LONG-ACTING GROWTH HORMONE DOSAGE FORMS WITH SUPERIOR EFFICACY TO DAILY SOMATROPIN

Abstract

The present invention relates to a long-acting growth hormone or a pharmaceutical formulation comprising such long-acting growth hormone for use in a method of treating growth hormone deficiency with improved outcomes.

Claims

1. A long-acting growth hormone or a pharmaceutical formulation comprising such long-acting growth hormone for use in a method of reducing the percentage of non-responders in a patient population suffering from growth hormone deficiency.

2. The long-acting growth hormone or the pharmaceutical formulation of claim 1, wherein the percentage of non-responders is reduced to less than 10%.

3. A long-acting growth hormone or a pharmaceutical formulation comprising such long-acting growth hormone for use in the treatment of growth hormone deficiency, wherein said treatment increases IGF-1 levels in plasma by a standard deviation score of at least 0.2 more than the equivalent dose of daily hGH.

4. The long-acting growth hormone or the pharmaceutical formulation of claim 3, wherein the increase is at least 0.3 SDS.

5. A long-acting growth hormone or a pharmaceutical formulation comprising such long-acting growth hormone for use in a method of increasing the percentage of responders in a patient population suffering from growth hormone deficiency.

6. The long-acting growth hormone or the pharmaceutical formulation of claim 5, wherein the percentage of responders is increased to at least 90%.

7. A long-acting growth hormone or a pharmaceutical formulation comprising the long-acting growth hormone for use in a method of treating, wherein said long-acting growth hormone or the pharmaceutical formulation is administered in a dose of 0.24 mg/kg/week growth hormone or growth hormone equivalents and administration of said long-acting growth hormone pharmaceutical composition comprising said long-acting growth hormone leads to superior efficacy compared to administration of a dose of 0.24 mg/kg/week of a daily somatropin.

8. The long-acting growth hormone or a pharmaceutical formulation of claim 7, wherein the superior efficacy is measured as annualized height velocity.

9. The long-acting growth hormone or a pharmaceutical formulation of any one of claims 1 to 8, wherein the growth hormone deficiency is growth hormone deficiency in children.

10. The long-acting growth hormone or a pharmaceutical formulation of any one of claims 1 to 9, wherein the long-acting growth hormone is administered no more than once per week.

11. The long-acting growth hormone or a pharmaceutical formulation of any one of claims 1 to 10, wherein the time between two consecutive administrations is 1 week.

12. The long-acting growth hormone or a pharmaceutical formulation of any one of claims 1 to 11, wherein the pharmaceutical formulation is a dry formulation.

13. The long-acting growth hormone or a pharmaceutical formulation of any one of claims 1 to 11, wherein the pharmaceutical formulation is a liquid formulation.

14. The long-acting growth hormone or a pharmaceutical formulation of any one of claims 1 to 13, wherein the long-acting growth hormone is of formula (Ia) or (Ib) ##STR00019## wherein -D is a hGH moiety connected to the rest of the molecule through an amine functional group; n is 0, 1, 2, 3, or 4; —X— is a chemical bond or a spacer; ═Y.sub.1, ═Y.sub.5 are selected independently from the group consisting of ═O and ═S; —Y.sub.2—, —Y.sub.3— are selected from the group consisting of —O— and —S—; —Y.sub.4— is selected from the group consisting of —O—, —NR.sup.5— and —C(R.sup.6R.sup.6a)—; —R.sup.1 is a carrier, preferably a water-soluble PEG-based moiety comprising at least 40% PEG; —R.sup.2, —R.sup.3, —R.sup.5, —R.sup.6, —R.sup.6a are independently of each other selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl; —R.sup.4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl; —W— is selected from the group consisting of C.sub.1-20 alkyl optionally interrupted by one or more groups selected from the group consisting of C.sub.3-10 cycloalkyl, 8- to 30-membered carbopolycyclyl, 3- to 10-membered heterocyclyl, —C(O)—, —C(O)N(R.sup.7)—, —O—, —S— and —N(R.sup.7)—; —Nu is a nucleophile selected from the group consisting of —N(R.sup.7R.sup.7a), —N(R.sup.7OH), —N(R.sup.7)—N(R.sup.7aR.sup.7b), —S(R.sup.7), —COOH, ##STR00020## —Ar— is selected from the group consisting of ##STR00021## wherein dashed lines indicate attachment to the rest of the prodrug, —Z.sup.1— is selected from the group consisting of —O—, —S— and —N(R.sup.7)—, and —Z.sup.2— is —N(R.sup.7)—; and —R.sup.7, —R.sup.7a, —R.sup.7b are independently of each other selected from the group consisting of —H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; wherein the prodrug of formula (Ia) and (Ib) is optionally further substituted.

15. The long-acting growth hormone or a pharmaceutical formulation of any one of claims 1 to 14, wherein the long-acting growth hormone is ACP-011.

16. The long-acting growth hormone or a pharmaceutical formulation of any one of claims 1 to 14, wherein the long-acting growth hormone is somapacitan.

Description

EXAMPLES

Methods

Cation Exchange Chromatography

[0307] The purification of conjugates by cation exchange chromatography was performed using an AKTA 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

[0308] 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 4×10 kDa mPEG-Linker-hGH Monoconjugate 1

[0309] ##STR00018##

[0310] 4×10 kDa mPEG-linker-hGH monoconjugate 1 was synthesized according to a similar procedure as described in WO2009/133137 A2; in detail the manufacturing process was conducted as follows:

[0311] 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 16±4 h. 4×10 kDa mPEG-linker-hGH monoconjugate 1 was purified by cation exchange chromatography.

[0312] Buffer exchange and adjustment to the desired concentration of 4×10 mPEG-linker-hGH monoconjugate 1 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 105±3 mg/mL of 4×10 kDa mPEG-linker-hGH monoconjugate 1 (corresponding to 35±1 mg hGH eq./mL). The formulations as shown in Table 2 were prepared based on this stock-solution of compound 1 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-00003 TABLE 1 Formulations of 4x 10 kDa mPEG-linker-hGH monoconjugate 1 Concentration of 4x 10 kDa mPEG-linker-hGH Formulation monoconjugate 1 Concentration of hGH eq. name: 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 2: Preparation of a formulation comprising 4×10 kDa mPEG-linker-hGH monoconjugate 1 for clinical studies

[0313] For the usage as an investigational drug in clinical studies 4×10 kDa mPEG-linker-hGH monoconjugate 1 was transformed into a lyophilized drug product in glass vials and was presented in single-use glass vials as lyophilized powder for reconstitution with sWFI and was formulated at a concentration suitable to deliver clinically relevant dose volumes for pediatric patients (<0.60 mL). It was supplied in two vial configurations: 12.1 mg hGH/vial and 24.2 mg hGH/vial.

TABLE-US-00004 TABLE 2 Formulation of 4x 10 kDa mPEG-linker-hGH monoconjugate 1 Name of ingredient Quality Function 4x 10 kDa mPEG- cGMP Prodrug form of the active linker-hGH (Manufacturer pharmaceutical ingredient monoconjugate 1 specification (API), hGH Succinic acid NF Buffering agent Trehalose Dihydrate Ph. Eur./USP Tonicifier/lyoprotectant Tris Ph. Eur./USP pH adjustment

[0314] Following reconstitution with water for injection (WFI), 4×10 kDa mPEG-linker-hGH monoconjugate 1 was presented as a single-use, sterile solution for subcutaneous (s.c.) injection.

Example 3: Phase 3 Pediatric Study

[0315] The formulation of example 3 comprising 4×10 kDa mPEG-linker-hGH monoconjugate 1 was studied in a Phase 3 pediatric growth hormone deficiency trial. Pediatric patients were enrolled across the North America, Europe and Oceania 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-I levels below -1 standard deviation score, or SDS. This phase 3 trial was a multicenter, open-label trial, enrolling approximately 161 treatment-naïve children with GHD who were randomized in a 2:1 ratio to receive either once-weekly 4×10 kDa mPEG-linker-hGH monoconjugate 1 (0.24 mg/kg/week subcutaneously) or daily Genotropin® (34 μg/kg/day or 0.24 mg/kg/week subcutaneously) for 52 weeks. The primary endpoint was annualized HV at 52 weeks. The secondary endpoints consisted of safety and tolerability; annualized HV over 52 weeks; change in height standard deviation score (SDS) over 52 weeks; serum IGF-1 and IGFBP-3 levels and change in corresponding SDS over 52 weeks; and incidence of anti-human growth hormone antibodies, including neutralizing antibodies. Additionally, both arms were analyzed for non-responders.

[0316] In conclusion, the randomized, open-label, active-controlled trial demonstrated that 4×10 kDa mPEG-linker-hGH monoconjugate 1 (n=105) met its primary objective of non-inferiority and, additionally, was superior to the daily Genotropin (n=56) on the primary endpoint of annualized height velocity (AHV) at 52 weeks. In the primary analysis of the intent-to-treat population using ANCOVA, 4x 10 kDa mPEG-linker-hGH monoconjugate 1 demonstrated an AHV of 11.2 cm/year compared to 10.3 cm/year for the daily hGH. The treatment difference was 0.86 cm/year with a 95 percent confidence interval of +0.22 to +1.50 cm/year and superiority was demonstrated (p=0.0088).

[0317] The AHV was greater for 4×10 kDa mPEG-linker-hGH monoconjugate 1 than for the daily hGH at each visit, with the treatment difference reaching statistical significance from week 26 and continued throughout the trial. Incidence of poor responders (AHV <8.0 cm/year) was 4 percent and 11 percent in the 4×10 kDa mPEG-linker-hGH monoconjugate 1 and daily hGH arms, respectively.

[0318] 4×10 kDa mPEG-linker-hGH monoconjugate 1 was safe and well-tolerated, with adverse events typical of daily hGH therapy and comparable between arms. In addition, observed peak and trough insulin-like growth factor 1 (IGF-1) SDS were approximately +1.3 and -0.5 over 52 weeks, respectively for 4×10 kDa mPEG-linker-hGH monoconjugate 1 compared to an approximate average IGF-1 SDS of 0.0 for the daily hGH at week 52. Furthermore, observed excursions of IGF-1 SDS >2.0 were uncommon (<10 percent of subjects) and IGF-1 SDS >3.0 were rare (<3 percent of subjects). Two subjects in each treatment arm experienced injection site reactions that were considered adverse events.

Example 4: Phase 2 Pediatric Study Somapacitan (NCT02616562, Novo Nordisk; https://clinicaltrials.gov/ct2/show/NCT02616562)

[0319] Somapacitan has the structure as shown elsewhere herein.

[0320] Design: The study was a multicenter, randomized, controlled, double-blind (somapacitan doses), phase-2 study with a 26-week main and 26-week extension phase performed at 29 sites in 11 countries. 59 GH treatment-naïve pre-pubertal children with GHD were randomized; 58 completed the trial.

[0321] Interventions: Three somapacitan doses (0.04 [n=16], 0.08 [n=15] or 0.16 mg/kg/week [n=14]) and daily GH (0.034 mg/kg/day [n=14]), administered subcutaneously.

[0322] Main Outcome Measures: Primary endpoint was HV at week 26. Secondary efficacy endpoints included HV SDS and IGF-I SDS.

[0323] Results: At week 26, mean (SD) annualized HV for somapacitan groups was 8.0 (2.0), 10.9 (1.9) and 12.9 (3.5)cm/year, respectively, versus 11.4 (3.3) cm/year for daily GH; estimated treatment difference (somapacitan 0.16 mg/kg/week-daily GH): 1.7 [95% CI—0.2; 3.6] cm/year. HV was sustained at week 52, and significantly greater with somapacitan 0.16 mg/kg/week versus daily GH. Mean (SD) change from baseline in HV SDS at week 52 was 4.72 (2.79), 6.14 (3.36) and 8.60 (3.15) for somapacitan groups, respectively, versus 7.41 (4.08) for daily GH. Model-derived mean (SD) IGF-I SDS for the somapacitan groups was -1.62 (0.86), -1.09 (0.78), and 0.31 (1.06), respectively, versus -0.40 (1.50) observed for daily GH. Safety and tolerability were consistent with the profile of daily GH.

Abbreviations

AHV Annual/Annualized Height Velocity

[0324] API active pharmaceutical ingredient
cGMP current good manufacturing practice
GH growth hormone
GHD growth hormone deficiency
hGH human growth hormone
mPEG methoxypoly(ethylene glycol)
PEG poly(ethylene glycol)
Ph. Eur. European Pharmacopeia

USP United States Pharmacopeia

[0325] Tris Tris(hydroxymethyl)-aminomethan