Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1996-12-30
2001-01-16
Romeo, David (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S108000, C514S808000, C514S874000, C530S307000, C530S303000, C930S120000
Reexamination Certificate
active
06174857
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns a method for the treatment of patients having osteoporosis in which such patients exhibit decreased bone mineral density and patients substantially at risk of developing such decreased bone mineral density through the administration of insulin-like growth factor I (IGF-I) and pharmaceutical compositions therefor.
BACKGROUND OF THE INVENTION
Osteoporosis encompasses a broad range of clinical syndromes having varving etiologies. In postmenopausal women, for example, two distinct types of osteoporosis have been identified. Type I osteoporosis occurs mainly in the early postmenopausal period from about age 50-65. It is characterized by excessive resorption, primarily in trabecular bone. Vertebral fractures are common and if given prior to significant bone loss, treatment which decreases or prevents bone resorption (such as estrogen or calcitonin) is considered effective therapy.
Type II osteoporosis (a.k.a. senile osteoporosis) occurs essentially in all aging women and, to a lesser extent, in men. It is characterized by proportionate loss of cortical and trabecular bone. Here decreased bone formation plays a major role, if not a more important role than increased bone resorption. Fractures of the hip are characteristic of this type.
Currently approved therapeutic agents for osteoporosis are antiresorptives. As such, they are not as effective in patients with established osteoporosis of either type (decreased bone density with fractures of the vertebrae and/or hip), or in patients with Type II osteoporosis. In addition, the most accepted preventive agent for osteoporosis currently in use is estrogen therapy, which is not really an acceptable therapeutic agent for women with a history of breast cancer or endometrial cancer or for men with osteoporosis.
Insulin-like Growth Factor I (IGF-I) is a 70 amino acid peptide belonging to a family of compounds under the class name somatomedins and retains structural and biological similarities to insulin. The somatomedins activity lie on a spectrum from hypoglycemic effects similar to insulin to growth promoting effects which are exemplified by growth hormone. IGF-I predominantly induces growth and cell proliferation. IGF-I has also been demonstrated to specifically bind to receptors on rat osteoblast-like bone cells (Bennett et al, Endocrin. 115 (4): 1577-1583, 1984). IGF-I is routinely fabricated in the liver and released for binding to carrier proteins in the plasma (Schwander et al, Endocrin. 113 (1):297-305, 1983), which bound form is inactive. In addition, there is a biofeedback regulating loop involving the somatomedins and growth hormone such that higher somatomedin concentrations inhibit growth hormone release which results in lesser production of endogenous IGF-I.
IGF-I infused into rats has been shown to result in markedly greater increases in body weight gain compared to controls, with increases in tibial epiphyseal width and thymidine incorporation into costal cartilage (Nature 107: 16-24, 1984) and directly stimulate osteoblasts to result in a greater number of functional osteoblasts. IGF-I is also mentioned as the vehicle through which growth horrnone's effects on bone is mediated in Simpson, Growth Factors Which Affect Bone, Physiol. 235, TIBS, 12/84.
Nevertheless, it is important to note that the foregoing pre-clinical studies were conducted with fetal or newborn rat cells. It is highly likely that such “young” cells are more responsive to IGF-I (as well as other influences) than older cells, especially those in the elderly with established osteoporosis or those with drug or environmentally induced defects leading to reduced bone density.
Surprisingly, IGF-I has now been found to be useful in the treatment of osteoporosis in mammals exhibiting decreased bone mineral density and those exposed to drugs or environmental conditions which tend to result in bone density reduction and potentially to an osteoporosis condition.
Accordingly, an object of the present invention is to provide a method of treatment of osteoporosis in mammals exhibiting decreased bone mineral density and preventing osteoporosis due to bone mineral density reduction in patients who are clinically prone to such bone mineral density reductions.
Another object of the invention is to provide pharmaceutical compositions useful in achieving the foregoing object.
SUMMARY OF THE INVENTION
The present invention is directed to a method for, and composition useful in, the treatment of osteoporosis in patients demonstrating bone mineral density reductions and preventing such osteoporosis in patients prone thereto by administering to a patient having such osteoporosis or prone thereto an effective amount of IGF-I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention concerns osteoporosis treatment and prevention, which osteoporosis is associated with decreased bone mineral density in mammals generally, but is especially suited for the treatment and prevention of such osteoporosis in humans.
IGF-I is a naturally occurring protein and can be obtained from a number of sources. Preferably, IGF-I from the same species, (or its synthetic twin) as is being treated therewith is employed but IGF-I from one species may be used to treat another species if the immune response elicited is slight or nonexistent. In addition, fragments of IGF-I having IGF-I activity, particularly IGF-I antiosteoporosis activity, are also suitably employed and unless the context of the disclosure clearly indicates otherwise, IGF-I as used herein is intended to include such active fragments. Where weights of IGF-I are presented, that weight of IGF-I and an approximately equipotent amount of active fragments is intended unless the text explicitly states otherwise. Where no type of IGF-1 is indicated, reference is to human −IGF-1 (meaning the structure, not the species source), unless the reasonable reading of the text indicates otherwise.
IGF-I can be synthetically produced, chemically or by recombinant techniques, although recombinant preparation is preferred. One such recombinant technique is disclosed in EP 123,228, incorporated herein by reference.
An effective amount of IGF-I is an amount sufficient to slow, stop, or reverse the bone mineral density reduction rate in a patient exhibiting bone mineral density reduction. In the Normal healthy 20-25 year old population bone mineral density in the spine (using dual photon densitometry) typically is in the range of 0.85 to 1.9 g/cm, usually 0.9 to 1.85 and most often 1.0 to 1.8; and in the mid radius and distal radius it is typically 0.7-1.4, usually 0.75-1.3, and most often 0.8-1.2 g/cm
2
. Exemplary non-limiting normal ranges are shown in the Figures along with osteoporosis distributions. Norms using other techniques will be apparent from the literature and general experience therewith as experience with such techniques grow. Of course, it is to be remembered that different sub-populations have different norms in bone mineral density. For example Caucasian women typically differ in this parameter from Caucasian men as well as from black women, oriental women and women of other racial types. It is also important to remember that the current invention is directed to treating those with bone mineral density which is (a) totally below either the normal bone mineral density range for the population generally or for the patient sub-population or (b) below 1.0 g/cm
3
or (c) below the fracture threshold (approximately 2 standard deviations below the mean bone mass for the population at age 35). The fracture threshold for the spine for example is defined as the bone mineral value below which 90% of all patients with one or more compression fractures of the spine are found (See Mayo Clin. Proc., Dec. 1985, Vol 60, p. 829-830). In addition, anyone who demonstrated a statistically significant reduction in bone density over a previous measurement, regardless of where that patient is in the typical ranges above, is a patient to whom the present invention treatment is directed. Statistical signif
Ferraro Gregory D.
Novartis Corporation
Romeo David
LandOfFree
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