Aldeyra's tears of joy fail to move investors
Aldeyra gets a win in its second pivotal dry eye trial of reproxalap, but only after some serious tinkering.
If at first you don’t succeed, keep tinkering. Aldeyra got a pivotal win today with reproxalap on the signs of dry eye disease at the second time of asking – but only after changing the primary endpoint analysis of the Tranquility-2 study, not once but twice.
The trial showed a benefit on both the Schirmer test, which measures tear production, and a Schirmer responder analysis. Assuming the FDA is on board with Aldeyra’s data package, reproxalap could be heading to market.
But after surging over 20% in premarket trading, Aldeyra was up just 4% this morning, suggesting that investors do not share the company’s confidence.
For approval in dry eye the FDA requires a project to show a benefit on both the signs and symptoms of the disorder in at least two clinical trials apiece. Regarding symptoms, Aldeyra’s strategy has long been clear: the group plans to use part one of the phase 3 Renew trial, as well as the phase 2 Formulation study, which found a benefit on ocular dryness.
On signs, the situation is less straightforward. In December, the first pivotal trial, Tranquility, failed to hit its primary endpoint of ocular redness; however, it did show a benefit on the Schirmer test, a secondary endpoint (Aldeyra needs more Tranquility, December 21, 2021). In response to this, Aldeyra changed Tranquility-2 to evaluate ocular redness and the Schirmer test as co-primaries; it had previously had ocular redness as the sole primary endpoint.
Last month, the company tinkered again, ditching ocular redness from the primary outcome analysis and focusing fully on Schirmer.
This move looks to have paid off: a day after dosing, patients receiving reproxalap had a statistically significant increase in Schirmer test scores versus those on vehicle. Those in the reproxalap group were also significantly more likely to be responders, defined as at least a 10mm increase in tear production.
Aldeyra execs admitted during a conference call today that the study did not meet secondary endpoints including ocular redness, making its decision look even more fortunate. Still, the company also hopes to get ocular redness on its label, based on a phase 2 dry eye chamber trial and a post-hoc analysis of Tranquility that used computer automated grading – which looks like a bit of a stretch.
Aldeyra hopes to have a pre-NDA meeting with the FDA in the third quarter, and is also awaiting data from a dry eye chamber crossover trial before filing. The company previously said it had hoped to submit reproxalap in mid-2022.
Aldeyra’s chances of getting a drug to market look much better than they did at the end of last year, but the really hard part could begin after approval.
True, existing dry eye drugs, such Abbvie’s Restasis and Novartis’s Xiidra, leave a lot to be desired, but there could be competition coming from the newly spun off Bausch & Lomb, whose NOV03 has shown a more consistent benefit on signs and symptoms of dry eye.
Meanwhile, Kala Pharmaceuticals could provide a cautionary tale in dry eye disease. That group, which had to carry out three pivotal trials to get Eysuvis approved, recently sold rights to the drug to Alcon, and is currently worth around $30m.
|Selected novel agents in phase 3 development for dry eye disease|
|NOV03||Bausch & Lomb/Novaliq||Lipid regulator||Gobi hit Apr 2021; Mojave hit Sep 2021; US filing planned H1 2022|
|Reproxalap ophthalmic solution||Aldeyra Therapeutics||Aldehyde inhibitor||Tranquility failed; Tranquility-2 hit|
|Tanfanercept (HL036)||Hanall Biopharma/Daewoong Pharmaceutical/Harbor Biomed||TNFa inhibitor||Velos-2 failed in Jan 2020 but showed some benefits; Velos-3 completes Jul 2022|
|ALY688 Ophthalmic Solution||Allysta Pharmaceuticals||Adiponectin receptor agonist||Ph2/3 Oasis-1 recruiting|
|AR-15512||Aerie Pharmaceuticals||TRPM8 agonist||Ph2b Comet-1 failed, ph3 Comet-2 completes Mar 2023|
|Tivanisiran||Pharmamar||RNAi eye drop inhibiting TRPV-1||Fydes completes Oct 2023|
|BRM421||Brim Biotechnology||Regenerative peptide therapy||Ph2/3 data reported Jun 2021; ph3 to start 2022|
|RGN-259||Regentree (Regenerx Biopharmaceuticals/HLB Therapeutics joint venture)||Thymosin β-4 receptor agonist||Ph3 Arise-3 study failed in Mar 2021, company had FDA pre-BLA meeting Feb 2022, appears more clinical data required|
|Source: Evaluate Pharma & clinicaltrials.gov.|