Aldeyra Therapeutics‘ Phase III dry eye disease (DED) trial for reproxalap has experts anticipating success because of strong previous results and a change in the primary endpoint. However, the dry eye chamber design evoked mixed views on how the FDA would evaluate it, as well as its relevance to real-world data.

Experts were impressed by topline sign and symptom data from the run-in cohort of the ongoing Phase III TRANQUILITY trial and expected the study to meet its sign endpoint. Previously, the Phase III TRANQUILITY trial had a primary endpoint of levels of tear reactive aldehyde species (RASP), but this was dropped in favour of a sign outcome of ocular redness after run-in cohort data was released on 7 January. This more typical endpoint has increased the likelihood of approval, experts said.

If the trial had targeted both signs and symptoms as primary endpoints, this would have raised the bar for approval, a regulatory expert said. The trial’s use of a dry eye chamber also caused one expert to doubt its approval prospects, while others had various perspectives about its impact on reproxalap’s chances.

Reproxalap’s testing through a dry eye chamber divided experts in terms of its true applicability. Some argued it may not replicate real-world conditions, while others thought it would provide a more adverse controlled test environment than presented by typical conditions.

Topline results from TRANQUILITY are expected in 2H, according to a February company press release. The company also announced plans to initiate a second Phase III TRANQUILITY-2 trial, with results also expected in 2H. One analyst report is confident about reproxalap because the run-in cohort data showed a faster onset of symptom improvement than competitors Novartis’ Xiidra (lifitegrast) and AbbVie’s Restasis (ciclosporin), which take two weeks and three months, respectively.

GlobalData forecasts reproxalap to have sales of $495m in 2027. Aldeyra, which has a market cap of $520.13m, did not respond to a request for comment.

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Positive trial reflective of run-in data, endpoint switch

While experts agreed it was difficult to definitively draw conclusions from a small run-in cohort (n=23), they expected a positive trial because of strong results and the drug’s mechanism of action.

The run-in cohort data demonstrated Schirmer tests scores directionally in favour of reproxalap over the vehicle, with the agent being superior in improvement in Visual Analog Scale dryness score (p = 0.003), ocular discomfort 4-symptom questionnaire (OD4SQ) dryness score (p = 0.006), OD4SQ grittiness score (p = 0.006) and OD4SQ discomfort score (p = 0.003), according to a 7 January media release. Based on this initial data, which showed an improvement in Schirmer’s score and symptom improvement, the trial is likely to be positive, said Dr Kyung Chul Yoon, professor of ophthalmology, Chonnam National University Hospital, Gwangju, South Korea. For Dr John Sheppard, president, Virginia Eye Consultant, Norfolk, the initial Phase III data positively addressed sign markers as well as a broad range of DED symptoms.

In addition to the strong data, the drug’s MOA as a RASP inhibitor also supports a positive Phase III, Yoon and Sheppard said. RASPs are pre-inflammation molecules known to break down tear production, meaning if the drug inhibits these, then the disease process gets interrupted, said Dr Joseph Tauber, ophthalmologist Tauber Centre of Excellence, Kansas City, Missouri.

As of 21 December 2020, tear RASP was the study’s primary endpoint on, but this was changed to a secondary endpoint to confirm its mechanism, according to a 4 February company media release. As of 14 April, the trial was updated on with the new primary endpoint of ocular redness. In addition to tear RASP, Schirmer’s test and dry eye disease symptoms will be secondary endpoints. Aldeyra said tear RASP levels from its run-in cohort were reduced after a single dose of reproxalap.

The change would have happened because Aldeyra was not seeing the desired results or because the primary endpoint was not clinically relevant, said Angela Mallery, regulatory strategist at the CRO NAMSA, Toledo, Ohio. Aldeyra has also increased its patient population from 220 to 320, which is sensible as the trial would need to be powered differently to account for this change of endpoint, said Alan Boyd, CEO of his eponymous healthcare regulatory consulting firm in Crewe, UK.

Aldeyra needs to prove reproxalap has limited adverse events for it to be clinically useful, said Dr William Whitson, ophthalmologist, Whitson Vision, Avon, Indiana. In the run-in cohort data, reproxalap was found to be well tolerated with no adverse findings on safety, according to a 7 January press release.

Approval a contested outcome with chamber impact

The FDA wants to see a DED therapy demonstrate an improvement in both the signs and symptoms of DED, but it has demonstrated it is willing to accept only a sign enhancement in the past, said Sheppard, noting the approval of Sun Pharma’s (NSE:SUNPHARMA) Cequa (cyclosporine) and Restasis as examples. DED symptoms will now be secondary endpoints in the TRANQUILITY trial, he added. He gave the drug an 80% chance of approval based on the earlier broad range of symptom improvements and its mechanism.

Adopting a more traditional endpoint like ocular redness would improve reproxalap’s approval chances, agreed Mallery. However, for the label to cover a broad range of symptoms, in line with the run-in cohort, it will need to demonstrate statistically significant data on symptoms as well, she said.

In terms of the trial design and approval, the dry eye chamber made all environmental conditions equal, which allows for a clearer assessment by regulators, said Mallery and Boyd. The chamber is an efficacious way of inducing dry eye symptoms, explained Whitson. Ordinarily, patients experience DED very differently and there are massive variables in conditions; the chamber limits these variables, leading to more clinically useful data, Whitson said.

On the other hand, the trial’s dry eye chamber design is not associated with any greater chance of approval, noted Sheppard. In the trial, patients are subject to 90 minutes in an adverse, controlled environment with minimal humidity, high airflow and forced visual tasking. The dry eye chamber was used in Xiidra’s Phase III OPUS-1 trial as a screening tool for responsive patients but was later dropped from the following Phase III OPUS-2 study, said OPUS-1 and OPUS-2 investigator Sheppard.

Aldeyra’s dry eye chamber has not resulted in an approved product and is not representative of how dry eye disease is experienced by patients in the real world, said Tauber. This very proprietary model does not truly represent the disease, he said, adding the most important thing is relieving a patient’s symptoms every day, rather than just in this controlled setting.

However, as the chamber produces difficult conditions above what patients would experience normally in a controlled situation, the expectation is the treatment would work even better in the real-world setting, countered Mallery and Boyd.

Sean Rai-Roche is a Healthcare Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.