Thyrogen (Thyrotropin Alfa Recombinant) - Description and Clinical Pharmacology

DESCRIPTION

Each vial of THYROGEN contains 1.1 mg thyrotropin alfa, 36 mg Mannitol, 5.1 mg Sodium Phosphate, and 2.4 mg Sodium Chloride.

THYROGEN (thyrotropin alfa for injection) contains recombinant human thyroid stimulating hormone (TSH).  Thyrotropin alfa is synthesized in a genetically modified Chinese hamster ovary cell line.

Thyrotropin alfa is a heterodimeric glycoprotein comprised of two non-covalently linked subunits, an alpha subunit of 92 amino acid residues containing two N-linked glycosylation sites and a beta subunit of 118 residues containing one N-linked glycosylation site. The amino acid sequence of thyrotropin alfa is identical to that of human pituitary TSH.

Both thyrotropin alfa and naturally occurring human pituitary TSH are synthesized as a mixture of glycosylation variants. Unlike pituitary TSH, which is secreted as a mixture of sialylated and sulfated forms, thyrotropin alfa is sialylated but not sulfated. The biological activity of thyrotropin alfa is determined by a cell-based bioassay. In this assay, cells expressing a functional TSH receptor and a cAMP-responsive element coupled to a heterologous reporter gene, luciferase, enable the measurement of thyrotropin alfa activity by measuring the luciferase response.  The specific activity of thyrotropin alfa is determined relative to an internal Genzyme reference standard that was calibrated against the World Health Organization (WHO) human TSH reference standard.

CLINICAL PHARMACOLOGY

Mechanism of Action

Thyrotropin (TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroid hormone.  Binding of thyrotropin alfa to TSH receptors on normal thyroid epithelial cells or on well-differentiated thyroid cancer tissue stimulates iodine uptake and organification, and synthesis and secretion of thyroglobulin (Tg), triiodothyronine (T3) and thyroxine (T4).

The effect of thyroid stimulating hormone activation of thyroid cells is to increase uptake of radioiodine to allow scan detection or radioiodine killing of thyroid cells.  TSH activation also leads to the release of thyroglobulin by thyroid cells.  Thyroglobulin functions as a tumor marker which is detected in blood specimens.

Pharmacokinetics

The pharmacokinetics of THYROGEN were studied in 16 patients with well-differentiated thyroid cancer given a single 0.9 mg IM dose.  Mean peak serum TSH concentrations of 116 ± 38 mU/L were reached between 3 and 24 hours after injection (median of 10 hours).  The mean apparent elimination half-life was 25 ± 10 hours.  The organ(s) of TSH clearance in man have not been identified, but studies of pituitary-derived TSH suggest the involvement of the liver and kidneys.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term toxicity studies in animals have not been performed with THYROGEN to evaluate the carcinogenic potential of the drug.  THYROGEN was not mutagenic in the bacterial reverse mutation assay.  Studies have not been performed with THYROGEN to evaluate the effects on fertility.

Animal Pharmacology and/or Toxicology

Four toxicology studies, two in rodents and two in primates, have been conducted using both single and repeated daily injections of thyrotropin alfa.  In a single-dose study utilizing male and female rats bolus injections were given at levels up to 7.14 IU/kg (equivalent to 50 times the expected single human dose). There were no effects, either gross or microscopic, in this study which could be attributed to the administration of thyrotropin alfa.  In a repeated-dose study, rats were given thyrotropin alfa in the form of 5 daily intramuscular injections at levels up to 1.43 IU/kg (equivalent to 10 times the expected single human dose) without dose-related toxic effects observed.

A single-dose study in male and female cynomolgus monkeys used single intramuscular injections of thyrotropin alfa at levels equivalent to the expected dose and 0.25 and 4 times the expected single human dose.  There were no changes that were regarded as indicative of an adverse or toxic response to thyrotropin alfa.  Cynomolgus monkeys were also administered thyrotropin alfa as three consecutive daily bolus intramuscular injections at levels extending to 4 times the dose in humans.  There were no changes that are considered to indicate an adverse or toxic response to thyrotropin alfa.

CLINICAL STUDIES

Clinical Trials of THYROGEN as an Adjunctive Diagnostic Tool

Two prospective, randomized phase 3 clinical trials were conducted in patients with well-differentiated thyroid cancer to compare ¹³¹I whole body scans obtained after THYROGEN injection to ¹³¹I whole body scans after thyroid hormone withdrawal.  A cross-over, non-blinded design was used in both trials.  Oral radioiodine was given 24 hours after the second injection of THYROGEN, and scanning was done 48 hours after the radioiodine administration.  Each patient was scanned first following THYROGEN and then scanned after thyroid hormone withdrawal.  In both studies, the primary endpoint was the rate of concordant scans (scan findings in agreement in a given patient using each preparation method).

Study 1 (n=127) compared the diagnostic scanning following a THYROGEN regimen of 0.9 mg IM daily on two consecutive days to thyroid hormone withdrawal.  In addition to body scans, Study 2 (n=229) also compared thyroglobulin (Tg) levels obtained after THYROGEN to those at baseline and to those after thyroid hormone withdrawal.  All Tg testing was performed in a central laboratory using a radioimmunoassay (RIA) with a functional sensitivity of 2.5 ng/mL.  Patients who were included in the Tg analysis were those who had undergone total or near-total thyroidectomy with or without ¹³¹I ablation, had < 1% uptake in the thyroid bed on a scan after thyroid hormone withdrawal, and did not have detectable anti-Tg antibodies.  The maximum THYROGEN Tg value was obtained 72 hours after the final THYROGEN injection, and this value was used in the analysis.

Diagnostic Radioiodine Whole Body Scan Results

Study 1 enrolled 127 patients, 71% were female and 29% male, and mean age was 44 years.  The study included the following forms of differentiated thyroid cancer:  papillary cancer (88%), follicular cancer (9%), and Hurthle cell (2%).  Study results are displayed in Table 2.

In Study 2, patients with differentiated thyroid cancer who had been thyroidectomized (n = 229) were randomized into one of two THYROGEN treatment regimens:  THYROGEN 0.9 mg IM daily on two consecutive days (n = 117), and THYROGEN 0.9 mg IM daily on days 1, 4 and 7 (n = 112).  Each patient was scanned first using THYROGEN, then scanned using thyroid hormone withdrawal.  The group receiving the THYROGEN 0.9 mg IM x 2 regimen was 63% female/27% male, had a mean age 44 years, and generally had low-stage papillary or follicular cancer (AJCC/TNM Stage I 61%, Stage II 19%, Stage III 14%, Stage IV 5%).  The group receiving the THYROGEN 0.9 mg IM x 3 regimen was 66% female/34% male, had a mean age 50 years, and generally had low-stage papillary or follicular cancer (AJCC/TNM Stage I 50%, Stage II 20%, Stage III 20%, Stage IV 9%).  The amount of radioiodine used for scanning was 4 mCi ± 10%, and scanning times were lengthened in some patients to capture adequate images (30 minute scans, or 140,000 counts).  Scan pairs were assessed by blinded readers.  Study results are presented in Table 2.

Table 2:  Concordance of Positive Thyroid Scans Following THYROGEN Treatment with Scans Following Thyroid Hormone Withdrawal

	Number of Scan Pairs by Disease Category	Concordance of scan pairs between THYROGEN scan and thyroid hormone withdrawal scan
Study 1 (0.9 mg IM qd x2)
Positive for remnant or cancer in thyroid bed	48	81%
Positive for metastatic disease	15	73%
Total positive withdrawal scans 1, 2	63	79%
Study 2 (0.9 mg IM qd x 2)
Positive for remnant or cancer in thyroid bed	35	86%
Positive for metastatic Disease	9	67%
Total positive withdrawal scans,	44	82%

Across the two clinical studies, and scoring all false positives in favor of thyroid hormone withdrawal, the majority of positive scans using THYROGEN and thyroid hormone withdrawal were concordant.  The THYROGEN scan failed to detect remnant and/or cancer localized to the thyroid bed in 17% (14/83) of patients in whom it was detected by a scan after thyroid hormone withdrawal.  In addition, the THYROGEN scan failed to detect metastatic disease in 29% (7/24) of patients in whom it was detected by a scan after thyroid hormone withdrawal.

Thyroglobulin (Tg) Results

THYROGEN Tg Testing Alone and in Combination with Diagnostic Whole Body Scanning: Comparison with Results after Thyroid Hormone Withdrawal

In anti-Tg antibody negative patients with a thyroid remnant or cancer (as defined by a withdrawal Tg ≥ 2.5 ng/mL or a positive scan [after thyroid hormone withdrawal or after radioiodine therapy]), the THYROGEN Tg was positive (≥ 2.5 ng/mL) in 69% (40/58) of patients after 2 doses of THYROGEN.

In these same patients, adding the whole body scan increased the detection rate of thyroid remnant or cancer to 84% (49/58) of patients after 2 doses of THYROGEN.

Among patients with metastatic disease confirmed by a post-treatment scan or by lymph node biopsy (35 patients), THYROGEN Tg was positive (≥ 2.5 ng/mL) in all 35 patients, while Tg on thyroid hormone suppressive therapy was positive (≥ 2.5 ng/mL) in 79% of these patients.

As with thyroid hormone withdrawal, the intra-patient reproducibility of THYROGEN testing with regard to both Tg stimulation and radioiodine imaging has not been studied.

Hypothyroid Signs and Symptoms

THYROGEN administration was not associated with the signs and symptoms of hypothyroidism that accompanied thyroid hormone withdrawal as measured by the Billewicz scale.  Statistically significant worsening in all signs and symptoms were observed during the hypothyroid phase (p<0.01) (Figure 1).

Figure 1:  Hypothyroid Symptom Assessment Billewicz Scale Diagnostic Indication 0.9 mg THYROGEN^® q 24 hours x 2 doses vs. Thyroid Hormone Withdrawal Phase

Clinical Trials of THYROGEN as an Adjunct to Radioiodine Therapy to Achieve Thyroid Remnant Ablation

A randomized prospective clinical trial compared the rates of thyroid remnant ablation achieved after preparation of patients with thyroid hormone withdrawal or THYROGEN. Patients (n = 63) with low-risk, well-differentiated thyroid cancer who underwent near-total thyroidectomy were made euthyroid after surgery by receiving thyroid hormone replacement and were subsequently randomized to a thyroid hormone withdrawal or THYROGEN.  Patients in the THYROGEN group received THYROGEN 0.9 mg IM daily on 2 consecutive days and radioiodine 24 hours after the second dose of THYROGEN.  Patients in the thyroid hormone withdrawal group had the thyroid replacement withheld until they became hypothyroid.  Patients in both groups received 100 mCi ¹³¹I ± 10% with the intent to ablate any thyroid remnant tissue.  The primary endpoint of the study, was the rate of successful ablation, and was assessed 8 months later by a THYROGEN-stimulated radioiodine scan.  Patients were considered successfully ablated if there was no visible thyroid bed uptake on the scan, or if visible, if uptake was less than 0.1%.  Table 3 summarizes the results of this evaluation.

Table 3: Remnant Ablation in Clinical Trial of Patients with Well-Differentiated Thyroid Cancer

Group60 per protocol patients with interpretable scan data. 95% CI for difference in ablation rates THYROGEN minus Thyroid Hormone Withdrawal, = 7% to 27%.	Mean Age (Yr)	Gender (F:M)	Cancer Type (Pap:Fol)	Ablation Criterion (Measure at 8 Months)
				Thyroid Bed Activity <0.1%	No Visible Thyroid Bed ActivityInterpretation by 2 of 3 reviewers. 95% CI for difference in ablation rates, THYROGEN minus Thyroid Hormone Withdrawal, = -31% to 9%. Abbreviations: fol = follicular, pap = papillary
Thyroid Hormone Withdrawal (N=28)	43	24:6	29:1	28/28 (100%)	24/28 (86%)
THYROGEN (N=32)	44	26:7	30:3	32/32 (100%)	24/32 (75%)

The mean radiation dose to blood was 0.266±0.061 mGy/MBq in the THYROGEN group and 0.395±0.135 mGy/MBq in the thyroid hormone withdrawal group.  Radioiodine residence time in remnant tissue was 0.9±1.3 hours in the THYROGEN group and 1.4±1.5 hours in the thyroid hormone withdrawal group.  It is not known whether this difference in radiation exposure would convey a clinical benefit.

Patients who completed were followed up for a median duration of 3.7 years (range 3.4 to 4.4 years) following radioiodine ablation.  Tg testing was also performed.The main objective of the follow-up study was to evaluate the status of thyroid remnant ablation by using THYROGEN-stimulated neck imaging.  Of the fifty-one patients enrolled, forty eight patients received THYROGEN for remnant neck/whole body imaging and/or thyroglobulin testing.  Only 43 patients had imaging.  Patients were still considered to be successfully ablated if there was no visible thyroid bed uptake on the scan, or if visible, uptake was less than 0.1%.  All patients from both original treatment groups who had scanning were found to still be ablated . Of 37 patients who were Tg–antibody negative, 16/17 (94%) of patients in the former thyroid hormone withdrawal group and 19/20 (95%) of patients in the former THYROGEN group maintained successful ablation measured as stimulated serum Tg levels of <2 ng/mL.

No patient had a definitive cancer recurrence during the 3.7 years of follow-up. Overall, 48/51 patients (94%) had no evidence of cancer recurrence, 1 patient had possible cancer recurrence (although it was not clear whether this patient had a true recurrence or persistent tumor from the regional disease noted at the start of the initial study), and 2 patients could not be assessed.

Two large prospective multi-center randomized studies compared THYROGEN to thyroid hormone withdrawal using two different doses of radioactive iodine in patients with differentiated thyroid cancer who had been thyroidectomized.  In both studies, patients were randomized to 1 of 4 treatment groups:  THYROGEN + 30 mCi ¹³¹I, THYROGEN + 100 mCi ¹³¹I, thyroid hormone withdrawal + 30 mCi ¹³¹I, or thyroid hormone withdrawal + 100 mCi ¹³¹I.  Patients were assessed for efficacy (ablation success rates) at approximately 8 months.

The first study (Study A) randomized 438 patients (tumor stages T1-T3, Nx, N0 and N1, M0).  Ablation success was defined as radioiodine uptake of <0.1% in the thyroid bed and stimulated thyroglobulin levels of < 2.0 ng/mL.

The second study (Study B) randomized 752 patients with low-risk thyroid cancer (tumor stages pT1 < 1 cm and N1 or Nx, pT1 >1-2 cm and any N stage, or pT2 N0, all patients M0).  Ablation success was defined by neck ultrasound and stimulated thyroglobulin of ≤ 1.0 ng/mL.

Results for both trials are summarized below.

Table 4:  Successful Remnant Ablation Rates in Study A  

95% CI of difference in ablation rate (low-dose minus high dose): -10.2% to 2.6%
95% CI of difference in ablation rate (THYROGEN - Thyroid Hormone Withdrawal): -6.0% to 6.8%
	THYROGEN	Thyroid Hormone Withdrawal	Total
Low-dose radioiodine	91/108 (84.3%)	91/106 (85.8%)	182/214 (85.0%)
High-dose Radioiodine	92/102 (90.2%)	92/105 (87.6%)	184/207 (88.9%)
Total	183/210 (87.1%)	183/211 (86.7%)	366/421 (86.9%)

Table 5:  Successful Remnant Ablation Rates in Study B

95% CI of difference in ablation rate (low-dose minus high dose): -5.8% to 0.9%
95% CI of difference in ablation rate (THYROGEN minus Thyroid Hormone Withdrawal): -4.5% to 2.2%
	THYROGEN	Thyroid   Hormone   Withdrawal	Total
Low-dose radioiodine	160/177 (90.4%)	156/170 (91.8%)	316/347 (91.1%)
High-dose Radioiodine	159/171 (93.0%)	156/166 (94.0%)	315/337 (93.5%)
Total	319/348 (91.6%)	312/336 (92.9%)	631/684 (92.3%)

Quality of Life

Quality of Life (QOL) was measured during both the diagnostic study [ see Clinical Studies ( 14.1 )] and the ablation of thyroid remnant study [ see Clinical Studies ( 14.2 )] using the SF-36 Health Survey, a standardized, patient-administered instrument assessing QOL across eight domains measuring both physical and mental functioning.  In the diagnostic study and in the remnant ablation study, following THYROGEN administration, little change from baseline was observed in any of the eight QOL domains of the SF-36. Following thyroid hormone withdrawal in the diagnostic study, statistically significant negative changes were noted in all eight QOL domains of the SF-36.  The difference between treatment groups was statistically significant (p<0.0001) for all eight QOL domains, favoring THYROGEN over thyroid hormone withdrawal (Figure 2).  In the remnant ablation study, following thyroid hormone withdrawal, statistically significant negative changes were noted in five of the eight QOL domains (physical functioning, role physical, vitality, social functioning and mental health).

Figure 2:  SF-36 Health Survey Results
Quality of Life Domains
Diagnostic Indication