Detecting and treating growth hormone deficiency

Abstract

To provide pharmaceutical compositions for use in the treatment of growth hormone deficiency (GHD) and theranostic tests in children with GHD.SOLUTION: Provided is a pharmaceutical composition containing MK-0677. A theranostic study includes: (i) testing the child for a peak serum GH of 5 μg / L or greater in response to a single oral dose of 0.4 to 1.2 mg / kg / day of the pharmaceutical composition (equivalent to MK-0677); and (ii) testing the child for a baseline serum IGF-I of greater than 30 ng / mL. The child is short in stature. The child is subjected to tests (i) and (ii), and those who satisfy both conditions are considered to have equivalent growth potential compared to those treated with rhGH. The pharmaceutical composition is administered to treat GHD in the child.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel oral method for using MK-0677 to detect growth hormone (GH) deficiency (GHD) in patients. The present invention also relates to a method for treating growth hormone (GH) deficiency (GHD) in children with a functional hypothalamic-pituitary GH axis. [Background technology]

[0002] Growth hormone (GH) is an anabolic anterior pituitary hormone that stimulates cell proliferation and differentiation through the synergistic action of GH and insulin-like growth factor-1 (IGF-1). In vivo, GH biosynthesis and secretion are regulated by the balance of growth hormone-releasing hormone (GHRH) and somatostatin (SST). GH secretion is also influenced by regulatory feedback mechanisms in both the hypothalamus and pituitary gland. GH secretion is important for normal skeletal growth during childhood, with peak secretion occurring during puberty. Inadequate GH secretion in children results in short stature, reduced height velocity, and delayed bone maturation.

[0003] Growth hormone deficiency (GHD), a subpopulation of children with short stature (3%), affects 1 in 3,700–4,000 children. Currently, the diagnosis of GHD is based on delayed growth, short stature, and delayed bone age. The diagnosis is then confirmed by performing GH stimulation tests. These standard stimulation tests include insulin-induced hypoglycemia, azinidine infusion, subcutaneous glucagon administration, or oral administration of levodopa or clonidine. While insulin-induced hypoglycemia is considered the most reliable, the two-hour test requires physician supervision of the child's management. Additionally, adverse reactions have occurred during insulin-induced hypoglycemia (REFS), including two reported deaths. For these reasons, insulin-induced hypoglycemia is not used by pediatric endocrinologists, and other tests are used instead. While the glucagon test is perhaps the most reliable, two additional tests are typically performed to further enhance reliability. Recently, growth hormone secretagogue receptor (GHS-R) agonists have been used and have the advantage of being highly reliable, but the peak GH response that defines GH deficiency is poorly characterized. It would be beneficial to develop a GHD test that is easier to use, safer, and / or more reliable than current tests.

[0004] Ibutamoren mesylate (MK-0677) was developed at Merck Research Laboratories (Merck) as a specific, orally active growth hormone secretagogue. Merck conducted a Phase IIb study in children with various degrees of short stature and growth hormone deficiency (GHD) between 1996 and 1998. Children were treated with either placebo, the growth hormone secretagogue receptor agonist MK-0677, or rhGH (recombinant hormone growth hormone). MK-0677 mimics the effects of the currently recognized natural ligand for the growth hormone secretagogue receptor (ghrelin). The study aimed to determine whether oral therapy with MK-0677 would effectively promote growth in children with short stature.

[0005] In a Phase IIb study, 24 children received 0.8 mg / kg / day of MK-0677. These children's baseline growth rate was 3.4 ± 1.7 cm / y (centimeters per year) and increased to 6.8 ± 2.0 cm / y at 6 months, representing a significant change in growth rate of 3.4 ± 2.1 cm / y. This can also be expressed as the standard deviation (SD) of height velocity at baseline of 0.4 ± 2.1 and 3.5 ± 2.0 at 6 months. In contrast, the group of 22 children treated with placebo had baseline growth rates of 4.2 ± 1.8 cm / y and 4.6 ± 1.4 cm / y at 6 months, representing no statistically significant change in growth rate of 0.4 ± 2.3 cm / y. The change in height velocity SD for chronological age was 0.4 ± 2.1 for placebo and 3.5 ± 2.0 for MK-0677 after 6 months of treatment at a dose of 0.8 mg / kg / day. Twenty of the 22 placebo-treated children were then given standard growth hormone (GH) treatment (daily subcutaneous injections of rhGH, 0.043 mg / kg / day). These children showed an increase in height velocity SD score for chronological age from 0.3 ± 2.2 at baseline (i.e., after 6 months of placebo treatment) to 7.6 ± 5.6. Because the increase in height velocity SD was twice as great with GH than with MK-0677 treatment, MK-0677 was deemed less effective and not competitive with standard GH therapy, and the project was discontinued.

[0006] GHD, which causes short stature (height for chronological age -2 SD), is a disorder found worldwide. Treatment for short-statured, growth hormone-deficient children typically continues for many years from childhood diagnosis until final height is achieved. Results from a 6-month treatment assessment in newly diagnosed children can be highly variable due to differences in the underlying etiology of GH deficiency, the pattern of treatment initiation, and the rate of catch-up growth. Establishing a new growth trajectory in response to treatment typically requires more than one year of treatment. Treatment then often requires more than 10 years for these children to reach optimal adult height. Children with GHD are typically treated with daily subcutaneous injections of GH, a treatment that is painful, inconvenient, and can be distressing for some children, especially young children. If such a treatment could be shown to have similar efficacy to GH in a subset of GHD patients, it would be beneficial in terms of ease of treatment, patient convenience, and long-term adherence to non-injection-based treatments (e.g., once-daily oral treatment). Summary of the Invention [Means for solving the problem]

[0007] In one aspect, the present invention provides novel methods for testing for GHD.

[0008] In one aspect, the present invention provides a novel method for treating GHD in children with adequate GH secretory capacity.

[0009] In one aspect, the present invention provides a novel method of treating GHD in children with comparable growth potential compared to treatment with rhGH.

[0010] In another aspect, the present invention provides a novel method for testing and identifying patients for adequate GH secretory capacity.

[0011] In another aspect, the present invention provides a novel method for testing and identifying patients with comparable growth potential compared to treatment with rhGH.

[0012] These and other aspects, which will become apparent in the detailed description that follows, were achieved by the inventors' discovery that MK-0677 can be used to study GHD and to treat a specific subset of children with GHD. [Brief explanation of the drawings]

[0013] [Figure 1] Figure 1 shows height velocity after 6 months of treatment with rhGH (0.3 mg / kg / week; approximately 0.043 mg / kg / day subcutaneous injection) (N=20) and once-daily oral MK-0677 (0.8 mg / kg / day) (N=24). Response to rhGH was superior to MK-0677 in all patient groups. [Figure 2] Figure 2 compares baseline IGF-I with the acute GH response to MK-0677. A close correlation is observed between baseline IGF-I and the acute GH response to MK-0677 (R2 = 0.7186). A weak correlation was observed between baseline IGF-I and the acute GH response to standard provocative diagnostic testing, but is not shown (R2 = 0.3316). [Figure 3] Figures 3A and 3B show the height velocity obtained for patients with low growth potential (LOW) (defined below) and patients with equal growth potential (EQUAL) who responded to MK-0677 0.8 mg / kJ / day compared with rhGH patients receiving GH or MK-0677, respectively. Figures 3A and 3B show that height velocity after 6 months of MK-0677 treatment was equivalent to GH treatment in the EQUAL patient group. [Figure 4] Figure 4A compares the response to GH and MK-0677 in all patients, and Figure 4B compares the response to GH and MK-0677 in EQUAL patients. The response to GH in all patient groups is superior to MK-0677. In contrast, the response to MK-0677 in the EQUAL patient group is equivalent to GH. [Figure 5]Figures 5A and 5B compare the responses to GH and MK-0677 in LOW and EQUAL patients. LOW patients are highly sensitive to GH. EQUAL patients have a smaller response to GH. Patients with LOW growth potential exhibit a poor growth response to MK-0677. In contrast, patients with EQUAL growth potential exhibit a growth response to MK-0677 that is not significantly different from their growth response to GH (P=0.125). DETAILED DESCRIPTION OF THE INVENTION

[0014] In one aspect of the present invention, a novel test was developed that has two objectives: (i) To provide a simple, reliable, and easily administered test to establish GHD that can be administered by a nurse without the need for a physician. (ii) To identify children with GHD who experience a growth velocity increase equivalent to that of daily subcutaneous (sc) recombinant GH (rhGH) injections upon once-daily oral MK-0677 treatment.

[0015] In the MK-0677 Phase IIb trial described above, all GHD children were grouped by Merck. However, when these characteristics were analyzed, these patients showed wide variation in GHD severity and height growth velocity. When these data were reanalyzed, taking into account GHD severity and the ability to respond to MK-0677 challenge with a GH response, the inventors surprisingly found that the growth response of a subset of children to oral treatment with MK-0677 was similar to this population's response to GH (i.e., rhGH) injections. Children who were severely GH deficient, as identified by an inability to increase peak GH levels above 5 μg / L and / or baseline IGF-I levels below 30 μg / L, increased height velocity in response to exogenous GH therapy. In contrast, children treated with MK-0677 showed poorer responses. However, children in the group with equivalent growth potential compared with rhGH (acute peak GH response of ≥5 μg / L and baseline serum IGF-I of >30 μg / L to a single dose of MK-0677) (EQUAL patient group) responded with equivalent growth responses to exogenous GH injections and daily oral dosing of MK-0677. By avoiding injections, once-daily oral administration of MK-0677 may have many advantages compared to GH injections, as the treatment regimen is significantly easier and may lead to greater patient adherence. Because adherence is a critical factor in any treatment, the ease of treatment with oral MK-0677 versus injected GH may allow physicians to choose long-term treatment with oral MK-0677 over injected GH, which provides similar efficacy in terms of height growth rate.

[0016] Severe GH deficiency is associated with low levels of serum IGF-I. Serum IGF-I is a biomarker of growth hormone action, and 80% of the serum IGF-I in the blood is produced in the liver. At baseline, the relationship between baseline serum IGF-I and peak responses to standard stimulation tests (clonidine, insulin, arginine, glucagon, and L-dopa) was r 2=0.3, while the relationship between baseline serum IGF-1 and peak GH response to MK-0677 was r 2 = 0.7, indicating that the MK-0677 test is a better indicator of endogenous growth hormone secretion than the standard test. Furthermore, the response to MK-0677 increases depending on the cutoff used for the standard test. Peak serum GH measured during the MK-0677 challenge test (single MK-0677 dose) remains stable. The presence of peak GH at 5 μg / L or greater indicates that the hypothalamic-pituitary GH axis can be stimulated by MK-0677, characterizing the patient as having GH secretory capacity. GH deficiency may be associated with severe deficiency, in which the hypothalamic-pituitary GH axis is damaged and does not respond to MK-0677 administration. Alternatively, hypothalamic-pituitary GH axis dysfunction may prevent the patient from secreting enough GH to maintain normal growth. In such patients, the MK-0677 test determines whether the GH axis is completely deficient or insufficiently secreting GH and can increase the GH response, indicating that the axis responds to MK-0677.

[0017] In another aspect, the present invention provides a novel method for treating growth hormone deficiency (GHD) in children, comprising administering a therapeutically effective amount of MK-0677 to a child known to have short stature and sufficient GH secretory capacity, or in another aspect, to a child known to have growth retardation.

[0018] In another embodiment, the present invention provides a novel method for treating GHD in children, comprising administering a therapeutically effective amount of MK-0677 to a child known to be short in stature and have comparable growth potential compared to rhGH. In another aspect, the child is known to have growth retardation.

[0019] In another aspect, the present invention provides a method of treating GHD in a child, comprising: a. Testing children for short stature; b. Testing for GHD using theranostic testing; c. A novel method is provided, comprising orally administering a therapeutically effective amount of MK-0677 to children who are known to be short in stature and have comparable growth potential compared to rhGH.

[0020] In another aspect, the present invention provides a novel method of treating GHD in a child, comprising: a. Testing children known to have short stature for GHD using theranostic testing; b. Orally administering a therapeutically effective amount of MK-0677 to a child known to have comparable growth potential compared to rhGH.

[0021] In another aspect, theranostic testing comprises: (i) Test for peak serum GH ≥ 5 μg / L in response to a single oral dose of MK-0677; (ii) testing for baseline serum IGF-I greater than 30 ng / mL.

[0022] In another aspect, theranostic testing comprises: (iii) further comprising testing for peak serum GH of less than 10 μg / L in response to a standard provocation test. Alternatively, the test is for peak serum GH levels less than 7 μg / L in response to a standard provocation test.

[0023] In another embodiment, pediatric GHD is treated.

[0024] In another embodiment, minitablets containing MK-0677 are administered orally.

[0025] In another embodiment, the number of minitablets can be adjusted to allow for weight-based dosing.

[0026] In another embodiment, the oral administration further comprises administering with a device capable of administering at least one MK-0677 minitablet.

[0027] In another aspect, the device comprises: a. reminding the patient or caregiver when medication should be administered; b. Dispensing the prescribed number of mini-pills; c. Recording the date and time of dispensing the mini-pills; d. Connecting remotely with healthcare professionals; e. have a dosage set by a healthcare professional or set with the approval of a healthcare professional; f. At least one of the devices is secure enough to prevent the patient from changing the number of pills dispensed.

[0028] In another embodiment, the device can have the dosage set remotely (e.g., via a wireless or wired connection to the internet) by or with the approval of a medical professional.

[0029] In some patients, particularly children, the hypothalamic-pituitary growth hormone axis is intact and further stimulation increases growth. Thus, the present invention also relates to the treatment of indications other than the classic GHD symptoms (e.g., pediatric GHD).

[0030] In another aspect, the present invention provides a novel method of treating a pediatric indication, comprising: a. Testing children for GHD using theranostic testing; and b. Oral administration of a therapeutically effective amount of MK-0677 to children known to have comparable growth potential compared to rhGH; Pediatric indications: (i) Small-for-gestational-age infants who fail to catch up with normal growth curves by age 2 years; (ii) Turner syndrome; (iii) SHOX gene deficiency; (iv) Noonan syndrome; (v) chronic renal failure; and (vi) idiopathic short stature.

[0031] In another aspect, the present invention provides a novel method of treating GHD in a child, comprising: (i) testing small (and possibly growth-retarded) children to determine whether they have adequate GH secretory capacity; (ii) if found to have sufficient GH secretory capacity, administering to the child a therapeutically effective amount of MK-0677.

[0032] In another aspect, (i) Testing for peak serum GH less than 10 μg / L in response to a standard provocation test; (ii) testing the children for adequate GH secretory capacity by a method that includes testing for peak serum GH of 5 μg / L or greater in response to a single oral dose of MK-0677. These cutoff values ​​for standard provocation testing are based on current generally accepted guidelines and rely on the use of well-validated clinical assays. Alternatively, the test is for peak serum GH levels of less than 7 μg / L for standard provocation testing.

[0033] In another aspect, the present invention provides a novel method of treating GHD in a child, comprising: (i) To test small (and possibly growth-retarded) children to determine whether they have equivalent growth potential compared to rhGH; (ii) administering to the child a therapeutically effective amount of MK-0677 if found to have equivalent growth potential compared to rhGH.

[0034] In another aspect, (i) testing for peak serum GH of 5 μg / L or greater in response to a single oral dose of MK-0677; and (ii) testing the children for equivalent growth potential compared to rhGH by some method, including testing for baseline serum IGF-I greater than 30 μg / L. These cutoff values ​​are based on current accepted guidelines and rely on the use of well-validated clinical assays.

[0035] In another aspect, the method of the invention further comprises testing the child to determine if the child is prepubertal, and continuing administration if the child is found to be prepubertal in addition to the findings above.

[0036] In another aspect, the method further comprises testing the child to determine if the child is peripubertal, and continuing the administration if the child is found to be peripubertal in addition to the findings above.

[0037] In another aspect, the present invention provides a novel theranostic test for determining whether a patient will respond to treatment with MK-0677, comprising: (i) testing patients for peak serum GH of 5 μg / L or greater in response to a single oral dose of MK-0677; (ii) testing the patient for a baseline serum IGF-I greater than 30 ng / mL; Patients who satisfy (i) and (ii) are considered responsive to treatment with MK-0677 and are offered theranostic trials.

[0038] In another aspect, testing the peak serum comprises: a. administering a single oral dose of MK-0677 to a patient; b. Testing the GH serum levels achieved after administering MK-0677 to determine the patient's peak serum GH levels; Includes:

[0039] In another aspect, the present invention provides a novel theranostic test for determining whether a patient will respond to treatment with MK-0677, comprising: (i) testing the patient for a peak serum GH of 5 μg / L or greater in response to a single oral dose of MK-0677; Patients who satisfy (i) will be considered responsive to treatment with MK-0677 and offered for theranostic testing.

[0040] In another aspect, the present invention provides a novel theranostic test for diagnosing growth hormone deficiency, comprising: (i) testing the patient for a peak serum GH of 5 μg / L or greater in response to a single oral dose of MK-0677; Patients who satisfy (i) are considered to have growth hormone deficiency and are offered theranostic testing.

[0041] In another aspect, the present invention provides a novel method for treating growth hormone deficiency (GHI) in children, comprising administering a therapeutically effective amount of MK-0677 to a child known to have short stature and sufficient GH secretory capacity, or in another aspect, to a child known to have growth retardation.

[0042] In another embodiment, the present invention provides a novel method for treating GHI in children, comprising administering a therapeutically effective amount of MK-0677 to a child known to be short in stature and have comparable growth potential compared to rhGH. In another aspect, the child is known to have growth retardation.

[0043] In another aspect, the present invention provides a novel theranostic test for diagnosing GHI, comprising: (i) testing patients for peak serum GH of 5 μg / L or greater in response to a single oral dose of MK-0677; (ii) testing the patient for a baseline serum IGF-I greater than 30 ng / mL; Patients who satisfy (i) and (ii) are considered growth hormone deficient and offered theranostic testing.

[0044] In another aspect, the present invention provides a novel theranostic test for diagnosing GHI, comprising: (i) testing the patient for a peak serum GH of 5 μg / L or greater in response to a single oral dose of MK-0677; Patients who satisfy (i) are considered growth hormone deficient and offered theranostic testing.

[0045] In another aspect, the present invention provides a novel method of treating GHI, comprising: (i) A method is provided, comprising orally administering minitablets containing 2 mg of MK-0677 once daily, wherein MK-0677 administered orally once daily as minitablets is equally effective compared to daily recombinant human growth hormone injections in treating short stature in children who are growth hormone deficient and who have been determined to have equivalent growth potential with MK-0677 treatment as with rhGH. Such children are identified by the finding that their pre-treatment serum IGF-I is greater than 30 μg / L and that their peak serum growth hormone is greater than 5 μg / L after a single dose of ibutamoren at 0.8 mg / kg body weight together with minitablets containing 2 mg of MK-0677.

[0046] The study for adequate and / or equivalent GH secretory capacity is an outpatient study that identifies a population of children who respond to oral MK-0677 therapy and a population of children who respond to standard daily GH treatment.

[0047] In another aspect, the present invention provides MK-0677 for use in therapy.

[0048] In another aspect, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of an indication listed herein.

[0049] In another aspect, the present invention provides novel compositions comprising an active agent that is MK-0677 for use in the treatment of the indications listed herein.

[0050] Patient refers to a human patient, either a child or an adult, including children, pre-adolescent children, peri-adolescent children, and adults.

[0051] In another embodiment, the child is known to have developmental delay.

[0052] In another embodiment, the child is prepubertal.

[0053] In another embodiment, the child is a periphormone.

[0054] Testing for GH: A subject's peak GH serum levels can be measured using well-known provocation tests.

[0055] Provocation tests: Provocation tests are well known and include clonidine tests, insulin tests, arginine tests, glucagon tests, and levodopa (L-dopa) tests (see Example 4 below). In these tests, the patient is administered the drug of interest (the dosage is typically set based on body weight), and sufficient blood samples are drawn (e.g., before administration and at t=15, 30, 60, and 120 minutes after administration) to determine peak GH secretion. The blood samples can be analyzed for GH using one of many well-known GH assays (e.g., GH immunoradiometric assay (IRMA) assay). In insulin tests, blood glucose levels are also measured.

[0056] Testing GH secretion using MK-0677: A single oral dose of MK-0677 is administered to the patient, and sufficient blood samples are taken before and after administration (e.g., 15 minutes before administration and t=0, 30, 60, 90, 120 minutes after administration) to measure peak GH secretion. An example of the amount of MK-0677 administered is 0.8 mg / kg. In one embodiment, the patient being tested is fasted overnight (all food and beverages other than water are prohibited).

[0057] Testing Pre-Treatment Serum IGF-I Levels: Pre-treatment serum IGF-I levels are the patient's IGF-I levels determined prior to treatment with either exogenous GH or MK-0677.

[0058] One or more children: male or female over 4 years of age

[0059] Adult: A male or female who has completed growth and has fused epiphyses according to the atlas of Grulich and Pyle.

[0060] Prepubertal: A child with a bone age of less than 8 years for female children and less than 9 years for male children. Bone age can be determined using well-known methods such as the atlas matching method of Greulich and Pyle or the weighted scoring system of Tanner and Whitehouse. Other examples of bone age include less than 7 years for females and less than 8 years for males.

[0061] Peripubertal: A child who has begun to experience puberty, as assessed clinically by the Tanner staging system. Tanner stage 1 is prepubertal, and any stage passed before the end of puberty (Tanner stage 4) is considered peripubertal.

[0062] Short stature: A child's height is below the 2.3 percentile (approximately -2 SD height for chronological age) for the child's chronological age. Other examples include height below the 5th, 4th, 3rd, 2nd, or 1st percentile for chronological age.

[0063] Growth retardation or slow height velocity: Height velocity below the 25th percentile for age and sex when recorded over a period of at least 6 months. Other examples include below the 24th, 23rd, 22nd, 21st, 20th, 19th, 18th, 17th, 16th, 15th, 14th, 13th, 12th, 11th, 10th, 9th, 8th, 7th, 6th, 5th, 4th, 3rd, 2nd, and 1st percentiles for age and sex when recorded over a period of at least 6 months.

[0064] Adequate GH secretion: If the patient: (i) peak GH less than 10 μg / L (or less than 7 μg / L) in response to a standard provocation test; (ii) A patient is considered to have sufficient GH secretory capacity if, in response to a single dose of MK-0677 (eg, 0.8 mg / kg), the peak serum GH is 5 μg / L or greater.

[0065] Equivalent growth potential compared to rhGH: patients (i) peak serum GH of 5 μg / L or greater in response to a single dose of MK-0677 (e.g., 0.8 mg / kg); (ii) If baseline serum IGF-I is greater than 30 μg / L, the patient is considered to have equivalent growth potential compared to chronic subcutaneous injection of rhGH (equivalent growth potential compared to rhGH).

[0066] Other examples of peak serum GH in response to a single dose of MK-0677 include: ≥5.5 μg / L, ≥6 μg / L, ≥6.5 μg / L, ≥7 μg / L, ≥7.5 μg / L, ≥8 μg / L, ≥8.5 μg / L, ≥9 μg / L, ≥9.5 μg / L, ≥10 μg / L, ≥15 μg / L, ≥20 μg / L, ≥25 μg / L, ≥30 μg / L, ≥35 μg / L, ≥40 μg / L, ≥40 μg / L, ≥5 ... g / L or more, 45 μg / L or more, 50 μg / L or more, 55 μg / L or more, 60 μg / L or more, 65 μg / L or more, 70 μg / L or more, 75 μg / L or more, 80 μg / L or more, 85 μg / L or more, 90 μg / L or more, 95 μg / L or more, 100 μg / L or more, 105 μg / L or more, 110 μg / L or more, 115 μg / L or more, 120 μg / L or more, and 125 μg / L or more.

[0067] Low GH Secretory Capacity: Patients are classified as having low GH secretory capacity (or severe GH deficiency) (LOW) if they exhibit peak serum GH of 5 μg / L or less in response to a single oral dose of MK-0677 (0.8 mg / kg).

[0068] In another embodiment, 0.8 mg / kg / day of MK-0677 is administered. Other examples of amounts of MK-0677 administered include 0.1 mg / kg / day, 0.2 mg / kg / day, 0.3 mg / kg / day, 0.4 mg / kg / day, 0.5 mg / kg / day, 0.6 mg / kg / day, 0.7 mg / kg / day, 0.9 mg / kg / day, 1 mg / kg / day, 1.1 mg / kg / day, 1.2 mg / kg / day, 1.3 mg / kg / day, 1.4 mg / kg / day, 1.5 mg / kg / day, 1.6 mg / kg / day, 1.7 mg / kg / day, 1.8 mg / kg / day, 1.9 mg / kg / day, 2.0 mg / kg / day, and divided doses within these ranges. Further examples of amounts of MK-0677 to be administered include at least 0.1 mg / kg / day, 0.2 mg / kg / day, 0.3 mg / kg / day, 0.4 mg / kg / day, 0.5 mg / kg / day, 0.6 mg / kg / day, 0.7 mg / kg / day, 0.8 mg / kg / day, 0.9 mg / kg / day, 1 mg / kg / day, 1.1 mg / kg / day, 1.2 mg / kg / day, 1.3 mg / kg / day, 1.4 mg / kg / day, 1.5 mg / kg / day, 1.6 mg / kg / day, 1.7 mg / kg / day, 1.8 mg / kg / day, 1.9 mg / kg / day, 2.0 mg / kg / day, and any divided doses within these ranges.

[0069] In another embodiment, the single oral dose of MK-0677 in the studies described herein is a single oral dose of 0.8 mg / kg. Other examples of amounts of MK-0677 administered for the studies include 0.1 mg / kg / day, 0.2 mg / kg / day, 0.3 mg / kg / day, 0.4 mg / kg / day, 0.5 mg / kg / day, 0.6 mg / kg / day, 0.7 mg / kg / day, 0.9 mg / kg / day, 1 mg / kg / day, 1.1 mg / kg / day, 1.2 mg / kg / day, 1.3 mg / kg / day, 1.4 mg / kg / day, 1.5 mg / kg / day, 1.6 mg / kg / day, 1.7 mg / kg / day, 1.8 mg / kg / day, 1.9 mg / kg / day, 2.0 mg / kg / day, and divided doses within these ranges. Further examples of amounts of MK-0677 administered for testing include at least 0.1 mg / kg / day, 0.2 mg / kg / day, 0.3 mg / kg / day, 0.4 mg / kg / day, 0.5 mg / kg / day, 0.6 mg / kg / day, 0.7 mg / kg / day, 0.8 mg / kg / day, 0.9 mg / kg / day, 1 mg / kg / day, 1.1 mg / kg / day, 1.2 mg / kg / day, 1.3 mg / kg / day, 1.4 mg / kg / day, 1.5 mg / kg / day, 1.6 mg / kg / day, 1.7 mg / kg / day, 1.8 mg / kg / day, 1.9 mg / kg / day, 2.0 mg / kg / day, and any divided doses within these ranges.

[0070] In another embodiment, MK-0677 is orally administered in the form of minitablets. In one example, the minitablets contain 2 mg of MK-0677. In another example, the minitablets contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of MK-0677. In another example, the minitablets consist essentially of 2 mg of MK-0677. In another example, the minitablets consist essentially of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of MK-0677.

[0071] MK-0677 minitablets are small tablets that can be mechanically dispensed (e.g., from a cartridge containing multiple tablets). In one embodiment, the maximum dimension (e.g., height, width, or depth) of the minitablet is about 1, 2, 3, 4, or 5 mm. Other examples include maximum dimensions of about 2, 3, or 4 mm. In a further example, the maximum dimension of the minitablet is about 3 mm.

[0072] In another embodiment, treatment is maintained for longer than 6 months. Other examples include treatment for at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months. Further examples include treatment for at least 2.5, 3, 3.5, 4, 4.5, 5 years, or until growth potential is lost.

[0073] In another embodiment, the child being treated is not being treated with growth hormone (naive).

[0074] In another embodiment, the child being treated may have been on previously discontinued GH therapy, provided that the child meets the criteria for adequate GH secretory capacity identified above.

[0075] In another example, if a child is shown to be GH deficient when growth is complete, treatment with MK-0677 may be continued to maintain normal GH secretion throughout adulthood.

[0076] In another embodiment, the level of GH after acute oral dosing of 0.8 mg / kg of MK-0677 is greater than or equal to 5 μg / mL by radioimmunoassay performed by Endocrine Sciences.

[0077] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention includes all combinations of the aspects of the present invention described herein. It is understood that any and all embodiments of the present invention may be combined with any other embodiment to describe additional embodiments. It is also understood that each individual element of an embodiment is intended to be considered separately as its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe additional embodiments. [Example]

[0078] Example 1

[0079] Therapeutic Study in Pediatric GH Deficiency: A Phase IIb study was conducted to determine whether MK-0677 can be used to treat pediatric GHD. MK-0677 was compared with placebo and rhGH injections according to the following protocol. Bone age was determined using the Greulich and Pyle atlas matching method.

[0080] Protocol: Oral sucrose formulation solution once daily for 6 months. Placebo n=22 Switched to rhGH at 6 months n=20 MK-0677(0.4mg / kg / day) n=22 MK-0677 (0.8 mg / kg / day) n=24

[0081] [Table 1]

[0082] [Table 2] Peak GH in response to MK-0677: Peak growth hormone in response to MK-0677 is determined by administering a single dose of MK-0677 (0.8 mg / kg) and then measuring the peak GH resulting from the MK-0677 dose. Low probability: low GH secretory capacity (excluded from the present invention). High probability: sufficient GH secretory capacity (included in the present invention). Prov.Test: Provocation test Baseline IGF-I (insulin-like growth factor): can be determined by serum measurement, for example, immunoassay or liquid chromatography mass spectrometry.

[0083] Table 3A shows the baseline characteristics of patients with low GH secretory capacity (peak GH ≤5 μg / L to MK-0677) treated with either MK-0677 (0.8 mg / kg / day) or placebo / rhGH 0.3 mg / kg / week (5 of 24 children who switched to rhGH after 6 months of placebo treatment had low GH secretory capacity). Based on height velocity SD for CA, patients treated with MK-0677 (0.8 mg / kg / day) were more growth-retarded than the placebo / GH treatment group. However, after correcting for bone age, the groups were similar.

[0084] [Table 3]

[0085] Table 3B shows that in patients with low GH secretory capacity, the response to GH injections was superior to the response to orally administered MK-0677.

[0086] [Table 4]

[0087] Table 4A shows the baseline characteristics of patients with adequate GH secretory capacity (peak GH ≥ 5 μg / L to MK-0677) treated with either MK-0677 (0.8 mg / kg / day) or placebo / rhGH 0.3 mg / kg / week (15 of 24 children who switched to rhGH after 6 months of placebo had adequate GH secretory capacity).

[0088] [Table 5]

[0089] Table 4B shows that for patients with adequate GH secretory capacity, the response to MK-0677 was lower than GH injections, but was comparable to and not statistically different from GH, indicating that MK-0677 is an effective growth-promoting therapy in GHD patients with adequate GH secretory capacity.

[0090] [Table 6]

[0091] Table 5A shows the baseline characteristics of patients with low growth potential (peak GH ≤5 μg / L to MK-0677) treated with either MK-0677 (0.8 mg / kg / day) or placebo / rhGH 0.3 mg / kg / week (9 of 24 children who received placebo for 6 months and then switched to rhGH had low growth potential).

[0092] [Table 7]

[0093] Table 5B shows the baseline characteristics of patients with high growth potential (peak GH ≤5 μg / L to MK-0677) treated with either MK-0677 (0.8 mg / kg / day) or placebo / rhGH 0.3 mg / kg / week (11 of 24 children who switched to rhGH after 6 months of placebo had high growth potential).

[0094] [Table 8]

[0095] Tables 6A-6E show the height velocity of children with equal growth potential treated with either 0.8 mg / kg / day (po) or 0.4 mg / kg / day (po) of MK-0677 compared to rhGH (0.3 mg / kg / week; approximately 42 μg / kg / day subcutaneous injection). Patients with low growth potential are those who do not meet equal growth potential compared to the rhGH (EQUAL) study described previously. Values ​​are means (SD).

[0096] [Table 9]

[0097] [Table 10]

[0098] [Table 11]

[0099] [Table 12]

[0100] [Table 13]

[0101] Tables 7A-7C compare height velocity in patients with low growth potential (LOW) with equal growth potential (EQUAL) compared to rhGH. Values ​​are means (SD).

[0102] [Table 14]

[0103] [Table 15]

[0104] [Table 16]

[0105] It is worth noting that with MK-0677, height velocity in the LOW group was lower than in the EQUAL group. In contrast, height velocity with GH was greater in the LOW group than in the EQUAL group (see Figures 5A and 5B). This is explained by the greater sensitivity to GH replacement in children with severe GH deficiency treated with rhGH. In children treated with 0.8 mg / kg / day (po), MK-0677, children with LOW growth potential were unable to secrete enough endogenous GH to maintain the same height velocity compared to exogenous rhGH injections, whereas patients with EQUAL growth potential were able to secrete enough endogenous GH to produce the same growth response compared to daily exogenous rhGH injections.

[0106] Example 2

[0107] [Table 17]

[0108] Example 3

[0109] Identification of children with growth hormone deficiency who experience comparable increases in growth velocity with once-daily oral MK-0677 treatment as with daily subcutaneous recombinant injections

[0110] Baseline serum IGF-1 vs. peak response to oral MK-0677 (0.8 mg / kg):

[0111] For each IGF1 cut point (30-100 x 10) used to define "truth," in the table below, the area under the ROC curve and the cut point for response to a theranostic test with MK-0677 (0.8 mg / kg, orally) for each criterion. (i) The distance from each point on the ROC curve to the upper left corner of the plot area (sensitivity = 1 and 1 - specificity = 0). The cut point is the value associated with the minimum distance from the curve to this point. (ii) Second, sensitivity and specificity are given equal weight and the absolute value of the difference between the two is calculated. The cut point is the value associated with the smallest difference between sensitivity and specificity. (iii) Third, we calculated the distance of each point from the uninformed diagonal of a curve. The cut point is the value that maximizes this distance. This is Youden's statistic.

[0112] The ranking of IGF1 and peak GH stimulated by MK-0677 was very similar, with a Spearman correlation of 0.82. [Table 18]

[0113] Results of a standard stimulation test and a theranostic study using MK-0677 (0.8g / kg) in children with growth hormone deficiency:

[0114] Three different criteria for determining the best cut point from each ROC curve (i) The distance from each point on the ROC curve to the upper left corner of the plot area (sensitivity = 1 and 1 - specificity = 0). The cut point is the value associated with the minimum distance from the curve to this point. (ii) Second, sensitivity and specificity are given equal weight and the absolute value of the difference between the two is calculated. The cut point is the value associated with the smallest difference between sensitivity and specificity. (iii) Third, we calculated the distance of each point from the uninformed diagonal of a curve. The cut point is the value that maximizes this distance. This is Youden's statistic.

[0115] Use a GH cut point of 3 μg / L and an MK-0677 cut point of 7 μg / L

[0116] Use a GH cut point of 4 μg / L and an MK-0677 cut point of 12 μg / L

[0117] Use a GH cut point of 5 μg / L or 6 μg / L and an MK-0677 cut point of 17 μg / L

[0118] Use a GH cut point of 7 μg / L or 8 μg / L and an MK-0677 cut point of 35 μg / L [Table 19]

[0119] Based on the above data, the following patient separations can be made: (i) Low Growth Potential: Children with growth hormone deficiency, as identified based on a theranostic test response of baseline serum IGF-1 less than 30 μg / L and / or serum GH less than 5 μg / L to a single dose of 0.8 mg / kg oral MK-0677, are considered to have low growth potential to MK-0677 but high growth potential to recombinant human growth hormone. (ii) Equivalent growth potential: However, if their baseline serum IGF-1 is greater than 30 μg / L and their peak serum GH is greater than or equal to 5 μg / L in response to a single dose of 0.8 mg / kg oral MK-0677, they are considered to have a growth potential in response to oral MK-0677 (0.8 mg / kg / day) that is equivalent to daily subcutaneous injections of recombinant human growth hormone (REH).

[0120] Example 4

[0121] MK-0677 Theranostics Trial:

[0122] Subjects report to the clinic in the morning after an overnight fast from all food and beverages except water. A catheter is inserted approximately 1 hour before MK0677 administration. Two baseline measurements are taken at t = -15 minutes and t = 0 minutes (the time the subject receives the dose). Subjects receive an oral dose of 0.8 mg / kg MK-0677 as a 2 mg tablet. Blood samples are then collected at t = 30, 60, 90, and 120 minutes. Additional samples are drawn for serum chemistry panels at t = -15 minutes and 120 minutes. At the end of the study, the catheter is removed. All blood samples are analyzed for GH, prolactin, and cortisol by a core clinical trial laboratory.

[0123] No data are available on combining MK-0677 response testing with standard GH provocation testing, so MK-0677 provocation testing should be separated from other provocation testing by at least 3 days.

[0124] Standard growth hormone provocation test

[0125] In addition to the MK-0677 theranostic study, patients must also undergo provocative GH testing. These tests include the well-known clonidine test, insulin test, arginine test, glucagon test, and levodopa (L-dopa) test. Example test protocols for these tests are provided below.

[0126] Clonidine test

[0127] A catheter is inserted at least 1 hour before clonidine administration. Two baseline blood samples should be obtained: one at t = -15 minutes and one immediately prior to clonidine administration. Clonidine is administered orally to the patient in tablet form. Patients weighing 20-35 kg are given a 100 μg dose. Patients weighing more than 35 kg are given a 200 μg dose. Subsequent blood samples are taken at t = 30, 60, 90, and 120 minutes. Blood pressure is monitored after each blood sampling.

[0128] Risks associated with clonidine testing include antihypertensive side effects and drowsiness.

[0129] Insulin testing

[0130] The catheter should be inserted at least 1 hour before insulin administration. Two baseline blood samples should be obtained, one at t = -15 minutes and one immediately before insulin administration. One-tenth of a kilogram of insulin is administered. Blood samples should be drawn at t = 15, 30, 45, 60, 90, and 120 minutes.

[0131] An insulin test is considered successful only if blood glucose levels fall to at least half of fasting levels. Possible risks of this test include palpitations, tremors, severe hypoglycemia, seizures, and even death. Glucose and glucagon must be available and injectable in case of an emergency. An experienced physician must be present at the bedside during the test to monitor for side effects. At the end of the test, the patient should be given a meal immediately.

[0132] Arginine test

[0133] A catheter and IV should be inserted 1 hour before arginine administration. Two baseline blood samples should be taken, one at t = -15 minutes and one immediately prior to arginine injection. Arginine should be administered at a dose of 0.5 g / kg with a maximum dose not to exceed 30 g. The intravenous infusion of arginine should be administered continuously over the first 30 minutes of the test. Subsequent blood samples should be taken at t = 30, 60, 90, and 120 minutes.

[0134] There are no serious risks associated with this study. Possible side effects include facial flushing, nausea, vomiting, numbness, headache, and local phlebitis.

[0135] Glucagon test

[0136] The catheter should be inserted at least 1 hour before glucagon administration. A baseline blood sample should be drawn at t = -15 minutes, immediately before injection. Glucagon is administered as an intramuscular injection in a 1 mL dose to patients weighing 10 to 35 kg. Subsequent blood samples should be taken at t = 30, 60, 90, 120, and 150 minutes.

[0137] There are no serious risks associated with this study. Nausea and vomiting may occur in some patients.

[0138] Levodopa (L-dopa) test

[0139] A catheter is inserted at least 1 hour before L-dopa administration. Blood samples should be drawn at t = -30 and -15 min, immediately prior to administration. 250 mg of L-dopa is administered orally in tablet form to patients weighing 15-30 kg, and 500 mg of L-dopa is administered orally in tablet form to patients weighing more than 30 kg. Subsequent blood samples are drawn at t = 30, 60, 90, and 120 min.

[0140] There are no serious risks associated with this study. Possible side effects include nausea, vomiting, and headache.

[0141] Many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

1. A method for treating growth hormone deficiency (GHD) in children, comprising administering a therapeutically effective amount of MK-0677 to children known to be short in stature and have comparable growth potential compared to rhGH.

2. 2. The method of claim 1, wherein a single oral dose of 0.8 mg / kg / day of MK-0677 is administered.

3. 10. The method of claim 1, wherein minitablets containing MK-0677 are administered orally.

4. 4. The method of claim 3, wherein the minitablets contain 2 mg of MK-0677.

5. 10. The method of claim 1, wherein pediatric GHD is treated.

6. 10. The method of claim 1, wherein said oral administration further comprises administering with a device capable of administering at least one MK-0677 minitablet.

7. 1. A method of treating GHD in a child, comprising: a. testing children known to have short stature due to GHD using theranostic testing; b. A method comprising orally administering a therapeutically effective amount of MK-0677 to children known to be short in stature and to have equivalent growth potential compared to rhGH.

8. 8. The method of claim 7, wherein MK-0677 is administered orally once at a dose of 0.8 mg / kg / day.

9. 8. The method of claim 7, wherein minitablets containing MK-0677 are administered orally.

10. 10. The method of claim 9, wherein the minitablets contain 2 mg of MK-0677.

11. 8. The method of claim 7, wherein said oral administration further comprises administering with a device capable of administering at least one MK-0677 minitablet.

12. 8. The method of claim 7, wherein pediatric GHD is treated.

13. The theranostics test comprises: (i) testing for peak serum GH ≥ 5 μg / L in response to a single oral dose of MK-0677; (ii) testing for baseline serum IGF-I greater than 30 ng / mL.

14. 14. The method of claim 13, wherein a single dose of 0.8 mg / kg / day of MK-0677 is orally administered in step (i).

15. A theranostics trial, comprising: (i) testing the patient for a peak serum GH of 5 μg / L or greater in response to a single oral dose of MK-0677; (ii) testing patients for baseline serum IGF-I greater than 30 ng / mL.

16. Testing on peak serum a. administering a single oral dose of MK-0677 to a patient; b. Testing the GH serum levels achieved after administering MK-0677 to determine the patient's peak serum GH levels; 16. The method of claim 15, comprising:

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