Pharmaceutical combination of everolimus with dactolisib

Abstract

The present invention relates to a combination comprising (a) RAD001, or a pharmaceutically acceptable salt thereof, and (b) BEZ235, or pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential use for enhancement of an immune response; a pharmaceutical composition comprising such combination; a method of enhancing immune response in a subject comprising administration of said combination to a subject in need thereof; use of such combination for preparation of a medicament for the enhancement of an immune response; and a commercial package thereto.

1 . A combination comprising (a) RAD001 or a pharmaceutically acceptable salt thereof, and (b) BEZ235, or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential use for the enhancement or promotion of an immune response in a subject. 
     
     
         2 . The combination of  claim 1 , wherein RAD001 is in the neutral form. 
     
     
         3 . The combination of  claim 1 , wherein BEZ235 is the monotosylate salt. 
     
     
         4 . The combination of  claim 1 , comprising about 0.01-0.2 mg of RAD001. 
     
     
         5 . The combination of  claim 1 , comprising about 1-20 mg of BEZ235. 
     
     
         6 . The combination of  claim 1 , wherein the subject is immunocompromised. 
     
     
         7 . The combination of  claim 1 , wherein the subject has an impaired immune response. 
     
     
         8 . The combination of  claim 1 , wherein the subject is immunoscenescent. 
     
     
         9 . The combination of  claim 1 , comprising treating the subject for an age related condition. 
     
     
         10 . The combination of  claim 9 , wherein the age related condition is selected from the group consisting of immunosenescence, sarcopenia, muscle wasting, tendon stiffness, tendon injury, tendonitis, Achilles rupture, adhesive capsulitis of shoulder, plantar fasciitis, polymyalgia rheumatica, rotator cuff tear, spinal stenosis, tennis elbow, dupuytren's contractures, restless leg syndrome, osteoporosis, osteoarthritis, rheumatoid arthritis, autoimmune disease, polymyositis, gout, dementia, Huntington's disease, Alzheimer's disease, brain atrophy, aging-related mobility disability (e.g., frailty), cognitive decline, age related dementia, memory impairment, Lewy body dementia, frontotemporal dementia, Parkinson's disease, mild cognitive impairment, vascular dementia, stroke, transient ischemic attack, trigeminal neuralgia, neuropathy, sleep disorders, insomnia, atherosclerosis, arteriosclerosis, hypertension, heart dysfunction such as cardiac hypertrophy, systolic dysfunction, or diastolic dysfunction, heart failure, dilated cardiomyopathy, heart failure with preserved ejection fraction, arrhythmias, valvular heart disease, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease exacerbations, pulmonary emphysema, idiopathic pulmonary fibrosis, pulmonary hypertension, pulmonary embolism, dyspnea, liver disease including NASH and cirrhosis, gallstones, kidney stones, Barrett's esophagus, hemorrhoids, decubitus ulcers, diverticulitis, constipation, colonic polyps, hemorrhoids, fecal incontinence, cachexia, malabsorption, erectile dysfunction, loss of libido, cataracts, age-related macular degeneration, glaucoma, retinal degeneration, retinal detachment, dry eye, presbyopia, falls, vertigo, benign prostatic hypertrophy, prostate cancer, diminished life expectancy, impaired kidney function, chronic renal failure, acute renal failure, glomerulosclerosis, glomerulosclerosis, nephrosclerosis, dehydration, neurogenic bladder, urinary tract infections, cystitis, urinary incontinence, cancer, obesity, metabolic syndrome, prediabetes, diabetes skin atrophy, skin aging, wrinkles, seborrheic keratosis, actinic keratosis, skin cancer, sun-damaged skin, rosacea, onychomycosis, greying of hair, baldness, age-related hearing loss, tinnitus, loss of smell, periodontal disease, tooth decay, dry mouth, thyroid disease, diseases associated with mitochondrial dysfunction, premature aging syndromes and progerias including Werner's syndrome and Hutchinson Guilford Progeria Syndrome, anemia, folic acid-deficiency anemia, coagulopathy, deep venous thrombosis, cachexia, depression, and diminished life expectancy. 
     
     
         11 . A pharmaceutical composition comprising a combination according to  claim 1  and at least one pharmaceutically acceptable carrier. 
     
     
         12 . A method of promoting or enhancing an immune response in a subject which comprises administering to said subject a combination according to  claim 1  in a quantity which is jointly therapeutically effective at promoting or enhancing an immune response. 
     
     
         13 . A method of treating a subject having an age related condition which comprises administering to said subject a combination according to  claim 1  in a quantity which is jointly therapeutically effective against said age related condition. 
     
     
         14 . A method according to  claim 13 , wherein the age related condition is selected from the group consisting of immunosenescence, sarcopenia, muscle wasting, tendon stiffness, tendon injury, tendonitis, Achilles rupture, adhesive capsulitis of shoulder, plantar fasciitis, polymyalgia rheumatica, rotator cuff tear, spinal stenosis, tennis elbow, dupuytren's contractures, restless leg syndrome, osteoporosis, osteoarthritis, rheumatoid arthritis, autoimmune disease, polymyositis, gout, dementia, Huntington's disease, Alzheimer's disease, brain atrophy, aging-related mobility disability (e.g., frailty), cognitive decline, age related dementia, memory impairment, Lewy body dementia, frontotemporal dementia, Parkinson's disease, mild cognitive impairment, vascular dementia, stroke, transient ischemic attack, trigeminal neuralgia, neuropathy, sleep disorders, insomnia, atherosclerosis, arteriosclerosis, hypertension, heart dysfunction such as cardiac hypertrophy, systolic dysfunction, or diastolic dysfunction, heart failure, dilated cardiomyopathy, heart failure with preserved ejection fraction, arrhythmias, valvular heart disease, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease exacerbations, pulmonary emphysema, idiopathic pulmonary fibrosis, pulmonary hypertension, pulmonary embolism, dyspnea, liver disease including NASH and cirrhosis, gallstones, kidney stones, Barrett's esophagus, hemorrhoids, decubitus ulcers, diverticulitis, constipation, colonic polyps, hemorrhoids, fecal incontinence, cachexia, malabsorption, erectile dysfunction, loss of libido, cataracts, age-related macular degeneration, glaucoma, retinal degeneration, retinal detachment, dry eye, presbyopia, falls, vertigo, benign prostatic hypertrophy, prostate cancer, diminished life expectancy, impaired kidney function, chronic renal failure, acute renal failure, glomerulosclerosis, glomerulosclerosis, nephrosclerosis, dehydration, neurogenic bladder, urinary tract infections, cystitis, urinary incontinence, cancer, obesity, metabolic syndrome, prediabetes, diabetes skin atrophy, skin aging, wrinkles, seborrheic keratosis, actinic keratosis, skin cancer, sun-damaged skin, rosacea, onychomycosis, greying of hair, baldness, age-related hearing loss, tinnitus, loss of smell, periodontal disease, tooth decay, dry mouth, thyroid disease, diseases associated with mitochondrial dysfunction, premature aging syndromes and progerias including Werner's syndrome and Hutchinson Guilford Progeria Syndrome, anemia, folic acid-deficiency anemia, coagulopathy, deep venous thrombosis, cachexia, depression, and diminished life expectancy.