Veligrotug

All content on Eyewiki is protected by copyright law and the Terms of Service. This content may not be reproduced, copied, or put into any artificial intelligence program, including large language and generative AI models, without permission from the Academy.

Article initiated by:

Jainam Shah, Sachin Pathuri, Bruce Becker, MD, Andrew Go Lee, MD

All contributors:

Jainam Shah, Sachin Pathuri, Andrew Go Lee, MD, Bruce Becker, MD

Assigned editor:

Review:

Assigned status Update Pending

.

add
Contributing Editors:	add

Veligrotug-vvze (Lumvoa) is a humanized monoclonal antibody targeting the insulin-like growth factor-1 receptor (IGF-1R) that was approved by the U.S. Food and Drug Administration (FDA) in June 2026 for the treatment of thyroid eye disease (TED). It is the second FDA-approved IGF-1R antagonist for TED and the first approved with pivotal Phase 3 evidence supporting both active and chronic disease at the time of initial approval. This article reviews the pharmacology, clinical trial evidence, safety profile, and current role of veligrotug in the management of TED.

Background

Thyroid eye disease (TED) is an autoimmune orbitopathy most commonly associated with Graves disease, with a pooled prevalence of approximately 40% among patients with Graves disease. TED pathogenesis centers on autoimmune activation of orbital fibroblasts through two receptors: the thyrotropin receptor (TSH-R) and the insulin-like growth factor-1 receptor (IGF-1R). IGF-1R is overexpressed and hyperfunctional on orbital fibroblasts and lymphocytes in TED, where it regulates fibroblast proliferation, adipogenesis, and lymphocyte activation via MAPK/ERK and PI3K/AKT signaling. Current evidence supports functional crosstalk between TSH-R and IGF-1R as an important contributor to TED pathogenesis, although the precise roles of receptor-specific autoantibodies and direct IGF-1R activation remain incompletely defined. IGF-1R antagonism can suppress TSH-R-mediated hyaluronic acid production and orbital fibroblast proliferation.

Veligrotug (VRDN-001) is a humanized IgG1 monoclonal antibody developed by Viridian Therapeutics that functions as a full antagonist of IGF-1R, in contrast to teprotumumab, which is a partial antagonist. By inhibiting IGF-1R signaling and its functional interaction with TSH-R, veligrotug is intended to interrupt downstream inflammatory and tissue-remodeling pathways contributing to TED.

FDA-Approved Indication

Veligrotug-vvze (brand name Lumvoa) received U.S. Food and Drug Administration (FDA) approval on June 26, 2026, for the treatment of TED, with labeling covering both active and chronic disease regardless of duration. This makes veligrotug the second FDA-approved IGF-1R antagonist for TED after teprotumumab (Tepezza, approved 2020), and the first agent with pivotal Phase 3 data supporting use in chronic as well as active disease at initial approval. Veligrotug received FDA Breakthrough Therapy Designation prior to approval.

Administration and Dosing

Per the FDA-approved label, the recommended dosage of veligrotug is 10 mg/kg administered by intravenous infusion every 3 weeks, for a total of 5 infusions. The first infusion is administered over 45 minutes; if well tolerated, subsequent infusions may be shortened to a minimum of 30 minutes, and if not well tolerated, the infusion time remains at 45 minutes. Veligrotug must not be administered as an intravenous push or bolus, and should not be infused concomitantly with other agents.

	Veligrotug	Teprotumumab
Dose	10 mg/kg	10 mg/kg (1st), then 20 mg/kg
Schedule	Every 3 weeks	Every 3 weeks
Total infusions	5	8
Total course length	12 weeks	~21 weeks
Infusion time	45 min (1st); ≥30 min (subsequent, if tolerated)	60–90 min

Veligrotug is supplied as a 500 mg/10 mL (50 mg/mL) single-dose vial and is diluted into a 250 mL 0.9% sodium chloride infusion bag prior to administration; the diluted solution is stable for 4 hours at room temperature or up to 72 hours refrigerated, protected from light.

Adverse Effects and Contraindications

Contraindications: The FDA prescribing information lists no contraindications to veligrotug.

Warnings and Precautions:

Warning	Detail
Infusion reactions	Reported in ~9% of patients; transient BP increase, fever, chills, headache, fatigue. Usually mild-moderate; manage with corticosteroids, antihistamines, antipyretics, or a slower infusion rate.
Inflammatory bowel disease (IBD)	May exacerbate pre-existing IBD; IBD has also been reported in patients without a prior diagnosis. Monitor for signs and symptoms and discontinue veligrotug if IBD is suspected.
Hyperglycemia	Occurred in 12% of patients (half with pre-existing diabetes/impaired glucose tolerance). Assess glucose before infusion and monitor throughout treatment.
Hearing impairment, including hearing loss	May be severe and in some cases permanent. Assess hearing before, during, and after treatment; weigh benefit-risk with the patient.

The safety of Veligrotug was evaluated through two randomized, double-masked, placebo-controlled clinical studies (THRIVE [NCT05176639] and THRIVE-2 [NCT06021054]) consisting of 113 patients with active thyroid eye disease (75 received veligrotug and 38 received placebo) and 188 patients with chronic TED (125 received veligrotug and 63 received placebo). Patients were treated with veligrotug 10 mg/kg or placebo given as an intravenous infusion every 3 weeks for a total of 5 infusions. The majority of patients completed 5 infusions (94% of veligrotug patients and 99% of placebo patients).

The most common adverse reactions (≥5%) that occurred at greater incidence in the veligrotug group than in the control group during the treatment period of THRIVE and THRIVE-2 are summarized in the table below. In addition, menstrual disorders (amenorrhea, menstruation irregular, dysmenorrhea, menstruation delayed, intermenstrual bleeding, and menstrual disorder) were reported in approximately 29% (24/82) of menstruating women treated with veligrotug compared to 6% (2/33) of patients treated with placebo in the clinical trials. Treatment-emergent anti-drug antibodies were detected in 20% (58/290) of evaluable patients, with no apparent correlation to pharmacokinetics, safety, or efficacy.

Adverse Reaction	Veligrotug	Placebo
Muscle spasms	40%	7%
Headache	17%	14%
Hearing impairment	15%	6%
Hyperglycemia	13%	5%
Fatigue	13%	11%
Diarrhea	11%	7%
Ear discomfort	10%	3%
Infusion-related reaction	9%	2%
Nausea	8%	6%
Nasopharyngitis	7%	1%
Blood creatine phosphokinase increased	6%	1%
Dry skin	6%	2%
Hypertension	6%	5%

Use in specific populations: Veligrotug may cause fetal harm (IGF-1R signaling is required for normal embryonic and placental development) and should not be used in pregnancy; effective contraception is required prior to initiation, during treatment, and for 6 months after the final dose. Safety and effectiveness have not been established in pediatric patients. No overall differences in safety or effectiveness were observed in patients ≥65 years of age (12% of the pooled trial population).

Clinical Evidence in Thyroid Eye Disease

Clinical Activity Score (CAS): CAS is a 7-point score (Mourits criteria) used to grade inflammatory activity in TED, with one point assigned for each of the following present at examination: spontaneous retrobulbar pain, pain on eye movement, eyelid erythema, eyelid swelling, conjunctival redness, chemosis, and swelling of the caruncle or plica. A CAS ≥3 is generally used to define clinically active disease and was a Study 1 baseline requirement in THRIVE; THRIVE-2 (chronic TED) permitted any CAS from 0 to 7 at baseline, since chronic disease need not be inflammatorily active. Both trials are referred to in the FDA label as Study 1 (active TED) and Study 2 (chronic TED). The trial names THRIVE and THRIVE-2 are used in the published/presented literature.

THRIVE Baseline Characteristics:

THRIVE was a global, multicenter, randomized, double-masked, placebo-controlled phase 3 trial requiring onset ≤15 months, proptosis ≥3 mm, and CAS ≥3, with patients randomized 2:1 to veligrotug or placebo.

Characteristic	Veligrotug	Placebo
N	75	38
Age, mean ± SD	48.9 ± 12.4	49.1 ± 12.5
Female	75%	82%
White	68%	50%
Black	5%	8%
Asian	4%	16%
Unknown or other	23%	26%
Current tobacco use	17%	16%
Baseline Hertel proptosis, mean ± SD	23.2 ± 3.1 mm	23.2 ± 3.3 mm
MRI/CT, mean ± SD	22.5 ± 2.9 mm	22.4 ± 3.0 mm
CAS at baseline, mean ± SD	4.5 ± 1.0	4.8 ± 1.1
Diplopia at baseline	67% (50)	68% (26)

Efficacy at Week 15:

Endpoint	Veligrotug	Placebo	Difference (95% CI), P-value
Proptosis responder rate (Hertel)	70%	5%	65% (52-78), P < 0.01
Mean proptosis change	-2.9 mm	-0.5 mm	-2.4 mm (-3.0 to -1.8), P < 0.01
Diplopia responder rate	59%	20%	39.2% (18.8-59.6), P < 0.01
Diplopia resolution rate	49%	12%	37.7% (18.9-56.6), P < 0.01

Durability at Week 52 (among week-15 responders):

Outcome	Veligotrug
Maintained proptosis response	71%
Maintained diplopia resolution	50%

Treatment completion was high in both arms (96% veligrotug, 100% placebo). The onset of effect is notable clinically, as proptosis improvement was measurable by week 3, following a single infusion, in both active and chronic TED.Given that medical therapy for TED has historically required months to produce measurable benefit, an effect apparent after a single infusion may represent a clinically meaningful advantage, particularly for patients with progressive disease.

The quality-of-life data provide additional context for the clinical significance of the anatomic findings. The mean 17.3-point improvement on the GO-QOL questionnaire exceeded twice the pre-specified 8-point threshold considered clinically meaningful, indicating that the observed reductions in proptosis and diplopia corresponded to a patient-reported improvement in visual function and appearance rather than a statistically significant but clinically marginal change.

THRIVE-2 (Chronic TED)

THRIVE-2 required onset >15 months, proptosis ≥3 mm, and any CAS (0–7), with patients randomized 2:1 to veligrotug or placebo. As of July 2026, THRIVE-2 has not been published as a full peer-reviewed trial manuscript; the most complete data available are from a conference abstract and the FDA label. The week 15 efficacy results presented below are derived from the conference abstract, whereas the FDA prescribing information provides additional regulatory results, including durability outcomes through week 52.

Baseline characteristics:

Characteristic	Veligrotug	Placebo
N	125	63
Baseline Hertel proptosis, mean	24.3 mm	23.8 mm
Diplopia at baseline	52% (65)	59% (37)
CAS ≥3 at baseline	57%	52%

Efficacy at Week 15:

Endpoint	Veligrotug	Placebo	P-value
Proptosis responder rate (Hertel)	56%	8%	P < 0.0001
Proptosis responder rate (MRI/CT)	48%	3%	P < 0.0001
Mean proptosis change	-2.34 mm	-0.46 mm	P < 0.0001
Overall responder rate	56%	7%	P < 0.0001
Diplopia responder rate	56%	25%	P = 0.0006
Diplopia resolution rate	32%	14%	P = 0.0152
CAS 0 or 1 achieved (among patients with baseline CAS ≥3)	54%	24%	P = 0.0060 (nominal/exploratory)

Treatment completion was 94%, and safety was generally consistent with THRIVE: the most common adverse event was muscle spasms (36% vs 6%), hearing impairment occurred in 13% versus 3%, and serious adverse events occurred in 2% versus 3% of patients (one treatment-related event in each arm). THRIVE-2 is described by its authors as the first randomized controlled trial of an IGF-1R antagonist in chronic TED to demonstrate statistically significant improvement in both proptosis and diplopia.According to the FDA prescribing information, 57% of week-15 proptosis responders maintained their response at week 52, and 80% of patients who achieved diplopia resolution at week 15 maintained resolution at week 52.

Cross-Trial Observations:

Key exclusion criteria in both studies included prior orbital irradiation, prior use of anti-IGF-1R monoclonal antibodies, clinically significant hearing impairment (by history or baseline audiometry), and biopsy-proven or clinically evident inflammatory bowel disease; prior orbital decompression surgery was permitted only if limited to bone.

The numerically lower proptosis responder rate in THRIVE-2 (56%) than in THRIVE (70%) may be compatible with the greater fibrotic and less inflammatory character often attributed to chronic TED. However, the trials were not designed for direct comparison, and differences in eligibility criteria, baseline populations, and analysis methods may also have contributed.

Notably, durability of diplopia resolution at week 52 was numerically higher in THRIVE-2 (80%) than in THRIVE (50%), which is contrary to the expectation that chronic disease would demonstrate less durable response. This finding may reflect the small sample size of the diplopia subgroups in both trials rather than a genuine difference in durability by disease chronicity, and should be interpreted with caution pending larger, adequately powered follow-up data.

Currently, a significant limitation for clinical decision-making is the absence of a head-to-head trial comparing veligrotug and teprotumumab. In the absence of such data, comparisons of relative efficacy, relative risk of hearing impairment, or patient selection between the two agents are based on cross-trial comparison rather than direct evidence, and should be interpreted accordingly. Veligrotug's principal differentiating feature relative to teprotumumab at present is a shorter infusion course (5 infusions over 12 weeks versus 8 infusions over approximately 21 weeks), rather than a demonstrated superiority in efficacy or safety at the moment.

Summary of Current Evidence

Across both pivotal trials, veligrotug produced statistically significant improvements in proptosis and diplopia by week 15, with improvement in proptosis observed as early as week 3. Among week-15 responders, a proportion maintained proptosis response or diplopia resolution through week 52 with a generally consistent safety profile across the active and chronic TED trials. Effect sizes were larger in active TED (THRIVE) than in chronic TED (THRIVE-2), consistent with the biological expectation that chronic, more fibrotic disease is less responsive to anti-inflammatory and anti-proliferative intervention than active, inflammation-predominant disease. Remaining questions include long-term safety and durability beyond 52 weeks, real-world adverse event rates (including hearing impairment) outside the trial setting, and the drug's comparative place in therapy relative to teprotumumab in the absence of head-to-head trial data.

Comparison to Existing and Emerging TED Therapies

Teprotumumab

Teprotumumab (Tepezza), a fully human monoclonal IGF-1R antibody, was the first FDA-approved therapy for TED (2020). In the pivotal Phase 3 OPTIC trial, 83% of patients treated with teprotumumab achieved a proptosis response, defined as a reduction of at least 2 mm without corresponding deterioration in the fellow eye, compared with 10% of patients receiving placebo at week 24. Teprotumumab also produced significant improvements in diplopia, inflammatory activity, and disease-specific quality of life. The OPTIC-X extension study demonstrated sustained efficacy, with an 89% proptosis response among patients who crossed over from placebo and additional benefit observed in patients retreated after disease flare. A subsequent RCT confirmed efficacy in chronic/low-activity TED. The FDA indication was subsequently expanded to include TED regardless of disease activity or duration.

Veligrotug-vvze was approved by the FDA in June 2026 and is now the second FDA-approved therapy for TED. No head-to-head randomized trial comparing veligrotug with teprotumumab has been published. Cross-trial comparisons should be interpreted cautiously because the trials differed in treatment schedules, eligibility criteria, disease activity and duration, outcome timing, and placebo response rates. Both agents are associated with class-related adverse effects that include hearing impairment, hyperglycemia, and muscle spasms.

Other Systemic Immunomodulatory Therapies

Although most of these therapies do not have a specific regulatory indication for TED, several are used in selected patients with active, moderate-to-severe disease, particularly when standard treatment is contraindicated, poorly tolerated, or ineffective:

Agent	Mechanism	Key Information
Intravenous methylprednisolone	Glucocorticoid with broad anti-inflammatory and immunosuppressive effects	A guideline-supported treatment for active, moderate-to-severe TED. EUGOGO recommends intravenous glucocorticoids in combination with mycophenolate sodium as first-line therapy and identifies a cumulative methylprednisolone dose of 4.5 g administered over 12 weekly infusions as the standard intermediate-dose regimen. Intravenous glucocorticoids primarily improve inflammatory activity; a matching-adjusted indirect comparison demonstrated smaller proptosis responses and no significant diplopia benefit compared with teprotumumab.
Mycophenolate sodium or mycophenolate mofetil	Inhibits inosine monophosphate dehydrogenase, thereby suppressing T- and B-lymphocyte proliferation	In the MINGO randomized trial, adding mycophenolate sodium to intravenous methylprednisolone did not significantly improve the prespecified response endpoint at week 12, but a post hoc analysis showed a higher overall response rate at week 24. Based on the totality of evidence, EUGOGO recommends mycophenolate sodium with intravenous methylprednisolone as first-line treatment for active, moderate-to-severe TED.
Rituximab	Anti-CD20 monoclonal antibody causing B-cell depletion	Randomized trials have produced conflicting findings, and the available evidence remains inconsistent. Rituximab may be considered as second-line therapy in selected patients with recent-onset, active, moderate-to-severe TED that is resistant to intravenous glucocorticoids, provided dysthyroid optic neuropathy is not present or imminent.
Tocilizumab	Monoclonal antibody against the interleukin-6 receptor	In a randomized placebo-controlled trial of 32 patients with corticosteroid-resistant, active, moderate-to-severe TED, 93.3% of patients receiving tocilizumab versus 58.8% receiving placebo achieved a reduction of at least 2 points in CAS at week 16. Tocilizumab is considered a second-line option for glucocorticoid-resistant active TED, although evidence is based principally on a small randomized trial and observational studies.

Emerging Agents

Several agents targeting IGF-1R, TSHR, or FcRn are under investigation for TED. Developmental status and efficacy data should be interpreted cautiously when results are available only from early-phase studies or sponsor-reported topline analyses.

Agent	Class	Developmental Status	Key Information
Lonigutamab	Subcutaneous anti-IGF-1R monoclonal antibody	Phase 1/2 study completed	In a small proof-of-concept cohort, 4 of 6 patients receiving 40 mg every 3 weeks achieved a proptosis response at week 6. Additional dose cohorts also showed preliminary improvements in proptosis and CAS, but the limited sample size and early-phase design preclude definitive efficacy or safety conclusions.
Linsitinib	Oral small-molecule inhibitor of IGF-1R and the insulin receptor	Phase 2b LIDS trial completed; described by the sponsor as a Phase 2b/3 trial	In sponsor-reported topline results, the selected linsitinib regimen produced a week-24 proptosis response in 52% of patients with active, moderate-to-severe TED and met the trial’s primary endpoint. These findings are based on sponsor-reported topline results, as a peer-reviewed publication is not yet available.
Elegrobart, formerly VRDN-003	Half-life-extended subcutaneous anti-IGF-1R monoclonal antibody	Two pivotal Phase 3 trials completed; BLA submission planned for 2027	Sponsor-reported topline results from REVEAL-1 showed week-24 proptosis response rates of 54% with every-4-week dosing and 63% with every-8-week dosing, compared with 18% for placebo, in active TED. In REVEAL-2, conducted in chronic TED, corresponding response rates were 50%, 54%, and 15%. A biologics license application is planned for 2027; peer-reviewed Phase 3 publications are not yet available.
K1-70	Human TSHR-blocking monoclonal autoantibody	Phase 1 completed	In an open-label, single-dose Phase 1 study involving 18 patients with Graves disease, including patients with Graves orbitopathy, K1-70 was generally well tolerated and produced the expected pharmacodynamic inhibition of TSHR activity. Because the study was small, uncontrolled, and designed primarily to assess safety, efficacy in TED remains unproven at this time.
Batoclimab	Subcutaneous monoclonal antibody against the neonatal Fc receptor, reducing circulating IgG	Phase 3 TED program unsuccessful	Early proof-of-concept studies demonstrated reductions in circulating IgG, TSHR autoantibodies, and inflammatory disease activity. However, two subsequent Phase 3 studies in active, moderate-to-severe TED failed to meet their primary endpoint of at least a 2-mm proptosis response at week 24. Batoclimab should therefore be described as an unsuccessful investigational program rather than an active Phase 3 candidate.