WO2022017599A1 - Méthode de criblage permettant le diagnostic d'une déficience en hormone de croissance chez des patients pédiatriques à l'aide de la macimoréline - Google Patents

Méthode de criblage permettant le diagnostic d'une déficience en hormone de croissance chez des patients pédiatriques à l'aide de la macimoréline Download PDF

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Publication number
WO2022017599A1
WO2022017599A1 PCT/EP2020/070691 EP2020070691W WO2022017599A1 WO 2022017599 A1 WO2022017599 A1 WO 2022017599A1 EP 2020070691 W EP2020070691 W EP 2020070691W WO 2022017599 A1 WO2022017599 A1 WO 2022017599A1
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Prior art keywords
macimorelin
growth hormone
minutes
subject
administration
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Nicola Ammer
Michael Teifel
Beate Aue
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Aeterna Zentaris GmbH
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Aeterna Zentaris GmbH
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Priority to AU2020460118A priority Critical patent/AU2020460118B2/en
Priority to KR1020217043189A priority patent/KR102635025B1/ko
Priority to EP20745175.8A priority patent/EP4185866A1/fr
Priority to MX2023000935A priority patent/MX2023000935A/es
Priority to CN202510496683.2A priority patent/CN120294343A/zh
Priority to NZ795810A priority patent/NZ795810B2/en
Priority to CA3185680A priority patent/CA3185680A1/fr
Priority to CN202080006891.5A priority patent/CN114258492A/zh
Priority to PCT/EP2020/070691 priority patent/WO2022017599A1/fr
Priority to JP2023504173A priority patent/JP7767387B2/ja
Priority to IL299918A priority patent/IL299918A/en
Priority to CN202510496684.7A priority patent/CN120294344A/zh
Priority to TW110122905A priority patent/TW202219511A/zh
Priority to PY202102157770A priority patent/PY2157770A/es
Priority to ARP210102035A priority patent/AR124626A1/es
Publication of WO2022017599A1 publication Critical patent/WO2022017599A1/fr
Anticipated expiration legal-status Critical
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/61—Growth hormones [GH] (Somatotropin)

Definitions

  • Growth hormone is a major body system-wide metabolic hormone that regulates protein, lipid, and carbohydrate homeostasis and is required for growth, development, and maintenance of the body and mind.
  • GH is produced in the anterior lobe of the pituitary gland upon stimulation by growth hormone releasing hormone (GHRH) from the hypothalamus gland.
  • GHRH growth hormone releasing hormone
  • GH is secreted from the pituitary in a pulsatile fashion of approximately 6-10 random bursts during a 24-hour period.
  • GHD Growth hormone deficiency
  • GHD may be classified broadly into four categories based on the source of the GH deficiency: 1) pituitary or “classic” GHD, 2) hypothalamic GHD, 3) functional GHD and 4) idiopathic GHD.
  • GHD may become clinically overt in childhood or in the adult. In the USA, it is estimated that the incidence of GHD in children is between 1 in 4,000 and 1 in 10,000. More than 50,000 adults in the US are GHD and 6,000 new cases are reported each year, including GHD children who transition to GHD as an adult (Human Growth Foundation www.hgfound.org).
  • GHD is a disease which in children is characterized by a reduction in auxological parameters, like growth failure and short stature.
  • ICPED International Classification of Pediatric Endocrine Diagnoses
  • GHSTs growth hormone stimulation tests
  • ITT insulin tolerance test
  • GST glucagon stimulation test
  • the ITT has been considered the gold standard for evaluation of GHD.
  • An intravenous administration of insulin is used to induce hypoglycaemia, which in turn leads to GH release.
  • this test is labor intensive as due to the potential risks associated with hypoglycaemia, which is associated with symptoms like tremor, somnolence, and tachycardia, intensive medical monitoring of the subject is required. The side effects are often reported as dangerous.
  • the ITT is contraindicated in in subjects with seizure disorders and ischemic heart disease (Yuen 2011; Yuen 2013). Therefore, ITT is not widely used because of its inconvenience and safety concerns.
  • the GST is an alternative that has grown in usage (Molitch 2011; Yuen 2011; Yuen 2013).
  • the common side effects of the GST include nausea, vomiting and headaches. There are the limitations of the length of the test (3-4 hours) and the need for an intramuscular injection. There remains a real unmet medical need for alternative tests that are safe and reliable.
  • Ghrelin potently stimulates GH release (Kojima 1999).
  • the GH-releasing effects of ghrelin are thought to be mediated by specific receptors mainly present at the pituitary and hypothalamic level (Nogueiras 2006).
  • membrane preparations containing the GHS-receptor derived from human hypothalamus and pituitary gland it was demonstrated that macimorelin shows binding potency to the human GHS receptor comparable to that of its natural ligand, ghrelin (Broglio 2002). Macimorelin is readily absorbed from the gastrointestinal tract and is assumed to exert its action in the same way as ghrelin.
  • Macimorelin Based on the ability of macimorelin to exert the release of a GH pulse shortly after oral administration in healthy subjects, macimorelin has been developed as an oral diagnostic agent for GH deficiency in adults. Macimorelin as a compound and its use in treatment of GHD has been disclosed by Martinez et al. in WO 01/96300 A1.
  • a Macimorelin GHST in adult GHD has been disclosed by Garcia et al. (J Clin Endocrinol Metab. 2013-1157, in J Clin Endocrinol Metab. 2018-00665 and a poster titled “Validation of Macimorelin As a Diagnostic Test for Adult Growth Hormone Deficiency (AGHD): A Phase 3 Study in Comparison with the Insulin Tolerance test (ITT)” presented on the 99th Annual Meeting of the Endocrine Society in 2017).
  • WO 2019/121762 A1 a method for measuring growth hormone level in a human or animal subject has been disclosed.
  • the method comprises oral administration of a macimorelin containing composition to a subject, collecting one, two or three post-administration samples within a range of 25 to 95 minutes after administration from said subject, and comparing the level of growth hormone in the one, the two or the three samples to a single threshold value, wherein the single threshold value is 2.8 ng/mL, and wherein “single threshold value” refers to a threshold growth hormone level to indicate adequate response to macimorelin stimulation.
  • the present invention provides a screening method for diagnosing growth hormone deficiency in pediatric patients by using macimorelin comprising:
  • step (b) measuring the growth hormone level of each blood sample provided in step (a);
  • step (c) comparing the measured growth hormone level obtained in step (b) with a single threshold value, wherein the single threshold value is 10.0 ng/mL or higher;
  • step (d) determining the subject, whose highest growth hormone level in the blood samples obtained in step (b) is lower than the single threshold value, as having growth hormone deficiency, and determining the subject, whose highest growth hormone level in the blood samples obtained in step (b) is no lower than the single threshold value, as having no growth hormone deficiency.
  • the present invention relates to the substance macimorelin for use in diagnosing growth hormone deficiency in pediatric patients, wherein
  • step (b) the growth hormone level of each blood sample provided in step (a) is measured; (c) the measured growth hormone level obtained in step (b) is compared with a single threshold value, wherein the single threshold value is 10.0 ng/mL or higher;
  • step (d) the subject, whose highest growth hormone level in the blood samples obtained in step (b) is lower than the single threshold value, is determined as having growth hormone deficiency, and the subject, whose highest growth hormone level in the blood samples obtained in step (b) is no lower than the single threshold value, is determined as having no growth hormone deficiency.
  • the present invention relates to a screening method for diagnosing growth hormone deficiency in pediatric patients by using macimorelin comprising:
  • step (c) comparing each of the measured growth hormone level with a single threshold value; (d) diagnosing whether the subject suffers from growth hormone deficiency or not based on the comparison of growth hormone level measured in step (b) with said single threshold value in said at least one blood sample; wherein determining the subject as having or not having growth hormone deficiency is exclusively based on the growth hormone level induction by a single macimorelin administration.
  • a “subject” or “pediatric patient” is a human child of either gender (a male or a female) between the age of about 2 to less than 18 years.
  • the subject is between the age of about 3 to less than 18, about 4 to less than 18, about 5 to less than 18, about 6 to less than 18, about 7 to less than 18, about 8 to less than 18, about 9 to less than 18, about 10 to less than 18, about 11 to less than 18, about 12 to less than 18, about 2 to less than 17, about 2 to less than 16, about 2 to less than 15, about 2 to less than 14, about 2 to less than 13, about 2 to less than 12, about 2 to less than 10, about 2 to less than 9 or about 2 to less than 8 years.
  • GHS growth hormone secretagogue
  • an effective amount refers to an amount of a given substance that is sufficient in quantity to produce a desired effect.
  • an effective amount of macimorelin for inducing growth hormone secretion in a recipient is an amount of the compound capable to achieve a detectable increase in the secretion of growth hormone upon its administration to the subject.
  • test and “testing”, as used in this application, describes to an act that leads to the clarification of a suspect of presence of a specific condition based on a subject’s symptoms and to the identification of the condition as being present or absent.
  • testing a condition encompasses the confirmation or exclusion of the condition.
  • treat or “treating” as used in this application, describes to an act that leads to the elimination, reduction, alleviation, reversal, or prevention or delay of onset or recurrence of any symptom of a relevant condition.
  • blood sample encompasses a whole blood sample as well as a fraction of whole blood such as serum or plasma sample. Whenever two or more blood samples are used for testing in the same method scheme, these blood samples are of the same type. For example, if the first sample is serum, then the second and any subsequent samples are also serum.
  • blood samples refers to blood samples taken at different time points following administration of an amount of macimorelin effective for inducing hormone secretion. Two blood samples may refer to blood samples taken, for example, at about 30 ⁇ 10 minutes and about 45 ⁇ 10 minutes or at about 30 ⁇ 10 minutes and about 60 ⁇ 10 minutes following administration of an amount of macimorelin effective for inducing hormone secretion.
  • Three blood samples may refer to blood samples taken, for example, at about 30 ⁇ 10 minutes, at about 45 ⁇ 10 minutes and about 60 ⁇ 10 minutes or preferably about 30 ⁇ 10 minutes, at about 45 ⁇ 10 minutes and about 90 ⁇ 10 minutes or, alternatively, at about 30 ⁇ 10 minutes, at about 60 ⁇ 10 minutes and about 90 ⁇ 10 minutes following administration of an amount of macimorelin effective for inducing hormone secretion.
  • single threshold value relates to a threshold growth hormone level to indicate adequate response to macimorelin stimulation: instead of the 2.8 ng/mL threshold value commonly used in adult tests, the threshold value used in the methods of the present invention is in a higher range of about 10.0 ng/mL or higher, for example about 10.0-25.0 ng/mL, about 10.0-20.0 ng/mL, about 10.1- 19.5 ng/mL, about 10.2-19.0 ng/mL, about 10.3-18.5 ng/mL, about 10.4-18.0 ng/mL, about 10.5-17.5 ng/mL, about 10.6-17.0 ng/mL, about 11.0-16.5 ng/mL, about 12.0-16.0 ng/mL, about 13.0-15.5 ng/mL, about 14.0-15.0 ng/mL, about 15.0-16.0 ng/mL, about 15.5-18.0 ng/mL, about 16.0-18.0 ng/mL, about 16.5-18.0 ng/m
  • the single threshold value used in the methods of the present invention can also be a single value, for example 10.5 ng/mL, 11.0 ng/mL, 11.5 ng/mL, 12.0 ng/mL, 12.5 ng/mL, 13.0 ng/mL, 13.5 ng/mL 14.0 ng/mL, 14.5 ng/mL, 15.0 ng/mL, 15.5 ng/mL, 16.0 ng/mL, 16.5 ng/mL, 17.0 ng/mL, 17.5 ng/mL, 18.0 ng/mL, 18.5 ng/mL, 19.0 ng/mL, 20.0 ng/mL or 25.0 ng/mL.
  • the single threshold value refers to ng per mL in whole blood or serum/plasma. Most preferably, the single threshold value refers to ng per mL in serum.
  • the terms “single threshold value” and “cut-off point” are used interchangeably. Weight percent, percent by weight, % by weight, % w/w and the like are synonyms that refer to the concentration of a substance as the weight of that substance divided by the weight of the composition and multiplied by 100.
  • PPS Pharmaacokinetic Analysis Set
  • N Number of Patients
  • ROC Receiver Operating Characteristic
  • An object of this invention is to provide a stand-alone method for measuring growth hormone level in pediatric patients and for detecting GHD in pediatric patients.
  • the aim is to develop a new method which not only reduces the burden on test administrators and test subjects by reducing the test time duration and number of blood draws but also should provide safe, reliable, and superior diagnostic performance.
  • the object of the invention has surprisingly been solved in one aspect by providing a screening method for diagnosing growth hormone deficiency in pediatric patients by using macimorelin comprising:
  • step (c) comparing the measured growth hormone level obtained in step (b) with a single threshold value, wherein the single threshold value is 10.0 ng/mL or higher;
  • step (d) determining the subject, whose highest growth hormone level in the blood samples obtained in step (b) is lower than the single threshold value, as having growth hormone deficiency, and determining the subject, whose highest growth hormone level in the blood samples obtained in step (b) is no lower than the single threshold value, as having no growth hormone deficiency.
  • the one to five blood samples are taken from a subject not earlier than about 15 minutes following an administration of an amount of macimorelin effective for inducing growth hormone secretion and not later than about 100 minutes following an administration of an amount of macimorelin effective for inducing growth hormone secretion.
  • the subject is determined as having no growth hormone deficiency.
  • the subject is determined as having growth hormone deficiency if the growth hormone level in all blood samples are lower than the single threshold value.
  • the screening method for diagnosing growth hormone deficiency in pediatric patients by using macimorelin is an in vitro screening method for diagnosing growth hormone deficiency in pediatric patients by using macimorelin.
  • the single threshold value for growth hormone is within a range from about 10.0 to about 25.0 ng/mL, preferably from about 10.2 to about 20.0 ng/mL, further preferably from about 12.0 to about 19.0 ng/mL, further preferably from about 14.0 to about 18.0 ng/mL, more preferably from about 16.0 to about 18.0 ng/mL and most preferably from about 17.0 to about 18.0 ng/mL.
  • step (a) one to four blood samples are provided, preferably wherein in step (a) one to three blood samples are provided, more preferably wherein in step (a) two or three blood samples are provided.
  • these blood samples are taken at different time points following administration of an amount of macimorelin effective for inducing hormone secretion.
  • the blood samples are taken from a subject within a range from about 20 to about 100 minutes, preferably within a range from about 25 to about 100 minutes, more preferably within a range from about 25 to about 95 minutes and most preferably within a range from about 30 to about 90 minutes, following an administration of an amount of macimorelin effective for inducing growth hormone secretion.
  • the blood samples are, for example, taken not earlier than about 20 minutes but not later than about 100 minutes, preferably not earlier than about 25 minutes but not later than about 100 minutes, more preferably not earlier than about 25 minutes but not later than about 95 minutes, and most preferably not earlier than about 30 minutes but not later than about 90 minutes following an administration of an amount of macimorelin effective for inducing growth hormone secretion.
  • the blood samples are taken from the subject at about 10 to about 60 minute intervals, preferably about 15 to about 30 minute intervals, if more than one blood sample is provided.
  • the blood samples can be taken at any time interval deemed appropriate by the attending physician.
  • the blood samples can be taken in about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 45 or about 60 minute intervals.
  • the blood samples are whole blood samples, serum samples or plasma samples.
  • the blood samples are serum samples or plasma samples. If more than one blood sample is taken, the two or more blood samples are from the same type, and these blood samples are therefore either whole blood samples, serum samples or plasma samples. Most preferably, the blood samples are serum samples.
  • step (a) in step (a) about 0.8 mg to about 1.2 mg per kg subject body weight of macimorelin is administered, preferably wherein in step (a) about 1.0 mg per kg subject body weight of macimorelin is administered.
  • an effective amount of macimorelin can be in the range of from about 0.8 to about 0.9 mg per kg body weight of the subject at the low-end, and from about 1.0, about 1.1 to about 1.2 mg/kg body weight of the subject at the high- end, or within a range defined by any one of the low-end amounts and any one of the high-end amounts, for instance, from about 0.9 to about 1.1 mg/kg body weight.
  • An effective amount of macimorelin can also be a single value, for example, of about 0.8, about 0.9, about 1.0, about 1.1 or about 1.2 mg/kg body weight.
  • Body weight (recorded in kg) may preferably be rounded to the closest integer.
  • one macimorelin unit dose consists of 1817.2 mg containing composition for preparation of an oral suspension in water.
  • the prepared suspension contains 0.5 mg macimorelin per ml_ suspension.
  • a body weight adjusted aliquot of the reconstituted suspension is administered to the pediatric subject, resulting in a dose of 1.0 mg/kg body weight in children.
  • Said unit dose is defined for a macimorelin calculated as a free base with a content of 100%. The mass of the macimorelin free base or its free base equivalent within said unit dose is adjusted according to the content.
  • step (a) the macimorelin is administered in a composition comprising macimorelin as a suitable pharmaceutical salt, wherein preferably the suitable pharmaceutical salt is selected from the acetate salt of macimorelin, the trifluoro acetate salt of macimorelin or a combination thereof.
  • the administration of macimorelin is oral administration.
  • the macimorelin may be prepared as an oral suspension.
  • the suspension may be administered within about 90 minutes, preferably within about 60 minutes, more preferably within about 30 minutes after preparation of the oral suspension.
  • the oral suspension is drunk over a time period of not more than about 1 minute, preferably over a time period of not more than about 30 seconds.
  • the subject has fasted for about 10 hours, preferably about 9 hours, more preferably about 8 hours, prior administration of macimorelin. Further preferably, in step (a) the subject fasts for about 100 minutes following macimorelin administration, meaning in step (a) the subject may fast throughout the about 100 minutes, about 95 minutes or about 90 minutes following administration of macimorelin.
  • one blood sample is provided, which is taken from the subject at about 60 ⁇ 30 minutes after administration of macimorelin.
  • the one blood sample may alternatively be taken from the subject at about 30 ⁇ 10, about 40 ⁇ 10, about 45 ⁇ 10, about 50 ⁇ 10, about 60 ⁇ 10, about 70 ⁇ 10, about 80 ⁇ 10, about 90 ⁇ 10 or about 100 ⁇ 10 minutes after administration of macimorelin.
  • the one blood sample may be taken at any time point within a range from about 15 to about 100 minutes following administration of macimorelin that is deemed appropriate by the attending physician.
  • step (a) two blood samples are provided, which are taken from the subject at about 30 ⁇ 10 minutes and at about 45 ⁇ 10 minutes after administration of macimorelin.
  • the two blood samples may alternatively be taken from the subject at about 20 ⁇ 10, about 30 ⁇ 10, about 40 ⁇ 10, about 45 ⁇ 10, about 50 ⁇ 10, about 60 ⁇ 10 about 70 ⁇ 10, about 80 ⁇ 10, about 90 ⁇ 10 or about 100 ⁇ 10 minutes after administration of macimorelin.
  • the two blood samples may be taken at any time points within a range from about 15 to about 100 minutes following administration of macimorelin that are deemed appropriate by the attending physician.
  • step (a) two blood samples are provided, which are taken from the subject at about 30 ⁇ 10 minutes and at about 60 ⁇ 10 minutes after administration of macimorelin.
  • step (a) wherein in step (a) three blood samples are provided, which are taken from the subject at about 30 ⁇ 10 minutes, at about 45 ⁇ 10 minutes and at about 60 ⁇ 10 minutes after administration of macimorelin or wherein in step (a) three blood samples are provided, which are taken from the subject at about 30 ⁇ 10 minutes, at about 45 ⁇ 10 minutes and at about 90 ⁇ 10 minutes after administration of macimorelin or wherein in step (a) three blood samples are provided, which are taken from the subject at about 30 ⁇ 10 minutes, at about 60 ⁇ 10 minutes and at about 90 ⁇ 10 minutes after administration of macimorelin.
  • the three blood samples may alternatively be taken from the subject at about 20 ⁇ 10, about 30 ⁇ 10, about 40 ⁇ 10, about 45 ⁇ 10, about 50 ⁇ 10, about 60 ⁇ 10, about 70 ⁇ 10, about 80 ⁇ 10, about 90 ⁇ 10 or about 100 ⁇ 10, minutes after administration of macimorelin.
  • the three blood samples may be taken at any time points within a range from about 15 to about 100 minutes following administration of macimorelin that are deemed appropriate by the attending physician.
  • step (a) blood samples may be taken at any time point within a range from about 15 to about 100 minutes following administration of macimorelin deemed appropriate by the attending physician.
  • suitable time points are about 20 ⁇ 10, about 30 ⁇ 10, about 40 ⁇ 10, about 45 ⁇ 10, about 50 ⁇ 10, about 60 ⁇ 10, about 70 ⁇ 10, about 80 ⁇ 10, about 90 ⁇ 10 or about 100 ⁇ 10 minutes after administration of macimorelin.
  • step (a) one to four, further preferred one to three, more preferred two or three blood samples are provided, which are taken from the subject at the times selected from the group consisting of at about 30 ⁇ 10 minutes, at about 45 ⁇ 10 minutes, at about 60 ⁇ 10 minutes and at about 90 ⁇ 10 minutes after administration of macimorelin.
  • the macimorelin in step (a) is administered in a composition comprising macimorelin and optionally further pharmaceutically acceptable excipients, such as carrier substances.
  • the macimorelin is administered in a composition comprising macimorelin and sweetener.
  • a suitable sweetener is, for example, saccharin.
  • saccharin was found to be a suitable taste masking agent for macimorelin.
  • step (a) the macimorelin is administered in a composition comprising about 3.5% (w/w) macimorelin (calculated as free base), about 93.1% (w/w) spray-dried lactose monohydrate, about 2.0% (w/w) crospovidone Type A, about 0.1% (w/w) colloidal silicon dioxide, about 1.0% (w/w) sodium stearyl fumarate, and about 0.3% (w/w) saccharin sodium dihydrate.
  • the subject is a human child from the age of 2 to less than 18 years, preferably the subject is a human child from the age of 2 to less than 17 years, more preferred the subject is a human child from the age of 2 to less than 16 years.
  • the method is a stand-alone test and does not need to be repeated and no alternative growth hormone stimulation test is required to reliably diagnose growth hormone deficiency in pediatric patients.
  • determining the subject as having or not having growth hormone deficiency according to step (d) is exclusively based on the growth hormone level induction by a single macimorelin administration.
  • the object of the invention has surprisingly been solved in another aspect by providing the substance macimorelin for use in diagnosing growth hormone deficiency in pediatric patients, wherein
  • step (a) one to five blood samples are provided, taken from a subject within a range from about 15 to about 100 minutes following an administration of an amount of macimorelin effective for inducing growth hormone secretion; (b) the growth hormone level of each blood sample provided in step (a) is measured;
  • step (c) the measured growth hormone level obtained in step (b) is compared with a single threshold value, wherein the single threshold value is 10.0 ng/mL or higher;
  • step (d) the subject, whose highest growth hormone level in the blood samples obtained in step (b) is lower than the single threshold value, is determined as having growth hormone deficiency, and the subject, whose highest growth hormone level in the blood samples obtained in step (b) is no lower than the single threshold value, is determined as having no growth hormone deficiency.
  • the one to five blood samples are taken from a subject not earlier than about 15 minutes following an administration of an amount of macimorelin effective for inducing growth hormone secretion and not later than about 100 minutes following an administration of an amount of macimorelin effective for inducing growth hormone secretion.
  • the substance macimorelin for use in diagnosing growth hormone deficiency in pediatric patients is a substance macimorelin for use in in vitro diagnosing growth hormone deficiency in pediatric patients.
  • the single threshold value for growth hormone is within a range from about 10.0 to about 25.0 ng/mL, preferably from about 10.2 to about 20.0 ng/mL, further preferably from about 12.0 to about 19.0 ng/mL, further preferably from about 14.0 to about 18.0 ng/mL, more preferably from about 16.0 to about 18.0 ng/mL and most preferably from about 17.0 to about 18.0 ng/mL.
  • step (a) one to four blood samples are provided, preferably wherein in step (a) one to three blood samples are provided, more preferably wherein in step (a) two or three blood samples are provided. If more than one blood sample is provided, these blood samples are taken at different time points following administration of an amount of macimorelin effective for inducing hormone secretion.
  • the blood samples are taken from a subject within a range from about 20 to about 100 minutes, preferably within a range from about 25 to about 100 minutes, more preferably within a range from about 25 to about 95 minutes and most preferably within a range from about 30 to about 90 minutes, following an administration of an amount of macimorelin effective for inducing growth hormone secretion.
  • the blood samples are, for example, taken not earlier than about 20 minutes but not later than about 100 minutes, preferably not earlier than about 25 minutes but not later than about 100 minutes, more preferably not earlier than about 25 minutes but not later than about 95 minutes, most preferably not earlier than about 30 minutes but not later than about 90 minutes following an administration of an amount of macimorelin effective for inducing growth hormone secretion.
  • the blood samples are taken from the subject at about 10 to about 60 minute intervals, preferably about 15 to about 30 minute intervals, if more than one blood sample is provided.
  • the blood samples can be taken at any time interval deemed appropriate by the attending physician.
  • the blood samples can be taken in about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 45 or about 60 minute intervals.
  • the blood samples are whole blood samples, serum samples or plasma samples.
  • the blood samples are serum samples or plasma samples. If more than one blood sample is taken, the two or more blood samples are from the same type, and these blood samples are therefore either whole blood samples, serum samples or plasma samples. Most preferably, the blood samples are serum samples.
  • step (a) in step (a) about 0.8 mg to about 1.2 mg per kg subject body weight of macimorelin is administered, preferably wherein in step (a) about 1.0 mg per kg subject body weight of macimorelin is administered.
  • an effective amount of macimorelin can be in the range of from about 0.8 to about 0.9 mg per kg body weight of the subject at the low-end, and from about 1.0, about 1.1 to about 1.2 mg/kg body weight of the subject at the high- end, or within a range defined by any one of the low-end amounts and any one of the high-end amounts, for instance, from about 0.9 to about 1.1 mg/kg body weight.
  • An effective amount of macimorelin can also be a single value, for example, of about 0.8, about 0.9, about 1.0, about 1.1 or about 1.2 mg/kg body weight.
  • Body weight (recorded in kg) may preferably be rounded to the closest integer.
  • one macimorelin unit dose consists of 1817.2 mg containing composition for preparation of an oral suspension in water.
  • the prepared suspension contains 0.5 mg macimorelin per ml_ suspension.
  • a body weight adjusted aliquot of the reconstituted suspension is administered to the pediatric subject, resulting in a dose of 1.0 mg/kg body weight in children.
  • Said unit dose is defined for a macimorelin calculated as a free base with a content of 100%. The mass of the macimorelin free base or its free base equivalent within said unit dose is adjusted according to the content.
  • step (a) the macimorelin is administered in a composition comprising macimorelin as a suitable pharmaceutical salt thereof, wherein preferably the suitable pharmaceutical salt is selected from the acetate salt of macimorelin, the trifluoro acetate salt of macimorelin or a combination thereof.
  • the administration of macimorelin is oral administration.
  • the macimorelin may be prepared as an oral suspension.
  • the suspension may be administered within about 90 minutes, preferably within about 60 minutes, more preferably within about 30 minutes after preparation of the oral suspension.
  • the oral suspension is drunk over a time period of not more than about 1 minute, preferably over a time period of not more than about 30 seconds.
  • the subject has fasted for about 10 hours, preferably about 9 hours, more preferably about 8 hours, prior administration of macimorelin.
  • the subject fasts for about 100 minutes following macimorelin administration, meaning in step (a) the subject may fast throughout the about 100 minutes, about 95 minutes or about 90 minutes following administration of macimorelin.
  • one blood sample is provided, which is taken from the subject at about 60 ⁇ 30 minutes after administration of macimorelin.
  • the one blood sample may alternatively be taken from the subject at about 30 ⁇ 10, about 40 ⁇ 10, about 45 ⁇ 10, about 50 ⁇ 10, about 60 ⁇ 10, about 70 ⁇ 10, about 80 ⁇ 10, about 90 ⁇ 10, about 100 ⁇ 10 minutes after administration of macimorelin.
  • the one blood sample may be taken at any time point within a range from about 15 to about 100 minutes following administration of macimorelin that is deemed appropriate by the attending physician.
  • two blood samples are provided, which are taken from the subject at about 30 ⁇ 10 minutes and at about 45 ⁇ 10 minutes after administration of macimorelin.
  • the two blood samples may alternatively be taken from the subject at about 20 ⁇ 10, about 30 ⁇ 10, about 40 ⁇ 10, about 45 ⁇ 10, about 50 ⁇ 10, about 60 ⁇ 10, about 70 ⁇ 10, about 80 ⁇ 10, about 90 ⁇ 10 or about 100 ⁇ 10, minutes after administration of macimorelin.
  • the two blood samples may be taken at any time points within a range from about 15 to about 100 minutes following administration of macimorelin that are deemed appropriate by the attending physician.
  • step (a) two blood samples are provided, which are taken from the subject at about 30 ⁇ 10 minutes and at about 60 ⁇ 10 minutes after administration of macimorelin.
  • step (a) three blood samples are provided, which are taken from the subject at about 30 ⁇ 10 minutes, at about 45 ⁇ 10 minutes and at about 60 ⁇ 10 minutes after administration of macimorelin or wherein in step (a) three blood samples are provided, which are taken from the subject at about 30 ⁇ 10 minutes, at about 45 ⁇ 10 minutes and at about 90 ⁇ 10 minutes after administration of macimorelin or wherein in step (a) three blood samples are provided, which are taken from the subject at about 30 ⁇ 10 minutes, at about 60 ⁇ 10 minutes and at about 90 ⁇ 10 minutes after administration of macimorelin.
  • the three blood samples may alternatively be taken from the subject at about 20 ⁇ 10, about 30 ⁇ 10, about 40 ⁇ 10, about 45 ⁇ 10, about 50 ⁇ 10, about 60 ⁇ 10, about 70 ⁇ 10, about 80 ⁇ 10, about 90 ⁇ 10, or about 100 ⁇ 10 minutes after administration of macimorelin.
  • the three blood samples may be taken at any time points within a range from about 15 to about 100 minutes following administration of macimorelin deemed appropriate by the attending physician.
  • these blood samples may be taken at any time points within a range from about 15 to about 100 minutes following administration of macimorelin deemed appropriate by the attending physician.
  • suitable time points are about 20 ⁇ 10, about 30 ⁇ 10, about 40 ⁇ 10, about 45 ⁇ 10, about 50 ⁇ 10, about 60 ⁇ 10, about 70 ⁇ 10, about 80 ⁇ 10, about 90 ⁇ 10 or about 100 ⁇ 10 minutes after administration of macimorelin.
  • step (a) one to four, further preferred one to three, more preferred two or three blood samples are provided, which are taken from the subject at the times selected from the group consisting of at about 30 ⁇ 10 minutes, at about 45 ⁇ 10 minutes, at about 60 ⁇ 10 minutes and at about
  • the macimorelin in step (a) is administered in a composition comprising macimorelin and optionally further pharmaceutically acceptable excipients, such as carrier substances.
  • the macimorelin is administered in a composition comprising macimorelin and sweetener.
  • a suitable sweetener is, for example, saccharin. Saccharin was found to be a suitable taste masking agent for macimorelin.
  • step (a) the macimorelin is administered in a composition comprising about 3.5% (w/w) macimorelin (calculated as free base), about 93.1% (w/w) spray-dried lactose monohydrate, about 2.0% (w/w) crospovidone Type A, about 0.1% (w/w) colloidal silicon dioxide, about 1.0% (w/w) sodium stearyl fumarate, and about 0.3% (w/w) saccharin sodium dihydrate.
  • the subject is a human child from the age of 2 to less than 18 years, preferably the subject is a human child from the age of 2 to less than 17 years, more preferred the subject is a human child from the age of 2 to less than 16 years.
  • the substance is used in a stand-alone test and does not need to be repeated and no alternative growth hormone stimulation test is required to reliably diagnose growth hormone deficiency in pediatric patients.
  • determining the subject as having or not having growth hormone deficiency according to step (d) is exclusively based on the growth hormone level induction by a single macimorelin administration.
  • this method of the present invention is suitable as stand-alone test since no further GHST is required to reliably diagnose GHD in pediatric patients.
  • the object of the invention has surprisingly been solved in a further aspect by providing a screening method for diagnosing growth hormone deficiency in pediatric patients by using macimorelin comprising: (a) providing at least one blood sample, taken from a subject within a range from about 15 to about 100 minutes following an administration of an amount of macimorelin effective for inducing growth hormone secretion;
  • step (d) diagnosing whether the subject suffers from growth hormone deficiency or not based on the comparison of growth hormone level measured in step (b) with said single threshold value in said at least one blood sample; wherein determining the subject as having or not having growth hormone deficiency is exclusively based on the growth hormone level induction by a single macimorelin administration.
  • the screening method for diagnosing growth hormone deficiency in pediatric patients by using macimorelin is an in vitro screening method for diagnosing growth hormone deficiency in pediatric patients by using macimorelin.
  • step (a) one to four, further preferred one to three, more preferred two or three blood samples are provided, which are taken from the subject at the times selected from the group consisting of at about 30 ⁇ 10 minutes, at about 45 ⁇ 10 minutes, at about 60 ⁇ 10 minutes and at about 90 ⁇ 10 minutes after administration of macimorelin.
  • step (d) the subject, whose highest growth hormone level measured in step (b) is lower than the single threshold value, is determined as having growth hormone deficiency, and the subject, whose highest growth hormone level measured in step (b) is no lower than the single threshold value, is determined as having no growth hormone deficiency
  • the single threshold value is within a range from about 10.0 to about 25.0 ng/mL, preferably from about 10.2 to about 20.0 ng/mL, further preferably from about 12.0 to about 19.0 ng/mL, further preferably from about 14.0 to about 18.0 ng/mL, more preferably from about 16.0 to about 18.0 ng/mL and most preferably from about 17.0 to about 18.0 ng/mL.
  • about 0.8 mg to about 1.2 mg per kg subject body weight of macimorelin is administered, preferably about 1.0 mg per kg subject body weight of macimorelin is administered.
  • the subject is a human child from the age of 2 to less than 18 years, preferably the subject is a human child from the age of 2 to less than 17 years, more preferred the subject is a human child from the age of 2 to less than 16 years.
  • One main feature of the methods of this invention is the single stimulation test format in contrast to the standard two-test format currently in use by medical professionals. Rather than having two separate tests, which are performed at least one day apart and involve as many as 8-12 blood draws, the new methods of this invention require only one test and as few as only 1 to 5, preferably 2 to 4 blood draws in order to achieve reliable diagnostic performance in accuracy, specificity, and sensitivity for detecting growth hormone deficiency, thus greatly reducing the testing burden and potential harm to the children being tested.
  • these blood samples can be collected within a short period of time, such as in a time period of a total of about 90 minutes after administration of macimorelin, in intervals of about 15 up to about 30 minutes.
  • the methods of the present invention have achieved significant improvement by using a higher threshold value for diagnosing growth hormone deficiency.
  • a higher threshold value for diagnosing growth hormone deficiency.
  • a single threshold value of about 2 to 3 ng/mL is used and when pediatric patients are tested for GHD, a single threshold value of below 10 ng/mL is used.
  • the present inventors have unexpectedly discovered that better diagnostic performance can be achieved for pediatric patients when a higher single threshold value of 10.0 ng/mL or higher is used.
  • a single threshold value of about 16.0 to 19.0 ng/mL, preferably of about 17.0 to 18.0 ng/mL has been found to very effectively indicate GHD in the stand-alone methods of this invention.
  • the methods of the present invention have achieved significant improvement by using a higher macimorelin dose for diagnosing growth hormone deficiency.
  • the conventional dose of macimorelin used in current practice is 0.5 mg/kg patient body weight
  • the present inventors have unexpectedly discovered that better diagnostic performance can be achieved when a higher dose of macimorelin is used in the growth hormone stimulation test for pediatric patients.
  • a macimorelin dose of about 0.8 to about 1.2 mg/kg, preferably about 1.0 mg/kg body weight has been found to very effectively indicate GHD in the one-test method of this invention.
  • the invention provides methods for measuring growth hormone level in a human child, including methods of assessing pituitary-related GH deficiency in a human child, after single oral administration of macimorelin to the child: as a stand-alone test (one test method and a single GH stimulation are required only), with two to four blood samples collected in a time period of, for example, a total of about 90 minutes after administration of macimorelin, in intervals of about 15 up to about 30 minutes with a GH cut-off point in a range of about 10.0 ng/mL or higher, preferably about 10.0 ng/mL to about 25.0 ng/mL, more preferably about 10.2 ng/mL to about 20 ng/mL, and most preferably about 17.0 to about 18.0 ng/mL.
  • GHD Growth hormone deficiency
  • GHD Growth hormone deficiency
  • AEZS-130-P01 was designed to investigate macimorelin acetate as a diagnostic test in children with suspected GHD.
  • the mean C max values were 3.46, 8.13 and 12.87 ng/mL for C1, C2, and C3, respectively.
  • the AUCs increased with dose; the mean AUCO-6 values were 6.69, 18.02 and 30.92 h*ng/ml_.
  • the mean elimination half-lives were 1.22, 1.61 and 1.71 h, respectively.
  • PK and PD profiles for all three cohorts were comparable, with peak GH levels mainly observed within 30-60 min following macimorelin intake.
  • Macimorelin acetate was safe and well tolerated in all dosing cohorts.
  • a dose-dependent increase in macimorelin C max and AUC in children and adolescents correlated well with data from adult subjects.
  • a robust dose-proportional GH response was also achieved.
  • PD results showed that GH response was comparable in all dose groups, with a slight shift to earlier t max at higher macimorelin doses.
  • Example 1 A macimorelin containing composition for diagnosing CGHD
  • the macimorelin containing composition comprises the following ingredients as listed in Table 1.
  • One macimorelin dose unit consists of 1817.2 mg containing composition for preparation of an oral suspension in water.
  • the prepared suspension contains 0.5 mg macimorelin per ml_ suspension.
  • a body weight adjusted aliquot of the reconstituted suspension is administered to the pediatric subject, resulting in a dose of 1.0 mg/kg body weight in children. It is to be noted that in adults a body weight adjusted aliquot of the reconstituted suspension is administered, resulting in a dose of 0.5 mg/kg body weight of the adult subject.
  • Said unit dose is defined for a macimorelin calculated as a free base with a content of 100%.
  • the mass of the macimorelin free base or its free base equivalent within said unit dose is adjusted according to the content Macimorelin can be included in said unit dose as a suitable pharmaceutical salt.
  • suitable pharmaceutical salts are the acetate salt and the trifluoro acetate salt.
  • Said unit dose might be filled into a suitable container for easy availability of the GHD test.
  • a suitable container are a sachet or containers of suitable size made of glass of plastic.
  • the container is an sachet made of polyethylene laminated aluminum foil with macimorelin containing composition comprises 63.6 mg macimorelin, 1691.8 mg spray-dried lactose monohydrate, 36.3 mg crospovidone Type A, 1.8 mg colloidal silicon dioxide, 18.2 mg sodium stearyl fumarate, and 5.5 mg saccharin sodium dihydrate.
  • 2 ml_ provides 1.0 mg macimorelin.
  • Example 2 Use of Saccharin in the macimorelin containing composition to mask bad taste
  • Example 3 Pharmacokinetic, Pharmacodynamic as well as explorative test characteristics of macimorelin as a diagnostic test
  • Study AEZS-130-P01 was an open label, group comparison, dose escalation trial to investigate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of macimorelin acetate after single oral dosing of 0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg in pediatric patients with suspected GHD.
  • PK pharmacokinetics
  • PD pharmacodynamics
  • Macimorelin plasma concentrations the analysis of plasma samples for macimorelin concentration was carried out at a central laboratory, Prolytic GmbH, Germany, using a validated liquid chromatography-mass spectrometry (LCMS/MS) method with a detection limit of 0.2 ng/mL (Franz, 2005).
  • Preliminary pharmacokinetics (PK) were determined by: time of maximum measured concentration ( ) and maximum concentration (Cmax) of macimorelin plasma concentrations in the sampling period.
  • GH serum concentration the analysis of serum samples for GH concentration was carried out at a central laboratory by a validated immunochemiluminometric assay (IDS-iSYS Human Growth Hormone (hGH), Immunodiagnostic Systems Ltd [UK]) (Manolopoulou et al. , 2012). This assay is standardized to the recombinant growth hormone calibration standard WHO 98/574, and complies with recommendations on assay standardization as outlined by Clemmons (Clemmons et al., 2011). The analytical laboratory applied for GH was: Central Laboratory Synevo Lodz, Krakusa Str. 28, 93-515 Lodz. Poland. The lower limit of quantification was ⁇ 0.05 ng/mL.
  • a subject with sex steroid priming prior to GHSTs that are part of the standard diagnostic procedures must also have sex steroid priming for the macimorelin GHST.
  • a single-use aluminum pouch contained 63.6 mg macimorelin, which provides 0.5 mg/mL of macimorelin when dissolved in 120 ml_ of water.
  • Sequential cohorts of trial participants received macimorelin at ascending single oral doses: i.e. 0.25 mg/kg body weight in Cohort 1 (C 1 ), 0.5 mg/kg body weight in
  • Cohort 2 (C2), and 1 mg/kg body weight in Cohort 3 (C3).
  • Macimorelin oral suspension was prepared by trial personnel and dosed according to the following instructions (Step #1- Step #5), considering here as example the dose of cohort C3 (i.e.; 1.0 mg/kg):
  • required volume of the suspension which corresponds to the patient body weight, i.e. required volume of suspension is 2 mL/kg (for example, a 30 kg patient requiring macimorelin dose of 1.0 mg/kg will require 60 ml_ of the prepared suspension);
  • the suspension must be used within 30 minutes after preparation.
  • the administration of the macimorelin oral suspension was done under the supervision of trial personnel.
  • the patient was advised to drink - over a period of no more than 30 seconds - the entire content of the glass container prepared in Step #4 of the cohort specific dosing instructions as given above.
  • Plasma samples were collected at the following time-points: pre-dose (sampling time window: +/- 15 minutes), then 15, 30, 45, 60, 90, 120 minutes (+/- 5 min window) and 360 minutes (+/- 10 minutes window) after administration of macimorelin. Serum concentrations of GH and plasma concentrations of macimorelin were analyzed in central laboratories.
  • the investigational macimorelin GHST was performed after the first sGHST had been completed. A recovery period of at least 1 week and a maximum of 4 weeks was introduced between GHSTs to avoid carry-over effects or interference between subsequent GHSTs and to provide an adequate follow-up period for observation of possibly drug-related adverse events to the previously used provocative agents. Standard GHSTs used in Study P01
  • sGHSTs Two standard growth hormone stimulation tests (sGHSTs) had to be performed in a patient according to local practice.
  • the sGHST agents were considered as ‘background’ and not as IMPs.
  • sGHSTs insulin (insulin tolerance test (ITT)), arginine, arginine/growth hormone releasing hormone (GHRH), clonidine, glucagon, L-dopa.
  • sGHST agent Single dose of a sGHST agent was administered intramuscular (i.m.), intravenous (i.v.), subcutaneous (s.c.) or peroral (depending on formulation) on the day of the sGHST. Batch numbers were recorded on-site in Patient Records and ‘standard GHST Patients Accountability Logs’. Criteria for Evaluation
  • Target parameters AUC, Cmax, T max , Ti /2.
  • Target parameters Cmax, T max ;
  • Macimorelin PK PK parameters were analyzed for the PK Analysis Set (PKS) and are summarized by n (number of measurements), arithmetic mean, standard deviation and coefficient of variation (CV), median, minimum, maximum value and, in addition (T max excluded) by geometric mean, geometric standard deviation, and geometric CV. For T max additionally frequency counts as well as median, minimum, and maximum are presented.
  • Macimorelin PD irrespective of the availability of PK data, GH concentration data were analyzed for the PD Analysis Set (PDS). GH peak concentrations were correlated with the outcome of the clinical diagnostic procedure (diagnosis of GHD confirmed or not confirmed).
  • Plasma concentrations of macimorelin of individual patients were correlated with the respective GH concentrations at the same time points, as well as the outcome of the clinical diagnostic procedure (diagnosis of GHD confirmed or not confirmed).
  • the safety population (SAF) as well as the PK analysis set (PKS), PD analysis set (PDS), and PK/PD set consisted of 24 patients.
  • Baseline characteristics In total, 17 (70.8%) of patients were male, 7 (29.2%) female, and 100% were of white origin. At screening, the median parameters for all three dosing cohorts were for age 10.5 years (range: 4 - 15 years), height 123.35 cm (range: 46.0 - 152.5 cm), weight 25.5 kg (range: 12 - 43 kg) and body mass index (BMI) 16.1 kg/m 2 (range: 12.4 - 21.4 kg/m 2 ).
  • the Tanner status was distributed as following: in C1 as well as C3, 4 patients showed Tanner I and 4 patients Tanner II, and in C2 5 patients showed Tanner I and 3 patients Tanner II. Sex steroid priming was applied in two male patients in C3 by i.m. administration of a testosterone depot preparation.
  • IGF-1 and IGF-BP3 values were captured in the electronic case report form (eCRF) as collected according to the local diagnostic standard.
  • IGF-1 values were presented for 7 patients in C1, and for 8 patients each in C2 and C3, with a median of 88.00 pg/L (SD 68.72) in C 1 , 100.00 pg/L (SD 97.90) in C2, and 119.50 pg/L (SD 68.88) in C3. IGF-BP3 values became available for one patient in C3.
  • the bone age showed in median a value of 102.2 months (range: 24 - 156 months).
  • height SDS was in median -2.35 (range -3.2 - 1.7), BMI SDS -0.60 (range -2.1 - 2.0), and annualized height velocity SDS -1.50 (range: -3.3 - 0.5).
  • SGHSTs Overall, the ITT was administered to 22 patients (i.e. to 5 patients (20.8%) at visit 1 (V1) and 17 patients (70.8%) at visit 3 (V3)), arginine to 8 patients (33.3%) at V1, and clonidine to 16 patients (i.e., 11 patients (45.8%) at V1 and 5 patients (20.8%) at V3). Glucagon was administered to one patient only, and L- dopa was not administered at all.
  • the AUCs and C max of macimorelin show a dose-dependent increase with an arithmetic mean AUCO-6 of 6.69 h*ng/ml_ in C1, 18.02 h*ng/ml_ in C2, 30.92 h*ng/ml_ in C3, and an arithmetic mean C max of 3.46 ng/mL in C1, 8.13 ng/mL in C2, and 12.87 ng/mL in C3 (Table 2).
  • Mean T max is comparable between all three groups with an arithmetic mean of 45.5 min in C1, 40.6 min in C2, and 31.9 min in C3.
  • Mean Ti 2 shows a slight increase with higher doses, i.e. 73.18 min in C1 , 96.31 min in C2, and 102.85 min in C3.
  • GH concentration is increasing following macimorelin administration with a tendency to higher values with ascending dose.
  • the large inter-patient variability is to be expected in the observed population with suspect of having GHD.
  • Peak GH values by GHD diagnosis were compared based on GHST results and investigator’s assessment. Diagnostic characteristics of GH values (i.e. , sensitivity, specificity, and Youden indices (non-weighted, weighted)) tested as cut-off points were listed with the most solid expression of diagnostic characteristics to be noted for C1 at a peak GH of 10.03 ng/mL, for C2 at a peak GH of 10.43 ng/mL, and for C3 at 17.13 ng/mL.
  • the diagnostic outcome of the GHSTs is presented in Table 4.
  • the diagnostic outcome of the sGHST is considered as ‘confirmed’, if both sGHSTs are available and both resulted in a peak GH ⁇ 7 ng/mL or ‘not confirmed’, if at least one of the peaks is above 7 ng/mL.
  • the outcome ‘not confirmed’ is categorized to ‘excluded’, if both sGHST results are available and the GH peaks are above 7 ng/ml, and to ‘equivocal’, if the case does not fit to any of the above described.
  • the investigator’s assessment is based on local diagnostic standard practice. The macimorelin GHST was tested against a cut-off point calculated from the individual peak GH values.
  • Table 4 is presenting agreement between principal investigator’s (Pi’s) assessment and outcome of both sGHSTs: in 21 (87.5%) patients (i.e., 8 confirmed and 13 not confirmed) there is an agreement between investigators assessment and sGHST outcomes. In 3 (12.5%) patients investigator concluded GHD, while sGHSTs excluded (in 1 patient) the diagnosis or were equivocal (in 2 patients).
  • the diagnostic results can be summarized as following (Table 5): the macimorelin GHST shows ‘GHD not confirmed’ only in 1 (9.09%) patient in C2 from overall 11 patients assessed as ‘GHD’ by the investigator in all three cohorts. From a total of 13 patients assessed by the investigator as ‘not confirmed’ of having GHD, the macimorelin GHST confirmed GHD in 3 (23.08%) patients in C1 and in 1 (7.69%) patient in C3, respectively.
  • Table 5 Summary of Diagnostic Results of Macimorelin GHST vs. sGHST and vs. Investigator’s Assessment
  • the ROC curve for C1 shows the lowest sensitivity and specificity if being compared with C2 and C3 ( Figure 3).
  • the related area under the curve (AUC) is increasing with ascending dose.
  • the cut-off point of 17.130 ng/mL GH for C3 shows the strongest test characteristics with a sensitivity of 1.0, specificity of 0.8, Youden indices > 0.80, and a ROC AUC of 0.93 (cf. Table 6).
  • a sensitivity analysis was performed observing the ROC AUC development based on the test outcome of the sGHSTs categorized as ‘confirmed’ vs. ‘not-confirmed’.
  • NPV negative predictive value
  • PPV positive predictive value
  • TEAEs treatment emergent adverse events
  • AEs Majority of AEs was related to the ITT, i.e. 62 (70.5%) events in 21 (91.3%) of the patients. Clonidine related AEs (13 (14.8%)) were observed in 7 (30.4%) of the patients, and an arginine related AE was reported in 1 (4.3%) patient. It is to be noted that the ITT was administered to 22 patients, arginine to 8 patients (33.3%), clonidine to 16 patients, and Glucagon to one patient only.
  • ITT related AEs comprised symptoms of hypoglycemia (e.g. tremor, sweating), which is a clinical endpoint of this sGHST.
  • hypoglycemia e.g. tremor, sweating
  • hypotension related symptoms were reported, which are known side effects of this sGHST agent.
  • Severe intensity was reported for TEAEs of one patient in Cohort 1: 5 AEs (i.e. , palpitations, tachycardia, hunger, hyperhidrosis, and tremor) as part of the expected hypoglycemia occurred in patient HU01-01 during an ITT.
  • 5 AEs i.e. , palpitations, tachycardia, hunger, hyperhidrosis, and tremor
  • the GHST Tolerability Questionnaire was to be completed by the patient or the parent/legal guardian.
  • This trial was performed to investigate the safety, tolerability, PK and PD of macimorelin acetate after single oral dosing of 0.25 mg/kg, 0.5 mg/kg, and 1.0 mg/kg in pediatric patients with suspected GHD. Furthermore, it served to identify a suitable macimorelin dose for further testing in a test validation trial, and to explore a GH cut-off point for testing.
  • C max and T max for macimorelin plasma levels were found to be in the range expected from the adult development program.
  • the PK parameters in the pediatric population were in a similar range to those in adults.
  • a macimorelin dose of 0.25 mg/kg (C1) has not resulted in a maximum stimulation of GFI secretion in children, which becomes evident in the review of PK/PD data as well as comparison with the agreement between an explored GFI cut-off point versus PI assessment and results of sGFISTs.
  • a dose of 0.5 mg/kg (C2) showed strong GFI release, a high level of agreement between the principal investigator (PI) assessment based on the macimorelin GHST vs. sGHST as well as a ROC AUC of 0.80.
  • PI principal investigator
  • a dose of 1.0 mg/kg (C3) appears to lead to a more consistent, strong GH stimulation, most probably due to sufficiently high macimorelin exposure in all subjects.
  • the sensitivity analysis supports the dosing in C3 with strongest test characteristics expressed at a cut-off point of approximately 17 ng/mL GH, with a specificity of 0.80, a sensitivity of 1.00, a Youden-index of 0.80 and a ROC AUC of 0.93.
  • the outcome of the macimorelin GFIST showed a surprisingly high agreement with the outcome of the two standard GFISTs as well as the final diagnose as assessed by the Principal Investigator. In C3, GFI secretion was stimulated evidently in all 8 patients. Finally, the outcome of the macimorelin GFIST applied as a single test showed agreement with the outcome of the combination of the two sGFISTs as well as with the PI assessment in 7 of 8 subjects.
  • macimorelin has shown good safety and tolerability without any AEs reported in the population observed.
  • PK and PD profile are in a range expected from the adult development program.
  • the overall characterization of macimorelin in this first pediatric trial supports the choice of a macimorelin dose of 1.0 mg/kg for the investigation in a Phase 3 trial on test validity.

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Abstract

La présente invention se rapporte à une méthode de criblage permettant de diagnostiquer une déficience en hormone de croissance chez des patients pédiatriques à l'aide de la macimoréline. La présente invention concerne en outre la substance macimoréline destinée à être utilisée dans le diagnostic d'une déficience en hormone de croissance chez des patients pédiatriques. La méthode consiste à fournir au moins un échantillon de sang, prélevé chez un sujet dans une plage d'environ 15 à environ 100 minutes après l'administration d'une quantité de macimoréline efficace pour induire la sécrétion d'hormone de croissance, à mesurer le taux d'hormone de croissance de chaque échantillon de sang, à comparer le niveau d'hormone de croissance mesuré à une valeur seuil unique, à diagnostiquer si le sujet souffre d'une déficience en hormone de croissance ou non en fonction de la comparaison du taux d'hormone de croissance à ladite valeur seuil unique dans ledit au moins un échantillon de sang. La méthode de l'invention constitue un essai autonome et ne nécessite pas de répétition et aucun autre essai de stimulation d'hormone de croissance n'est nécessaire pour diagnostiquer de manière fiable des patients pédiatriques.
PCT/EP2020/070691 2020-07-22 2020-07-22 Méthode de criblage permettant le diagnostic d'une déficience en hormone de croissance chez des patients pédiatriques à l'aide de la macimoréline Ceased WO2022017599A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
AU2020460118A AU2020460118B2 (en) 2020-07-22 2020-07-22 A screening method for diagnosing growth hormone deficiency in pediatric patients by using macimorelin
KR1020217043189A KR102635025B1 (ko) 2020-07-22 2020-07-22 마시모렐린을 사용하여 소아 환자의 성장 호르몬 결핍증을 진단하는 스크리닝 방법
EP20745175.8A EP4185866A1 (fr) 2020-07-22 2020-07-22 Méthode de criblage permettant le diagnostic d'une déficience en hormone de croissance chez des patients pédiatriques à l'aide de la macimoréline
MX2023000935A MX2023000935A (es) 2020-07-22 2020-07-22 Un metodo de deteccion para diagnosticar la deficiencia de la hormona del crecimiento en pacientes pediatricos utilizando macimorelina.
CN202510496683.2A CN120294343A (zh) 2020-07-22 2020-07-22 一种通过使用马昔瑞林诊断儿科患者中生长激素缺乏症的筛选方法
NZ795810A NZ795810B2 (en) 2020-07-22 A screening method for diagnosing growth hormone deficiency in pediatric patients by using macimorelin
CA3185680A CA3185680A1 (fr) 2020-07-22 2020-07-22 Methode de criblage permettant le diagnostic d'une deficience en hormone de croissance chez des patients pediatriques a l'aide de la macimoreline
CN202080006891.5A CN114258492A (zh) 2020-07-22 2020-07-22 一种通过使用马昔瑞林诊断儿科患者中生长激素缺乏症的筛选方法
PCT/EP2020/070691 WO2022017599A1 (fr) 2020-07-22 2020-07-22 Méthode de criblage permettant le diagnostic d'une déficience en hormone de croissance chez des patients pédiatriques à l'aide de la macimoréline
JP2023504173A JP7767387B2 (ja) 2020-07-22 2020-07-22 マシモレリンを使用することにより小児科患者における成長ホルモン分泌不全症を診断するためのスクリーニング方法
IL299918A IL299918A (en) 2020-07-22 2020-07-22 A screening method for diagnosing growth hormone deficiency in patients who are children using McMurlin
CN202510496684.7A CN120294344A (zh) 2020-07-22 2020-07-22 一种通过使用马昔瑞林诊断儿科患者中生长激素缺乏症的筛选方法
TW110122905A TW202219511A (zh) 2020-07-22 2021-06-23 藉由使用馬西瑞林診斷兒科患者中之生長激素缺乏的篩選方法
PY202102157770A PY2157770A (es) 2020-07-22 2021-07-15 Un método de detección para diagnosticar la deficiencia de la hormona del crecimiento en pacientes pediátricos utilizando macimorelina
ARP210102035A AR124626A1 (es) 2020-07-22 2021-07-20 Un método de detección para diagnosticar la deficiencia de la hormona del crecimiento en pacientes pediátricos utilizando macimorelina

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NZ795810A (en) 2025-06-27
CN120294344A (zh) 2025-07-11
KR102635025B1 (ko) 2024-02-07
CN114258492A (zh) 2022-03-29
AU2020460118A1 (en) 2023-02-02
PY2157770A (es) 2022-03-30
AR124626A1 (es) 2023-04-19
IL299918A (en) 2023-03-01
KR20220015466A (ko) 2022-02-08
EP4185866A1 (fr) 2023-05-31
JP7767387B2 (ja) 2025-11-11
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