of its components;

[0150] (12) Patients who have received sodium polystyrene sulfonate, calcium polystyrene sulfonate, patisiran (Veltassa), or zirconium silicate sodium cyclate within 3 days prior to the first dose of study drug;

[0151] (13) Patients with difficult venous access;

[0152] (14) Patients who have undergone coronary artery bypass grafting, percutaneous intervention (e.g., cardiac, cerebrovascular, aortic), or major surgery including thoracic and cardiac surgery within 3 months prior to screening, or who are expected to undergo such procedures during the study;

[0153] (15) Patients who have received a heart or kidney transplant, or who are expected to require a transplant during the study;

[0154] (16) Patients with an AST or ALT more than 3 times the upper limit of normal at screening;

[0155] (17) Patients with a diagnosis of malignancy who are currently receiving antineoplastic therapy that is not under control, or who have uncontrolled systemic or psychiatric disease, who, in the investigator’s opinion, are not suitable for participation in the study;

[0156] (18) Patients with a life expectancy of less than 3 months;

[0157] (19) Patients who are positive for any of the following at screening: human immunodeficiency virus (HIV) antibody, Treponema pallidum antibody, hepatitis C virus (HCV) antibody, or hepatitis B surface antigen (HBsAg) (active hepatitis B as assessed by the investigator);

[0158] (20) Subjects who have received any other investigational drug treatment or participated in another interventional clinical trial within 3 months prior to the screening visit;

[0159] (21) Pregnant or lactating women, or female subjects who have had unprotected sexual intercourse within the last 2 weeks, or female subjects with a positive pregnancy test; subjects (or their partners) who are willing to donate sperm / ova, have a plan to conceive, or are unwilling to take one or more contraceptive measures during the trial and for 6 months after the end of the study;

[0160] (22) Any condition that, in the opinion of the investigator, might affect the subject's ability to give informed consent or to comply with the trial regimen, or that might affect the trial outcome or the subject's safety.

[0161] 4.4 Trial Design

[0162] This study is a multicenter, randomized, double-blind, placebo-controlled, dose exploration design. The study is divided into two parts: Part A (acute treatment period) and Part B (maintenance treatment period).

[0163] Part A (acute treatment period)

[0164] The 140 subjects who meet the requirements will be randomly assigned to the following 4 groups (21 subjects in the low-dose group, 42 subjects in the medium-dose group and the high-dose group, and 35 subjects in the control group) to enter the acute treatment period of 48 hours, with 3 doses per day (at least half an hour before meals) and a total of 6 doses.

[0165] Table 1 Grouping and administration method in acute treatment period

[0166] The day the subject starts taking the drug is defined as D1. Blood potassium is measured once before the first dose. Blood potassium is measured at 1 h, 2 h, and 4 h (before the second dose) after the first dose, 1 h before the fourth dose, and 1 h and 4 h after the fourth dose (before the fifth dose), 48 h after the first dose.

[0167] Part B (maintenance treatment period)

[0168] After the acute treatment period, according to the measured blood potassium value at 48 h after the first dose, subjects in the low-dose, medium-dose, and high-dose groups are randomly assigned again to the trial group and the control group in a ratio of 3:1 if they reach normal blood potassium (3.5-5.0 mmol / L, including the boundary value) to enter the 12-day maintenance treatment period with 1 dose per day (qd) (at least half an hour before breakfast); subjects in the control group are randomly assigned again to the low-dose, medium-dose, and high-dose trial groups in a ratio of 1:1:1 if they reach normal blood potassium to enter the 12-day maintenance treatment period with 1 dose per day (qd) (at least half an hour before breakfast).

[0169] Table 2 Grouping and medication method in maintenance treatment period

[0170] The subjects were measured for blood potassium once within 1 hour before administration on D3, D7, and D10, and once on D15. After the end of the maintenance treatment period, the subjects underwent a safety check, and were followed up 7 ± 2 days after the last administration at the end of the maintenance treatment period, and were measured for blood potassium.

[0171] 4.5 Test indicators

[0172] Primary effectiveness indicators:

[0173] Part A (acute treatment period): the exponential change rate of the blood potassium value (S-K) level within 48 hours of treatment.

[0174] Part B (maintenance treatment period): the exponential change rate of the blood potassium value (S-K) level during the maintenance treatment period (D3-D15).

[0175] Secondary effectiveness indicators:

[0176] Part A (acute treatment period)

[0177] (1) the average change of the blood potassium value at all time points within 48 hours of the treatment period from the baseline;

[0178] (2) the average percentage change of the blood potassium value at all time points from the baseline;

[0179] (3) the percentage of subjects whose blood potassium value returned to normal at all time points within 48 hours of the treatment period;

[0180] (4) the time at which the blood potassium value of the subjects returned to normal;

[0181] (5) the time at which the blood potassium value of the subjects decreased by 0.5 mmol / L from the baseline.

[0182] Part B (maintenance treatment period)

[0183] (1) the average change of the blood potassium value at all time points during the maintenance treatment period from the baseline of the maintenance treatment period;

[0184] (2) the average percentage change of the blood potassium value at all time points during the maintenance treatment period from the baseline of the maintenance treatment period;

[0185] (3) the time (days) during which the blood potassium value of the subjects remained normal (3.5-5.0 mmol / L);

[0186] (4) the time at which the blood potassium value of the subjects increased by 0.5 mmol / L from the baseline;

[0187] (5) Percentage of subjects who maintained normal serum potassium values (values between 3.5-5.0 mmol / L) at the end of the maintenance treatment period (D15);

[0188] (6) Time to recurrence of hyperkalemia (defined as return to acute treatment period baseline value or higher) during the maintenance treatment period.

[0189] Safety measures

[0190] Safety assessments were based on serious adverse events, adverse events, vital signs, physical examinations, laboratory tests, and 12-lead electrocardiogram tests.

[0191] 4.6 Trial results

[0192] Analysis was performed on 140 subjects, and the results showed that:

[0193] Within 48 h of the acute treatment period, the change rate of the potassium index of the 3 g, 6 g, and 12 g treatment groups of the polymer salt of the application was 0.19%, 0.17%, and 0.33% per hour, respectively, and that of the placebo group was only 0.13%. The change rate of the potassium index of the 12 g treatment group of the polymer salt of the application was statistically different from that of the placebo group (P<0.0001). One hour after the first administration in the acute treatment period, the average decrease in serum potassium from baseline was 0.22, 0.19, and 0.20 mmol / L for the 3 g, 6 g, and 12 g groups of the polymer salt of the application, respectively, and was only 0.05 mmol / L for the placebo group. In the 48 h of the acute treatment period, the decrease in serum potassium of the three treatment groups of the polymer salt of the application showed an obvious increasing trend with the extension of the treatment time. The decrease in serum potassium of the 3 g and 12 g treatment groups of the polymer salt of the application exceeded 0.5 mmol / L at 25 h and 24 h after the first administration, respectively. At 48 h after the first administration, the average decrease in serum potassium from baseline was 0.56, 0.51, and 0.86 mmol / L for the 3 g, 6 g, and 12 g treatment groups of the polymer salt of the application, respectively, and was only 0.35 mmol / L for the placebo group. The proportion of the 3 g, 6 g, and 12 g treatment groups of the polymer salt of the application in which serum potassium returned to normal was more than 70%, and was 71.4%, 72.5%, and 82.5%, respectively, while that of the placebo group was only 51.4%. The average serum potassium of the 3 g, 6 g, and 12 g treatment groups of the polymer salt of the application decreased to the normal range, and was 4.72, 4.79, and 4.57 mmol / L, respectively, while that of the placebo group was >5.0 mmol / L (5.08 mmol / L).

[0194] During the maintenance treatment period (D3-D15), the blood potassium index of the treatment groups of the polymer salt of the present application increased compared to the end of the acute treatment period, wherein the rate of change of the blood potassium index of the 6g and 12g treatment groups increased less per day than the corresponding placebo groups, the 6g treatment group and the corresponding placebo group increased the rate of change of the blood potassium index at the end of the acute treatment period by 0.47% and 0.85% per day, respectively, and the 12g treatment group and the corresponding placebo group increased the rate of change of the blood potassium index at the end of the acute treatment period by 0.90% and 1.24% per day, respectively. At the end of the maintenance treatment period (D15), the proportion of subjects in the 6g and 12g treatment groups of the polymer salt of the present application whose blood potassium remained in the normal range was greater than the corresponding placebo groups, 72.2% and 50% of subjects in the 6g treatment group and the corresponding placebo group, respectively, had blood potassium in the normal range, and 76.5% and 33.3% of subjects in the 12g treatment group and the corresponding placebo group, respectively, had blood potassium in the normal range. At the end of the maintenance treatment period, the measured blood potassium of the 3g treatment group and the corresponding placebo group of the polymer salt of the present application was 4.99 mmol / L and 4.92 mmol / L, respectively, the measured blood potassium of the 6g treatment group and the corresponding placebo group was 4.79 mmol / L and 5.14 mmol / L, respectively, and the measured blood potassium of the 12g treatment group and the corresponding placebo group was 4.84 mmol / L and 5.11 mmol / L, respectively.

[0195] The above data suggest that, during the acute treatment period, a single dose of 3g, administered 3 times a day for 2 consecutive days, for a total of 6 doses, can effectively reduce blood potassium, and the onset time is about 1 hour. The results of the acute treatment period show that even the 3g group had a significantly higher blood potassium target rate than the placebo group. During the maintenance treatment period, the polymer salt of the present application also effectively maintains blood potassium in the normal range and prevents the recurrence of hyperkalemia.

[0196] During the acute treatment period, 28 subjects (26.9%) in all treatment groups of the polymer salt of the application reported AEs, and 7 subjects (20.0%) in the placebo group; during the maintenance treatment period, 17 subjects (27.0%) in all treatment groups of the polymer salt of the application reported adverse events, and 5 subjects (31.3%) in the placebo group. During the study, a total of 9 AEs were grade 3 and above, of which only 2 were SAEs (1 in the 12g treatment group of the acute treatment period and 1 in the 12g treatment group of the maintenance treatment period), but both were judged to be unrelated to the test drug; a total of 6 AEs were judged to be related to the test drug, of which 1 was hard stool, which occurred in the 6g treatment group of the maintenance treatment period, was grade 2 in severity, and recovered after symptomatic treatment with Klyant; 2 were diarrhea, both of which occurred in the acute treatment period, were grade 1 in severity (1 in the 6g treatment group, recovered without special treatment, and 1 in the 12g treatment group, recovered after symptomatic treatment with Smecta); 2 were hypokalemia, both of which occurred in the 12g treatment group of the acute treatment period, were grade 1 in severity (1 recovered without special treatment, and the outcome of the other adverse event was lost to follow-up); and 1 was sinus bradycardia, which occurred in the 6g treatment group of the acute treatment period, was grade 1 in severity, and recovered without special treatment. None of the 6 AEs judged to be related to the test drug affected the administration of the test drug. The serum magnesium in the treatment groups decreased slightly from baseline, but there was no significant clinical significance, and no hypomagnesemia-related AE was reported. There was no significant change in other electrolytes (serum phosphorus, serum calcium, serum sodium) from baseline.

[0197] Example 5. Phase III clinical trial of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt

[0198] 5.1 Name of the trial

[0199] A multi-center, randomized, double-blind, placebo-controlled phase III clinical study to evaluate the effectiveness and safety of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt in the treatment of patients with hyperkalemia

[0200] 5.2 Description of the trial

[0201] This clinical trial includes two parts, Part A and Part B.

[0202] Part A is a multi-center, multi-dose group, prospective, randomized, double-blind, placebo-controlled study, aiming to evaluate the effectiveness and safety of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt in patients with hyperkalemia.

[0203] Part A includes 2 phases: the first phase is a 2-day correct phase (CP) (also known as a correct hyperkalemia treatment phase), which is a randomized, double-blind, placebo-controlled design, aiming to correct hyperkalemia within 48 hours; the second phase is a maintenance phase (MP), which is a randomized, double-blind, placebo-controlled design; after the 2-day correct hyperkalemia treatment, subjects whose blood potassium returns to the normal range can be randomly assigned to different treatment dose groups and placebo groups for maintenance treatment for 28 days, aiming to maintain the blood potassium of the subjects in the normal range. The main study of this trial is to compare the effectiveness of oral administration of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt once a day with placebo in maintaining the normal concentration range (3.5-5.0 mmol / L, including the boundary value) of blood potassium in hyperkalemia subjects after 2 days of correct hyperkalemia treatment and blood potassium reaching the target.

[0204] The subjects of Part B (open label extension, OLE) come from Part A and meet certain blood potassium inclusion criteria for an open, 11-month long-term safety study.

[0205] 5.3 Purpose of the trial

[0206] The main purpose of Part A: to evaluate the effectiveness and safety of different doses of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in maintaining blood potassium in the normal range (blood potassium: 3.5-5.0 mmol / L, including the boundary value) in subjects whose blood potassium reached the target after the initial 2-day correction period treatment, by oral administration once a day for 28 consecutive days.

[0207] The secondary purpose of Part A: to evaluate the effectiveness and safety of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in the initial 2-day correction of hyperkalemia; to evaluate the effect of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt on other electrolytes.

[0208] The main purpose of Part B: to evaluate the long-term safety of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in the extension phase.

[0209] The secondary purpose of Part B: to evaluate the long-term effectiveness of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in the extension phase.

[0210] 5.4 Subjects

[0211] The sample size calculation of this trial is mainly based on the primary endpoint of Part A, and about 420 adult patients diagnosed with hyperkalemia will be included.

[0212] Inclusion Criteria for Part A:

[0213] (1) Adult male or female aged > 18 years;

[0214] (2) Serum potassium concentration > 5.0 mmol / L and < 6.5 mmol / L at screening (serum potassium concentration can be measured by i-STAT portable biochemical detector);

[0215] (3) Negative pregnancy test at screening and ensure to take contraceptive measures during the trial period;

[0216] (4) Understand and voluntarily sign the informed consent form.

[0217] Exclusion Criteria for Part A:

[0218] (1) History of serious drug allergy, or clear allergy to the study drug or its drug ingredients;

[0219] (2) Pseudohyperkalemia, such as blood potassium elevation caused by hemolysis of blood samples due to improper blood collection methods (such as too tight tourniquet, too heavy local rubbing, repeated fist-clenching and hand-unclenching); hemolysis of blood samples due to difficult or traumatic venipuncture; severe leukocytosis (> 50 x 10^9 / L) or thrombocytosis (> 500 x 10^9 / L);

[0220] (3) Patients with acute hyperkalemia caused by tumor lysis syndrome or hemolytic anemia, etc.;

[0221] (4) Patients with severe cerebrovascular diseases such as cerebral infarction or cerebral hemorrhagic diseases, and have language barriers or delayed response, or severe limb movement disorders;

[0222] (5) Subjects with myocardial infarction or coronary arteriosclerotic heart disease such as angina pectoris within 3 months before screening, or patients with heart failure and cardiac function classification IV (New York Heart Association, NYHA classification standard) at screening;

[0223] (6) Patients with arrhythmias requiring emergency treatment at screening, such as ventricular tachycardia, ventricular fibrillation, II-III degree atrioventricular block, severe bradycardia (heart rate < 40 times / min), etc., or patients with obvious PR interval prolongation (PR interval prolongation to more than 0.25 seconds without atrioventricular block), decreased or disappeared P wave amplitude, widened QRS wave (widened to more than 0.14 seconds without bundle branch block) in electrocardiogram at screening;

[0224] (7) Patients who have previously undergone major gastrointestinal surgery such as subtotal gastrectomy, short bowel syndrome, etc. affecting normal peristalsis of the gastrointestinal tract; or patients with intractable constipation;

[0225] (8) Patients who have received treatment with polyacrylate exchange resin or similar drugs such as sodium zirconium cyclosilicate within 3 days prior to screening;

[0226] (9) Patients who have participated in clinical trials of other unapproved marketed drugs or devices within 3 months prior to the first dose;

[0227] (10) Patients who are undergoing dialysis treatment;

[0228] (11) Subjects with severe liver function impairment: serum glutamic-pyruvic transaminase or glutamic-oxalacetic transaminase more than 3 times the upper limit of normal; or

[0229] (12) Patients with any other illness or mental condition that, in the investigator's assessment, would prevent them from completing the trial, or in whom the risks of participating in the trial far outweigh the potential benefits, according to the investigator's assessment.

[0230] Inclusion criteria for Part B:

[0231] Patients who have completed the visit on Day 29 of Part A and have a blood potassium level of 3.5-6.2 mmol / L (including the boundary values) as measured by i-STAT; or patients who have prematurely withdrawn from the maintenance treatment period of Part A due to low or high blood potassium, and patients who have a blood potassium level of <3.5 mmol / L or >6.2 mmol / L on Day 29 of the maintenance treatment period, can be included in the Part B extension study if they have a blood potassium level of 3.5-6.2 mmol / L (including the boundary values) within 2 days after the last dose and have not been treated with other similar potassium-lowering drugs. Patients who meet the above blood potassium criteria can start the medication of Part B within 2 days after the last dose of Part A.

[0232] 5.5 Dose and administration method

[0233] 5.5.1 Dose and administration method of Part A

[0234] Initial treatment: poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt, 12 g each time, oral, 3 times a day, continuously for 2 days, a total of 6 doses; placebo, 3 times a day, oral, a total of 6 doses.

[0235] Maintenance treatment: poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt, 6 g, 12 g, 18 g and placebo, 1 time a day, oral, continuously for 28 days.

[0236] For each subject individually, if the subject is potassium responsive, the study duration includes a screening period of up to 7 days, a high potassium correction treatment period of 2 days, a maintenance treatment period of 28 days, and a safety visit period of 7 days after treatment completion. If the subject is not potassium responsive, the individual study duration includes a screening period of up to 7 days, a correction treatment period of 2 days, and a safety visit period of 7 days after treatment completion. If the subject is unable to enter Part B of the study, the study duration includes a screening period of up to 7 days, a correction treatment period of 2 days, a maintenance treatment period of up to 28 days, and a safety visit period of 7 days.

[0237] 5.5.2 Dose and administration method for Part B

[0238] For subjects with potassium between 3.5-5.5 mmol / L (inclusive) at Visit D29 of Part A, the subjects are directly administered 12 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt per day orally. If the subject has potassium >5.5 mmol / L and <6.2 mmol / L, the subject is first administered 12 g per dose, 3 times per day orally for 24 h or 48 h, and the potassium is detected 24 h or 48 h after administration. If the potassium is between 3.5-5.0 mmol / L (inclusive), the subject can enter the extended administration phase, and is administered 12 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt per day orally. If the fasting morning potassium is not between 3.5-5.0 mmol / L (inclusive) at the latest 48 h (D3 after administration), the subject is withdrawn from the study and cannot be administered the extended medication.

[0239] For subjects who are withdrawn from the maintenance treatment period of Part A due to hypokalemia or hyperkalemia during the maintenance treatment period, or for subjects whose potassium is <3.5 mmol / L or >6.2 mmol / L at Day 29 of the maintenance treatment period, the potassium is detected within 2 days after the last administration. If the potassium is between 3.5-5.5 mmol / L (inclusive), the subject is administered 12 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt per day orally on the same day. If the potassium is >5.5 mmol / L and <6.2 mmol / L, the subject enters a 24-48 h treatment period, and the method and judgment are the same as above. During the extended administration period, the potassium is detected according to the protocol. If the subject has potassium >5.5 mmol / L, the dose is adjusted to 18 g per day orally. If the subject has potassium between 3.5-4.0 mmol / L (inclusive), the dose is adjusted to 6 g per day orally. If the subject has persistent potassium between 3.5-4.0 mmol / L (inclusive), the subject is administered 6 g every other day. If the subject has potassium >4.0 mmol / L and <5.5 mmol / L, the subject is administered 12 g per day orally.

[0240] If a subject who participated in Part A can enter the extension trial phase, it includes a screening period of up to 7 days, a correction treatment period of 2 days, a maintenance treatment period of up to 28 days, and an extension treatment period of 11 months, for a total of 12 months and 10 days or so.

[0241] 5.6 Trial Endpoints

[0242] 5.6.1 Endpoints for Part A

[0243] Primary Endpoint: Mean serum potassium value after 28 days of once-daily oral administration of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt compared with placebo.

[0244] Secondary Endpoints:

[0245] Secondary efficacy endpoints for the correction treatment period:

[0246] • Exponential change rate of serum potassium ion within 48 h;

[0247] • Absolute and percentage changes in serum potassium at different time points after administration compared with baseline;

[0248] • Proportion of subjects whose serum potassium values reached the normal range at 24 h and 48 h after treatment;

[0249] • Time to reach the normal range of serum potassium.

[0250] Secondary efficacy endpoints for the maintenance treatment period:

[0251] • Cumulative duration (calculated in days) of serum potassium remaining in the normal range;

[0252] • Absolute and percentage changes in serum potassium at different time points compared with the baseline of the correction treatment period and the baseline of the maintenance treatment period.

[0253] To the change value;

[0254] • Time to first exceed the normal range of serum potassium (> 5.0 mmol / L);

[0255] • Proportion of subjects whose serum potassium remained in the normal range (serum potassium: 3.5-5.0 mmol / L, including the boundary value) on days 8, 15, 22, and 29 of the maintenance treatment period;

[0256] • Changes in serum potassium in subjects in different treatment groups compared with the baseline of the correction treatment period and the baseline of the maintenance treatment period.

[0257] Exploratory endpoints: Changes in the concentrations of serum magnesium ion, calcium ion, sodium ion, and iron ion during the correction period and the maintenance treatment period.

[0258] Primary endpoints: Incidence of adverse events and serious adverse events, adverse events related to study drug, and adverse events in subjects in the Extension Phase.

[0259] Secondary endpoints: Proportion of subjects with a mean serum potassium < 5.0 mmol / L and a mean serum potassium < 5.5 mmol / L during the period from Day 8 to Day 337 in the Extension Phase.

[0260] 5.6.3 Safety Endpoints

[0261] Incidence of adverse events and serious adverse events, adverse events related to study drug, and adverse events in subjects in Part A and Part B phases.

[0262] The foregoing description of exemplary embodiments of the application has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the application to the precise form disclosed. Many modifications and variations are possible in light of the above teaching. It is intended that the scope of the application be limited not with this detailed description, but rather by the claims appended hereto.

Claims

1. A method of treating hyperkalemia in an individual comprising a first phase dosing regimen of orally administering to the individual poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in 3 doses per day for 2 consecutive days at 3-48 g per dose.

2. The method of claim 1 comprising a first phase dosing regimen of orally administering to the individual poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in 6-36 g per dose for 2 consecutive days.

3. The method of claim 1 comprising a first phase dosing regimen of orally administering to the individual poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in 6-18 g per dose for 2 consecutive days.

4. The method of claim 1 comprising a first phase dosing regimen of orally administering to the individual poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in 12 g per dose for 2 consecutive days.

5. The method of any one of claims 1 to 4 further comprising a second phase dosing regimen of orally administering to the individual poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in 3-48 g once daily or every other day.

6. The method of claim 5 wherein the second phase dosing regimen is orally administering to the individual poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in 6-24 g once daily or every other day.

7. The method of claim 6 wherein the second phase dosing regimen is orally administering to the individual poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in 6-18 g once daily or every other day.

8. The method of claim 5 wherein the first phase dosing regimen is orally administering to the individual poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in 3 doses per day for 2 consecutive days at 12 g per dose and the second phase dosing regimen is orally administering to the individual poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt in 6-18 g, preferably 12 g, once daily.

9. The method of any one of claims 1 to 8 wherein the individual is an adult.

10. Poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt for use in treating hyperkalemia in an individual, wherein the poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt is administered to the individual according to the dosing regimen of any one of claims 1-9.

11. A dry suspension for oral administration comprising 1 g, 3 g or 6 g of poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt, and optionally a pharmaceutically acceptable excipient, for use in the treatment of hyperkalemia in an individual, wherein the poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt is administered to the individual according to the dosage regimen of any one of claims 1-9.

12. The dry suspension of claim 11 comprising 1 g, 3 g, or 6 g of poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt, xanthan gum, and silicon dioxide or a solid powder flavor comprising silicon dioxide, wherein, Xanthan gum is present at > 0.5% (e.g., 0.5% to 20%, 0.5% to 15%, 0.5% to 10%, 0.5% to 5%, 0.5% to 2%) by weight of the poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt, and silica is present at > 0.05% to < 3% (e.g., > 0.05% to < 3%, e.g., > 0.05% to 2.5%, 0.06% to 2.4%, 0.07% to 2.3%, 0.08% to 2.2%, 0.09% to 2.1%, or 0.1 to 2%) by weight of the poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt.

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