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The Dream of a Big Dog Life-Extension Drug Is Not So Far Off

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    There’s a well-established inverse relationship between a dog’s size and its expected lifespan. Bernese mountain dogs and Great Danes live just six to eight years, for example, while corgis can live up to 15 years and Chihuahuas up to two decades.

    San Francisco biotech company Loyal wants to close that gap, and is developing an experimental drug to extend the lifespan and improve the quality of life of large and giant dog breeds. Today, the company announced that based on early data, the US Food and Drug Administration has determined that Loyal’s drug has a “reasonable expectation of effectiveness.” The company hasn’t yet shown that its drug actually extends lifespan, but the FDA decision signals the agency’s confidence in Loyal’s approach, and the drug will soon be tested in a bigger trial.

    “Big dog owners want more time with their dogs,” says Loyal CEO Celine Halioua. “It’s really heartbreaking to people that they don’t live that long.” She argues that the wide variety in dog sizes isn’t natural, but a result of selective breeding by humans to create dogs with certain physical traits or that can perform specific tasks. On average, mixed-breed dogs live longer than their purebred counterparts.

    So far, the FDA has not approved any drugs to expand the lifespan of animals—or humans, for that matter. “This is completely novel,” says Linda Rhodes, former CEO of pet biotech company Aratana Therapeutics and a consultant for Loyal. It’s difficult to study life-extension drugs in people, she says, because humans live relatively longer lives than other species. But starting with dogs—and the breeds with the shortest lives—could yield important clues. “The implication for other species, including humans, is pretty profound,” she says.

    Loyal’s experimental drug is an injection designed to be given every three to six months by a veterinarian. The drug is meant to lower levels of a hormone called IGF-1, which is involved in growth and metabolism and has been linked to dog size. Large dogs have a genetic variant that leads to high levels of IGF-1 and small dogs have a different variant that results in lower levels.

    Inhibiting this hormone has been shown to increase lifespan in worms, flies, and rodents. In humans, both very high and very low levels increase mortality risk, while a midrange is associated with the lowest mortality.

    In early studies, Loyal dosed 130 research dogs with its investigational drug. Halioua says the company has shown that it can reduce IGF-1 levels in large dogs to those seen in medium-size dogs. Two dogs had loose stools for a day or two after receiving the injection, but beyond that, Halioua says, no major side effects have been observed.

    To determine the drug’s effect on lifespan, the company is planning a bigger study that will start in 2024 or 2025, and enroll about 1,000 large and giant breed companion dogs that are at least 7 years old. Each will receive either the experimental drug or a placebo.

    Halioua says the company aims to have its drug on the market by 2026. But first, Loyal still has to prove to the FDA—which regulates both human and veterinary medicines—that the injection is safe and that the drug can be reliably manufactured. At that point, the FDA can grant conditional approval, a temporary authorization that lasts five years and allows the drug to be sold by prescription. During that time, Loyal will collect effectiveness data and apply for full approval.

    Loyal is also working on two other drugs: a pill version for large and giant dog breeds, and a pill for older dogs of all breeds.

    Danika Bannasch, a veterinary geneticist at the University of California, Davis, who specializes in canine genetics, says that IGF-1 is only one factor thought to be associated with dog size and longevity. “As for targeting it, I think it’s a bit premature. We know that smaller breed dogs live longer than larger breed dogs, but we don’t know how much of that is due to the influence of IGF-1,” she says.

    In a study published last month, Bannasch and her colleagues identified another possible driver of dog longevity, a gene called ERBB4. Studying more than 300 golden retrievers, they compared the DNA from blood samples of dogs that were still alive at 14 years of age to those that died before age 12. They found that dogs with certain variants of the gene survived longer—on average, 13.5 years compared to 11.6 years. Bannasch cautions that the work was conducted in only one breed and that it’s not known whether these variants are associated with longer life in other types of dogs.

    The ERBB4 gene is the canine version of HER4, a human gene closely related to HER2, which is associated with cancer. Studying the canine gene could have implications for human health. Researchers are also testing new cancer treatments in dogs with the hope that these therapies could help people.

    Giving an experimental drug to healthy dogs is different from treating sick dogs. Bannasch says Loyal’s drug will need to clear a high safety bar for owners to be comfortable giving it to their pets. She also thinks a drug would need to show more than a few months of life extension before people would want to buy it for their dogs. “As a pet owner, I think anything over a year would be great. I suspect people would be really interested in that,” she says.

    Linda Rhodes says that humans owe it to dogs to make up for the genetic misfortunes they’ve inherited due to hundreds of years of breeding. “We’ve bred dogs to have problems because we want them to look or act a certain way,” she says. “It’s our responsibility to figure out how we can help.”


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