2017-05-06 06:17:58 UTC
Inside Novartis’s push to produce the first legitimate anti-aging drug
One afternoon in the early 1980s, Suren Sehgal brought a strange package home from work and stashed it in his family’s freezer. Wedged beside the ice cream, it was wrapped in heavy plastic and marked, “DON’T EAT!” Inside were several small glass vials containing a white paste—all that remained of a rare bacterium that today is the foundation of the most promising anti-aging drug in decades. Sehgal had been studying it since 1972, when he’d first isolated it in a soil sample at Ayerst Laboratories, a pharmaceutical company in Montreal.
A Canadian medical expedition had collected the soil from beneath one of the mysterious stone heads on Easter Island, a speck in the middle of the Pacific Ocean. In the dirt, Sehgal had discovered Streptomyces hygroscopicus, a bacterium that secreted a potent antifungal compound. This intrigued him; he thought perhaps it could be made into a cream for athlete’s foot or other fungal conditions. He purified the stuff and named it rapamycin, after Easter Island’s native name, Rapa Nui.
It soon proved its potential. When a neighbor’s wife developed a stubborn fungal skin condition, Sehgal mixed up a rapamycin ointment for her. “It was probably illegal,” says his son Ajai Sehgal, but the infection cleared up quickly. Suren, a biochemist who’d immigrated to Canada from a tiny village in what’s now Pakistan, became convinced that he’d stumbled upon something special. Before he could develop it any further, however, Ayerst abruptly closed its Montreal lab, and his bosses ordered all “nonviable” compounds destroyed—including the rapamycin. Sehgal couldn’t bring himself to do it and instead squirreled a few vials of Streptomyces hygroscopicus into his freezer at home. Most of the staff was fired, but Sehgal was transferred to the company’s lab in Princeton, N.J. The plastic package made the move packed in dry ice.
When Wyeth, the global health-care company based in Pennsylvania, bought Ayerst in 1987, Sehgal persuaded his bosses to let him resume his work on the rare bacterium. Sehgal found that, besides its antifungal properties, rapamycin also suppressed the immune system. It tamps down the body’s natural reaction to a new kidney or other organ. Eventually, in 1999, the U.S. Food and Drug Administration approved rapamycin as a drug for transplant patients. Sehgal died a few years after the FDA approval, too soon to see his brainchild save the lives of thousands of transplant patients and go on to make Wyeth hundreds of millions of dollars.
In the years since, rapamycin has been adapted for numerous uses. Like penicillin, it’s a biological agent, so it can’t be patented, although derivatives of it can. It’s now used routinely as a coating on cardiac stents to prevent scarring and blocking. Derivatives of rapamycin have been approved for use against certain kidney, lung, and breast cancers. That may be just the beginning. Over the past decade, it’s shown promise as a drug that not only can extend life by delaying the onset of aging-related diseases such as cancer, heart disease, and Alzheimer’s disease, but also postpone the effects of normal aging. With an eye toward changing the way millions grow older, Novartis, the $260 billion Swiss pharmaceutical giant, has begun taking the first steps to position a version of rapamycin as the first true anti-aging drug.
Pharmacological history is full of substances that have been purported to delay aging or lengthen life span, from resveratrol (the “red wine pill”) in the 2000s to testicular implants in the 1920s, all the way back to medieval alchemists (gold was thought to possess anti-aging properties). Until rapamycin came along, however, nothing has actually worked in rigorously designed clinical studies.
“People have shown that rapamycin extends life span again and again and again,” says Matt Kaeberlein, a scientist at the University of Washington and a leading researcher in the biology of aging. So far it’s demonstrated it can lengthen the lives of mice, not men, but what’s particularly exciting is how it did so, Kaeberlein says. The drug appears to delay “age-related decline in multiple different organ systems, which is something we would expect if we were fundamentally slowing the aging process.”
The promise of rapamycin, he and others contend, is to treat aging as a contributing factor to the chronic diseases that kill people later in life, the way we now lower cholesterol to prevent heart disease. “I view it as the ultimate preventive medicine,” says Kaeberlein, who’s leading a rapamycin study on dogs.
Not everyone is convinced. “There are no interventions that have been documented to slow, stop, or reverse aging in humans,” says S. Jay Olshansky, a professor of public health at the University of Illinois at Chicago and a leading critic of purported life-extending supplements and treatments. “The batting average is zero.”
Olshansky welcomes the advent of therapies like rapamycin, but he doesn’t think we know enough yet: “My caution is always no, no, no: Let science do what it does and evaluate these interventions for safety and efficacy first,” he says. Such admonitions are justified. And yet the enthusiasm of scientists such as Kaeberlein is hard to resist. “We have the potential to delay the onset of all of these diseases at the same time by understanding and intervening in the molecular processes that drive aging,” he says. “We now know that that is possible.”
Rapamycin works at a fundamental level of cell biology. In the early 1990s, scientists at Novartis’s predecessor, Sandoz, discovered that a rapamycin molecule inhibits a key cellular pathway regulating growth and metabolism. This pathway was eventually dubbed “target of rapamycin,” or TOR, and it’s found in everything from yeast to humans (it’s known as mTOR in mammals).
MTOR is like the circuit breaker in a factory: When it’s activated, the cell grows and divides, consuming nutrients and producing proteins. When mTOR is turned down, the “factory” switches into more of a conservation mode, as the cell cleans house and recycles old proteins via a process called autophagy. One reason caloric restriction extends life span in animals, researchers believe, is because it slows down this mTOR pathway and cranks up autophagy. Rapamycin does the same thing, only without the gnawing hunger.
“Really what rapamycin is doing is tapping into the body’s systems for dealing with reduced nutrition,” says Brian Kennedy, chief executive officer of the Buck Institute for Research on Aging in Novato, Calif. “We’ve evolved over billions of years to be really good at that. When things are good, we’re going to grow and make babies. And when things are not so good, we go into a more stress-resistant mode, so we survive until the next hunt. And it just so happens that stress resistance is good for aging.”
One of the most passionate advocates for rapamycin as an anti-aging drug is a Russian scientist named Mikhail Blagosklonny, who now works at the Roswell Park Cancer Institute in Buffalo. A native of St. Petersburg, he was working on cancer treatments in the early 2000s when he realized the same qualities that made rapamycin effective at slowing tumor growth might also help it slow the aging process. He became so convinced of rapamycin’s potential, and its safety, that he tried it himself. “Some people ask me, is it dangerous to take rapamycin?” Blagosklonny says. “It’s more dangerous to not take rapamycin than to overeat, smoke, and drive without belt, taken together.”
Many colleagues have regarded his advocacy as a bit over-the-top. When Blagosklonny submitted papers to major journals making these arguments, they were brutally rejected. “Sometimes, the reviewers would call me names,” he says. That started to change in 2009, when a large National Institutes of Health-funded study established that rapamycin and its derivatives helped mice live longer. The NIH scientists started mice on the drug at 20 months, or late middle age in mouse terms (mice typically live two to three years). Male mice on rapamycin lived 9 percent longer. The females’ life span was extended by 14 percent. This is roughly the equivalent of giving 60-year-old women a pill that would enable them to see their 95th birthday.
There’s one catch: Rapamycin suppresses the immune system (that’s why it’s effective with transplants). That fact, many scientists and physicians believe, is its Achilles’ heel as a drug to treat aging. Giving such a drug to older patients, whose immune systems are often already diminished, would make them vulnerable to life-threatening infections, defeating the purpose.
For believers like Blagosklonny, a breakthrough came on Christmas Eve 2014. That’s when a paper appeared in Science Translational Medicine, part of the Science family of journals. According to the study, conducted with volunteers in Australia and New Zealand, a derivative of rapamycin called everolimus had been shown to improve the immune response of elderly patients when administered in limited doses. It wasn’t the sort of thing that makes CNN, but in the world of scientists who work on human aging, it was big. “A watershed,” says Nir Barzilai, director of aging research at New York’s Albert Einstein College of Medicine.
For the first time, the study showed, rapamycin appeared to enhance aspects of the immune response, boosting the efficacy of a flu vaccination in the study population, who were all 65 or older. “It seems to modulate the immune response, not suppress it,” says Barzilai. “It’s very exciting.” The study was noteworthy also because Novartis paid for it. For the most part, Big Pharma has shied away from aging, which conventional wisdom had deemed to be a quackery-ridden money pit. In 2008, GlaxoSmithKline paid $720 million to buy Sirtris Pharmaceuticals, a biotech startup founded by Harvard professor David Sinclair that was developing drugs based on resveratrol, the antifungal compound found in the skins of red-wine grapes. Resveratrol received a tremendous amount of coverage in the media, including 60 Minutes, the New York Times, and Barbara Walters. It was said to be responsible for the “French paradox”: Although the French eat fatty foods, they remain healthy. A highly publicized Nature paper had shown that mice on a high-fat diet had lived longer with resveratrol. After the study appeared, sales of resveratrol supplements rocketed from basically zero to about $100 million a year. But the drugs all flopped in human trials, and in 2013 GSK shuttered its Sirtris division and fired all but a handful of staffers.
“The difference between rapamycin and resveratrol is that rapamycin really works as advertised and resveratrol doesn’t,” says the University of Washington’s Kaeberlein. “If you look at the data, you have to agree.” Kaeberlein, who went to graduate school with Sinclair at MIT, was an early critic of resveratrol, which he points out has actually never extended life span or otherwise slowed aging in normal mice—it appeared to work only in fat mice.
Rapamycin has been found to reduce age-related bone loss, reverse cardiac aging, and reduce chronic inflammation in mice. It’s even been shown to reverse Alzheimer’s disease in them. The Novartis study was the first to examine rapamycin’s effect on aging-related parameters in healthy older people. “It’s a landmark study,” says the Buck Institute’s Kennedy. “It’s the kind of study we need more of.”
That doesn’t mean everyone should be asking their doctors for a prescription to an mTOR inhibitor. Critics say it may be too risky for people who are otherwise fine. Besides the possibility of immune suppression, rapamycin’s side effects can include canker sores and impaired wound healing. “Rapamycin works on pathways that are too fundamental to normal cellular function to be used as a drug in healthy people until we have much more safety data,” says Valter Longo, a professor at the University of Southern California who discovered key pathways related to TOR. He points out that periodic fasting also shuts down the same pathways, without the side effects.
The Novartis researchers tried to get around the immune-suppression side effect by giving the drug in very low doses and for a defined period. They found its benefits persisted long after the drug was discontinued. But the Novartis study is far from definitive on the issue, says Janko Nikolich-Zugich, chair of the department of immunobiology at the University of Arizona and co-director of the Arizona Center on Aging.
The study measured response to a vaccine, not to an infectious agent. Nikolich-Zugich fears that rapamycin would stop immune cells from multiplying quickly enough to fight off an army of invading pathogens. “I don’t think this in any way, shape, or form settles concerns about what mTOR inhibitors would do in cases of infection,” he says.
An innovative clinical trial set to begin in March may resolve some of these issues. Kaeberlein and his University of Washington colleague Daniel Promislow plan to test the drug in small doses in middle-aged pet dogs. Rather than looking at life span, which would take years, they will look for signs that the drug is affecting key aging-related parameters, such as arterial stiffness and cardiac function. If successful, rapamycin and its derivatives could end up as the first anti-aging drug—for dogs. Kaeberlein wouldn’t mind: “I love my dogs,” he says. “If there’s anything we can do to make them live longer, healthier lives, we have to do it. I feel like I personally have to do this.”
In September, Novartis Chairman Joerg Reinhardt announced the company’s new commitment to aging research. “Over the long term, one could argue that R&D productivity has relentlessly declined,” he said in a keynote at a drug development conference in Basel, Switzerland. Aging represents a fertile field of discovery: Identifying the pathways and proteins associated with aging could yield promising drug targets, he said. By tweaking the right pathways, researchers could theoretically prevent a host of age-related diseases. Novartis is not alone in this: Chicago-based AbbVie has complete a $750 million partnership with Calico, an aging-research venture founded by Google.
Rapamycin isn’t the only widely used medication that’s turning out to have possible anti-aging properties. Millions of diabetics take a drug called metformin, which has been around for decades. Like rapamycin, metformin extended the life of federally funded mice in a clinical trial. And there is evidence that it might do the same for people. Diabetes typically shaves about five years off a person’s life. But a large retrospective analysis found that diabetics on metformin had a 15 percent lower mortality rate than nondiabetic patients in the same doctors’ offices. “To me that suggests that it’s actually targeting aging,” says Kennedy.
The problem they’ll all face, though, is the same one that tripped up GSK: The FDA is unlikely to approve any drug intended to “treat” aging, because aging is not considered a disease. Another obstacle is the high safety standards required of any drug that would, in effect, be used to treat healthy people. “It would have to have fewer side effects than aspirin,” says Randy Strong, a pharmacologist at the University of Texas Health Science Center at San Antonio who worked on the 2009 NIH study.
This may explain why Novartis is taking an incremental approach with therapies aimed at specific conditions, says Dr. Mark Fishman, head of the Novartis Institutes for BioMedical Research in Cambridge, Mass., and a member of the company’s executive committee. “We’re therapeutically oriented, rather than looking for the pill that will make everybody live to 120,” he says.
The company’s age-related drug pipeline includes a novel drug aimed at treating heart failure, which the European Union recently fast-tracked for approval. Another, bimagrumab, is meant to reverse muscle loss. Designated a “breakthrough” by the FDA, it’s soon set to enter Phase III clinical trials for a rare condition called sporadic inclusion body myositis, but it could have wider application for muscle wasting and frailty in older people. “This whole frailty business is right up there with Alzheimer’s as a cause of incapacitation and sadness for the elderly,” Fishman says.
Also in the works are a drug that could potentially restore cartilage in aging joints and, most interestingly, a radical gene therapy meant to reverse the loss of “hair cells” in the ear canal that are crucial for good hearing, but which are knocked out by things like antibiotics, chemotherapy, and “too much Lady Gaga,” Fishman says.
He’s cautious about the anti-aging potential of rapamycin, a derivative of which the company sells under the Afinitor brand name for cancer treatments and as Zortress for transplants, with 2012 sales of just more than $1 billion. (Pfizer, which purchased Wyeth in 2009, also sells a version under the brand name Rapamune.) “I remain skeptical that there will be one magic bullet,” Fishman says, “but [the 2014 study] is a good proof-of-concept, and it’s provocative enough that we’ll at least think of how and whether we should proceed.”
Blagosklonny isn’t so measured or patient. In his view, rapamycin has been approved for use for more than 15 years, with no serious problems reported. “I have read all papers about side effects,” he says, “and there are less side effects than with aspirin.” When he took it, he says, it made him feel better, “like with exercising.”
Novartis strongly discourages such off-label use. In an e-mail, spokeswoman Mariellen Gallagher wrote: “It is far too early to tell whether low-dose rapamycin will lengthen human life span. A favorable risk/benefit ratio needs to be demonstrated in clinic trials to be sure that mTOR inhibitors such as rapamycin have acceptable safety and efficacy in aging-related conditions in humans.”
In any case, one imagines Sehgal would be proud. After he was diagnosed with cancer in 1998, his son Ajai says, Sehgal began taking rapamycin, too—despite the drug not having been approved for anything yet. He had a hunch that it might help slow the spread of his cancer, which had metastasized to his liver and other organs. His doctors gave him two years to live, but he survived for much longer, as the tumors appeared to go dormant. The only side effect he suffered from was canker sores, a relatively small price to pay.
But in 2003, after five years, Sehgal, age 70, decided to stop taking the drug. Otherwise, he told his wife, he’d never know whether it was really holding back his cancer. The tumors came back quickly, and he died within months, says Ajai. “On his deathbed, he said to me, ‘The stupidest thing I’ve ever done is stop taking the drug.’ ”