Aerie brushes off dry eye trial failure

Endpoints, schmendpoints.

Mid-stage clinical trial endpoints are unnecessary, according to Aerie Pharmaceuticals. The company reported a miss yesterday on the primary goals of Comet-1, assessing its dry eye contender AR-15512.

As such, the company is steaming ahead into phase 3 on the strength of positive glimmers on secondary endpoints. But the 28% downturn in its stock so far today suggests that shareholders are sceptical of the bullish rhetoric.

Several products are approved for dry eye, but many patients remain unsatisfied with their treatment. AR-15512 is an eyedrop formulation of a TRPM8 agonist, intended to produce a cooling sensation in the eye and stimulate tear production. It is the only such agent in clinical development for dry eye or any other indication, according to Evaluate Pharma. Comet-1 compared two doses, 0.0014% and 0.003% twice a day, versus vehicle control.

Mid-stage dry eye trials, especially those testing projects with novel mechanisms, often include a raft of endpoints in the hope that something sticks; this can then be used as the primary outcome for phase 3. 

Comet-1’s missed co-primary endpoints were a measure of eye discomfort, and one of tear production, assessed after 28 days’ treatment. Aerie claimed hits on several other outcomes, including ocular discomfort and tear production at different time points. On ocular discomfort at 84 days it claimed a p value of 0.028, though this can only be regarded as exploratory since the primary analysis failed.

The group declared further hits on measures including eye dryness and conjunctival redness, but again all the p values it gave were nominal only. Aerie did not specify the exact doses at which these alleged hits were achieved, though it did say the higher dose was the more effective.

Crashing to Earth: Aerie's Comet-1 data
Endpoint Time point Nominal p value
Ocular discomfort Day 28 Miss*
Tear production** Day 28 Miss*
Ocular discomfort Day 84 0.028
Tear production** Day 1 and day 14 0.0001
Sande (Symptom Assessment iN Dry Eye) Days 14, 28 and 84 Between 0.025 and 0.0005
Eye dryness Day 84 0.03
Conjunctival redness Day 84 0.022
Ocular surface staining Day 14 0.012
Ocular surface staining Day 84 0.037
*Co-primary endpoint. **Based on unanaesthetised Schirmer’s score. Source: company release. 

It is this dose that will go forward into phase 3 in mid-2022, assuming that the end of phase 2 meeting Aerie expects to have with the FDA in the first quarter is positive. The company plans two three-month phase 3 trials as well as a separate safety study. The phase 3 endpoints are yet to be decided.

A clear path

As to whether the project does in fact have “a clear path toward approval”, as Aerie’s chief executive, Vicente Anido, claimed, at least some members of the sellside seem to have bought in. Stifel analysts wrote that other industry watchers were “myopically focused” on the missed primary endpoint, claiming that it had "no bearing” on the asset’s future prospects.

Stifel pointed out that Novartis’s Xiidra, the only dry eye therapy approved for signs and symptoms, needed three pivotal studies since the trials showed variable results. Abbvie’s Restasis and Sun Pharmaceutical’s Cequa do not have as broad a label as Xiidra, only being approved to increase tears.

AR-15512 could be filed in the US in 2024, if there are no more setbacks. But several events are likely to occur in the dry eye space in the meantime. 

An approval decision on Oyster Point Pharma’s nasal formulation of Chantix is due in October, and phase 3 data on Aldeyra’s Reproxalap and Bausch/Novaliq’s Nov-03 are imminent (Bausch boosted ahead of eye spin-off, April 14, 2021). If AR-15512 does, despite everything, make it all the way, the market could be much more crowded than it is now. 

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