Developing drugs to treat autism spectrum disorder, or ASD, is notoriously difficult, largely because scientists have yet to pin down the mechanisms behind the social and learning deficits that characterize it. But one company, Beyond Air, is betting on a new culprit: neural nitric oxide.
The biotech announced June 15 that it has acquired the exclusive commercialization rights to several compounds that partially inhibit the enzyme neuronal nitric oxide synthase, or nNOS, which increases production of nitric oxide in the brain. The drugs were developed by Hebrew University in Israel, which published a paper in May detailing how the mechanism of action could curb physiological markers and behavioral symptoms of autism in mouse models.
“We believe that the path to move into human clinical studies is very clear given where we are today,” Beyond Air CEO Steve Lisi said in a conference call with investors on June 15. He noted later that it’s too soon to say what degree of impairment the individuals in the trial will have, nor where the limits might be regarding how early patients would need to be treated for the therapy to be effective.
“I think the sky’s the limit until we learn more in human studies,” Lisi said.
Beyond Air did not disclose exactly how much it paid for the assets but the CEO said during the call that the company expects to spend $4 million to get one of the compounds through additional preclinical research and to a first-in-human clinical trial. Payouts will be made to the university on the completion of preclinical, clinical and sales milestones; the company will also pay low single-digit royalties on net sales.
Nitric oxide is at the heart of Beyond Air’s business. The company’s primary products are nitric oxide delivery systems; its LungFit PH and LungFit Pro platforms are used in hospitals to deliver nitric oxide to infants with pulmonary hypertension and adults with lung infections, respectively. A third system, LungFit GO, is designed to treat patients with lung infections at home.
Beyond Air also has a nitric oxide-based solid tumor therapy under development by its subsidiary Beyond Cancer. It expects results from a phase 1 trial on the drug in the second half of 2023, according to the company’s website.
Given that the company is centered on nitric oxide, what’s the basis for its foray into neuro? Put simply, neural nitric oxide is critical to blood flow and signaling in the brain. But it can have detrimental effects, too: Some evidence points to its involvement in neurodegeneration, as it may react with molecules called reactive oxygen species to form compounds that ultimately drive protein accumulation.
“While perhaps more intuitive for pulmonary applications such as pulmonary hypertension, the well-established understanding of nitric oxide’s function as a neurotransmitter makes it unsurprising to discover its involvement in neurologic disorders such as [autism],” Chief Medical Officer Jeff Myers, M.D., Ph.D., said during the investor call. High levels of nitric oxide and nitrogen dioxide have been implicated in other neurologic diseases such as Alzheimer’s, he noted.
The Hebrew University lab of Haitham Amal, Ph.D., which developed the assets licensed by Beyond Air, described in their latest publication how they found a similar connection in autism. Compared to typical mice, mouse models of ASD had more nitric oxide production in their brains, which appeared to stunt the growth of dendritic spines on neurons. These spines—tiny protrusions from dendrites, the part of the neuron that receives electrical signals from other neurons—are vital to communication between brain cells.
The researchers were also able to use nitric oxide to induce autism-like changes in the brains of mice without ASD. Ten days of administering a chemical that upregulates neural nitric oxide production altered neurotransmitter levels and decreased dendritic spine density to the point that the neurons of the wildtype mice looked like the ones in the ASD models. The animals began to act like the autism mouse models, too, losing interest in exploring unfamiliar objects and in interacting with mice they hadn’t met before.
“Collectively, these data suggest that high levels of NO may potentially induce ASD-like behaviors in [normal] mice,” the researchers wrote in their paper.
Those aberrations could be reversed with an nNOS inhibitor called 7-nitroindazole (7-NI). The scientists gave 700 mice across two different mouse models of autism daily injections of the drug. After seven days, 7-NI restored the density of dendritic spines and lowered levels of 3-nitrotyrosine, a marker of NO production, inflammation and cell damage. Neurons in the treated mice also formed more synapses, or connections, with other cells.
In addition, there were clear changes in the animals’ behavior. They now sought out new objects and could later recognize them, and were more willing to interact with unfamiliar mice. They also spent more time in open areas of a maze, a sign of diminished anxiety. The treatment appeared to have no toxicity or impact on normal behavior.
The compound Beyond Air plans to commercialize is a follow-on version of 7-NI that the company claims has superior deliverability, Myers said during the call, which will be delivered via a weekly shot. The company anticipates that it will have the first data from human studies in 2025. It may not go beyond those studies, however; instead, it may seek out partnerships, out-licensing, or some “other strategic opportunity at the appropriate time,” according to a slide from the conference call presentation.
If the company were to succeed at getting the drug to work in humans, it would be the first. There are no FDA-approved drugs to treat ASD, though there’s been no shortage of effort to develop one—and no shortage of failures. Roche’s neuropeptide nasal spray balovaptan was awarded breakthrough status for the treatment of autism by the FDA in 2018, only to be removed from the company’s pipeline in 2020 after ultimately failing to improve social cognition and behavior in patients.
Servier and Neurochlore’s investigation of the blood pressure drug bumetanide met a similar fate the following year after two disappointing phase 3 clinical trials. Sangamo and Finch have been forced to abandon their autism programs in recent years too.
But the hunt continues, with a variety of mechanisms of action in play. Axial Therapeutics’ gut-focused small molecule is currently in phase 2 clinical trials, while Swedish biotech Stalica’s pair of precision medicines are in phase 1. And preclinical research abounds: Tau proteins, histamine receptors and the microbiome are all therapeutic contenders.
Whether or not the compounds work for autism, the company may find another fit for them in other neurological indications. Though any additional applications are “theoretical” at this point, Lisi said during the conference call, the Amal lab and others have found evidence for nitric oxide’s involvement in Alzheimer’s disease.
“There is a history of nitric oxide in a number of neurologic conditions. It’s been implicated in Alzheimer’s for a long time,” Myers added. “I think there’s probably a spectrum of neurologic diseases that might be affected by this.”