Serostim 4 mg-in-vial, 5 mg-in-vial, 6 mg-in-vial, 8.8 mg-in-vial - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Serostim 4 mg-in-vial, 5 mg-in-vial, 6 mg-in-vial, 8.8 mg-in-vial - Scientific Information

Manufacture: EMD Serono, Inc
Country: Canada
Condition: AIDS Related Wasting, Cachexia, Prader-Willi Syndrome, Short Stature for Age
Class: Growth hormones
Form: Subcutaneous (SC), Powder
Ingredients: somatropin, sucrose, phosphoric acid

Pharmaceutical Information

Drug Substance

Proper name: Somatropin for injection
Chemical name: recombinant human Growth Hormone for Injection (r-hGH)
Molecular Formula : C990H1528N262O300S7
Structural Formula: -PHE-PRO-THR-ILE-PRO-LEU-SER-ARG-LEU-PHE-ASP-ASN-ALA-MET-LEU-ARG-ALA-HIS-ARG-LEU-HIS-GLN-LEU-ALA-PHE-ASP-THR-TYR-GLN-GLU-PHE-GLU-GLU-ALA-TYR-ILE-PRO-LYS-GLU-GLN-LYS-TYR-SER-PHE-LEU-GLN-ASN-PRO-GLN-THR-SER-LEU-CYS-PHE-SER-GLU-SER-ILE-PRO-THR-PRO-SER-ASN-ARG-GLU-GLU-THR-GLN-GLN-LYS-SER-ASN-LEU-GLU-LEU-LEU-ARG-ILE-SER-LEU-LEU-LEU-ILE-GLN-SER-TRP-LEU-GLU-PRO-VAL-GLN-PHE-LEU-ARG-SER-VAL-PHE-ALA-ASN-SER-LEU-VAL-TYR-GLY-ALA-SER-ASP-SER-ASN-VAL-TYR-ASP-LEU-LEU-LYS-ASP-LEU-GLU-GLU-GLY-ILE-GLN-THR-LEU-MET-GLY-ARG-LEU-GLU-ASP-GLY-SER-PRO-ARG-THR-GLY-GLN-ILE-PHE-LYS-GLN-THR-TYR-SER-LYS-PHE-ASP-THR-ASN-SER-HIS-ASN-ASP-ASP-ALA-LEU-LEU-LYS-ASN-TYR-GLY-LEU-LEU-TYR-CYS-PHE-ARG-LYS-ASP-MET-ASP-LYS-VAL-GLU-THR-PHE-LEU-ARG-ILE-VAL-GLN-CYS-ARG-SER-VAL-GLU-GLY-SER-CYS-GLY-PHE .
Molecular Weight : 22, 125 daltons
Description of Drug Substance: Somatropin is a polypeptide hormone consisting of 191 amino acid residues and its structure is identical to that of growth hormone extracted from human pituitary glands. A large loop is formed by a disulfide bond between Cys 53 and Cys 165 . A second, smaller loop is formed by a disulfide bond near the carboxyl-terminal between Cys 182 and Cys 189 . The solution is a slightly opalescent liquid.
Biological Activity : The biological activity of growth hormone is approximately 3.0 international units/1mg

Clinical Trials

The clinical efficacy of SEROSTIM (somatropin for injection) was assessed in a short term metabolic study and two placebo-controlled Phase III clinical trials.

Study Demographics and Trial Design

Table 1 - Summary of patient demographics for clinical trials
Study # Trial design Dosage, route of
administration
and duration
Total number
of study
subjects
(n=number)
Mean age
(Range) in Years
Gender
GF 4795 Open, parallel group, controlled (volunteers and HIV+) 0.1 mg/kg/day s.c. once daily for 7 days 12

HIV negative (n=6)

HIV+ (n=6)
HIV-negative subjects: 31.8 (25- 41)

HIV+ subjects: 35.8 (28-44)
Male (12)
GF 5341 Randomized, doubleblind, placebocontrolled, in HIV+ subjects 0.1 mg/kg/day s.c. once daily for 12 weeks 178

GH (n=90)

Placebo (n=88)
39.2 (26-70) GH group

39.1 (27-73) Placebo group
Male (172) and Female (6)
GF 5511 Open-label long-term extension. Continuation treatment after Serono protocol GF5341 0.1 mg/kg/day s.c. once daily 136

GH-GH (n=66)

PL-GH (n=70)
39.67 (26-70) GH- GH group

39.29 (27-72) Placebo- GH group
Male (134) and Female (2)
GF 7033 Randomized, doubleblind, placebocontrolled, in HIV+ subjects 6 mg/day s.c. once daily for 12 weeks 177

GH (n=115)

Placebo (n=62)
38.2 (24-69) GH group

37.5 (25-64) Placebo group
Male (173) and Female (4)

Study Results

Narrative Summary of Study Results

Metabolic data were obtained on HIV + men (with an average weight loss of 19%) and healthy HIV - volunteers (with a normal weight for height) who were treated with SEROSTIM for 7 days while consuming a constant metabolic diet. Resting energy expenditure was paradoxically increased in the HIV + individuals at baseline. The rate of resting energy expenditure increased during SEROSTIM treatment in both groups 136 (32.4) ± 2 (0.5) kJ (Cal)/kg LBM.day and 123 (29.3) ± 2 (0.2) kJ (Cal)/kg LBM.day (in HIV positive and HIV negative subjects, respectively). SEROSTIM therapy led to a prompt and sustained increase in body weight in HIV + and HIV - individuals. Cumulative weight gain averaged 2.6 kg (4.5 ± 0.8%) in HIV positive subjects, and 2.3 kg (3.4 ± 0.5 %) among HIV negative subjects, respectively after 7 days. Urinary nitrogen excretion decreased in both groups while stool nitrogen was unchanged, indicating a positive nitrogen balance and retention of ingested protein. A decrease in blood urea nitrogen and the measured ratio of retained potassium to nitrogen were consistent with incorporation of dietary protein into lean tissue. Protein oxidation decreased, whereas lipid oxidation increased significantly. Thus short -term SEROSTIM treatment exerted an anti-catabolic, protein-sparing effect with significantly decreased protein oxidation and significantly increased lipid oxidation.

Table 2 - GF 4795 – Change in percent body weight, resting energy expenditure and urinary nitrogen excretion from baseline
Mean ±
SEM
Body weight (a)

(Δ vs baseline, %)
Resting Energy Expenditure(b)

(Δ kcal/d vs baseline)
Urinary N Excretion (c)

(Δ g/d vs baseline)
Study day HIV positive HIV negative HIV positive HIV negative HIV positive HIV negative
0 -0.1± 0.1 -0.1± 0.3 7.0± 11.0 -29.0± 8.0 -0.10± 0.40 -0.18± 0.38
7 4.5± 0.8 3.4± 0.5 190.0± 32.0 185.0± 24.0 -5.56± 0.57 -4.24± 0.66

(a) Change in body weight is expressed as the mean (± SEM) of the differences (%) of that day’s weight, compared to the average weight measured during the Baseline period*.

(b) Mean (± SEM) of differences between daily REE and average Baseline REE*

(c) Mean(± SEM) of differences between daily urinary nitrogen excretion and average Baseline urinary nitrogen excretion*

* Baseline values equaled of the average value for inpatient days –6, -5,-4,-3, -2, and -1

The clinical efficacy of SEROSTIM was assessed in two placebo-controlled clinical trials (GF 5341 and GF 7033). Of the 205 AIDS subjects exposed to HIV, only 5 were women. All study subjects received concomitant anti-HIV therapy. A multicenter, double-blind, placebo-controlled study compared SEROSTIM, at an average daily dose of 6 mg (0.1 mg/kg/day) administered subcutaneously, to placebo in 178 patients with AIDS wasting. The study participants had unintentional weight loss of at least 10% or weighed less than 90% of the lower limit of ideal body weight. In the 140 evaluable patients (those completing a 12 week course of treatment and who were at least 80% compliant with study drug), the mean weight increase in the SEROSTIM treated group was 1.6 kg (3.5 lb). Mean differences in lean body mass change between the SEROSTIM-treated group and the placebo-treated group was 3.1 kg (6.82 lb) as measured by DEXA. Mean increase in weight and lean body mass and mean decrease in body fat were significantly greater in the SEROSTIM-treated group than in the placebo group (p = 0.011, p < 0.001, p < 0.001, respectively). Patients in the SEROSTIM group also had significant gains in strength and endurance, as evidenced by a 13% greater maximal work output on treadmill testing, as well as significant improvement in overall quality of life. Increases in lean body mass were also correlated with a decrease in the rate of new AIDS-associated diagnoses.

Table 3 - GF 5341 – Body weight at baseline and Endpoint and change in body weight at Endpoint by treatment group (ITT population)
Variable Visit Treatment
group
N Mean SD Median Range p-value (a)
Body Weight (kg) Baseline r-hGH
Placebo
88
83
61.67
61.49
7.92
7.44
61.36
62.27
(40.30-83.18)
(41.36-77.27)
Endpoint(b) r-hGH
Placebo
88
83
62.75
61.58
9.45
7.93
63.64
61.36
(38.64-90.45)
(40.91-80.91)
Change in weight (kg) Endpoint(b) r-hGH
Placebo
88 83 1.08
0.09
3.97
2.92
1.82
0.00
(-12.27-9.09)
(-7.00-9.09)
0.009*

(a) p-values are from Wilcoxon Rank Sum

(b) Endpoint is equal to the latest post-baseline weight measurement

* Statistically significant at the 0.05 level

Table 4 - GF 5341 – Summary statistics and change from baseline for body weight (Evaluable population)
Variable Visit Treatment group N Mean SD Range p-value (a)
Body Weight (kg) Baseline r-hGH
Placebo
69
71
61.73
61.99
7.01
7.27
(40.30-82.27)
(47.27-77.27)
Week 12 r-hGH
Placebo
69
71
63.37
62.11
8.62
7.81
(40.60-90.45)
(46.36-80.91)
Change in weight (kg) Week 12 r-hGH
Placebo
69
71
1.63
0.12
3.71
3.11
(-5.91-9.09)
(-7.00-9.09)
0.011*

(a) p-values for significance of treatment group differences are from an analysis of variance model with group and site as the factors

* Statistically significant at the 0.05 level

Patients completing 12 weeks of treatment were eligible to receive open-label SEROSTIM therapy. There were 48 GH-GH subjects and 53 PL-GH subjects who had body weight measurements obtained at baseline and at Month 3. Since this phase of the trial was open-label, and due to limited numbers of evaluable patients, it is difficult to interpret weight and LBM changes. The patients who initially received placebo had significant increases in median weight (1.4 kg, p=0.012) and lean body mass (2.4 kg, p<0.001), compared to Baseline, during their first 12 weeks on SEROSTIM. These changes were similar in magnitude to those observed in patients initially treated with SEROSTIM. For those patients who had initially received SEROSTIM in the placebo-controlled trials, the mean weight change during 12-weeks of open label treatment with SEROSTIM and LBM change were not significant. There was a significantly lower occurrence rate of new AIDS-defining diagnoses during open-label therapy for the group who had received SEROSTIM in the three previous months.

Table 5 - GF 5511 – Body weight at baseline and Month 3 and change in body weight at Month 3 (by enrollment group)
Variable Visit Treatment group N Mean SD Median Range p-value (a)
Weight (kg) Baseline GH-GH
PL-GH
48
53
64.30
62.39
7.02
7.96
64.62
62.27
(48.18, 78.90)
(46.36, 79.55)
Month 3 GH-GH
PL-GH
48
53
64.02
63.26
7.45
8.70
64.77
64.55
(47.27, 79.50)
(39.55, 80.91)
Change in weight (kg) Month 3 GH-GH
PL-GH
48
53
-0.27
0.87
3.20
3.27
-0.15
1.36
(-11.36, 10.00)
(-9.09, 6.36)
0.700
0.012*

(a) p-values are from the Wilcoxon Signed Rank Test

* Statistically significant at the 0.05 level

Figure 1: Studies GF5341 and 5511: Changes in Body Composition (mean±SEM)

Figure 2: Study GF 5341: Treadmill Analysis Placebo versus r-hGH[m] (Evaluable Population)

A second multicenter, double-blind, placebo-controlled study comparing SEROSTIM, 6 mg/day administered subcutaneously vs. placebo, in AIDS patients with wasting enrolled 177 patients who were randomized in a 2:1 ratio, to receive SEROSTIM or placebo. In the evaluable patients (those completing a 12-week course of treatment and who were at least 80% compliant with study drug), there was a mean increase in body weight of 1.6 kg but this change was not significant compared to placebo (p=0.110). The most common reason for drop-out was concurrent medical events including opportunistic infections.

Combined Clinical Results

When results of the two major Phase III clinical trials (GF5341 and GF7033) were combined, the group receiving SEROSTIM had a significantly greater improvement in overall quality of life compared to the placebo group, using two different instruments, the HIV-PARSE questionnaire, and the Well-Being scale. There was also a significant increase in the absolute neutrophil count in the group receiving SEROSTIM compared to placebo. The table below summarizes the key 3-month efficacy results of the two placebo-controlled studies combined.

Table 6: Summary of Three Month Efficacy Results from Placebo-Controlled Clinical Trials (Change from Baseline)
SEROSTIM Placebo
n Results n Results
Lean Body Mass (kg) 69 +3.0* 69 -0.1
LBM Responders¥ 69 70%* 69 12%
Absolute neutrophil count (cells/cm2) 194 +290* 143 -170
Overall Quality of Life
  Well-Being questionnaire (score) 69 6.6* 44 5.7
  PARSE (% responders) 138 61%* 114 45%
  Treadmill work (kg ,m/min) 63 98.62* 60 20.07

¥ Major LBM response defined as >4% increase of LBM

* Statistically significantly different from placebo at p<0.05

Comparative Bioavailability Studies

Somatropin 8.8 mg reconstituted with Bacteriostatic Water for Injection, 0.3% w/v metacresol has been determined to be bioequivalent to Somatropin 8.8 mg reconstituted with Bacteriostatic Water for Injection, 0.9% Benzyl Alcohol based on the statistical evaluation for Cmax, AUClast and AUC (0- 4 ). Summaries of the pharmacokinetic parameters are presented below.

Summary of the pharmacokinetic parameters of Somatropin in healthy volunteers
PK metrics Cmax
(mcg/L)
AUClast
(hr*mcg/L)
AUC(infin)
(hr*mcg/L)
AUC(infin)-
%extrapol.
tmax (h)
Median values
t1/2 (h)
Mean values
Somatropin 8.8 mg Benzyl alcohol Mean (Min-Max) 39.0
(20.8-61.5)
280
(140-411)
291
(145-418)
4.11
(1.25-10.5)
4.5
(3-7)
2.6
(1.6-4.1)
Somatropin 8.8 mg metacresol Mean
(Min-Max)
45.1
(21.5-69.2)
306
(191-458)
320
(205-495)
4.23
(1.84-13.5)
4.0
(2-7)
2.7
(1.2-5.8)
Summary of average bioequivalence without correction for potency
Bioequivalence of Somatropin Diluents
Meta-cresol (T) vs. Benzyl alcohol (R)
Parameter Estimated
Ratio (T/R) of
Relative
Means
Estimated
Intra-subject
CV(%)
90% C.I. (%) Standards Decision
Cmax 115.6% 19.8 105.2 – 127.0 Mean Ratio within 80% – 125% BE
AUCT 110.3% 10.8 104.8 – 116.0 90% C.I. within 80% – 125% BE

T = Test, R = Reference, BE = Bioequivalent

Median hGH Serum Concentration versus Time Profiles after Subcutaneous Administration of 4 mg r-hGH as Somatropin 8.8 mg benzyl alcohol (Reference) or Somatropin 8.8 mg meta-cresol (Test)

Toxicology

A series of toxicology studies including acute, subacute, subchronic and long-term studies were conducted with somatropin. The animal species used for these studies included mice, rats and monkeys.

Single Dose Studies

Six acute toxicity studies were conducted in mice, rats and monkeys.

Species Route of
Administration
Dose Observations
Rats and mice Subcutaneous 40 IU/kg (approx. 13.3 mg/kg) Mortality, Clinical Signs, Behaviour Body Weight, Toxic Effects
Rats and mice Intravenous 40 IU/kg (approx. 13.3 mg/kg)
Rats Subcutaneous and Oral 250 IU/kg (approx. 83.33 mg/kg)
Rats Oral 5, 10, 20, 40 IU/kg (approx. 1.67, 3.33, 6.67, 13.3 mg/kg)
Monkeys Subcutaneous 5, 10, 20 IU/kg (approx. 1.67, 3.33, 6.67 mg/kg)
Mice Oral 5, 10, 20, 40 IU/kg (approx. 1.67, 3.33, 6.67, 13.3 mg/kg)

Animals were sacrificed and gross pathology examinations showed no abnormal finding, except for a vacuole in hepatocytes and a hyaline droplet in renal epithelium in one female monkey of the 20 IU/kg dose group.

Long-Term Studies

Six long-term studies by the subcutaneous route of administration were conducted with somatropin: 2 four-week subacute toxicity studies (one in rats and the other in monkeys), two thirteen-week studies (one in rats and one in monkeys) and 2 fifty-two-week studies (rats and monkeys).

Four-Week Studies
RATS (4 week study) MONKEYS (4 week study)
# Animals 15/sex/group 3-5/sex/group
Dosage Daily injections of 0, 0.2, 1.0, 5.0 and 10.0 IU/kg (approximately 0, 0.067, 0.33, 1.6 and 3.33 mg/kg) in bacteriostatic saline Daily injections of 0, 0.2, 1.0 and 5.0 IU/kg (approximately 0, 0.067, 0.33 and 1.6 mg/kg) of somatropin or 0.2 and 5 IU/kg Asellacrin (pituitary-derived hGH) in 0.9% NaCl
Observations Clinical signs, mortality, behaviour, ophthalmoscopic examinations, body weight, food consumption (rats) laboratory analyses and post-mortem examinations
Results The drug was well tolerated up to 10 IU/kg (approximately 3.33 mg/kg). Small number of slight hematological, biochemical and morphological changes, most notably in 5 and 10 IU/kg (approximately 1.6 and 3.33 mg/kg) groups. These were for the most part reversible, and none appeared detrimental to the health of the animals. Local tolerability was satisfactory. The drug was well tolerated up to 5 IU/kg (approximately 1.6 mg/kg). None of the observations appeared to be treatment-related and no clearly identifiable antibodies to hGH were observed.  
Thirteen-week Studies
RATS (13 week study) MONKEYS (13 week study)
# Animals 15/sex/group 3-5/sex/group
Dosage Daily injections of 0, 0.2, 1.0 and 10 IU/kg (approximately 0, 0.067, 0.33 and 3.33 mg/kg) of somatropin, or 0.2 and 10 IU/kg Asellacrin (pituitary-derived hGH) in 0.9% NaCl Daily injections of 0, 0.2, 1 and 5.0 IU/kg (approximately 0.067, 0.33 and 1.67 mg//kg) in 0.9% NaCl
Observations Clinical signs, mortality, behaviour, ophthalmoscopic examinations, body weight, food consumption, laboratory analyses, antihGH antibodies (monkeys) and post-mortem examinations.
Results No overt signs of toxicity, a number of slight changes were observed due mainly to the biological activity of a heterologous hormone administered for a prolonged period of time. Slightly higher values of GOT, GPT, γ-GTP and LAP found in males of the 5 IU (approx. 1.67 mg) group (but without any underlying histological change in liver) were the only findings. No antibodies to hGH were detected.
Fifty-two-week Studies
RATS (52 week study) MONKEYS (52 week study)
# Animals 15/sex/group 3-5/sex/group
Dose Daily injections of 0, 0.2, 0.6 and 1.8 IU/kg (approximately 0, 0.067, 0.2 and 0.6 mg/kg) in 0.9% NaCl Daily injections of 0, 0.2, 0.6 and 1.8 IU/kg (approximately 0, 0.067, 0.2 and 0.6 mg/kg) in 0.9% NaCl
Observations Clinical signs, mortality, behaviour, ophthalmoscopic examinations, body weight, food consumption (rat), laboratory analyses, anti-hGH antibodies and post-mortem examinations
Results No treatment-related deaths. Ten rats died from incidental causes or spontaneous incidental pathology. No treatment-related clinical signs. No clinical changes at the injection site. Body weight and food consumption unaffected. No treatment-related eye abnormalities were seen. Minor increase in mean serum glucose levels in top-dose males. All rats developed high levels of antibodies to hGH by week 12, still present 8 weeks after end of study. Slight tendency towards increase of adrenal gland and spleen mean absolute weights without dose-correlation possible partial correlation with the slight increase in fasting body weight. No systemic drug-related modifications in gross pathology and histology. Some local changes due to needle trauma in treated and control rats. No treatment-related deaths. One male (0.6 IU/kg/day [approximately 0.2 mg/kg]) died on day 245 (accidental trauma). No clinical or laboratory modifications attributable to the drug. No gross alterations at injection sites. No anti-hGH antibodies detected. Postmortem examination showed no changes attributable to the drug. Histological examination of injection sites revealed needle trauma, with comparable frequency and severity among control and treated animals.

Other Studies

Sensitization potential

The potential of somatropin, bacteriostatic saline and metacresol for sensitization were assessed in the guinea pig maximization test. Groups of 20 male Dunkin Hartley albino guinea pigs were dosed intradermally and epicutaneously with somatropin reconstituted with bacteriostatic saline or 0.3% metacresol, with bacteriostatic saline, with 0.9% NaCl solution or with 0.3% metacresol alone. None of the animals showed a positive reaction when challenged with an occlusive skin patch. In the group treated with drug reconstituted in bacteriostatic saline, 40% and 50% of the animals showed positive at the first and second intradermal challenges respectively. When reconstituted in metacresol, the drug caused severe anaphylaxis after intradermal challenge, due to the high dose used in the study. In the study using bacteriostatic saline as the diluent, lower doses were injected and only a moderate skin reaction due to sensitization was observed in guinea pigs. The drug appears to be a moderate sensitizer in guinea pigs, which is understandable since the human protein present in the drug is heterologous to this species but such events are not expected to occur in humans.

One local tolerance study was conducted in rabbits to compare the drug reconstituted in metacresol, and metacresol alone. In rabbits which were injected with the drug reconstituted with 0.3% metacresol at the concentrations of 5 and 10 mg/ml, the 5mg/ml concentration caused minimal changes that were similar in type and degree to the negative control (physiological saline). The 10 mg/ml solution was slightly more irritant.

Irritating potential

One study investigating the ocular and dermal irritation potentials of the drug in rabbits showed no abnormalities.

Mutagenicity

A series of mutagenicity studies, consisting of Ames Test, Gene Conversion Test in S. cerevisiae, Unscheduled DNA Synthesis in Cultured HeLa Cells, Chromosome Aberration in Human Lymphocytes Cultured In Vitro and a Bone Marrow Micronucleus Test, were conducted in order to evaluate the mutagenic potential of somatropin.

Neither mutagenic nor clastogenic activity was observed with somatropin for any of the mutagenicity tests listed above.