Summary Basis of Decision for Tepezza

Clinical Pharmacology

Teprotumumab, the medicinal ingredient in Tepezza, binds to insulin-like growth factor-1-receptor (IGF-1R) and blocks its activation and signalling. The pharmacokinetic characteristics of teprotumumab align with those of other immunoglobulin G1 monoclonal antibodies, showing low systemic clearance, a low volume of distribution, and a long elimination half-life.

The pharmacokinetic profile of teprotumumab administered intravenously was derived and well characterized from five clinical studies: four in acute thyroid eye disease (TED01RV, OPTIC, OPTIC-X, OPTIC-J) and one in chronic thyroid eye disease (HZNP-TEP-403). Both non-compartmental and population pharmacokinetic analyses were utilized in this assessment.

The dosing regimen of 20 mg/kg every three weeks for seven doses, following an initial 10 mg/kg dose, was chosen to maintain trough concentrations above 20 mcg/mL in most thyroid eye disease patients, which is expected to result in greater than 90% saturation of IGF-1R. This dose regimen was later justified based on the clinical efficacy and safety data.

The pharmacokinetics of teprotumumab was described by a two-compartment population pharmacokinetic model. Among all the covariates tested, body weight was identified as the only covariate with a statistically significant impact on the pharmacokinetics.

No formal pharmacodynamic studies have been conducted with teprotumumab.

No dedicated drug-drug interaction studies were conducted, which is acceptable given that the risk of a direct drug-drug interaction with teprotumumab is low, as antibodies are cleared by proteolytic catabolism.

No clinically relevant exposure-response relationships were observed between teprotumumab exposure and the efficacy or safety endpoints in studies TED01RV, OPTIC, OPTIC-X, OPTIC-J, and HZNP-TEP-403 for patients with thyroid eye disease.

The overall incidence of anti-teprotumumab antibodies was low among patients receiving teprotumumab treatment. There was no apparent impact of anti-drug antibodies on the efficacy, safety, and pharmacokinetics of teprotumumab.

For further details, please refer to the Product Monograph for Tepezza, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Tepezza in treating adult patients with moderate to severe active thyroid eye disease was based primarily on two Phase III randomized, double-masked, placebo-controlled, parallel-group, multicentre clinical studies, OPTIC and OPTIC-J.

OPTIC and OPTIC-J were both conducted in patients with moderate-to-severe active thyroid eye disease, which was defined by one or more of the following criteria: eyelid retraction of 2 mm or more, moderate to severe soft tissue involvement, exophthalmos of at least 3 mm above the normal range for race and gender (OPTIC study only), and/or non-constant or constant diplopia. Active thyroid eye disease was defined as Clinical Activity Score (CAS) greater than or equal to 4/7 (OPTIC study) or CAS greater than or equal to 3/7 (OPTIC-J study) for the more severely affected eye at screening and baseline. Patients were euthyroid or had thyroxine and free triiodothyronine levels less than 50% above or below normal limits. Prior surgical treatment for thyroid eye disease was not permitted. At baseline, the median proptosis in the OPTIC study was 23.0 mm, with a range off 16.0 to 33.0 mm. In the OPTIC-J study, the median proptosis was 20.0 mm and ranged from 14.5 to 27.0 mm. The median clinical activity score in the study eye at baseline was 5 (range: 4 to 7) in the OPTIC study, and the median time since diagnosis of thyroid eye disease was 6.78 months (range: 0.9 to 10.3 months). In the OPTIC-J study, the median clinical activity score at baseline was 4 (range: 3 to 7), with a median disease duration of 4.72 months (range: 0.53 to 8.9 months).

In both studies, patients were randomized in a 1:1 ratio stratified by tobacco use status (yes versus no) to receive either Tepezza or a placebo. Treatment consisted of eight infusions administered every three weeks with an initial dose infusion of 10 mg/kg followed by seven doses of 20 mg/kg. Both studies were conducted over a 24-week period with the initial infusion given on Day 1 (baseline), followed by seven subsequent infusions given at weeks 3, 6, 9, 12, 15, 18 and 21. A final follow-up visit was then conducted at Week 24. All treatment dosing was performed at the clinic under the supervision of clinic staff. After each infusion, patients were instructed to contact the site if they were experiencing any infusion-associated events. An additional phone/email contact and clinic visit was conducted for any participant experiencing an infusion-associated event.

The primary endpoint in both the OPTIC and OPTIC-J study was the proptosis responder rate at Week 24. This was defined as the percentage of patients who showed a clinically significant decrease of at least 2 mm or more in proptosis (eyeball protrusion) from baseline in their study eye, without a worsening (increase of 2 mm or more) in proptosis in their fellow eye. The OPTIC study enrolled 83 patients and OPTIC-J enrolled 54 patients.

The results from both studies demonstrated that the proptosis responder rate in the study eye at Week 24 was statistically significant and clinically meaningful in the Tepezza treatment group compared to the placebo treatment group. In the OPTIC study, 83% of patients who received Tepezza had a clinically meaningful improvement in proptosis, compared to 10% of patients who received a placebo. Overall, this resulted in a 73% (95% confidence interval [CI]: 59%, 88%; p<0.05) treatment difference in response rates between the two groups. In the OPTIC-J study, 89% of patients treated with Tepezza had a clinically meaningful improvement in proptosis, compared to 11% of patients who received a placebo, resulting in a treatment difference of 78% (95% CI: 61%, 95%; p<0.05) between the two groups.

Supportive Study

Active Thyroid Eye Disease

In a multicentre, randomized, double-masked, placebo-controlled, parallel-group Phase II study, TED01RV, the efficacy results for the proptosis endpoints were consistent to that observed in OPTIC and OPTIC-J.

Other Study

Inactive Thyroid Eye Disease

The Tepezza New Drug Submission included a single study (HZNP-TEP-403) which evaluated the efficacy and safety of Tepezza in patients with inactive thyroid eye disease. This study had some important limitations. Therefore, the evidence provided to support the use of Tepezza for the treatment of inactive thyroid eye disease was not deemed sufficient at this time to conclude on a favourable benefit-risk profile. As such, the indication for Tepezza has been restricted to patients with active thyroid eye disease only.

Indication

The New Drug Submission for Tepezza was filed by the sponsor with the following proposed indication:

Tepezza (teprotumumab for injection) is indicated in adults for the treatment of moderate to severe thyroid eye disease.

The data provided in this New Drug Submission support a favorable benefit-risk profile for Tepezza in adults for the treatment of moderate to severe active thyroid eye disease. However, the evidence provided at this time is not sufficient to conclude on a favourable benefit-risk profile for Tepezza for the treatment of inactive thyroid eye disease. Therefore, Tepezza is not recommended for the treatment of inactive thyroid eye disease.

Health Canada approved the following indication:

Tepezza (teprotumumab for injection) is indicated in adults for the treatment of moderate to severe active thyroid eye disease.

For more information, refer to the Product Monograph for Tepezza, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Tepezza for patients with moderate to severe active thyroid eye disease was evaluated based on a single treatment course of Tepezza, consisting of seven 20 mg/kg intravenous infusions administered every three weeks, following an initial dose of 10 mg/kg. The safety population consisted of 224 patients with active thyroid eye disease (111 received Tepezza and 113 received placebo) from three randomized, double-masked, placebo-controlled clinical studies (OPTIC, OPTIC-J, and TED01RV).

No deaths were reported during the clinical trial program. However, several serious adverse events associated with Tepezza were identified, including hyperglycemia-related events, hearing impairment, and exacerbation of inflammatory bowel disease. Tepezza is also a teratogen based on its mechanism of action and the non-clinical studies; there were no pregnancies reported during the clinical trial program. The identified frequent but usually non-serious adverse events associated with Tepezza include infusion reactions (4%), muscle spasms (23%), dry skin (9%), alopecia (16%), nail disorders (5%), diarrhea (13%), nausea (13%), dysgeusia (9%), weight loss (14%), urinary tract infections (7%), and menstrual disorders (14%). Additionally, a potential risk of encephalopathy was identified based on the review of the clinical studies and post-marketing data.

The reversibility of many of the Tepezza associated adverse events, including hyperglycemia and hearing impairment, is not yet fully characterized as many of the events were ongoing or continued to require medical treatment at the end of the study.

Post-market cases of diabetic ketoacidosis and hyperosmolar hyperglycemic state, both serious potentially life-threatening conditions, have been reported in patients with pre‑diabetes (elevated glycosylated hemoglobin or hyperglycemia without overt diabetes) or existing diabetes treated with Tepezza. Therefore, patients with pre-existing hyperglycemia or diabetes must be under appropriate glycemic control before starting and while receiving Tepezza. A Serious Warnings and Precautions box with this information has been included in the Product Monograph for Tepezza.

The clinical trial and post-marketing safety databases for Tepezza are relatively small, in keeping with a treatment for a rare disease, and may not allow identification of less common drug-related adverse events at this time. The identified risks associated with Tepezza treatment have been properly labelled in the Product Monograph for Tepezza and will be monitored through pharmacovigilance activities. It is also worth noting that a post‑marketing safety study (HZNP-TEP-402) is currently underway, with final results expected in the second quarter of 2026. Study HZNP-TEP-402 aims to better characterize the serious risks identified in the thyroid eye disease clinical trial program, notably hyperglycemia, hearing impairment, and inflammatory bowel disease.

For more information, refer to the Product Monograph for Tepezza, approved by Health Canada and available through the Drug Product Database.

In vitro primary pharmacodynamic data support the molecular mechanism of action of teprotumumab (the medicinal ingredient in Tepezza) as an anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody that inhibits IGF-1R.

Toxicology studies were conducted in cynomolgus monkeys and consisted of repeat-dose studies in juvenile and mature animals and an embryo-fetal development study. Adverse reductions in body weight due to body weight loss or less weight gain were observed in all studies, including in pregnant animals. Teprotumumab administration also resulted in teratogenicity (external and skeletal abnormalities of the head and skull) and general growth retardation in fetuses. It also reduced overall growth, bone development, and strength in juvenile animals. These effects are consistent with the mechanism of action of teprotumumab in inhibiting IGF-1R signalling, as IGF-1R plays a physiological role in metabolism and a critical role in growth and development. As such, Tepezza is contraindicated in pregnancy and the adverse effects are labelled as warnings for both pregnant women and pediatrics in the Product Monograph for Tepezza.

For more information, refer to the Product Monograph for Tepezza, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Teprotumumab, the medicinal ingredient in Tepezza, is a recombinant humanized monoclonal antibody of the immunoglobulin G1 subclass. Although the exact mechanism of action of teprotumumab in thyroid eye disease has not been fully characterized, it is known to bind to the insulin-like growth factor-1 receptor, thereby inhibiting its activation and signalling.

Detailed characterization studies were performed to provide assurance that teprotumumab consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The drug substance, teprotumumab, is produced by recombinant deoxyribonucleic acid (DNA) technology in a Chinese Hamster Ovary cell line. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines.

The manufacturing process of the drug substance consists of a series of stages which include fermentation, harvesting the cell culture, clarification, and subsequent purification using a series of chromatographic and viral inactivation steps. Following purification, the bulk drug substance is then filtered into the drug substance containers. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

The manufacturing process of the drug product consists of a series of stages which include thawing, pooling, and diluting of the drug substance followed by bioburden reduction, sterile filtration, and aseptic filling into glass vials prior to lyophilization, stoppering, and crimping. The data demonstrate that the drug product manufacturing process is capable of consistently manufacturing teprotumumab drug product of acceptable quality and of consistently meeting the label claim.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the teprotumumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product manufacturing processes are controlled by process parameters, in-process controls, and tests that have defined operating targets/ranges, acceptance criteria, and action limits. The criticality of the process parameters and in‑process controls were based on the outcome of product quality attribute assessment, risk assessments, and process characterization studies. The in-process and specification acceptance criteria were suitably justified and ensure the safety, identity, strength, potency, and purity of the drug substance and drug product. The in-house analytical methods were validated according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines and compendial methods complied with pharmacopeia standards. A two-tiered reference standard program has been established for Tepezza, which consists of primary and working reference standards. Overall, the control strategy ensures suitable drug substance and drug product quality over the product lifetime.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 48 months shelf life is acceptable when Tepezza is stored at 5 ± 3 °C and protected from light.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

Based on a risk assessment score determined by Health Canada, on-site evaluation of the drug substance and drug product manufacturing facilities were not deemed necessary.

The sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

Adventitious agents are excluded from the process stream through the careful selection of raw materials and control of the manufacturing process. The potential load of retrovirus-like particles in the unprocessed bulk was assessed using the maximum dose and viral clearance data and was determined to be within safe limits under worst-case conditions.