WO2001078764A1 - Treatment of hypertrophic cardiomyopathy with a substance that increases the level of growth hormone receptor antagonists - Google Patents

Abstract

Use of a substance that upon administration to a patient leads to an increased level of a growth hormone receptor antagonist, and in particular use of a growth hormone receptor antagonist, for the production of a pharmaceutical composition for treatment of hypertrophic cardiomyopathy is disclosed. A method for treatment of hypertrophic cardiomyopathy, wherein a pharmaceutically effective amount of the above mentioned substance is administered to a patient is also disclosed.

Description

TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY WITH A SUBSTANCE THAT INCREASES THE LEVEL OF GROWTH HORMONE RECEPTOR

ANTAGONISTS

Background of the invention Hypertrophic cardiomyopathy (HCM) is a cardiac disease characterised by a pronounced left ventricular (LV) wall thickening and a small LV cavity. Usually, the wall thickening is asymmetric and predominantly affects the interventricular septum. A consequence of the LV hypertrophy is a sometimes occurring LV outflow obstruction and abnormal systolic anterior motion of the mitral valve. This often leads to mitral regurgitation. Similar processes can occur, although less frequently, on the right side of the heart as well as on both sides of the heart. The clinical features include syncope and palpitations from a variety of arrhythmias, which in severe cases may lead to sudden death. Angina can develop with- out coronary artery disease. Because of the thickened myocardium an inflow obstruction can develop and lead to heart failure from a raised filling pressure. At a later stage of the disease an enlarged heart may present and there is a risk of systemic embolism. HCM is inherited as an autosomal dominant diseases although it is considered that sporadic occurrence account for the majority of cases. Recent investigations indicate that HCM is considerably widespread in the population (1:500) (Schulte et al . , Z Kardiol 1999; 88:163- 172) . So far, no consensus has been reached regarding treatment of HCM due to the heterogeneity of ethiology and progress of symptoms (Frank & Braunwald, Circulation 1968; 37:759-788, Goodwin, Lancet 1970; 1:731-739, Wigle et al . , Prog Cardiovasc Dis 1985; 28:1-83, Maron et al . , N Engl J Med 1987; 316:780-789 and 844-852). The generally accepted treatment options currently available to clinicians include drugs such as beta-blockers, verapamil and disopyramid or surgery for the management of congestive symptoms and the implantable cardioverter- defibrilitator or amiodarone for those patients judged to be at high risk for sudden death (Spirito & Maron J. Am Coll Cardiol 1999; 33:1071-1075).

Although the exact underlying mechanisms for HCM remain obscure, microscopically it has been observed that the muscle fibres are thickened and appear to be arranged haphazardly, although the pattern is unspecific. It has been reported that expression of insulin-like growth factor I (IGF-I) is increased in cardiac tissue from patients with HCM and this has been suggested to contribute to development of hypertrophy (Li et al . , Circulation 1997; 96:874-881, Li et al . , Circulation 1998; 98(19 suppl) : 11144-149) . This concept is supported by experimental studies, which have demonstrated that addition of IGF-I to cultured neonatal cardiomyocytes results in hypertrophy (Ito et al . , Circulation 1993; 87:1715-1721).

In the studies by Li and collaborators it is assumed that the mechanism for the increased IGF-I production in heart is unknown or related to hemodynamic load rather than being GH dependent .

Summary of the invention The inventors have found that development of cardio- myocyte hypertrophy in HCM appears to be at least in part dependent on the synthesis of IGF-I and that locally produced IGF-I may be in part dependent on circulating GH, and thus that HCM may be treated with growth hormone re- ceptor (GH-R) antagonistic compounds.

The invention thus relates to the use of a substance that upon administration to a patient leads to an increased level of a growth hormone receptor antagonist in treatment of hypertrophic cardiomyopathy. More precisely the invention relates to the use of a substance that upon administration to a patient leads to an increased level of a growth hormone receptor antago- nist for the production of a pharmaceutical composition for treatment of hypertrophic cardiomyopathy (HCM) . The invention also relates to a method for treatment of HCM, wherein a pharmaceutically active amount of a substance that upon administration leads to an increased level of a growth hormone receptor antagonist is administered to a patient .

Detailed description of the invention As stated above the invention relates to the use of a substance that upon administration to a patient leads to an increased level of a growth hormone receptor antagonist treatment of treatment of hypertrophic cardiomyopathy (HCM) . The term "patient", as it is used herein, relates to any human or non-human mammal in need of treatment according to the invention.

The term "treatment" used herein relates to both treatment in order to cure or alleviate a disease or a condition, and to treatment in order to prevent the development of a disease or a condition. The treatment may either be performed in an acute or in a chronic way.

The substance according to the invention may be a substance that indirectly leads to an increased level of a growth hormone receptor antagonist by activation of an endogenous growth hormone receptor antagonist . The substance according to the invention may also be a growth hormone receptor antagonist .

When the substance used according to the invention is a growth hormone receptor (GH-R) antagonist, it may be any substance that prevents dimerisation of the growth hormone receptor, GH-R (or the somatotropin receptor) , and thus the signalling of the GH-R. The antagonist used may either be a naturally occurring substance, or a syn- thetically produced substance, such as a mimetic of a natural GH-R antagonist. One example of a suitable GH-R antagonist for use according to the invention is a recently described and tested new modified GH compound which is a GH receptor antagonist developed for treatment of acromegaly (Thorner et al., J Clin Endocrinol Metab 1999; 84:2098-2103). This new GH-R antagonist B2036-PEG, available under the commercial name Pegvisomant, is based on an analogue of GH that is PEG-modified to prolong its action. Due to specific mutations, binding properties are altered and GH-R dimerisation and signalling are prevented. This GH-R antagonist is a polypeptide analog of GH of recombinant DNA origin with nine mutations. These mutations change the binding properties of the GH-R with this GH analog at site 1, where affinity is increased and at site 2 where binding is abolished. As a result, receptor dimerisation is prevented and GH action inhibited. In addition, the PEG modification of the molecule lengthens the biological half-life of the compound and reduces the risk of antibody formation. Consequently, circulating levels of IGF-I have been shown to decrease in acromegalic patients after administration of this GH-R antagonist. Acromegaly is a well known disease that is characterised by high levels of IGF-I in blood and multiple tissues due to a GH producing tumour in the pituitary. It is however a disease completely different from HCM.

The pharmaceutical composition produced according to the invention or used according to the invention may also comprise other substances, such as an inert vehicle, or pharmaceutical acceptable adjuvants, carriers, preserva- tives etc., which are well known to persons skilled in the art .

As stated above, the invention also relates to a method for treatment of hypertrophic cardiomyopathy. In this method a pharmaceutically effective amount of a sub- stance as described above is administered to a patient. The expression "pharmaceutically effective amount" relates to an amount that will have the desired effect, i.e. to increase the level of a growth hormone receptor antagonist, which e.g. may result in the prevention of dimerisation of the GH receptor in an extent such that the signalling of the GH-R is substantially or completely prevented.

The substance or pharmaceutical composition according to the invention is administered once or repeatedly until a sustained improvement of the patient's condition is observed. The pharmaceutical composition according to the invention may also comprise other substances, such as an inert vehicle, or pharmaceutical acceptable adjuvants, carriers, preservatives etc., which are well known to persons skilled in the art. The compounds or compositions of the invention can be administered in a variety of dosage forms, e.g., orally (per os) , in the form of tablets, capsules, sugar or film coated tablets, liquid solutions; rectally, in the form of suppositories; parenterally, e.g., intramus- cularly (i.m.), subcutaneous (s.c), intracerebroven- tricular (i.c.v.), intrathecal (i.t.), epidurally, tran- sepidermally or by intravenous (i.v.) injection or infusion; by inhalation; or intranasally.

A preferred administration route is by subcutaneous injection. A suitable dosage may then be 1-100 mg, preferably 5-50 mg and more preferably 10-20 mg.

The therapeutic regimen may be adapted to the medical history of the patient as would be know to the skilled artisan or clinician. Factors to be considered are, but not limited to, the route of administration, the form in which the compound is administered, the age, weight, sex, and condition of the subject involved.

Preferably, the oral route is employed. In emergency cases, preference is sometimes given to intravenous in- jection.

The nature of the pharmaceutical composition containing the compounds of the invention in association with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired route of administration. The composition may be formulated in the conventional manner with the usual ingredients. For example, the compounds of the invention may be administered in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatin capsules (hard or soft ones) , syrups, drops or suppositories.

For oral administration, the pharmaceutical composi- tions containing the compounds of the invention are preferably tablets, pills or gelatine capsules, which contain the active substance or substances together with diluents, such as lactose, dextrose, sucrose, mannitol, sor- bitol, cellulose; lubricants, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatine, methyl cellulose, carboxymethylcellu- lose, gum arabic, tragacanth, polyvinylpyrrolidone; disaggregating agents such as starches, alginic acid, algi- nates, sodium starch glycolate, microcrystalline cellulose; effervescing agents, such a carbonates and acids; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates ; and in general non-toxic and pharmaceutically inert substances used in the formu- lation of pharmaceutical compositions. Said pharmaceutical compositions may be manufactured in known manners, e.g., by means of mixing, granulating, tableting, sugar- coating or film-coating processes. Film providing compounds can be selected to provide release in the right place or at the appropriate time in the intestinal tract with regard to absorption and maximum effect. Thus pH- dependent film formers can be used to allow absorption in the intestines as such, whereby different phthalates are normally used or acrylic acid/methacrylic acid deriva- tives and polymers.

The liquid dispersions for oral administration may be, e.g., syrups, emulsions, and suspensions. The syrups may contain as carrier, e.g., saccharose, or saccharose with glycerine and/or mannitol and/or sor- bitol .

Suspensions and emulsions may contain as Garner, e.g., a natural gum, such as gum arabic, xanthan gum, agar, sodium alginate, pectin, methyl cellulose, car- boxymethylcellulose, polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain together with the active compound, a pharmaceutically acceptable carrier, such as e.g., sterile water, olive oil (or other vegetable or nut derived oil), ethyl oleate, glycols", e.g., propylene glycol , and if so desired, a suitable amount of lidocaine hydrochlo- ride. Adjuvants for triggering the injection effect can be added as well .

The solutions for intravenous injection or infusion may contain as carrier, e.g., sterile water, or preferably, a sterile isotonic saline solution, as well as adjuvants used in the field of injection of active compounds. Such solutions would also be suitable for i.m. and i.e.v. injection.

Example When B2036-PEG is administered as subcutaneous injections in a pharmaceutically effective amount (10-20 mg) to patients with HCM, there is a significant decrease in serum and cardiac IGF-I expression.

Claims

1. Use of a substance that upon administration to a patient leads to an increased level of a growth hormone receptor antagonist for the production of a pharmaceutical composition for treatment of hypertrophic cardiomyopathy.

2. Use according to claim 1, wherein said substance is a growth hormone receptor antagonist .

3. Use according to claim 2, wherein said growth hormone receptor antagonist is B2036-PEG.

4. A method for treatment of hypertrophic cardiomyopathy, wherein a pharmaceutically effective amount of a substance that upon administration to an increased level of a growth hormone receptor antagonist administered to a patient .

5. A method according to claim 4, wherein said substance is a growth hormone receptor antagonist.

6. A method according to claim 5, wherein said growth hormone receptor antagonist is B2036-PEG.