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New Oral COVID Drug Saves Life By Reversing Immune Aging – Scientists

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Oral drug treatment against SARS-COV-2 has the potential to cure COVID mutations that are able to bypass vaccine-based immunity.

COVID-19 is especially fatal in older people because their immune systems decline with age, yet there is currently no clinically accessible medicine that addresses this critical risk factor.

An oral drug that reverses various aspects of immunological aging efficiently avoids death in a mouse model of COVID-19, according to a study published today in Nature, suggesting that the prescription could be used to protect the elderly individuals who are most at danger in the pandemic.

In the research, Asapiprant (BGE-175) was found to be effective in protecting aged mice from a deadly dosage of SARS-CoV-2, the virus that causes COVID-19, in a recent study. Ninety percent of the drug-treated mice survived, but all of the untreated control mice died. Treatment with BGE-175 began two days after infection, when the mice were already sick, a timeframe that is comparable to real-life clinical circumstances in which patients are treated only after they become symptomatic.

The study’s animal model closely matched human COVID-19 pathology. The researchers created a mouse-adapted strain of SARS-CoV-2 that induced an illness with many of the same symptoms as human COVID-19: fluid accumulation in the lungs’ air sacs, significant immune cell infiltration of lung tissue, and high levels of pro-inflammatory proteins called cytokines.

BGE-175 is currently being tested in Phase 2 clinical trial to see if it will decrease disease progression and mortality in older COVID-19 patients. BioAge Labs, a California-based biotechnology firm involved in developing drugs that treat human disease and increase lifespan by addressing the molecular causes of aging, is now testing BGE-175 in humans.

“The COVID-19 pandemic has devastated elderly populations around the world,” says Kristen Fortney. “The promising preclinical data in this paper show that BGE-175 almost completely protects aged mice from lethality in a compelling model of human COVID-19. By reversing age-related declines in critical immune mechanisms, BGE-175 could allow older patients to more effectively fight off this disease.”

Reversing immune aging via a dual mechanism

As we age, a biochemical pathway involving the signaling molecule PGD2 becomes more active, impairing immunity in two major ways: First, antigen-presenting cells called dendritic cells migrate less efficiently, slowing the adaptive T-cell and antibody responses. Second, white blood cells called neutrophils infiltrate infected tissues more aggressively, leading to damaging inflammation. Thus, the aged immune system is both slower to respond to new infections and more likely to overreact once it does mount a response. 

BGE-175 inhibits this pathway by blocking the interaction between PGD2 and its receptor, a protein called DP1. BioAge’s AI-based drug discovery platform identified the PGD2-DP1 pathway as a key target for immune aging. In the study described in the Nature paper, BGE-175 increased migration of dendritic cells from the lungs into the lymph nodes, decreased the levels of neutrophils in lung tissue, and dramatically improved overall survival. From the standpoint of PGD2 pathway activity, the drug restored the immune system to a more youthful state.

As with the drug-treated animals, genetically engineered mice that were unable to synthesize PGD2 or lacked DP1 had lower viral loads, exhibited less inflammation and tissue damage, and were less susceptible to death from viral infection, confirming that BGE-175 acts through the PGD2 pathway.

“Our findings clearly show that the therapeutic target of BGE-175 plays a key role in making the aged lung environment conducive for optimal immune function, and thereby counters immune aging,” adds Stanley Perlman. “The drug’s protective effect in mice supports the idea that BGE-175 corrects age-related declines in immunity, providing a strong rationale for testing in older patients who are hospitalized with COVID-19.”

Clinical applications in human beings — for COVID and beyond

A Phase 2 clinical trial, initiated in March 2021, is testing whether BGE-175 can prevent respiratory failure and mortality in older patients hospitalized with COVID-19. Because some cases of COVID-19 are associated with uncontrolled inflammation, which increases disease severity and morbidity, the trial will also measure BGE-175’s effect on levels of inflammatory markers, providing insight into BGE-175’s ability to restore normal regulation of the immune system. Full details of the trial are available at ClinicalTrials.gov, and efficacy data are anticipated in the first half of 2022.  

Antiviral drugs against COVID-19, as well as antibodies raised by vaccines, bind to specific viral proteins to exert their effect, and could therefore could lose efficacy if the SARS-CoV-2 virus continues to mutate — as already observed for the highly contagious omicron variant. 

Because BGE-175 targets the host immune system rather than the invading virus, it has the potential to retain its efficacy against emerging strains that can resist antiviral drugs or evade vaccine-based immunity. Similarly, because its mechanism of action is not specific to COVID-19, the drug could help older patients fight off other viruses. Consistent with this, in the Nature study, BGE-175 prevented lethality from SARS-CoV, the original SARS virus, which like SARS-CoV-2 also causes more severe disease in older animals.

“A properly functioning immune system is our first defense against any virus, and we know that age-associated immune abnormalities place the elderly at a much increased risk for death and complications from COVID-19,” says Eric Verdin. “New therapeutics that target age-associated pathways, especially those involved in immunity, will provide important tools for decreasing the burden of mortality and disability caused by COVID-19, as well as other infections that disproportionately harm the elderly.”

Pending positive results in the Phase 2 trial, BioAge intends to pursue broad clinical applications for BGE-175, including diseases such as influenza and viral pneumonia.

Source: 10.1038/s41586-022-04630-3

Image Credit: Getty

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