THYROGEN Powder for solution for injection Ref.[7880] Active ingredients: Thyrotropin

Pharmacotherapeutic group: Pituitary and Hypothalamic Hormones and Analogues, Anterior Pituitary Lobe Hormones and Analogues
ATC code for thyrotropin alfa: H01AB01

Mechanism of action

Thyrotropin alfa (recombinant human thyroid stimulating hormone) is a heterodimeric glycoprotein produced by recombinant DNA technology. It is comprised of two non-covalently linked subunits. The cDNAs encode for 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. It has comparable biochemical properties to natural human Thyroid Stimulating Hormone (TSH). Binding of thyrotropin alfa to TSH receptors on thyroid epithelial cells stimulates iodine uptake and organification, and synthesis and release of thyroglobulin, triiodothyronine (T₃) and thyroxine (T₄).

In patients with well-differentiated thyroid cancer, a near total or total thyroidectomy is performed. For optimal diagnosis of thyroid remnants or cancer via either radioiodine imaging or thyroglobulin testing and for radioiodine therapy of thyroid remnants, a high serum level of TSH is needed to stimulate either radioiodine uptake and/or thyroglobulin release. The standard approach to achieve elevated TSH levels has been to withdraw patients from thyroid hormone suppression therapy (THST), which usually causes patients to experience the signs and symptoms of hypothyroidism. With the use of Thyrogen, the TSH stimulation necessary for radioiodine uptake and thyroglobulin release is achieved while patients are maintained euthyroid on THST, thus avoiding the morbidity associated with hypothyroidism.

Clinical efficacy and safety

Diagnostic use

The efficacy and safety of Thyrogen for use with radioiodine imaging together with serum thyroglobulin testing for the diagnosis of thyroid remnants and cancer was demonstrated in two studies. In one of the studies, two dose regimens were examined: 0.9 mg intramuscular every 24 hours for two doses (0.9 mg x 2) and 0.9 mg intramuscular every 72 hours for three doses (0.9 mg x 3). Both dose regimens were effective and not statistically different from thyroid hormone withdrawal in stimulating radioiodine uptake for diagnostic imaging. Both dose regimens improved the sensitivity, accuracy and negative predictive value of Thyrogen-stimulated thyroglobulin alone or in combination with radioiodine imaging as compared to testing performed while patients remained on thyroid hormones.

In clinical trials, for the detection of thyroid remnants or cancer in ablated patients using a thyroglobulin assay with a lower limit of detection of 0.5 ng/ml, Thyrogen-stimulated thyroglobulin levels of 3 ng/ml, 2 ng/ml and 1 ng/ml corresponded with thyroglobulin levels after withdrawal of thyroid hormone of 10 ng/ml, 5 ng/ml and 2 ng/ml, respectively. In these studies the use of thyroglobulin testing on Thyrogen was found to be more sensitive than thyroglobulin testing on TSHT. Specifically in a Phase III study involving 164 patients the detection rate of tissue of thyroid origin after a Thyrogen thyroglobulin test ranged from 73-87%, whereas, by using thyroglobulin on TSHT it was 42-62% for the same cut-off values and comparable reference standards.

Metastatic disease was confirmed by a post-treatment scan or by lymph node biopsy in 35 patients. Thyrogen-stimulated thyroglobulin levels were above 2 ng/ml in all 35 patients, whereas, thyroglobulin on THST was above 2 ng/ml in 79% of these patients.

Pre-therapeutic stimulation

In a comparator study involving 60 evaluable patients, the rates of successful ablation of thyroid remnants with 100 mCi/3.7 GBq (± 10%) radioiodine in post-thyroidectomy patients with thyroid cancer, were comparable for patients treated after thyroid hormone withdrawal versus patients treated after Thyrogen administration. Patients studied were adults (>18 years), with newly diagnosed differentiated papillary or follicular thyroid carcinoma, including papillary-follicular variant, characterised, principally (54 of 60), as T1-T2, N0-N1, M0 (TNM classification). Success of remnant ablation was assessed with radioiodine imaging and with serum thyroglobulin testing at 8 ± 1 months after treatment. All 28 patients (100%) treated after withdrawal of THST and all 32 patients (100%) treated after Thyrogen administration had either no visible uptake of radioiodine in the thyroid bed or, if visible, thyroid bed uptake <0.1% of the administered activity of radioiodine. The success of thyroid remnant ablation also was assessed by the criterion of Thyrogen-stimulated serum Tg level <2 ng/ml eight months after ablation, but only in patients who were negative for interfering anti-Tg antibodies. Using this Tg criterion, 18/21 patients (86%) and 23/24 patients (96%) had thyroid remnants successfully ablated in the THST withdrawal group and the Thyrogen treatment group, respectively.

Quality of life was significantly reduced following thyroid hormone withdrawal, but maintained following either dosage regimen of Thyrogen in both indications.

A follow-up study was conducted on patients who previously completed the initial study, and data is available for 51 patients. The main objective of the follow-up study was to confirm the status of thyroid remnant ablation by using Thyrogen-stimulated radioiodine static neck imaging after a median follow-up of 3.7 years (range 3.4 to 4.4 years) following radioiodine ablation. Thyrogen-stimulated thyroglobulin testing was also performed.

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 considered ablated in the initial study were confirmed to be ablated in the follow-up study. In addition, no patient had a definitive 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 tumour from the regional disease noted at the start of the original study), and 2 patients could not be assessed.

In summary, in the pivotal study and its follow-up study, Thyrogen was non-inferior to thyroid hormone withdrawal for elevation of TSH levels for pre-therapeutic stimulation in combination with radioiodine for post-surgical ablation of remnant thyroid tissue.

Two large prospective randomised studies, the HiLo study (Mallick) and the ESTIMABL1 study (Schlumberger), compared methods of thyroid remnant ablation in patients with differentiated thyroid cancer who had been thyroidectomised. In both studies, patients were randomised 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, and patients were assessed about 8 months later. The HiLo study randomised 438 patients (tumour stages T1-T3, Nx, N0 and N1, M0) at 29 centres. As assessed by radioiodine imaging and stimulated Tg levels (n=421), ablation success rates were approximately 86% in all four treatment groups. All 95% confidence intervals for the differences were within ±10 percentage points, indicating in particular non-inferiority of the low to the high radioiodineactivity. Analyses of T3 patients and N1 patients showed that these subgroups had equally good ablation success rates as did lower-risk patients. The ESTIMABL1 study randomised 752 patients with low-risk thyroid cancer (tumour stages pT1 <1 cm and N1 or Nx, pT1 >1-2 cm and any N stage, or pT2 N0, all patients M0) at 24 centres. Based on 684 evaluable patients, the overall ablation success rate assessed by neck ultrasounds and stimulated Tg levels was 92%, without any statistically significant difference among the four groups.

For the ESTIMABL1 study, 726 (97%) of the original 752 patients were followed up for disease recurrence. The median follow-up was 5.4 years (0.5 to 9.2 years).

The tables below provide long term follow up information for the ESTIMABL1 and HiLo studies.

Table 1. ESTIMABL1 study recurrence rates in patients who received low or high dose RAI and those who prepared with Thyrogen or THW:

For the HiLo study, 434 (99%) of the original 438 patients were followed up for disease recurrence. The median follow-up was 6.5 years (4.5 to 7.6 years).

Table 2. HiLo study recurrence rates in patients who received low or high dose activity RA:

HR: 1.10 [95% CI 0.47–2.59]; p=0.83

Table 3. HiLo study recurrence rates in patients who prepared for ablation with Thyrogen or Thyroid Hormone Withdrawal:

HR: 1.62 [95% CI 0.67-3.91], p=0.28

The long term follow-up data in ESTIMABL1 and HiLo confirmed similar outcomes for patients in all four treatment groups.

In summary, these studies support the efficacy of low activity radioiodine plus thyrotropin alpha (with reduced radiation exposure). Thyrotropin alfa was non-inferior to thyroid hormone withdrawal for pre-therapeutic stimulation in combination with radioiodine for post-surgical ablation of thyroid remnant tissue.