Long-Acting Growth Hormone Treatment

Abstract

The present invention relates a pharmaceutical formulation comprising a long-acting growth hormone for use in a method of treating growth hormone deficiency, wherein the long-acting growth hormone formulation is administered to a patient in a bracketed dosage regimen, to a multitude of unit dosage forms comprising a long-acting growth hormone formulation, wherein the unit dosage forms comprise increasing amounts of growth hormone equivalents and wherein the amount of growth hormone equivalents increases by at least 10% between one unit dosage form and the next higher dosage form; their use in a method of treating growth hormone deficiency and method of treating growth hormone deficiency in a bracketed dosing regimen.

Claims

1-58. (canceled)

59. A multitude of unit dosage forms comprising a long-acting growth hormone formulation, wherein the unit dosage forms comprise increasing amounts of growth hormone equivalents and wherein the amount of growth hormone equivalents increases by at least 10% between one unit dosage form and the next higher unit dosage form.

60. The multitude of unit dosage forms of claim 59, wherein the long-acting growth hormone is selected from the group consisting of ACP-011, ACP-001, VRS-317, MOD-4023, Lagova, hGH-CTP, albutropin, AR.sup.x201, ALTU-238, PHA-794428, hGH-OctoDex, NNC126-0083, Nutropin Depot, LB03002, Somatropin Biopartners, LAPS-hGH, NNC0195-0092 and TV-1106.

61. The multitude of unit dosage forms of claim 59, wherein the long-acting growth hormone is ACP-011.

62. The multitude of unit dosage forms of claim 59, wherein the long-acting growth hormone is ACP-001.

63. The multitude of unit dosage forms of claim 59, wherein all increases between one unit dosage form and the next higher unit dosage form comprised in the multitude of unit dosage forms is by a constant percentage value.

64. The multitude of unit dosage forms of claim 59, wherein the number of dosage forms ranges from 3 to 15.

65. The multitude of unit dosage forms of claim 59, wherein after administration of a pharmaceutically acceptable dose of the long-acting growth hormone formulation to a patient in need thereof less than 10% of the long-acting growth hormone formulation remains as waste in the unit dosage form.

66. The multitude of unit dosage forms of claim 59, wherein the long-acting growth hormone formulation comprises a hGH prodrug.

67. The multitude of unit dosage forms of claim 59, wherein the long-acting growth hormone formulation is a lyophilized formulation.

68. The multitude of unit dosage forms of claim 59, wherein the long-acting growth hormone formulation is a liquid formulation.

69. The multitude of unit dosage forms of claim 59, wherein the unit dosage form is in the form of a dual chamber cartridge that is loaded into a pen device or electronic injector.

70. A method of treating growth hormone deficiency comprising administering to patients in need thereof the multitude of unit dosage forms of claim 59 in a bracketed dosage regimen.

71. The method of claim 70, wherein the growth hormone deficiency is selected from the group consisting of growth hormone deficiency (GHD) in children, idiopathic short stature (ISS), short stature homeobox (SHOX) gene mutations, Turner syndrome (TS), Noonan syndrome (NS), Prader-Willi syndrome (PWS), children born small for gestational age (SGA), chronic renal insufficiency (CRI), growth hormone deficiency (GHD) in adults, wasting due to HIV or AIDS or other malignancies, short bowel syndrome (SBS), sarcopenia, and frailty.

72. The method of claim 70, wherein the growth hormone deficiency is growth hormone deficiency in children.

Description

EXAMPLES

Methods

Cation Exchange Chromatography

[0457] The purification of conjugates by cation exchange chromatography was performed using an KTA Pure system (GE Healthcare) equipped with a Macrocap SP column with a column volume of 279 mL. The respective reaction mixture was applied to the column which was pre-equilibrated in 20 mM sodium acetate, 10 mM L-methionine buffer, pH 4.0 (buffer A). After loading, the column was washed with three column volumes of buffer A to remove any unreacted PEG reagent. Mono-Conjugates were eluted using a gradient of 0-30% buffer B (20 mM sodium acetate, 1 M sodium chloride, pH 4.5) over 15 column volumes. A gradient of 30-80% B over three column volumes was used to elute unreacted growth hormone. The column was cleaned with 3 column volumes of 100% buffer B. The flow rate was 20 mL/min for loading and 25 mL/min during the elution. The elution was monitored by detection at 280 nm.

Height and Height Velocity Measurements

[0458] Height measurements were performed using a calibrated wall-mounted (e.g. Harpenden or similar) stadiometer. The results were derived as an arithmetic mean from three separate measurements at each visit. The time of measurement and the auxologist's name, as well as the result were recorded. The calculation of height velocity was performed centrally.

Example 1: Synthesis of Transient 4 20 kDa mPEG-Linker-hGH Monoconjugate 1

[0459] 4 20 kDa mPEG-linker-hGH monoconjugate 1 was synthesized according to a similar procedure as described in WO2009/133137 A2. The formulations of 4 20 kDa mPEG-linker-hGH monoconjugate 1 as shown in Table 1 were prepared.

##STR00018##

TABLE-US-00011 TABLE 1 Formulations of 4x 20 kDa mPEG-linker-hGH monoconjugate 1 Concentration of 4x 20 kDa mPEG-linker-hGH Concentration Formulation monoconjugate 1 formulation of hGH eq. name: [mg conjugate/mL] [mg hGH eq./mL] 1A 30 6 1B 45 9 1C 75 15

Example 2: Synthesis of Transient 4 10 kDa mPEG-Linker-hGH Monoconjugate 2

[0460] ##STR00019##

[0461] 4 10 kDa mPEG-linker-hGH monoconjugate 2 was synthesized according to a similar procedure as described in WO2009/133137 A2; in detail the manufacturing process was conducted as follows:

[0462] hGH was buffer exchanged to 100 mM sodium borate pH 9 and the concentration of hGH was adjusted to 10 mg/mL. A molar excess of 4-arm branched 40 kDa mPEG-pentafluorophenylcarbonate derivative relative to the amount of hGH was dissolved in water to form a 6% (w/w) reagent solution. The reagent solution was added to the hGH solution in a 1-to-1 ratio (based on weight) and mixed. The reaction mixture was incubated under stirring for 105 min at 12-16 C. and subsequently quenched by adding 4 volumes of a solution comprising 27 mM acetic acid and 12.5 mM L-methionine to 1 volume of the reaction mixture to lower the pH of the solution to 4-4.5. After sterile filtration, the reaction mixture was incubated at room temperature for 164 h. 4 10 kDa mPEG-linker-hGH monoconjugate 2 was purified by cation exchange chromatography.

[0463] Buffer exchange and adjustment to the desired concentration of 4 10 kDa mPEG-linker-hGH monoconjugate 2 was achieved using a tangential-flow filtration system. Herewith the eluate from the cation exchange chromatography was ultra-filtrated and dia-filtrated to formulation buffer (10 mM succinic acid, 85 g/L trehalose dihydrate, pH 5.0 with 1M Tris-solution). Using the same system the trehalose concentration was lowered to 65 g/L and the concentration of this stock solution adjusted to 1053 mg/mL of 4 10 kDa mPEG-linker-hGH monoconjugate 2 (corresponding to 351 mg hGH eq./mL). The formulations as shown in Table 2 were prepared based on this stock-solution of compound 2 by diluting the stock solution with high strength formulation buffer (10 mM succinic acid, 89 g/L trehalose dihydrate, adjusted to pH 5.0 with 1M Tris-base).

TABLE-US-00012 TABLE 2 Formulations of 4x 10 kDa mPEG-linker-hGH monoconjugate 2 Concentration of 4x 10 kDa Concentration Formulation mPEG-linker-hGH monoconjugate of hGH eq. name: 2 formulation [mg/mL] [mg hGH eq./mL] 2A 103.8 34.6 2B 95.1 31.7 2C 81.9 27.3 2D 65.1 21.7 2E 47.4 15.8

Example 3: Preparation of a Formulation Comprising 4 20 kDa mPEG-Linker-hGH Monoconjugate 1 for Clinical Studies

[0464] For the usage as an investigational drug in clinical studies 4 20 kDa mPEG-linker-hGH monoconjugate 1 was transformed into a lyophilized drug product in Din2R glass vials. Each vial was filled with 1.1100.056 mL Drug Substance of 4 20 kDa mPEG-linker-hGH monoconjugate 1 formulated to contain a nominal PEGylated protein content of 45 mg TransCon PEG hGH/mL (equivalent to 9 mg hGH/mL) which, following lyophilization, contains 50.0 mg TransCon PEG hGH (nominal) together with the excipients succinic acid, trehalose dihydrate and Tris as depicted in Table 3. Closing and capping of the vials was performed with the low pressure present during the secondary drying phase of lyophilization maintained in the vial.

TABLE-US-00013 TABLE 3 Formulation of 4x 20 kDa mPEG-linker-hGH monoconjugate 1 (lyophilizate, 50 mg (10 mg hGH)) Nominal Name of quantity ingredient Quality Function (per vial) 4x 20 kDa mPEG- cGMP Prodrug form of the 50.0 mg linker-hGH (Manufacturer active pharmaceutical (equivalent monoconjugate 1 specification ingredient (API), hGH to 10.0 mg hGH) Succinic acid USP NF Buffering agent 1.31 mg Trehalose Ph. Eur./USP Tonicifier 88.8 mg Dihydrate lyoprotectant Tris Ph. Eur./USP pH adjustment q.s. to pH 5.0

[0465] Following reconstitution with water for injection (WFI), 4 20 kDa mPEG-linker-hGH monoconjugate 1 was presented as a single-use, sterile solution for subcutaneous (s.c.) injection. Each glass vial (Type I) contains 50.0 mg lyophilized 4 20 kDa mPEG-linker-hGH monoconjugate 1 (nominal) which is stoppered with a FluroTec coated, bromobutyl rubber stopper, secured with a plastic/aluminum cap. Upon reconstitution with 1.00 mL WFI, the formulation of the resulting 1.11 mL of drug product is as presented in Table 4.

TABLE-US-00014 TABLE 4 Formulation of reconstituted 4x 20 kDa mPEG- linker-hGH monoconjugate 1 Strength Name of ingredient Quality Function (nominal) 4x 20 kDa mPEG- cGMP Prodrug form 45 mg 4x linker-hGH (Manufacturer of the active 20 kDa monoconjugate 1 specification pharmaceutical mPEG-linker- ingredient hGH mono- (API), hGH conjugate 1 Succinic acid USP NF Buffering agent 10 mM Trehalose Dihydrate Ph. Eur./USP Tonicifier 80 mg/mL Tris Ph. Eur./USP pH adjustment q.s. to pH 5.0 Water for injection Ph. Eur./USP Solvent 1.00 mL

Example 4: Phase 2 Pediatric Study

[0466] The formulation of example 3 comprising TransCon hGH compound 1 was studied in a Phase 2 pediatric in around 48 treatment-nave pre-pubertal patients with GHD. Pediatric patients were enrolled across Europe and North Africa who meet internationally recognized criteria for GHD, including short stature as measured by height and height velocity, two hGH stimulation tests, a bone age evaluation and IGF-1 levels below 1 standard deviation score, or SDS. The Phase 2 pediatric study was a six-month multi-center, randomized study comparing three fixed doses of the formulation of example 3 comprising TransCon hGH compound 1 administered once per week at doses of 0.14 mg/kg/week, 0.21 mg/kg/week and 0.30 mg hGH/kg/week. The main efficacy endpoint was annualized height velocity at six months.

[0467] An interim analysis consisting of 25 patients, representing approximately 50% of the anticipated total enrollment in the study, completing three months of the total six months of treatment, demonstrated that mean annualized height velocities were comparable, ranging from 13.0 cm to 14.1 cm for the three weekly dose levels of TransCon hGH compound 1

[0468] In conclusion, chronic administration of TransCon hGH compound 1 for 13 weeks is safe and well tolerated and is associated with acceleration of growth at a rate comparable to daily hGH administered at a comparable weekly dose. The annualized height velocities were very similar across the dose range from 0.14 mg/kg/week to 0.30 mg hGH/kg/week, with a flat dose response curve which led to the surprising observation that fixed dose adjustment according to weight of a long acting growth hormone is not required across the dose range commonly used for treatment of growth hormone deficiency with daily hGH in Europe and US.

ABBREVIATIONS

[0469] AIDS acquired immune deficiency syndrome [0470] API active pharmaceutical ingredient [0471] cGMP current good manufacturing practice [0472] CRI chronic renal insufficiency [0473] GHD growth hormone deficiency [0474] hGH human growth hormone [0475] HIV human immunodeficiency virus [0476] ISS idiopathic short stature [0477] mPEG methoxypoly(ethylene glycol) [0478] NS Noonan syndrome [0479] PEG poly(ethylene glycol) [0480] Ph. Eur. European Pharmacopeia [0481] PWS Prader-Willi syndrome [0482] SBS short bowel syndrome [0483] SGA children born small for gestational age [0484] SHOX short stature homeobox [0485] USP United States Pharmacopeia [0486] Tris Tris(hydroxymethyl)-aminomethan [0487] TS Turner syndrome