Saying it’s too early to gauge the potential economic benefit of a marketed COVID-19 therapy for his firm, Aldeyra Therapeutics Inc. CEO Todd Brady cited “a strong feeling of altruism” among researchers addressing the crisis, as they turn over discoveries likely to be helpful beyond it. “We're not making strategic changes [at Aldeyra], but I do think we're being nimble and reactive” to the pandemic, he said, which “helps us to accelerate the testing of our compounds in a clinical disease where there is severe inflammation.”
Brady’s remarks came during a conference call with investors after Aldeyra made known its plan to advance heat-shock protein 90 (Hsp90) inhibitor ADX-1612 to clinical investigation against COVID-19, and provided an update on ADX-629, an inhibitor of RASP that’s also a possible treatment for the virus. ADX-1612 has been tested in more than 1,600 subjects as a would-be cancer therapy. Here, “we have seen no evidence of myelosuppression, at least not at the doses we would intend to test clinically with COVID-19,” Brady said. “I don't think that, at the level we would intend to use for COVID-19 treatment, we'll see any down-regulation of the immune system that turns out to be pathologic,” he said.
By way of expression profiling of human cell lines infected with COVID-19, Hsp90 was recently identified as a key pharmaceutical target for viral inhibition. In an in vitro model, blocking the chaperone protein showed a nanomolar potency similar to or greater than that of Foster City, Calif.-based Gilead Sciences Inc.’s remdesivir, Aldeyra said. An IND submission for ADX-1612 is expected in the third quarter of this year, pending FDA feedback. Hsp90 is widely implicated in viral disease, the company said, pointing to a summer 2017 paper in Archives of Virology.
For the oral ADX-629 prospect, Aldeyra has completed pre-IND discussions with the FDA and expects to submit an application next month. Severe COVID-19 is characterized by cytokine release syndrome, which may lead to respiratory compromise, which often means the patient goes on a ventilator. In a preclinical model of cytokine storm, ADX-629 showed broad-based reductions across a variety of TH1, TH2 and TH17 inflammatory cytokines, while up-regulating interleukin-10.
Both candidates “are broadly applicable,” Brady said, calling Aldeyra “systems-based. That is, we focus on drugs that have the potential to modulate numerous targets and thus would apply to many different diseases.” Eudario, the ongoing phase II investigator-sponsored trial of ADX-1612 in ovarian cancer, is expected to complete enrollment in June 2020. Aldeyra previously disclosed that phase IIa studies with ADX-629 in psoriasis and atopic asthma should kick off in the second half of this year.
As for COVID-19, the two compounds represent “very different treatment approaches that have roles in different parts of the treatment paradigm,” Brady said. “ADX-1612, like other antivirals such as remdesivir, would be used for severe infection. These are patients that have intravenous lines and where severe respiratory compromise and other morbidities of COVID-19 are already apparent. ADX-629 would be administered, theoretically, prior to severe COVID-19.”
Eyeing the road ahead
Brady said he was “not aware of any” other Hsp90 therapies in the works for COVID-19, at least so far. “Viruses generally require the host system for protein synthesis and folding, which means for viruses to replicate nucleic acids, for them to exit the cell via exosomes, for them to lyse the cell for viruses to infect new cells,” he said. “All of that is Hsp90-dependent for many viruses, again, not just for SARS-CoV-2. I wouldn't be surprised if there are other Hsp90 programs” directed at COVID-19 in the future.
In Aldeyra’s May 7 earnings report, the firm said that reproxalap, a first-in-class RASP inhibitor for topical ocular administration, continues to advance toward an NDA filing in allergic conjunctivitis and dry eye disease (DED). The phase III trial called Guard with ADX-2191, a formulation of methotrexate for intravitreal administration, in patients with proliferative vitreoretinopathy remains active, the company said, though enrollment has been delayed due to the pandemic.
Stifel analyst Xiaodong Zhang, during the latest conference call, asked big-picture questions. “You recently announced the company will prioritize the late-stage program in eye disease. Now we have two assets to be tested in COVID-19, which is great, and we also know that you are looking for opportunities in psoriasis, atopic asthma and cancer. How do you balance your current financial and human resources in these different therapeutic areas going forward?” Brady said Aldeyra’s “mission all along in developing systems-based, immune-mediating products has been to advance products in the eye initially and then progress towards retinal disease and systemic disease. The COVID-19 pandemic has accelerated that progression, and that's what you're witnessing at Aldeyra in the last couple of months.”
The scramble by researchers to find COVID-19 therapies could help drug research across the board, in Brady’s view. “All drugs in development for COVID-19, or most drugs, assuming they're not vaccines, are, in a sense, advancing medical science in several different ways,” and most are not specific to COVID-19, he said. “We're allowing for the development of therapeutics that could address future pandemics, if not the second and/or third waves of COVID-19.”
Shares of Aldeyra (NASDAQ:ALDX) closed at $4.37, up 53 cents, or 13.8%.