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 (NHVs) and subjects with thyroid eye disease (TED)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Viridian Therapeutics Inc.

Participant type

Healthy volunteers, Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Eye Diseases [C11]

Trial duration

25 Oct 2022 → 5 Apr 2025

Decision date (initial)

2024-10-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Viridian Therapeutics, Inc., USA

External identifiers

EU CT number

2024-512244-36-00

EudraCT number

2021-006794-37

ClinicalTrials.gov

NCT05176639

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety, Dose response, Pharmacodynamic, Pharmacokinetic

To establish the safety, tolerability, and efficacy of VRDN-001, and the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of VRDN-001 in NHV and TED patients over a dose range of 3.0 to 20.0 mg/kg.

Conditions and MedDRA coding

Thyroid eye disease (TED)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Enrollment in the HV and Active TED MAD cohorts has been completed. The inclusion criteria corresponding to the HV and Active and Chronic TED MAD cohorts are now described in Appendices 4 and 5, respectively.
2. Active TED Pivotal (THRIVE) participants Participants must: 1. Be able to understand the study procedures and the risks involved and be willing to provide written informed consent before the first study- related activity
3. Be an adult male or female participant, at least 18 years of age or older
4. Have had a clinical diagnosis of TED with a CAS of ≥ 3 on the 7-item scale for the study eye
5. Have moderate to severe (i.e., has an appreciable impact on daily living) active TED associated with proptosis of ≥3 mm above normal values for race and gender in the opinion of the investigator and at least one of the following: lid retraction of ≥2 mm, moderate or severe soft tissue involvement, inconstant or constant diplopia, spontaneous retrobulbar pain or pain on eye movement, swelling of the conjunctiva, eyelids or plica, or redness of the eyelids or plica in the study eye
6. Have documented evidence of ocular symptoms or signs associated with active TED that began within 15 months prior to study screening
7. VRDN-001 can be started concomitantly with attempts to achieve euthyroid status. Underlying thyroid status is not an inclusion criterion.
8. Not require expected immediate surgical ophthalmological or orbital surgery in the study eye for any reason
9. VRDN-001 can be used with caution in patients with diabetes mellitus. Diabetic participants should be monitored by their endocrinologist or other appropriately trained personnel and have at study entry a glycated hemoglobin (HbA1c) of <8.5%
10. If female, have a negative serum pregnancy test at screening and further negative urine tests immediately before each dose of study medication following the last dose of study medication as described in Appendix 1C if the participant is a woman of childbearing potential (including those with <2 years since the onset of menopause, amenorrhea for <2 year, or not surgically sterile); such participants must agree to use an acceptable method of contraception such as a condom and a second highly effective method of contraception as described in Section 4.4 from Screening up to and including 100 days after the last dose of study medication. If the participant is initiating hormonal contraception at time of Screening or within one cycle of Day 1, participant agrees to use a double-barrier method of contraception until completing one-full cycle of hormonal contraception. An acceptable double-barrier combination method is a condom with either diaphragm or sponge with spermicide
11. Be surgically sterile males for at least 6 weeks, or agree to use an acceptable method of contraception such as a condom and a second highly effective method of contraception as described in Section 4.4 from Screening up to and including 100 days after the last dose of study medication
12. Be willing and able to comply with all the requirements of the protocol for the entire duration of the study.

Exclusion criteria 23

1. Exclusion Criteria Enrollment in the HV and Active TED MAD cohorts has been completed. The exclusion criteria corresponding to the HV and Active and Chronic TED MAD cohorts are now described in Appendices 4 and 5, respectively.
2. Active TED Pivotal (THRIVE) participants Participants must not: Have used systemic corticosteroids for any condition, including TED, or selenium within 2 weeks prior to the first dose of study medication (topical steroids or multivitamins that contain selenium are permitted)
3. Have received other immunosuppressive agents, including rituximab, or tocilizumab, for any condition, including TED, within 8 weeks prior to the first dose of study medication
4. Have received any other therapy for TED within 8 weeks prior to the first dose of study medication (artificial tears are permitted)
5. Have received an investigational agent for any condition within 8 weeks prior to the first dose of study medication
6. Have a pre-existing ophthalmic condition in the study eye which in the opinion of the Investigator, would confound interpretation of the study results
7. Be a pregnant or lactating woman
8. Be an active alcoholic or illicit drug user or considered at high risk of relapse by the Investigator
9. Active TED Pivotal (THRIVE) participants Participants must not: 1. Have received prior treatment with another anti-IGF-1R therapy or any investigational agent for TED
10. Have a compressive optic neuropathy of TED that is expected to require surgical decompression in the immediate future.
11. Have corneal decompensation in the study eye unresponsive to medical management
12. Have a decrease in CAS of ≥2 points in the study eye between screening assessment and Day -1
13. Have a decrease in proptosis of ≥2 mm in the study eye between screening assessment and Day -1
14. Have had previous orbital irradiation or decompression surgery involving excision of fat for TED to the study eye's orbit
15. Have history of or screening audiometry assessment of significant (as determined by the Investigator) ear pathology, relevant ear surgery or hearing loss
16. Have inflammatory bowel disease (e.g., biopsy proven or clinical evidence of inflammatory bowel disease)
17. Have a known hypersensitivity to any of the components of VRDN- 001 or placebo formulations, or prior hypersensitivity to monoclonal antibodies (mAbs)
18. Have any condition, which in the opinion of the Investigator, would preclude inclusion in the study
19. Have a positive test for human immunodeficiency virus (HIV-1 and HIV-2)
20. Have a positive test for active hepatitis B or hepatitis C infection
21. Have previously participated in this study or any study of VRDN-001
22. French participating sites only: In accordance with the provisions of articles L.1121-5 et seq. of the Public Health Code, pregnant or breast- feeding women, persons deprived of their liberty by a judicial or administrative decision, persons under psychiatric care without their consent, minors and adults under a legal protection measure must not be included
23. Note: Prior thyroidectomy, radioactive iodine (RAI) treatment, or orbital decompression surgery limited to bone only are NOT exclusions.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. - SAFETY ENDPOINTS Adverse Events (AEs) and Serious Adverse Events (SAEs) will be monitored and recorded throughout the duration of the study. All clinically significant changes in other safety measurements will be recorded as AEs.
2. - PRIMARY EFFICACY ENDPOINT IN THE USA, CANADA AND CHINA IN THE PIVOTAL PORTION OF THE STUDY (THRIVE) Proptosis Responder Rate in the study eye (i.e., reduction of proptosis of ≥ 2 mm from baseline [without a corresponding increase of ≥ 2 mm in the fellow eye] as measured by exophthalmometer) at 3 weeks post the fifth infusion (i.e., Week 15)
3. - AUS, EU AND UK: Overall Responder Rate comprised of Proptosis Responder Rate in the study eye (i.e., reduction of proptosis of ≥ 2 mm from baseline [without a corresponding increase of ≥ 2 mm in the fellow eye] as measured by exophthalmometer) at 3 weeks post the fifth infusion (i.e., Week 15) and Clinical Activity Responder Rate in the study eye (i.e., reduction in CAS ≥ 2 points from baseline [without a corresponding increase of ≥ 2 points in the fellow eye]) at 3 weeks post the 5 infusion

Secondary endpoints 29

1. Key Secondary Endpoints in Australia, EU and UK in the Pivotal portion of the Study (THRIVE): • Change from Baseline in proptosis in the study eye as measured by exophthalmometer at Week 15
2. Change from baseline in CAS in the study eye at Week 15
3. Diplopia Resolution Rate at (i.e., reduction in Gorman Subjective Diplopia Score to 0 from baseline for participants with baseline Gorman Subjective Diplopia Score >0) Week 15
4. Proportion of participants with a CAS score of zero or one in the study eye at Week 15
5. Exploratory Endpoints in Australia, Canada, China, EU, UK and US in the Pivotal portion of the Study (THRIVE): • Proptosis Responder Rate in the study eye as measured by exophthalmometer) at Week 24 (12 weeks post fifth infusion), Week 36 (24 weeks post fifth infusion) and Week 52
6. Proptosis Responder Rate in the fellow eye (i.e., reduction of proptosis of ≥ 2 mm from baseline as measured by exophthalmometer) at Weeks 15, 24, 36 and 52
7. Durability of Proptosis Response in the study eye at Weeks 24, 36 and 52
8. Time to First Proptosis Response in the study eye
9. Clinical Activity Responder Rate in the study eye at Weeks 24, 36 and 52
10. Clinical Activity Responder Rate in the fellow eye at Weeks 15, 24, 36 and 52
11. Change from baseline in CAS in the study eye at Weeks 24, 36 and 52
12. Change from baseline in CAS in the fellow eye at Weeks 15, 24, 36 and 52
13. Time to first CAS Response in the study eye
14. Overall Responder Rate in the study eye at Weeks 24, 36 and 52
15. Overall Responder Rate in the fellow eye at Weeks 15, 24, 36 and 52
16. Time to First Overall Response in the study eye
17. Diplopia Resolution Rate at Weeks 24, 36 and 52
18. Proportion of participants with a CAS score of zero or one in the study eye at Weeks 24, 36 and 52
19. Proportion of participants with a CAS score of zero or one in the fellow eye at Weeks 15, 24, 36 and 52
20. Proptosis Response Rate in the study eye as measured by magnetic resonance imaging [MRI] or Computed Tomography [CT – where allowed by local health authorities] at Weeks 15, 24, 36 and 52
21. Change from Baseline in the following parameters at Weeks 15, 24, 36 and 52: - Proptosis in the study eye by MRI (or CT – where allowed by local health authorities)
22. - Extraocular muscles in the study eye as determined by MRI (or CT – where allowed by local health authorities)
23. - Orbital fat in the study eye as measured by MRI (or CT – where allowed by local health authorities)
24. - Manual measurement of lid retraction in the study eye
25. - Graves' Orbitopathy-Quality of Life (GO-QoL) combined score
26. - GO-QoL activity subscale
27. - GO-QoL appearance subscale - EQ-5D-5L QoL questionnaire
28. - Visual Acuity (VA); - Gorman Subjective Displopia Score
29. • VRDN-001, IGF-1 and ADA at various time points pre- and post- infusions as described in Appendix 1C.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Viridian Therapeutics Inc.

Sponsor organisation

Viridian Therapeutics Inc.

Address

221 Crescent Street Suite 103a

City

Waltham

Postcode

02453-3425

Country

United States

Scientific contact point

Organisation

Viridian Therapeutics S.à.r.l.

Contact name

Chief Medical Officer

Public contact point

Organisation

Viridian Therapeutics S.à.r.l.

Contact name

Chief Medical Officer

Third parties 8

Locations

4 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications