WO2007083119A2

WO2007083119A2 - Methods

Info

Publication number: WO2007083119A2
Application number: PCT/GB2007/000146
Authority: WO
Inventors: Stephan Anker; Stephen Von Haehling; Jochen Springer; Thomas Thum
Original assignee: Imperial Innovations Limited
Priority date: 2006-01-18
Filing date: 2007-01-18
Publication date: 2007-07-26
Also published as: GB0600967D0; JP2009523778A; AU2007206776A1; EP1973542A2; WO2007083119A3

Abstract

The use of at least one statin in the manufacture of a medicament for the prevention or treatment of cachexia in a patient, wherein the patient is human or a domestic or farm animal

Description

Methods

The present invention relates to the medical use of statins for the treatment of cachexia.

Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, were originally designed to lower plasma cholesterol levels. They have revolutionized the treatment of hypercholesterolaemia. These drugs are usually well tolerated and generally safe.

A number of different statin classifications have been suggested. In essence, statins are currently subdivided according to their chemical structure (open-ring vj. closed-ring structure), their origin (natural vs. synthetic), and their solubility (hydrophilic vs. lipophilic), as set out in Example 1. It is interesting to note that only compounds with an open-ring structure inhibit HMG-CoA reductase. Thus, closed-ring statins undergo metabolic changes that eventually yield an open-ring structure.

Natural statins, like mevastatin or lovastatin, are derived^' from fungal fermentation. Replacing the highly functionalized decalin ring of the fungal products with a variety of aromatic and heteroaromatic nuclei has yielded synthetic compounds, such as atorvastatin and fluvastatin. Lipophilic statins were originally thought to penetrate cell membranes more effectively than hydrophilic ones (Liao JK, J Clin Invest. 2002;l 10:285-288), however, the evidence suggests otherwise.

Effects beyond mere cholesterol reduction, the so-called pleiotropic effects, have recently received tremendous attention. These pleiotropic effects include improvement of endothelial dysfunction, release of endothelial progenitor cells, anti-inflammatory properties, and a number of anti-tumour activities.

Recent work on statins has largely focused on these pleiotropic effects. Promising results suggest beneficial effects in patients with multiple sclerosis (Sena et al, J Neurol 2003;250:754-755; Vollmer et al, Lancet 2004;363:1607-1608), Alzheimer's disease (Jick et al, Lancet 2000;356: 1627-1631), osteoporosis (Pasco et al Arch Intern Med 2002;162:537-540), age-related macular degeneration (with mixed results) (McGwin et al Br J Ophthalmol 2003 Sep;87:l 121-1125; Klein et al Arch Ophthalmol 2003;121:1151-1155). some types of cancer (Graaf et al Cancer Treat Rev. 2004 Nov;30(7):609-641), and heart failure (Horwich et al J Am Coll Cardiol. 2004;43: 642-648; Anker et al Circulation 2002; 106 Suppl 11:2535 (Abstract)).

Cachexia (unintentional weight loss) is a devastating disorder with a poor prognosis. It is seen as a consequence of many chronic diseases, including acquired immune deficiency syndrome (AIDS), liver cirrhosis, chronic obstructive pulmonary disease (COPD), chronic renal failure (ie chronic kidney disease), chronic infections including pneumonia, cancer (cancer cachexia), diabetes and heart disease including hypertension and chronic heart failure (CHF) (cardiac cachexia). Cachexia may also occur idiopathically. Cachexia is also associated with ageing, rheumatoid arthritis, diabetes, stroke, burns, trauma and other acute injury, sepsis, HIV/AIDS and other infections.

Although a final common pathway of all forms of cachexia has as yet not been established, it is thought that pro-inflammatory cytokines play a crucial role in. this sense. For example, TNF α, interleukin (IL) 1, and IL-6 are known to stimulate the ubiquitin-proteasome pathway in skeletal muscle (Zamir et al Arch Surg 1992;127:170-174; Zamir et al Metabolism 1993;42:204-208; Goodman, Proc Soc Exp Biol Med 1994;205 : 182-185). Among these substances, tumour necrosis factor-α (TNFα) has been considerably researched during the last several years. TNFα plays a considerable role in chronic heart failure and its progression to cardiac cachexia, as this cytokine is involved in endothelial dysfunction and left ventricular impairment (von Haehling et al Basic Res Cardiol 2004;99: 18-28). High plasma levels of TNFα and its soluble receptors TNFR-I and TNFR-2 predict a poor survival (Deswal et al Circulation 2001;103:2055-2059; Rauchhaus et al Circulation 2000 19; 102:3060-3067). Several studies have shown that statins may inhibit the production of such proinflammatory substances. Lovastatin, for example, was found to inhibit the induction of TNFa₅ IL-I₅ and IL-6 in certain rat cell lines (Pahan et al J Clin Invest 1997;100:2671-2679). In a study in 40 hypercholesterolaemic patients, pravastatin 40 mg once daily led to a significant reduction in TNFα plasma levels after eight weeks of treatment as compared to placebo (pravastatin 1.10, placebo 1.33 ρg/ml, ρ=0.032) (Solheim et al Atherosclerosis 2001,157:411-415). This effect was most pronounced in the subgroup of smokers. IL-6 plasma values were left unaffected. Another study found a significant decrease in TNFα release into the supernatant of phorbol myristate acetate (PMA) stimulated human monocytes after the addition of increasing doses of pravastatin as compared to PMA treated samples (p<0.01) (Grip et al Eur J Pharmacol 2000;410:83-92). Pravastatin had no effect on PMA induced IL-6 production. Data from large-scale clinical studies are currently not available.

Furthermore, C-reactive protein (CRP) levels are an independent predictor of future coronary events (Ridker et al N Engl J Med. 1997,336:973-979). Its plasma values are positively correlated with weight loss, the occurrence of cachexia, and recurrence in advanced cancer (Mahmoud and Rivera, Curr Oncol Rep 2002;4:250-255). Its role as a predictor of survival has been shown in multiple myeloma, melanoma, lymphoma, ovarian, renal, pancreatic, and gastrointestinal tumours (Mahmoud and Rivera, Curr Oncol Rep 2002;4:250-255). Recent studies suggest that CRP is much more than a mere marker of the body's inflammatory load. In cultured human umbilical vein endothelial cells, CRP was shown to activate endothelial cells, which, in turn, express Intracellular Adhesion Molecule- 1 (ICAM-I) (Pasceri et al Circulation. 2000;102:2165-2168). CRP also induces other adhesion molecules in endothelial cells such as vascular-cell adhesion molecule-1 (VCAM-I) and E-selectin. These molecules are involved in leukocyte- binding to the endothelial layer. CRP also activates the expression of monocyte chemotactic protein- 1 (MCP-I) (Pasceri et al Circulation. 2001; 103: 2531-2534). Several recent large-scale studies have shown that plasma CRP levels can be reduced with statin therapy. The Pravastatin Inflammation/CRP Evaluation (PRINCE) study demonstrated a significant CRP reduction in 1182 patients with a history of myocardial infarction, stroke, or arterial revascularisation procedure using pravastatin 40 mg once daily (Albert et al JAMA 2001;286:64-70). The reduction was 13,1% as compared to baseline. A re-analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy - Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) database found recently that both drugs reduce CRP levels within 30 days of initiation significantly among 3,745 patients with acute coronary syndromes (Ridker et al N Engl J Med 2005;352:20-28). Atorvastatin 80 mg once daily was more effective than pravastatin 40 mg once daily at 30 days (median CRP level: 1.6 vs. 2.3 mg/1, pO.001) and at four months (1.3 vs. 2.1 mg/1, p<0.001). It is interesting to note that the achieved CRP and LDL levels were independent of each other (Ridker et al N Engl J Med 2005;352:20-28).

Statins also appear to reduce the number of inflammatory cells in atherosclerotic plaques. This observation is in line with reports that showed a statin-mediated reduction in the number of adhesion sites on the cell surfaces of leukocytes. A study in isolated human monocytes recently found that both pravastatin and fluvastatin inhibited the expression of ICAM-I on these cells (Takahashi et al J Leukoc Biol 2005:77:400-407). In this study, the release of TNFα and interferon-γ (IFN-γ) was inhibited by both statins only in the presence of IL-18 (formerly known as IFN-γ-inducing factor). Another study described a statin-mediated reduction of the expression of a counterreceptor of ICAM-I on leukocytes (Weitz- Schmidt G et al Nat Med 2001; 7: 687 - 692). This down-regulation reduced their adhesion to endothelial cells (Weitz-Schmidt G et al Nat Med 2001; 7: 687 - 692). These results are consistent with reports in which simvastatin pretreatment inhibited Staphylococcus aureus-in&ac&ά leukocyte rolling and adherence in the rat mesenteric circulation as assessed using intravital microscopy (Pruefer et al Circulation 2002; 106:2104-2110). Leukocyte transmigration was also significantly decreased by such treatment. Some of these statin-mediated effects on immunological responses might be regulated by Rho proteins. These form a family of proteins that activate various kinases. Extracellular stimuli convert the inactive form of Rho (GDP -Rho) to its active form (GTP -Rho). In fact, efficient leukocyte extravasation requires Rho signaling not only within the migrating leukocytes but also within the endothelial lining of the vessel wall (Strey et al FEBS Lett 2002;517:261-266). Moreover, Rho mediates dynamic reorganization of cytoskeletal proteins, such as stress fibre and focal adhesion formation (Amano et al Exp Cell Res 2000;261:44-51). Thus, Rho is believed to play an important role in local inflammatory responses.

Endothelial dysfunction is frequently seen in cachectic patients. Statins have been shown to improve endothelial dysfunction by a number of mechanisms, to possess anti-inflammatory properties, and to have various anti-tumour effects (the latter applies mostly for lovastatin, which has been studied in greatest detail).

The so-called pleiotropic effects of statins appear independent of their cholesterol- lowering features. In fact, cholesterol reduction itself does not yield, for example, beneficial effects on endothelial function. Pleiotropic effects, however, appear to be dose-dependent, and it is likely that pleiotropic effects appear even without cholesterol reduction, i.e. at doses that are so low that no cholesterol reduction is seen. At present clinical studies to support this view are missing. Achieving pleiotropic effects without cholesterol reduction might be important, as a number of diseases do have better outcomes with high cholesterol levels (e.g. chronic heart failure, some types of cancer). Very low doses of statins may therefore exert pleiotropic effects without cholesterol reduction. In this sense, cholesterol reduction would merely be a side effect.

The only study in an animal model of cancer cachexia ended in disappointment (Muscaritoli et al Nutrition 2003;19:936-939). In essence, simvastatin (20 mg/kg per day) negatively affected the wasting pattern induced by Yoshida AH-130 ascites hepatoma in rats. The organ weights of liver, spleen, heart, gastrocnemius, and soleus decreased by four days of simvastatin treatment. The administration of simvastatin to control animals (without hepatoma) yielded no effects with the exception of a significant reduction in heart weight (controls without simvastatin: 501±58 mg, controls with simvastatin: 426±65 mg, p<0.05).

However, the effect of the statin on the rats was measured after only 4 days. This duration was not even able to affect cholesterol/triglyceride levels, although HDL levels were increased. Moreover, the amount of statin used in this study may not have been the correct quantity.

We have now determined that statin can be used to treat cachexia.

The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

A first aspect of the invention provides the use of at least one statin in the manufacture of a medicament for the prevention or treatment of cachexia in a patient, wherein the patient is human or a domestic or farm animal.

As shown in the accompanying examples, contrary to the finding of Muscaritoli et al supra we have determined that statin can be used to treat cachexia.

The term "patient" includes a human patient and also domestic animals such as cats and dogs, and farm animals such as cows, pigs, horses, sheep, goats and the like. The patient is not a rat. It is preferred that the patient is human.

The medicament of the first aspect of the invention may be used to treat a patient diagnosed with cachexia, and to treat a patient at risk of developing cachexia. Preferably the patient has been diagnosed as having cachexia.

Cachexia can be defined as a history of weight loss, for example >5% (preferably >6%) weight loss over a period of at least six months. However, in patients with cancer and aging at least 4% weight loss over three months can be used as a basis to diagnose cachexia. Cachexia can also be defined as a low body mass index, for example <20, <21, <21.5, <22 kg/m² over a period of time, for example six months.

Diagnosis can be made by asking the patient for their weight over the preceding months. Alternatively, the weight of an individual can be monitored over a period of time, for example six months.

The medicament may comprise an appropriate quantity of statin to treat cachexia. Existing dosage regimes for human patients are provided in the accompanying examples.

However, as discussed above, low amounts of statin may induce beneficial pleiotropic effects on the patient without substantially reducing cholesterol level.

Accordingly, an embodiment of this aspect of the invention is wherein the medicament is for administering an amount of statin that does not substantially reduce cholesterol level.

As discussed above, low amounts of statin may induce beneficial pleiotropic effects on the patient. These pleiotropic effects may be of benefit for the treatment of cachexia. Therefore the medicament may be for administering an amount of statin that induces pleiotropic effects on the patient. This amount of statin may also not substantially reduce cholesterol levels in a patient treated with the medicament.

By "pleiotropic effects" we include improvement of endothelial dysfunction, release of endothelial progenitor cells, anti-inflammatory properties, and a number of anti-tumour activities.

By "not substantially reduce cholesterol level" we include that the cholesterol level of a patient treated with the medicament is substantially similar to the cholesterol level of a patient who has not been treated with the medicament. We also include where the cholesterol level of a patient treated with the medicament is substantially similar to the cholesterol level of the same patient before administration of the medicament. We also include where the cholesterol levels of a population of patients treated with the medicament is substantially similar to the cholesterol levels of a population of patients who has not been treated with the medicament. In each of these cases, the medicament can be considered not to have substantially reduced cholesterol levels.

In each of the above cases, the cholesterol level is considered to be "substantially similar" if it is at least 90% of the reference cholesterol levels, preferably, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110% of those levels.

By "statin" we include atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, cerivastatin, mevastatin or pravastatin. Preferably the statin is simvastatin or atorvastatin.

Statins are well known compounds and may be obtained from a number of sources. For example, rosuvastatin (AstraZeneca); atorvastatin (Pfizer); simvastatin (Merck); fluvastatin (Novartis); pravastatin (Bristol-Myers Squibb); lovastatin (Merck), pitvastatin (Kowa).

It is preferred that the medicament comprises a daily unit dose of less than 5mg of rosuvastatin or simvastatin per day; or less than 10 mg of atorvastatin, lovastatin or pravastatin per day; or less than 20 mg of fluvastatin per day.

By "less than 5 mg" we include between 0.01 mg and 4.9 mg per day, for example less than or equal to 4.9, 4.8, 4.7, 4.6 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, 0.1, 0.05, 0.04, 0.03, 0.02 or 0.01 mg per day.

By "less than 10 mg" we include between 0.01 mg and 9.9 mg per day, for example less than or equal to 9.9, 9.8, 9.7, 9.6, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, 0.1, 0.05, 0.04, 0.03, 0.02 or 0.01 mg per day. By "less than 20 nig" between 0.01 mg and 19.9 nig per day, for example we include less than or equal to 19.9, 19.8, 19.7, 19.6, 19.5, 19, 18.5, 18, 17.5, 17, 16.5, 16, 15.5, 15, 14.5, 14, 13.5, 13, 12.5, 12, 11.5, 11, 10.5, 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, 0.1, 0.05, 0.04, 0.03, 0.02 or 0.01 mg per day.

The medicament may comprise a quantity of the statin equivalent to the daily unit dose. Alternatively, the medicament may comprise a slow release formulation of the statin having the property of releasing the daily unit dose.

As mentioned above, "cachexia" can occur in patients with a wide variety of diseases including infectious diseases such as acquired immune deficiency syndrome (AIDS), liver cirrhosis, chronic obstructive pulmonary disease (COPD), chronic renal failure, chronic infections including pneumonia, cancer (cancer cachexia), diabetes mellitus and heart disease including hypertension and chronic heart failure (CHF) (cardiac cachexia). Cachexia may also occur idiopathically. Cachexia is also associated with ageing, rheumatoid arthritis, diabetes, stroke, burns, trauma and other acute injury, sepsis, HIV/ AIDS and other infections.

Preferably, the cachexia is cancer cachexia, cardiac cachexia (for example cachexia due to CHF or cardiomyopathy) or chronic obstructive pulmonary disease (COPD) cachexia.

The cachexia may instead be, for example, cachexia associated with liver cirrhosis, chronic renal failure, rheumatoid arthritis, diabetes, stroke, burns, trauma or other acute injury, sepsis, HIV/ AIDS or other infections or ageing. Thus, the medicament (or method of treatment) may be for treating patients selected as above 60, 65, 70 or 75 years of age. Preferably, the statin used in this aspect of the invention has been prepared using the micro-crystallisation method disclosed in WO 03/103640 (herein incorporated by reference).

The procedure of micro crystallization (NanoCrystal Technology) can improve drug activity and final product characteristics. Poor water solubility (including simvastatin, atorvastatin, and lovastatin; fluvastatin and cerivastatin) correlates with slow dissolution rate, and decreasing particle size increases the surface area, which leads to an increase in dissolution rate. This can be accomplished using micro crystallization, because such particles are small particles of drug substance, typically less than 1000 nanometers (nm) in diameter, which are produced by milling the drug substance using a wet milling technique.

The micro crystallized particles of the drug are stabilized against agglomeration by surface adsorption of selected stabilizers. The result is an aqueous dispersion of the drug substance that behaves like a solution-a NanoCrystal colloidal dispersion, which can be processed into finished dosage forms for all routes of administration.

This has been shown to be particularly effective at enhancing oral bioavailability.

Any statin might be treated in such a way, however, the oral bioavailability of pravastatin and rosuvastatin (which are hydrophilic) appears to be less likely to benefit from such treatment. The lipophilic drugs cerivastatin and pravastatin have per se a high bioavailability (of approximately 60%) which could be enhanced by micro crystallization.

The statin will normally be administered orally or by any parenteral route, in the form of a pharmaceutical formulation comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the medicament may be administered at varying doses.

hi human therapy, the statin can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

For example, the statin can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled- release applications. The stain may also be administered via intracavernosal injection.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropyhnethylcellulose (HPMC), hydroxy-propylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the statin may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

The statin can also be administered parenterally, for example, intravenously, intra- arterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intra-muscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished ^■ by standard pharmaceutical techniques well-known to those skilled in the art.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

The statin can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant., e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoro-ethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A3 or 1,1,1,2,3,3,3-heptafluoroρropane (HFA 227EA3), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a statin and a suitable powder base such as lactose or starch.

Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff contains precise quantity of statin for delivery to the patient. It will be appreciated that he overall daily dose with an aerosol will vary from patient to patient, and may be administered in a single dose or, more usually, in divided- doses throughout the day.

Alternatively, the statin can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. The statin may also be transdermally administered, for example, by the use of a skin patch. They may also be administered by the ocular route, particularly for treating diseases of the eye.

For ophthalmic use, the statin can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

For application topically to the skin, the statin can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia," and mouth-washes comprising the active ingredient in a suitable liquid carrier.

Generally, in humans, oral or topical administration of the statin is the preferred route, being the most convenient. In circumstances where the recipient suffers from a swallowing disorder or from impairment of drug absorption after oral administration, the drug may be administered parenterally, e.g. sublingually or buccally.

For oral and parenteral administration to human patients, the daily dosage level of statin are provided above.

The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.

As mentioned above, the medicament can be used for the prevention or treatment of cachexia. Existing treatment for this disorder include the following therapeutic agents: growth hormone, anabolic steroids, and appetite stimulants for some subgroups of cachexia.

In a further embodiment of the invention the medicament comprises one or more of such therapeutic agents for preventing or treating cachexia.

A further aspect of the invention provide a method of treating a patient with or at risk of developing cachexia comprising administering an appropriate quantity of at least one statin, wherein the patient is human or a domestic or farm animal. Preferably the patient is human.

An embodiment of this aspect of the invention is wherein the patient is administered an amount of statin that does not substantially reduce cholesterol level.

An embodiment of this aspect of the invention is wherein the statin is atorvastatin, fmvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, cerivastatin, mevastatin or pitavastatin. Preferably the statin is simvastatin or atorvastatin. An embodiment of this aspect of the invention is wherein the method uses a quantity of the statin equivalent to a daily unit dose.

An embodiment of this aspect of the invention is wherein the method uses a slow release formulation of the statin having the property of releasing a daily unit dose.

An embodiment of this aspect of the invention is wherein the statin has been prepared using micro-crystallisation.

An embodiment of this aspect of the invention is wherein the method further comprises using one or more further therapeutic agents for preventing or treating cachexia.

An embodiment of this aspect of the invention is wherein the cachexia is cancer cachexia, cardiac cachexia or chronic obstructive pulmonary disease (COPD) cachexia.

The medicament or method is considered to be useful in assisting weight gain. Example 2 shows a higher likelihood of experiencing weight gain (assessed as weight gain of more than 5%) for patients treated with statins. Example 3 also shows a positive trend for low dose statin on body weight.

The medicament or method is considered to be useful in assisting increase in lean tissue or skeletal muscle mass. Example 3 shows a positive trend for low dose statin on lean tissue and skeletal muscle mass.

An example (NMR scans) of how lean tissue mass can be measured is described in Example 3.

Muscle mass can be measured in humans in several ways, as will be well known to the person skilled in the art, for example: - antropometry (using calipers to assess skin fold thickness and then estimate muscle mass)

- DEXA scanning (dual X-ray absorptiometry, as described in, for example Anker et al (1999) 20, 683-693). DEXA is the method most often used in cachexia research projects

- CT scanning (for example as described in Anker et al (1997) Eur Heart J 18(2), 259-69)

- MRI scanning.

The skeletal muscle mass increase may be relative to the starting point of muscle mass in the patient or as the proportion of the patient's body mass. From a muscle mass and strength point of view either is desirable. Preferably after treatment there is more muscle than before: whether this is accompanied by an increase in body weight or not is of lesser importance for muscle anabolic interventions. It is preferable that muscle increases without loss of fat, i.e. that muscle gain leads to overall weight gain.

AU documents referred to herein are hereby incorporated by reference.

The invention will now be described by reference to the following, non-limiting Examples and Figures.

Figure 1. Chemical structures of various statins. Mevastatin is not in clinical use, but it is largely used in in vitro studies. Pravastatin is currently approved in Japan only.

Figure 2: Pathway of cholesterol biosynthesis. Statins block the rate-limiting step in the cascade by inhibition of HMG-CoA reductase. The inhibition can be overcome by addition of mevalonate in experimental models. CoA - coenzyme A, HMG- 3-hydroxy-3-methylglutaryl, PP - pyrophosphate. Figure 3: Overview of the principal pleiotropic effects of statins on (A) the endothelium, (B) the immune system, and (C) tumour development and metastasis. Several statins have been shown to improve endothelial function by increasing nitric oxide (NO) production and release. Statins also increase the number of endothelial progenitor cells in the bloodstream. Production of proinflammatory mediators (e.g. TNF-a, IL-I, IL-6) and adhesion molecule expression (e.g. ICAM-I) are all reduced with statin treatment in experimental models. The release of C-reactive protein (CRP) has been proven in several clinical settings. Anti-tumour activities of statins comprise the induction of apoptosis, growth arrest by inhibiting the cell cycle of malignant cells, and the reduction of the invasiveness of malignant cells at secondary sites.

Example 1: Characteristics of statins

The following table includes information on the characteristics of statins that may be used in the invention.

TABLEl:

O

to

O

* The 80 mg dose of fluvastatin is available as an extended release formulation only.

** C_max may vary according to the administered dose and the patient population investigated. to

Example 2: Use of statins for the treatment of cachexia

In an analysis of the ELITE 2 trial database (Pitt et al., (2000) Lancet 355, 1582- 1587), we found that in patients with heart failure who also have COPD statins are associated with a higher likelihood of experiencing weight gain >5% independently of tables below.

The statins used in the ELITE 2 trial were:

- atorvastatin , n=79, 10-40 mg/d (10 unknown)

- cerivastatin , n=12 , 0.2-0.3 mg/d (1 unknown)

- fluva , n=43 , 20-80 mg/d (6 unknown)

- prava , n=141, 1-80 mg/d (16 unknown)

- simva , n=300 , 5-80 mg/d (27 unknown) - lova, n=51 , 10-60 mg/d (3 unknown)

This data is presented in the following tables.

RESULTS: ELITE 2 study. Cox Proportional Hazard Analysis of the impact of being on statin at baseline (BL) on the subsequent development of weight gain >5%. The impact is highly significant (p<0.0001) and independent of the severity of heart failure as measured by LVEF, NYHA class, clinical oedema status, degree of kidney dysfunction (i.e. creatinine [crea] levels) and heart failure aetiology. In 3030 patients all information for this analysis was available.

Table 2

Model Coefficients for FU days gain 5%. Censor Variable: gain 5% y=0/no=l. Model: Proportional Hazards. Row exclusion: ELITE2 ll-05B-w-change-080805.

Below is a survival summary table for Table 2.

Censor Variable: gain 5% y=0/no=l. Model: Proportional Hazards. Row exclusion: ELITE2 11- 05B-w-change-080805.

Below are the individual hazard ratios and their 95% confidence interval related to the analysis in Table 2

Confidence Intervals for FU days gain 5%. Censor Variable: gain 5% y=0/no=l. Model: Proportional Hazards. Row exclusion: ELITE2 l l-05B-w-change-080805.

RESULTS AND CONCLUSIONS: ELITE 2 study - the subgroup of patients with a diagnosis of chronic obstructive pulmonary disease (COPD).

Cox Proportional Hazard Analysis of the impact of being on statin at baseline on the subsequent development of weight gain >5%. The analysis below in Table 3 shows an important trend for a 33.4% increase in the occurrence of >5% weight- gain when a patient was on a statin.

These results are independent of the severity of heart failure as measured by LVEF, NYHA class, clinical oedema status, and the degree of kidney dysfunction (i.e. creatinine [crea] levels). This analysis was performed on 259 patients with COPD and in 60 patients a weight gain >5% event occurred.

Importantly this analysis shows a) that good cardiac function (e.g. high LVEF) was not related to experiencing weight gain. In fact per % increase in LVEF a 2.1% decrease in the frequency of >5% weight gain was observed, and

B) that statin therapy was associated with weight gain only in patients with COPD (33.4% increase in the event rate of weight gain), unlike the general population of the ELITE 2 trial in which the occurrence of weight gain due to statin therapy was 17% reduced (see Table 2).

Table 3

Model coefficients for FU days gain 5%. Censor Variable: gain 5% y=0/no=l . Model: Proportional Hazards. Row exclusion: ELITE2 ll-05B-w-ch-COPD-090805.

Below are the individual hazard ratios and their 95% confidence interval related to the analysis in

Table 3

Confidence Intervals for FU days gain 5%. Censor Variable: gain 5% y=0/no=l. Model: Proportional Hazards. Row exclusion: ELITE2 ll-05B-w-ch-COPD-090805. Example 3: Effect of Simvastatin in Cancer Cachexia

1) Material and methods Animal model The ascites hepatoma Yoshida AH-130 cells (10⁸) were inoculated into 200 g male Wistar rats. The animals are housed in groups of three. The day after inoculation animals are randomized into various groups. The rats then receive treatment with simvastatin in 4 doses: O.lmg, l.Omg, 10 mg and 20 mg vs placebo. The primary endpoints of the study include assessment of body weight, body composition and survival. Organ weight is assessed at the end of the study (or after death) as a secondary endpoint. The animals were killed 14 days after tumour inoculation.

Time line

Day -2/-l Locomotor activity

Day 0: NMR (Body composition), Echocardiography

Day 1 : Tumor-inoculation

Day 2: Randomisation, start therapy

Day 3 : NMR (Body composition) Day 6: NMR (Body composition)

Day 9: NMR (Body composition)

Day 10/11 : Locomotor activity

Day 12: NMR (Body composition), Echocardiography

Day 15: NMR (Body composition), end of therapy, sacrifice, storage of tissue and plasma

Analysis, primary endpoints

Survival

The animals were seen at least twice per day to ensure precise survival data.

Body Weight Body weight was monitored every two days throughout the entire study period.

Analysis, secondary endpoints

Body Composition Body composition was measured the day before tumour inoculation and in two day intervals after that until the end of the study using NMR-scans (EchoMRI systems). Read-out is fat, lean mass, total water and free water. Locomotor Activity Assessed using Supermex system over a period of 24 hours in cages where the animals are placed individually (type 3 cage).

Heart function / echocardiography

Echocardiography was performed in all animals on day 0 and on day 12 using a high resolution echocardiography system (Vevo770, Visual Sonics) to determine the following parameters:

LVEF (left ventricular ejection fraction)

LVFS (left ventricular fractional shortening) LVEDD and LVESD (left ventricular end-diasolic and end-systolic diameters) septum and inferior wall thickness (M-Mode) rVSd and IVSs (thickness of the inter- ventricular septum in diastole and systole) diastolic filling (E-wave)

Stroke Volume Organ weights

The weight of the heart, skeletal muscle (gastrocnemius, soleus, EDL, tibialis) and liver was assessed whether at the end of the study or post-mortem.

2) Results

Survival

Neutral results were observed in the survival analysis. Very few events occurred during the 14-day study period indicating that the model may have been shorter than optimal and no statistical test could be applied.

Events: ^l Plac l of lO

O.lmg l of l l l.Omg O of 11 lOmg 1 of 15

20mg O of 14

Heart function Heart function was assessed by high resolution echocardiography using the Vevo 770 system (Visualsonics, Toronto, Canada). The left ventricular (LV) ejection fraction, LV fractional shortening, LV end-diastolic diameter, LV end-systolic diameter, LV posterior wall thickness in diastole and systole, thickness of the inter-ventricular septum in diastole and systole, the LV stroke volume and the diastolic function (E/ A) were assessed. The results showed neutral results for all parameter assessed (ANOVA, all p>0.4).

Body weight

The ANOVA did not show a significant difference between the treatment groups. However, a trend was observed in body weight (without tumour) for O.lmg simvastatin (mean + 8.1% vs placebo; p=0.23)

Fat and lean tissue mass (NMR assessment)

Fat mass did not show any significant difference between the simvastatin groups and the placebo group. The ANOVA for lean mass was also not significant, but a trend was seen for the O.lmg simvastatin group (mean +8.2% vs placebo, p=0.26).

Organ weight

While the weights of the liver, brown fat as well as white fat did not shown any differences, the skeletal muscle mass of important leg muscles of the O.lmg simvastatin group showed a positive trend vs placebo (Musculus gastrocnemius mean +16%; ρ=0.18; Musculus tibialis mean +10.7%; ρ=0.083).

Tumour size (total cell number) The cell number showed a trend in the ANOVA analysis (p=0.18) and the cell number was lower in the l.Omg simvastatin group vs placebo (mean -19.3%; ρ=0.091). Table 4: Results - parameters other than heart function

Table 5: heart function results

3) Summary In summary, only the low dose simvastatin showed positive trends, while the high ^{■ •} dose has detrimental effects on the animals in this cancer cachexia model.

Claims

1. The use of at least one statin in the manufacture of a medicament for the prevention or treatment of cachexia in a patient, wherein the patient is human or a domestic or farm animal.

2. The use of claim 1 wherein the patient is human.

3. The use of claim 1 or 2 wherein the medicament is for administering an amount of statin that does not substantially reduce cholesterol level.

4. The use of any of the previous claims wherein the statin is atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, cerivastatin, mevastatin or pravastatin.

5. The use of claim 4 wherein the statin is simvastatin or atorvastatin.

6. The use of any of the previous claims wherein the medicament comprises a quantity of the statin equivalent to a daily unit dose.

7. The use of any of the previous claims wherein the medicament a slow release formulation of the statin having the property of releasing a daily unit dose.

8. The use of any of the previous claims wherein the statin has been prepared using micro-crystallisation.

9. The use of any one of the previous claims wherein the medicament further comprises one or more further therapeutic agents for preventing or treating cachexia.

10. The use of any one of the previous claims wherein the cachexia is cancer cachexia, cardiac cachexia (for example cachexia due to CHF or cardiomyopathy), chronic obstructive pulmonary disease (COPD) cachexia, or cachexia associated with liver cirrhosis, chronic renal failure, rheumatoid arthritis, diabetes, stroke, burns, trauma or other acute injury, sepsis, HIV/ AIDS or other infections or ageing.

11. The use of any one of the preceding claims wherein the medicament is for treating patients selected as above 60, 65, 70 or 15 years, of age.

12. A method of treating a patient with or at risk of developing cachexia comprising administering an appropriate quantity of at least one statin, wherein the patient is human or a domestic or farm animal.

13. The use of any one of claims 1 to 11 or method of claim 12 wherein the medicament or method is for assisting weight gain.

14. The use of any one of claims 1 to 11 or 13 or method of claim 12 or 13 wherein the medicament or method is for assisting increase in lean tissue or skeletal muscle mass.