Status - approved; marketed

Organizations involved:

Genzyme General – Manuf.; R&D; Tech.; USA mark.

Genzyme Corp. – Intl. mark.; Parent

Abbvie – USA mark.

Knoll Pharmaceutical Co. – Former

Abbott Laboratories – Former

Hospira –Manuf. other

Abbott Laboratories – Former

National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), NIH – R&D; Tech.

National Institutes of Health (NIH) – Parent org.

Columbia University – Tech.; Patent dispute

Hospira – Manuf. other

Description: Thyrogen is a lyophilized (freeze-dried) formulation of purified recombinant thyrotropin alfa (thyroid stimulating hormone; rTSH) glycoprotein produced by a transformed Chinese hamster ovary (CHO) cell line. The amino acid sequence of thyrotropin alfa is identical to that of human pituitary-derived thyroid stimulating hormone (hTSH). Thyrotropin alfa is a heterodimeric glycoprotein comprised of two different non-covalently linked polypeptides– 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. Both rTSH and hTSH are mixtures of glycosylation variants, i.e., have different glycosylation (covalently-bound oligosaccharide side chains) patterns. Unlike hTSH, which is secreted as a mixture of sialylated and sulfated forms, thyrotropin alfa is sialylated only (not sulfated). rTSH has biochemical properties comparable to hTSH. Binding of rTSH (like binding of hTSH) 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).

rTSH is used as a diagnostic tool in patients having received treatment for thyroid cancer to assist in determining their response to therapy and disease advancement. In patients with thyroid cancer, a near total or total thyroidectomy is performed, and patients are treated with synthetic thyroid hormone supplements (not rTSH) to replace endogenous hormone and to suppress secretion of endogenous thyroid stimulating hormone (hTSH), in order to avoid further TSH-stimulation of thyroid tumor growth. However, a high level of TSH in a patient’s bloodstream is required in order for radioiodine radiologic imaging to detect remnant thyroid tissue and metastatic thyroid tumors, and to achieve optimal sensitivity of serum thyroglobulin (Tg) testing. Thyrogen is used as an exogenous source of TSH (as rTSH). Thyrogen, administered prior to radiologic iodine imaging, allows patients to avoid halting thyroid hormone supplementation and associated hormone withdrawal symptoms (hypothyroidism) while undergoing radioiodine diagnostic imaging. Prior to Thyrogen, patients had to stop taking their thyroid hormone supplements for two to six weeks prior to testing. This causes thyroid hormone withdrawal/(hypothyroidism, with adverse reactions including fatigue, weight gain, constipation, mental dullness, lethargy, and depression.

The biological activity of thyrotropin alfa is determined using in vivo and in vitro bioassays. The in vivo bioassay in mice measures an increase in thyroxine (T4) level in response to the intraperitoneal injection of thyrotropin alfa after suppression of endogenous TSH levels. The in vitro assay measures the amount of cyclic adenosine monophosphate (cAMP) produced by a bovine thyroid-derived microsome preparation in response to thyrotropin alfa. The biological activity of thyrotropin alfa has been determined to be no less than 4 IU/mg by the in vitro bioassay. The specific activity of thyrotropin alfa is calibrated against the World Health Organization (WHO) human pituitary derived TSH reference standard (NIBSC 84/703).

Thyrogen is packaged as a kit containing two single-use Thyrogen vials with two 10 mL vials of Sterile Water for Injection, USP for reconstitution and intramuscular administration into the buttock. Each vial contains 1.1 mg thyrotropin alfa (> 4 IU), 36 mg mannitol, 5.1 mg sodium phosphate, and 2.4 mg sodium chloride. After reconstitution with 1.2 mL of Sterile Water for Injection, USP, the thyrotropin alfa concentration is 0.9 mg/mL with a pH of ~7.0. The product contains no preservatives. Thyrogen is stored at 2-8˚C (refrigerated). Shelf life is three years.

Nomenclature: TSH, rDNA [BIO]; Thyrogen [TR]; Thymopentin alfa for Injection [FDA]; thyroid stimulating hormone, recombinant [SY]; rTSH [SY]

TSH [SY]; NDC 58468-1849-4 [ NDC]

Companies.: Thyrogen was developed and is manufactured by Genzyme General, a subsidiary of Genzyme Corp. Thyrogen is co-marketed in the U.S. by Genzyme and Knoll Pharmaceutical Co., formerly a subsidiary of BASF AG, later a subsidiary Abbott Labs. (acquired in early 2001, now Abbvie. It is co-marketed in Canada by Genzyme Canada Inc. and Theramed Corp., a subsidiary of Meta Health Services Inc.

Thyrogen was in development for an extended period,with Phase III trials starting in 1992. The National Institute of Diabetes, Digestive and Kidney Disease- (NIDDK), National Institutes of Health (NIH), was significantly involved in the invention and development of Thyrogen (see the Tech. transfer section). Development was at least partially funded through Neozyme, a limited partnership or other special funding entity formed by Genzyme. [See “Recombinant Human Thyroid Stimulating Hormone: Development of a Biotechnology Product for Detection of Metastatic Lesion of Thyroid Carcinoma,” in BIOTECHNOLOGY, vol. 11, Sept. 1993, p. 1014-1024].

Genzyme concluded an agreement in Aug. 1998 with Knoll/BASF originally granting the company five years of exclusive U.S. co-promotion rights. Knoll made an up-front payment to Genzyme, and continues co-marketing and payment of unspecified royalties.

In Dec. 2009, after Genzyme halted production at its Allston facility due to animal virus (porcine vesivirus) contamination, and in Nov. 2009 reported contamination in fill and finish operations at the same facility. See the Cerezyme entry for further discussion of Genzyme's Allston, MA,l manufacturing facility's problems and its operating under a consent decree.

Revalidation of fill/finish equipment caused a delay in fall 2010 in Thyrogen shipping. At that time, fill/finish was the only part of Thyrogen production taking place at Genzyme's Allston Landing site, then operating under consent decree with the FDA. Genzyme was then in the process of moving the fill/finish operations out of the Boston area site in accordance with the decree. Thyrogen short supplies persisted into mid-late 2011.

In July 2010, a part of its consent decree with FDA, Genzyme extended it contract with Hospira for fill and finish operations for Thyrogen.

In Nov. 2012, Genzyme reported that its supply problems were resolved, with enough being manufactured to meet demand.

FDA class: Drug NDA

Approvals: Date = 19981130; first approval, NDA 20-898; orphan designation (expires 11/30/2005)

Date = 20060201; NDA supplement; Indication = addition of information the insert/labeling regarding positive patient outcomes based on a new analysis of the pivotal study data that supported original approval

Date = 20071217; NDA supplement; Indication = use with radioiodine to ablate, or destroy, the remaining thyroid tissue in patients who have had their cancerous thyroids removed (remnant ablation)

Indications: [full text of the "INDICATIONS AND USAGE” section from product insert/labeling, not including the " Considerations in the Use of Thyrogen" portion, 9/9/2009]:

Thyrogen (thyrotropin alfa for injection) is indicated for use as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer.

Thyrogen (thyrotropin alfa for injection) is indicated for use as an adjunctive treatment for radioiodine ablation of thyroid tissue remnants in patients who have undergone a neartotal or total thyroidectomy for well-differentiated thyroid cancer and who do not have evidence of metastatic thyroid cancer.

Potential Clinical Uses:

1. Thyrogen Tg testing may be used in patients with an undetectable Tg on thyroid hormone suppressive therapy to exclude the diagnosis of residual or recurrent thyroid cancer

2. Thyrogen treatment may be used in combination with radioiodine (131I) to ablate thyroid remnants following near-total thyroidectomy in patients without evidence of metastatic disease.

3. Thyrogen testing may be used in patients requiring serum Tg testing and radioiodine imaging who are unwilling to undergo thyroid hormone withdrawal testing and whose treating physician believes that use of a less sensitive test is justified.

4. Thyrogen treatment and testing may be used in patients who are either unable to mount an adequate endogenous TSH response to thyroid hormone withdrawal or in whom withdrawal is medically contraindicated.

Status: The NDA was submitted on Dec. 12, 1997; received priority review; and the six month approval target was postponed after Genzyme filed an amendment. Thyrogen was approved with orphan drug status on Nov. 30, 1998; review time of ~11.6 months (0.97 years). This was the product’s first approval in any country.

Thyrogen received European Union (EU) approval on March 9, 2000 and was launched in 2001. Supplemental approval was granted in the EU on Sept. 25, 2003, to include diagnostic testing for thyroid cancer using serum thyroglobulin (Tg) with, or without, whole body scanning. Previously, EU labeling required whole body scanning be part of the follow-up test used to determine any recurrence of thyroid cancer. This put European indications: more in line with those in the U.S. Thyrogen was approved in Canada in June 2002.

Genzyme pursued a label expansion in the U.S., European Union (EU) and other markets for Thyrogen use in combination with radioiodine for ablation of remnant thyroid tissue, a therapeutic procedure that patients commonly undergo when being treated for thyroid cancer (after surgical removal of the cancerous thryoid; see the Medical section below). Genzyme submitted a supplemental NDA to FDA on Nov. 3, 2004. An approvable letter with conditions was issued by FDA in fall 2005.

On March 3, 2005, Thyrogen received EU approval for ablation of remnant thyroid tissue.

In Feb. 2006, FDA approved a NDA supplement for a labeling change to include data from re-analysis of Thyrogen’s pivotal Phase III study showing significant quality-of-life data in favor of the Thyrogen-treated arm for all 8 domains of the SF-36 quality-of-life survey. The original labeling reported a significant difference in 4 domains of the survey including physical functioning, physical role, bodily pain and emotional role. The new labeling adds that improvements in general health, vitality, social functioning and mental health also were significant. The original NDA filing was in error in its use of the measurement tool’s scoring algorithm, showing significance in only 4 areas.

In Dec. 2007, FDA granted approval of Thyrogen for remnant ablation, a procedure that patients commonly undergo when being treated for thyroid cancer to remove any remaining thyroid tissue. This permits patients to maintain a good quality of life during the course of their thyroid cancer treatment and follow-up testing (i.e., avoid surgery and hospitalization). This new indication extended Thyrogen to patients during their initial treatment for thyroid cancer, in addition to its use in follow-up diagnostic procedures to detect recurrence.

In May 2010, FDA sent a letter to U.S. healthcare professionals alerting them that the supply of Thyrogen will be temporarily limited (due to Genzyme's Allston facility problems). Genzyme's consent decree restricts Genzyme's U.S. distribution of Thyrogen to customers (meaning entities that purchase Thyrogen kits directly from Genzyme, such as distributors and wholesalers) who sign a Certificate of Procedures Related to Medical Necessity. This Certificate notes the customer's agreement to distribute the product with a Dear Healthcare Provider Letter, which describes the patients for whom FDA considers Thyrogen to be medically necessary. This restriction was to remain in place until Genzyme corrects manufacturing issues at their Allston Landing facility, where the fill/finish manufacturing operations for Thyrogen were performed, or transfers fill/finish manufacturing operations for Thyrogen to other manufacturing facilities operating in compliance with FDA regulations (with Genzyme contracting out filling and finishing to Hospira).

Genzyme resolved its problems and resumed manufacture and supply in early-mid 2012.

On Dec. 7, 2012, the EU approved supplemental use of Thyrogen with a wider irradiation dose range for postoperative thyroid remnant ablation. The decision to approve the expanded indication for use of Thyrogen in Europe is based on the results of the two largest studies, HiLo and ESTIMABL, ever conducted in thyroid remnant ablation.

Tech. transfer: Genzyme, originally through its Integrated Genetics, Inc. and Neozyme Corp. subsidiaries/affilates, exclusively licensed technology from and formally collaborated with the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), National Institutes of Health (NIH), in the development of Thyrogen. Licensed patents include U.S. 6,117,991, Wondisford, F.E. and Weintraub, B.D., “Biologically Active Synthetic Thyrotropin and Cloned Gene Producing Same,” Sept. 12, 2000. The abstract states, “Substantially pure recombinant TSH has been prepared from a clone comprising complete nucleotide sequence for the expression of the TSH. Diagnostic and therapeutic applications of the synthetic TSH are described.” The single claim states, “pAV2-hTSH.beta on deposit as ATCC 75505,” referring to the pAV2-hTSHbeta plasmid vector for cell expression of recombinant TSH. Integrated Genetics’ license (L-018-91) was active as early as Oct. 1993, and the company was involved in a Collaborative R&D Agreement (CRADA) with NIDDK.

Genzyme has received its own patents concerning recombinant TSH, including 6,455,282, “Cells, vectors and methods for producing biologically active TSH,” with priority filing back to 1983. The exemplary claim (no. 1) states, “An expression vector encoding two subunits of thyroid stimulating hormone (TSH), each under the control of a separate promoter.

Genzyme was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Genzyme and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.

Trials: The NDA submission included data from four clinical studies: a Phase I/II dose-ranging study, a pharmacokinetics study detailing biochemical activity in the body, and two well-controlled Phase III clinical trials. The second Phase III trial showed that there was no statistical difference between Thyrogen-produced thyroid radiodiagnostic imaging scans and scans produced after withdrawing patients from thyroid hormone supplements. The combination of a Thyrogen-stimulated scan and a serum thyroglobulin test, although not as sensitive as combination testing performed after patients were withdrawn from thyroid hormone supplements, did detect all patients with metastatic thyroid tumors. The quality of life of patients after Thyrogen administration, as measured using two validated survey instruments, was the same as that of patients taking thyroid hormone, while the quality of life of patients who underwent thyroid hormone withdrawal was significantly reduced. Thyrogen produced a relatively benign safety profile with the most common adverse events being nausea and headache. When patients remained on thyroid hormone, the sensitivity of thyroglobulin testing performed after Thyrogen administration was markedly improved. In clinical studies, no patients developed antibodies to rTSH, even after repeated use.

In 2012, Thyrogen is in Phase III trials for use in thyroid cancer ablation (treatment). It is also in trials for treatment of non-toxic multinodular goiter.

Medical: Thyrogen is an important adjunct to thyroid cancer therapy used (in the U.S.) to aid earlier detection of disease recurrence. The product is additionally indicated for use in Europe in thyroid remnant ablation procedures.

The primary treatment for thyroid cancer is either partial or total surgical removal of the thyroid gland (thyroidectomy), usually followed by radioiodine therapy to destroy any remaining thyroid tissue. Following primary treatment, patients must take a synthetic thyroid hormone supplement daily to replace the hormones normally produced by the thyroid gland. Long-term monitoring of thyroid cancer patients includes testing once or twice a year to determine if the cancer has recurred or spread. Serum thyroglobulin testing and radioiodine-based whole body scanning are the diagnostic procedures most commonly used with patients being examined for remaining thyroid tissue, thyroid cancer recurrence, or metastases. Radioiodine scanning requires blood TSH levels to be elevated above normal, in order to stimulate thyroid cells to absorb and retain the radioactive iodine, and TSH also stimulates the release of thyroglobulin into the bloodstream. Thyroglobulin (Tg) testing can be performed without increasing TSH levels, but testing is more sensitive when TSH levels are elevated, e.g., with use of Thyrogen. The approved indication allows physicians to use Thyrogen with a broad group of thyroid cancer patients, with or without radioiodine imaging.

In thyroid remnant ablation, patients take a drink or a capsule that contains radioactive iodine, which is taken up by any remaining thyroid cells. To enhance the uptake of radioiodine, the level of thyroid stimulating hormone (TSH) in a patient’s bloodstream must be elevated. Patients currently stop taking thyroid hormone supplements to elevate TSH levels. However, this often causes side effects associated with hypothyroidism, which may include fatigue, lethargy, difficulty concentrating, short-term memory impairment and depression. Thyrogen (recombinant TSH) is administered by injection, allowing patients to continue taking hormone supplements and avoid the symptoms associated with hormone withdrawal. Clinical trials have shown that treatment with Thyrogen is similar to withdrawal from thyroid hormone in achieving ablation, and that Thyrogen use can significantly reduce the side-effects of thyroid hormone withdrawal by allowing patients to remain on hormone replacement therapy.

Disease: The American Cancer Society estimates that in 2007 about 33,550 new cases of thyroid cancer will be diagnosed in the United States. Approximately 90 percent of all thyroid cancers are well-differentiated, making those patients candidates for the remnant ablation procedure.

Thyroid cancer is three times more common in women than in men. Most cases of thyroid cancer are discovered during a routine physical examination when a painless lump is found in the thyroid. Although well-differentiated thyroid cancer is very treatable, ongoing monitoring is important as disease can recur in up to 30% of patients. Approximately 188,000 Americans and 100,000 Europeans, mostly women, have had thyroid cancer. Most of these patients are retested annually (or more frequently) for recurrence and spread of thyroid tumors. Data from the National Cancer Institute (NCI) show that thyroid cancer is now ranked first among all cancers in incidence growth in women.

The National Cancer Institute (NCI) reports that thyroid cancer is ranked first among all cancers in incidence growth in both women and men.

In the U.S., physicians order ~135,000 thyroglobulin tests each year for patients who have had thyroid cancer. They also perform approximately 25,000 whole body scans in these patients. Similar numbers of thyroglobulin tests and whole body scans are performed in Europe.

Genzyme reports, “Approximately 35,000 ablation procedures are performed annually in the United States and Europe combined, and Thyrogen has the potential to be used by up to 80 percent of these patients.”

Market: Total sales were $170.6 million in 2009, $149 millio in 2008, $114 million in 2007, $94 million in 2006, $78 million in 2005, $63.5 million in 2004, $43 million in 2003, and $28.3 million in 2002. Sales growth reflects approval in new markets, strong patient demand, and increased U.S. market penetration. Genzyme stated in June 1998 that it “believes the drug...has a market potential of $75 million in annual sales in the U.S., Canada, and Europe.”

The 2007 Average Wholesale Price (AWP) is $1,740.00/vial (Red Book, 2007). The AWP was $1,584.00/vial in 2005, and $1,444.80 in 2004.

In Sept. 2006, Thyrogen was added to the Medicare Part B Competitive Acquisition Program (CAP). This allows Thyrogen to be ordered for Medicare-covered patients through BioScrip, the approved CAP vendor. Physicians electing to participate in the program no longer have to buy and bill Thyrogen (for Medicare patients) under the average sales price (ASP) system, but instead obtain it directly through BioScrip, i.e,. the physician buys it and does not have to later file for reimbursement. Physicians continue to be paid by Medicare for the cost of administering the drugs to Medicare patients.     

Genzyme maintains its own team of clinical specialists to collaborate with Knoll on Thyrogen educational efforts and to facilitate relationships with leading endocrinologists. Knoll also markets Synthroid (levothyroxine sodium tablets, USP), the leading synthetic thryoid hormone replacement therapy in the U.S. Knoll markets Synthroid to endocrinologists, the physicians who primarily treat thyroid diseases and prescribe Thyrogen.

Ongoging: In late 2012, Genzyme was collaborating with Veracyte to develop the molecular diagnostics company's gene expression test Afirma, which resolves inconclusive thyroid nodule results and lowers the chances of unnecessary surgery.