Serostim (Somatropin) - Description and Clinical Pharmacology

DESCRIPTION

Serostim^® [somatropin (rDNA origin) for injection] is a human growth hormone (hGH) produced by recombinant DNA technology. Serostim^® has 191 amino acid residues and a molecular weight of 22,125 daltons. Its amino acid sequence and structure are identical to the dominant form of human pituitary GH. Serostim^® is produced by a mammalian cell line (mouse C127) that has been modified by the addition of the hGH gene. Serostim^® is secreted directly through the cell membrane into the cell-culture medium for collection and purification.

Serostim^® is a highly purified preparation. Biological potency is determined by measuring the increase in the body weight induced in hypophysectomized rats.

Serostim^® is available in 5 mg and 6 mg vials for single dose administration.  Serostim^® is also available in 4 mg and 8.8 mg vials for multi-dose administration. Each 4 mg vial contains 4.0 mg (approximately 12 IU) somatropin, 27.3 mg sucrose, 0.9 mg phosphoric acid. Each 5 mg vial contains 5.0 mg (approximately 15 IU) somatropin, 34.2 mg sucrose and 1.2 mg phosphoric acid. Each 6 mg vial contains 6.0 mg (approximately 18 IU) somatropin, 41.0 mg sucrose and 1.4 mg phosphoric acid.  Each 8.8 mg vial contains 8.8 mg (approximately 26.4 IU) somatropin, 60.19 mg sucrose and 2.05 mg phosphoric acid. The pH is adjusted with sodium hydroxide or phosphoric acid to give a pH of 7.4 to 8.5 after reconstitution with Water for Injection, USP.  The pH is adjusted with sodium hydroxide or phosphoric acid to give a pH of 6.5 to 8.5 after reconstitution with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol).

CLINICAL PHARMACOLOGY

Serostim^® [somatropin (rDNA origin) for injection] is an anabolic and anticatabolic agent which exerts its influence by interacting with specific receptors on a variety of cell types including myocytes, hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Some, but not all of its effects, are mediated by insulin-like growth factor-I (IGF-I).

Human immunodeficiency virus (HIV)-associated wasting or cachexia, which commonly involves involuntary loss of lean body mass or body weight, is a metabolic disorder characterized by abnormalities of intermediary metabolism resulting in weight loss, inappropriate depletion of lean body mass (LBM), and paradoxical preservation of body fat. LBM includes primarily skeletal muscle, organ tissue, blood and blood constituents, and both intracellular and extracellular water. Depletion of LBM results in muscle weakness, organ failure, and death.  Unlike nutritional intervention for HIV-associated wasting, in which supplemental calories are converted predominantly to body fat, Serostim^® treatment resulted in a significant increase in LBM and a decrease in fat mass with a significant increase in body weight due to the dominant effect of LBM gain.

HIV-associated adipose redistribution syndrome (HARS) is characterized by abnormal accumulation of trunk fat, including visceral adipose tissue (VAT), in patients infected with HIV/acquired immune deficiency disorder (AIDS), the vast majority of whom have been treated with highly active antiretroviral therapy (HAART). VAT is comprised of the deep fat in the abdomen in the omental-mesenteric and retroperitoneal compartments. HARS, a subset of HIV lipodystrophy, is more specifically defined as maldistribution of body fat characterized by central fat accumulation (lipohypertrophy) with or without lipoatrophy (subcutaneous fat depletion primarily in the face and limbs). In HARS patients, fat may additionally accumulate in the upper body subcutaneous area such as the dorsocervical area (i.e., “buffalo hump"). These changes may be accompanied by metabolic disturbances including insulin resistance, glucose intolerance, and dyslipidemia, as well as belly image distress. Initial 12-week treatment with Serostim^® resulted in decreases in VAT, trunk fat, and patient-reported belly appearance distress (see CLINICAL STUDIES). The clinical significance of these changes with respect to improved cardiovascular risk profile or compliance with HAART has not been studied.

Effects on Protein, Lipid, and Carbohydrate Metabolism:

A one-week study in 6 patients with HIV-associated wasting has shown that treatment with Serostim^® 0.1 mg/kg/day improved nitrogen balance, increased protein-sparing lipid oxidation, and had little effect on overall carbohydrate metabolism.

Decreases in trunk fat and total body fat, and increases in lean body mass were observed during two double-blind, placebo-controlled studies wherein Serostim^® vs. placebo were administered daily for 12 weeks to patients with HARS. (see CLINICAL STUDIES).

Effects on Nitrogen and Mineral Retention:

In the one-week study in 6 patients with HIV-associated wasting, treatment with Serostim^® resulted in the retention of phosphorous, potassium, nitrogen, and sodium. The ratio of retained potassium and nitrogen during Serostim^® therapy was consistent with retention of these elements in lean tissue.

Physical Performance:

Cycle ergometry work output and treadmill performance were examined in separate 12-week, placebo-controlled trials (see ‘Clinical Studies'). In both studies, work output improved significantly in the group receiving Serostim^® 0.1 mg/kg/day subcutaneously vs placebo. Isometric muscle performance, as measured by grip strength dynamometry, declined, probably as a result of a transient increase in tissue turgor known to occur with Serostim^® therapy.

PHARMACOKINETICS

Subcutaneous Absorption: The absolute bioavailability of Serostim^® [somatropin (rDNA origin) for injection] after subcutaneous administration of a formulation not equivalent to the marketed formulation was determined to be 70-90%. The t½ (Mean ± SD) after subcutaneous administration is significantly longer than that seen after intravenous administration in normal male volunteers down-regulated with somatostatin (3.94 ± 3.44 hrs. vs. 0.58 ± 0.08 hrs.), indicating that the subcutaneous absorption of the clinically tested formulation of the compound is slow and rate-limiting.

Distribution: The steady-state volume of distribution (Mean ± SD) following IV administration of Serostim^® in healthy volunteers is 12.0 ± 1.08 L.

Metabolism: Although the liver plays a role in the metabolism of GH, GH is primarily cleaved in the kidney. GH undergoes glomerular filtration and, after cleavage within the renal cells, the peptides and amino acids are returned to the systemic circulation.

Elimination: The t½ (Mean ± SD) in nine patients with HIV-associated wasting with an average weight of 56.7 ± 6.8 kg, given a fixed dose of 6.0 mg recombinant hGH (r-hGH) subcutaneously was 4.28 ± 2.15 hrs. The renal clearance of r-hGH after subcutaneous administration in nine patients with HIV-associated wasting was 0.0015 ± 0.0037 L/h. No significant accumulation of r-hGH appears to occur after 6 weeks of dosing as indicated.

Special Populations:

Pediatric: Available evidence suggests that r-hGH clearances are similar in adults and children, but no pharmacokinetic studies have been conducted in children with HIV.

Gender: Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based analysis is available in normal volunteers or patients infected with HIV.

Race: No data are available.

Renal Insufficiency: It has been reported that individuals with chronic renal failure tend to have decreased r-hGH clearance compared to normals, but there are no data on Serostim^® use in the presence of renal insufficiency.

Hepatic Insufficiency: A reduction in r-hGH clearance has been noted in patients with severe liver dysfunction.  However, the clinical significance of this in HIV+ patients is unknown.

CLINICAL STUDIES

HIV-Associated Wasting or Cachexia

The clinical efficacy of Serostim^® [somatropin (rDNA origin) for injection] in HIV-associated wasting or cachexia was assessed in two placebo-controlled trials. All study subjects received concomitant antiretroviral therapy.

Clinical Trial 1: A 12-week, randomized, double-blind, placebo-controlled study followed by an open-label extension phase enrolled 178 patients with severe AIDS wasting taking nucleoside analogue therapy (pre-HAART era).  The primary endpoint was body weight.  Body composition was assessed using dual energy X-ray absorptiometry (DXA) and physical function was assessed by treadmill exercise testing.  Patients meeting the inclusion/exclusion criteria were treated with either placebo or Serostim^® 0.1 mg/kg daily.  Ninety-six percent (96%) were male.  The average baseline CD4 count/µL was 85.  The results from one hundred forty (140) evaluable patients were analyzed  (those completing the 12-week course of treatment and who were at least 80% compliant with study drug).  After 12 weeks of therapy, the mean difference in weight increase between the Serostim^®-treated group and the placebo-treated group was 1.6 kg (3.5 lb).  Mean difference in lean body mass (LBM) change between the Serostim^®-treated group and the placebo-treated group was 3.1 kg (6.8 lbs) as measured by DXA.  Mean increase in weight and LBM, 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) after 12 weeks of treatment (Figure 1).  There were no significant changes with continued treatment beyond 12 weeks suggesting that the original gains of weight and LBM were maintained (Figure 1).

Treatment with Serostim^® resulted in a significant increase in physical function as assessed by treadmill exercise testing. The median treadmill work output increased by 13% (p=0.039) at 12 weeks in the group receiving Serostim^® (Figure 2). There was no improvement in the placebo-treated group at 12 weeks. Changes in treadmill performance were significantly correlated with changes in LBM.

Figure 1:  Mean Changes in Body Composition

Figure 2:  Median Treadmill Work Output

Clinical Trial 2:   A 12-week, randomized, double-blind, placebo-controlled study enrolled 757 patients with HIV-associated wasting, or cachexia.  The primary efficacy endpoint was physical function as measured by cycle ergometry work output.  Body composition was assessed using bioelectrical impedance spectroscopy (BIS) and also by dual energy X-ray absorptiometry (DXA) at a subset of centers.  Patients meeting the inclusion/exclusion criteria were treated with either placebo, approximately 0.1 mg/kg every other day (qod) of Serostim^®, or approximately 0.1 mg/kg daily (qhs) of Serostim^®.   All results were analyzed in intent-to-treat populations (for cycle ergometry work output, n=670). Ninety-one percent (91%) were male and 88% were on HAART anti-retroviral therapy.  The average baseline CD4 count/µL was 446.  Six hundred forty-six patients (646) completed the 12-week study and continued in the Serostim^® treatment extension phase of the trial.

Clinical Trial 2 results are summarized in Tables 1 and 2:

Table 1: Mean (Median) of Cycle Work Output (kJ) Response after 12 weeks of Treatment ITT Population

	Placebo	Half-Dose Serostimb	Full-Dose Serostima
(a)  approximately 0.1 mg/kg daily
(b)  approximately 0.1 mg/kg every other day
(c)  p<0.01
Cycle work output (kJ)	n=222	n=230	n=218
Baseline	25.92 (25.05)	27.79 (26.65)	27.57 (26.30)
Change from baseline	-0.05 (-0.25)	2.48 (2.30)	2.52 (2.40)
Percent change from baseline	0.2%	8.9%	9.1%
Difference from Placebo
Mean (2-sided 95% C.I.)	-	2.53c (0.81, 4.25)	2.57c(0.83, 4.31)
Median		2.55	2.65

Table 2: Mean (Median) Change from Baseline for Lean Body Mass, Fat Mass and Body Weight

	Placebo		Half-Dose Serostimb		Full-Dose Serostima
	n	Mean (Median)	n	Mean (Median)	n	Mean(Median)
(a)  approximately 0.1 mg/kg daily
(b)  approximately 0.1 mg/kg every other day
Lean body mass (kg) (by BIS)	222	0.97 (0.67)	223	3.89 (3.65)	205	5.84 (5.47)
Fat mass (kg) (by DXA)	94	0.03 (0.01)	100	-1.25 (-1.23)	85	-1.72 (-1.51)
Body weight (kg)	247	0.69 (0.68)	257	2.18 (2.15)	253	2.79 (2.65)

The mean maximum cycle work output until exhaustion increased after 12 weeks by 2.57 kilojoules (kJ) in the Serostim^® 0.1 mg/kg daily group (p<0.01) and by 2.53 kJ in the Serostim^® 0.1 mg/kg every other day group (p<0.01) compared with placebo (Table 1).  Cycle work output improved approximately 9% in both active treatment arms and decreased <1% in the placebo group. Lean body mass (LBM) and body weight (BW) increased, and fat mass decreased, in a dose-related fashion after treatment with Serostim^® and placebo (Table 2). The LBM results obtained by BIS were confirmed with DXA.

Patients' perceptions of the impact of 12 weeks of treatment on their wasting symptoms as assessed by the Bristol-Meyers Anorexia/Cachexia Recovery Instrument improved with both doses of Serostim^® in Clinical Trial 2.

Extension Phase: All patients (n=646) completing the 12-week placebo-controlled phase of Clinical Trial 2 continued Serostim^® treatment into an extension phase. Five hundred and forty eight of these patients completed an additional 12 weeks of active treatment. In these patients, changes in cycle ergometry work output, LBM, BW, and fat mass either improved further or were maintained with continued Serostim^® treatment.

HIV-Associated Adipose Redistribution Syndrome (HARS )

The clinical efficacy of Serostim^® [somatropin (rDNA origin) for injection] for the treatment of patients with HARS was assessed in two double-blind, placebo-controlled trials. The inclusion and exclusion criteria were essentially identical in both studies. Patients with a history of diabetes, impaired fasting glucose or impaired glucose tolerance were excluded. Approximately 20% of the patients screened were excluded from study enrollment as a result of a diagnosis of diabetes or glucose intolerance.  Study subjects received concomitant antiretroviral therapy and met the generally accepted criteria for excess central adipose tissue deposition assessed by anthropometric methodology (e.g., waist circumference, waist:hip ratio).

HARS Study 1 (24 weeks)

Induction Phase (12 weeks): A double-blind, placebo-controlled, parallel group study randomized 245 patients with HARS. The co-primary efficacy endpoints were change in visceral adipose tissue (VAT) and trunk:limb fat ratio after 12 weeks of treatment. Secondary efficacy endpoints included changes from baseline to Week 12 in trunk fat, abdominal subcutaneous adipose tissue (SAT), total body fat, lean body mass, various lipid parameters and patient reported outcome (PRO) scores. Patients meeting the inclusion/exclusion criteria were treated with either placebo, Serostim^® 4 mg every other day (qod) or Serostim^® 4 mg daily qhs. Eighty seven percent (87%) of patients were male, 80% were Caucasian, 97% were receiving treatment with nucleoside reverse transcriptase inhibitors (NRTIs), and 30% were receiving treatment for dyslipidemia. 

Maintenance Phase (12 Weeks): Patients completing the 12-week induction phase who were treated with Serostim^® 4 mg daily were rerandomized to therapy with either Serostim^® 4 mg qod or placebo for an additional 12 weeks. Patients completing the 12 week induction phase who were treated with Serostim^® 4 mg qod received Serostim^® 4 mg qod for an additional 12 weeks, while patients who were treated with placebo received Serostim^® 4 mg daily for an additional 12 weeks. Two hundred and eight patients received study drug and had a maintenance phase visit. The primary and secondary efficacy endpoints were the same as described above.

HARS Study 2 (36 weeks)

Induction Phase (12 Weeks): A double-blind, placebo-controlled, parallel group study randomized 326 patients with HARS. The primary efficacy endpoint was change in VAT after 12 weeks of treatment. The secondary endpoints were similar to those in HARS Study 1. Patients meeting the inclusion/exclusion criteria were treated with either placebo or Serostim^® 4 mg daily qhs. Baseline demographic characteristics were very similar to Study 1.

Maintenance Phase (24 Weeks): Patients completing the 12-week induction phase were rerandomized to treatment with either Serostim^® 2 mg qod or placebo for an additional 24 weeks. Two hundred fifty six patients received study drug and had a maintenance phase visit. The primary and secondary efficacy endpoints were the same as described above.

Induction Phase (Weeks 0-12) Results For Both Studies

The difference in the change from baseline to Week 12 in VAT (approximately -20 cm²) was statistically significant after treatment with Serostim^® 4 mg qod vs. placebo in Study 1 (Table 3). As seen in Tables 3 and 4, the differences in the change from baseline to Week 12 in VAT (approximately -17-18 cm²) were also statistically significant after treatment with Serostim^® 4 mg daily vs. placebo in both studies. The VAT response to treatment with Serostim^® 4 mg qod vs. placebo in Study 1 was very similar to the response observed after treatment with Serostim^® 4 mg daily (Table 3). Patients with the largest VAT levels at baseline manifested the largest reductions in VAT in response to Serostim^® treatment (data not shown).

Table 3: HARS Study 1 Induction Phase — Mean Change from Baseline to Week 12 in Visceral Adipose Tissue (cm²)^a by Treatment Group (Modified ITT Population with LOCF)

	Placebo	Serostim® 4 mg qod	Serostim® 4 mg daily
	n=57	n=58	n=61
(a) Measured by computed tomography (CT) scan;
(b) Analysis of variance model with terms for treatment group, gender, and treatment-by-gender interaction;
(c) Analysis of covariance model with terms for treatment group, gender, and treatment-by-gender interaction, and baseline VAT as covariate;
(d) CI = confidence interval and SE = standard error
Baseline (SE)b	133 (12)	130 (14)	138 (12)
Change from Baseline (SE)c	-9 (6)	-28 (7)	-27 (6)
Difference from Placebo for Change (95% CI)c		-20 (-38, -2) p=0.034	-18 (-35, -2) p=0.031

Table 4: HARS Study 2 Induction Phase — Mean Change from Baseline to Week 12 in Visceral Adipose Tissue (cm²)^a by Treatment Group (Modified ITT Population with LOCF)

	Placebo	Serostim® 4 mg daily
	n=74	n=210
(a) through (d) Same as Table 3
Baseline (SE)b	110 (11)	116 (6)
Change from Baseline (SE)c	-12 (5)	-29 (3)
Difference from Placebo for Change (95% CI) c		-17 (-29, -5) p=0.005

Subgroup analysis by gender revealed that women did not have a significant reduction in VAT in response to Serostim^® 4 mg daily as indicated by the descriptive statistics by gender in Table 5 (only results from Study 2 are shown, but the results from Study 1 were similar).

Table 5: HARS Study 2 Induction Phase — VAT (cm²)^a Descriptive Statistics by Gender

	Female		Male
Variable as Mean (SD)b	Placebo	Serostim® 4 mg daily	Placebo	Serostim® 4 mg daily
(a) Measured by computed tomography (CT) scan;
(b) SD = standard deviation
	n=9	n=31	n=65	n=179
Baseline	77 (50)	87 (34)	143 (54)	144 (65)
Change from Baseline	-7 (44)	-7 (19)	2 (33)	-37 (39)

Improvements in some secondary body composition endpoints (trunk fat, abdominal SAT, total body fat, and lean body mass) were observed in both Serostim^® dose groups regardless of gender. Although a greater response was observed with 4 mg daily dosing, this dose was associated with a higher rate of adverse events, dose reductions and study discontinuation (see PRECAUTIONS and ADVERSE REACTIONS).  Improvements were not observed in other secondary endpoints including non-HDL cholesterol.

Maintenance Phase Results 

In Study 2, VAT reaccumulated to the same extent in patients treated with Serostim^® 2 mg qod and placebo.

The maintenance phase results from Study 1 are summarized in Table 6. In patients initially treated with Serostim^® 4 mg daily during the induction phase, rerandomization to Serostim^® 4 mg qod (vs. placebo) resulted in less reaccumulation of VAT, trunk fat and total body fat.

Table 6: HARS Study 1 Maintenance Phase: Descriptive Statistics for Mean Changes from Week 12 to Week 24 in Various Body Composition Endpoints in Patients Randomized to Placebo vs. Serostim^® 4 mg qod After 12 Weeks of Induction Therapy with Serostim^® 4 mg Daily

Variable as Mean (SD)c		Placebo	Serostim® 4 mg qod
(a) Measured by computed tomography (CT) scan;
(b) Assessed by dual energy X-Ray absorptiometry (DEXA) scan;
(c) SD = standard deviation
Visceral Adipose Tissuea (cm2)	Week 12	138.7 (46.2)	114.1 (75.0)
		(n=25)	(n=27)
	Change	17.7 (32.3)	5.7 (41.4)
		(n=25)	(n=27)
Trunk Fatb (kg)	Week 12	8.3 (3.7)	6.6 (3.3)
		(n=27)	(n=23)
	Change	1.2 (1.5)	0.3 (1.2)
		(n=27)	(n=23)
Total Body Fatb (kg)	Week 12	13.9 (7.1)	10.7 (5.5)
		(n=27)	(n=23)
	Change	1.3 (2.2)	0.2 (1.9)
		(n=27)	(n=23)

Patient Reported Outcomes 

Belly appearance distress, belly size estimation and belly profile assessment (the essential PRO secondary efficacy endpoints) were measured using a validated PRO instrument, the Body Image Impact Module (BIIM) in both studies. Only results for belly appearance distress and belly size estimation are discussed in that the belly profile assessment was used to establish responder criteria for the belly appearance distress and the belly size estimation. Both Serostim^® treatment groups manifested more improvement in belly appearance distress and belly size estimation than placebo-treated patients. Although a greater response was observed with 4 mg daily dosing during the induction phase, this dose was associated with a higher rate of adverse events, dose reductions and study discontinuation (see PRECAUTIONS and ADVERSE REACTIONS). The improvements in belly appearance distress and belly size estimation were sustained during the maintenance phase of Study 1.

The clinical significance of the changes described above in the HARS subsection of the CLINICAL STUDIES section with respect to improved cardiovascular risk profile or compliance with HAART has not been studied.