WO2016092504A1

WO2016092504A1 - Pasireotide for use in the treatment of effusion

Info

Publication number: WO2016092504A1
Application number: PCT/IB2015/059517
Authority: WO
Inventors: Reinhard DUMMER
Original assignee: University Of Zurich
Priority date: 2014-12-12
Filing date: 2015-12-10
Publication date: 2016-06-16

Abstract

The present invention relates to pasireotide or any pharmaceutically acceptable salt thereof 5 for use in the treatment of effusion, such as ascites and pleural effusion.

Description

PASIREOTIDE FOR USE IN THE TREATMENT OF EFFUSION

Description FIELD OF THE INVENTION

The present invention relates to pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion, such as ascites and pleural effusion. BACKGROUND OF THE INVENTION

More recently, a new somatostatin analogue, i.e. pasireotide, has become available under the brand name Signifor® for the indication Cushing's disease. According to the product's package leaflet, the recommended pasireotide dosage is 600 μg b.i.d. (twice a day). This initial dose might be increased to 900 μg b.i.d. for some patients. Thus, the maximum recommended daily dose is 1800 μg pasireotide.

SUMMARY OF THE INVENTION The present inventor used pasireotide for a patient suffering from ascites and pleural effusion at doses of 300 to 600 μg t.i.d. (thrice a day) which are daily doses also applied for pasireotide in its first approved indication Cushing's disease. However, those daily doses did not show a beneficial therapeutic effect with respect the the symptoms of ascites and pleural effusion. Thus, at the maximum recommended daily dose of 1800 μg pasireotide no therapeutic effect with respect to the patients' effusion was observed.

Despite of said lack of success at the maximum recommended daily dose, the present inventor further increased the dose significantly to 900 μg pasireotide t.i.d. (i.e. 2700 μg daily dose) and surprisingly found a remarkable reduction of patient's body weight as well as a remarkable reduction of the symptoms of ascites and pleural effusion.

Based on these surprising clinical findings, the present invention is provided in its following aspects. In accordance with a first aspect of the present invention, there is provided:

Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion, including ascites and pleural effusion. Alternatively, the present invention provides a method for the treatment of effusion, including ascites and pleural effusion, in human patients in need of such treatment which comprises administering an effective amount of pasireotide or any pharmaceutically acceptable salt thereof. As a further alternative the present invention provides the use of pasireotide or any pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of effusion, including ascites and pleural effusion.

As a further alternative the present invention provides a medicament for the treatment of effusion, including ascites and pleural effusion, comprising pasireotide or any

pharmaceutically acceptable salt thereof.

In accordance with a second aspect of the present invention, there is provided:

Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion wherein the daily dose of pasireotide referred to as free base is 2000 - 4000 μg, preferably 2400 - 3600 μg, more preferably 2400 - 2700 μg.

Alternatively, the present invention provides a method for the treatment of effusion, including ascites and pleural effusion, in human patients in need of such treatment which comprises administering an effective amount of pasireotide or any pharmaceutically acceptable salt thereof, characterized in that the daily dose of pasireotide referred to as free base is 2000 - 4000 μg, preferably 2400 - 3600 μg, more preferably 2400 - 2700 μg.

As a further alternative the present invention provides the use of pasireotide or any pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of effusion, including ascites and pleural effusion, characterized in that the daily dose of pasireotide referred to as free base is 2000 - 4000 μg, preferably 2400 - 3600 μg, more preferably 2400 - 2700 μg. As a further alternative the present invention provides a medicament for the treatment of effusion, including ascites and pleural effusion, comprising pasireotide or any

pharmaceutically acceptable salt thereof, characterized in that the daily dose of pasireotide referred to as free base is 2000 - 4000 μg, preferably 2400 - 3600 μg, more preferably 2400 - 2700 μg.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following the present invention is described in detail with reference to accompanying figures in which:

Figure 1 shows the body weight of the patient versus time during the treatment with pasireotide (squares/rectangles: daily dose; circles: body weight) from 4 days before treatment start until day 250 after treatment start. Figure 2 shows the body weight of the patient versus time during the treatment with pasireotide (squares/rectangles: daily dose; circles: body weight) from 4 days before treatment start until day 120 after treatment start.

Figure 3 shows the body weight of the patient versus time during the treatment with pasireotide (squares/rectangles: daily dose; circles: body weight) from day 1 10 after treatment start until day 200 after treatment start.

Figures 4 - 7 show the CT imaging analysis with the droplet-like arrow "1 " pointing to areas of pleural effusion and "2" pointing to areas of ascites.

Figure 4: Ascites-focused CT analysis before pasireotide treatment.

Figure 5: Pleural-effusion focused CT analysis before pasireotide treatment.

Figure 6: Ascites-focused CT analysis after 10 weeks treatment with 3 x 1200 μg pasireotide. Only small areas of ascites remained detactable.

Figure 7: Pleural-effusion focused CT analysis after 10 weeks treatment with 3 x 1200 μg pasireotide. No ascites or pleural effusion are detectable.

DETAILED DESCRIPTION OF THE INVENTION

Herein after, the present invention is described in further detail and is exemplified. The present invention provides pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion. Alternatively, the present invention provides a method for the treatment of effusion in human patients in need of such treatment which comprises administering an effective amount of pasireotide or any pharmaceutically acceptable salt thereof into said patient.

As a further alternative the present invention provides the use of pasireotide or any pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of effusion.

As a further alternative the present invention provides a medicament for the treatment of effusion comprising pasireotide or any pharmaceutically acceptable salt thereof.

The term "effusion" refers to the pathological condition, disorder, sign or symptom of the abnormal, excessive accumulation of fluids in the body's cavities.

Examples of said effusion according to the present invention include but are not limited to ascites or pleural effusion.

Ascites is referred to herein as the abnormal, excessive accumulation of fluids in the peritoneal cavity (space between parietal peritoneum and visceral peritoneum) and is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum, hydroperitonia, hydrops addominis, peritoneal dropsy or abdominal dropsy.

If said fluid is serous fluid the ascites is also referred to as hydrous ascites. If said fluid is chyle the ascites is also referred to as chylous ascites. Pleural effusion is referred to herein as the abnormal, excessive accumulation of fluids in the pleural cavity, i.e. the fluid-filled space that surrounds the lungs, or in other words, the space between the layers of tissue that line the lungs and the chest cavity. Pleural effusion is also known under the terms, fluid in the chest, fluid in the lung, pleural fluid. If said fluid is serous fluid the pleural effusion is also referred to as hydrothorax. If said fluid is chyle the pleural effusion is also referred to as chylothorax.

Depending on their cause, effusion can be divided into two different types:

First type: Transudative effusion are caused by fluid leaking into the pleural space as a result of increased pressure in the blood vessels or a low blood protein count. Congestive heart failure is an example for such cause. Second type: Exudative effusion are caused by blocked blood vessels or lymph vessels, inflammation, injury, organ failures, and/or tumors.

Said cancer/tumor caused effusion are also referred to as malignant effusion, cancerous effusion, carcinoid effusion.

Depending on the organ failure effusion are also referred to as e.g. hepatic effusion, pancreatic effusion.

If the injury is derived from a surgery said effusion are also referred to as post-operative effusion or more specifically e.g. post-esophagectomy effusion.

If the cause of the effusion is unknown or the effusion has a spontaneous origin, said effusion is also referred to as idiophatic effusion or spontaneous effusion. Depending on the severity of the effusion, said effusion are also referred to as e.g. refractory effusion, persistent effusion, or recurrent effusion.

Depending on the patient suffering from said effusion, the effusion are also referred to as e.g. congenital effusion, neonatal effusion, infant effusion, child effusion, or adult effusion.

In the aspects of the invention, pasireotide may be in free form or salt form. Salts include acid addition salts with e.g. inorganic acids, polymeric acids or organic acids, 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, e.g. for pasireotide, are the lactate, aspartate, benzoate, succinate and pamoate including mono- and di-salts, more preferably the aspartate di-salt and the pamoate monosalt. In one embodiment, pasireotide is in the form of aspartate di-salt. In one embodiment, pasireotide is in the form of pamoate monosalt.

In one embodiment, there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion wherein said effusion is ascites.

In a preferred embodiment, there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion wherein said ascites is hydrous ascites or chylous ascites, more preferably chylous ascites, even more preferably cancerous chylous ascites, even more preferably adult cancerous chylous ascites.

In one embodiment, there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion, wherein said effusion is pleural effusion.

In a preferred embodiment, there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion, wherein said pleural effusion is hydrothorax or chylothorax, more preferably chylothorax, even more preferably cancerous chylothorax, even more preferably adult cancerous chylothorax.

In a preferred embodiment, there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion wherein the effusion is a transudative effusion or an exudative effusion, more preferably said effusion is an exudative effusion, even more preferably the effusion is caused by tumor or cancer.

In a preferred embodiment, there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion, wherein the effusion is of severe grade. The severity in this regard may lie in the nature of the condition as being refractory, persistent, recurrent and/or chronic.

With respect to ascites, the severity may in addition or as alternative be indicated by categorizing the conditions into the three grades system according to K. P. Moore et al. Hepatology 2003, 38, 258-266. According to this categorization a grade 1 ascites is a mild condition which is visible only on ultrasound and computer tomography (CT). The more severe grade 2 ascites is detectable with flank bulging and shifting dullness. The even more severe grade 3 ascites is directly visible and can be confirmed with the so-called fluid wave/fluid thrill test (this test is positive when upon tapping or pushing on one side a wavelike effect through the fluid is generated that can be felt in the opposite side of the abdomen indicating a grade 3 ascites).

In one embodiment severe grade refers to the effusion being refractory, persistent, recurrent and/or chronic, preferably refractory.

In one embodiment there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of ascites, wherein the ascites is of severe grade and wherein severe grade refers to the ascites being of grade 2 or 3 according to K. P. Moore et al. Hepatology 2003, 38, 258-266, preferably being of grade 3.

In one embodiment there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion, wherein the daily dose of pasireotide referred to as free base is 2000 - 4000 μg, preferably 2400 - 3600 μg, more preferably 2400 - 2700 μg.

In one embodiment, said daily dose of pasireotide referred to as free base is delivered three times with 700 - 1200 μg per time, preferably 900 μg per time or two times with 1000 - 1800 μg per time, preferably 1200 μg per time. In one embodiment the above said daily dose of pasireotide is applied as initial dose until the excess fluids of the effusion have been sufficiently removed from the bodily cavities and the treatment is then continued with a daily dose of 1000 - 2000 μg as maintenance daily dose.

In one embodiment the above said maintenance daily dose of pasireotide is delivered two or three times with 600 μg per time.

In one embodiment there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion, including ascites and pleural effusion, wherein the pasireotide doses are delivered subcutaneously (s.c.) or intramuscularly (i.m.). ln one embodiment there is provided a method for the treatment of effusion, including ascites and pleural effusion, in human patient in need of such treatment which comprises

administering an effective amount of pasireotide or any pharmaceutically acceptable salt thereof, wherein said treatment is characterized in that the pasireotide doses are delivered subcutaneously (s.c.) or intramuscularly (i.m.).

In one embodiment there is provided the use of pasireotide or any pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of effusion, including ascites and pleural effusion, characterized in that the pasireotide doses are delivered subcutaneously (s.c.) or intramuscularly (i.m.).

In one embodiment there is provided a medicament for the treatment of effusion, including ascites and pleural effusion, comprising pasireotide or any pharmaceutically acceptable salt thereof, characterized in that the pasireotide doses are delivered subcutaneously (s.c.) or intramuscularly (i.m.).

S.c. (also referred to as hypodermic) delivery in this aspect means an injection into the fatty tissue under the skin via a short and small needle (e.g. 23-25 gauge, 5/8"). The thighs (upper legs), the abdomen, or the upper arms are typically used areas for such subcutaneous injections. However, as in the case of the present invention the patients suffer from ascites, the thighs, depending on the situation, can be the preferred injections areas.

The s.c. injection may be performed with the help of an autoinjector device, a microneedle device, or a needleless injection device.

The s.c. injection may be performed by a clinical practitioner (physician or nurse) or by the patient himself. I.m. delivery means an injection into the muscle tissue via a 22 - 25 gauge needle long enough to reach the muscle tissue area taking into account the patient individual fatty tissue. E.g. a 5/8" needle is sufficient in adults weighing less than 130 lbs (<60 kg) for IM injection in the deltoid muscle only if the subcutaneous tissue is not bunched and the injection is made at a 90-degree angle; a 1 " needle is sufficient in adults weighing 130-152 lbs (60-70 kg); a 1-1 ½" needle is recommended in women weighing 152-200 lbs (70-90 kg) and men weighing 152-260 lbs (70-1 18 kg); a 1 ½" needle is recommended in women weighing more than 200 lbs (90 kg) or men weighing more than 260 lbs (more than 1 18 kg). Alternatively to the deltoid muscle the gluteal muscle, the buttock, the thigh or the shoulder muscles may be used as injection sites.

In one embodiment there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion, including ascites and pleural effusion, wherein the pasireotide doses are delivered by an immediate release formulation.

In one embodiment there is provided a method for the treatment of effusion, including ascites and pleural effusion, in human patient in need of such treatment which comprises

administering an effective amount of pasireotide or any pharmaceutically acceptable salt thereof, wherein said treatment is characterized in that the pasireotide doses are delivered by an immediate release formulation.

In one embodiment there is provided the use of pasireotide or any pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of effusion, including ascites and pleural effusion, characterized in that the pasireotide doses are delivered by an immediate release formulation.

In one embodiment there is provided a medicament for the treatment of effusion, including ascites and pleural effusion, comprising pasireotide or any pharmaceutically acceptable salt thereof, characterized in that the pasireotide doses are delivered by an immediate release formulation.

Said immediate release formulation may comprise the pasireotide as free base, as water- soluble salt or as poorly water-soluble salt, preferably as water-soluble salt, more preferably as diaspartate salt.

Said immediate release formulation may further comprise at least one of the following:

A tonicity adjusting agent (e.g. mannitol), a pH adjustment agent/buffer (e.g. tartaric acid, sodium hydroxide), and water. Preferably said immediate release formulation comprises pasireotide diaspartate, mannitol, tartaric acid, sodium hydroxide and water. More preferably said immediate release formulation consists of pasireotide diaspartate, mannitol, tartaric acid, sodium hydroxide and water.

In one aspect the present invention provides a pharmaceutical composition comprising pasireotide for use in the treatment of effusion, preferably said pasireotide is in the form of the diaspartate salt. More preferably the composition comprises pasireotide diaspartate and at least of a tonicity adjusting agent (e.g. mannitol), a pH adjustment agent/buffer (e.g.

tartaric acid, sodium hydroxide), and water. Even more preferably said composition comprises pasireotide diaspartate, mannitol, tartaric acid, sodium hydroxide and water. Even more preferably said composition consists of pasireotide diaspartate, mannitol, tartaric acid, sodium hydroxide and water.

In one embodiment there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion, including ascites and pleural effusion, wherein the pasireotide doses are delivered by a sustained release formulation.

administering an effective amount of pasireotide or any pharmaceutically acceptable salt thereof, wherein said treatment is characterized in that the pasireotide doses are delivered by a sustained release formulation.

In one embodiment there is provided the use of pasireotide or any pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of effusion, including ascites and pleural effusion, characterized in that the pasireotide doses are delivered by a sustained release formulation.

In one embodiment there is provided a medicament for the treatment of effusion, including ascites and pleural effusion, comprising pasireotide or any pharmaceutically acceptable salt thereof, characterized in that the pasireotide doses are delivered by a sustained release formulation. Said sustained release formulation may comprise the pasireotide as free base, as water- soluble salt or as poorly water-soluble salt, preferably as poorly water-soluble salt, more preferably as pamoate salt. Said sustained release formulation may further comprise a biodegradable polymer, e.g. polylactide-co-glycolide (PLGA). Preferably said sustained release formulation comprises pasireotide pamoate and a PLGA polymer. More preferably said sustained release formulation consists of pasireotide pamoate and PLGA polymer. Even more preferably said sustained release formulation is in the form a microparticles and is delivered i.m. after resuspension with an aqueous vehicle. Said aqueous vehicle may comprise at least one of a surfactant (e.g. poloxamer), a tonicity agent (e.g. mannitol) and a viscosity-increasing agent to prevent fast sedimentation of the microparticles (e.g. carboxy methylcellulose sodium, Na- CMC). As an example, said microparticles comprising pasireotide in its pamoate salt form, a linear polymer (e.g. a Resomer RG) and a star polylactide-co-glycolide polymer having a weight average molecular weight of about 50Ό00 Da, wherein the ratio of linear to branched polylactide-co-glocolide is 50:50. Such microparticles are described in WO 2005/046645, the contents of which are herein incorporated by reference.

In one aspect the present invention provides a pharmaceutical composition comprising pasireotide for use in the treatment of effusion, preferably said pasireotide is in the form of the pamoate salt. More preferably the composition comprises pasireotide pamoate and a biodegradable polymer (e.g. PLGA). Even more preferably said composition consists of pasireotide in its pamoate salt form, a linear polymer (e.g. a Resomer RG) and a star polylactide-co-glycolide polymer having a weight average molecular weight of about 50Ό00 Da, wherein the ratio of linear to branched polylactide-co-glocolide is 50:50.

As preventive or curative pasiretodie treatment with a sustained release formulation microparticles, such as described above, are filled into glass vials in an amount

corresponding to 40 mg and 60 mg pasireotide per vial.

Vehicle for resuspending said microparticles is produded e.g. according to Example 9, table 3, column D ("Vehicle D") in WO 2005/046645. The microparticles are resuspended with 2 mL of the vehicle. The resulting suspension is injected into the gluteal muscle of a human patient via e.g. a 20 gauge needle of appropriate length to reach the muscle tissue. An initial dose of 40 mg is delivered i.m. to the patient. If no new effusion symptoms are noticed or existing effusion symptoms are getting reduced after 2 weeks, a second injection with 40 mg is delivered i.m. after 1 month from the first injection. If the effusion remains under control 40 mg dose is delivered i.m. once every month.

If after the first 40 mg injection, however, new effusion symptoms are noticed or the existing effusion symptoms are not getting reduced after 2 weeks, a second injection with 40 mg is then delivered i.m. If after further 2 weeks the then effusion symptoms are reduced, the patient is treated with 40 mg every second week. The patient may be switched from 40 mg every second week to 60 mg once a month if desired.

In case the 40 mg every second week regimen is not sufficient to control the effusion, 60 mg every second week is injected i.m. If also this regimen fails, the patient receives 2 injections of 40 mg every second week. If required the dose to be delivered every second week is to be further escalated until the effusion are under control.

In one embodiment there is provided pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion, wherein the patient receiving said treatment is an newborn, infant, child or an adult. In one embodiment, the patient is an adult, or the patient is an elderly adult, e.g. an adult with age of 50 years or older, even more preferably of 60 years or older, even more preferably of 70 years or older. In the various aspects of the present invention the pasireotide treatment as described herein may be preventive or curative: The pasireotide treatment may be started even before the patient suffers from any symptoms of effusion or started when the patient is diagnosed with effusion. The pasireotide treatment may be continued even after the symptoms are completely gone to keep the patient's abnormal development of fluids under control. Said continuing pasireotide treatment may be done at doses lower than the initial doses (lower maintanence dose). The pasireotide treatment may also be palliative in the sense that it provides the treatment provides relief for the patient from experiencing the discomfort of e.g. abdomal pressure, dyspnea or short breath. The present invention provides the following advantages:

It, i.e. the present invention, provides a strong and long lasting anti-secretory and absorptive effect, preventing the abnormal formation of new fluids (e.g. serous fluid, chyle) and reducing the existing volumens of excess fluids in the body's cavities, such as the peritoneal and peural cavity.

It prolongs the time until a next paracentesis/thoracentesis is required, providing by this more comfort for the patient, less risks for the patient to develop complications due to the invasive paracentesis/thoracentesis, such as lung damage, pneumothorax, or infections.

It reduces the need for paracentesis, providing by this more comfort for the patient, reduces the risks for the patient to develop complications due to the invasive

paracentesis/thoracentesis, and reduceshealth costs associated with

paracentesis/thoracentesis.

It is effective to remove of excess fluids from the body's cavities.

It is effective to remove the excess fluids from the body's cavities within a short time period. It provides a high degree of success in reducing the new formation of excess fluids and reducing the existing excess fluids of patients suffering from effusion.

It provides a better control of the effusion.

It provides a well-tolerable treatment of effusion.

It provides improved quality of life e.g. by providing relief from the discomfort of e.g. abdomal pressure, dyspnea or short breath.

It allows sending hospitalized patients home, providing by this more comfort for the patient and reduces health costs.

It allows treating patients with a relatively low maintenance dose avoiding side- effects/adverse events.

EXAMPLES

Hereinafter, the present invention is described in more details and specifically with reference to the examples, which however are not intended to limit the present invention.

Example 1 :

Medicament and its administration: The drug pasireotide is available as ampoules each filled with nominal 1 mL aqueous solution for subcutaneous injections and is commercialized by Novartis under the brand name Signifor® in three different dose strength: 0.3, 0.6, and 0.9 mg. The solution contains pasireotide as pasireotide diaspartate. The solution further contains as inactive ingredients mannitol, tartaric acid, sodium hydroxide, and water. The medicament is injected through a short needle into the fatty tissue under the skin. The thighs and the abdomen are typically used areas for such subcutaneous injections. However, as in the case of the present invention the patients suffer from ascites, the thighs are the preferred injections areas and have been used for the treatment of the patient herein.

Patient:

A 76 old male patient was diagnosed with metastatic melanoma stage IV (pT4b N3 M1 c, BRAF wildtype, NRAS wildtype). Two years before the treatment with pasireotide the patient was subjected to a primary excision, followed by a re-excision, SLNB, and a neck-dissection. Chemotherapies with dacarbazine (DTIC) and eldesine and immunotherapies with Ipililumab and anti-PD-1 antibodies followed. About 1 year before treatment with pasireotide the patient developed ascites and pleural effusion (associated with distant metastasis) which was treated by several paracentesis. Cytological investigations did not indicate any pertoneal carcinosis.

Four days before the treatment start the patient's body was analysed by computer- tomography (CT). Large volumes of excess fluids in the peritoneal and peritoneal cavity were found (ca. 1200 and ca. 1600 cm³, respectively, see Fig. 4 and 5, respectively).

Ascites puncturing (performed several times during the following treatment) delivered a yellowish, turbid fluid comprising mesothelial cells, histiocytes, and lymphocytes.

At initial treatment start the patient had a body weight of 85 kg.

Treatment:

An initial dose of three times 300 microgram pasireotide per day (3 x 300 μg day = 900 μg/day were administered subcutaneously (s.c). As this initial daily dose did not provided any relief to the patient suffering from ascites/pleural effusion and his body weight even further increased to values close to 90 kg, the daily dose was increased to 3 x 600 μg day. However, also at a daily dose of 3 x 600 μg day, the body weight remained at high values of about 85 kg. After two weeks unsuccessful treatment with 3 x 600 μg day the excess fluids in the peritoneal and peritoneal cavities were found to be as high as ca. 2600 and ca. 1300 cm³, respectively). The dose was consequently escalated to 3 x 900 μςΛ^. From that moment the body weight decreased steadily down to about 75 kg indicating therapeutic effect. After 2 weeks treatment 3 x 900 μg/day a further dose escalation step to 3 x 1200 μg/day was done and the body weight further decreased. CT analysis after two weeks of treatment with 3 x 1200 μg/day revealed a significant reduction of the excess fluid volumes: ca. 800 cm³ for the peritoneal cavity and ca. 400 cm³ for the pleural cavity. After 10 weeks treatment with 3 x 1200 μg/day the excess fluids in the pleural cavity completely disappeared (see Fig. 7) and only a negligible volume of ca. 100 cm³ remained in the peritoneal cavity (see Fig. 6). The treatment was then discontinued. Short (four days) after the last dosing a body weight of ca. 64 kg was measured.

The following table provides the exact data monitored/measured.

Time Pasireotide daily Body Ascites: Pleural effusion: point/period dose, s.c. ^g] weight Volume of excess Volume of excess

[no. of day [kg] fluid in peritoneal fluid in pleural after initial cavity as cavity as

start of determined by CT determined by CT treatment] analysis [cm³] analysis [cm³]

-4 Before start of 1225 (Fig. 4) 1567 (Fig. 5)

treatment

0 At start of treatment 85.0

0 - 15 3 x 300

16 - 28 3 x 600

29 After ca. 2 weeks 85.0 2589 1260

treatment with 3 x

600 Mg

29 - 42 3 x 900

43 - 1 14 3 x 1200

57 After 2 weeks 73.3 761 428

treatment with 3 x

1200 Mg

113 After 10 weeks 119 (Fig. 6) 0 (Fig. 7)

treatment with 3 x 1200 Mg

1 18 0 64.4

Fig. 1 and 2 provide a graphical presentation of the patient's body weight and excess fluids volumes over time during the dose escalation phases of treatment. During the about one and a half month time of treatment pause, the body weight increased again up to values of about 80 kg and symptons of ascites and pleural effusion re-appeared. Upon resumption of the treatment with pasireotide at a daily dose of 3 x 1200 μg day said symptoms started to disappear again and the body weight decreased to values of below 70 kg. The patient's symptoms of ascites and pleural effusion were then successfully controlled (i.e. patient did not experience a feel of abdomal tension or shortness of breath, patient did not suffer from dyspnea) under the maintances dosages of 2 x 1200 μg day, and later 2 x 600 μg day.

Fig. 1 and Fig. 3 provide a graphical presentation of the patient's body weight after the resumption of the pasiretoide treatment.

As a result, initial doses of pasireotide of 3 x 900 = 2700 μg day to 3 x 1200 = 3600 μg day are sufficient to get the excess fluids in the peritoneal and pleural cavities removed. Once a patient is free of symptoms maintenance doses of pasireotide of 2 x 600 = 1200 μg day to 2 x 1200 = 2400 μg day can be administered to keep patients under symptom control.

Claims

Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion.

Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to claim 1 , wherein said effusion is ascites.

Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to claim 2, wherein said ascites is chylous ascites.

Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to claim 1 , wherein said effusion is pleural effusion.

Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to claim 4, wherein said pleural effusion is hydrothorax or chylothorax.

Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to any one of the claims 1 to 5, wherein the effusion is of severe grade.

Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to any one of the claims 1 to 6, wherein the effusion is caused by cancer.

Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to any one of the claims 1 to 7, wherein the daily dose of pasireotide referred to as free base is 2000 - 4000 μg.

9. Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to claim 8, wherein said daily dose of pasireotide referred to as free base is delivered three times with 700 - 1200 μg per time or two times with 1000 - 1800 μg per time.

10. Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to claims 8 or 9 wherein said daily dose of pasireotide is applied as initial dose until the excess fluids of the effusion have been sufficiently removed from the bodily cavities and the treatment is then continued with a daily dose of 1000 - 2000 μg as maintenance dose.

1 1 . Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to claim 10 wherein the maintenance daily dose of pasireotide is delivered two or three times with 600 μg per time.

12. Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to any one of the preceding claims, wherein pasireotide is delivered subcutaneously (s.c.) or intramuscularly (i.m.).

13. Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to any one of the preceding claims, wherein pasireotide is delivered by an immediate release formulation.

14. Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to any one of the claims 1 - 12 wherein pasireotide is delivered by a sustained release formulation.

15. Pasireotide or any pharmaceutically acceptable salt thereof for use in the treatment of effusion according to any one of the claims 1 - 14 wherein the patient receiving said treatment is an adult.