WO2016077370A1

WO2016077370A1 - Novel methods for treatment and prophylaxis of polycystic kidney disease

Info

Publication number: WO2016077370A1
Application number: PCT/US2015/059988
Authority: WO
Inventors: Giovanni Antonio FERRARA
Original assignee: Ferrara Giovanni Antonio
Priority date: 2014-11-10
Filing date: 2015-11-10
Publication date: 2016-05-19

Abstract

The disclosure provides a novel method of treating polycystic kidney disease (PKD) comprising administering an effective amount of lixivaptan to a patient in need thereof, e.g., for a period of greater than 30 days, together with formulations for use in this method.

Description

NOVEL METHODS FOR TREATMENT AND PROPHYLAXIS OF POLYCYSTIC

KIDNEY DISEASE

BACKGROUND

[0001] Lixivaptan is N-[4-(5H-pyrrolo[2,l-c][l,4]benzodiazepin-10(l lH)ylcarbonyl)-3- chlorophenyl]-5-fluoro-2-methylbenzamide [IUPAC name: N-[3-chloro-4-(6,l l- dihydropyrrolo[2, 1 -c] [ 1 ,4]benzodiazepine-5-carbonyl)phenyl] -5-fluoro-2-methylbenzamide] , described in Example 482 of US 5516774, which patent is incorporated herein by reference. Lixivaptran is a non-peptidic selective vasopressin 2 receptor antagonist.

[0002] Vasopressin (arginine vasopressin) is a peptide hormone that causes the kidneys to retain water and is also a potent vasoconstrictor. It increases water permeability of the kidney's collecting duct and distal convoluted tubule by inducing translocation of aquaporin-CD water channels in the kidney nephron collecting duct plasma membrane, and at the same time, it also increases peripheral vascular resistance, which in turn increases arterial blood pressure. It is important for homeostasis, helping to regulate water retention and osmolality and to maintain blood pressure, for example when an individual is suffering from dehydration or hypovolemic schock. Vasopressin is also structurally related to oxytocin and has a variety of CNS effects.

[0003] Vasopressin 2 receptors are located in the basolateral membrane of the cells lining the collecting ducts of the kidneys (especially the cortical and outer medullary collecting ducts). These receptors activate aquaporin-2 (AQP2) channels, allowing water to be reabsorbed down an osmotic gradient, so water is retained and the urine becomes more concentrated. Overstimulation of these receptors causes hyponatremia.

[0004] Vasopressin 2 receptor antagonists are therefore currently used primarily to treat hyponateremia. They are particularly useful in treating hypervolemic hyponatremia, where the patient has increased water retention together with low sodium concentration. This is often associated with, for example, cirrhosis of the liver or congestive heart failure. Vasopressin 2 receptor antagonists can help these patients eliminate excess fluids while still retaining electrolytes.

[0005] Polycystic kidney disease (PKD) is a multisystemic and progressive disorder

characterized by cyst formation and enlargement in the kidney. The condition may in some cases involve cysts in other organs (e.g, liver, pancreas, and/or spleen), as well as cerebral aneurysms, and cardiac valvular abnormalities. PKD results in the progressive development of kidney cysts, kidney pain, hypertension, and, ultimately, kidney failure. PKD usually has a genetic component, but may be of unknown etiology or may occur in patients having serious preexisting kidney problems, for example patients who already suffer from renal failure and/or are on dialysis. This latter form is sometimes referred to as acquired cystic kidney disease (ACKD).

[0006] There are several different types of inherited PKD. Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and the fourth leading cause of end-stage kidney disease in adults worldwide. Approximately 85-90% of patients with ADPKD have an abnormality on the short arm of chromosome 16 (ie, ADPKD type 1

[ADPKD 1]). Another mutation, termed ADPKD type 2 (ADPKD2), is responsible for 10-15% of ADPKD cases and is found on the long arm of chromosome 4. Type 1 is generally more severe and has an earlier age of onset as compared with type 2. A third genotype has been reported, but no genomic locus is assigned. Up to 50% of patients with ADPKD suffer kidney failure and require renal replacement therapy by 60 years of age. There is no effective treatment for

ADPKD. Autosomal Recessive PKD (ARPKD) is much less common than ADPKD, partly because both parents must carry the gene for the disease to be expressed in their children.

[0007] It has been suggested that overstimulation of vasopressin 2 receptors may contribute to the development of cysts in the kidneys, and some have suggested vasopressin 2 receptor antagonists for treatment of PKD. The clinical results obtained, however, have been

disappointing. Tolvaptan, a compound originally approved to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH), was tried for PKD. The compound showed efficacy in reducing cyst formation, but several patients suffered severe liver damage. As a result, tolvaptan cannot be used for more than 30 days, and it cannot be used in cirrhosis patients. The effects of tolvaptan also seem to vary from patient to patient, and to be somewhat unpredictable. Tolvaptan has a "black box" warning for risk of osmotic demyelination syndrome (ODS), which is serious nerve damage that may be caused by quick increases in sodium levels, e.g., by overcorrection of sodium levels by tolvaptan, and treatment must be initiated in a hospital setting.

[0008] It has been suggested that the vaptans as a class have significant liver toxicity and other risks which make them unsuitable for long term administration in a non-hospital setting, and tolvaptan is structurally and functionally similar to lixivaptan. Lixivaptan, moreover, was rejected by the US FDA for approval to treat symptomatic hypervolemic and euvolemic hyponatremia associated with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH), respectively.

[0009] The only "vaptan" other than tolvaptan which has been approved for use in humans is conivaptan, an injectable mixed vasopressin la and vasopressin 2 receptor antagonist. As conivaptan is not a pure vasopressin 2 receptor antagonist and, moreover, is not approved for oral use, it is not suitable for treating PKD.

[0010] Accordingly, the feasibility of using vaptans to treat PKD have not been supported by the clinical results. As of this filing, there are no vasopressin 2 receptor antagonists which have been approved for treating PKD, or which (in view of the experience with the existing vasopressin 2 receptor antagonists) would be considered to be potentially safe and effective for long term use in treating PKD. Treatment of PKD, therefore, remains a significant unmet medical need.

BRIEF SUMMARY

[0011] The disclosure provides a new method of treating PKD, using lixivaptan. Lixivaptan is suitable for oral administration over extended periods, without unacceptable side effects, at dosages sufficient to treat and inhibit the development of PKD. Accordingly, the disclosure provides, in one embodiment, a method of treating polycystic kidney disease PKD comprising administering an effective amount of lixivaptan for a period of greater than 30 days to a patient in need thereof.

[0012] Further areas of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

DETAILED DESCRIPTION

[0013] The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.

[0014] Accordingly, the disclosure provides, in one embodiment, Method 1, which is a method of treating polycystic kidney disease (PKD) comprising administering an effective amount of lixivaptan for a period of greater than 30 days to a patient in need thereof; for example, the disclosure provides

1.1. Method 1, wherein the lixivaptan is administered once a day (q.d.);

1.2. Method 1 or 1.1 wherein the lixivaptan is administered orally;

1.3. Any foregoing method wherein the daily dosage of lixivaptan is from lOmg to 200 mg per day;

1.4. Any foregoing method wherein the dosage of lixivaptan is

1.4.1. 20mg-30mg, q.d. orally; e.g.,

1.4.1.1. 25 mg, q.d. orally;

1.4.2. 40mg to 60 mg, q.d. orally; e.g.,

1.4.2.1. 50 mg, q.d. orally;

1.4.3. 80 mg to 120 mg, q.d. orally; e.g.,

1.4.3.1. 100 mg, q.d. orally;

1.5. Any foregoing method wherein the lixivaptan is administered over a period of at least 60 days;

1.6. Any foregoing method wherein the lixivaptan is administered over a period of at least three months;

1.7. Any foregoing method wherein the patient is at elevated risk of PKD;

1.8. Any foregoing method wherein the patient has been diagnosed as having a mutation associated with autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD);

1.9. Any foregoing method wherein the diagnosis of PKD is made using ultrasound imaging, computerized tomography (CT) scan, and/or magnetic resonance imaging (MRI) scan; e.g., wherein a patient in need of treatment by the method is a patient having at least two cysts in the kidneys and/or a total kidney volume of at least 750 mL, for example a patient exhibiting one or more of the following

1.9.1. At least 2 cysts in 1 kidney or 1 cyst in each kidney in a patient younger than 30 years with a family history of PKD;

1.9.2. At least 2 cysts in each kidney in a patient aged 30-59 years with a family history of PKD; .9.3. At least 4 cysts in each kidney for a patient aged 60 years or older with a family history of PKD;

.9.4. Three or more (unilateral or bilateral) renal cysts in a patient aged 15-39 years with no or unknown family history of PKD;

.9.5. Two or more cysts in each kidney in a patient aged 30-59 years with no or

unknown family history of PKD;

. Any foregoing method wherein the patent has normal blood serum sodium levels, e.g., greater than 125 mEq/L, e.g., at least 135 mEq/L, e.g., 135 to 145 mEq/L ;

. Any foregoing method wherein the patient has normal urine sodium excretion. Any foregoing method wherein the lixivaptan is administered outside of a hospital setting.

. Any foregoing method wherein the blood sodium levels of the patent are monitored, and if appropriate, the dose of lixivaptan is adjusted based on the blood serum sodium levels, for example:

.13.1. wherein the dosage of lixivaptan is reduced if the blood serum sodium levels exceed 145 mEq/L;

. Any foregoing method wherein the dosage of lixivapatan is initially titrated and blood serum sodium levels in the patient monitored, to obtain a dosage which does not elevate blood sodium above the normal range, e.g., above 145 mEg/L;

. Any foregoing method wherein the lixivaptan is administered in extended release form;

. Any foregoing method wherein the patient receives a low sodium diet for the duration of treatment; e.g., a diet comprising less than 3000 mg/day of sodium, for example less than 2000mg/day of sodium, e.g., a diet comprising 500-1500mg/day of sodium;

. Any foregoing method wherein the patient concurrently receives an effective dose of an antihypertensive drug, e.g., wherein the antihypertensive drug is selected from angiotensin-converting enzyme (ACE) inhibitors (for example, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramapril, or trandopril) and angiotensin II receptor blockers (ARBs) (for example, valsartan, telmisartan, losartan, irbesartan, candesartan, azilsartan, or olmesartan); 1.18. Any foregoing method wherein the effectiveness of the method is monitored by one or more of the following parameters measured periodically during the course of treatment: (a) reduction or minimal increase in the size and/or number of cysts in the kidneys, e.g., as measured by ultrasound, CT scan and/or MRI scan; (b) reduction or minimal increase (e.g., <2 /yr increase) in total kidney volume; (c) reduction or minimal increase (e.g., <10 /yr increase) in serum creatinine levels; and/or increase or minimal decrease in glomerular filtration rate;

1.19. Any foregoing method which further comprises surgical removal of one or more renal cysts;

[0015] In another embodiment, the disclosure provides lixivaptan for use in the treatment of polycystic kidney disease, e.g., for use in any of Methods 1, et seq.

[0016] In another embodiment, the disclosure provides the use of lixivaptan in the manufacture of a medicament for treatment of polycystic kidney disease, e.g., for use in any of Methods 1, et seq.

[0017] In another embodiment, the disclosure provides a pharmaceutical composition comprising lixivaptan, e.g., a pharmaceutical composition comprising lixivaptan in unit dosage form, for use in any of Methods 1, et seq.

[0018] In another embodiment, the disclosure provides a kit comprising lixivaptan in unit dose form, e.g., for oral administration, together with instructions for use in any of Methods 1, et seq.

[0019] In certain embodiments, the disclosure provides a sustained or extended release formulation of lixivaptan, e.g., for use in any of Methods 1, et seq.

[0020] Synthesis of lixivaptan is described, e.g., in Example 482 in US 5516774, incorporated herein by reference. Formulations of lixivaptan for oral administration include those described in WO 2011025771, US 6656931, and US 6352718, the contents of which are incorporated herein by reference. Combination therapies and formulations using lixivaptan together with diuretics are described in US 6420358, also incorporated herein by reference.

[0021] As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by referenced in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls. [0022] Unless otherwise specified, all percentages and amounts expressed herein and elsewhere in the specification should be understood to refer to percentages by weight. The amounts given are based on the active weight of the material.

EXAMPLES

Example 1 - Phase 2 Trial Design for Lixivaptan in PKD

[0023] Eligible patients are enrolled in the trial, being from 18 to 50 years of age, with a diagnosis of PKD, a total kidney volume of 750 ml or more as measured with the use of magnetic resonance imaging (MRI), and a creatinine clearance of 60 ml per minute or more as estimated by means of the Cockcroft-Gault formula. Randomization is carried out centrally, with patients randomly assigned in a 2: 1 ratio to receive lixivaptan or placebo and with stratification according to hypertension status (present vs. absent), creatinine clearance (<80 vs. >80 ml per minute), total kidney volume (<1000 vs. >1000 ml), and geographic area.

[0024] Lixivaptan is administered orally in daily doses of 50 mg over a period of 36 months.

[0025] Evaluations are performed at baseline, at randomization, and monthly during treatment, and at one month after the completion of treatment at 36 months. Evaluations include physical examination, assessment of vital signs, electrocardiography, and blood and urine tests. The serum creatinine level is measured centrally with the use of the IDMS -traceable Roche enzymatic method and is reported to two decimal points. Standardized MRI scans of the kidneys are obtained at baseline and at months 12, 24, and 36 (+2 weeks); for patients who do not complete the study, the final MRI scans are obtained within 2 weeks before or after withdrawal if not acquired during the previous 6 months.

[0026] The primary end point is the annual rate of percentage change in total kidney volume. The composite secondary end point is the time to investigator-assessed clinical progression, defined as worsening kidney function (a 25% reduction in the reciprocal of the serum creatinine level from the value at the end of the dose-adjustment period, reproduced after at least 2 weeks); clinically significant kidney pain necessitating medical leave, pharmacologic treatment (narcotic or last-resort analgesic agents), or invasive intervention; worsening hypertension (changes in blood-pressure category, as defined in the protocol, or worsening of hypertension requiring an increase in hypertensive treatment); and worsening albuminuria.

[0027] The next secondary end point is the change in the slope of kidney function as measured by the reciprocal of the serum creatinine level. The reciprocal of the serum creatinine level has a linear relationship with the GFR, unlike the serum creatinine level, which has a curvilinear relationship. These values, expressed as (mg per milliliter)^"1, can be used to estimate approximate GFR values. Kidney- function end points are analyzed during treatment, with the use of measurements obtained at the end of the dose-escalation period and at the last treatment visit.

[0028] All efficacy end points are analyzed statistically, and confidence intervals and P values are provided for subsequent comparisons and sensitivity analyses.

Claims

1. A method of treating polycystic kidney disease (PKD) comprising administering an

effective amount of lixivaptan for a period of greater than 30 days to a patient in need thereof.

2. The method of claim 1 wherein the lixivaptan is administered once a day (q.d.).

3. The method of any foregoing claim wherein the lixivaptan is administered orally.

4. The method of any foregoing claim wherein the daily dosage of lixivaptan is from lOmg to 200 mg per day.

5. The method of any foregoing claim wherein the dosage of lixivaptan is 80mg to 120 mg, q.d. orally; e.g., 100 mg, q.d. orally.

6. The method of any foregoing claim wherein the lixivaptan is administered over a period of at least 60 days.

7. The method of any foregoing claim wherein the patient has been diagnosed as having a mutation associated with autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD).

8. The method of any foregoing claim wherein the patent has normal blood serum sodium levels, e.g., greater than 125 mEq/L, e.g., at least 135 mEq/L, e.g. ,135 to 145 mEq/L.

9. The method of any foregoing claim wherein the lixivaptan is administered outside of a hospital setting.

10. The method of any foregoing claim wherein the blood sodium levels of the patent are monitored, and if appropriate, the dose of lixivaptan is adjusted based on the blood serum sodium levels, for example wherein the dosage of lixivaptan is reduced if the blood serum sodium levels exceed 145 mEq/L.

11. The method of any foregoing claim wherein the lixivaptan is administered in extended release form.

12. The method of any foregoing claim wherein the patient receives a low sodium diet for the duration of treatment; e.g., a diet comprising less than 3000 mg/day of sodium, for example less than 2000mg/day of sodium, e.g., a diet comprising 500-1500mg/day of sodium.

13. The method of any foregoing claim wherein the patient concurrently receives an effective dose of an antihypertensive drug, e.g., wherein the antihypertensive drug is selected from angiotensin-converting enzyme (ACE) inhibitors (for example, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramapril, or trandopril) and angiotensin II receptor blockers (ARBs) (for example, valsartan, telmisartan, losartan, irbesartan, candesartan, azilsartan, or olmesartan).

14. Lixivaptan for use in the treatment of polycystic kidney disease; e.g., for use in a method of any of the foregoing claims.