Biopharmaceutical Report I
Aldeyra Therapeutics’ (NASDAQ:ALDX) focus on seasonal allergies in its Phase III study of reproxalap in allergic conjunctivitis has three experts unsure on renewed success prospects given its Phase IIb primary endpoint miss in perennial and seasonal allergy. They noted the Phase IIb data did not give sufficient information on why the perennial allergy group performed poorer than the seasonal group or by how much, while a general lack of studies in literature about this novel mechanism prompts caution.
However, an expert who had been an investigator in reproxalap’s trials in other indications said that success in those trials, along with the understanding that seasonal allergies are less likely to be at risk of a placebo effect, could tip reproxalap over into a successful Phase III.
Reproxalap is in a 300-patient Phase III trial, ALLEVIATE (NCT03494504), with results expected in 2H18, according to the company.
Reproxalap had positive Phase IIb data in dry eye (NCT03404115) released on 26 September, and is in an ongoing Phase III trial for noninfectious uveitis (NCT03131154).
That said, experts agreed reproxalap has shown to be well-tolerated in the Phase IIb data and in other indications. However, some experts inquired about its long-term rebound safety, which will require longer follow-up data.
Analysts say despite the Phase II miss, reproxalap provided evidence of effectiveness in allergic conjunctivitis and, pending success in pivotal trials, could be approved before other indications under investigation. They said a successful Phase III could prompt a second Phase III trial for a possible 2020 NDA filing. Analysts noted there is an unmet need for durable treatment options in allergic conjunctivitis, and as reproxalap has shown signs of better durability than current options, it could achieve USD 1bn in sales by 2030. Aldeyra has a market cap of USD 288m.
Aldeyra did not respond for comment.
Mixed opinions on Phase III success
While it would seem that excluding the perennial allergic conjunctivitis group from the Phase III study could tip the results toward success, the failed Phase IIb release provides insufficient subgroup data to rule on success in the seasonal allergic group, Dr John Dart, consultant ophthalmologist, Moorfields Eye Hospital, London and Dr Stephen Foster, president of Massachusetts Eye Research and Surgery Institution said.
The Phase IIb (NCT03012165) data, announced in a June 2017 press release, saw that in 154 patients with allergic conjunctivitis, reproxalap did not meet the primary endpoint of having a statistically significant difference in patients with a one-point improvement in the allergen challenge at one hour versus placebo. However, the difference in improvement it did achieve was statistically significant (p<0.03), and in the seasonal allergy subgroup, the improvement was 0.8 (p=0.02).
There is a general lack of clinical studies beyond Aldeyra’s trials to prove the trap theory, and the Phase IIb data did not seem to offer a definitive proof of concept
As the seasonal allergy group already missed its primary endpoint in Phase IIb, it would require some close reexamination of trial design to gear reproxalap for success in a modified Phase III, Foster said.
The Phase III primary endpoint is ocular itching using the same scale as in the Phase IIb, but the efficacy assessment period is day -21 through day 1, while the Phase IIb assessed days 3 through 15. Experts said it was not clear what the changing of the timeframe could mean for the Phase III outcome, but noted the drug has shown a rapid onset of action, one hour post treatment.
The June release also stated patients with seasonal allergies demonstrated a 37% improvement in ocular itching at 20 minutes posttreatment, which would have corresponded with a one-point improvement. Those patients also exhibited 55% and 65% itching improvement at 30 and 60 minutes post treatment, respectively.
The seasonal allergy group data indeed looks promising, and the >37% improvements are clinically significant, said Dr John Sheppard, professor of ophthalmology, Eastern Virginia Medical School, Norfolk and Dr Neel Desai, ophthalmologist, Eye Institute of West Florida.
Yet, Foster said the magnitude of benefit was welcome but not overwhelmingly good, and a 50% improvement might have been more encouraging.
There is a general lack of clinical studies beyond Aldeyra’s trials to prove the trap theory, and the Phase IIb data did not seem to offer a definitive proof of concept (POC) of its benefit in seasonal allergic conjunctivitis—since it was designed to look at both seasonal and perennial—thus making Phase III predictions difficult, Dart said. He noted preclinical studies linking aldehydes to ocular inflammation, but aldehydes have been more extensively studied in autoimmune disease.
Sheppard agreed that understanding of reproxalap’s MOA—trapping aldehydes thought to mediate downstream inflammatory processes—is nascent, but consecutive successful trials where lowered aldehyde levels have led to improved inflammatory symptoms lend optimism for allergic conjunctivitis, even if Phase IIb was a miss, he said.
As an investigator in the dry eye and uveitis trials, Sheppard said he has seen a clear benefit between the reduction of aldehyde levels and improvement of inflammatory symptoms. He acknowledged that the etiologies of allergic conjunctivitis might differ from dry eye syndrome or uveitis, but noted the obtained POC in the other indications as promising for ALLEVIATE’s success.
It could be possible that focusing only on seasonal allergy patients could prompt better success versus placebo, as seasonal allergy symptoms tend to be more intense and less likely improved with placebo vs perennial allergy patients with lower intensity symptoms, Sheppard said. Desai and Foster said there is no clear-cut difference in symptom severity and it varies greatly.
Robust safety signals, but rebound effect unclear
The Phase IIb data showed reproxalap to be welltolerated, with no concerning adverse events, according to the June 2017 release.
Reproxalap was also shown to be welltolerated in the Phase IIb (NCT03404115) dry eye trial, with adverse events mostly mild, and this is encouraging for its safety in the allergic conjunctivitis trial, Sheppard said. He noted that side effects were mostly eye irritation, and agreed that reproxalap stings more than saline, but is of low concern.
However, the Phase IIb data is unable to show longer-term and chronic-use safety, especially with regards to a rebound effect, Desai said. Some of the current drugs used for allergic conjunctivitis, including ocular vasoconstrictors, carry the risk of a rebound effect when used chronically, he said. If such a risk was present, it would mean an increasing amount of agent would be needed to be effective, and physicians might advise for cautious use when prescribing to avoid triggering the rebound effect, Foster and Desai said.
Dart said as reproxalap is targeting the aldehydes itself rather than receptors, rebound might be less of a concern, but noted the impact of longterm aldehyde trapping is not yet known.
Reporter, New York
Shuan has a Bachelors degree in linguistics and journalism from New York University. He had previously worked in various trade publications covering technology, precious metals and diamond trade and more. Shuan has worked as a breaking news reporter covering Asia and an international reporter in the Czech Republic. He’s also fluent in Mandarin and proficient in Japanese.