Viridian Therapeutics, Inc. released positive topline data from its global phase 3 THRIVE-2 clinical trial evaluating veligrotug (originally referred to as VRDN-001) for the treatment of chronic thyroid eye disease (TED).
Let’s start with a rundown on veligrotug.
To understand this investigational candidate, you’ll need some background information on its origins—specifically in regards to Viridian’s portfolio, which includes:
- Veligrotug
- VRDN-003
Both of these differentiated candidates are anti-insulin-like factor-1 receptor (IGF-IR) monoclonal antibodies that block cell surface receptor activity and are designed to target antibody and protein engineering for specific diseases and autoimmune disorders (including TED).
What’s the difference between these two?
While both veligrotug and VRDN-003 have the potential to reduce tissue swelling and inflammation associated with TED (among other capabilities), they differ in their dosing and administration routes:
- Veligrotug
- Intravenous (IV) administration
- Dosing: Five 30-minute infusions (3 weeks apart)
- Intravenous (IV) administration
- VRDN-003
- Subcutaneous self-injection
- Dosing: Every 4 or 8 weeks
- Subcutaneous self-injection
Gotcha. Now talk about veligrotrug’s clinical journey thus far.
Backtracking to phase 1/2, Viridian previously reported positive data supporting veligrotug’s:
- Safety and tolerability profile
- Influence in leading to:
- Lower mean proptosis at baseline versus placebo
- A 50% to 72% reduction in mean clinical activity score (CAS) by week 6
- Measurement of inflammatory signs and symptoms of TED based on a scale of 0 to 7
See the 6-week and preliminary findings from that study, reported in January and July 2023, respectively.
And its phase 3 experience?
Our topic of choice (the THRIVE-2 trial) isn’t the first phase 3 trial to evaluate veligrotug; that designation would extend to the global phase 3 THRIVE trial (NCT05176639).
While that study is ongoing, Viridian most recently reported (in September 2024) positive topline results. The highlights of that data can be found here.
Next up: THRIVE-2.
This randomized, double-masked, placebo-controlled global study (NCT06021054) enrolled 188 adult patients diagnosed with chronic TED (participant criteria details here):
- Veligrotug-treated patients (n = 125)
- Placebo-treated patients (n = 63)
The setup: A five-dose treatment arm of VRN-001 10 mg/kg compared to a placebo, with each dose administered 3 weeks apart.
Outcome measures:
- Primary: Proptosis responder rate (PRR) in the study eye, as measured by a reduction of proptosis of ≥2 mm from baseline at 3 weeks following the fifth dose infusion.
- Secondary: See here for those.
At last: the findings.
Big picture: The study met all primary and secondary endpoints at the 15-week primary analysis time points following five veligrotug infusions—with statistically significant responses noted for:
- Proptosis
- CAS
- Diplopia
Let’s get into specifics on those.
- The PRR was 56% for veligrotug patients versus 8% of placebo patients(48% placebo-adjusted, p < 0.0001), with the company reporting: “PRR was statistically significant at all timepoints, including as early as 3 weeks after just one infusion.”
- Proptosis mean reduction was 2.4 mm (from baseline) in veligrotug patients versus 0.4 mm among placebo patients (1.9mm placebo-adjusted, p < 0.0001).
- Response: A total of 56% of veligrotug patients achieved a diplopia response versus 25% of placebo patients (31% placebo-adjusted, p = 0.0006)
- Complete resolution: Achieved by 32% of veligrotug patients versus 14% of placebo patients (1.9mm placebo-adjusted, p < 0.0001).
Notably: A rapid onset was observed at 6 weeks following two infusions for both proptosis mean reduction and diplopia mean resolution.
How did CAS fare?
For patients with a CAS of ≥ 3 at baseline:
- Reduction to 0 or 1: A total of 54% of veligrotug patients and 24% of placebo patients achieved maximal or near-maximal therapeutic effect on CAS (29% placebo-adjusted, p = 0.006)
- Mean reduction from baseline was 2.9 points for veligrotug patients versus 1.3 points for placebo patients (1.6-point placebo-adjusted, p < 0.0001)
Let’s talk overall response.
In all, 56% of veligrotug patients versus 7% of placebo patients (50% placebo-adjusted, p < 0.0001) achieved an overall response.
How this was defined: Achieving a proptosis response without worsening of CAS from baseline (≥ 1 point increase) and without worsening in the fellow eye in either proptosis (2 mm increase) or CAS.
Any adverse events?
Veligrotug was found to be “generally well-tolerated” with a safety profile similar to that observed in its previous clinical trials—including the original THRIVE.
As for adverse events (AEs): All occurrences were considered mild, with 94% of veligrotug patients completing their treatment course.
Further: A low rate of hearing impairment AEs was observed, with the company reporting a “9.6% placebo-adjusted rate of hearing impairment AEs (12.8% incidence in veligrotug patients, compared with 3.2% incidence in placebo patients).”
Let’s break down what this all means.
In speaking on the diplopia results, Viridian President and CEO Steve Mahoney stated: “This is the first product candidate to demonstrate a diplopia response and resolution rate in a global chronic TED phase 3 study.”
Chief Operating Officer Tony Casciano added: “Together with the robust activity in both THRIVE and THRIVE-2, favorable safety profile, and a shorter dosing regimen, we believe (veligrotug) is positioned to become a market leading TED therapeutic.”
Another major “first”: Veligrotug could also potentially become the only approved therapy with data in chronic TED patients included in its labeling.
How exciting! So what’s next for the therapeutic?
With this latest positive data from the phase 3 THRIVE program under its belt, Viridian reported it is still on track to submit a Biologics License Application (BLA) for veligrotug by the second half (H2) of 2025.
As for VRDN-003: The company plans to report topline data from the global phase 3 REVEAL-1 and REVEAL-2 studies in the first half (H1) of 2026—with a potential BLA submission for TED by the end of 2026.