Sage’s technical tremor win fails to move

 When a disease has no available treatments for its underlying cause any clinical success is welcome. This holds true for essential tremor and for Sage/Biogen’s Sage-324, whose phase 2 Kinetic study just about cleared the efficacy bar in this disease.

However, investors wondering whether Sage-324 is now derisked are not celebrating just yet, and the stock crept down 2% this morning. Among the concerns are the win’s narrow margin, a high rate of adverse events, and Sage’s admission that, rather than going into phase 3, a new mid-stage study was now needed.

The purpose of such a trial, which on an investor call today Sage termed phase 2b, would be to explore new formulations and different dose frequencies for Sage-324, presumably to counteract side effects. This study is expected to begin later this year.

The biggest worries to emerge from Kinetic are that 68% and 38% of patients on Sage-324 experienced somnolence and dizziness respectively, and though there were no falls 15% had balance disorder. 38% of subjects on active treatment discontinued, while dosing had to be reduced in 62%.

Stifel analysts wrote that such levels of somnolence and dizziness were “simply too high” to differentiate Sage-324, a Gaba A modulator. In other diseases even a high rate of adverse events might not be disastrous, but essential tremor patients tend to be old and afflicted by comorbidities.

Paper thin

There is a silver lining: given the remarkably high dropout rate, for Sage-324 to show significance seems unexpectedly positive. 

Still, Sage's analysis does not appear to comprise the all-comers population of 69, but rather 67 patients in Kinetic. And the success Sage is claiming is paper thin: the p value for Sage-324 versus placebo for Kinetic’s primary efficacy metric, change from baseline in an essential tremor scale at day 29, was 0.049.

Sage had been hoping to see a 30-50% absolute reduction versus placebo, and in the event saw 36%.

The group added a further positive, saying this metric also met the standard for statistical significance at all time points up to day 29. And the effect was apparently most pronounced in 47 patients with the most severe tremor at baseline, though this hints at the possibility of Sage-324 being limited to this population.

Such issues might seem trivial, but for a company valued at $4.5bn they cannot be ignored. Sage does have the endorsement of Biogen, which last November gave it $1.5bn for rights to Sage-324 as well as the more advanced antidepressant asset, zuranolone (Biogen’s Sage advice amounts to $1.5bn, November 30, 2020).

But zuranolone has already failed one depression trial, Mountain. Waterfall, a separate study with a different design and testing a higher zuranolone dose, is due to yield results in the current quarter and represents Sage’s most important catalyst.

The positive topline hit in Kinetic notwithstanding, Sage-324 falls into the same category as zuranolone did after the Mountain readout: needs more work.

Sage's clinical-stage pipeline
Project	Description	Lead indication & trial details	2026e sales ($m)
Marketed
Zulresso	IV Gaba A modulator	Postpartum depression	67
Phase 3
Zuranolone (Sage-217)*	Oral Gaba A modulator	Major depressive disorder, Waterfall data due Q2 2021	2,231
Phase 2
Sage-324*	Oral Gaba A modulator	Essential tremor, ph2 Kinetic study met primary endpoint	132
Sage-718	Oral NMDA modulator	Cognitive impairment linked with Alzheimer's (NCT04602624) & Parkinson's (NCT04476017), completion Jun 2021	38
Phase 1
Sage-904	Oral NMDA modulator	NMDA hypofunction	-
Sage-689	Intramuscular Gaba A modulator	Acute Gaba hypofunction	-
*Partnered with Biogen. Source: Evaluate Pharma & company presentations. https://www.evaluate.com/vantage/articles/news/trial-results/sages-technical-tremor-win-fails-move