A chronic disappointment for Viridian

Without full placebo data, it is hard to handicap VRDN-001’s chances in thyroid eye disease.

At first glance the topline six-week data on Viridian’s VRDN-001 in chronic thyroid eye disease, released last night, make the anti-IGF-1R MAb look competitive with Horizon’s Tepezza. But Viridian did not release full placebo results, meaning any cross-trial comparison – always an imperfect metric – comes with even more caveats. 

Tepezza – soon to become the property of Amgen if that company's purchase of Horizon goes through – is the only drug available for TED. Lining the two agents up against each other is a crucial means of judging their likely market reach. Denied the opportunity to do this, Viridian’s investors assumed the news was bad; the company opened down 14% today.

Viridian’s data come from a small phase 1/2 trial, with just six patients in each of the two dose groups. Patients in both cohorts saw reductions in proptosis – the eye bulging that is the most noticeable symptom of the disease – to slightly greater degrees than Tepezza showed in a similar setting at the same time point.

More patients given the lower dose of VRDN-001 than the higher met the criteria for response, which could be considered a red flag. Still, this level of variation is perhaps not surprising in a trial as tiny as this.

A cross-trial non-comparison: Viridian and Horizon in thyroid eye disease
Trial Ph1/2 in chronic TED Ph4 (NCT04583735) in mild, chronic TED
Project and dose VRDN-001 3mg/kg q 3wk VRDN-001 10mg/kg q 3wk VRDN-001 both doses combined Placebo Tepezza* Placebo
N 6 6 12 5 42 20
Mean reduction in proptosis from baseline (measured by exophthalmometry) -1.5mm -1.8mm -1.6mm N/A -1.2mm -0.6mm
Mean reduction in proptosis from baseline (measured by MRI) -2.6mm -1.5mm -2.0mm -0.2mm N/A N/A
Proptosis responder rate
33% 50% 42% N/A 36% 15%
All data at 6wk. *Administered as one infusion of 10mg/kg followed 3wk later with 20mg/kg. Source: company release, SVB, Stifel.

In its investor presentation concerning the data, Viridian admitted that two placebo-treated patients hit the metrics for response as determined by exophthalmometry. These responses could not be confirmed by MRI. 

A spokesperson for the company told Evaluate Vantage via email that the main reason Viridian has not given a placebo figure for the exophthalmometry measurement is because it does not “find it important in light of the MRI data refuting the two placebo proptosis responders”. There is variability with exophthalmometry based on the device itself and how physicians use it, the spokesperson said, and the small trial size amplifies this.

VRDN-001 was generally well tolerated, with no reported serious adverse events, including no cases of hearing impairment or hyperglycaemia, which are concerns with Tepezza.

Viridian itself is sufficiently happy with the data to push into phase 3 in chronic disease. The Thrive-2 trial will begin this quarter and could generate data in 2024.

The quick and the TED

VRDN-001 is already in phase 3 in active disease, and yesterday Viridian said it would amend the ongoing Thrive trial in this setting, abandoning an eight-infusion regimen to focus on a shorter five-dose plan. 60 patients will receive a 10mg/kg dose every three weeks, with the primary endpoint of proptosis responder rate being assessed at 15 weeks. 30 patients will receive placebo.

Stifel analysts wrote that this was the “right move”, pointing out that based on what Tepezza showed, proptosis improvement plateaus after around 18 weeks. The shorter course “may improve the drug’s overall safety profile”, they wrote, and if this regimen has similar efficacy to Tepezza it would be favourable for the drug’s commercial prospects; Tepezza is usually administered for around 20 weeks. 

Topline data from Thrive ought to come in the middle of next year.

Simultaneously Viridian is working on subcutaneous TED therapies, and yesterday said it would use a 300mg/2ml dose in the trials of these three programmes. It expects to select its lead subcutaneous program this year and to push it into a pivotal phase 2/3 trial in the middle of 2024.

Another group is going one better in TED, however. A phase 1/2 study of Sling Therapeutics' oral IGF-1R inhibitor, linsitinib, could report this year. If a pill looks like it might be competitive with Tepezza, subcutaneous forms might lose their lustre.

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