Batoclimab for Graves' Eye Disease

Recruiting at 40 trial locations

Overseen By Central Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Immunovant Sciences GmbH

Must not be taking: Steroids

Disqualifiers: Optic neuropathy, Autoimmune diseases, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have used steroids for TED or other conditions within 4 weeks before the trial starts.

What data supports the effectiveness of the drug Batoclimab for Graves' Eye Disease?

Research shows that Batoclimab, an FcRn inhibitor, can reduce harmful antibodies that cause thyroid eye disease, suggesting it may be effective in treating this condition. ^{1 2 3 4 5}

Is Batoclimab safe for humans?

The safety of Batoclimab, also known as an FcRn inhibitor, has been evaluated in clinical trials for thyroid eye disease, where it was used to reduce harmful antibodies. While specific safety data from these trials is not detailed here, the fact that it has been tested in humans suggests that some safety assessments have been conducted. ^{4 5 6 7 8}

How is the drug Batoclimab unique in treating Graves' Eye Disease?

Batoclimab is unique because it works by blocking the neonatal Fc receptor (FcRn), which reduces harmful antibodies that contribute to the symptoms of Graves' Eye Disease. This mechanism is different from other treatments that may not target these specific antibodies. ^{4 7 9 10 11}

What is the purpose of this trial?

To evaluate the efficacy of batoclimab 680 milligrams (mg) subcutaneous (SC) once a week (QW) for 12 weeks followed by 340 mg SC QW for 12 weeks versus placebo on proptosis responder rate at Week 24.

Eligibility Criteria

This trial is for adults over 18 with active Thyroid Eye Disease (TED) diagnosed within the last year. Participants should have moderate to severe TED, not require immediate surgery, and have their thyroid disease under control or only mildly off-balance. They can't join if they've had recent steroid treatments, other autoimmune diseases that could affect the study, or past eye surgeries/irradiation for TED.

Inclusion Criteria

I have moderate to severe active thyroid eye disease.

My eye condition started less than a year ago.

My thyroid condition is stable or only mildly off.

Exclusion Criteria

I have not used steroids for TED or any condition in the last 4 weeks.

My eye condition improved by at least 2 points or my eye bulging reduced by 2 mm before the study.

I have taken steroids equivalent to 1g of methylprednisolone for TED.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive batoclimab 680 mg SC weekly for 12 weeks followed by 340 mg SC weekly for 12 weeks or placebo SC weekly for 24 weeks

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Batoclimab

Trial Overview The study tests Batoclimab's effectiveness on eye bulging in TED patients. It compares a high dose followed by a lower dose of Batoclimab against a placebo over 24 weeks to see if there's an improvement in proptosis (eye protrusion).

Participant Groups

Group I: Batoclimab Experimental Treatment 1 Intervention

Participants will be administered batoclimab 680 mg SC weekly for 12 weeks followed by 340 mg SC weekly for 12 weeks.

Group II: Placebo Placebo Group 1 Intervention

Participants will be administered matching placebo SC weekly for 24 weeks.

Batoclimab is already approved in European Union, United States for the following indications:

Approved in European Union as Batoclimab for:

• Thyroid Eye Disease (TED)

Approved in United States as Batoclimab for:

• Thyroid Eye Disease (TED)

Who Is Running the Clinical Trial?

Immunovant Sciences GmbH

Lead Sponsor

Trials

12

Recruited

1,400+

Findings from Research

Patients with active Graves' orbitopathy (GO) showed significantly higher levels of CD19+ B cells and memory B cells compared to healthy individuals, indicating a potential abnormality in B cell regulation in this condition.

The study found that elevated serum levels of CXCL13 in active GO patients correlated strongly with disease activity and that blocking CXCL13 or its receptor CXCR5 reduced B cell migration, suggesting that this pathway may play a critical role in B cell dysregulation in active GO.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Altered Expression of CXCL13 and Its Chemokine Receptor CXCR5 on B Lymphocytes during Active Graves' Orbitopathy. Wan, S., Lin, M., Mao, Y., et al.[2021]

Depleting regulatory T cells in mice increased the production of TSHR-stimulating antibodies (TSAbs) after immunization with a TSHR plasmid, suggesting a potential mechanism for enhancing immune response in Graves' disease models.

Despite successful antibody production with adenoviral immunization, the methods used did not lead to significant orbital inflammation, indicating that current immunization protocols may need further refinement to fully replicate the symptoms of Graves' disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examination of orbital tissues in murine models of Graves' disease reveals expression of UCP-1 and the TSHR in retrobulbar adipose tissues. Johnson, KT., Wiesweg, B., Schott, M., et al.[2016]

In a mouse model of hyperthyroid Graves' disease, blocking the signals from BAFF and APRIL significantly reduced hyperthyroidism and the levels of thyroid stimulating antibodies (TSAbs), indicating a potential therapeutic approach for this autoimmune disorder.

The study found that while treatment reduced TSAbs, it did not affect the overall number of plasma cells in the spleen, suggesting that the reduction in autoantibody production is linked to the survival and maturation of autoreactive B cells rather than a decrease in plasma cell quantity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of autoimmune hyperthyroidism in a murine model of Graves' disease with tumor necrosis factor-family ligand inhibitors suggests a key role for B cell activating factor in disease pathology. Gilbert, JA., Kalled, SL., Moorhead, J., et al.[2013]

Batoclimab, an FcRn inhibitor, significantly reduced pathogenic antibodies associated with thyroid eye disease (TED) in clinical trials, indicating its potential efficacy as a treatment.

While the randomized trial did not show a significant improvement in proptosis (eye bulging) at 12 weeks compared to placebo, earlier timepoints showed positive effects, and batoclimab was generally well tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease. Kahaly, GJ., Dolman, PJ., Wolf, J., et al.[2023]

In a study of 128 Graves' disease patients treated for 18 months, two new M22-based assays for measuring TSH-receptor antibodies (TRAb) showed significant variability compared to the established human TRAb assay (hTRAK), with the Cobas assay yielding higher and the ELISA yielding lower results.

Despite the differences in assay results, neither of the M22-based assays improved the ability to predict relapse of hyperthyroidism compared to the hTRAK, highlighting the need for harmonization of testing methods to ensure accurate patient classification.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical value of M22-based assays for TSH-receptor antibody (TRAb) in the follow-up of antithyroid drug treated Graves' disease: comparison with the second generation human TRAb assay. Massart, C., Gibassier, J., d'Herbomez, M.[2009]

In patients with Graves' orbitopathy (GO), the use of rabbit anti-T lymphocyte globulin (rATG) significantly increases the frequency and potency of regulatory T (Treg) cells, which are important for immune regulation, compared to controls.

This study highlights that rATG can enhance the suppressive ability of Treg cells in GO patients, suggesting a potential therapeutic approach to modulate the immune response in this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory T-cells in Graves' orbitopathy: baseline findings and immunomodulation by anti-T lymphocyte globulin. Kahaly, GJ., Shimony, O., Gellman, YN., et al.[2022]

The study found that the neonatal Fc receptor (FcRn) is expressed in thyrocytes, but its levels are significantly lower in thyrocytes from patients with Hashimoto's thyroiditis (HT) compared to normal thyrocytes, suggesting a potential role in the disease's pathogenesis.

FcRn facilitates the internalization of IgG antibodies, including thyroglobulin antibodies (TgAb), in a pH-dependent manner, indicating that it may play a crucial role in the transport and metabolism of these antibodies within thyrocytes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The expression and function of the neonatal Fc receptor in thyrocytes of Hashimoto's thyroiditis. Zhao, C., Gao, Y., Zhao, L., et al.[2018]

In a mouse model of Graves' orbitopathy (GO), rapamycin significantly reduced the incidence of the disease by decreasing CD4+ cytotoxic T lymphocytes (CTLs) and associated orbital inflammation, adipogenesis, and fibrosis.

In patients with refractory GO, low-dose rapamycin treatment led to substantial improvements in symptoms like diplopia and reduced clinical activity scores, indicating its potential as an effective therapy for managing CD4+ CTL-mediated inflammation in this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin improves Graves' orbitopathy by suppressing CD4+ cytotoxic T lymphocytes. Zhang, M., Chong, KK., Chen, ZY., et al.[2023]

The small molecule inverse agonist of TSHR, NCGC00229600 (referred to as compound 1), effectively inhibits hyaluronan (HA) production and relevant signaling pathways in orbital fibroblasts from patients with Graves ophthalmopathy, demonstrating a dose-dependent effect with a half-maximal inhibitory dose of 830 nM.

Compound 1 blocks both basal and stimulated signaling pathways related to TSHR, suggesting that TSHR antagonists could be a promising therapeutic approach for treating or preventing Graves ophthalmopathy by targeting the underlying mechanisms of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. Turcu, AF., Kumar, S., Neumann, S., et al.[2022]

The study reveals that anti-TSH-receptor antibodies function differently in adults compared to children with Graves disease, indicating a need for age-specific approaches in treatment.

It also emphasizes the ongoing debate about the role of these antibodies in causing ophthalmopathy, a common complication of Graves disease, suggesting that further research is necessary to clarify their impact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thyroid function. Pathogenesis of Graves ophthalmopathy--a role for TSH-R? Wall, JR.[2021]

In a study of 12 female patients with euthyroid Graves' disease, there was a significant decrease in T cells with suppressor functions, which may relate to the autoimmune nature of the disease.

In contrast, patients with Hashimoto's thyroiditis and eye changes showed normal or elevated levels of T cells, suggesting different immune profiles between these thyroid conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating T cell subsets in euthyroid Graves' disease. Bagnasco, M., Canonica, GW., Ferrini, S., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Altered Expression of CXCL13 and Its Chemokine Receptor CXCR5 on B Lymphocytes during Active Graves' Orbitopathy. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Examination of orbital tissues in murine models of Graves' disease reveals expression of UCP-1 and the TSHR in retrobulbar adipose tissues. [2016]

3. United States pubmed.ncbi.nlm.nih.gov

Treatment of autoimmune hyperthyroidism in a murine model of Graves' disease with tumor necrosis factor-family ligand inhibitors suggests a key role for B cell activating factor in disease pathology. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical value of M22-based assays for TSH-receptor antibody (TRAb) in the follow-up of antithyroid drug treated Graves' disease: comparison with the second generation human TRAb assay. [2009]

6. United States pubmed.ncbi.nlm.nih.gov

Regulatory T-cells in Graves' orbitopathy: baseline findings and immunomodulation by anti-T lymphocyte globulin. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

The expression and function of the neonatal Fc receptor in thyrocytes of Hashimoto's thyroiditis. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Rapamycin improves Graves' orbitopathy by suppressing CD4+ cytotoxic T lymphocytes. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Thyroid function. Pathogenesis of Graves ophthalmopathy--a role for TSH-R? [2021]

11. Italy pubmed.ncbi.nlm.nih.gov

Circulating T cell subsets in euthyroid Graves' disease. [2018]