Somatostatin analogs and compositions and uses thereof

Abstract

Disclosed herein are compositions and methods for increasing lifespan, promoting longevity, and / or preventing, reducing the severity of, or delaying the onset of, various aging-associated conditions in a companion animal in need thereof. The compositions and methods comprise therapeutically effective amounts of octreotide or a variant of octreotide, and / or a salt thereof.

Description

WSGR Docket No. 58989-728.601 SOMATOSTATIN ANALOGS AND COMPOSITIONS AND USES THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 664,343 filed June 26, 2024, which is hereby incorporated by reference in its entirety. BACKGROUND

[0002] Throughout history, products and methods that promote longevity and extend lifespan have been eagerly sought. Capitalizing on this widespread desire, it is unsurprising that the sale of supposed anti-aging products has been perennially lucrative. Generally, these products and methods have proven to be ineffective and / or unsafe. Accordingly, there remains an unmet need for safe and effective products and methods that promote, at least, longevity and extend lifespan. SUMMARY

[0003] The size of dogs is determined in large part by blood levels of growth hormone (GH) and Insulin-Like Growth Factor-1 (IGF-1). Although large and giant dogs seem healthy, their increased GH / IGF-1 blood levels – which remain elevated through adulthood – result in metabolic changes, including increased fasting insulin, that lead to early and increased frailty, diminished quality of life, and early death in comparison to smaller dogs. Somatostatin is a hormone that reduces release of GH / IGF-1 that is not suitable for therapeutic use due to its short half-life. Disclosed herein are pharmaceutical compositions comprising a somatostatin analogue, or a pharmaceutically acceptable salt thereof, in the form of an extended release injection or drug depot injection. Also disclosed herein are methods of treating or preventing shortened lifespan in large and giant dogs comprising administering a pharmaceutical composition to the dogs, wherein the pharmaceutical composition comprises a somatostatin analogue, or a pharmaceutically acceptable salt thereof, and is in the form of an extended release injection or drug depot injection.

[0004] An aspect of the present invention is a method of increasing lifespan, increasing quality of life, or maintaining healthy function in a companion animal, the method comprising reducing, or preventing age-related increase of, a fasting insulin value of the companion animal, wherein the reducing, or preventing age-related increase of, the fasting insulin value comprises administering to the companion animal a pharmaceutical composition comprising atWSGR Docket No. 58989-728.601 least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot.

[0005] Another aspect of the invention is a method of delaying mortality due to age-associated diseases in a companion animal, the method comprising administering to the companion animal a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot.

[0006] Another aspect of the invention is a method of preventing or reducing frailty or death by euthanasia in a companion animal, the method comprising reducing growth hormone (GH) and / or insulin-like growth factor-1 (IGF-1) in the companion animal, wherein the reducing GH and / or IGF-1 comprises administering to the companion animal a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot.

[0007] Another aspect of the invention is a method of treating an aging-induced insulin resistance in a companion animal in need thereof, the method comprising administering to the companion animal a therapeutically effective amount of a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot.

[0008] In some embodiments, the pharmaceutical composition comprises from about 1 mg to about 1 g of the somatostatin analogue, or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises from about 50 mg to about 500 mg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises from about 75 mg to about 300 mg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg or more of the somatostatin analogue, or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 10 mg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof, per kg of body weight of the companion animal. In some embodiments, the pharmaceutical composition comprises about 1 mg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof, per kg of body weight of the companion animal.WSGR Docket No. 58989-728.601

[0009] In some embodiments, the somatostatin analogue is octreotide, lanreotide, or pasireotide, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the somatostatin analogue, or the pharmaceutically acceptable salt thereof is octreotide acetate, octreotide trifluoroacetate, or octreotide HCl. In some embodiments, the somatostatin analogue, or the pharmaceutically acceptable salt thereof is octreotide acetate.

[0010] In some embodiments, the pharmaceutical composition is a subcutaneous or intramuscular drug depot of octreotide, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a subcutaneous drug depot injection of octreotide, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is an extended release injection of octreotide, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a polymer microparticle. In some embodiments, the pharmaceutical composition is a subcutaneous drug depot of octreotide, or a pharmaceutically acceptable salt thereof, wherein the octreotide or the pharmaceutically acceptable salt thereof is enveloped in a polymer microsphere.

[0011] In some embodiments, the extended release injection or drug depot releases the somatostatin analogue, or the pharmaceutically acceptable salt thereof, over the course of about 1 month to about 2 years. In some embodiments, the extended release injection or drug depot releases the somatostatin analogue, or the pharmaceutically acceptable salt thereof, over the course of about 3 months to about 6 months. In some embodiments, the pharmaceutical composition is administered no more than once per month. In some embodiments, the pharmaceutical composition is administered about once per month to about once per year. In some embodiments, the pharmaceutical composition is administered about once every 3 months to about once every 6 months. In some embodiments, the pharmaceutical composition is administered for a period of a year or more.

[0012] In some embodiments, the companion animal is a canine. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal has a mass of about 0.5 kg to about 150 kg. In some embodiments, the companion animal is a dog having a mass of about 2 kg to about 12 kg. In some embodiments, the companion animal is a dog having a mass of about 13 kg to about 26 kg. In some embodiments, the companion animal is a dog having a mass of about 26 kg to about 45 kg. In some embodiments, the companion animal is a dog having a mass of about 45 kg or more. In some embodiments, the companion animal is a dog having a mass of about 18 kg or more. In some embodiments, the companion animal has an age of about 2 years to about 18 years. In some embodiments, the companion animal has anWSGR Docket No. 58989-728.601 age of about 4 years to about 7 years. In some embodiments, the companion animal has an age of about 7 years or more. In some embodiments, the companion animal is a dog having a mass of about 18 kg or more, and / or an age of about 7 years or more.

[0013] In some embodiments, the companion animal is a healthy dog (e.g., non-diabetic, and / or free of cancer or cancerous tumor diseases, and / or free of a hormonal disorder such as acromegaly and / or free of a cardiovascular disease). In some embodiments, the companion animal has a metabolic disease or disorder (e.g., diabetes), or has an elevated risk of developing a metabolic disease or disorder based on its age (e.g., 7 years or older) and / or size (e.g., 18 kg or more). In some embodiments, the companion animal has an insulin-like growth factor-1 concentration of about 100 ng / mL or higher.

[0014] In some embodiments, the increasing lifespan comprises an at least 5% increase in lifespan relative to the median lifespan of the companion animal. In some embodiments, the increasing lifespan comprises about a 5% increase to about a 50% increase in lifespan relative to the median lifespan of the companion animal.

[0015] In some embodiments, the method further comprises detecting one or more biomarkers in a first blood sample, wherein the first blood sample is obtained from the companion animal before administering the pharmaceutical composition. In some embodiments, the method further comprises detecting one or more biomarkers in a second blood sample, wherein the second blood sample is obtained from the companion animal after administering the pharmaceutical composition. In some embodiments, the one or more biomarkers comprises insulin, insulin sensitivity, glucose, insulin-like growth factor-1, growth hormone, thyroxine, and / or fatty acid concentrations. In some embodiments, the one or more biomarkers comprises fasting insulin.

[0016] In some embodiments, the method further comprises evaluating the companion animal in a health survey. In some embodiments, the health survey is performed before the pharmaceutical composition is administered. In some embodiments, the health survey is performed after the pharmaceutical composition is administered. In some embodiments, the health survey is a health-related quality of life (HRQL) assessment, physical examination, body condition score, muscle condition score, or assessment of frailty (e.g., a canine frailty index (CFI)).

[0017] In some embodiments, the administering the pharmaceutical composition improves the healthspan of the companion animal. In some embodiments, the improving the healthspan of the companion animal comprises improving the quality of life of the companion animal, as determined based on a health-related quality of life (HRQL) assessment or a canine frailtyWSGR Docket No. 58989-728.601 index (CFI) assessment, wherein the quality of life is measured by an HRQL score and / or a CFI score, and wherein the HRQL score or the CFI score is improved by about 5% to about 100%. In some embodiments, the improving the healthspan of the companion animal comprises preventing, delaying, treating, or reducing a symptom of an age-associated disease relative to the median incidence, severity, or age of onset. In some embodiments, the age-associated disease is a metabolic disease or disorder. In some embodiments, the age-associated disease is a musculoskeletal disease or disorder (e.g., a degenerative orthopedic disease). In some embodiments, the age-associated disease is not a cardiovascular disease or disorder.

[0018] In some embodiments, the age-associated disease comprises cognitive dysfunction or decline. In some embodiments, the age-associated disease is selected from the group consisting of frailty, dementia, sarcopenia, osteopenia, osteoporosis, osteoarthritis, obesity, hypertension, diabetes mellitus, metabolic syndrome, chronic inflammation, chronic pain, pancreatitis, liver disease, renal disease, hyperlipidemia, hepatic steatosis, and steatohepatitis, or a combination thereof.

[0019] Another aspect of the invention is a pharmaceutical composition comprising a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot, for use in any one of methods disclosed herein.

[0020] Also provided herein is a pharmaceutical composition comprising a somatostatin analogue, or a pharmaceutically acceptable salt or prodrug thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot, for use in the manufacture of a medicament for increasing lifespan or healthspan; maintaining healthy function; delaying or preventing age-associated diseases; or reducing, delaying, or preventing frailty, in a companion animal.

[0021] In some embodiments, the pharmaceutical composition is for use in a dog having a mass of about 18 kg or more, and / or an age of about 7 years or more. In some embodiments, the pharmaceutical composition comprises a somatostatin analogue that is octreotide, or a pharmaceutically acceptable salt or prodrug thereof, provided in an amount of about 50 mg to about 500 mg. In some embodiments, the somatostatin analogue is octreotide, or a pharmaceutically acceptable salt or prodrug thereof, provided in an amount of about 75 mg to about 300 mg. In some embodiments, the octreotide, or the pharmaceutically acceptable salt or prodrug thereof, is formulated in a polymer microparticle.WSGR Docket No. 58989-728.601 BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIG. 1 shows blood insulin levels, calculated as the standardized natural- log(insulin), in relation to age in years. Points are colored based on weight groups:below 50 lbs, 50 lbs to 100 lbs, 100 lbs to 150 lbs, and above 150 lbs.

[0023] FIG. 2 shows HRQL total scores in relation to insulin levels, calculated as standardized natural-log(insulin). Points are colored based on age groups: below 3 yrs of age, 3 yrs to 6 yrs of age, 6 yrs to 9 yrs of age, 9 yrs to 12 yrs of age, 12 yrs to 15 yrs of age, and above 15 yrs of age.

[0024] FIG.3 shows Canine Frailty Score in relation to insulin, on its natural scale (mIU / L), for each age in years: 4, 7, 10, 15, 18 with 4 being the lower band line and progressing up to 18 being the higher band line.

[0025] FIG.4 shows serum IGF-1 levels in dogs dosed with instant release octreotide daily from days 0-14.

[0026] FIG. 5 shows Group Mean Concentration vs Time Results for 10 and 20 mg Octreotide LAR Exposure.

[0027] FIG. 6 shows serum octreotide concentrations on Days 14, 29, 55 and 84 following dosing TI at Day 0 and Day 42. All error bars are expressed as mean ± SEM.

[0028] FIG. 7 shows percentage change from baseline (Day 0) in IGF-1 levels by group on Days 14, 29, 55 and 84 following dosing TI at Day 0 and Day 42. All error bars are expressed as mean ± SEM.

[0029] FIG. 8 shows group averages for baseline Day 0 and Day 70 (A-B) and percent change in fasting insulin (C-D). All error bars are expressed as mean ± SEM.

[0030] FIG. 9 shows group averages of percent change from baseline of insulin sensitivity (SI) from IVGTT. All error bars are expressed as mean ± SEM. All data were analyzed using statistical package STATA 17MP using a linear regression model and a p- criterion for statistical significance. (* = p < 0.05). DETAILED DESCRIPTION OF THE INVENTION

[0031] The present disclosure is based, in part, on the discovery of compositions and methods that increase lifespan, promote longevity, and / or prevent, reduce the severity of, or delay the onset of various aging-associated conditions. The compositions and methods further improve the healthspan of the mammal, which may include treating a cancer and / or preventing, reducing the severity of, or delaying the onset of the cancer in the mammal.WSGR Docket No. 58989-728.601

[0032] Age is the greatest risk factor for nearly every major cause of morbidity and mortality in living organisms, including companion animals. Even in the absence of observable disease, the physiology of organ systems and tissues progressively declines throughout life. However, the aging process is malleable, and some interventions have been identified that can delay mortality and promote healthy lifespan (shortened herein as the term “healthspan”).

[0033] The first compelling evidence of a specific intervention that resulted in increased lifespan was the observation that reduced caloric intake significantly increased lifespan in rodents. This finding has been reproduced in dogs and in many other species including yeast, nematodes, fish, flies, and nonhuman primates. Not only is the lifespan of many organisms increased under caloric restriction, but healthspan is also improved, as measured by the reduced incidence of many age-related morbidities. Subsequent genetic and pharmacological studies have identified specific genes and protein targets in nutrient sensing pathways that mediate the lifespan promoting benefits of reduced caloric intake.

[0034] Growth hormone (GH) is a hormone that promotes growth and maturation in a developing organism, and in the livestock industry, is used to hasten and enhance physical maturation. However, after reaching an adult phenotype, the useful effects of having elevated levels of GH may diminish in some organisms. Thereafter, persistently high GH may lead to accelerated aging and increasing frailty. Frailty is identified to correlate with morbidity, and by reducing frailty, it may be possible to reduce morbidity in an organism as well. Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.

[0035] Some organisms, i.e., companion animals such as dogs and cats, some of which have been selectively bred over generations to achieve a desired size or phenotype, may have levels of GH / IGF-1 persisting into adulthood that result in advanced aging. As used herein, the term “companion animal” generally refers to any non-human mammal unless otherwise specified. Common companion animals include dogs, cats, rabbits, ferrets, hamsters, gerbils, guinea pigs, and mice, but also encompasses uncommon ones including horses, non-human primates (e.g., chimpanzees, bonobos, orangutans, capuchins, gorillas), pigs, cows, sheep, goats, or donkeys.

[0036] An aspect of the present invention is the identification of companion animals that may benefit (i.e., achieve relief from accelerated aging, or achieve an extension of lifespan or healthspan) by modulation of GH and / or IGF-1, particularly in subjects not diagnosed with GH / IGF-1 hypersecretion disorders such as acromegaly. Another aspect is the prevention of age-related diseases, including frailty, in a companion animal, comprising administering to theWSGR Docket No. 58989-728.601 companion animal a pharmaceutical intervention that lowers serum GH and / or IGF-1 levels (i.e., by about 10% to about 99%, or more preferably, by about 25% to about 90%). In some embodiments, the pharmaceutical intervention comprises an injectable composition or drug depot capable of releasing a GH-lowering therapeutic over an extended period of time (e.g., at least about 3 months to about 12 months, or more). In some embodiments, the companion animal is a dog having a mass of about 18 kg (or about 40 lbs) or more.

[0037] Some companion animals (such as dogs) having a high adult body mass (e.g., about 40 lbs or more) are more likely to die of musculoskeletal diseases than smaller ones. This observation may be related to the difficulty for owners to handle large companion animals with impaired mobility, leading to earlier euthanasia than for smaller companion animals with similar disease. Furthermore, musculoskeletal disease-related urinary and / or fecal incontinence is easier to manage in small companion animals compared to large ones. Because most companion animals (specifically dogs) die by euthanasia rather than directly from the effects of their disease, body size may affect mortality risk.

[0038] While increased fasting insulin is a natural occurrence in all dogs as they age, large dogs show accelerated increases in fasting insulin at younger ages relative to small dogs. Insulin significantly increases with age in both small and large dogs. This effect appears to be exacerbated by age and size: within old dogs, ages 7+ years old, large dogs show substantially higher rates of age-related increases in insulin compared to old small, dogs.

[0039] High GH / IGF-1 may be associated with insulin resistance. Higher fasting insulin can be predictive of insulin resistance in dogs, and fasting insulin rises in dogs as they age. Furthermore, large dogs have faster age-related increases in insulin than small dogs. Increased fasting insulin is associated with lower Health Related Quality of Life (HRQL).

[0040] The VetMetrica HRQL questionnaire is a survey tool designed to measure owner perceptions of the quality of life of their dog. It encompasses the impacts of aging, disease, and clinical management of disease. The VetMetrica instrument includes 22 questions for the pet owner regarding the dog’s behavior across four domains of quality of life – Energetic / Enthusiastic (E / E), Happy / Content (H / C), Active / Comfortable (A / C), Calm / Relaxed (C / R). VetMetrica provides instantaneous computation and reporting of a profile of scores across the 4 domains listed above and can be combined into a single total score (sometimes referred to as “HRQL total” or simply as “HRQL”).

[0041] Data obtained from a Healthspan Study showed that insulin levels are significantlynegatively associated with HRQL, adjusting for age, weight, and BCS ( =-1.42, 95% CI = (-2.19, -0.64)). These results show that every standard deviation increase in log(insulin) isWSGR Docket No. 58989-728.601 associated with a 1.42 point lower median HRQL total scores, independent of the effects of age, weight or BCS. That is, when comparing the HRQL total scores of two companion animals of the same age, weight and BCS, companion animals with higher insulin values will have lower HRQL total scores. In conclusion, the data show that every 1% increase in fasting insulin levels correlates to a 0.0225 point decline in median HRQL total scores.

[0042] The Healthspan Study was an unblinded pilot observational clinical study conducted at 11 sites across the United States. It included one study visit and had no interventions. The owner completed a VetMetrica® Health Related Quality of Life (HRQL) assessment prior to the single study visit. On day 0, each enrolled dog received all scheduled study events including a Physical Examination (PE), Body Condition Score (BCS), Muscle Condition Score (MCS), Complete Blood Count (CBC), biochemical profile, serum T4 measurement, urinalysis, insulin-like growth factor-1 (IGF-1) measurement, and the veterinarian assessment of frailty using the Canine Frailty Index (CFI).

[0043] Data obtained from a Healthspan Study also showed a significant interaction effect between age and insulin (p=0.028), such that higher insulin is associated with increased frailty- an effect that becomes stronger with age ( =-0.10, 95% CI = (-0.23, 0.04)). The CanineFrailty Index (CFI) is a broad multimorbidity assessment incorporating criteria such as disease diagnoses, physical examination and clinical laboratory abnormalities, physical performance measures, and others. The CFI is an adapted and validated predictor of mortality risk in dogs. Banzato et al. developed the instrument based on broad criteria commonly included in human frailty indices, and the calculated frailty scores have been shown to positively correlate with all-cause mortality during the 6-month follow-up period. CFI is based on a series of 33 questions relating to the medical history and physical examination, performed by a veterinarian.

[0044] The CFI is calculated by summing the question responses (0, 0.5, or 1) and dividing by the total number of questions (33). The total CFI therefore lies between 0 and 1, where a frailty index of 0 denotes a dog that is not frail. As measured by CFI, frailty is then defined as a set proportion of elements present. Therefore, this index is not only reflective of frailty through its composite score, but also is representative of disease burden. 1. Assistance when standing up 18. Chronic inflammation 2. Decreased appetite 19. Acute vascular problems 3. Assistance when eating 20. Cancer 4. Incontinence 21. Diabetes 5. Assistance when climbing stairs 22. OsteoarthrosisWSGR Docket No. 58989-728.601 6. Decreased activity over the last year 23. Hearing impairment 7. Reduced cognitive ability 24. Cardiomyopathy 8. Reduced vitality over the last year 25. Chronic respiratory disease 9. Weakness during exercise 26. Hepatopathy 10. Congenital defects 27. Neurological deficits 11. Weight loss (not due to diet or exercise) 28. Disease of the oral cavity 12. Weight loss (not due to diet or exercise) 29. Visual impairment 13. Chronic therapies 30. Chronic digestive disease 14. Epilepsy 31. Disease of the hematopoietic system 15. Episodes of disorientation 32. Dermatological disease 16. Chronic infectious disease 33. Chronic kidney disease 17. Endocrine disease

[0045] The Canine Frailty Index (CFI) and Health-Related Quality of Life (HRQL) assessments reflect the main factors driving natural death and euthanasia in senior companion dogs; age-associated disease and disability and a decline in owner-perceived quality of life. The decision to euthanize a companion dog is heavily influenced by the negative health impacts of the diseases associated with old age and the decline in owner-perceived quality of life. Specific changes cited at high rates by owners include poor appetite, impaired mobility, incontinence, and symptoms of cognitive dysfunction, all related to age-associated disease. The CFI assessment explicitly includes these, and other clinical problems owners frequently cited as reasons for electing euthanasia.

[0046] The CFI incorporates diagnoses of specific age-associated diseases, including those most commonly associated with natural death and euthanasia in dogs: neoplasia, musculoskeletal disease, cardiac diseases, chronic kidney disease, and CNS dysfunction. CFI scores increase with age and are predictive of mortality. Changes in CFI score capture both direct causes of natural death (age-associated disease) and indirect (owner-mediated) causes of euthanasia, which help to determine lifespan for individual aging dogs, and particularly large and giant breed dogs. HRQL is specifically designed to assess the primary driver of euthanasia in dogs, owner perceptions of quality of life. HRQL is reflective of the decline in quality of life that comes with age, and with illness. HRQL also correlates closely with CFI. Both HRQL and CFI measure parameters that lead to euthanasia, including specific disease categories in the CFI. Scores in these two instruments are associated with overall mortality risk.WSGR Docket No. 58989-728.601

[0047] High GH / IGF-1 in dogs correlates to high fasting insulin, which is associated with lower quality of life, greater frailty, and a greater disease burden. High levels of GH / IGF-1 may also lead to insulin resistance. High GH / IGF-1 causes insulin resistance when cells in the muscles, fat, and liver don’t respond efficiently to insulin and therefore cannot easily take up glucose from the blood.

[0048] The inverse relationship between GH levels and insulin sensitivity is well documented and can be partially explained by several molecular mechanisms. The intracellular signaling cascade initiated by GH binding to its receptor interferes with the downstream effects of insulin receptor (IR) activation on the same cell, resulting in an inhibitory effect on insulin-induced glucose disposal. Chronic exposure to GH is associated with decreased response to IR activation, including reduced IR-association of insulin receptor substrate-1 (IRS-1) and -2, reduced association of the p85 phosphatidylinositol 3-kinase (PI3K) subunit with IRS-1 and reduced PI3K activity in rodents. Activation of PI3K is necessary for many, if not all of insulin’s actions, including stimulation of glucose transport, activation of glycogen synthase and inhibition of hepatic gluconeogenesis. In liver and skeletal muscle, GH leads to chronic activation of the IR / IRS-1 / PI3K pathway and blocks insulin- induced intracellular activation by sequestering essential substrates of insulin signaling. In addition, GH reduces insulin sensitivity further by enhancing events that negatively modulate insulin signaling. GH dose-dependently upregulates suppressors of cytokine signaling-1 (SOCS-1), an intracellular protein that directly interacts with IR, inhibits insulin-stimulated activation of extracellular signal-related protein kinase (Erk1 / 2) and AK transforming (Akt) kinases and blocks phosphorylation of IRS-1).

[0049] The search for pharmaceutical interventions to treat medical conditions of GH excess in humans led to the identification of several synthetic peptide analogs of the naturally occurring GH inhibitory hormone, somatostatin. Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects cell proliferation via interaction with somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin also inhibits insulin and glucagon secretion. Somatostatin is a fourteen- membered cyclic peptide comprising the sequence Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys- Thr-Phe-Thr-Ser-Cys, cyclised by a disulfide bridge between the two Cys residues at positions 3 and 14, represented by the following structure:WSGR Docket No. 58989-728.601

[0050] Somatostatin has a short half-life of only about 2-3 minutes. However, somatostatin analogues with longer half-lives have been developed, which may be useful in the methods of preventing age-related diseases and associated morbidity disclosed herein.

[0051] Octreotide (brand name Sandostatin® (Novartis, NJ)) is an octapeptide that mimics natural somatostatin pharmacologically. Octreotide is a somatostatin analogue comprising an octapeptide with the sequence, H-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-OH that exerts its pharmacological activity by binding and activating somatostatin receptor 2 and, with lesser potency, somatostatin receptors 3 and 5. Octreotide has been shown to reduce GH and IGF-1 levels in humans, and it gained FDA approval for use in humans in 1988. Octreotide is a more potent inhibitor of GH, glucagon, and insulin than the natural hormone somatostatin, and has a half-life of about 1.7 to 1.9 hours, making it much more suitable for therapeutic use – particularly for use in extended release formulations suitable to chronically treat elevated GH / IGF-1. Octreotide has the following structure:WSGR Docket No. 58989-728.601.

[0052] Octreotide can be formulated as a non-salt or salt form. Examples of salts include, but are not limited to, octreotide acetate, octreotide trifluoroacetate, or octreotide hydrochloride. The octreotide acetate salt is approved for human use to treat acromegaly or diarrhea associated with metastatic carcinoid tumors or vasoactive intestinal peptide secreting tumors. Sandostatin® comes in dosage forms comprising of 10 mg, 20 mg, or 30 mg of octreotide acetate, and has two formulations approved for human use: Sandostatin® Immediate-Release Injection (2 to 4 times per day, subcutaneously), and Sandostatin® Long- Acting Release Depot (once every 28 days, intramuscularly).

[0053] Another somatostatin analogue is pasireotide. Pasireotide is somatostatin analog with a 40-fold increased affinity to somatostatin receptor 5 compared to other somatostatin analogs. The drug is indicated for the treatment of Cushing’s disease, specifically for those patients whom pituitary surgery has not been curative or is not an option. Pasireotide is a six-membered cyclic peptide comprising L-phenylglycyl, D-tryptophyl, L-lysyl, O-benzyl-L-tyrosyl, L- phenylalanyl, and modified L-hydroxyproline residues joined in sequence, and having the structure:WSGR Docket No. 58989-728.601.

[0054] Another somatostatin analogue is lanreotide. Lanreotide is a synthetic peptide analogue of somatostatin that copies the native hormone in its ability to suppress levels and activity of growth hormone, insulin, glucagon and many other gastrointestinal peptides. The half-life of lanreotide is about 2 hours in an immediate-release formulation, and about 5 days in a sustained release formulation. Lanreotide is used clinically to treat neuroendocrine tumors that secrete excessive amounts of growth hormone or other active hormones or neuropeptides, including carcinoid syndrome. It is a long-acting analog of somatostatin, like octreotide. It is available in several countries, including the United Kingdom, Australia, and Canada, and was approved for sale in the United States by the Food and Drug Administration on August 30, 2007. Lanreotide is a cyclic peptide represented by the formula H-D-2Nal-Cys(1)-Tyr-D-Trp- Lys-Val-Cys(1)-Thr-NH2, where (1) denotes a disulfide bridge. Lanreotide has the structure:Pharmaceutical Compositions

[0055] The compositions of the present disclosure are formulated to be suitable for in vivo administration to a mammal. Such compositions can optionally comprise a suitable amount ofWSGR Docket No. 58989-728.601 a pharmaceutically acceptable excipient so as to provide the form for proper administration. Pharmaceutical excipients can be liquids, such as water or saline. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. The pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any composition described herein is administered intravenously. In some embodiments, the compositions described herein are suspended in a saline buffer (including, without limitation Ringer’s, TBS, PBS, HEPES, HBSS, and the like). Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, glycerol monostearate, mannitol, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any composition described herein, if desired, can also comprise pH buffering agents. As used herein, the terms “composition” or “pharmaceutical composition” may be used interchangeably to encompasses any composition suitable (non-lethal, preferably non-toxic or minimally toxic) for use in a living subject. The subject may be a human or a non-human. Accordingly, the term “pharmaceutical composition” encompasses compositions for both human use and veterinary use. Unless otherwise specified, the pharmaceutical compositions disclosed herein are suitable for use in any organism, particularly a mammal, preferably a companion animal such as a dog or a cat, and / or a human.

[0056] One aspect of the present invention is a pharmaceutical composition comprising a somatostatin analogue (e.g., octreotide, pasireotide, or lanreotide), or a pharmaceutically acceptable salt thereof, formulated for non-human (veterinary) use in a companion animal, (in some embodiments, in a formulation tailored for the physiology of the companion animal), wherein the somatostatin analogue is released (e.g., into circulation in a companion animal to which the pharmaceutical composition has been administered) over a period of about 3 months to about 6 months. In some embodiments, the pharmaceutical composition releases the somatostatin analogue over a period of about 12 months. In some embodiments, the pharmaceutical composition releases the somatostatin analogue over a period of at least about 4 weeks, 6 weeks, 2 months, 3 months, or more. In some embodiments, the pharmaceutical composition comprises from about 1 mg to about 1 g of the somatostatin analogue. In some embodiments, the composition comprises more than about 40 mg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the pharmaceutical composition comprises from about 50 mg to about 500 mg (e.g., about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, 50 mg toWSGR Docket No. 58989-728.601 about 100 mg, or about 50 mg to about 75 mg) of the somatostatin analogue, or the pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 75 mg to about 300 mg (e.g., about 75 mg to about 250 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, or about 75 mg to about 100 mg) of the somatostatin analogue, or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg or more of the somatostatin analogue, or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 10 mg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof, per kg of body weight of the companion animal. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 10 mg (e.g., about 0.5 mg to about 5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 2 mg, or about 0.5 mg to about 1 mg) of the somatostatin analogue, or the pharmaceutically acceptable salt thereof, per kg of body weight of the companion animal. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 10 mg (e.g., about 1 mg to about 5 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg) of the somatostatin analogue, or the pharmaceutically acceptable salt thereof, per kg of body weight of the companion animal. In some embodiments, the pharmaceutical composition comprises about 1 mg / kg, about 2 mg / kg, about 3 mg, about 4 mg, about 5 mg, or about 10 mg / kg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof, per kg of body weight of the companion animal.

[0058] In some embodiments, the somatostatin analogue is octreotide, lanreotide, or pasireotide, or a pharmaceutically acceptable salt thereof. In some embodiments, the somatostatin analogue is a hydrochloride, sodium, sulfate, acetate, phosphate or diphosphate, chloride, potassium, maleate, calcium, citrate, mesylate, nitrate, tartrate, aluminum, or gluconate salt. In some embodiments, the pharmaceutically acceptable salt of the somatostatin analogue is octreotide acetate, octreotide trifluoroacetate, or octreotide hydrochloride.

[0059] In some embodiments, the pharmaceutical composition comprises the somatostatin analogue (e.g., octreotide or octreotide acetate) formulated as a drug depot. A depot is a volume of a composition that is administered to a subject in a discrete location, and the composition is released from the discrete location over an extended period of time. The drug depot may be administered by intraperitoneal injection, intramuscular injection, or subcutaneous injection. In depot administration, the formulation is designed to release the composition from the depot at a steady rate over the extended period of time, thereby, obviating the need for repeated, distinct administrations, e.g., via injection or infusion. As usedWSGR Docket No. 58989-728.601 herein, the terms “drug depot” and “extended release injection” may be used interchangeably unless otherwise specified.

[0060] In some embodiments, the pharmaceutical composition is formulated as a subcutaneous or intramuscular drug depot of octreotide, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is formulated as a subcutaneous drug depot injection of octreotide acetate. In some embodiments, the pharmaceutical composition is an extended release injectable composition of octreotide, or a pharmaceutically acceptable salt thereof.

[0061] The formulation may comprise microcapsules, such as liposomes, an albumin microspheres, microemulsions, nanoparticles (e.g., a lipid nanoparticles), and nanocapsules and / or may comprise one or more of capralactone, polylactide (PLA), polylactic-co-glycolic (PLGA), polyethylene glycol (PEG), polylactic-co-hydroxymethylglycolic acid (PLHMGA), carboxymethylcellulose, hydroxylmethylcellulose, gelatin-microcapsules, a poloxamer, polymethylmethacrylate, or a phospholipid-based phase separation gel (PPSG; e.g., comprising a phosphatidyl choline. In some embodiments, the pharmaceutical composition comprises a polymer microparticle. The pharmaceutical composition may be formulated as a subcutaneous drug depot of octreotide, or a pharmaceutically acceptable salt thereof, wherein the octreotide or the pharmaceutically acceptable salt thereof is enveloped in a polymer microsphere.

[0062] A commercially-available composition for depot delivery of octreotide is Sandostatin® LAR Depot, sold by Novartis, NJ. Sandostatin® LAR Depot is sold in quantities of 10 mg, 20 mg, and 30 mg, which is released into a mammalian subject over a period of about four weeks. One aspect of the invention is a pharmaceutical composition for depot delivery of octreotide, specifically octreotide acetate, in quantities of greater than 30 mg, and releasing the treatment over a duration greater than 4 weeks.

[0063] In some embodiments, the pharmaceutical composition (e.g., the drug depot) releases the somatostatin analogue, or the pharmaceutically acceptable salt thereof, over the course of about 1 month to about 2 years. More specifically, provided herein is a pharmaceutical composition comprising about 50 to about 500 mg of octreotide or a salt thereof (preferably octreotide acetate), wherein the octreotide is released over the course of at least a month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, or at least eleven months. In some embodiments, the composition releases octreotide into circulation of the subject over the course of about 3 months, about 6 months, about 9 months,WSGR Docket No. 58989-728.601 about 12 months, about 15 months, about 18 months, or about 24 months. In some embodiments, the composition releases octreotide over the course of 6 weeks to about 52 weeks. In some embodiments, the pharmaceutical composition releases the somatostatin analogue, or the pharmaceutically acceptable salt thereof, over the course of about 3 months to about 6 months.

[0064] A composition may comprise octreotide or a variant of octreotide, and / or a salt thereof loaded into an extended release injectable composition, which is injected into a mammal (e.g., a companion animal). The extended release injection may release the composition over an extended period of time, thereby, obviating the need for repeated, distinct administrations, e.g., via injection or infusion. Preferably, the composition is released at a steady rate over the extended period of time (i.e., a controlled release).

[0065] Typically, the extended release injectable composition is injected under the skin, e.g., subcutaneously and intraperitoneally. The extended release injectable composition is loaded with a formulation that is designed to release the composition from the device at a steady rate over the extended period of time, thereby, obviating the need for repeated, distinct administrations, e.g., via injection or infusion. The formulation may comprise microcapsules, such as liposomes, an albumin microspheres, microemulsions, nanoparticles (e.g., a lipid nanoparticles), and nanocapsules and / or may comprise one or more of capralactone, polylactide (PLA), polylactic-co-glycolic (PLGA), polyethylene glycol (PEG), polylactic-co- hydroxymethylglycolic acid (PLHMGA), carboxymethylcellulose, hydroxylmethylcellulose, gelatin-microcapsules, a poloxamer, polymethylmethacrylate, or a phospholipid-based phase separation gel (PPSG; e.g., comprising a phosphatidyl choline.

[0066] In some embodiments, the administering comprises implantation of an implantable drug delivery device. The implantable drug delivery device may be implanted subcutaneously. The implantable drug delivery device may be implanted after the mammal has received an at least first administering via intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection or after an at least first administering via depot.

[0067] In some embodiments, the extended release injection releases the composition at a consistent rate for at least a month, at least two months, or at least three months. The extended release injection may release the composition as a consistent rate for at least a month, at least three months, at least six months, at least nine months, at least twelve months, at least fifteen months, or at least eighteen months. In some embodiments, the extended release injectionWSGR Docket No. 58989-728.601 releases the composition at a consistent rate for at least one year, at least two years, or at least three years. Methods

[0068] Another aspect of the present invention is a composition comprising at least about 50 mg of a somatostatin analogue, or a pharmaceutically acceptable salt or prodrug thereof, in an extended release injection or depot formulation, for use in a method of any one of the following: increasing lifespan or healthspan of a subject, increasing quality of life of a subject, maintaining healthy function of a subject, delaying mortality of a subject due to age-associated diseases, preventing, delaying, or reducing frailty of a subject, preventing delaying, or reducing or death by euthanasia of a subject, or treating an aging-induced insulin resistance of a subject; wherein the method comprises administering to the subject the aforementioned composition. In some embodiments, the subject is a mammal. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a human. In some embodiments, the companion animal is a dog. Another aspect of the invention is the use of a somatostatin analogue (e.g., octreotide), or a pharmaceutically acceptable salt or prodrug thereof (e.g., octreotide acetate), in the manufacture of a medicament for use in the treatment or prevention of an age-associated disease or disorder (particularly for use in the manufacture of a medicament that is an extended release injectable or drug depot). In some embodiments, the compositions disclosed herein are used in the manufacture of a medicament for increasing the lifespan or healthspan of a subject, increasing quality of life of a subject, maintaining healthy function of a subject, delaying mortality of a subject due to age-associated diseases, preventing, delaying, or reducing frailty of a subject, preventing, delaying, or reducing or death by euthanasia of a subject, or treating an aging-induced insulin resistance of a subject.

[0069] As used herein, the term “healthspan” refers to the part of a subject’s life during which they are generally in good health or a period of life spent in good health, free from chronic diseases and disabilities / conditions of aging. Accordingly, a herein-disclosed composition or method that treats, prevents, reduces the severity of, and / or delay the onset of various aging-associated conditions, as mentioned above, improves the healthspan of aWSGR Docket No. 58989-728.601 mammal. In some embodiments, improving the healthspan of a mammal comprise a reduction in the incidence and / or severity of one or more age-related diseases.

[0070] In some embodiments, provided herein is a method of increasing lifespan, increasing quality of life, or maintaining healthy function in a companion animal, the method comprising reducing, or preventing age-related increase of, a fasting insulin value of the companion animal, wherein the reducing, or preventing age-related increase of, the fasting insulin value comprises administering to the companion animal a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot. In some embodiments, provided herein is a method of delaying mortality due to age-associated diseases in a companion animal, the method comprising administering to the companion animal a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot. Also provided herein is method of preventing or reducing frailty or death by euthanasia in a companion animal, the method comprising reducing growth hormone (GH) and / or insulin-like growth factor-1 (IGF-1) in the companion animal, wherein the reducing GH and / or IGF-1 comprises administering to the companion animal a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot. In some embodiments, provided herein is a method of treating an aging-induced insulin resistance in a companion animal in need thereof, the method comprising administering to the companion animal a therapeutically effective amount of a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot. In some embodiments, the method comprises administering to the subject (e.g., companion animal) a pharmaceutical composition comprising at least 40 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising at least 50 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising about 100 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof. In some embodiments, the somatostatin analogue is octreotide. In some embodiments, the somatostatin analogue, or the pharmaceutically acceptable salt thereof, is octreotide acetate.WSGR Docket No. 58989-728.601

[0071] Another aspect of the invention is a method of: increasing lifespan or healthspan of a subject, increasing quality of life of a subject, maintaining healthy function of a subject, delaying mortality of a subject due to age-associated diseases, preventing, delaying, or reducing frailty of a subject, preventing, delaying, or reducing or death by euthanasia of a subject, or treating an aging-induced insulin resistance of a subject; wherein the method comprises administering to the subject an effective amount of a composition comprising a somatostatin analogue, or a pharmaceutically acceptable salt or prodrug thereof, no more than once per month. In some embodiments, the method comprises administering the effective amount of the composition no more than once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, or once per year. Preferably, the composition is administered to the subject no more than once about every three to about every six months. In some embodiments, the composition is administered once ever year, once every two years, or once every three years.

[0072] Another aspect of the present invention is the duration of treatment comprising the somatostatin analogue, or the pharmaceutically acceptable salt thereof, wherein the treatment is administered to the subject for a period of a year or more (e.g., two years or more, three years or more, five years or more, seven years or more, ten years or more, twelve years or more, fifteen years or more, or for the remainder of the subject’s life). In some embodiments, the method comprises administering to the subject (e.g., a companion animal) an effective amount of the composition comprising the somatostatin analogue (e.g., octreotide), or a pharmaceutically acceptable salt thereof (e.g., octreotide acetate) for a period of about one year to about twelve years (e.g., about one to about ten years, about one to about eight years, about one to about five years, about one to about three years, about two to about twelve years, about two to about ten years, about two to about eight years, about two to about five years, about two to about three years, about three to about twelve years, about three to about ten years, about three to about eight years, about three to about five years, about five to about twelve years, about five to about ten years, or about five to about eight years).

[0073] The herein-disclosed compositions and methods treat, prevent, reduce the severity of, and / or delay the onset of various aging-associated conditions, e.g., chronic diseases andWSGR Docket No. 58989-728.601 disabilities / conditions of aging. Illustrative aging-associated conditions include age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cancer, cataracts, constipation, decrease in visual acuity, decrease in overall energy, delirium, dementia, depression, diminished peripheral vision, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), memory loss, metabolic syndrome, muscle atrophy, osteoporosis, reduced metabolism (including increased risk for obesity), reduced reflexes and coordination including difficulty with balance, respiratory disease, shingles, type 2 diabetes, urologic changes (including incontinence), whitening or graying of hair, and wrinkling and sagging skin (including loss of skin elasticity).

[0074] In some embodiments, the age-associated disease is metabolic disease or disorder. In some embodiments, the age-associated disease is a musculoskeletal disease or disorder (e.g., a degenerative orthopedic disease). In some embodiments, the age-associated disease is not a cardiovascular disease or disorder. In some embodiments, the age-associated disease comprises cognitive dysfunction or decline. In some embodiments, the age-associated disease is selected from the group consisting of frailty, dementia, sarcopenia, osteopenia, osteoporosis, osteoarthritis, obesity, hypertension, diabetes mellitus, metabolic syndrome, chronic inflammation, chronic pain, pancreatitis, liver disease, renal disease, hyperlipidemia, hepatic steatosis, and steatohepatitis, or a combination thereof. In some embodiments, the age- associated disease comprises difficulty, inability, or pain resulting from standing up, walking, running, or other forms of locomotion. In some embodiments, the age-associated disease comprises decreased appetite or malnutrition. In some embodiments, the age-associated disease comprises incontinence. In some embodiments, the age-associated disease comprises a reduction in activity. In some embodiments, the age-associated disease comprises reduced vitality or cognitive ability (e.g., confusion, disorientation, lack of recognition of a companion, etc.). In some embodiments, the age-associated disease comprises an endocrine disease. In some embodiments, the age-associated disease comprises chronic inflammation, including arthritis (e.g., osteoarthritis, rheumatoid arthritis, psoriatic arthritis, or osteoarthrosis). Additional age-associated diseases include vascular disorders, cancers, diabetes, cardiomyopathy, chronic respiratory disease, hepatopathy, chronic kidney disease, hearing and / or visual impairment, or neurological deficits. In some embodiments, the improving the healthspan of the companion animal comprises preventing, delaying, treating, or reducing a symptom of an age-associated disease (e.g., by about 5% to about 10%, by about 10% to aboutWSGR Docket No. 58989-728.601 20%, by about 20% to about 30%, or by up to about 50%) relative to the median incidence, severity, or age of onset.

[0075] Aged human and non-human subjects may experience similar, homologous, and / or equivalent aging-associated conditions, for which the methods and compositions provided herein may also be used to treat.

[0076] In some aspects, the composition for use in increasing lifespan of a mammal may also increase the healthspan of the mammal. Improving the healthspan of the mammal may comprise a reduction in the incidence and / or severity of one or more aging-associated conditions or diseases listed above. In some embodiments, the increasing lifespan comprises an at least 5% increase in lifespan relative to the median lifespan of the companion animal. In some embodiments, the increasing lifespan comprises an at least 5% increase (e.g., an at least 10%, at least 15%, at least 20%, or at least 25% increase) in lifespan relative to the median lifespan of the companion animal. In some embodiments, the increasing lifespan comprises about a 5% increase to about a 50% increase in lifespan relative to the median lifespan of the companion animal.

[0077] In any of the herein disclosed aspects or embodiments, octreotide or a variant of octreotide, and / or a salt thereof is delivered in a polymer microparticle and / or in a formulation that delays release into the mammal, e.g., from a depot or from within an extended release injectable composition or dissolvable implant. Subjects

[0078] In some embodiments, the subject is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a canine (e.g., a dog, a fox, a coyote, a wolf, etc.). In some embodiments, the subject is a dog. In other embodiments, the subject is a human.

[0079] In some embodiments, the subject has a mass of about 0.5 kg to about 150 kg. In some embodiments, the subject is a companion animal having a mass of about 0.5 kg to about 150 kg. In some embodiments, the companion animal is a dog having a mass of about 0.5 kg to about 150 kg. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is a dog having a mass of about 2 kg to about 12 kg (i.e., a small dog breed). In some embodiments, the companion animal is a dog having a mass of about 13 kg to about 26 kg (i.e., a medium dog breed). In some embodiments, the companion animal is a dog having a mass of about 26 kg to about 45 kg (i.e., a large dog breed). In some embodiments,WSGR Docket No. 58989-728.601 the companion animal is a dog having a mass of about 45 kg or more (i.e., a giant dog breed). In certain embodiments, the companion animal is a large or giant dog breed, having a mass of about 26 kg to about 150 kg.

[0080] In some embodiments, the companion animal is a dog having a mass of about 18 kg to about 120 kg. In some embodiments, the companion animal is a dog having a mass of about 18 kg or more. In some embodiments, the subject is a dog whose breed is associated with a lifespan of about 12 years or less. In some embodiments, the subject is a dog whose breed is associated with a lifespan of about 10 years or less. In some embodiments, the subject is a dog whose breed is associated with a lifespan of about 8 years or less. In some embodiments, the subject is a dog whose breed is associated with high levels of a biomarker (e.g., a biomarker selected from IGF-1, IGF-2, IGF-1R, phosphorylated IGF-1R, glucose, Growth Hormone (GH), GH-receptor, phosphorylated GH-receptor, IGFBP1, IGFBP3, IGFBP3-IGF-1 isoform levels, insulin, pregnancy-associated plasma protein A (PAPP-A), PAPP-A2, P13Kinase, IRS- 1, Ras / Raf, MEK, ERK, Akt, and Rac). In some embodiments, the subject is a dog whose breed is associated with high levels of a biomarker (e.g., a biomarker selected from insulin (e.g., fasting insulin), insulin sensitivity, glucose, insulin-like growth factor-1, growth hormone, thyroxine, and / or fatty acid concentrations (e.g., palmitic acid, oleic acid, linoleic acid, free fatty acids, saturated fatty acids)). In some embodiments, the subject has reached maturity. In some embodiments, the subject is a dog whose breed is associated with, or is a dog that has been identified as having, high levels of IGF-1 and / or GH and has reached maturity. As used herein, the term mature or maturity refers to a mammal that is capable of sexual reproduction and / or a mammal that has achieved its adult height, length, and / or body mass.

[0081] In some embodiments, the subject is administered a herein-disclosed composition as it is nearing or once it has reached halfway to its expected lifespan for the mammal’s species, strain, breed, sex, and / or age. The subject may have reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, strain, breed, sex, and / or age.

[0082] It is known that small dog breeds (e.g., Chihuahua) have longer expected lifespans than large or giant dog breeds (e.g., an English Mastiff, Great Dane, Newfoundland, St. Bernard, or Irish Wolfhound). Accordingly, a Chihuahua, which has an expected lifespan of 15 years, will reach halfway to its expected lifespan at about 7 years (or earlier); thus, a Chihuahua may be administered a composition beginning around 7 years of age. On the other hand, a Great Dane, which has an expected lifespan of 7 years, will halfway to its expectedWSGR Docket No. 58989-728.601 lifespan at about 3 years; thus, a Great Dane may be administered a composition beginning around 3 years of age (or earlier). As disclosed herein, a mammal may be administered a composition once it has reached maturity; thus, either dog breed may be administered a composition about its first-year birthday.

[0083] In some embodiments, the companion animal has an age of about 1 year or more (e.g., about 1 to about 20 years, about 1 to about 18 years, about 1 to about 15 years, about 1 to about 12 years, about 1 to about 10 years, about 1 to about 8 years, about 1 to about 7 years, about 1 to about 6 years, about 1 to about 5 years, about 1 to about 4 years, about 1 to about 3 years, or about 1 to about 2 years). In some embodiments, the companion animal has an age of about 2 years or more (e.g., about 2 to about 20 years, about 2 to about 18 years, about 2 to about 15 years, about 2 to about 12 years, about 2 to about 10 years, about 2 to about 8 years, about 2 to about 7 years, about 2 to about 6 years, about 2 to about 5 years, about 2 to about 4 years, or about 2 to about 3 years). In some embodiments, the companion animal has an age of about 3 years or more (e.g., about 3 to about 20 years, about 3 to about 18 years, about 3 to about 15 years, about 3 to about 12 years, about 3 to about 10 years, about 3 to about 8 years, about 3 to about 7 years, about 3 to about 6 years, about 3 to about 5 years, or about 3 to about 4 years).

[0084] In some embodiments, the companion animal has an age of about 4 years or more (e.g., about 4 to about 20 years, about 4 to about 18 years, about 4 to about 15 years, about 4 to about 12 years, about 4 to about 10 years, about 4 to about 8 years, about 4 to about 7 years, about 4 to about 6 years, or about 4 to about 5 years). In some embodiments, the companion animal has an age of about 5 years or more (e.g., about 5 to about 20 years, about 5 to about 18 years, about 5 to about 15 years, about 5 to about 12 years, about 5 to about 10 years, about 5 to about 8 years, about 5 to about 7 years, or about 5 to about 6 years).

[0085] In some embodiments, the companion animal has an age of about 7 years or more (e.g., about 7 to about 20 years, about 7 to about 18 years, about 7 to about 15 years, about 7 to about 12 years, or about 7 to about 10 years). In some embodiments, the companion animal has an age of about 8 years or more (e.g., about 8 to about 20 years, about 8 to about 18 years, about 8 to about 15 years, about 8 to about 12 years, or about 8 to about 10 years). In some embodiments, the companion animal has an age of about 10 years or more (e.g., about 10 to about 20 years, about 10 to about 18 years, or about 10 to about 15 years). In some embodiments, the companion animal has an age of about 12 years or more (e.g., about 12 to about 20 years, about 12 to about 18 years, or about 12 to about 15 years). In someWSGR Docket No. 58989-728.601 embodiments, the companion animal has an age of about 15 years or more (e.g., about 15 to about 20 years, or about 15 to about 18 years).

[0086] The companion animal may have a combination of age and weight that make it a candidate for particularly effective treatment with one of the compositions disclosed herein. For example, a companion animal may have an age of about 1 or more years and a mass of about 18 kg or more. In some embodiments, the companion animal has an age of about 2 or more years (e.g., 3 or more years, 4 or more years, 5 or more years, etc.) and a mass of about 18 kg or more. In some embodiments, the companion animal has an age of about 7 or more years and a mass of about 18 kg or more. In some embodiments, the companion animal has an age of about 3 or more years and a mass of about 26 kg or more. In some embodiments, the companion animal has an age of about 3 or more years and a mass of about 45 kg or more. In some embodiments, the companion animal has an age of about 5 or more years and a mass of about 18 kg or more. In some embodiments, the companion animal has an age of about 5 or more years and a mass of about 26 kg or more. In some embodiments, the companion animal has an age of about 5 or more years and a mass of about 45 kg or more. In some embodiments, the companion animal has an age of about 7 or more years and a mass of about 18 kg or more. In some embodiments, the companion animal has an age of about 7 or more years and a mass of about 26 kg or more. In some embodiments, the companion animal has an age of about 7 or more years and a mass of about 45 kg or more.

[0087] Any dog breed can be administered a composition of the present disclosure and treated by a herein-described method. Illustrative common dog breeds include Retrievers (Labrador), German Shepherd Dogs, Retrievers (Golden), French Bulldogs, Bulldogs, Beagles, Poodles, Rottweilers, Pointers (German Shorthaired), Yorkshire Terriers, Boxers, Dachshunds, Pembroke Welsh Corgis, Siberian Huskies, Australian Shepherds, Great Danes, Doberman Pinschers, Cavalier King Charles Spaniels, Miniature Schnauzers, Shih Tzu, Boston Terriers, Bernese Mountain Dogs, Pomeranians, Havanese, Shetland Sheepdogs, Brittanys, Spaniels (English Springer), Pugs, Mastiffs, Spaniels (Cocker), Vizslas, Cane Corso, Chihuahuas, Miniature American Shepherds, Border Collies, Weimaraners, Maltese, Collies, Basset Hounds, and Newfoundlands.

[0088] In some embodiments, the companion animal is a healthy dog (e.g., non-diabetic, and / or free of cancer or cancerous tumor diseases, and / or free of a hormonal disorder such as acromegaly and / or free of a cardiovascular disease). In some embodiments, the companion animal has a metabolic disease or disorder (e.g., diabetes), or has an elevated risk of developing a metabolic disease or disorder based on its age (e.g., 7 years or older) and / or sizeWSGR Docket No. 58989-728.601 (e.g., 18 kg or more). In some embodiments, the companion animal has an insulin-like growth factor-1 concentration of about 100 ng / mL or higher.

[0089] In some embodiments, the subject is an adult human. In some embodiments, the human has an age in a range of from about 25 to about 100 years old (e.g., from about 30 to about 100 years old, from about 35 to about 100 years old, from about 40 to about 100 years old, from about 45 to about 100 years old, from about 50 to about 100 years old, from about 55 to about 100 years old, from about 60 to about 100 years old, from about 65 to about 100 years old, from about 70 to about 100 years old, from about 75 to about 100 years old, from about 80 to about 100 years old, from about 85 to about 100 years old, from about 90 to about 100 years old or from about 95 to about 100 years old, or older).

[0090] The herein-disclosed compositions and methods treat, prevent, reduce the severity of, and / or delay the onset of various aging-associated conditions, e.g., cellular senescence, chronic diseases and disabilities / conditions of aging. Illustrative aging-associated conditions include age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cancer, cardiovascular decline, cataracts, constipation, decrease in visual acuity, decrease in overall energy, delirium, dementia, depression, diminished peripheral vision, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased inflammation, increased susceptibility to infection (including influenza and pneumonia), kidney disease, memory loss, metabolic syndrome, muscle atrophy, osteoporosis, reduced metabolism (including increased risk for obesity), reduced reflexes and coordination including difficulty with balance, respiratory disease, shingles, type 2 diabetes, urologic changes (including incontinence), whitening or graying of hair, and wrinkling and sagging skin (including loss of skin elasticity). Aged non-human subjects experience similar, homologous, and / or equivalent aging- associated conditions. Biomarkers

[0091] Methods of the present disclosure may further comprise detecting (e.g., detecting the presence, amount, or level of) one or more biomarkers in a first blood sample, wherein the first blood sample is obtained from the companion animal before administering the pharmaceutical composition. In some embodiments, the methods further comprise detecting one or more biomarkers in a second blood sample, wherein the second blood sample is obtained from the companion animal after administering the pharmaceutical composition. In some embodiments, the methods disclosed herein modulate (e.g., increase or decrease, e.g.,WSGR Docket No. 58989-728.601 by about 5%, 10%, 15%, 20% or more) one of the biomarkers disclosed herein. In some embodiments, the methods disclosed herein prevent an age-associated increase or decrease (e.g., by about 5%, 10%, 15%, 20% or more) of the biomarkers disclosed herein.

[0092] The methods disclosed herein may further comprise identifying and / or causing a change of one or more biomarkers selected from IGF-1, IGF-2, IGF-1R, phosphorylated IGF- 1R, glucose, Growth Hormone (GH), GH-receptor, phosphorylated GH-receptor, IGFBP1, IGFBP3, IGFBP3-IGF-1 isoform levels, insulin, pregnancy-associated plasma protein A (PAPP-A), PAPP-A2, P13Kinase, IRS-1, Ras / Raf, MEK, ERK, Akt, and Rac, or a homolog thereof in the second sample relative to the first sample and / or relative to a historical control. In some embodiments, the methods disclosed herein comprise modulating the amount of free IGF-1 to IGF-1 that is bound to an insulin-like growth factor-binding protein (IGFBP, e.g., one of IGFBP1 to IGFBP6) in the second sample relative to the first sample and / or relative to a historical control.

[0093] As used herein, a change in a biomarker may be an increase in the biomarker in a second sample obtained from a mammal relative to a first sample or relative to a historical control. The terms increased or increase, and the like, are used herein to generally mean an increase by any measurable amount. In some embodiments, an increase may be by a statistically significant amount. In some embodiments, the terms increased or increase means an increase of at least 10% as compared to a reference level, for example an increase of at least about 10%, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase, or a greater increase, as compared to a reference level, e.g., an earlier-collected sample from a subject (e.g., before administration of a composition of the present disclosure), standard, or control, including historical control. Other examples of increase include an increase of at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold or as compared to a reference level, e.g., an earlier-collected sample from a subject (e.g., before administration of a composition of the present disclosure), standard, or control, including historical control.

[0094] Alternately, a change in a biomarker may be a decrease in the biomarker in a second sample obtained from a mammal relative to a first sample or relative to a historical control. The terms decreased, or decrease, and the like, are used herein generally to mean a decrease by any measurable amount. In some embodiments, a decrease may be by a statistically significant amount. In some embodiments, decreased or decrease means a reduction by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at leastWSGR Docket No. 58989-728.601 about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease, as compared to a reference level, e.g., an earlier-collected sample from a subject (e.g., before administration of a composition of the present disclosure), standard, or control, including historical control.

[0095] As used herein, a historical control is where previous-obtained data is used to compare with new data. Information, e.g., the standard, median, normal, or pre-treatment serum amount / level / concentration of a biomarker, is essentially borrowed from historical data. The historical data is usually from a subject with the same characteristics, e.g., species, strain, breed, sex, age, weight, size, health, and / or disease status.

[0096] Another aspect of the invention is a method of: increasing lifespan or healthspan of a subject, increasing quality of life of a subject, maintaining healthy function of a subject, delaying mortality of a subject due to age-associated diseases, preventing, delaying, or reducing frailty of a subject, preventing, delaying, or reducing or death by euthanasia of a subject, or treating an aging-induced insulin resistance of a subject; wherein the method further comprises reducing the amount or concentration of one or more biomarkers in the serum of the subject by an effective amount (e.g., by about 10% to about 99%), by administering to the subject any one of the compositions disclosed herein (e.g., a pharmaceutical composition comprising at least 1 mg (preferably about 50 mg to about 500 mg) of a somatostatin analogue (preferably octreotide), or a pharmaceutically acceptable salt thereof (preferably octreotide acetate), wherein the pharmaceutical composition is in the form of an extended release injectable composition or drug depot). In some embodiments, the one or more biomarkers comprises insulin (e.g., fasting insulin), insulin sensitivity (or resistance), glucose, insulin-like growth factor-1, growth hormone, thyroxine, and / or fatty acid concentrations (e.g., palmitic acid, oleic acid, linoleic acid, free fatty acids, saturated fatty acids). In some embodiments, the one or more biomarkers comprises insulin. In some embodiments, the one or more biomarkers comprises fasting insulin. In some embodiments, the one or more biomarkers is blood glucose. In some embodiments, the one or more biomarkers is insulin-like growth factor-1 (IGF-1). In some embodiments, the one or more biomarkers is growth hormone (GH). In some embodiments, the one or more biomarkers is thyroxine. In some embodiments, the one or more biomarkers is a fatty acid concentrationWSGR Docket No. 58989-728.601 (e.g., palmitic acid, oleic acid, linoleic acid, free fatty acids, saturated fatty acids). For example, the methods disclosed herein may further comprise reducing the serum concentration of palmitic acid, oleic acid, or linoleic acid. In some embodiments, the methods disclosed herein may further comprise reducing the serum concentration of free fatty acids and / or saturated fatty acids. Health Surveys

[0097] Another aspect of the present invention is the use of a composition disclosed herein for improving not only the health of a subject, but also the perception of health by a companion of the subject. For example, it is known that one of the leading causes of death for companion animals such as dogs, particularly in old age, is death by euthanasia. A key driver of death by euthanasia is poor health, or the perception of poor health by an owner of the companion animal. Therefore, not only is it critical that the compositions provided herein improve the healthspan of a companion animal, but also that the companion animal is perceived as being healthy (i.e., free of pain and / or chronic or degenerative diseases). As described herein, the VetMetrica Health Related Qualify of Life (HRQL) questionnaire is a health survey designed to measure owner perceptions of the quality of life of their dog. It therefore follows that improvements in the HRQL (i.e., improved perceptions of quality of life) correlate to decreased death by euthanasia. In some embodiments, provided herein is a method of preventing, delaying, or reducing or death by euthanasia of a subject, the method comprising administering to the subject a composition disclosed herein, thereby improving the HRQL score of the subject and preventing, delaying, or reducing or death by euthanasia.

[0098] Another health survey described herein is the Canine Frailty Index (CFI). The CFI is a validated predictor of mortality risk in dogs. It is a survey administered to the owner of the companion animal to assess the perceived frailty of the companion animal, which also correlates to disease burden associated with advanced age. In some embodiments, provided herein is a method of preventing, delaying, or reducing or death by euthanasia of a subject, the method comprising improving the CFI score of the subject, thereby preventing, delaying, or reducing or death by euthanasia. In some embodiments, the improving the CFI score of the subject comprises administering to the subject a composition disclosed herein.

[0099] In some embodiments, the methods disclosed herein comprise evaluating the companion animal in a health survey. In some embodiments, the health survey is performed before the pharmaceutical composition is administered. In some embodiments, the health survey is performed after the pharmaceutical composition is administered. In someWSGR Docket No. 58989-728.601 embodiments, the health survey is a health-related quality of life (HRQL) assessment, physical examination, body condition score, muscle condition score, or assessment of frailty (e.g., a canine frailty index (CFI)). In some embodiments, the improving the healthspan of the companion animal comprises improving the quality of life of the companion animal, as determined based on a health-related quality of life (HRQL) assessment or a canine frailty index (CFI) assessment, wherein the quality of life is measured by an HRQL score and / or a CFI score, and wherein the HRQL score or the CFI score is improved by about 5% to about 100% (e.g., about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 75%, about 5% to about 80%, about 5% to about 90%, about 5% to about 95%, or about 5% to about 99%). In some embodiments, the method comprises improving the HRQL score or the CFI score by about 0.1 points, 0.2 points, 0.3 points, 0.4 points, 0.5 points, 1 point, 1.5 points, 2 points, 2.5 points, 3 points, 4 points, 5 points, or more. Definitions

[0100] The terminology used herein is for the purpose of describing particular cases only and is not intended to be limiting.

[0101] As used herein, unless otherwise indicated, the terms “a”, “an” and “the” are intended to include the plural forms as well as the single forms, unless the context clearly indicates otherwise.

[0102] The terms “comprise”, “comprising”, “contain,” “containing,” “including”, “includes”, “having”, “has”, “with”, or variants thereof as used in either the present disclosure and / or in the claims, are intended to be inclusive in a manner similar to the term “comprising.”

[0103] By preventing is meant, at least, avoiding the occurrence of a disease and / or reducing the likelihood of acquiring the disease. By treating is meant, at least, ameliorating or avoiding the effects of a disease, including reducing a sign or symptom of the disease.

[0104] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean 10% greater than or less than the stated value. In another example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the given value.WSGR Docket No. 58989-728.601

[0105] Where particular values are described in the application and claims, unless otherwise stated the term “about” should be assumed to mean an acceptable error range for the particular value.

[0106] The term “acceptable” or “pharmaceutically acceptable”, with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.

[0107] The terms “effective amount” or “therapeutically effective amount,” as used herein, generally refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount (i.e., an amount effective for prevention or delay of onset of a condition). An “effective amount” of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effective amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism, age, weight, general condition of the subject, the condition being treated. By way of example only, therapeutically effective amounts may be determined by a dose escalation clinical trial.

[0108] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein. Examples

[0109] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art.WSGR Docket No. 58989-728.601 Example 1. Metabolic Aging Biomarkers in the HRQL Study

[0110] An observational Healthspan study was performed which involved a health related quality of life assessment (HRQL). The study endpoints included owner assessment of Health Related Quality of Life (HRQL), and veterinarian assessment of Physical Examination, Body Condition Score (BCS), Muscle Condition Score, Complete Blood Count, biochemical profile, serum T4 measurement, urinalysis, insulin-like growth factor-1 measurement, and Canine Frailty Index score (CFI). Blood samples were collected to assess serum for fasted insulin and adiponectin levels. DNA samples were also collected. Target demographics were collected within 451 eligible adult dogs, 43.6% of which were mixed breed and 56.4% of which were pure breed. Target age and size of dogs on which enrollment was based is shown below in Table 1. Table 1: Demographics of dogs enrolled in HRQL study

[0111] Approximately 451 dogs were evaluated, and about 450 dogs were assessed using the HRQL. Approximately 409 dogs were assessed for fasted insulin levels, and approximately 352 dogs were assessed for adiponectin levels. Bivariate relationships found between insulinWSGR Docket No. 58989-728.601 and age, insulin and weight, insulin and BCS, insulin and HRQL, and insulin and CFI are shown below in Table 2. Table 2: Correlation coefficients evaluating bivariate relationships between factors of interest in HRQL study

[0112] The data from the HRQL study were analyzed using a quantile regression model to estimate joint effects of the variables in Table 2. Multiple median regression was performed using a full main effects model, an interaction model with age multiplied by weight, and an interaction model with age and BCS, shown below in Table 3. A graphical representation of the association between age and standardized log(insulin) for dogs is shown in FIG. 1. Table 3: Multiple median regression results for variables in the HRQL studyWSGR Docket No. 58989-728.601scores in the Healthspan Study. To determine HRQL, a survey was administered to owners of participants to measure owner perceptions of their dog’s quality of life. The questionnaire included about 22 questions concerning the impacts of aging, disease, and clinical management of disease. These questions encompassed inquiries about the dog’s behavior for areas including Energetic / Enthusiastic (E / E), Happy / Content (H / C), Active / Comfortable (A / C), and Calm / Relaxed (C / R). The answers to these questions were composited or combined into a single score known as total HRQL. The Davies transformation was applied to normalize the scores. Multiple median regression models were used to discern the relationship between insulin and HRQL. Standardized log(insulin) was the primary variable, with age, weight, and BCS as covariates, results of which are shown below in Table 4 and FIG 2. Multiple ordinary least squares regression models were used to discern the relationship between insulin and CFI, and its acceleration with age. Standardized log(insulin) and its interaction with age was the primary with, weight and BCS as covariates, results of which are shown in Table 5 and FIG 3. Table 4: Multiple median regression of insulin blood levels with HRQL adjusting for age, weight, and BCSTable 5: Multiple linear regression of interaction effect between age and standardized insulin on standardized CFI.WSGR Docket No. 58989-728.601 Variable Coefficient (95% CI) p-valueIntercept -0.72 (-1.16, -0.28) 0.001** Age (yrs) 0.18 (0.16, 0.20) <0.001*** Standardized(Insulin) -0.10 (-0.23, 0.04) 0.161 Weight (kg) 0.00 (0.00, 0.01) 0.222 BCS -0.14 (-0.22, -0.06) <0.001*** Age (yrs) x Standardized(Insulin) 0.02 (0.00, 0.04) 0.028* Example 2. A 14 day study of octreotide acetate by BID subcutaneous injection in dogs

[0114] Two female and one male 8-11-month-old Beagle dogs were subcutaneously injected 1 to Day 14). Administration of octreotide acetate by twice daily subcutaneous injection successfully lowered IGF-1 levels in the dog and this effect was maintained for the duration of active dosing (FIG. 4). A maximum percent decrease of 55.30% (mean 55.30% ± 6.02, p = 0.03) in IGF-1 levels was seen on Day 12 of octreotide exposure. Example 3. A Single-dose Study of Sandostatin LAR by Intramuscular Injection and Clonidine by Intravenous Bolus in Dogs

[0115] A 42-day dose determination study was run in twelve 6-7 month old mongrel dogs with two doses, 10 mg or 20 mg, of Sandostatin Long-Acting Release (LAR), administered as a single intramuscular injection on Day 1. The 10mg LAR achieved 22.8% average IGF-1 reduction from baseline levels and 20 mg LAR achieved 23.1% average IGF-1 reduction from baseline levels (FIG. 5). IGF-1 inhibition was less variable and more consistent in the 20 mg LAR group across the 42 days. This study included male and female subjects, and no significant differences were observed in any analysis between the sexes. Example 4. Octreotide prevents increases of fasting insulin in an accelerated aging model, and preserves insulin sensitivity

[0116] High fat diets have been commonly used to temporarily induce certain disease states in otherwise healthy laboratory animals. In dogs, high fat diet feeding leads to reductions in insulin sensitivity, accumulation of visceral and whole body adiposity, dyslipidemia, and hyperinsulinemia. While this phenotype is observed to occur over several years in healthy dogs due to natural aging, the high fat diet manifests these effects within a significantly shorterWSGR Docket No. 58989-728.601 vicious cycle that drives the tissue decline in aging is apparent with high fat diet feeding in dogs. The consumption of the high fat diet leads to expanded adipose tissue, increased fatty acid concentrations and the formation of ectopic lipids. Aged and higher weight companion dogs have been shown to exhibit changes to their plasma lipidome, including a rise in triglycerides and several lipid species. This high fat diet induced phenotype leads to peripheral insulin resistance, dyslipidemia and hyperinsulinemia, with adult dogs being more prone to these effects from the diet due to their age-related susceptibility to metabolic dysfunction.

[0117] This phenotype resulting from high fat diet feeding is conserved across preclinical species, as this has been consistently demonstrated in rodent models of varying feed duration. These studies in rodents show a consistent pattern of increased adiposity, declines in insulin sensitivity, dyslipidemia and hyperinsulinemia. While the primary endpoint of many high fat diet rodent studies is not related to lifespan, it has been previously demonstrated that high fat diet feeding leads to increased mortality in certain strains of mice. Taken together, the hallmarks of high fat diet feeding mirror the physiological decline that occurs with aging, and therefore high fat diet is a predictive model of accelerated metabolic aging.

[0118] In a laboratorystudy conducted over 12 weeks in 44 healthy dogs, subjects were fed a high fat diet to induce an accelerated aging phenotype. Octreotide mitigated the deleterious effect of the high fat diet on insulin sensitivity and metabolic dysfunction. The study was run in male dogs ages 4 to 7 years old of mixed castration status. The study was run in males only because of the known impact of the estrous cycle on IVGTT readouts. Before initiation of the high fat diet, the dogs ranged between a 4 to 6 on body condition score (BCS) and 13 to 26 kg in weight, with an average BCS of 5 ± 0.38 and body weight of 17.8 ± 3.4 kg.

[0119] Dogs in this study were maintained at baseline on a diet consisting of 55% fat prior to enrollment. Although the macronutrient composition of this diet would generally be considered “high fat”, the vast majority of the fat in the baseline diet was derived from salmon oil and ostrich which have been demonstrated to have minimal detrimental metabolic signature. During the high fat diet phase of the study, the diets were supplemented with pork lard to reach 74% fat.

[0120] Dogs were randomly assigned to one of the following groups (Table 6) and injected i.m. with placebo (0.9% sterile saline) or octreotide (Sandostatin LAR, a long-acting release formulation of octreotide acetate) on days 0 and 42. Table 6: Study groups for the High Fat Diet StudyWSGR Docket No. 58989-728.601

[0121] Metabolic homeostasis was assessed by several metabolic health parameters, including insulin sensitivity, generated by intravenous glucose tolerance tests (IVGTT) at baseline and after 12 weeks of normal diet or high fat diet, with or without octreotide treatment. Fasting blood samples were taken on Day -12 (pre-treatment baseline) and Day 70 (post-treatment) for levels of glucose and insulin. Blood was separated into serum fraction for glucose measurements and plasma fraction for insulin measurements.

[0122] IVGTTs were performed on Day -12 (pre-treatment baseline) and Day 70 (post- treatment). Dogs were fasting overnight prior to conducting the procedure. Blood was sampled and serum and plasma separated at -10 and -1 minutes pre-glucose bolus to establish fasting glucose and insulin values. At 0 minutes (t=0), a glucose bolus (0.3g / kg, i.v.) was delivered. At t=20 minutes a bolus of insulin (0.03 U / kg, i.v.) was delivered. Blood was collected at 2, 4, 6, 10, 14, 19, 22, 30, 40, 50, 60, 80, 100, 120, 150, and 180 minutes post-glucose bolus. For each time point, serum was analyzed for glucose and plasma was analyzed for insulin levels. In a masked fashion, glucose and insulin values were entered into the MINMOD Millennium 6.02 software to generate parameter estimates including insulin sensitivity (SI).

[0123] All dogs were presumed equal during the pre-treatment (baseline) and pre-diet phase of the study, and therefore all baseline data from the 43 dogs that participated in the study through Day 70 were pooled to give a “Pooled Baseline”. The mixed-effects statistical model used for analysis takes into account each individual dog’s baseline parameter values when comparing to its Day 70 values, thereby measuring the contribution of each animal to the overall variance of the dataset. Therefore, the Day 70 vs. Pooled Baseline comparison allows for the interpretation of how much each individual within each group changed from its own baseline due to the effect of the diet and to what degree the octreotide prevented that change from baseline from occurring. Octreotide levels were measured to ensure target plasma concentrations were maintained across the study. Both the octreotide-treated groups (Group 2 and Group 4) achieved and maintained and receded at Day 84WSGR Docket No. 58989-728.601 -treated groups (2 and 4). No detectable level of octreotide was found in placebo-treated dogs from Groups 1 and 3 (FIG. 6).

[0124] The serum IGF-1 levels in dogs on the normal diet with placebo remained steady throughout the study. The dogs on the normal diet treated with octreotide had reduced IGF-1 levels, as expected. Dogs on the high fat diet with placebo had a large increase in IGF-1 levels, which was mitigated in dogs on the high fat diet treated with octreotide. These data are presented in FIG. 7.

[0125] In FIG. 7, Group 1 dogs were treated with placebo on days 0 and 42, on a normal diet; Group 2 dogs were treated with a single dose of octreotide on days 0 and 42, on a normal diet; Group 3 dogs were treated with placebo on days 0 and 42, on a high fat diet; and Group 4 dogs were treated with a single dose of octreotide on days 0 and 42, on a high fat diet.

[0126] At baseline, all groups had similar fasting insulin concentrations (FIG. 8). By Day 70, insulin levels in the dogs on the high fat diet treated with placebo were significantly higher as compared to the dogs on the high fat diet treated with octreotide (FIG. 8, Panel B). When expressed as a percent change from baseline (FIG. 8, Panel D), fasting insulin in the dogs on the high fat diet treated with placebo had a significantly larger increase (104.3%) than in the dogs on the high fat diet treated with octreotide (39.5%), suggesting that octreotide blunted the high fat diet-induced elevation of fasting insulin. While there was no statistically significant difference in percent change between the dogs on the normal diet treated with placebo and those on the normal diet treated with octreotide, FIG. 8, Panels A and C show that octreotide treatment led to reduced insulin levels.

[0127] Day 70 SI values are shown in Table 7. By Day 70, only dogs on the high fat diet treated with placebo showed significantly lower average SIvalues relative to the pooled baseline and dogs on the normal diet treated with octreotide. The dogs on the high fat diet treated with octreotide did not show a significant difference from any other group, suggesting that the drop in SIcaused by high fat diet was mitigated by octreotide. Likewise, the dogs on the normal diet treated with placebo did not show a statistically significant difference in SIvalues from any other Group. Table 7: Insulin sensitivity (SI) at day 70. All values are presented as mean ± SEM.WSGR Docket No. 58989-728.601

[0128] Percent change in SI from baseline values are represented in FIG. 9. By Day 70, SI values declined more in the dogs on the high fat diet treated with placebo than in the dogs on the high fat diet treated with octreotide. Furthermore, the dogs on the normal diet treated with placebo and the dogs on the normal diet treated with octreotide showed similar percent change in SI values. Relative to the dogs on the normal diet treated with placebo and the dogs on the normal diet treated with octreotide, the dogs on the high fat diet treated with placebo demonstrated a statistically significant decline in SI values. The percent change in SI values in the dogs on the high fat diet treated with octreotide was not statistically different from any of the other groups, providing supportive evidence of a protective effect of octreotide on changes within this parameter. INCORPORATION BY REFERENCE

[0129] The synthesis of biodegradable polymer microspheres are generally described in the US patent application No. 17 / 773520, filed October 30, 2020 and published as US20220409730A1; US patent application No. 17 / 281902, filed October 2, 2019 and published as US20220062177A1; US patent application No. 14 / 233961, filed July 23, 2012 and published as US20140199385A1; US patent application No. 15 / 677442, filed August 15, 2017 and published as US20180085318A1; and US patent application No. 17 / 765389, filed September 30, 2020 and published as US20220332900A1. The microspheres disclosed in the incorporated references may be used in conjunction with the present invention. Compositions comprising octreotide described in PCT / US2024 / 021723, filed March 27, 2024, may also be used in conjunction with the present invention. The above-identified patent applications are incorporated by reference in their entirety. In the event of a conflict between a term herein and a term in an incorporated reference, the term herein controls.

[0130] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understoodWSGR Docket No. 58989-728.601 that various alternatives to the embodiments described herein may be employed. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No. 58989-728.601 CLAIMS We claim:

1. A method of increasing lifespan, increasing quality of life, or maintaining healthy function in a companion animal, the method comprising reducing, or preventing age-related increase of, a fasting insulin value of the companion animal, wherein the reducing, or preventing age-related increase of, the fasting insulin value comprises administering to the companion animal a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot.

2. A method of delaying mortality due to age-associated diseases in a companion animal, the method comprising administering to the companion animal a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot.

3. A method of preventing or reducing frailty or death by euthanasia in a companion animal, the method comprising reducing growth hormone (GH) and / or insulin-like growth factor-1 (IGF-1) in the companion animal, wherein the reducing GH and / or IGF-1 comprises administering to the companion animal a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot.

4. A method of treating an aging-induced insulin resistance in a companion animal in need thereof, the method comprising administering to the companion animal a therapeutically effective amount of a pharmaceutical composition comprising at least 1 mg of a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended-release injection or drug depot.

5. The method of any one of claims 1-4, wherein the pharmaceutical composition comprises from about 1 mg to about 1 g of the somatostatin analogue, or the pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1-5, wherein the pharmaceutical composition comprises from about 50 mg to about 500 mg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof.WSGR Docket No. 58989-728.601 7. The method of any one of claims 1-6, wherein the pharmaceutical composition comprises from about 75 mg to about 300 mg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1-4, wherein the pharmaceutical composition comprises about 100 mg or more of the somatostatin analogue, or the pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1-8, wherein the pharmaceutical composition comprises about 0.1 mg to about 10 mg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof, per kg of body weight of the companion animal.

10. The method of any one of claims 1-4, wherein the pharmaceutical composition comprises about 1 mg of the somatostatin analogue, or the pharmaceutically acceptable salt thereof, per kg of body weight of the companion animal.

11. The method of any one of claims 1-10, wherein the somatostatin analogue is octreotide, lanreotide, or pasireotide, or a pharmaceutically acceptable salt or prodrug thereof.

12. The method of any one of claims 1-11, wherein the somatostatin analogue, or the pharmaceutically acceptable salt thereof is octreotide acetate, octreotide trifluoroacetate, or octreotide HCl.

13. The method of any one of claims 1-12, wherein the somatostatin analogue, or the pharmaceutically acceptable salt thereof is octreotide acetate.

14. The method of any one of claims 1-13, wherein the pharmaceutical composition is a subcutaneous or intramuscular drug depot of octreotide, or a pharmaceutically acceptable salt thereof.

15. The method of any one of claims 1-14, wherein the pharmaceutical composition is a subcutaneous drug depot injection of octreotide, or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1-15, wherein the pharmaceutical composition is an extended-release injection of octreotide, or a pharmaceutically acceptable salt thereof.

17. The method of any one of claims 1-16, wherein the pharmaceutical composition comprises a polymer microparticle.WSGR Docket No. 58989-728.601 18. The method of any one of claims 1-17, wherein the pharmaceutical composition is a subcutaneous drug depot of octreotide, or a pharmaceutically acceptable salt thereof, wherein the octreotide or the pharmaceutically acceptable salt thereof is enveloped in a polymer microsphere.

19. The method of any one of claims 1-13, wherein the extended-release injection or drug depot releases the somatostatin analogue, or the pharmaceutically acceptable salt thereof, over the course of about 1 month to about 2 years.

20. The method of any one of claims 1-13, wherein the extended-release injection or drug depot releases the somatostatin analogue, or the pharmaceutically acceptable salt thereof, over the course of about 3 months to about 6 months.

21. The method of any one of claims 1-18, wherein the pharmaceutical composition is administered no more than once per month.

22. The method of any one of claims 1-18, wherein the pharmaceutical composition is administered about once per month to about once per year.

23. The method of any one of claims 1-18, wherein the pharmaceutical composition is administered about once every 3 months to about once every 6 months.

24. The method of any one of claims 1-18, wherein the pharmaceutical composition is administered for a period of a year or more.

25. The method of any one of claims 1-24, wherein the companion animal is a canine.

26. The method of any one of claims 1-24, wherein the companion animal is a dog.

27. The method of any one of claims 1-26, wherein the companion animal has a mass of about 0.5 kg to about 150 kg.

28. The method of any one of claims 1-27, wherein the companion animal is a dog having a mass of about 2 kg to about 12 kg.

29. The method of any one of claims 1-27, wherein the companion animal is a dog having a mass of about 13 kg to about 26 kg.WSGR Docket No. 58989-728.601 30. The method of any one of claims 1-27, wherein the companion animal is a dog having a mass of about 26 kg to about 45 kg.

31. The method of any one of claims 1-27, wherein the companion animal is a dog having a mass of about 45 kg or more.

32. The method of any one of claims 1-27, wherein the companion animal is a dog having a mass of about 18 kg or more.

33. The method of any one of claims 1-32, wherein the companion animal has an age of about 2 years to about 18 years.

34. The method of any one of claims 1-33, wherein the companion animal has an age of about 4 years to about 7 years.

35. The method of any one of claims 1-33, wherein the companion animal has an age of about 7 years or more.

36. The method of any one of claims 1-26, wherein the companion animal is a dog having a mass of about 18 kg or more, and / or an age of about 7 years or more.

37. The method of any one of claims 1-36, wherein the companion animal is a healthy dog (e.g., non-diabetic, and / or free of cancer or cancerous tumor diseases, and / or free of a hormonal disorder such as acromegaly and / or free of a cardiovascular disease).

38. The method of any one of claims 1-36, wherein the companion animal has a metabolic disease or disorder (e.g., diabetes), or has an elevated risk of developing a metabolic disease or disorder based on its age (e.g., 7 years or older) and / or size (e.g., 18 kg or more).

39. The method of any one of claims 1-38, wherein the companion animal has an insulin- like growth factor-1 concentration of about 100 ng / mL or higher.

40. The method of claim 1, wherein the increasing lifespan comprises an at least 5% increase in lifespan relative to the median lifespan of the companion animal.

41. The method of claim 1, wherein the increasing lifespan comprises about a 5% increase to about a 50% increase in lifespan relative to the median lifespan of the companion animal.WSGR Docket No. 58989-728.601 42. The method of any one of claims 1-41, further comprising detecting one or more biomarkers in a first blood sample, wherein the first blood sample is obtained from the companion animal before administering the pharmaceutical composition.

43. The method of any one of claims 1-41, further comprising detecting one or more biomarkers in a second blood sample, wherein the second blood sample is obtained from the companion animal after administering the pharmaceutical composition.

44. The method of claim 42 or 43, wherein the one or more biomarkers comprises insulin, insulin sensitivity, glucose, insulin-like growth factor-1, growth hormone, thyroxine, and / or fatty acid concentrations.

45. The method of any one of claims 42-44, wherein the one or more biomarkers comprises fasting insulin.

46. The method of any one of claims 1-45, further comprising evaluating the companion animal in a health survey.

47. The method of claim 46, wherein the health survey is performed before the pharmaceutical composition is administered.

48. The method of claim 46 or 47, wherein the health survey is performed after the pharmaceutical composition is administered.

49. The method of any one of claims 46-48, wherein the health survey is a health-related quality of life (HRQL) assessment, physical examination, body condition score, muscle condition score, or assessment of frailty (e.g., a canine frailty index (CFI)).

50. The method of any one of claims 1 to 49, wherein the administering the pharmaceutical composition improves the healthspan of the companion animal.

51. The method of claim 50, wherein the improving the healthspan of the companion animal comprises improving the quality of life of the companion animal, as determined based on a health-related quality of life (HRQL) assessment or a canine frailty index (CFI) assessment, wherein the quality of life is measured by an HRQL score and / or a CFI score, and wherein the HRQL score or the CFI score is improved by about 5% to about 100%.WSGR Docket No. 58989-728.601 52. The method of claim 50 or 51, wherein the improving the healthspan of the companion animal comprises preventing, delaying, treating, or reducing a symptom of an age-associated disease relative to the median incidence, severity, or age of onset.

53. The method of claim 2 or 52, wherein the age-associated disease is a metabolic disease or disorder.

54. The method of claim 2 or 52, wherein the age-associated disease is a musculoskeletal disease or disorder (e.g., a degenerative orthopedic disease).

55. The method of claim 2 or 52, wherein the age-associated disease is not a cardiovascular disease or disorder.

56. The method of claim 2 or 52, wherein the age-associated disease comprises cognitive dysfunction or decline.

57. The method of claim 2 or 52, wherein the age-associated disease is selected from the group consisting of frailty, dementia, sarcopenia, osteopenia, osteoporosis, osteoarthritis, obesity, hypertension, diabetes mellitus, metabolic syndrome, chronic inflammation, chronic pain, pancreatitis, liver disease, renal disease, hyperlipidemia, hepatic steatosis, and steatohepatitis, or a combination thereof.

58. A pharmaceutical composition comprising a somatostatin analogue, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot, for use in the method of any one of claims 1-57.

59. A pharmaceutical composition comprising a somatostatin analogue, or a pharmaceutically acceptable salt or prodrug thereof, wherein the pharmaceutical composition is in the form of an extended release injection or drug depot, for use in the manufacture of a medicament for increasing lifespan or healthspan; maintaining healthy function; delaying or preventing age-associated diseases; or reducing, delaying, or preventing frailty, in a companion animal.

60. The pharmaceutical composition of claim 58 or 59, for use in a dog having a mass of about 18 kg or more, and / or an age of about 7 years or more.WSGR Docket No. 58989-728.601 61. The pharmaceutical composition of claim 58 or 59, wherein the somatostatin analogue is octreotide, or a pharmaceutically acceptable salt or prodrug thereof, provided in an amount of about 50 mg to about 500 mg.

62. The pharmaceutical composition of claim 61, wherein the somatostatin analogue is octreotide, or a pharmaceutically acceptable salt or prodrug thereof, provided in an amount of about 75 mg to about 300 mg.

63. The pharmaceutical composition of claim 62, wherein the octreotide, or the pharmaceutically acceptable salt or prodrug thereof, is formulated in a polymer microparticle.

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