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1. WO2013131879 - NEW APPLICATION FOR PASIREOTIDE

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New Application for Pasireotide

Present invention relates to new fields of application for pasireotide (SOM230) and any of pharmaceutically acceptable salts, in particular for the treatment of high blood pressure.

Pasireotide is a cyclohexapeptide with the following formula (I)


.

Pasireotide is also called cyclo[{4-(NH2-C2H4-NH-CO-O-)Pro}-Phg-DTrp-Lys-Tyr(4-Bzl)-Phe], in free form, in salt or complex form or in protected form, wherein Phg means -HN-CH(C6H5)-CO- and Bzl means benzyl.

Pasireotide is a somatostatin analogues, engineered to bind to multiple somatostatin receptor subtypes (i.e. 1 , 2, 3, and 5) to mimic the action of natural somatostatin. Pasireotide has a broader receptor binding profile than octreotide or lanreotide. it binds to four of the five ssts with high affinity, with highest affinity for sstrs.

A comprehensive clinical development program is currently investigating the effects of pasireotide in the treatment of Gushing' s disease, acromegaly and gastroenteropancreatic neuroendocrine tumors (GEP/NETs). Cushing's disease is a rare disorder of chronic hypercortisolism due to an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor. ACTH-secreting putitary adenomas predominatly express sstrs. This is believed to be responsible for the action of pasireotide against Cushing's disease and its success in lowering the increased Cortisol levels.

An abstracts "Promising phase III results of pasireotide, a new therapy for Cushing's disease" posted on Sept 24th, 2010, in the context of the phase III trial of Cushing's disease, reported that pasireotide led to rapid and sustained decreases in urinary free Cortisol (UFC)s, which are major biomarkers of biochemical control of the disease. Furthermore it was reported that reduction of UFC was accompanied by improved symptoms, including reduced blood pressure, decreased total cholesterol and reduced body mass index.

Despite the disclosure it remains non-obvious to a skilled person that pasireotide and any of its pharmaceutical acceptable salts could be used in the treatment of hypertension in patients without Cushing's disease due to the following reasons:

Firstly the abstract focused on the reduction of urinary free Cortisol (UFC) level. The wording "improved symptoms" did not indicate at all clinical relevance. Secondly although somatostatin and its analogues, particular the natural somatostatin and octreotide, have been widely used in the medical fields for more than 30 years, no clear clinical data have been produced leading to the conclusion that somatostatin and its analogues could be used for the treatment of hypertension. If other somatostatin analogues indeed had efficacy in treating hypertension, this could not have been missed out in view of the high prevalence of hypertension. Thirdly even though high levels of Cortisol found in Cushing's disease may cause or contribute to elevations in blood pressure. This does, however, not imply that reduction of Cortisol In subjects without Cushing's disease also affects their blood pressure.

The data from the phase III Cushing's disease trial have been further evaluated with the focus on the effect on hypertension. It has been surprisingly found that pasireotide effectively reduced blood pressure both in SBP and DBF in patients (see Fig, 1 ) having baseline hypertension. Although the reduction in blood pressure was strongest in those patients with normalized UFC levels during pasireotide treatment, there was no general correlation between reduction of Cortisol and reduction of blood pressure. These results led to the speculation that pasireotide can reduce BP in patients with hypertension irrespective of baseline Cortisol values.

Particularly interesting is that blood pressure was not reduced due to pasireotide treatment in patient group who do not have baseline hypertension. These data support the above notion that there is no correlation between reduction of UFC and blood pressure by pasireotide and it also suggests that hypotension as a potential side-effect of pasireotide treatment will not be a major concern.

Furthermore the majority of patients having baseline hypertension took anti-hypertensive drug before and during the clinical study, we have found that at 6 months and at 12 months pasireotide treatment further reduced the blood pressure, reinforcing the notion that pasireotide brings additional reduction by targeting pathways not hit by the conventional hypertensive drugs.

Thus in one aspect the present invention provides a medicament comprising pasireotide, or any one of its pharmaceutically acceptable salts, and optionally at least one pharmaceutically acceptable carrier, for use in the treatment of hypertension in patients, wherein said patient does not have dishing- s disease.

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329, incorporated herein by reference). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

A pharmaceutical acceptable salt of pasireotide could be an inorganic acid, a polymeric acid or an organic acid salt. For example with hydrochloric acid, acetic acid, lactic acid, aspartic acid, benzoic acid, succinic acid or pamoic acid. Acid addition salts may exist as mono- or divalent salts, e.g. depending whether 1 or 2 acid equivalents are added. Preferred salts are the lactate, aspartate, benzoate, succinate and pamoate including mono- and di-salts, more preferably the aspartate di-salt and the pamoate monosalt. Certain salts of pasireotide forms gel in a aqueous enviroment, such as salt of aspartate, e.g. mono- or diaspartate, glutamate, e.g. mono- or diglutamate, or succinate, e.g. mono- or disuccinate. lactate, acetate or citrate. In one preferred embodiment, the pasireotide pharmaceutically acceptable salt is pamoate salt.

The term "Cushing's disease" as used herein refers to a group of patients having a mean 24-hour urinary free Cortisol≥1.5x the upper limit of normal (ULN), calculated from four 24-hour samples collected within 2 weeks; morning plasma ACTH≥5ng/L (≥1.1nmol/L); a confirmed pituitary source of Cushing's syndrome. The ULN for the 24-hour Urine Free Cortisol was defined as 145 nmol/day. Urinary free Cortisol was determined by high pressure liquid chromatography (HPLC) as described in Turpeinen et al 1997. The normal ranges of 30-145 nmol/24 hours published by Turpeinen were used for this study.

Adrenocorticotropic hormone (ACTH), also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress (along with corticotropin-releasing hormone from the hypothalamus). Its principal effects are increased production and release of corticosteroids and. as its name suggests, Cortisol from the adrenal cortex. Morning plasma ACTH is normally measured by HPLC method.

The term "hypertension" (HTN) or "high blood pressure" including baseline hypertension according to the invention is defined as systolic blood pressure SBP > 130mmHg; or diastolic blood pressure DBP > 90mmHg.

"Baseline" means at the beginning of the therapy.

In one embodiment of the invention, the patient having hypertension in the meantime has obesity, depression, long term stress and/or alcoholism.

Obesity in the meaning of present invention means a BMI higher than 25 kg/m2. Obesity is an abnormal accumulation of body fat and is associated with various diseases, particularly cardiovascular diseases, diabetes niellitus type 2, certain types of cancer, and musculoskeletal disorders (in particular osteoarthritis). As a result, obesity has been found to reduce life expectancy. Present invention in particular relates to central obesity, i.e. weight gain particularly of the trunk and face with sparing of the limbs. Preferably, obesity in the meaning of present invention is accompanied with increased ACTH and/or Cortisol levels and hypertension.

Depression is a common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration. These problems can become chronic or recurrent and lead to substantial impairments in an individual's ability to take care of his or her everyday responsibilities. Preferably, depression in the meaning of present invention is accompanied with increased ACTH and7or Cortisol levels and hypertension.

Stress in the meaning of present invention relates to the body's reaction to any stimuli that disturb its equilibrium. In particular, stress according to the definition of present invention relates to long term or chronic stress, i.e. a state of prolonged tension from internal or external stressors, which may cause various physical manifestations, e.g. asthma, back pain, arrhythmias, fatigue, headaches, hypertension, irritable bowel syndrome, ulcers, and suppress the immune system. During long term stress, Cortisol is constantly higher than normal level, causing fewer receptors to be produced on immune cells so that inflammation cannot be ended. Preferably, stress in the meaning of present invention is accompanied with increased ACTH and/or Cortisol levels and hypertension.

Alcoholism in the meaning of present invention relates to a primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and

manifestations. Alcoholism is characterized by: a prolonged period of frequent, heavy alcohol use; the inability to control drinking once it has begun; physical dependence manifested by withdrawal symptoms when the individual stops using alcohol; and tolerance, or the need to use more and more alcohol to achieve the same effects. Preferably, stress in the meaning of present invention is accompanied with increased ACTH and/or Cortisol levels and

hypertension.

Thus without being limited or bound to the theory, we speculate that pasireotide effectively reduces blood pressure through lowering the level of ACTH and/or Cortisol. Targeting ACTH and/or Cortisol to treat hypertension provides a new mode of action in treating hypertension.

In one embodiment of the invention, patients having hypertension have higher-than-Lower Limit of Normal (LLN) level of ACTH. ACTH levels change with the body's natural 24-hour cycle of processes (circadian rhythms). Test is most accurate if it is performed early in the morning. Taking steroid drugs is normally stopped before test. The normal value of ACTH is usually 9 - 52 pg/mL, may vary slightly among different labs. Thus the term "higher than LLN level of ACTH" refers to the level of ACTH being higher than the lower limit of normal range plasma ACTH measured in early morning (normally before 8 or 9am) by a particular

method. Normal range is understood as the range in which the ACTH level of the majority health population statistically fall, preferably taking into consideration of age, gender, race, living condition etc.

In one embodiment, patients having hypertension have higher-than-normal level of ACTH. The term "higher-than-normal level of ACTH" refers to the level of ACTH being higher than the upper limit of normal range plasma ACTH.

Preferably the term "higher-than-normal level of ACTH" refers to the level of plasma ACTH measured in the morning being higher than 50pg/ml, higher than 100pg/ml, higher than 200pg/ml, higher than 300pg/ml, higher than 500pg/ml, higher than 1ng/ml or even higher than 2ng/ml or even higher than 5ng/ml. Preferably the measuring method is High-performance liquid chromatography (HPLC).

In addition to elevated ACTH level due to ACTH-secreting pituitary tumor, other tissues, for instance, tumors outside the normal pituitary-adrenal system, such as small cell lung cancer, can produce ACTH that affects the adrenal glands. Thus in one embodiment the patient having hypertension has elevated level of ACTH of non-pituitary origin.

In one embodiment the patent having hypertension has Pseudo-Cushing's syndrome. Pseudo-Cushing's syndrome is a medical condition in which patients display the signs, symptoms, and abnormal hormone levels seen in Cushing's syndrome. However, pseudo-Cushing's syndrome is not caused by a problem with the hypothalamic-pituitary-adrenal axis as Cushing's is; it is an idiopathic condition.

In one embodiment of the invention, patients having hypertension has elevated level of Cortisol. The term "elevated level of Cortisol" as used here refers to the level of Cortisol higher than an individual's own normal range of Cortisol. The normal range of urinary free Cortisol (UFC) for population is 10 - 100 micrograms per 24 hours (mcg/24h or μg/24h). Thus for an individual having hypertension, the term "elevated level of Cortisol" could be defined as higher than 30 μg/24h, higher than 50 μg/24h, higher than 70 μg/24h, higher than 85 μg/24h or higher than 100 μg/24h. The urinary free Cortisol (UFC) is measured as a mean 24-hour urinary free Cortisol, calculated from four 24-hour samples collected within 2 weeks.

Preferably the term "elevated level of Cortisol" refers to a level higher than 80 μg /24h, higher than 100 μg /24h or higher than 120 μg /24h.

High level of Cortisol could be caused by high level of ACTH. ACTH acts on the adrenal cortex to stimulate secretion of Cortisol and other steroids.

in one embodiment the patient having hypertension does not have an elevated level of Cortisol or a higher than normal level of ACTH. Pasireotide and any of its pharmaceutical acceptable salt exerts its inhibitory effect by binding on sstr1 , 2, 3 and/or 5 expressed by cells/tissues, the secreted factors from which lead to elevated blood pressure, such as the cells/tissues secret renin or angiotensin I, etc. Our data showed, although the reduction in blood pressure was strongest in those patients with normalized UFC levels during pasireotide treatment, there was no general correlation between reduction of Cortisol and reduction of blood pressure. Thus it is possible that pasireotide reduces blood pressure, in addition to or independent of the ACTH/ Cortisol/ adolsterone pathway.

In one aspect, the present invention provides a medicament comprising pasireotide and any one of its pharmaceutically acceptable salt for use in the treatment of resistant hypertension in patients. In a further preferred embodiment the resistant hypertension is resistant to at least one diuretic drug. In a further preferred embodiment the resistant hypertension is triple resistant hypertension.

A conventional anti-hypertensive drug refers to at least one anti-hypertensive drug out of any one of the following categories: (i) an inhibitor targeting the renin-angiotensin-aldosterone (RAA) hormonal system (ii) a calcium channel blocker (CCB); and (iii) a diuretic. Drugs as beta-blockers are also used commonly in treating hypertension.

An inhibitor targeting the renin-angiotensin-aldosterone (RAA) includes but is limited to renin inhibitor (such as aliskiren). an angiotensin receptor (Type 1, ATj) blocker (ARB) and an angiotensin converting enzyme (ACE) inhibitor. An ARB includes but is not limited to candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisailan, tasosartan, telmisartan, valsartan, E-41 77. SC-52458, and ZD8731 , and pharmaceutically acceptable salts thereof; an ACE inhibitor includes but is limited to benazepril, captopril, lisinopril, quinapril, and ramipril, and pharmaceutically acceptable salts thereof.

A calcium channel blocker (CCB) can be selected from the group consisting of amlodipine, felodipine, isradipine, lacidipinc, nicardipine, nifedipine, niguldipine, niludipine, nimodipine. nisoldipine, nitrendipine, nivaldipine, ryosidine, anipamil, diltiazem, fendiline, flunarizine, gallopamil, mibefradil, prenylamine, tiapamil. and verapamil, and pharmaceutically acceptable salts thereof.

The term "diuretic" is very broad, and refers generally to any substance that cause the kidneys to get rid of extra water and salt. There are many kinds of diuretics, and each diuretic works on different parts of the kidneys.

Some of the common classes of diuretics include but are not limited to bumetanide, ethacrynic acid, furosemide, torsemidc, amiloride, spironolactone, triamterene, chlorothalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, metolazone, and dichlorphenamide, and pharmaceutically acceptable salts thereof.

Each class of diuretic has a different specific mechanism of action, but all typically share the ultimate outcome of changing the way the kidneys handle salt, water, and other substances.

The term "resistant hypertension" refers to the situation that despite receiving at least one conventional anti-hypertensive drug, the blood pressure of the treated patients could not reach the goal blood pressure. Preferably the at least one anti-hypertensive drug is a diuretic.

Further preferably, the anti-hypertensives are given to the full dose. The term "goal blood pressure" is defined as SBP≤ 130mmHg and the DBP≤ 90mmHg.

The term "resistant hypertension" also encompasses the situation in the patients receive combination use of at least two drugs out of any two of the three categories of the

conventional anti-hypertensives drags above and could not reach goal blood pressure.

Preferably at least one of the anti-hypertensive drug is a diuretic. Further preferably, the anti-hypertensives are given to the full dose.

The term "resistant hypertension" also encompasses the situation of triple resistant. The term "triple resistant hypertension" according to the invention, is defined as hypertension that remains above goal blood pressure in spite of concurrent use of three or more

antihypertensive agents belonging to different anti-hypertensive drug classes. Preferably, one of the three or more anti-hypertensive agents is a diuretic. Preferably the term "triple resistant hypertension" refers to hypertension that remains above goal blood pressure in spite of concurrent use of three drugs, each out of categories (i), (ii) and (iii) respectively. Further preferably, the antihypertensives are given to the full dose.

The term "full dose" in this sense means the highest dose of the respective antihypertensive depending on the age, weight and gender of the patient.

As stated above pasireotide may effectively reduce blood pressure through lowering the level of ACTH and thereby its down-stream mediators, including Cortisol and adolsterone, which may not be inhibited by the conventional anti-hypertensive drug.

Thus in one embodiment, the present invention provides medicament comprising pasireotide for use in treating resistant hypertension in patients having a higher than lower limit of normal (LLN) level of ACTH, preferably in patients having a higher than normal level of ACTH, with or without elevated level of Cortisol.

In one preferred embodiment, the present invention provides a medicament comprising a sustained release formulation of pasireotide.

Conventional anti-hypertensive drugs need to be taken daily, leading easily to non-compliance. Patients' non-compliance is as well a cause for resistant hypertension. It has been shown that various sustained release formulations of pasireotide and any of its

pharmaceutically acceptable salts, preferably pasireotide pamoate salt, can be made.

WO2005/046645 describes a sustained release formulation comprising microparticles, wherein the microparticles comprises pasireotide pamoate and one branched and one linear polylactide-co-glycolide polymers.

WO2005/120453 discloses a liquid pharmaceutical composition comprising a polylactide-co-glycolide polymer, polyethylene glycol having a molecular weight of less than 600 Daltons, and pasireotide and its pharmaceutically acceptable salt and less than 1% of a suitable organic solvent,

WO2006/066868 describes an autogel formulation bases on the finding that various pasireotide salts, particularly mono- or diaspartate, mono- or diglutamate, mono- or disuccinate, acetate or citrate and water forms a gelling depot system after injection in contact with body fluid.

WO2008/152401 discloses the use of the fluidcrystal technology for making a sustained release formulation comprising pasireotide, at least one diacyl glycerol, at least one

phosphatidyl choline and at least one oxygen containing organic solvent, wherein preferably it is ethanol.

In addition to the specific disclosure above, other formulation technologies in the form, of implants, semisolids (gels), liquid solutions or suspensions which solidify in situ may be used to prepare the sustained release formulation of pasireotide.

The term "sustained release formulation of pasireotide" as used herein refers to a formulation comprising at least one active ingredient being pasireotide and any of its pharmaceutically acceptable salts, that, after administration, releases pasireotide over an extended period of at least two weeks, at least 21 days, preferably at least 28 days, at least one month or at 6 weeks in human body. Preferably pasireotide is released in a slowly and constantly way

characterized that Cmin is at least higher than 0.1ng/ml, higher than 0.3ng/ml, higher than 0.5ng/ml.

Apparently the possible longer administration intervals due to sustained release formulations of pasireotide offers a great benefit over other anti-hypertensive drugs with respect to patients' compliance and thus would demonstrate higher efficacy or overcome resistance.

In one aspect the present invention provides a combination of pasireotide, or any of its pharmaceutical acceptable salts, and at least one conventional anti-hypertensive drug for simultaneous, separate or sequential use in hypertension patients. Hypertension patients may benefit from this combination use as all known anti-hypertensives are different from the mode of action of Pasireotide and the mode of action of pasireotide is likely complementary.

In one aspect, the present invention provides a combination of pasireotide, or any of its pharmaceutical acceptable salts, and at least one a 11 beta-hydroxy lase inhibitor for simultaneous, separate or sequential use in hypertension patients. In one embodiment the 11beta-hydroxylase inhibitor is Compound B having formula (II):

Compound B is also called (R)-4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile. Compound B can be synthesized or produced and characterized by methods as described in WO2007/024945. The preferred salt of Compound B is phosphate salt.

EXPERIMENTAL DATA

Example 1 Pasireotide treatment is associated with improvements in hypertension: 12-month results from a large Phase III study of pasireotide in Cushing's disease

Introduction: Patients with Cushing's disease (CD) have increased risk of hypertension (HTN). Phase III data have shown that pasireotide leads to rapid reductions in UFC levels and significant improvements in CD symptoms. We now present further analyses of these data, evaluating the effects of pasireotide on HTN in patients with CD.

Methods: Patients with persistent/recurrent or de novo (if not surgical candidates) CD and

UFC≥ 1.5 times the upper limit of normal (ULN) were randomized to pasireotide 600μg (n=82) or 900μg (n=80) sc bid. Systolic (SBP) and diastolic blood pressure (DBP) were evaluated by single measurements at baseline (n=162) and month 12 (n=78). Baseline HTN was defined as at least one of: history of anti-HTN medications; medical history of HTN; SBP>130mmHg; or DBP>90mmHg. The addition of medications for HTN was allowed per investigator discretion.

Results At baseline, 77.8% of patients had HTN (n=126), of whom 97 took anti-HTN medication during the study. Mean SBP decreased from 133.5mmHg at baseline to

126.1 mmHg at month 12 (-6.1 ; 95% CI: -9.8, -2.4, Fig 1 A). Mean DBP decreased from

86.3mmHg to 82.8mmHg (-3.7; 95% CI : -6.2, -1 .2, Fig 1B). When stratified by UFC response, these improvements were only significant in those with UFC≤ ULN at month 6. Significant improvements from baseline to month 12 were seen in patients with baseline HTN (SBP: -8.0 [-12.4, -3.6]; DBF: -4.7 [-7.7. -1 .7]). There were no significant changes in SBP or DBF in patients without baseline HTN (SBP: 0.2 [-6.1, 6.4]; DBF: -0.4 [-4.6, 3.9]). Decreases in DBF tended to be larger in patients with higher baseline DBF: similar trends were seen with SBP (Fig 2). A >5mniHg decrease in DBF was seen in 42% (33/78) of patients at month 12. This was higher in those with baseline HTN (50% [30/60]) than in those without (17% [3/18]). Of those with baseline HTN, a >5mmHg decrease in DBF was seen in 63% (10/16) of patients who did not take anti-HTN medication during the study and in 46% (20/44) of those who did.

Example 2

Patients with Cushing's disease achieve normal urinary Cortisol with Compound B, a potent 11 β-hydroxylase inhibitor: preliminary results from a multicenter, proof-of-concept study

Introduction: The clinical features and complications of Cushing's syndrome result from chronic excess of circulating Cortisol, typically quantified by 24-hour urinary free Cortisol (UFC). COMPOUND B is a potent inhibitor of 11β-hydroxylase. Since 11β-hydroxylase catalyzes the final step of Cortisol synthesis, COMPOUND B is a potential new treatment for all forms of Cushing's syndrome.

Methods: Adult patients with mild-to-severe Cushing's disease (UFC >1.5x the upper limit of normal [ULN], mean of three collections in 14 days) received oral COMPOUND B for 10 weeks in an open-label study. COMPOUND B was initiated at 2mg bid. Dose escalation was planned every 2 weeks to 5, 10, 20 and 50mg bid until UFC normalized, in which case the dose was maintained until day 70, when treatment stopped. Dose reduction for tolerability was permitted. UFC was assessed on the penultimate day of each 2-week period. Patients were monitored until day 84. The primary endpoint was UFC≤ULN or a≥50% decrease from baseline at day 70 using the mean of 3 UFC samples collected during the week before day 70.

Results: Eleven patients (aged 25-55 years; 4 men) have been enrolled and 9 have completed the study to date. Nine patients had prior surgery. Baseline UFC range was 1.6-17.0xULN. UFC levels were normal on at least one assessment in 11 of 11 patients during the study. The primary endpoint was achieved by all 9 patients who have completed the

active treatment phase, 8 of whom had normal UFC levels on day 70. After treatment discontinuation, UFC was >ULN in 6 patients with measurements at day 84. The median dose of COMPOUND B associated with UFC normalization was between 5 and 10mg bid. At day 70, mean SBP decreased by 13.1 mmHg from baseline. COMPOUND B was generally well tolerated; the most frequently reported adverse events were fatigue (5/11), nausea (4/11) and headache (3/11). Five patients experienced ACTH levels >2xbaseline. Four patients experienced study drug-related hypokalemia (K+<3.5mmol/L; min 3.1 mmol/L). There were no serious AEs of suspected drug relationship.

Conclusion: COMPOUND B demonstrated efficacy with a satisfactory safety profile in this proof-of-concept study in patients with Cushing's disease.