A Safety, Tolerability and Efficacy Study of VRDN 001 in Healthy Volunteers and Persons With Thyroid Eye Disease (TED)

Study Overview
=================
Brief Summary
-----------------
Please note that Phase 1/2 (HV & MAD) cohort - recruitment is completed and Phase 3 Component (THRIVE) - is actively recruiting. The investigational drug, VRDN-001, is a monoclonal antibody that inhibits the activity of a cell surface receptor called insulin-like growth factor-1 receptor (IGF-1R). Inhibition of IGF-1R may help to reduce the inflammation and associated tissue swelling that occurs in patients with thyroid eye disease (TED). This clinical trial will evaluate the safety, tolerability and pharmacokinetics (the concentration of drug in the blood over time) of VRDN-001 in healthy volunteers and in patients with TED. Study participants with TED will also be evaluated over time for changes in their signs and symptoms of TED compared to their baseline measurements.

Official Title
-----------------
A Multiple Ascending Dose (MAD) Safety, Tolerability and Efficacy Study of VRDN 001, a Humanized Monoclonal Antibody Directed Against the IGF-1 Receptor, in Normal Healthy Volunteers (HV(s) and Participants With Thyroid Eye Disease (TED)

Conditions
-----------------
Thyroid Eye Disease

Intervention / Treatment
-----------------
* Drug: VRDN-001 Phase 1/2 MAD (HV and TED)
* Drug: VRDN-001 Phase 3 Cohort (THRIVE)
* Drug: VRDN-001 Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria for Healthy Volunteers: Must be free of clinically significant disease or medical conditions as determined by the Investigator Female volunteers must not be of child-bearing potential Key Exclusion Criteria for Healthy Volunteers: ∙ Must not have a history of or any evidence of diabetes mellitus, recently diagnosed renal impairment or inflammatory bowel disease, or clinically significant ear pathology or earing impairment Key Inclusion Criteria for Participants with TED in Phase 1/2 MAD cohorts: Must have moderate to severe active TED with documented evidence of ocular symptoms or signs that began within 1 year prior to screening OR moderate to severe chronic TED with documented evidence of ocular symptoms or signs that began over 1 year prior to screening Must have active TED and a Clinical Activity Score (CAS) of ≥ 4 on the 7-item scale for the study (more proptotic) eye OR chronic TED with no CAS requirement Must agree to use highly effective contraception as specified in the protocol Female TED participants must have a negative serum pregnancy test Key Exclusion Criteria for Participants with TED in Phase 1/2 MAD cohorts: Must not have received prior treatment with another anti-IGF-1R monoclonal antibody Must not have used oral corticosteroids within 4 weeks prior to Day 1 Must not have received rituximab, tocilizumab or other immunosuppressive agents within 90 days prior to Day 1 Must not have evidence of optic nerve involvement within the previous 6 months Must not have corneal decompensation in the study eye unresponsive to medical management Must not have had previous orbital irradiation or surgery for TED in the study eye Must not have a history inflammatory bowel disease Must not have clinically significant ear pathology or hearing impairment Must not have received an investigational agent for any condition within 60 days Female TED participants must not be pregnant or lactating Key Inclusion Criteria for Participants with TED in Phase 3 study: Must have moderate to severe active TED with documented evidence of ocular symptoms or signs that began within 15 months prior to screening Must have Clinical Activity Score (CAS) of ≥ 3 on the 7-item scale for the study (more proptotic) eye Must agree to use highly effective contraception as specified in the protocol Female TED participants must have a negative serum pregnancy test Key Exclusion Criteria for Participants with TED in Phase 3 study: Must not have received prior treatment with another anti-IGF-1R monoclonal antibody Must not have used oral corticosteroids within 2 weeks prior to Day 1 Must not have received rituximab, tocilizumab or other immunosuppressive agents within 8 weeks prior to Day 1 Must not have a pre-existing ophthalmic condition in the study eye that in the opinion of the Investigator would confound interpretation of the study results Must not have had previous orbital irradiation or surgery for TED in the study eye Must not have a history inflammatory bowel disease Must not have a history or screening audiometry assessment of clinically significant (as determined by investigator) ear pathology, relevant ear surgery, or hearing l loss Must not have received an investigational agent for any condition Female TED participants must not be pregnant or lactating

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1/2 MAD (HV and TED)<br>Healthy participants and participants with TED will be randomized to receive two intravenous infusions of VRDN-001 or placebo with an interval of 3 weeks. | Drug: VRDN-001 Phase 1/2 MAD (HV and TED)<br>* 2 Infusions of multiple ascending doses of VRDN-001, ranging from 3 mg/kg to 20 mg/kg<br>|
| Experimental: Phase 3 Cohort (THRIVE)<br>Participants with TED will be randomized to either VRDN-001 10mg/kg or placebo. | Drug: VRDN-001 Phase 3 Cohort (THRIVE)<br>* 5 Infusions of VRDN-001 10mg/kg<br>Drug: VRDN-001 Placebo<br>* 5 Infusions of VRDN-001 placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent adverse events as assessed by CTCAE v5.0 |  | Up to Day 50 for MAD healthy volunteers, up to Day 169 for MAD TED subjects, and up to Week 52 for the Phase 3 study subjects | 
| Proptosis responder rate | Proportion of TED participants with a reduction of proptosis of ≥ 2 mm from baseline as determined by exophthalmometer | Week 6 for MAD TED participants, and Week 15 for Phase 3 study subjects | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in measurement of proptosis as determined by exophthalmometer |  | Up to Week 12 for MAD TED subjects, and up to Week 52 for Phase 3 subjects | 
| Change from baseline in volume of orbital fat as determined by MRI |  | Up to Week 12 for MAD TED participants, and up to Week 52 for Phase 3 subjects | 
| Change from baseline in volume of extraocular muscles as determined by MRI |  | Up to Week 12 for MAD TED participants, and up to Week 52 for Phase 3 subjects | 
| Change from baseline in facial fat volume as determined by MRI |  | Up to Week 12 for MAD TED participants, and up to Week 52 for Phase 3 subjects | 
| Change from baseline in Clinical Activity Score (CAS) | Each of 7 clinical signs and symptoms of ocular inflammation is scored as present or absent (score of 1 or 0, respectively). The CAS is the sum of the individual scores (range from 0 to 7) where a higher score indicates a greater level of inflammation. | Up to Week 12 for MAD TED participants, and up to Week 52 for Phase 3 subjects | 
| Change from baseline in Subjective Diplopia Score | Diplopia grade is assessed using the Gorman Subjective Diplopia Score (range from 0 to 3) based on verbal responses by the study subject. A higher score indicates a worse diplopia grade. | Up to Week 12 for MAD TED participants, and up to Week 52 for Phase 3 subjects | 
| Change from baseline in Graves Orbitopathy-Quality of Life (GO-QoL) combined score |  | Up to Week 12 for MAD TED participants, and up to Week 52 for Phase 3 subjects | 
| Change in measurement of proptosis by MRI/CT |  | Up to Week 12 for MAD TED participants, and up to Week 52 for Phase 3 subjects | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Graves Ophthalmopathy, Thyroid Eye Disease, Thyroid-Associated Ophthalmopathy, Dysthyroid Ophthalmopathy, Graves Eye Disease, Graves Orbitopathy, Myopathic Ophthalmopathy, Congestive Ophthalmopathy, Edematous Ophthalmopathy, Infiltrative Ophthalmopathy