Breakthrough Clinical Results
Viridian Therapeutics announced that the FDA granted Breakthrough Therapy Designation to veligrotug, its lead drug candidate for treating Thyroid Eye Disease (TED). This designation is for drug candidates showing substantial improvement over existing therapies. Veligrotug met primary and secondary endpoints in the THRIVE and THRIVE-2 clinical trials, demonstrating statistically significant improvement and resolution of diplopia, a key symptom of TED. The BLA submission is on track for the second half of 2025, with a potential US launch in 2026 if approved. This designation supports eligibility for Priority Review.
Key Highlights
- FDA grants Breakthrough Therapy Designation to veligrotug for TED.
- Veligrotug met all primary and secondary endpoints in THRIVE and THRIVE-2 phase 3 trials.
- First drug to show statistically significant diplopia improvement and resolution in chronic TED in a global phase 3 trial.
- BLA submission expected in second half of 2025, potential US launch in 2026.
Incidence and Prevalence
Incidence of Thyroid Eye Disease (TED):
- A US study using claims data (up to 2019) estimated incidence rates of 8.97 (sensitive definition) and 4.37 (specific definition) per 100,000 person-years. The rates were higher in women (13.49 and 6.59, respectively) than in men (4.27 and 2.05, respectively).
- A Danish nationwide registry study (2000-2018) found a mean annual incidence rate of 5.0 per 100,000 person-years (8.0 in women and 1.9 in men).
- A Japanese claims database study (fiscal year 2020) reported incidence rates ranging from 7.3 to 11.1 per 100,000 person-years, depending on the definition used.
Prevalence of Thyroid Eye Disease (TED):
- The US claims data study (up to 2019) estimated prevalence rates of 44.13 (sensitive definition) and 20.55 (specific definition) per 100,000 persons. Again, rates were higher in women (66.00 and 31.18, respectively) than in men (21.39 and 9.50, respectively).
- The Japanese claims database study (fiscal year 2020) found prevalence rates between 24.65 and 37.58 per 100,000 persons, depending on the definition.
- A meta-analysis including 57 studies found an overall pooled prevalence of TED among Graves' disease patients of 40%. Prevalence varied by region: Europe (38%), Asia (44%), North America (27%), and Oceania (58%). Subgroup analysis showed a lower prevalence in predominantly Caucasian regions (37%) compared to Asian regions (45%).
Key Observations:
- Higher rates in women: All studies consistently show a significantly higher incidence and prevalence of TED in women compared to men.
- Variability in estimates: The incidence and prevalence estimates vary across studies, likely due to differences in methodologies, data sources (claims data vs. registries), and case definitions (sensitive vs. specific). The meta-analysis highlights the impact of case definitions and regional variations.
- Data limitations: The US claims data study did not capture the impact of teprotumumab, as the data only went up to 2019. The meta-analysis acknowledges potential limitations due to study heterogeneity.
- Importance of standardized reporting: The variability in estimates underscores the need for standardized case definitions and reporting methods in future epidemiological studies to allow for better comparisons and a more accurate understanding of the global burden of TED.
Key Unmet Needs and Targeted Populations in Thyroid Eye Disease (TED) Research (Based on PubMed Publications from 2021-2024):
1. Management of Chronic/Low-Inflammation TED:
- Traditional therapies like steroids and radiation offer limited long-term benefit for proptosis and diplopia, highlighting a need for more effective treatments in chronic TED. Studies on teprotumumab have shown promising results in reducing proptosis and improving quality of life in patients with chronic TED, regardless of disease duration or activity. However, further research is needed to optimize treatment strategies and address the persistent impact on quality of life and mental health. A study found that despite TED becoming stable and chronic, it continues to severely impact patient quality of life, with vision and appearance impairment and psychosocial impact reported long after acute TED subsides. This highlights the need for better management strategies for chronic TED. Another study showed that around one-third of a TED cohort presented with 'low-CAS, progressive', moderate-to-severe or vision-threatening TED, while only one-fifth were clinically active (CAS3). This highlights the limitations of the existing 'high-CAS only' approach and the unmet need for managing 'non-inflammatory' TED, especially in non-Caucasian populations.
2. Addressing the limitations of existing diagnostic tools and approaches:
- Current diagnostic tools, such as the clinical activity score (CAS), may not adequately capture the full spectrum of TED, particularly in cases of low inflammation or non-inflammatory TED. This emphasizes the need for more comprehensive diagnostic approaches that consider the chronic and persistent nature of TED symptoms, even in the absence of high inflammatory activity. Research suggests the need for more comprehensive diagnostic approaches that consider the chronic and persistent nature of TED symptoms, even in the absence of high inflammatory activity. One study highlighted the limitations of the existing 'high-CAS only' approach and the unmet need for managing 'non-inflammatory' TED, prevalent in non-Caucasian populations.
3. Improving Patient-Reported Outcomes and Quality of Life:
- TED significantly impacts patients' quality of life, even after inflammation subsides. There is a need for interventions that address the persistent symptoms and functional limitations associated with chronic TED, such as ocular dryness, proptosis, diplopia, and psychosocial issues. Research has shown that TED severely impacts patient quality of life, even after becoming stable and chronic, with patients reporting vision and appearance impairment and psychosocial impact long after acute TED subsides. This highlights the need for interventions that address the persistent symptoms and functional limitations associated with chronic TED. Another study found that quality of life was impacted by non-inflammatory TED, although to a lesser degree than inflammatory TED. However, mental health issues were similarly reported, suggesting that moderate-to-severe TED should be considered a robust symptomatic chronic disease, regardless of its inflammatory status.
4. Targeted Therapies and Personalized Medicine:
- Research on targeted therapies, such as teprotumumab (IGF-1R inhibitor), has shown promise in improving TED outcomes. However, further research is needed to optimize the use of these therapies, identify appropriate patient subgroups, and explore combination therapies to address the complex pathophysiology of TED. Studies have shown that teprotumumab significantly reduces proptosis, inflammation, diplopia, strabismus, and orbital soft tissue volume in patients with chronic TED. However, additional research is needed to optimize the use of these therapies, identify appropriate patient subgroups, and explore combination therapies. Other studies have also explored the use of antibodies targeting the neonatal Fc receptor (FcRn) in TED, suggesting that advances in understanding TED pathophysiology are leading to more targeted therapeutic options.
5. Addressing Unmet Information Needs and Patient Education:
- Many patients with TED report unmet information needs regarding their condition, treatment options, and long-term management. There is a need for improved patient education and communication strategies to empower patients and facilitate shared decision-making. Research has shown that expanded efforts are needed to improve the delivery of information about prevention medications to promote medication adherence, control of risk factors, and potentially prevent unmet needs following stroke/TIA. This suggests that improved patient education and communication strategies are needed to empower patients and facilitate shared decision-making.
Targeted Populations:
- Patients with chronic/low-inflammation TED: This population often experiences persistent symptoms and functional limitations despite a lack of active inflammation, highlighting the need for effective long-term management strategies.
- Non-Caucasian populations: Research suggests that non-Caucasian populations may have different clinical presentations and responses to treatment, emphasizing the need for tailored approaches.
- Patients with unmet information needs: These patients may benefit from improved patient education and communication strategies to enhance their understanding of TED and its management.
- Patients with moderate-to-severe TED: Regardless of inflammatory status, these patients experience a significant impact on their quality of life and mental health, requiring comprehensive care and support.
- Patients with an inadequate initial response or flare of TED: These patients may benefit from additional or alternative therapies, such as re-treatment with teprotumumab.
In summary, recent research on TED has highlighted the need for better management of chronic/low-inflammation TED, improved diagnostic tools, enhanced patient-reported outcomes, optimized targeted therapies, and better patient education. These unmet needs are particularly relevant for specific patient populations, including those with chronic TED, non-Caucasian individuals, and those with unmet information needs. Addressing these unmet needs will require a multidisciplinary approach involving clinicians, researchers, and patients to improve the quality of life for individuals affected by TED.
Study Design Parameters
Several studies have investigated teprotumumab for Thyroid Eye Disease (TED), employing various designs and endpoints. Here's a summary:
1. Phase 2 and 3 Trials (e.g., OPTIC):
- Design: Randomized, double-masked, placebo-controlled, multicenter.
- Participants: Adults with active, moderate-to-severe TED (Clinical Activity Score [CAS] ≥ 4).
- Intervention: Eight intravenous infusions of teprotumumab (10 mg/kg for the first infusion, 20 mg/kg for subsequent infusions) or placebo every 3 weeks.
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Primary Endpoint:
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Phase 2: Overall responder rate (reduction of ≥2 CAS points and ≥2 mm proptosis reduction).
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Phase 3: Proptosis response (≥2 mm reduction in the study eye without similar deterioration in the fellow eye at week 24).
- Secondary Endpoints: Diplopia improvement, overall response (proptosis and CAS reduction), mean change in proptosis, mean change in Graves' Ophthalmopathy Quality of Life (GO-QOL) questionnaire scores, and disease inactivation (CAS 0 or 1).
- Key Findings: Teprotumumab significantly improved proptosis and other TED outcomes compared to placebo. In the phase 3 trial, 77% of teprotumumab patients achieved proptosis response vs. 15% placebo (p<0.0001). Numbers needed to treat (NNT) were 1.6 for proptosis, 2.5 for diplopia, 1.7 for overall response, and 2.5 for disease inactivation.
2. Integrated Analysis of Two Trials:
- Design: Integrated data from two randomized, double-masked, placebo-controlled trials.
- Focus: Short-term and long-term responses to teprotumumab, particularly proptosis and diplopia, up to 51 weeks.
- Subgroup Analyses: Assessed outcomes by tobacco use, age, sex, time to diagnosis, CAS, and thyrotropin binding inhibiting immunoglobulin concentration.
- Additional Outcomes: Ophthalmic composite outcome (improvement in ≥1 eye without deterioration in either eye in ≥2 of the following: absence of eyelid swelling; CAS ≥2; proptosis ≥2 mm; lid aperture ≥2 mm; diplopia disappearance or grade change; or improvement of 8 degrees of globe motility).
- Key Findings: Confirmed significant improvements with teprotumumab across various subgroups and sustained responses at long-term follow-up.
3. OPTIC-X Extension Study:
- Design: Open-label treatment and re-treatment trial following the OPTIC trial.
- Participants: OPTIC nonresponders or those who flared (≥2-mm proptosis increase, ≥2-point CAS increase, or both).
- Intervention: Eight teprotumumab infusions over 24 weeks.
- Primary Outcome: Proptosis response.
- Secondary Outcomes: Proptosis, CAS, subjective diplopia, and quality of life.
- Key Findings: 89.2% of placebo-treated OPTIC patients achieved proptosis response when treated with teprotumumab in OPTIC-X. Responses were maintained in most patients at week 48. Some nonresponders and those who flared also benefited from additional teprotumumab.
4. Chronic TED Study:
- Design: Retrospective review.
- Participants: Consecutive patients with chronic stable TED (>2 years) who received ≥3 teprotumumab infusions.
- Measurements: Proptosis, CAS, diplopia scores, strabismus scores, and orbital 3D volumetric analysis (in some patients).
- Key Findings: Teprotumumab significantly reduced proptosis, inflammation, diplopia, strabismus, and orbital soft tissue volume in chronic TED patients.
5. Batoclimab Trials:
- Design: Proof-of-concept and randomized, double-blind, placebo-controlled trials.
- Participants: Patients with moderate-to-severe, active TED.
- Intervention: Batoclimab (various doses and schedules) or placebo.
- Main Outcomes: Change in serum anti-TSH-R-Ab and total IgG (POC); proptosis response (randomized trial).
- Key Findings: Batoclimab significantly reduced anti-TSH-R-Ab and total IgG. The randomized trial was terminated early due to an unanticipated increase in serum cholesterol, but some positive trends in proptosis, orbital muscle volume, and quality of life were observed with batoclimab.
These trials demonstrate the evolving landscape of TED research, with a focus on developing and refining effective therapies and appropriate outcome measures.
Drug used in other indications
The provided text discusses trials for thyroid eye disease (TED) treatments, specifically mentioning Teprotumumab (Tepezza) and Batoclimab. It does not mention Veligrotug or any trials for this drug in other indications.
Teprotumumab trials focused on its efficacy in treating TED, including:
- Phase II and III trials: These compared teprotumumab to placebo in patients with active, moderate-to-severe TED. The primary outcomes were proptosis response rate, overall response rate, Clinical Activity Score, diplopia, and disease-specific quality of life. Intravenous infusions were given every 3 weeks for a total of 8 infusions. Results showed significant improvement in proptosis and other TED outcomes. Benefits were maintained for up to 51 weeks post-treatment. Common adverse events included muscle spasms, hearing loss, and hyperglycemia.
- OPTIC-X (Open-Label Clinical Extension Study): This trial evaluated teprotumumab's safety and efficacy in patients who didn't respond to treatment in the OPTIC trial or experienced a disease flare. Patients received 8 infusions over 24 weeks. Results showed that a significant percentage of previous placebo patients became proptosis responders. Patients with longer disease duration responded similarly to those treated earlier. No new safety risks were identified.
Batoclimab trials also investigated its potential for TED treatment:
- Proof-of-Concept (POC) Trial: Patients received weekly subcutaneous injections of batoclimab (680 mg for 2 weeks, followed by 340 mg for 4 weeks). The main outcome was the change in serum anti-TSH-R-Ab and total IgG levels.
- Randomized, Double-Blind, Placebo-Controlled Trial: Patients were randomized to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks. The primary outcome was the 12-week proptosis response. This trial was terminated early due to an unanticipated increase in serum cholesterol. Results showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG levels. While there was no significant difference in proptosis response at 12 weeks between batoclimab and placebo, significant differences were observed at earlier time points. Orbital muscle volume decreased, and quality of life (appearance subscale) improved in the 680-mg group. Adverse events included albumin reductions and increases in lipids, which reversed upon discontinuation.
Since the provided text does not mention Veligrotug, no information about its trials for other indications or intervention models can be provided.