WO2022162021A1 - Verinurad compositions and methods of use - Google Patents

Verinurad compositions and methods of use Download PDF

Info

Publication number
WO2022162021A1
WO2022162021A1 PCT/EP2022/051794 EP2022051794W WO2022162021A1 WO 2022162021 A1 WO2022162021 A1 WO 2022162021A1 EP 2022051794 W EP2022051794 W EP 2022051794W WO 2022162021 A1 WO2022162021 A1 WO 2022162021A1
Authority
WO
WIPO (PCT)
Prior art keywords
day
verinurad
pharmaceutically acceptable
pharmaceutical composition
acceptable salt
Prior art date
Application number
PCT/EP2022/051794
Other languages
French (fr)
Inventor
Per Fredrik ERLANDSSON
Åsa Susanne JOHANSSON
Joanna Romana PARKINSON
Johan Hoegstedt
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2022162021A1 publication Critical patent/WO2022162021A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

Definitions

  • Uric acid is a product of the metabolic breakdown of purine nucleotides. Most uric acid dissolves in blood and passes to the kidneys, where it is excreted by glomerular filtration and tubular secretion. A substantial fraction of uric acid is reabsorbed by the renal tubules. A uric acid concentration in blood plasma above the normal range is known as hyperuricemia. Hyperuricemia has been associated with chronic kidney disease and renal dysfunction, and identified as an independent risk factor for renal function decline. See Levy, G. D., et al. J. Rheum. 2014; 41(5): 955; X. Su et al. PLoS ONE 2017; 12(11): e0187550.
  • Hyperuricemia has also been associated with cardiovascular disease and heart failure. See M. Li, et al. Sci. Rep. 2016; 6: 19520. Thus, a need exists for therapeutic methods and compositions for reducing serum uric acid level that may be used in therapeutic and prophylactic methods, e.g. to treat or prevent conditions associated with hyperuricemia such as chronic kidney disease and heart failure.
  • URAT1 urate transporters
  • Verinurad (2-[3-(4- cyanonaphthalen-l-yl)pyridin-4-yl]sulfanyl-2-methylpropanoic acid) is a URATl inhibitor, and therefore may be useful in therapeutic and prophylactic methods, e.g. to treat or prevent conditions associated with hyperuricemia such as chronic kidney disease and heart failure.
  • xanthine oxidase inhibitors XOIs
  • a Phase 2 randomised, placebo-controlled clinical study of a once daily dose of verinurad 9 mg + febuxostat 80 mg (ClinicalTrials.gov identifier: NCT03118739) was conducted in patients with type 2 diabetes, albuminuria, and hyperuricemia.
  • Serum uric acid (sUA) was reduced by 57% in the verinurad/febuxostat group vs an increase of 7% in the placebo group at 12 weeks (p ⁇ 0.0001), and this effect was sustained at 24 weeks (62% reduction in the verinurad/febuxostat WO 2022/162021 PCT/EP2022/051794-PCT group vs 5% increase in the placebo group; p ⁇ 0.0001) (Terkeltaub et al., OP0207, Annals of the Rheumatic Diseases 2019;78: 179-180).
  • a further Phase 2b, randomised, placebo-controlled study of verinuad and allopurinol in patients with heart failure with preserved ejection fraction (HFpEF) (AMETHYST; ClinicalTrials.gov identifier: NCT04327024) is currently underway and is examining the effect of verinurad + allopurinol on exercise capacity (peak VO2) among patients with diagnosis of symptomatic HFpEF.
  • SAPPHIRE and AMETHYST clinical studies are examining an oral, once daily dose of verinurad 3 mg + allopurinol 300 mg, verinurad 7.5 mg + allopurinol 300 mg, or verinurad 12 mg + allopurinol 300 mg.
  • the instant disclosure provides methods of treating or preventing a condition associated with hyperuricemia in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
  • the condition is gout, a recurrent gout attack, gouty arthritis, hypertension, a WO 2022/162021 PCT/EP2022/051794-PCT cardiovascular disease, coronary heart disease, heart failure, Lesch-Nyhan syndrome, Kelley- Seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic kidney disease, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination thereof.
  • HPRT hypoxanthine-guanine phosphoribosyltransferase
  • a method of treating or preventing chronic kidney disease in a subject in need thereof comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
  • a method of treating or preventing heart failure in a subject in need thereof comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
  • a method of reducing the serum uric acid level in a subject in need thereof comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
  • a method of reducing UACR in a subject in need thereof comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
  • verinurad or a pharmaceutically acceptable salt thereof for use in the methods disclosed herein.
  • a pharmaceutical composition comprising verinurad or a pharmaceutically acceptable salt thereof in an amount greater than 12 mg and less than or equal to 24 mg for use in the methods disclosed herein.
  • a pharmaceutical composition comprising a plurality of pellets, wherein each pellet comprises: an inert core; a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof that encapsulates the inert core; and a modified release layer that encapsulates the drug layered inert core; WO 2022/162021 PCT/EP2022/051794-PCT wherein the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 12 mg and less than or equal to 24 mg.
  • a pharmaceutical composition for use in the methods disclosed herein comprising a plurality of pellets, wherein each pellet comprises: an inert core; a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof that encapsulates the inert core; and a modified release layer that encapsulates the drug layered inert core; wherein the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 12 mg and less than or equal to 24 mg.
  • the methods comprise administering to the subject a pharmaceutical composition comprising a plurality of pellets, wherein each pellet comprises: an inert core; a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof that encapsulates the inert core; and a modified release layer that encapsulates the drug layered inert core; wherein the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 12 mg and less than or equal to 24 mg.
  • Figure 1 shows interim data from the SAPPHIRE clinical study (ClinicalTrials.gov identifier: NCT03990363).
  • Figure 1 shows UACR by visit (weeks from start of treatment), MMRM, Geometric LSMeans (95% CI).
  • Treatment A verinurad 3 mg + allopurinol 300 mg;
  • Treatment B verinurad 7.5 mg + allopurinol 300 mg;
  • Treatment C verinurad 12 mg + allopurinol 300 mg;
  • Treatment D allopurinol 300 mg;
  • Treatment E placebo.
  • the number of patients for each data point is as described in the table below: WO 2022/162021 PCT/EP2022/051794-PCT
  • Figure 2 shows interim data from the SAPPHIRE clinical study (ClinicalTrials.gov identifier: NCT03990363).
  • Figure 2 shows the % reduction in serum uric acid (sUA) level from baseline at Visit 6 (12 weeks from start of treatment) for each treatment arm (verinurad 3 mg + allopurinol 300 mg; verinurad 7.5 mg + allopurinol 300 mg; verinurad 12 mg + allopurinol 300 mg; allopurinol 300 mg; and placebo).
  • the number of patients for each data point is as described in the table below:
  • FIG. 3 shows interim data from the SAPPHIRE clinical study (ClinicalTrials.gov identifier: NCT03990363). Exposure-response data (% reduction in serum uric acid (sUA) level from baseline vs verinurad predose concentration) from the SAPPHIRE study are shown in the data points marked SAPPHIRE. Similar exposure-response data from three previous studies of verinurad and allopurinol in healthy patients or patients with gout (Study A, described in Kankam M et al. J Clin Pharmacol 2018, 58(9): 1214-22; Study B, described in Fleischmann R, et al.
  • patient refers to individuals suffering from a disorder, and the like. None of the terms require that the individual be under the care and/or supervision of a medical professional. In some embodiments, the subject of the methods disclosed herein is human.
  • treat include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion
  • topical and rectal administration include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical and rectal administration.
  • Those of skill in the WO 2022/162021 PCT/EP2022/051794-PCT art are familiar with administration techniques that can be employed with the compounds, compositions, and methods described herein.
  • an “effective amount,” “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, refer to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease.
  • An appropriate “effective” amount may differ from one individual to another.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • salts refers to salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable.
  • Compounds described herein may possess acidic or basic groups and therefore may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • These salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • verinurad is provided as a base addition salt, such as the sodium salt.
  • composition refers to a composition comprising at least one active ingredient mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, excipients and the like.
  • co-administration are meant to encompass administration of the active ingredients to a single individual, and are intended to include treatment regimens in which the agents are WO 2022/162021 PCT/EP2022/051794-PCT administered by the same or different route of administration, in the same or different pharmaceutical compositions, and at the same or different times. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which all active ingredients are present.
  • Hyperuricemia is an abnormally high level of uric acid in the blood. Hyperuricemia may be asymptomatic. In certain instances, hyperuricemia is associated with at least one other disease or condition. In certain instances, hyperuricemia is associated with gout, a recurrent gout attack, gouty arthritis, hypertension, a cardiovascular disease, coronary heart disease, heart failure, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic kidney diseasejoint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof. In some embodiments, the condition is gout. In some embodiments, the condition is chronic kidney disease. In some embodiments, the condition is heart failure.
  • the instant disclosure provides methods of treating or preventing a condition associated with hyperuricemia in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
  • the condition is gout, a recurrent gout attack, gouty arthritis, hypertension, a cardiovascular disease, coronary heart disease, heart failure, Lesch-Nyhan syndrome, Kelley- Seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic kidney diseasejoint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination thereof.
  • the condition is gout.
  • the condition is chronic kidney disease.
  • the condition is heart failure.
  • the condition is heart failure with preserved ejection fraction.
  • kidney disease is WO 2022/162021 PCT/EP2022/051794-PCT acute kidney disease, acute kidney failure, chronic kidney disease, chronic kidney failure, or diabetic kidney disease.
  • the kidney disease is chronic kidney disease. In some embodiments, the kidney disease is diabetic kidney disease.
  • a method of treating or preventing heart failure in a subject in need thereof comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
  • the cardiovascular disease is heart failure with preserved ejection fraction.
  • the instant disclosure provides methods of reducing the serum uric acid level in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
  • the serum uric acid level is reduced by 55% or more compared to pre-treatment baseline level.
  • the serum uric acid level is reduced by 60% or more compared to pre-treatment baseline level.
  • the serum uric acid level is reduced by 65% or more compared to pretreatment baseline level.
  • the serum uric acid level is reduced by 70% or more compared to pre-treatment baseline level. In some embodiments, the serum uric acid level is reduced by 55% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks. In some embodiments, the serum uric acid level is reduced by 60% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks.
  • the serum uric acid level is reduced by 65% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks. In some embodiments, the serum uric acid level is reduced by 70% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks.
  • Albuminuria (UACR > 30 mg/g) is a marker of kidney disease.
  • the instant disclosure provides methods of reducing the urine albumin-to-creatinine ratio (UACR) in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
  • the UACR is reduced by WO 2022/162021 PCT/EP2022/051794-PCT
  • the UACR is reduced by 10% or more compared to pre-treatment baseline level. In some embodiments, the UACR is reduced by 20% or more compared to pre-treatment baseline level. In some embodiments, the UACR is reduced by 30% or more compared to pre-treatment baseline level. In some embodiments, the UACR is reduced by 5% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks.
  • the UACR is reduced by 10% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks. In some embodiments, the UACR is reduced by 20% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks. In some embodiments, the UACR is reduced by 30% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks.
  • verinurad or a pharmaceutically acceptable salt thereof is verinurad.
  • a pharmaceutically acceptable salt of verinurad is the sodium salt of verinurad, i.e. sodium 2-[3-(4-cyanonaphthalen- l-yl)pyridin-4-yl]sulfanyl-2-methylpropanoate.
  • xanthine oxidase inhibitor a xanthine oxidase inhibitor
  • the XOI is a purine analog, such as allopurinol, oxypurinol, or tisopurine.
  • the XOI is another molecule, such as febuxostat or topiroxostat.
  • the XOI is allopurinol or febuxostat. In some embodiments, the XOI is febuxostat. In embodiments, the XOI is allopurinol.
  • WO 2022/162021 PCT/EP2022/051794-PCT
  • the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day. In some embodiments, the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 15 mg/day and less than or equal to 24 mg/day. In some embodiments, the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 15 mg/day and less than 24 mg/day.
  • the dose of verinurad or a pharmaceutically acceptable salt thereof is selected from about 12.5 mg/day, about 13 mg/day, about 13.5 mg/day, about 14 mg/day, about 14.5 mg/day, about 15 mg/day, about 15.5 mg/day, about 16 mg/day, about 16.5 mg/day, about 17 mg/day, about 17.5 mg/day, about 18 mg/day, about 18.5 mg/day, about 19 mg/day, about 19.5 mg/day, about 20 mg/day, about 20.5 mg/day, about 21 mg/day, about 21.5 mg/day, about 22 mg/day, about 22.5 mg/day, about 23 mg/day, about 23.5 mg/day, and about 24 mg/day.
  • the dose of verinurad or a pharmaceutically acceptable salt thereof is selected from about 13 mg/day, about 14 mg/day, about 15 mg/day, about 16 mg/day, about 17 mg/day, about 18 mg/day, about 19 mg/day, about 20 mg/day, about 21 mg/day, about 22 mg/day, about 23 mg/day, and about 24 mg/day.
  • the dose of verinurad or a pharmaceutically acceptable salt thereof is 12.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 13 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 13.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 14 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 14.5 mg/day. In some embodiments, WO 2022/162021 PCT/EP2022/051794-PCT the dose of verinurad or a pharmaceutically acceptable salt thereof is 15 mg/day.
  • the dose of verinurad or a pharmaceutically acceptable salt thereof is 15.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 16 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 16.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 17 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 17.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 18 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 18.5 mg/day.
  • the dose of verinurad or a pharmaceutically acceptable salt thereof is 19 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 19.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 20 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 20.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 21 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 21.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 22 mg/day.
  • the dose of verinurad or a pharmaceutically acceptable salt thereof is 22.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 23 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 23.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 24 mg/day.
  • the dose of verinurad or a pharmaceutically acceptable salt thereof is not 20 mg/day.
  • the xanthine oxidase inhibitor is allopurinol, and the dose of allopurinol is about 100 mg/day to about 400 mg/day. In some embodiments, the dose of allopurinol is about 100 mg/day to about 300 mg/day. In some embodiments, the dose of allopurinol is selected from about 100 mg/day, about 200 mg/day and about 300 mg/day. In some embodiments, the dose of allopurinol is about 300 mg/day. In some embodiments, the dose of allopurinol is 300 mg/day.
  • the xanthine oxidase inhibitor is febuxostat, and the dose of febuxostat is about 10 mg/day to about 160 mg/day. In some embodiments, the xanthine oxidase inhibitor is febuxostat, and the dose of febuxostat is about 40 mg/day to about 160 mg/day. In WO 2022/162021 PCT/EP2022/051794-PCT some embodiments, the dose of febuxostat is selected from about 10 mg/day, about 20 mg/day, about 40 mg/day, and 80 mg/day. In some embodiments, the dose of febuxostat is about 80 mg/day. In some embodiments, the dose of febuxostat is 80 mg/day.
  • the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day, and allopurinol at a dose of 300 mg/day.
  • the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day, and febuxostat at a dose of 80 mg/day.
  • the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 15 mg/day and less than or equal to 24 mg/day, and allopurinol at a dose of 300 mg/day.
  • the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 15 mg/day and less than or equal to 24 mg/day, and febuxostat at a dose of 80 mg/day.
  • verinurad or a pharmaceutically acceptable salt thereof for use in the methods disclosed herein. In some embodiments, there is provided verinurad for use in the methods disclosed herein.
  • a pharmaceutical composition comprising verinurad or a pharmaceutically acceptable salt thereof in an amount greater than 12 mg and less than or equal to 24 mg for use in the methods disclosed herein.
  • the instant disclosure further provides pharmaceutical compositions comprising verinurad or a pharmaceutically acceptable salt thereof for use in the methods described herein.
  • the pharmaceutical compositions comprise verinurad or a pharmaceutically acceptable salt thereof in an amount greater than 12 mg and less than or equal to 24 mg.
  • the pharmaceutical compositions comprise verinurad or a pharmaceutically acceptable salt thereof in an amount greater than 12 mg and less than or equal to 24 mg, and at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical compositions are useful for treating or preventing a condition disclosed herein. WO 2022/162021 PCT/EP2022/051794-PCT
  • compositions described herein may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are optionally prepared according to known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid
  • binding agents for example starch, gelatin, polyvinyl-pyrrolidone
  • the tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols.
  • WO 2022/162021 PCT/EP2022/051794-PCT include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the pharmaceutical compositions described herein may be formulated using the methods and formulations described in WO2017/097845 which is incorporated herein by reference. Accordingly, in an embodiment there is provided a pharmaceutical composition comprising a plurality of pellets, wherein each pellet comprises: an inert core; a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof that encapsulates the inert core; and a modified release layer that encapsulates the drug layered inert core; wherein the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 12 mg and less than or equal to 24 mg.
  • the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 15 mg and less than 24 mg. In some embodiments, the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 15 mg and less than or equal to 24 mg. In some embodiments, the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 15 mg and less than 24 mg.
  • the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg, about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg, about 23.5 mg, and about 24 mg.
  • the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, and about 24 mg.
  • the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is not 20 mg.
  • modified release means that the escape or release of the verinurad or pharmaceutically acceptable salt thereof from the pellet has been modified so that the release rate is slower than that from an unmodified or immediate release pellet.
  • Modified release coatings as known in the art may be employed to fabricate the modified release layer, especially polymer coatings, such as a cellulose ester or ether, an acrylic polymer, or a mixture of WO 2022/162021 PCT/EP2022/051794-PCT polymers. Such materials include ethyl cellulose, cellulose acetate and cellulose acetate butyrate.
  • the polymer may be applied as a solution in an organic solvent or as an aqueous dispersion or latex.
  • the coating operation may be conducted in standard equipment such as a fluid bed coater, a Wurster coater, or a rotary bed coater. If desired, the permeability of the coating may be adjusted by blending of two or more materials.
  • a useful process for tailoring the porosity of the coating comprises adding a pre-determined amount of a finely-divided water-soluble material, such as sugars or salts or water-soluble polymers (e.g. hydroxypropyl cellulose and poly (N- vinyl-2-pyrrolidinone)) to a solution or dispersion (e.g., an aqueous latex) of the coating polymer to be used.
  • a finely-divided water-soluble material such as sugars or salts or water-soluble polymers (e.g. hydroxypropyl cellulose and poly (N- vinyl-2-pyrrolidinone))
  • a solution or dispersion e.g., an aqueous latex
  • modified release layer When the pellet is ingested into the aqueous medium of the GI tract, these water soluble additives are leached out of the modified release layer, leaving pores which facilitate release of the drug.
  • the modified release layer can also be modified by the addition of plasticizers, as known in the art.
  • the plurality of pellets each comprise an inert core layered with a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof and coated with a modified release layer comprising a polymeric material of the type useful for providing modified release of the verinurad or a pharmaceutically acceptable salt thereof.
  • the pellets may be prepared by building the drug layer up on an inert core by a drug-layering technique such as powder coating or by applying the spraying a solution or dispersion of verinurad or a pharmaceutically acceptable salt thereof in an appropriate solution/dispersion vehicle (e.g. a binder dispersion, for example hydroxypropyl methyl cellulose (HPMC), e.g.
  • a binder dispersion for example hydroxypropyl methyl cellulose (HPMC), e.g.
  • the inert core can be comprised of a sugar (for example a non-pareil seed), starch or microcrystalline cellulose, conveniently microcrystalline cellulose.
  • a suitable composition and method is to spray an aqueous dispersion of verinurad or a pharmaceutically acceptable salt thereof and a binder (e.g. HPMC) in water on to the inert core.
  • Modified release coatings as known in the art and as previously described, especially polymer coatings, may be employed to fabricate the modified release layer, which is applied over the drug layered inert cores.
  • the modified release layer comprises a mixture of waterinsoluble and water-soluble polymers, for example, ethylcellulose and hydroxypropylcellulose, respectively; or ethylcellulose and poly (N-vinyl-2-pyrrolidinone), respectively.
  • water-soluble polymers for example, ethylcellulose and hydroxypropylcellulose, respectively; or ethylcellulose and poly (N-vinyl-2-pyrrolidinone), respectively.
  • the inert core comprises microcrystalline cellulose. In some embodiments, the inert core comprises microcrystalline cellulose in an amount between 90wt% and 100wt%. In some embodiments, the inert core consists of microcrystalline cellulose.
  • the modified release layer comprises ethyl cellulose. In some embodiments, the modified release layer comprises hydroxypropyl cellulose. In some embodiments, the modified release layer comprises poly (N-vinyl-2-pyrrolidinone). In some embodiments, the modified release layer comprises ethyl cellulose and hydroxypropyl cellulose. In some embodiments, the modified release layer comprises ethyl cellulose and poly (N-vinyl-2- pyrrolidinone). In some embodiments, the modified release layer comprises ethyl cellulose and hydroxypropyl cellulose, wherein the weight ratio of ethylcellulose to hydroxypropyl cellulose ranges from about 1 : 1 to about 4: 1.
  • the modified release layer comprises ethyl cellulose and poly (N-vinyl-2-pyrrolidinone), wherein the weight ratio of ethylcellulose to poly (N-vinyl-2-pyrrolidinone) ranges from about 1 : 1 to about 4: 1.
  • the modified release layer comprises ethyl cellulose and hydroxypropyl cellulose, wherein the weight ratio of ethylcellulose to hydroxypropyl cellulose ranges from about 3:2 to about 3: 1.
  • the modified release layer comprises ethyl cellulose and poly (N-vinyl-2- pyrrolidinone), wherein the weight ratio of ethylcellulose to poly (N-vinyl-2-pyrrolidinone) ranges from about 3:2 to about 3: 1.
  • the modified release layer comprises ethyl cellulose and hydroxypropyl cellulose, wherein the weight ratio of ethylcellulose to hydroxypropyl cellulose ranges from about 2: 1 to about 3: 1.
  • the modified release layer comprises ethyl cellulose and poly (N-vinyl-2-pyrrolidinone), wherein the weight ratio of ethylcellulose to poly (N-vinyl-2-pyrrolidinone) ranges from about 2: 1 to about 3: 1.
  • the drug layer comprises a binder.
  • the binder is hydroxypropyl methylcellulose.
  • the weight ratio of the verinurad or a pharmaceutically acceptable salt thereof to the binder ranges from about 4: 1 to about 19: 1.
  • the weight ratio of the verinurad or a pharmaceutically acceptable salt thereof to the binder ranges from about 8: 1 to about 11 : 1.
  • the weight ratio of the verinurad or a pharmaceutically acceptable salt thereof to the binder ranges is about 9: 1.
  • the inert core is present in an amount ranging from about 10% to about 90% (w/w) of the combined weight of the inert core, drug layer and modified release layer;
  • the drug layer is present in an amount ranging from about 5% to about 80% (w/w) of the combined weight of the inert core, drug layer and modified release layer;
  • the modified release WO 2022/162021 PCT/EP2022/051794-PCT layer is present in an amount ranging from about 5% to about 50% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
  • the inert core is present in an amount ranging from about 40% to about 75% (w/w) of the combined weight of the inert core, drug layer and modified release layer. In some embodiments, the inert core is present in an amount ranging from about 50% to about 75% (w/w) of the combined weight of the inert core, drug layer and modified release layer. In some embodiments, the inert core is present in an amount ranging from about 50% to about 70% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
  • the drug layer is present in an amount ranging from about 5% to about 25% (w/w) of the combined weight of the inert core, drug layer and modified release layer. In some embodiments, the drug layer is present in an amount ranging from about 5% to about 20% (w/w) of the combined weight of the inert core, drug layer and modified release layer. In some embodiments, the drug layer is present in an amount ranging from about 5% to about 15% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
  • the modified release layer is present in an amount ranging from about 20% to about 40% (w/w) of the combined weight of the inert core, drug layer and modified release layer. In some embodiments, the modified release layer is present in an amount ranging from about 20% to about 30% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
  • the inert core is present in an amount ranging from about 50% to about 70% (w/w) of the combined weight of the inert core, drug layer and modified release layer;
  • the drug layer is present in an amount ranging from about 5% to about 20% (w/w) of the combined weight of the inert core, drug layer and modified release layer;
  • the modified release layer is present in an amount ranging from about 20% to about 40% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
  • the inert core is present in an amount ranging from about 10% to about 90% (w/w) of the total weight of the pellet; the drug layer is present in an amount ranging from about 5% to about 80% (w/w) of the total weight of the pellet; the modified release layer is present in an amount ranging from about 5% to about 50% (w/w) of the total weight of the pellet.
  • the inert core is present in an amount ranging from about 40% to about 75% (w/w) of the total weight of the pellet.
  • the inert core is present in an amount ranging from about 50% to about 75% (w/w) of the total weight of the pellet.
  • the inert core is present in an amount ranging from about 50% to about 70% (w/w) of the total weight of the pellet.
  • the drug layer is present in an amount ranging from about 5% to about 25% (w/w) of the total weight of the pellet. In some embodiments, the drug layer is present in an amount ranging from about 5% to about 20% (w/w) of the total weight of the pellet. In some embodiments, the drug layer is present in an amount ranging from about 5% to about 15% (w/w) of the total weight of the pellet.
  • the modified release layer is present in an amount ranging from about 20% to about 40% (w/w) of the total weight of the pellet. In some embodiments, the modified release layer is present in an amount ranging from about 20% to about 30% (w/w) of the total weight of the pellet.
  • the inert core is present in an amount ranging from about 50% to about 70% (w/w) of the total weight of the pellet; the drug layer is present in an amount ranging from about 5% to about 20% (w/w) of the total weight of the pellet; the modified release layer is present in an amount ranging from about 20% to about 40% (w/w) of the total weight of the pellet.
  • each pellet may comprise a lubricant such as magnesium stearate.
  • the lubricant is present at about 0.1% to about 5% (w/w) of the total weight of the pellet. In some embodiments, the lubricant is present at about 0.1% to about 0.5% (w/w) of the total weight of the pellet.
  • a sub-coat can be applied between the drug layer and the modified release layer if separation is needed. In some embodiments, the coat can be comprised of hydroxypropyl methylcellulose or magnesium stearate.
  • the pellets range in size from about 150 pm to about 400 pm, more conveniently about 350 pm.
  • the pharmaceutical composition comprises a plurality of pellets that may be packaged, for example, in a capsule such as a gelatin capsule or a capsule formed from a polymer such as HPMCAS, HPMC or starch; dosed as a suspension or slurry in a liquid; dosed in a sachet; or they may be formed into a tablet (e.g. a caplet) or pill by compression or other processes known in the art.
  • the pellet composition comprising the plurality of pellets is packaged in a capsule, such as a gelatin capsule or a capsule formed from a polymer such as HPMCAS, HPMC or starch.
  • a capsule such as a gelatin capsule or a capsule formed from a polymer such as HPMCAS, HPMC or starch.
  • the plurality of pellets is contained within one or more capsules.
  • the plurality of pellets is contained within one capsule.
  • the pharmaceutical composition comprises other medicinal or pharmaceutical agents.
  • the pharmaceutical composition comprises a xanthine oxidase inhibitor.
  • the pharmaceutical composition comprises allopurinol.
  • the pharmaceutical composition comprises about 100 mg to about 400 mg of allopurinol.
  • the pharmaceutical composition comprises about 100 mg to about 300 mg of allopurinol.
  • the pharmaceutical composition comprises about 100 mg, about 200 mg or about 300 mg of allopurinol.
  • the pharmaceutical composition comprises about 300 mg of allopurinol.
  • the pharmaceutical composition comprises 300 mg of allopurinol.
  • the pharmaceutical composition comprises about 10 mg to about 160 mg of febuxostat. In some embodiments, the pharmaceutical composition comprises about 40 mg to about 160 mg of febuxostat. In some embodiments, the pharmaceutical composition comprises about 10 mg, about 20 mg, about 40 mg or about 80 mg of febuxostat. In some embodiments, the pharmaceutical composition comprises about 80 mg of febuxostat. In some embodiments, the pharmaceutical composition comprises 80 mg of febuxostat.
  • the total daily dosage may be divided and administered in portions during the day if desired. Accordingly, the total daily dose may be subdivided into unit doses containing appropriate quantities of the pharmaceutical composition described herein and xanthine oxidase inhibitor to achieve the desired purpose.
  • Unit dosage forms may be prepared by any of the methods well known in the art of pharmacy. In general, unit dosage forms may be prepared similarly to the formulations described herein.
  • the pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, or suspension.
  • the active ingredients are administered in separate dosage units.
  • each active ingredient is administered in a separate tablet.
  • the active ingredients are administered in a single dosage unit.
  • all active ingredients may be administered in the same tablet.
  • the unit dosage form comprises, for example, three separate tablets individually comprising one active ingredient), two tablets wherein one tablet comprises two of active ingredients and the other tablet comprising a third active ingredient), or a single tablet which comprises all active ingredients.
  • the additional agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, a purine nucleoside phosphorylase (PNP) inhibitor, a uric acid transporter inhibitor, a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor, a solute carrier family 2 (facilitated glucose transporter), member 9 (SLC2A9) inhibitor, an organic anion transporter (OAT) inhibitor, an OAT-4 inhibitor, or a combination thereof.
  • URAT 1 inhibitor a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor
  • PNP purine nucleoside phosphorylase
  • a uric acid transporter inhibitor a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor
  • SLC2A9 solute carrier family
  • the one or more additional therapeutic agents are selected from 2-((5-bromo-4-(4- cyclopropyl-l-naphthalenyl)-4H-l,2,4-triazol-3-yl)thio)acetic acid, allopurinol, febuxostat (2-(3- cyano-4-isobutoxyphenyl)-4-methyl-l,3-thiazole-5-carboxylic acid), FYX-051 (4-(5-pyridin-4- yl-U/-[l,2,4]triazol-3-yl)pyridine-2-carbonitrile), probenecid, sulfinpyrazone, benzbromarone, acetaminophen, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH), colchicine, a glucorticoid, an adrogen, a cox-2 inhibitor, a PPAR agonist, naprox
  • Example 1 A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled Study of Verinurad and Allopurinol in Patients with Chronic Kidney Disease and Hyperuricaemia
  • Serum cystatin C [ Time Frame: At 6 months, 12 months. ]
  • Serum uric acid [ Time Frame: At 6 months, 12 months. ] Change from baseline in Serum uric acid (sUA)
  • Verinurad (RDEA3170) is a novel URAT1 inhibitor in Phase 2 development WO 2022/162021 PCT/EP2022/051794-PCT for chronic kidney disease and heart failure. Verinurad combined with the xanthine oxidase (XO)inhibitor (XOI) febuxostat or allopurinol has been shown to lower sUA in patients with recurrent gout in Phase 2 studies by up to 80%.
  • XO xanthine oxidase
  • XOI xanthine oxidase
  • febuxostat febuxostat or allopurinol
  • the primary objective of this study is to assess the effects of treatment with verinurad and allopurinol, allopurinol alone, and placebo on UACR at 6 months.
  • change in UACR at 6 months of treatment is the primary endpoint for the efficacy evaluation of treatment with the combination of verinurad and allopurinol vs. placebo.
  • a key secondary objective is evaluation of verinurad plus allopurinol on the reduction in UACR at 12 months.
  • AEs adverse event
  • SAEs serious adverse event
  • laboratory evaluations will be employed to assess the safety profile of the study drugs. Verinurad, allopurinol and oxypurinol plasma concentrations over time will also be measured. The study will recruit patients with Chronic Kidney Disease and Hyperuricaemia.
  • Female patients Negative pregnancy test for childbearing potential. 1 year postmenopausal, surgically sterile, or using an acceptable method of contraception during the study and 4 weeks after the last dose of study treatment.
  • Example 2 A Phase 2, Multicentre, Double-Blind, Three-Arm, Placebo and Active Control Efficacy and Safety Study to Evaluate Verinurad Combined With Allopurinol in Heart Failure With Preserved Ejection Fraction
  • KCCQ-TSS Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score
  • KCCQ-TSS Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score
  • HFpEF heart failure
  • sUA serum uric acid
  • HFpEF preserved ejection fraction
  • Uric acid transporter 1 is responsible for reabsorption of uric acid (UA) in the proximal tubule. Inhibition of URAT1 results in increased urinary excretion of UA and lowering of uric acid in the blood.
  • Verinurad is a novel URAT1 inhibitor in Phase 2 development for chronic kidney disease (CKD) and HF. Verinurad combined with the xanthine oxidase (XO) inhibitors (XOI) febuxostat or allopurinol has been shown to lower sUA in patients with recurrent gout in Phase 2 studies by up to approximately 80%.
  • the primary objective of this Phase 2 study is to assess the effect of a combination of verinurad and allopurinol on exercise capacity in patients with HFpEF.
  • the secondary objectives are to assess effect of combination of verinurad and allopurinol in comparison to allopurinol monotheraphy on excercise capacity dwhich will be measured in peak VO2 as well as effect of verinurad and allopurinol compared to placebo and to allopurinol monotheraphy on Kansas City cardiomyopathy questionnaire (KCCQ)-total symptom score (TSS).
  • KCCQ Kansas City cardiomyopathy questionnaire
  • TSS total symptom score
  • NT -proBNP > 125 pg/mL (> 14.75 pmol/L) at Visit 2 for patients without ongoing atrial fibrillation/flutter.
  • HLA-B Human Leukocyte Antigen -B
  • Pellet formulations were prepared by a drug layering process.
  • An inert core of a solid material of a mean size of from 100-700 pm was coated with 2-((3-(4-cyanonaphthalen-l- yl)pyridine-4-yl)thio)-2-methylpropanoic acid in a drug layering process.
  • a solution or suspension containing said compound was sprayed onto the solid material and the solvent was evaporated.
  • inert cores that can be used include microcrystalline cellulose such as Celphere CP-203 (200-300 pm), Celphere CP-305 (300-500 pm) or Celphere 507 (500-700 pm), silicon dioxide (sand) or sucrose.
  • Step 1 coating of an inert core pellet
  • a solution of the verinurad or a pharmaceutically acceptable salt thereof is prepared in a concentration of from 1-30 % w/w, such as from 5-15 % w/w.
  • the verinurad or a pharmaceutically acceptable salt thereof is mixed with a binder, such as HPC, HPMC or other polymer and dispersed in a solvent.
  • a binder such as HPC, HPMC or other polymer
  • solvents examples include water or an alcohol such as ethanol, or a mixture thereof.
  • the solution or suspension is held at a temperature of from 15°C and 40°C.
  • the solution or suspension of said compound is sprayed onto the core material in a fluidised bed equipment such as Aeromatic MP1, LabCC (Graniten LabCC) or Glatt GPCG at a temperature of from 50-100°C, such as from 35-80°C, or from 50-75°C, for example for s duration of 30 - 500 minutes.
  • a fluidised bed equipment such as Aeromatic MP1, LabCC (Graniten LabCC) or Glatt GPCG at a temperature of from 50-100°C, such as from 35-80°C, or from 50-75°C, for example for s duration of 30 - 500 minutes.
  • Batch sizes useful are typically from 10 g - 400 kg.
  • a spray rate of from 5 - 40 g/min is used.
  • the crystalline compound can be dissolved in a solvent and then re-crystallised onto the inert cores in the fluid bed. This may be initiated or effected with or without seeding with crystals of said compound and can be performed in one step or be divided in several sub-bathes.
  • Step 2 polymer coating of pellets from step 1
  • the pellet granules formed in step 1 are coated with a polymer such as ethyl cellulose (EC), hydroxypropyl cellulose (HPC), poly (N-vinyl-2-pyrrolidinone) or a mixture thereof.
  • a polymer such as ethyl cellulose (EC), hydroxypropyl cellulose (HPC), poly (N-vinyl-2-pyrrolidinone) or a mixture thereof.
  • the polymer and/or the mixture thereof is dissolved in a solvent such as water, a ketone or an alcohol such as ethanol and/or mixtures thereof.
  • the solution is sprayed onto the granules in fluidized bed equipment such as Aeromatic MP1, LabCC or Glatt GPCG at a temperature of from 60- 120°C, such as from 75-100°C.
  • the solution is sprayed onto the granules for a sufficient period of time, such as from 10 min to 400 minutes.
  • the time required is dependent on the batch size and the
  • Step 3 capsule filling or tableting
  • the pellets comprising the verinurad or a pharmaceutically acceptable salt thereof prepared according to step 2 may be filled into a capsule.
  • a capsule material that may be used in accordance with the invention is hydroxypropyl methylcellulose or gelatine. It will be appreciated that a given dose of verinurad or a pharmaceutically acceptable salt thereof within the capsule may be obtained by incorporating a suitable fill weight of pellets within the capsule to obtain the required dose. Alternatively, the pellets can be formed into a tablet.
  • a pellet formulation was prepared with the following composition:
  • This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation.
  • 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills).
  • the resultant particle size Dio was less than 1 pm, D50 less than 5 pm and D90 less than 20 pm.
  • a polymer solution of 15.0 g of HPMC 6 cps in 1350.0 g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-l-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid was added. The resultant suspension was protected from light and stirred overnight. The suspension was held at RT °C. Before spraying, the suspension was sieved through a 200pm mesh. The spray rate was between 8-12 g suspension/min for the first 5 minutes and there after 10 to 20 g suspension/min for another 105 minutes. Inlet temperature was 72°C.
  • a polymer solution of 57.6 g ethyl cellulose 10 cP (EC) and 38.4 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95 % ethanol was prepared.
  • the drug layered pellets (150g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42 °C with a spray rate of approximately 10-18 g /min. After spraying 1395 g of polymer solution the polymer coated pellets were dried for 10 minutes in fluidized bed equipment. See process parameters below.
  • the polymer coated pellets were screened through a 710 pm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver 5mg of 2-((3-(4- cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.
  • a pellet formulation was prepared with the following composition:
  • This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation.
  • 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills).
  • the resultant particle size Dio was less than 1 pm, D50 less than 5 pm and D90 less than 20 pm.
  • a polymer solution of 15.0 g of HPMC 6 cps in 1350.0g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-l-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid was added. The spray rate was between 5-12 g suspension/min for the first 5 minutes and there after 10-20 g suspension/min for another 105 minutes. Inlet temperature was 72°C.
  • the drug layered pellets (150 g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42°C with a spray rate of approximately 10-18 g /min. After spraying 1302.9 g of polymer solution the polymer coated pellets were dried for 10 minutes in fluidized bed equipment. See process parameters below.
  • the polymer coated pellets were screened through a 710 pm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver 5mg of 2-((3-(4- cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.
  • a pellet formulation was prepared with the following composition:
  • This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation.
  • 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- WO 2022/162021 PCT/EP2022/051794-PCT methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills).
  • the resultant particle size Dio was less than 1 pm, D50 less than 5 pm and D90 less than 20 pm.
  • a polymer solution of 15.0 g of HPMC 6 cps in 1350.0g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-l-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid was added. The spray rate was between 5-12 g suspension/min for the first 5 minutes and there after 10-20 g suspension/min for another 105 minutes. Inlet temperature was 72°C.
  • a polymer solution of 64.8 g ethyl cellulose 10 cP (EC) and 31.3 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95 % ethanol was prepared.
  • the drug layered pellets (150 g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42 °C with a spray rate of approximately 10-18 g /min. After spraying 1395 g of polymer solution the polymer coated pellets were dried for 10 minutes in a fluidized bed equipment. See process parameters below.
  • the polymer coated pellets were screened through a 710 pm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver lOmg of 2-((3-(4- cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.
  • a pellet formulation was prepared with the following composition: WO 2022/162021 PCT/EP2022/051794-PCT
  • This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation.
  • 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills).
  • the resultant particle size Dio was less than 1 pm, D50 less than 5 pm and D90 less than 20 pm.
  • a polymer solution of 15.0 g of HPMC 6 cps in 1350.0g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-l-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid was added. The spray rate was between 5-12 g suspension/min for the first 5 minutes and there after 10-20 g suspension/min for another 105 minutes. Inlet temperature was 72°C.
  • a polymer solution of 68.2 g ethyl cellulose 10 cP (EC) and 27.8 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95 % ethanol was prepared.
  • the drug layered pellets (150 g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42 °C with a spray rate of approximately 10-18 g /min. After sprayingl395 g of polymer solution the polymer coated pellets were dried for 10 minutes in a fluidized bed equipment. See process parameters below.
  • polymer coated pellets were screened through a 425-710 pm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver lOmg of 2-((3-(4- cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.
  • Example 8 Preparation of pellet formulation using water-based coating [00124] A pellet formulation was prepared with the following composition:
  • 35 g dispersion was sprayed onto 10 g of 2-((3-(4-cyanonaphthalen-l- yl)pyridine-4-yl)thio)-2-methylpropanoic acid drug layered core seeds (produced as described in Example 6) in a fluidised bed drier (MiniGlatt).
  • the temperature of outlet air was about 25 °C
  • Example 9 Preparation of pellet formulation (8-hour Profile) at doses 4.5, 6 and 12mg [00126] Pellet formulations were prepared with the following compositions:
  • compositions of modified release pellet capsules 4.5, 6 and 12mg
  • a polymer solution of 19.0 g of HPMC 6 cps in 1710.3 g water was prepared. After a clear solution was obtained, 171.0 g micronized 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4- yl)thio)-2-methylpropanoic acid was added. The suspension was protected from light and stirred overnight. The suspension was held at RT °C. Before spraying, the suspension was sieved through 200pm mesh. The spray rate was between 8-11g suspension/min for the first 5 minutes and there after 15-20 g suspension/min for another 111 minutes. Inlet temperature was 73°C.
  • pellet formulations were prepared in accordance with the process described In Example 3.
  • the table below provides details of composition and process parameters along with the dissolution time to 80% release in pH 6.8 media (ionic strength 0.1, 50.0 mM KH2PO4 + 23.6 mM NaOH, dissolution media at 37 °C, 900 ml media, 100 rpm), tested in according to the general procedure of the United States Pharmacopeia Apparatus II (paddle).
  • HPC LF supplied by Ashland.
  • HPC L and SSL supplied by Nisso.
  • Tin Inlet temperature
  • T ou t Outlet temperature
  • FF Fludizing air flow
  • AP Pressure to atomise API or polymer solution
  • AF Atomizer air flow

Abstract

The present disclosure provides methods and compositions useful in reducing serum uric acid in a subject in need thereof, and reducing UACR in a subject in need thereof, and pharmaceutical compositions useful in such methods. The methods and compositions described herein are also useful in the treatment or prevention of conditions associated with hyperuricemia, such as chronic kidney disease and heart failure, in a subject in need thereof.

Description

WO 2022/162021 PCT/EP2022/051794-PCT
VERINURAD COMPOSITIONS AND METHODS OF USE
BACKGROUND
[0001] Uric acid is a product of the metabolic breakdown of purine nucleotides. Most uric acid dissolves in blood and passes to the kidneys, where it is excreted by glomerular filtration and tubular secretion. A substantial fraction of uric acid is reabsorbed by the renal tubules. A uric acid concentration in blood plasma above the normal range is known as hyperuricemia. Hyperuricemia has been associated with chronic kidney disease and renal dysfunction, and identified as an independent risk factor for renal function decline. See Levy, G. D., et al. J. Rheum. 2014; 41(5): 955; X. Su et al. PLoS ONE 2017; 12(11): e0187550. Hyperuricemia has also been associated with cardiovascular disease and heart failure. See M. Li, et al. Sci. Rep. 2016; 6: 19520. Thus, a need exists for therapeutic methods and compositions for reducing serum uric acid level that may be used in therapeutic and prophylactic methods, e.g. to treat or prevent conditions associated with hyperuricemia such as chronic kidney disease and heart failure.
[0002] Levels of urate anion in the blood are regulated in part by urate transporters such as URAT1. In some instances, single nucleotide polymorphisms of the gene which expresses URAT1 are significantly associated with increased or decreased reabsorption of uric acid by the kidneys, which contributes to hyperuricemia and hypouricemia, respectively. Verinurad (2-[3-(4- cyanonaphthalen-l-yl)pyridin-4-yl]sulfanyl-2-methylpropanoic acid) is a URATl inhibitor, and therefore may be useful in therapeutic and prophylactic methods, e.g. to treat or prevent conditions associated with hyperuricemia such as chronic kidney disease and heart failure.
[0003] The oxidation of hypoxanthine to xanthine and further the oxidation of xanthine to uric acid can be catalyzed by xanthine oxidase. Febuxostat and allopurinol are xanthine oxidase inhibitors (XOIs).
[0004] A Phase 2 randomised, placebo-controlled clinical study of a once daily dose of verinurad 9 mg + febuxostat 80 mg (ClinicalTrials.gov identifier: NCT03118739) was conducted in patients with type 2 diabetes, albuminuria, and hyperuricemia. Urine albumin-to-creatinine ratio (UACR) was reduced by 39% vs placebo (95% CI, -62% to -4%; p=0.0747) at 12 weeks and by 49% (95% CI, -68% to -19%; p=0.0174) at 24 weeks) (Stack et al., Nephrology Dialysis Transplantation 34 (Supplement 1): i449-i460, 2019). Serum uric acid (sUA) was reduced by 57% in the verinurad/febuxostat group vs an increase of 7% in the placebo group at 12 weeks (p<0.0001), and this effect was sustained at 24 weeks (62% reduction in the verinurad/febuxostat WO 2022/162021 PCT/EP2022/051794-PCT group vs 5% increase in the placebo group; p<0.0001) (Terkeltaub et al., OP0207, Annals of the Rheumatic Diseases 2019;78: 179-180).
[0005] A Phase 2b, randomised, placebo-controlled study of verinuad and allopurinol in patients with chronic kidney disease and hyperuricaemia (SAPPHIRE; ClinicalTrials.gov identifier: NCT03990363) is currently underway and is examining the effect of verinurad + allopurinol on albuminuria among patients with chronic kidney disease (CKD) and hyperuricaemia. A further Phase 2b, randomised, placebo-controlled study of verinuad and allopurinol in patients with heart failure with preserved ejection fraction (HFpEF) (AMETHYST; ClinicalTrials.gov identifier: NCT04327024) is currently underway and is examining the effect of verinurad + allopurinol on exercise capacity (peak VO2) among patients with diagnosis of symptomatic HFpEF. Both of the SAPPHIRE and AMETHYST clinical studies are examining an oral, once daily dose of verinurad 3 mg + allopurinol 300 mg, verinurad 7.5 mg + allopurinol 300 mg, or verinurad 12 mg + allopurinol 300 mg.
[0006] As disclosed herein in Figure 1, an interim analysis of the SAPPHIRE clinical study data shows that no significant reduction of UACR in patients was observed compared to placebo after 12 weeks of treatment with any of the verinurad + allopurinol doses studied.
[0007] As further disclosed herein in Figure 2, an interim analysis of the SAPPHIRE clinical study data shows that reduction of serum uric acid after 12 weeks was found to be lower than predicted from a PKPD model (Aksenov et al, Physiol Rep. 2018 6(5):el 3614) applied and extended to data from the 12 verinurad studies listed in Table A.
[0008] As further disclosed herein in Figure 3, patients in the SAPPHIRE clinical study exhibited lower sensitivity to verinurad URAT1 inhibition compared to the patients in the clinical studies listed in Table A, when assessed as effect on serum uric acid.
[0009] Accordingly, there is a need for further methods of reducing serum uric acid, methods of reducing UACR, methods of treating or preventing chronic kidney disease and heart failure, and pharmaceutical compositions useful in such methods.
SUMMARY
[0010] Accordingly, in some embodiments, the instant disclosure provides methods of treating or preventing a condition associated with hyperuricemia in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor. In some embodiments, the condition is gout, a recurrent gout attack, gouty arthritis, hypertension, a WO 2022/162021 PCT/EP2022/051794-PCT cardiovascular disease, coronary heart disease, heart failure, Lesch-Nyhan syndrome, Kelley- Seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic kidney disease, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination thereof.
[0011] In some embodiments, disclosed herein is a method of treating or preventing chronic kidney disease in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
[0012] In some embodiments, disclosed herein is a method of treating or preventing heart failure in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
[0013] In some embodiments, disclosed herein is a method of reducing the serum uric acid level in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
[0014] In some embodiments, disclosed herein is a method of reducing UACR in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
[0015] In some embodiments, disclosed herein is verinurad or a pharmaceutically acceptable salt thereof for use in the methods disclosed herein.
[0016] In some embodiments, disclosed herein is a pharmaceutical composition comprising verinurad or a pharmaceutically acceptable salt thereof in an amount greater than 12 mg and less than or equal to 24 mg for use in the methods disclosed herein.
[0017] In some embodiments, disclosed herein is a pharmaceutical composition comprising a plurality of pellets, wherein each pellet comprises: an inert core; a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof that encapsulates the inert core; and a modified release layer that encapsulates the drug layered inert core; WO 2022/162021 PCT/EP2022/051794-PCT wherein the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 12 mg and less than or equal to 24 mg.
[0018] In some embodiments, disclosed herein is a pharmaceutical composition for use in the methods disclosed herein, comprising a plurality of pellets, wherein each pellet comprises: an inert core; a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof that encapsulates the inert core; and a modified release layer that encapsulates the drug layered inert core; wherein the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 12 mg and less than or equal to 24 mg.
[0019] In some embodiments, the methods comprise administering to the subject a pharmaceutical composition comprising a plurality of pellets, wherein each pellet comprises: an inert core; a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof that encapsulates the inert core; and a modified release layer that encapsulates the drug layered inert core; wherein the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 12 mg and less than or equal to 24 mg.
[0020] Further aspects of Applicant's invention will be apparent to one skilled in the art from reading this specification.
LIST OF FIGURES
[0021] Figure 1 shows interim data from the SAPPHIRE clinical study (ClinicalTrials.gov identifier: NCT03990363). Figure 1 shows UACR by visit (weeks from start of treatment), MMRM, Geometric LSMeans (95% CI). Treatment A = verinurad 3 mg + allopurinol 300 mg; Treatment B = verinurad 7.5 mg + allopurinol 300 mg; Treatment C = verinurad 12 mg + allopurinol 300 mg; Treatment D = allopurinol 300 mg; Treatment E = placebo. The number of patients for each data point is as described in the table below:
Figure imgf000005_0001
WO 2022/162021 PCT/EP2022/051794-PCT
Figure imgf000006_0001
[0022] Figure 2 shows interim data from the SAPPHIRE clinical study (ClinicalTrials.gov identifier: NCT03990363). Figure 2 shows the % reduction in serum uric acid (sUA) level from baseline at Visit 6 (12 weeks from start of treatment) for each treatment arm (verinurad 3 mg + allopurinol 300 mg; verinurad 7.5 mg + allopurinol 300 mg; verinurad 12 mg + allopurinol 300 mg; allopurinol 300 mg; and placebo). The number of patients for each data point is as described in the table below:
Figure imgf000006_0002
[0023] Figure 3 shows interim data from the SAPPHIRE clinical study (ClinicalTrials.gov identifier: NCT03990363). Exposure-response data (% reduction in serum uric acid (sUA) level from baseline vs verinurad predose concentration) from the SAPPHIRE study are shown in the data points marked SAPPHIRE. Similar exposure-response data from three previous studies of verinurad and allopurinol in healthy patients or patients with gout (Study A, described in Kankam M et al. J Clin Pharmacol 2018, 58(9): 1214-22; Study B, described in Fleischmann R, et al. RMD Open 2018, 4:e000584; and JADE, ClinicalTrials.gov identifier: NCT03836599) are also shown. The solid line is an exposure-response model fitted to the SAPPHIRE data, and the broken line is a PKPD model (described in Aksenov et al, Physiol Rep. 2018 6(5):el3614) applied and extended to data from the 12 verinurad studies listed in Table A including 434 subjects. The lower part of Figure 3 shows the pre-dose exposure range observed in SAPPHIRE at each verinurad dose (3 mg, 7.5 mg or 12 mg) (median and 5th and 95th quantile).
Table A: Verinurad studies used for PKPD model
Figure imgf000006_0003
WO 2022/162021 PCT/EP2022/051794-PCT
Figure imgf000007_0001
DETAILED DESCRIPTION
Definitions
[0024] The term "patient," "subject" or "individual" are used interchangeably. As used herein, they refer to individuals suffering from a disorder, and the like. None of the terms require that the individual be under the care and/or supervision of a medical professional. In some embodiments, the subject of the methods disclosed herein is human.
[0025] The terms "treat," "treating" or "treatment," and other grammatical equivalents as used herein, include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
[0026] The terms "administer," "administering," "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical and rectal administration. Those of skill in the WO 2022/162021 PCT/EP2022/051794-PCT art are familiar with administration techniques that can be employed with the compounds, compositions, and methods described herein.
[0027] The terms "effective amount," "therapeutically effective amount" or "pharmaceutically effective amount" as used herein, refer to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease. An appropriate "effective" amount may differ from one individual to another. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.
[0028] The term "pharmaceutically acceptable" as used herein, refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
[0029] The term "pharmaceutically acceptable salt" as used herein, refers to salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. Compounds described herein may possess acidic or basic groups and therefore may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. These salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. In some embodiments, for example, verinurad is provided as a base addition salt, such as the sodium salt.
[0030] The term "pharmaceutical composition," as used herein, refers to a composition comprising at least one active ingredient mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, excipients and the like.
[0031] The terms "co-administration," "administered in combination with" and their grammatical equivalents, as used herein, are meant to encompass administration of the active ingredients to a single individual, and are intended to include treatment regimens in which the agents are WO 2022/162021 PCT/EP2022/051794-PCT administered by the same or different route of administration, in the same or different pharmaceutical compositions, and at the same or different times. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which all active ingredients are present.
Therapeutic Methods
[0032] Hyperuricemia is an abnormally high level of uric acid in the blood. Hyperuricemia may be asymptomatic. In certain instances, hyperuricemia is associated with at least one other disease or condition. In certain instances, hyperuricemia is associated with gout, a recurrent gout attack, gouty arthritis, hypertension, a cardiovascular disease, coronary heart disease, heart failure, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic kidney diseasejoint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof. In some embodiments, the condition is gout. In some embodiments, the condition is chronic kidney disease. In some embodiments, the condition is heart failure.
[0033] In some embodiments, the instant disclosure provides methods of treating or preventing a condition associated with hyperuricemia in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor. In some embodiments, the condition is gout, a recurrent gout attack, gouty arthritis, hypertension, a cardiovascular disease, coronary heart disease, heart failure, Lesch-Nyhan syndrome, Kelley- Seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic kidney diseasejoint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination thereof. In some embodiments, the condition is gout. In some embodiments, the condition is chronic kidney disease. In some embodiments, the condition is heart failure. In some embodiments, the condition is heart failure with preserved ejection fraction.
[0034] In some instances, disclosed herein is a method of treating or preventing kidney disease in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor. In some embodiments, the kidney disease is WO 2022/162021 PCT/EP2022/051794-PCT acute kidney disease, acute kidney failure, chronic kidney disease, chronic kidney failure, or diabetic kidney disease. In some embodiments, the kidney disease is chronic kidney disease. In some embodiments, the kidney disease is diabetic kidney disease.
[0035] In some instances, disclosed herein is method of treating or preventing heart failure in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor. In some embodiments, the cardiovascular disease is heart failure with preserved ejection fraction.
[0036] In some embodiments, the instant disclosure provides methods of reducing the serum uric acid level in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor. In some embodiments, the serum uric acid level is reduced by 55% or more compared to pre-treatment baseline level. In some embodiments, the serum uric acid level is reduced by 60% or more compared to pre-treatment baseline level. In some embodiments, the serum uric acid level is reduced by 65% or more compared to pretreatment baseline level. In some embodiments, the serum uric acid level is reduced by 70% or more compared to pre-treatment baseline level. In some embodiments, the serum uric acid level is reduced by 55% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks. In some embodiments, the serum uric acid level is reduced by 60% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks. In some embodiments, the serum uric acid level is reduced by 65% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks. In some embodiments, the serum uric acid level is reduced by 70% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks.
[0037] Albuminuria (UACR > 30 mg/g) is a marker of kidney disease. In some embodiments, the instant disclosure provides methods of reducing the urine albumin-to-creatinine ratio (UACR) in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor. In some embodiments, the UACR is reduced by WO 2022/162021 PCT/EP2022/051794-PCT
5% or more compared to pre-treatment baseline level. In some embodiments, the UACR is reduced by 10% or more compared to pre-treatment baseline level. In some embodiments, the UACR is reduced by 20% or more compared to pre-treatment baseline level. In some embodiments, the UACR is reduced by 30% or more compared to pre-treatment baseline level. In some embodiments, the UACR is reduced by 5% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks. In some embodiments, the UACR is reduced by 10% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks. In some embodiments, the UACR is reduced by 20% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks. In some embodiments, the UACR is reduced by 30% or more compared to pre-treatment baseline level after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks.
Verinurad
[0038] Disclosed herein are methods and pharmaceutical composition which utilize verinurad or a pharmaceutically acceptable salt thereof. In some embodiments, verinurad or a pharmaceutically acceptable salt thereof is verinurad. In some embodiments, a pharmaceutically acceptable salt of verinurad is the sodium salt of verinurad, i.e. sodium 2-[3-(4-cyanonaphthalen- l-yl)pyridin-4-yl]sulfanyl-2-methylpropanoate.
Xanthine Oxidase Inhibitors
[0039] The oxidation of hypoxanthine to xanthine and further the oxidation of xanthine to uric acid can be catalyzed by xanthine oxidase. Disclosed herein are methods and pharmaceutical composition which utilize a xanthine oxidase inhibitor (XOI) in urate lowering combination therapy. In some embodiments, the XOI is a purine analog, such as allopurinol, oxypurinol, or tisopurine. In other embodiments, the XOI is another molecule, such as febuxostat or topiroxostat. In some embodiments, the XOI is allopurinol or febuxostat. In some embodiments, the XOI is febuxostat. In embodiments, the XOI is allopurinol. WO 2022/162021 PCT/EP2022/051794-PCT
Figure imgf000012_0001
Allopurinol Oxypurinol Tisopurine
Figure imgf000012_0002
Dosing
[0040] In some embodiments, the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day. In some embodiments, the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 15 mg/day and less than or equal to 24 mg/day. In some embodiments, the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 15 mg/day and less than 24 mg/day.
[0041] In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is selected from about 12.5 mg/day, about 13 mg/day, about 13.5 mg/day, about 14 mg/day, about 14.5 mg/day, about 15 mg/day, about 15.5 mg/day, about 16 mg/day, about 16.5 mg/day, about 17 mg/day, about 17.5 mg/day, about 18 mg/day, about 18.5 mg/day, about 19 mg/day, about 19.5 mg/day, about 20 mg/day, about 20.5 mg/day, about 21 mg/day, about 21.5 mg/day, about 22 mg/day, about 22.5 mg/day, about 23 mg/day, about 23.5 mg/day, and about 24 mg/day. [0042] In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is selected from about 13 mg/day, about 14 mg/day, about 15 mg/day, about 16 mg/day, about 17 mg/day, about 18 mg/day, about 19 mg/day, about 20 mg/day, about 21 mg/day, about 22 mg/day, about 23 mg/day, and about 24 mg/day.
[0043] In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 12.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 13 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 13.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 14 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 14.5 mg/day. In some embodiments, WO 2022/162021 PCT/EP2022/051794-PCT the dose of verinurad or a pharmaceutically acceptable salt thereof is 15 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 15.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 16 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 16.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 17 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 17.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 18 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 18.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 19 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 19.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 20 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 20.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 21 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 21.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 22 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 22.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 23 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 23.5 mg/day. In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is 24 mg/day.
[0044] In some embodiments, the dose of verinurad or a pharmaceutically acceptable salt thereof is not 20 mg/day.
[0045] In some embodiments, the xanthine oxidase inhibitor is allopurinol, and the dose of allopurinol is about 100 mg/day to about 400 mg/day. In some embodiments, the dose of allopurinol is about 100 mg/day to about 300 mg/day. In some embodiments, the dose of allopurinol is selected from about 100 mg/day, about 200 mg/day and about 300 mg/day. In some embodiments, the dose of allopurinol is about 300 mg/day. In some embodiments, the dose of allopurinol is 300 mg/day.
[0046] In some embodiments, the xanthine oxidase inhibitor is febuxostat, and the dose of febuxostat is about 10 mg/day to about 160 mg/day. In some embodiments, the xanthine oxidase inhibitor is febuxostat, and the dose of febuxostat is about 40 mg/day to about 160 mg/day. In WO 2022/162021 PCT/EP2022/051794-PCT some embodiments, the dose of febuxostat is selected from about 10 mg/day, about 20 mg/day, about 40 mg/day, and 80 mg/day. In some embodiments, the dose of febuxostat is about 80 mg/day. In some embodiments, the dose of febuxostat is 80 mg/day.
[0047] In some embodiments, the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day, and allopurinol at a dose of 300 mg/day.
[0048] In some embodiments, the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day, and febuxostat at a dose of 80 mg/day.
[0049] In some embodiments, the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 15 mg/day and less than or equal to 24 mg/day, and allopurinol at a dose of 300 mg/day.
[0050] In some embodiments, the methods disclosed herein comprise administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 15 mg/day and less than or equal to 24 mg/day, and febuxostat at a dose of 80 mg/day.
[0051] In some embodiments, there is provided verinurad or a pharmaceutically acceptable salt thereof for use in the methods disclosed herein. In some embodiments, there is provided verinurad for use in the methods disclosed herein.
[0052] In some embodiments, there is provided a pharmaceutical composition comprising verinurad or a pharmaceutically acceptable salt thereof in an amount greater than 12 mg and less than or equal to 24 mg for use in the methods disclosed herein.
Pharmaceutical Compositions
[0053] The instant disclosure further provides pharmaceutical compositions comprising verinurad or a pharmaceutically acceptable salt thereof for use in the methods described herein. In some embodiments, the pharmaceutical compositions comprise verinurad or a pharmaceutically acceptable salt thereof in an amount greater than 12 mg and less than or equal to 24 mg. In some embodiments, the pharmaceutical compositions comprise verinurad or a pharmaceutically acceptable salt thereof in an amount greater than 12 mg and less than or equal to 24 mg, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical compositions are useful for treating or preventing a condition disclosed herein. WO 2022/162021 PCT/EP2022/051794-PCT
[0054] The pharmaceutical compositions described herein may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are optionally prepared according to known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
[0055] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
[0056] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[0057] Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. WO 2022/162021 PCT/EP2022/051794-PCT
[0058] In one embodiment, the pharmaceutical compositions described herein may be formulated using the methods and formulations described in WO2017/097845 which is incorporated herein by reference. Accordingly, in an embodiment there is provided a pharmaceutical composition comprising a plurality of pellets, wherein each pellet comprises: an inert core; a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof that encapsulates the inert core; and a modified release layer that encapsulates the drug layered inert core; wherein the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 12 mg and less than or equal to 24 mg.
[0059] In some embodiments, the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 15 mg and less than 24 mg. In some embodiments, the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 15 mg and less than or equal to 24 mg. In some embodiments, the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 15 mg and less than 24 mg.
[0060] In some embodiments, the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg, about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg, about 23.5 mg, and about 24 mg.
[0061] In some embodiments, the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, and about 24 mg.
[0062] In some embodiments, the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is not 20 mg.
[0063] As used herein, the term "modified release" means that the escape or release of the verinurad or pharmaceutically acceptable salt thereof from the pellet has been modified so that the release rate is slower than that from an unmodified or immediate release pellet. Modified release coatings as known in the art may be employed to fabricate the modified release layer, especially polymer coatings, such as a cellulose ester or ether, an acrylic polymer, or a mixture of WO 2022/162021 PCT/EP2022/051794-PCT polymers. Such materials include ethyl cellulose, cellulose acetate and cellulose acetate butyrate. The polymer may be applied as a solution in an organic solvent or as an aqueous dispersion or latex. The coating operation may be conducted in standard equipment such as a fluid bed coater, a Wurster coater, or a rotary bed coater. If desired, the permeability of the coating may be adjusted by blending of two or more materials. A useful process for tailoring the porosity of the coating comprises adding a pre-determined amount of a finely-divided water-soluble material, such as sugars or salts or water-soluble polymers (e.g. hydroxypropyl cellulose and poly (N- vinyl-2-pyrrolidinone)) to a solution or dispersion (e.g., an aqueous latex) of the coating polymer to be used. When the pellet is ingested into the aqueous medium of the GI tract, these water soluble additives are leached out of the modified release layer, leaving pores which facilitate release of the drug. The modified release layer can also be modified by the addition of plasticizers, as known in the art.
[0064] The plurality of pellets each comprise an inert core layered with a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof and coated with a modified release layer comprising a polymeric material of the type useful for providing modified release of the verinurad or a pharmaceutically acceptable salt thereof. The pellets may be prepared by building the drug layer up on an inert core by a drug-layering technique such as powder coating or by applying the spraying a solution or dispersion of verinurad or a pharmaceutically acceptable salt thereof in an appropriate solution/dispersion vehicle (e.g. a binder dispersion, for example hydroxypropyl methyl cellulose (HPMC), e.g. 6 cps) onto inert cores in a fluidized bed such as a Wurster coater or a rotary processor. The inert core can be comprised of a sugar (for example a non-pareil seed), starch or microcrystalline cellulose, conveniently microcrystalline cellulose. An example of a suitable composition and method is to spray an aqueous dispersion of verinurad or a pharmaceutically acceptable salt thereof and a binder (e.g. HPMC) in water on to the inert core. Modified release coatings as known in the art and as previously described, especially polymer coatings, may be employed to fabricate the modified release layer, which is applied over the drug layered inert cores. In one embodiment, the modified release layer comprises a mixture of waterinsoluble and water-soluble polymers, for example, ethylcellulose and hydroxypropylcellulose, respectively; or ethylcellulose and poly (N-vinyl-2-pyrrolidinone), respectively. When placed in an aqueous medium, the water-soluble polymers are leached out of the modified release layer, leaving pores which facilitate delivery of the drug. WO 2022/162021 PCT/EP2022/051794-PCT
[0065] In some embodiments, the inert core comprises microcrystalline cellulose. In some embodiments, the inert core comprises microcrystalline cellulose in an amount between 90wt% and 100wt%. In some embodiments, the inert core consists of microcrystalline cellulose.
[0066] In some embodiments, the modified release layer comprises ethyl cellulose. In some embodiments, the modified release layer comprises hydroxypropyl cellulose. In some embodiments, the modified release layer comprises poly (N-vinyl-2-pyrrolidinone). In some embodiments, the modified release layer comprises ethyl cellulose and hydroxypropyl cellulose. In some embodiments, the modified release layer comprises ethyl cellulose and poly (N-vinyl-2- pyrrolidinone). In some embodiments, the modified release layer comprises ethyl cellulose and hydroxypropyl cellulose, wherein the weight ratio of ethylcellulose to hydroxypropyl cellulose ranges from about 1 : 1 to about 4: 1. In some embodiments, the modified release layer comprises ethyl cellulose and poly (N-vinyl-2-pyrrolidinone), wherein the weight ratio of ethylcellulose to poly (N-vinyl-2-pyrrolidinone) ranges from about 1 : 1 to about 4: 1. In some embodiments, the modified release layer comprises ethyl cellulose and hydroxypropyl cellulose, wherein the weight ratio of ethylcellulose to hydroxypropyl cellulose ranges from about 3:2 to about 3: 1. In some embodiments, the modified release layer comprises ethyl cellulose and poly (N-vinyl-2- pyrrolidinone), wherein the weight ratio of ethylcellulose to poly (N-vinyl-2-pyrrolidinone) ranges from about 3:2 to about 3: 1. In some embodiments, the modified release layer comprises ethyl cellulose and hydroxypropyl cellulose, wherein the weight ratio of ethylcellulose to hydroxypropyl cellulose ranges from about 2: 1 to about 3: 1. In some embodiments, the modified release layer comprises ethyl cellulose and poly (N-vinyl-2-pyrrolidinone), wherein the weight ratio of ethylcellulose to poly (N-vinyl-2-pyrrolidinone) ranges from about 2: 1 to about 3: 1. [0067] In some embodiments, the drug layer comprises a binder. In some embodiments, the binder is hydroxypropyl methylcellulose. In some embodiments, the weight ratio of the verinurad or a pharmaceutically acceptable salt thereof to the binder ranges from about 4: 1 to about 19: 1. In some embodiments, the weight ratio of the verinurad or a pharmaceutically acceptable salt thereof to the binder ranges from about 8: 1 to about 11 : 1. In some embodiments, the weight ratio of the verinurad or a pharmaceutically acceptable salt thereof to the binder ranges is about 9: 1. [0068] In some embodiments, the inert core is present in an amount ranging from about 10% to about 90% (w/w) of the combined weight of the inert core, drug layer and modified release layer; the drug layer is present in an amount ranging from about 5% to about 80% (w/w) of the combined weight of the inert core, drug layer and modified release layer; the modified release WO 2022/162021 PCT/EP2022/051794-PCT layer is present in an amount ranging from about 5% to about 50% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
[0069] In some embodiments, the inert core is present in an amount ranging from about 40% to about 75% (w/w) of the combined weight of the inert core, drug layer and modified release layer. In some embodiments, the inert core is present in an amount ranging from about 50% to about 75% (w/w) of the combined weight of the inert core, drug layer and modified release layer. In some embodiments, the inert core is present in an amount ranging from about 50% to about 70% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
[0070] In some embodiments, the drug layer is present in an amount ranging from about 5% to about 25% (w/w) of the combined weight of the inert core, drug layer and modified release layer. In some embodiments, the drug layer is present in an amount ranging from about 5% to about 20% (w/w) of the combined weight of the inert core, drug layer and modified release layer. In some embodiments, the drug layer is present in an amount ranging from about 5% to about 15% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
[0071] In some embodiments, the modified release layer is present in an amount ranging from about 20% to about 40% (w/w) of the combined weight of the inert core, drug layer and modified release layer. In some embodiments, the modified release layer is present in an amount ranging from about 20% to about 30% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
[0072] In some embodiments, the inert core is present in an amount ranging from about 50% to about 70% (w/w) of the combined weight of the inert core, drug layer and modified release layer; the drug layer is present in an amount ranging from about 5% to about 20% (w/w) of the combined weight of the inert core, drug layer and modified release layer; the modified release layer is present in an amount ranging from about 20% to about 40% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
[0073] In some embodiments, the inert core is present in an amount ranging from about 10% to about 90% (w/w) of the total weight of the pellet; the drug layer is present in an amount ranging from about 5% to about 80% (w/w) of the total weight of the pellet; the modified release layer is present in an amount ranging from about 5% to about 50% (w/w) of the total weight of the pellet. [0074] In some embodiments, the inert core is present in an amount ranging from about 40% to about 75% (w/w) of the total weight of the pellet. In some embodiments, the inert core is present in an amount ranging from about 50% to about 75% (w/w) of the total weight of the pellet. In WO 2022/162021 PCT/EP2022/051794-PCT some embodiments, the inert core is present in an amount ranging from about 50% to about 70% (w/w) of the total weight of the pellet.
[0075] In some embodiments, the drug layer is present in an amount ranging from about 5% to about 25% (w/w) of the total weight of the pellet. In some embodiments, the drug layer is present in an amount ranging from about 5% to about 20% (w/w) of the total weight of the pellet. In some embodiments, the drug layer is present in an amount ranging from about 5% to about 15% (w/w) of the total weight of the pellet.
[0076] In some embodiments, the modified release layer is present in an amount ranging from about 20% to about 40% (w/w) of the total weight of the pellet. In some embodiments, the modified release layer is present in an amount ranging from about 20% to about 30% (w/w) of the total weight of the pellet.
[0077] In some embodiments, the inert core is present in an amount ranging from about 50% to about 70% (w/w) of the total weight of the pellet; the drug layer is present in an amount ranging from about 5% to about 20% (w/w) of the total weight of the pellet; the modified release layer is present in an amount ranging from about 20% to about 40% (w/w) of the total weight of the pellet.
[0078] In some embodiments, each pellet may comprise a lubricant such as magnesium stearate. In some embodiments, the lubricant is present at about 0.1% to about 5% (w/w) of the total weight of the pellet. In some embodiments, the lubricant is present at about 0.1% to about 0.5% (w/w) of the total weight of the pellet. In some embodiments, a sub-coat can be applied between the drug layer and the modified release layer if separation is needed. In some embodiments, the coat can be comprised of hydroxypropyl methylcellulose or magnesium stearate.
[0079] Conveniently, the pellets range in size from about 150 pm to about 400 pm, more conveniently about 350 pm. As described hereinbefore, the pharmaceutical composition comprises a plurality of pellets that may be packaged, for example, in a capsule such as a gelatin capsule or a capsule formed from a polymer such as HPMCAS, HPMC or starch; dosed as a suspension or slurry in a liquid; dosed in a sachet; or they may be formed into a tablet (e.g. a caplet) or pill by compression or other processes known in the art. Conveniently, the pellet composition comprising the plurality of pellets is packaged in a capsule, such as a gelatin capsule or a capsule formed from a polymer such as HPMCAS, HPMC or starch. In some embodiments the plurality of pellets is contained within one or more capsules. In some embodiments the plurality of pellets is contained within one capsule. WO 2022/162021 PCT/EP2022/051794-PCT
[0080] In some embodiments, the pharmaceutical composition comprises other medicinal or pharmaceutical agents. In some embodiments, the pharmaceutical composition comprises a xanthine oxidase inhibitor. In some embodiments, the pharmaceutical composition comprises allopurinol. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 400 mg of allopurinol. In some embodiments, the pharmaceutical composition comprises about 100 mg to about 300 mg of allopurinol. In some embodiments, the pharmaceutical composition comprises about 100 mg, about 200 mg or about 300 mg of allopurinol. In some embodiments, the pharmaceutical composition comprises about 300 mg of allopurinol. In some embodiments, the pharmaceutical composition comprises 300 mg of allopurinol.
[0081] In some embodiments, the pharmaceutical composition comprises about 10 mg to about 160 mg of febuxostat. In some embodiments, the pharmaceutical composition comprises about 40 mg to about 160 mg of febuxostat. In some embodiments, the pharmaceutical composition comprises about 10 mg, about 20 mg, about 40 mg or about 80 mg of febuxostat. In some embodiments, the pharmaceutical composition comprises about 80 mg of febuxostat. In some embodiments, the pharmaceutical composition comprises 80 mg of febuxostat.
[0082] For convenience, the total daily dosage may be divided and administered in portions during the day if desired. Accordingly, the total daily dose may be subdivided into unit doses containing appropriate quantities of the pharmaceutical composition described herein and xanthine oxidase inhibitor to achieve the desired purpose. Unit dosage forms may be prepared by any of the methods well known in the art of pharmacy. In general, unit dosage forms may be prepared similarly to the formulations described herein.
[0083] The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, or suspension.
[0084] In addition, they may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc. In some embodiments, the active ingredients are administered in separate dosage units. In some embodiments, for example, each active ingredient is administered in a separate tablet. In other embodiments, the active ingredients are administered in a single dosage unit. For example, all active ingredients may be administered in the same tablet. In some embodiments, the unit dosage form comprises, for example, three separate tablets individually comprising one active ingredient), two tablets wherein one tablet comprises two of active ingredients and the other tablet comprising a third active ingredient), or a single tablet which comprises all active ingredients. The particular choice of the one or more additional therapeutic agents will depend WO 2022/162021 PCT/EP2022/051794-PCT upon the diagnosis of the attending physicians and their judgment of the condition of the individual and the appropriate treatment protocol. In some embodiments, the additional agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, a purine nucleoside phosphorylase (PNP) inhibitor, a uric acid transporter inhibitor, a glucose transporter (GLUT) inhibitor, a GLUT-9 inhibitor, a solute carrier family 2 (facilitated glucose transporter), member 9 (SLC2A9) inhibitor, an organic anion transporter (OAT) inhibitor, an OAT-4 inhibitor, or a combination thereof. In some embodiments, the one or more additional therapeutic agents are selected from 2-((5-bromo-4-(4- cyclopropyl-l-naphthalenyl)-4H-l,2,4-triazol-3-yl)thio)acetic acid, allopurinol, febuxostat (2-(3- cyano-4-isobutoxyphenyl)-4-methyl-l,3-thiazole-5-carboxylic acid), FYX-051 (4-(5-pyridin-4- yl-U/-[l,2,4]triazol-3-yl)pyridine-2-carbonitrile), probenecid, sulfinpyrazone, benzbromarone, acetaminophen, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH), colchicine, a glucorticoid, an adrogen, a cox-2 inhibitor, a PPAR agonist, naproxen, sevelamer, sibutmaine, troglitazone, proglitazone, another uric acid lowering agent, losartan, fibric acid, benziodarone, salisylate, anlodipine, vitamin C, dapagliflozin, and combinations thereof.
[0085] The methods and pharmaceutical compositions described in this specification are further illustrated in the following Examples. These Examples are given by way of illustration only and are non-limiting.
EXAMPLES
Example 1: A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled Study of Verinurad and Allopurinol in Patients with Chronic Kidney Disease and Hyperuricaemia
[0086] The purpose of this clinical research study is to establish the dose of verinurad combined with allopurinol 300 mg once daily that will elicit the desired response; ie, reduction in urinary albumin to creatinine ratio (UACR) at 6 months. WO 2022/162021 PCT/EP2022/051794-PCT
Figure imgf000023_0001
Study Design:
• Study Type: Interventional
• Primary Purpose: Treatment
• Study Phase: Phase 2
• Intervention Study Model: Parallel Assignment
• Masking: Subject, Caregiver, Investigator, Outcomes Assessor
• Allocation: Randomized
Primary Outcome Measures:
• Ratio of urinary albumin to urinary creatinine [ Time Frame: At 6 months ]
Change from baseline in urinary albumin to creatinine ratio (UACR).
Secondary Outcome Measures:
• Estimated glomerular filtration rate (eGFR) [ Time Frame: At 6 months, 12 months. ]
Change from baseline in estimated glomerular filtration rate
• Serum cystatin C [ Time Frame: At 6 months, 12 months. ]
Change from baseline in cystatin-C.
• Serum creatinine [ Time Frame: At 6 months, 12 months. ]
Change from baseline in creatinine.
• Ratio of urinary albumin to urinary creatinine [ Time Frame: At 6 months, 12 months. ]
Change from baseline in urinary albumin to urinary creatinine ratio (UACR). WO 2022/162021 PCT/EP2022/051794-PCT
• Serum uric acid [ Time Frame: At 6 months, 12 months. ] Change from baseline in Serum uric acid (sUA)
Arms and Interventions
Figure imgf000024_0001
WO 2022/162021 PCT/EP2022/051794-PCT
Figure imgf000025_0001
Detailed Description
[0087] Evidence shows independent associations between hyperuricaemia and the risk of hypertension, myocardial infarction, chronic kidney disease (CKD), type 2 diabetes, heart failure, and metabolic syndrome, including obesity. Furthermore, gout, an inflammatory arthritis caused by deposition of monosodium urate crystals in joints, is associated with an increased risk of allcause death, as well as cardiovascular (CV) death. Hyperuricaemia is a prerequisite for development of gout, thus linking high levels of sUA to gout and to poor outcomes. However, the causal relationship between hyperuricaemia / gout and the aforementioned diseases and outcomes remains to be proven. Uric acid transporter 1 (URAT1) is responsible for reabsorption of uric acid (UA in the proximal tubule. Inhibition of URAT1 results in increased urinary excretion of UA. Verinurad (RDEA3170) is a novel URAT1 inhibitor in Phase 2 development WO 2022/162021 PCT/EP2022/051794-PCT for chronic kidney disease and heart failure. Verinurad combined with the xanthine oxidase (XO)inhibitor (XOI) febuxostat or allopurinol has been shown to lower sUA in patients with recurrent gout in Phase 2 studies by up to 80%.
[0088] The primary objective of this study is to assess the effects of treatment with verinurad and allopurinol, allopurinol alone, and placebo on UACR at 6 months. In this study, change in UACR at 6 months of treatment is the primary endpoint for the efficacy evaluation of treatment with the combination of verinurad and allopurinol vs. placebo. A key secondary objective is evaluation of verinurad plus allopurinol on the reduction in UACR at 12 months.
[0089] Further, standard safety parameters such as adverse event (AEs), serious adverse event (SAEs), and laboratory evaluations will be employed to assess the safety profile of the study drugs. Verinurad, allopurinol and oxypurinol plasma concentrations over time will also be measured. The study will recruit patients with Chronic Kidney Disease and Hyperuricaemia.
Eligibility
• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: Both
• Gender Based: No
• Gender Eligibility Criteria:
• Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
• The subject has given written informed consent prior to any mandatory study specific procedures, sampling, and analyses, and is able to understand and comply with all study procedures
• Adult Patient >18 years of age with CKD for >3 months.
• Patients with background standard of care treatment for albuminuria and/or T2DM and treated according to locally recognised guidelines. Therapy optimised and stable for >4 weeks before study entry and including an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, unless justified.
• If treated with a sodium-glucose transport protein (SGLT2) inhibitor, stable dose for >4 weeks before randomisation. WO 2022/162021 PCT/EP2022/051794-PCT
• Meeting screening criteria for sUA and eGFR (Visit 2): sUA >6.0 mg/dL. • eGFR >25 mL/min/1.73 m2 Chronic Kidney Disease Epidemiology Collaboration
• UACR between 30 mg/g and 5000 mg/g.
• Female patients: Negative pregnancy test for childbearing potential. 1 year postmenopausal, surgically sterile, or using an acceptable method of contraception during the study and 4 weeks after the last dose of study treatment.
Exclusion Criteria:
• Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasmic antibody associated vasculitis (granulomatosis with polyangiitis [Wegener's granulomatosis], microscopic polyangiitis, or eosinophilic granulomatosis with polyangiitis [Churg-Strauss syndrome]).
• History of renal transplantation
• Known carrier of the Human Leukocyte Antigen -B *58:01 allele.
• Patients diagnosed with tumor lysis syndrome or Lesch-Nyhan syndrome
• Patients who in the opinion of investigator are unable to perform the patients’ tasks associated with the protocol or Presence of any condition which, places the patient at undue risk or potentially jeopardises the quality of the data to be generated
• History of stroke, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft in the past 6 months
• Uncontrolled hypertension presenting with systolic blood pressure >180 mm Hg and/or diastolic blood pressure >100 mm Hg
• Diagnosed with heart failure and New York Heart Association Functional Classification Class IV at the time of randomization
• QT interval corrected by the Fridericia formula >470 msec; patients diagnosed with long QT syndrome; patients with a family history of long QT syndrome.
• Subjects with severe hepatic impairment, as judged by the investigator, of Child-Pugh Class C (decompensated cirrhosis), or with major cirrhosis complications (eg, hepatorenal syndrome)
• Receiving cytotoxic or immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment
• Treated with any drug for hyperuricaemia in the 6 months preceding randomisation. WO 2022/162021 PCT/EP2022/051794-PCT
• Dose of ACEi, ARBs, fenofibrate, guaifenesin, or SGLT2 inhibitors changed within 4 weeks of randomisation or further dose titration expected after randomization
[0090] While certain embodiments of the claims have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments described herein are, in some circumstances, employed in practicing the invention. [0091] It is intended that methods and structures within the scope of these claims and their equivalents be covered thereby. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described and claimed. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.
Example 2: A Phase 2, Multicentre, Double-Blind, Three-Arm, Placebo and Active Control Efficacy and Safety Study to Evaluate Verinurad Combined With Allopurinol in Heart Failure With Preserved Ejection Fraction
[0092] International, Multicenter, Double-Blind, 3 -Arm, Placebo and Active Control Efficacy and Safety Study to Evaluate Verinurad combined with Allopurinol in Heart Failure with Preserved Ejection Fraction.
Figure imgf000028_0001
Study Design:
• Study Type: Interventional (Clinical Trial)
• Primary Purpose: Treatment
• Study Phase: Phase 2 WO 2022/162021 PCT/EP2022/051794-PCT
• Intervention Study Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Allocation: Randomized
Primary Outcome Measures:
• Change from baseline at Week 32 in peak V02 [ Time Frame: From baseline at Week 32 ]
To assess effect of verinurad + allopurinol compared to placebo or allopurinol monotherapy on exercise capacity.
Secondary Outcome Measures:
• Change from baseline at Week 32 in Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) [ Time Frame: From baseline at Week 32 ]
To assess effect of verinurad + allopurinol compared to placebo or allopurinol monotherapy on Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS). The score ranges from 0 to 100, where a higher score represents a better patient outcome.
Arms and Interventions
Figure imgf000029_0001
WO 2022/162021 PCT/EP2022/051794-PCT
Figure imgf000030_0001
Detailed Description
[0093] Evidence shows independent associations between hyperuricaemia and the risk of cardiorenal conditions, including heart failure (HF). Serum uric acid (sUA) is also a strong prognostic factor and correlates with other markers of poor prognosis in HF patients with preserved ejection fraction (HFpEF), and an estimated 1/2-2/3 of HFpEF patients have hyperuricaemia. HFpEF is a microvascular disease likely partly driven by endothelial dysfunction and inflammation in WO 2022/162021 PCT/EP2022/051794-PCT coronary vessel walls. Uric acid crystals have been identified in coronary vessel walls in some hyperuricaemic patients.
[0094] Uric acid transporter 1 (URAT1) is responsible for reabsorption of uric acid (UA) in the proximal tubule. Inhibition of URAT1 results in increased urinary excretion of UA and lowering of uric acid in the blood. Verinurad is a novel URAT1 inhibitor in Phase 2 development for chronic kidney disease (CKD) and HF. Verinurad combined with the xanthine oxidase (XO) inhibitors (XOI) febuxostat or allopurinol has been shown to lower sUA in patients with recurrent gout in Phase 2 studies by up to approximately 80%.
[0095] The primary objective of this Phase 2 study is to assess the effect of a combination of verinurad and allopurinol on exercise capacity in patients with HFpEF.
[0096] The secondary objectives are to assess effect of combination of verinurad and allopurinol in comparison to allopurinol monotheraphy on excercise capacity dwhich will be measured in peak VO2 as well as effect of verinurad and allopurinol compared to placebo and to allopurinol monotheraphy on Kansas City cardiomyopathy questionnaire (KCCQ)-total symptom score (TSS). A sub-study aims to investigate the relationship between UA crystals and inflammation.
Eligibility
• Ages Eligible for Study: 40 Years to 130 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
• Patient must be > 40 years of age at the time of signing the ICF
• Patients with hyperuricaemia defined as sUA level of > 6 mg/dL.
• Patients with documented diagnosis of symptomatic HFpEF according to all of the following criteria:
1. Have NYHA functional class II-III at enrolment
2. Have medical history of typical symptoms/signs of HF > 6 weeks before enrolment
3. LVEF > 45% WO 2022/162021 PCT/EP2022/051794-PCT
4. NT -proBNP > 125 pg/mL (> 14.75 pmol/L) at Visit 2 for patients without ongoing atrial fibrillation/flutter.
• Patients able to exercise to near exhaustion during a CPET as exhibited by RER > 1.05 during CPET conducted during screening. If patient does not achieve RER > 1.05 the CPET may be repeated once, at least 48 hours but less than 2 weeks (but before randomisation) after the initial test; in such cases the second test will serve as baseline.
• Male or female
Exclusion Criteria:
• eGFR < 30ml/min/l ,73m2 (based on CKD-EPI formula)
• Presence of any condition that precludes exercise testing
• Known history of a documented LVEF < 40%
• Probable alternative or concomitant diagnoses which in the opinion of the Investigator could account for the patient's HF symptoms and signs (eg, anaemia, hypothyroidism)
• Known carrier of the Human Leukocyte Antigen -B (HLA-B) *58:01 allele: HLA-B *58:01 genotyping is mandatory prior to randomization for all patients.
• Patients diagnosed with tumor lysis syndrome or Lesch-Nyhan syndrome
• Patients who are severely physically or mentally incapacitated and who in the opinion of investigator are unable to perform the patients' tasks associated with the protocol
• Presence of any condition which, in the opinion of the investigator, places the patient at undue risk or potentially jeopardises the quality of the data to be generated
• Current acute decompensated HF or hospitalisation due to decompensated HF < 4 weeks prior to enrolment
• Myocardial infarction, unstable angina, coronary revascularisation (percutaneous coronary intervention or coronary artery bypass grafting), ablation of atrial flutter/fibrillation, valve repair/replacement, implantation of a cardiac resynchronisation therapy device, stroke or transient ischemic attack within 6 months prior to enrolment.
• Planned coronary revascularisation, ablation of atrial flutter/fibrillation and/or valve repair/replacement
• Atrial fibrillation with persistent resting heart rate > 110 beats per minute. WO 2022/162021 PCT/EP2022/051794-PCT
[0097] While certain embodiments of the claims have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments described herein are, in some circumstances, employed in practicing the invention. It is intended that methods and structures within the scope of these claims and their equivalents be covered thereby. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described and claimed. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.
Example 3: Process for preparation of pellet formulations
[0098] Pellet formulations were prepared by a drug layering process. An inert core of a solid material of a mean size of from 100-700 pm was coated with 2-((3-(4-cyanonaphthalen-l- yl)pyridine-4-yl)thio)-2-methylpropanoic acid in a drug layering process. A solution or suspension containing said compound was sprayed onto the solid material and the solvent was evaporated. Examples of inert cores that can be used include microcrystalline cellulose such as Celphere CP-203 (200-300 pm), Celphere CP-305 (300-500 pm) or Celphere 507 (500-700 pm), silicon dioxide (sand) or sucrose.
[0099] After 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-m ethylpropanoic acid has been layered onto the inert core, a film layer is formed to provide a release rate controlling layer. Step 1 : coating of an inert core pellet
[00100] A solution of the verinurad or a pharmaceutically acceptable salt thereof is prepared in a concentration of from 1-30 % w/w, such as from 5-15 % w/w. The verinurad or a pharmaceutically acceptable salt thereof is mixed with a binder, such as HPC, HPMC or other polymer and dispersed in a solvent. Examples of solvents that may be used are water or an alcohol such as ethanol, or a mixture thereof. The solution or suspension is held at a temperature of from 15°C and 40°C. The solution or suspension of said compound is sprayed onto the core material in a fluidised bed equipment such as Aeromatic MP1, LabCC (Graniten LabCC) or Glatt GPCG at a temperature of from 50-100°C, such as from 35-80°C, or from 50-75°C, for example for s duration of 30 - 500 minutes. Batch sizes useful are typically from 10 g - 400 kg. For a batch size of 1 kg, a spray rate of from 5 - 40 g/min is used. WO 2022/162021 PCT/EP2022/051794-PCT
[00101] It is also possible to use a crystallisation process without the need for a binder. In this case the crystalline compound can be dissolved in a solvent and then re-crystallised onto the inert cores in the fluid bed. This may be initiated or effected with or without seeding with crystals of said compound and can be performed in one step or be divided in several sub-bathes.
Step 2, polymer coating of pellets from step 1
[00102] The pellet granules formed in step 1 are coated with a polymer such as ethyl cellulose (EC), hydroxypropyl cellulose (HPC), poly (N-vinyl-2-pyrrolidinone) or a mixture thereof. The polymer and/or the mixture thereof is dissolved in a solvent such as water, a ketone or an alcohol such as ethanol and/or mixtures thereof. The solution is sprayed onto the granules in fluidized bed equipment such as Aeromatic MP1, LabCC or Glatt GPCG at a temperature of from 60- 120°C, such as from 75-100°C. The solution is sprayed onto the granules for a sufficient period of time, such as from 10 min to 400 minutes. The time required is dependent on the batch size and the desired thickness of the polymer film to achieve the desired Agent release profile. The batch size may be from 10 g up to 400 kg.
Step 3, capsule filling or tableting
[00103] The pellets comprising the verinurad or a pharmaceutically acceptable salt thereof prepared according to step 2 may be filled into a capsule. Examples of a capsule material that may be used in accordance with the invention is hydroxypropyl methylcellulose or gelatine. It will be appreciated that a given dose of verinurad or a pharmaceutically acceptable salt thereof within the capsule may be obtained by incorporating a suitable fill weight of pellets within the capsule to obtain the required dose. Alternatively, the pellets can be formed into a tablet.
Example 4: Preparation of pellet formulation (3-hour Profile)
[00104] A pellet formulation was prepared with the following composition:
Composition of modified release pellet capsules 5 mg
Components Quantity Supplier
(mg per capsule)
Active compound1 5.0
MCC spheres 0.15-0.3 mm 22.2 Asahi Kasei
HPMC 6 cps 0.6 Dow
HPC LF 6.2 Ashland
EC 9.3 Dow
Ethanol, 95 per cent qs Kemetyl A
Water purified qs WO 2022/162021 PCT/EP2022/051794-PCT
Composition of modified release pellet capsules 5 mg
Components Quantity Supplier
(mg per capsule)
HPMC capsule NA Qualicaps
1 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2 -methylpropanoic acid
[00105] This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation. 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size Dio was less than 1 pm, D50 less than 5 pm and D90 less than 20 pm.
[00106] A polymer solution of 15.0 g of HPMC 6 cps in 1350.0 g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-l-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid was added. The resultant suspension was protected from light and stirred overnight. The suspension was held at RT °C. Before spraying, the suspension was sieved through a 200pm mesh. The spray rate was between 8-12 g suspension/min for the first 5 minutes and there after 10 to 20 g suspension/min for another 105 minutes. Inlet temperature was 72°C. 1250 g of the 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/HPMC suspension was sprayed onto 500 g microcrystalline cellulose (MCC) powder spheres (Celphere CP-203 (150-300 pm)) in a fluidised bed equipment (LabCC3). The temperature of outlet air was approximately 30 °C, fluidising air flow about 35 Nm h and an atomizer air pressure of approximately 2.5 bar. The product could be made in one or several steps depending on batch sizes.
[00107] A polymer solution of 57.6 g ethyl cellulose 10 cP (EC) and 38.4 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95 % ethanol was prepared. The drug layered pellets (150g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42 °C with a spray rate of approximately 10-18 g /min. After spraying 1395 g of polymer solution the polymer coated pellets were dried for 10 minutes in fluidized bed equipment. See process parameters below.
Process parameters Ranges:
Inlet temperature 72-74°C
Outlet temperature 42-60°C
Fluidizing air flow 35 Nm3/h
Spray Rate 10-18 g/min
Atomization air pressure 2.5 bar WO 2022/162021 PCT/EP2022/051794-PCT
Atomization air flow 2.6-2.7 Nm3/h
[00108] The polymer coated pellets were screened through a 710 pm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver 5mg of 2-((3-(4- cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.
Example 5: Preparation of pellet formulation (5-hour Profile)
[00109] A pellet formulation was prepared with the following composition:
Composition of modified release pellet capsules 5 mg
Components Quantity Supplier
(mg per capsule)
Active compound1 5.0
MCC spheres 0.15-0.3 mm 22.2 Asahi Kasei
HPMC 6 cps 0.6 Dow
HPC LF 5.6 Ashland
EC 9.9 Dow
Ethanol, 95 per cent qs Kemetyl A
Water purified qs
HPMC capsule NA Qualicaps
2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2 -methylpropanoic acid
[00110] This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation. 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size Dio was less than 1 pm, D50 less than 5 pm and D90 less than 20 pm.
[00111] A polymer solution of 15.0 g of HPMC 6 cps in 1350.0g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-l-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid was added. The spray rate was between 5-12 g suspension/min for the first 5 minutes and there after 10-20 g suspension/min for another 105 minutes. Inlet temperature was 72°C. 1250 g of the 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- methylpropanoic acid/HPMC suspension was sprayed onto 500 g microcrystalline cellulose (MCC) powder spheres (Celphere CP-305 (300-500 pm) in fluidized bed equipment. The temperature of outlet air was approximately 30 °C, fluidizing air flow approximately 35 Nm3/h and an atomizer air pressure approximately 2.5 bar. The product could be made in one or several steps depending on batch sizes. WO 2022/162021 PCT/EP2022/051794-PCT
[00112] A polymer solution of 61.4 g ethyl cellulose 10 cP (EC) and 34.6 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95 % ethanol was prepared. The drug layered pellets (150 g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42°C with a spray rate of approximately 10-18 g /min. After spraying 1302.9 g of polymer solution the polymer coated pellets were dried for 10 minutes in fluidized bed equipment. See process parameters below.
Process parameters: Ranges
Inlet temperature 72-74°C
Outlet temperature 42-60°C
Fluidizing air flow 35 Nm3/h
Spray Rate 10-18 g/min
Atomization air pressure 2.5 bar
Atomization air flow 2.6-2.7 Nm3/h
[00113] The polymer coated pellets were screened through a 710 pm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver 5mg of 2-((3-(4- cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.
Example 6: Preparation of pellet formulation (8-hour Profile)
[00114] A pellet formulation was prepared with the following composition:
Composition of modified release pellet capsules 10 mg
Components Quantity Supplier
(mg per capsule)
Active Compound1 10.0
MCC spheres 0.15-0.3 mm 44.5 Asahi Kasei
HPMC 6 cps 1.1 Dow
HPC LF 10.1 Ashland
EC 20.9 Dow
Ethanol, 95 per cent qs Kemetyl A
Water purified qs
HPMC capsule NA Qualicaps
2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2 -methylpropanoic acid
[00115] This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation. 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- WO 2022/162021 PCT/EP2022/051794-PCT methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size Dio was less than 1 pm, D50 less than 5 pm and D90 less than 20 pm.
[00116] A polymer solution of 15.0 g of HPMC 6 cps in 1350.0g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-l-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid was added. The spray rate was between 5-12 g suspension/min for the first 5 minutes and there after 10-20 g suspension/min for another 105 minutes. Inlet temperature was 72°C. 1250 g of the 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- methylpropanoic acid/HPMC suspension was sprayed onto 500 g microcrystalline cellulose (MCC) powder spheres (Celphere CP-305 (300-500 pm)) in fluidized bed equipment. The temperature of outlet air was approximately 30 °C, fluidizing air flow approximately 35 Nm3/h and an atomizer air pressure approximately 2.5 bar. The product could be made in one or several steps depending on batch sizes.
[00117] A polymer solution of 64.8 g ethyl cellulose 10 cP (EC) and 31.3 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95 % ethanol was prepared. The drug layered pellets (150 g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42 °C with a spray rate of approximately 10-18 g /min. After spraying 1395 g of polymer solution the polymer coated pellets were dried for 10 minutes in a fluidized bed equipment. See process parameters below.
Process parameters Ranges
Inlet temperature 72-74°C
Outlet temperature 42-60°C
Fluidizing air flow 35 Nm3/h
Spray Rate 10-18 g/min
Atomization air pressure 2.5 bar
Atomization air flow 2.6-2.7 Nm3/h
[00118] The polymer coated pellets were screened through a 710 pm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver lOmg of 2-((3-(4- cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.
Example 7: Preparation of pellet formulation (15-hour Profile)
[00119] A pellet formulation was prepared with the following composition: WO 2022/162021 PCT/EP2022/051794-PCT
Composition of modified release pellet capsules 10 mg
Components Quantity Supplier
(mg per capsule)
Active compound1 10
MCC spheres 0.15-0.3 mm 44.5 Asahi Kasei
HPMC 6 cps 1.1 Dow
HPC LF 9.0 Ashland
EC 22.0 Dow
Ethanol, 95 per cent qs Kemetyl A
Water purified qs
HPMC capsule NA Qualicaps
2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2 -methylpropanoic acid
[00120] This example formulation was prepared by a drug layering and polymer coating fluidized bed process and encapsulation. 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- methylpropanoic acid was micronized using an air jet mill (Fluid Energy Mills). The resultant particle size Dio was less than 1 pm, D50 less than 5 pm and D90 less than 20 pm.
[00121] A polymer solution of 15.0 g of HPMC 6 cps in 1350.0g purified water was prepared. After a clear solution was obtained, 135.0 g micronized 2-((3-(4-cyanonaphthalen-l-yl)pyridine- 4-yl)thio)-2-methylpropanoic acid was added. The spray rate was between 5-12 g suspension/min for the first 5 minutes and there after 10-20 g suspension/min for another 105 minutes. Inlet temperature was 72°C. 1250 g of the 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2- methylpropanoic acid/HPMC suspension was sprayed onto 500 g microcrystalline cellulose (MCC) powder spheres (Celphere CP-305 (300-500 pm)) in fluidized bed equipment. The temperature of outlet air was approximately 30 °C, fluidizing air flow approximately 35 Nm3/h and an atomizer air pressure approximately 2.5 bar. The product could be made in one or several steps depending on batch sizes.
[00122] A polymer solution of 68.2 g ethyl cellulose 10 cP (EC) and 27.8 g hydroxypropyl cellulose (HPC) dissolved in 1504 g of 95 % ethanol was prepared. The drug layered pellets (150 g) were coated with the polymer solution in fluidized bed equipment at an outlet air temperature of approximately 42 °C with a spray rate of approximately 10-18 g /min. After sprayingl395 g of polymer solution the polymer coated pellets were dried for 10 minutes in a fluidized bed equipment. See process parameters below.
Process parameters: Inlet temperature 72-74°C WO 2022/162021 PCT/EP2022/051794-PCT
Outlet temperature 42-60°C
Fluidizing air flow 35 Nm3/h Spray Rate 10-20 g/min
Atomization air pressure 2.5 bar
Atomization air flow 2.6-2.7 Nm3/h
[00123] The polymer coated pellets were screened through a 425-710 pm sieve, assayed and then filled into hypromellose capsules, fill weight adjusted for dose to deliver lOmg of 2-((3-(4- cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-methylpropanoic acid.
Example 8: Preparation of pellet formulation using water-based coating [00124] A pellet formulation was prepared with the following composition:
Composition of modified release pellet capsules 5 mg
Components Quantity Supplier
(mg per capsule)
Active Compound1 5.0
MCC spheres 0.15-0.3 mm 22.2 Asahi Kasei
HPMC 6 cps 0.54 Dow
Eudragit NM30D 2.75 Evonik
Kollicoat IR 0.775 BASF
Talc 1.175 Sigma-Aldrich
Magnesium stearate 0.06 Peter Greven
Water purified Qs
HPMC capsule NA Qualicaps
2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2 -methylpropanoic acid
[00125] 2.47 g Kollicoat IR (polyvinyl alcohol/polyethylene glycol grafted copolymer, manufactured by BASF) and 3.75 g Talc powder was suspended in 64.52 g water. After stirring overnight, 29.25 g Eudragit NM30D dispersion was added. The dry content in the suspension was 15% w/w. The dispersion was held at RT °C. Before spraying, the dispersion was sieved through a 200pm mesh. The speed of the pump was between 1 and 2 g dispersion/min. Inlet temperature was 41 °C. 35 g dispersion was sprayed onto 10 g of 2-((3-(4-cyanonaphthalen-l- yl)pyridine-4-yl)thio)-2-methylpropanoic acid drug layered core seeds (produced as described in Example 6) in a fluidised bed drier (MiniGlatt). The temperature of outlet air was about 25 °C, WO 2022/162021 PCT/EP2022/051794-PCT fluidising air flow about 14 Nm3/h and an atomizer air pressure of about 1.6 bar giving 8.5 % (w/w) active drug /MR granules.
Process parameters
Tin 38-43°C
Tout 25-35°C
FF 14 Nm h
Coat speed 1-2 g/min
Atom. press 1.6 bar
Atom, flow 1.6-1.8 Nm3/h
Example 9: Preparation of pellet formulation (8-hour Profile) at doses 4.5, 6 and 12mg [00126] Pellet formulations were prepared with the following compositions:
Compositions of modified release pellet capsules 4.5, 6 and 12mg
Components Quantity Quantity Quantity Supplier
(mg per (mg per (mg per capsule) capsule) capsule)
Active Compound1 4.5 6 12
MCC spheres 0.3-0.5 15.4 20.8 41.9 Asahi Kasei mm
HPMC 6 cps 0.44 0.6 1.2 Dow
HPC LF 1.82 2.45 4.94 Ashland
EC 3.9 5.25 10.6 Dow
Ethanol, 95 per cent Qs Qs Qs Kemetyl A
Water purified Qs Qs Qs
Magnesium Stearate 0.05 0.07 0.15
HPMC capsule NA NA NA Qualicaps
2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2 -methylpropanoic acid
[00127] A polymer solution of 19.0 g of HPMC 6 cps in 1710.3 g water was prepared. After a clear solution was obtained, 171.0 g micronized 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4- yl)thio)-2-methylpropanoic acid was added. The suspension was protected from light and stirred overnight. The suspension was held at RT °C. Before spraying, the suspension was sieved through 200pm mesh. The spray rate was between 8-11g suspension/min for the first 5 minutes and there after 15-20 g suspension/min for another 111 minutes. Inlet temperature was 73°C. 1587.5 g the 2-((3-(4-cyanonaphthalen-l-yl)pyridine-4-yl)thio)-2-methylpropanoic acid/HPMC suspension was sprayed onto 500 g microcrystalline cellulose (MCC) powder spheres (Celphere WO 2022/162021 PCT/EP2022/051794-PCT
CP-305 (300-500 pm)) in a fluidised bed equipment (LabCC3). The temperature of outlet air was approximately 30 °C, fluidising air flow approximately 35 Nm h and an atomizer air pressure of approximately 2.5 bar. The product could be made in one or several steps depending on batch sizes.
[00128] 100 g of these granules were coated with a solution of 20.0 g ethyl cellulose 10 cP (EC) and 9.4 g hydroxypropyl cellulose (HPC) dissolved in 460 g of 95 % ethanol in a fluidised bed equipment (LabCC3) at a temperature of outlet air of 42°C with a spray rate of in average 20 g solution/min. Process parameters were as follows:
Process parameters Tin 70-75°C Tout 40-60°C FF 35 Nm h Coat speed 18-22 g/min Atom. press 2.5 bar Atom, flow 2.6-2.7 Nm3/h
Example 10: Preparation of various pellet formulations by drug layering process
[00129] A number of pellet formulations were prepared in accordance with the process described In Example 3. The table below provides details of composition and process parameters along with the dissolution time to 80% release in pH 6.8 media (ionic strength 0.1, 50.0 mM KH2PO4 + 23.6 mM NaOH, dissolution media at 37 °C, 900 ml media, 100 rpm), tested in according to the general procedure of the United States Pharmacopeia Apparatus II (paddle).
Composition and process parameters for preparation of various pellet formulations.
Figure imgf000042_0001
HPC LF supplied by Ashland. HPC L and SSL supplied by Nisso.
Abbreviations: Tin (Inlet temperature), Tout (Outlet temperature), FF (Fluidizing air flow), AP (Pressure to atomise API or polymer solution) and AF (Atomizer air flow).

Claims

WO 2022/162021 PCT/EP2022/051794-PCT CLAIMS
1. A method of treating or preventing a condition associated with hyperuricemia in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
2. The method of claim 1, wherein the condition is gout, a recurrent gout attack, gouty arthritis, hypertension, a cardiovascular disease, coronary heart disease, heart failure, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, chronic kidney disease, kidney stones, kidney failure, diabetic kidney disease, joint inflammation, arthritis, urolithiasis, plumbism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination thereof.
3. The method of claim 2, wherein the condition is chronic kidney disease.
4. The method of claim 2, wherein the condition is heart failure, optionally wherein the condition is heart failure with preserved ejection fraction.
5. A method of treating or preventing chronic kidney disease in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
6. A method of treating or preventing heart failure in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor; optionally wherein the heart failure is heart failure with preserved ejection fraction.
7. A method of reducing the serum uric acid level in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
42 WO 2022/162021 PCT/EP2022/051794-PCT
8. The method of claim 7, wherein the serum uric acid level is reduced by 55% or more compared to pre-treatment baseline level, optionally wherein the serum uric acid level is reduced by (a) 60% or more or (b) 65% or more, or (c) 70% or more, compared to pre-treatment baseline level.
9. The method of claim 8, wherein the reduction in serum uric acid level is achieved after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks.
10. A method of reducing UACR in a subject in need thereof, comprising administering to the subject: verinurad or a pharmaceutically acceptable salt thereof at a dose greater than 12 mg/day and less than or equal to 24 mg/day; and a xanthine oxidase inhibitor.
11. The method of claim 10, wherein the reduction in UACR is achieved after administration of the verinurad or a pharmaceutically acceptable salt thereof and the xanthine oxidase inhibitor for 12 weeks.
12. The method of any one of claims 7-11, wherein the subject has chronic kidney disease.
13. The method of any one of claims 7-12, wherein the subject has heart failure, optionally wherein the subject has heart failure with preserved ejection fraction.
14. The method of any one of the preceding claims, wherein the dose of verinurad or a pharmaceutically acceptable salt thereof is selected from about 12.5 mg/day, about 13 mg/day, about 13.5 mg/day, about 14 mg/day, about 14.5 mg/day, about 15 mg/day, about 15.5 mg/day, about 16 mg/day, about 16.5 mg/day, about 17 mg/day, about 17.5 mg/day, about 18 mg/day, about 18.5 mg/day, about 19 mg/day, about 19.5 mg/day, about 20 mg/day, about 20.5 mg/day, about 21 mg/day, about 21.5 mg/day, about 22 mg/day, about 22.5 mg/day, about 23 mg/day, about 23.5 mg/day, and about 24 mg/day.
15. The method of any one of the preceding claims, wherein verinurad or a pharmaceutically acceptable salt thereof is verinurad.
16. The method of any one of the preceding claims, wherein the xanthine oxidase inhibitor is allopurinol.
43 WO 2022/162021 PCT/EP2022/051794-PCT
17. The method of claim 16, wherein the dose of allopurinol is about 100 mg/day to about 400 mg/day, optionally wherein the dose of allopurinol is about 300 mg/day.
18. The method of any one of claims 1-15, wherein the xanthine oxidase inhibitor is febuxostat.
19. The method of claim 18, wherein the dose of febuxostat is about 10 mg/day to about 160 mg/day, optionally wherein the dose of febuxostat is about 80 mg/day.
20. Verinurad or a pharmaceutically acceptable salt thereof for use in the method of any one of the preceding claims.
21. A pharmaceutical composition comprising verinurad or a pharmaceutically acceptable salt thereof in an amount greater than 12 mg and less than or equal to 24 mg for use in the method of any one of claims 1-19.
22. A pharmaceutical composition comprising a plurality of pellets, wherein each pellet comprises: an inert core; a drug layer comprising verinurad or a pharmaceutically acceptable salt thereof that encapsulates the inert core; and a modified release layer that encapsulates the drug layered inert core; wherein the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is greater than 12 mg and less than or equal to 24 mg.
23. The pharmaceutical composition of claim 22, wherein the inert core comprises microcrystalline cellulose.
24. The pharmaceutical composition of any one of claims 22-23, wherein the modified release layer comprises ethyl cellulose.
25. The pharmaceutical composition of any one of claims 22-24, wherein the modified release layer comprises hydroxypropyl cellulose.
26. The pharmaceutical composition of any one of claims 22-24, wherein the modified release layer comprises poly (N-vinyl-2-pyrrolidinone).
27. The pharmaceutical composition of claim 22, wherein: the inert core is present in an amount ranging from about 10% to about 90% (w/w) of the combined weight of the inert core, drug layer and modified release layer;
44 WO 2022/162021 PCT/EP2022/051794-PCT the drug layer is present in an amount ranging from about 5% to about 80% (w/w) of the combined weight of the inert core, drug layer and modified release layer; and the modified release layer is present in an amount ranging from about 5% to about 50% (w/w) of the combined weight of the inert core, drug layer and modified release layer.
28. The pharmaceutical composition of any one of claims 22-27, wherein the modified release layer comprises ethyl cellulose and hydroxypropyl cellulose, optionally wherein the weight ratio of ethylcellulose to hydroxypropyl cellulose ranges from about 1 : 1 to about 4: 1.
29. The pharmaceutical composition of any one of claims 22-27, wherein the modified release layer comprises ethyl cellulose and poly (N-vinyl-2-pyrrolidinone), optionally wherein the weight ratio of ethylcellulose to poly (N-vinyl-2-pyrrolidinone) ranges from about 1 : 1 to about 4: 1.
30. The pharmaceutical composition of any one of claims 22-29, wherein the drug layer further comprises a binder, and optionally wherein the weight ratio of the verinurad or a pharmaceutically acceptable salt thereof to the binder ranges from about 4: 1 to about 19: 1.
31. The pharmaceutical composition of claim 30, wherein the binder is hydroxypropyl methylcellulose.
32. The pharmaceutical composition of any one of claims 22-31, wherein the plurality of pellets is contained within one or more capsules, optionally one capsule.
33. The pharmaceutical composition of any one of claims 22-32, wherein the amount of verinurad or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg, about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg, about 23.5 mg, and about 24 mg.
34. The pharmaceutical composition of any one of claims 22-33, further comprising a xanthine oxidase inhibitor.
35. The pharmaceutical composition of claim 34, wherein the xanthine oxidase inhibitor is allopurinol.
36. The pharmaceutical composition of claim 35, wherein the allopurinol is present in an amount between about 100 mg and about 400 mg, optionally about 300 mg. WO 2022/162021 PCT/EP2022/051794-PCT
37. The pharmaceutical composition of claim 34, wherein the xanthine oxidase inhibitor is febuxostat.
38. The pharmaceutical composition of claim 37, wherein the febuxostat is present in an amount between about 10 mg and about 160 mg, optionally about 80 mg.
39. The pharmaceutical composition of any one of claims 22-38, for use in the method of any one of claims 1-19.
40. The method of any one of claims 1-19, comprising administering to the subject the pharmaceutical composition of any one of claims 22-38.
PCT/EP2022/051794 2021-01-27 2022-01-26 Verinurad compositions and methods of use WO2022162021A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163142176P 2021-01-27 2021-01-27
US63/142,176 2021-01-27

Publications (1)

Publication Number Publication Date
WO2022162021A1 true WO2022162021A1 (en) 2022-08-04

Family

ID=80682662

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2022/051794 WO2022162021A1 (en) 2021-01-27 2022-01-26 Verinurad compositions and methods of use

Country Status (1)

Country Link
WO (1) WO2022162021A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017097845A1 (en) 2015-12-08 2017-06-15 Ardea Biosciences, Inc. Pharmaceutical composition comprising a potent inhibitor of urat1
WO2020070539A1 (en) * 2018-10-01 2020-04-09 Astrazeneca Ab Compositions for reducing serum uric acid
US10772886B2 (en) * 2016-03-11 2020-09-15 Ardea Biosciences, Inc. CXCR-2 inhibitors for treating crystal arthropathy disorders
CA3145997A1 (en) * 2019-07-16 2021-01-21 Astrazeneca Ab Dose dumping resistant pharmaceutical compositions comrising verinurad

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017097845A1 (en) 2015-12-08 2017-06-15 Ardea Biosciences, Inc. Pharmaceutical composition comprising a potent inhibitor of urat1
US10772886B2 (en) * 2016-03-11 2020-09-15 Ardea Biosciences, Inc. CXCR-2 inhibitors for treating crystal arthropathy disorders
WO2020070539A1 (en) * 2018-10-01 2020-04-09 Astrazeneca Ab Compositions for reducing serum uric acid
CA3145997A1 (en) * 2019-07-16 2021-01-21 Astrazeneca Ab Dose dumping resistant pharmaceutical compositions comrising verinurad

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
AKSENOV ET AL., PHYSIOL REP, vol. 6, no. 5, 2018, pages e13614
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; 29 October 2020 (2020-10-29), STACK AUSTIN G ET AL: "Effect of Intensive Urate Lowering With Combined Verinurad and Febuxostat on Albuminuria in Patients With Type 2 Diabetes: A Randomized Trial.", XP002806559, Database accession no. NLM33130235 *
FLEISCHMANN R ET AL., RMD OPEN, vol. 4, 2018, pages e000584
HALL JESSE ET AL: "Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Administration of Verinurad and Febuxostat in Healthy Male Volunteers", CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT UNITED STATES JUL 2017, CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT UNITED STATES JUL 2017, CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT UNITED STATES JUL 2017, vol. 8, no. 2, 24 April 2018 (2018-04-24), pages 179 - 187, XP002792122, ISSN: 2160-7648, DOI: 10.1002/CPDD.463 *
KANKAM M ET AL., J CLIN PHARMACOL, vol. 58, no. 9, 2018, pages 1214 - 22
KANKAM MARTIN ET AL: "Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Multiple Dose Administration of Verinurad (RDEA3170) and Allopurinol in Adult Male Subjects With Gout", JOURNAL OF CLINICAL PHARMACOLOGY,, vol. 58, no. 9, 1 September 2018 (2018-09-01), pages 1214 - 1222, XP002792123, DOI: 10.1002/JCPH.1119 *
LEVY, G. D. ET AL., J. RHEUM., vol. 41, no. 5, 2014, pages 955
M. LI ET AL., SCI. REP., vol. 6, 2016, pages 19520
PEREZ-RUIZ FERNANDO ET AL: "Combination urate-lowering therapy in the treatment of gout: What is the evidence?", SEMINARS IN ARTHRITIS AND RHEUMATISM, ELSEVIER, AMSTERDAM, NL, vol. 48, no. 4, 20 June 2018 (2018-06-20), pages 658 - 668, XP085613090, ISSN: 0049-0172, DOI: 10.1016/J.SEMARTHRIT.2018.06.004 *
STACK ET AL., NEPHROLOGY DIALYSIS TRANSPLANTATION, vol. 34, 2019, pages i449 - i460
TERKELTAUB ET AL., ANNALS OF THE RHEUMATIC DISEASES, vol. 78, 2019, pages 179 - 180
X. SU ET AL., PLOS ONE, vol. 12, no. 11, 2017, pages e0187550

Similar Documents

Publication Publication Date Title
DK169987B1 (en) Orally administrable pharmaceutical composition containing as an active ingredient an acid labile compound or an alkali salt thereof, and a process for the preparation of the composition
KR101230731B1 (en) Pharmaceutical formulation
JP6976946B2 (en) A pharmaceutical composition containing an inhibitor of URAT1 having strong bioactivity.
TW201202249A (en) Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors
CZ300745B6 (en) Dual-release compositions of a cyclooxygenase-2 inhibitor
US20110213004A1 (en) Method of using combination preparation comprising angiotensin-ii-receptor blocker and hmg-coa reductase inhibitor
ZA200108539B (en) An oral formulation for ileum administering comprising an inhibitor compound of the ileal bile acid transport.
JP2004511521A (en) Oral formulation comprising a compound inhibiting ileal bile transport and an HMG-CoA reductase inhibitor
JP5968927B2 (en) Drug composition used for the treatment of hypertension and metabolic syndrome and its application
WO2001076635A1 (en) Preparations for preventing bile acid diarrhea
KR20170098897A (en) Method of treatment
TW201020240A (en) Compositions comprising 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid and pharmaceutically acceptable salts thereof, and methods for preparing and using same
WO2005053659A1 (en) An improved pharmaceutical formulation containing tamsulosin salt and a process for its preparation
US20220257522A1 (en) Dose dumping resistant pharmaceutical compositions comprising verinurad
WO2022162021A1 (en) Verinurad compositions and methods of use
KR20090107954A (en) Pharmaceutical formulation
KR20090107959A (en) Pharmaceutical formulation
CN116018133A (en) Targeted release rifaximin compositions
KR20090107956A (en) Pharmaceutical formulation
KR20090107955A (en) Pharmaceutical formulation
MXPA01010515A (en) An oral formulation for ileum administering comprising an inhibitor compound of the ileal bile acid transport

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22708355

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22708355

Country of ref document: EP

Kind code of ref document: A1