Lexington, Mass.-based Aldeyra Therapeutics Inc.’s phase III win in the study called Invigorate with reproxalap for allergic conjunctivitis (AC) restarted speculation about odds of the drug, a small-molecule, immune-modulating covalent inhibitor of reactive aldehyde species (RASP), to treat dry eye disease (DED).
“I do think there is potential read-through,” CEO Todd Brady said, especially with regard to the redness endpoint. A six-week safety study necessary before going to the FDA has not yet started, he told investors during a conference call. “That will require some discussions with the FDA, but I do not think, given the length of the trial, the safety study would impair our guidance of potentially filing NDAs by the end of this year.”
The Invigorate study hit statistical significance for the primary endpoint, ocular itching, at all prespecified time points. Reproxalap also rang the bell on every secondary endpoints, including redness, tearing and total ocular severity score. Findings are consistent with the phase II AC trial and with the run-in cohort of the ongoing phase III experiment called Tranquility in DED. Shares (NASDAQ:ALDX) closed at $14.85, up $3.74, or 34%.
Bearing a randomized, double-masked, vehicle-controlled, two-way crossover design, the allergen-chamber Invigorate effort enrolled 95 patients. Specifically, the primary efficacy endpoint was change from baseline in subject-reported itching score on a 0‑4 point scale over a majority of 11 timepoints from 110 to 210 minutes after allergen chamber entry. The key secondary endpoint was change from baseline in redness on a 0‑4 point scale over the duration of the allergen chamber (about three and a half hours).
Relative to patients treated with vehicle, patients treated with reproxalap reported statistically significant itching score reduction over all 11 prespecified primary endpoint comparisons (p<0.0001 for each) from the period in the allergen chamber. Reproxalap-treated patients demonstrated statistically significant reduction from baseline compared to vehicle (p<0.0001) for the key secondary endpoint of investigator-assessed redness over the duration of the allergen chamber period. Statistical significance was also achieved for the two secondary endpoints of change from baseline in patient-reported tearing score on a 0‑3 point scale over the duration of the allergen chamber (p<0.0001) and change from baseline in total ocular severity score (an 11-point composite of the itching, redness and tearing scores) over the duration of the allergen chamber (p<0.0001).
SVB Leerink analyst Marc Goodman predicted the Invigorate victory in a report about a week ago, saying reproxalap “should work” in AC, based on data produced so far. About half of the AC patient population also has DED, and Goodman said the “quick conclusion is that if the redness endpoint is met in the AC trial, then we should be incrementally more optimistic, as it may support a potentially broad effect in redness improvement for both AC and DED patients.” DED results are due in the second half of this year from the studies known as Tranquility and Tranquility-2.
CEO Brady said Aldeyra will not wait for the DED results to speak with U.S. regulators, a conversation due to happen soon. “The timing of the filing of the NDA in allergy vs. the timing of the filing of the NDA in DED really depends on the conversations with the FDA,” he said. “In fact, our preference is to ask them how they would prefer to receive the NDA. It could be together, such that two labels are negotiated at the same time,” or separately, he said, adding that the company is “more or less agnostic as to how that happens.” Aldeyra will aim to launch in the busy space of DED first, he said, because of “more optimal” pricing possibilities and the firm’s hope of listing on formularies with that indication before AC.
Laidlaw analyst Yale Jen said reproxalap in AC “is likely to be positioned as a first preferred prescribed treatment, after patients might have already used over-the-counter anti-histamine medication and without experiencing durable symptom relief.” He wrote in a report that the drug, with its new RASP mechanism of action, could be a safer and effective alternative to topical corticosteroids. RASP are reactive molecules that covalently bind to cellular biomolecules, disrupting their function and activating pro-inflammatory mediators. They are formed by a variety of processes, including lipid peroxidation, alcohol oxidation, polyamine and glucose metabolism.
The Invigorate outcome represents a home run for the compound, in Jen’s view. “Even with positive expectations from the Street based on the encouraging run-in allergen-chamber test results reported in the second quarter of 2019, today’s readout certainly beats expectations,” he said. “With proper marketing, we believe reproxalap could potentially become a new paradigm [in] treating ocular surface diseases.” BTIG analyst Julian Harrison was on board, too. “Of all registrational signs for DED, redness is arguably the most relevant to the end user, so we view Aldeyra's pivotal development (and by extension, labeling) plan announced earlier this year as the best path forward for this indication,” Harrison wrote in a report.