“My parents used to always say “aging is beautiful. Look at your grandfather, isn’t it awesome?,” but in my mind I was saying like “This is bullshit…he is decaying and it can’t be awesome at all!” It’s a stupid thing for people to say because, in some sense, they lack the ability to change,” says Nathaniel David. It may sound like hyperbole, but the biochemist as the founder of Unity Biotechnology is indeed working towards making the sunset years a less painful and a pleasant phase of human life. For someone who set up three biotech ventures and tasted success, David terms his current venture as the “coolest biology experiment” he has ever worked on. But the serial entrepreneur’s journey into Unity was more accidental but, nonetheless, an exciting one.
David ventured out pretty young. When he was 18, he founded Syrrx, which was engaged in discovering compounds through protein crystallography. In 2005, Japanese drug major Takeda Pharmaceutical bought the company for $270 million. Three years later, Takeda launched a drug Alogliptin, an orally administered anti-diabetic drug that was developed by Syrrx. Currently, millions of people take the type II diabetes drug everyday. “At the grad school, we had this cool observation that allowed us to crystallise proteins in very small drops. That’s what we did at Syrrx, but it was more of a techie trick,” smiles David. After moving out of Syrxx, David co-founded Achaogen, an antibiotic company which is currently in phase three trials. Around the same time, he set up a Kythera, which created an injectable drug named Kybella for selective destruction of fat cells, primarily responsible for double chin. It was a big moment for David when the company got sold for $2.1 billion to Allergan last year.
But it was in 2011, that David, enroute on a flight, came across a news report in The New York Times that two researchers Jan van Deursen, from the Mayo Clinic in Rochester, and Judith Campisi, of the Buck Institute for Research on Aging, found senescent cells that could hold the secret to aging gracefully. Though exciting, the research was confined to mice but the researchers believed it held the recipe for human longevity as well. During the research, mice that were 12 months old, equivalent to 45 in human years, were injected with a drug that cleared away the marked cells. Mice, whose senescent cells were routinely eradicated, were healthier in their old age and had fewer eyesight problems, less fat, and improved kidney and heart function. But, more importantly, they lived longer. The outcome was good enough for David to get excited. “I sent an e-mail to the folks who wrote the paper and said I need to talk to you right away. So, 72 hours later we met up and agreed to start a company. That was November of 2011,” says David, who incubated Unity at the Buck Institute with Campisi and van Deursen joining as scientific co-founders.
Making sense of senescent
In the ’60s, American anatomist Leonard Hayflick had discovered that human fetal cells divide anywhere between 40 and 60 times before they wear out or turn senescent. Though beneficial early in life, the process, named Hayflick limit, turns problematic in later years. These cells secrete proteins; some of which cause inflammation that trigger the onset of diseases such as osteoarthritis, glaucoma and even cancer. “As you age the cells begin to accumulate in the body. So, my son who is 8 years old has no detected senescent cells, whereas my stepfather who died at the age of 87 was full of these cells,” reveals David. While the first research in 2011 eliminated senescent cells from genetically modified mice, the current research at Unity is being carried out on healthy, regular mice born within seconds of each other from the same mother and also genetically identical. The findings thus far have been encouraging. The mice with senescent cells saw its femur (the longest bone in body) turning brittle suggesting that these senescent cells are dissolving the bone by eating into the cartilage, whereas in the mice injected with the drug, the there was a 25% thickening of the bone wall. “The disease in which you lose cartilage is osteoarthritis and it’s the primary reason why it hurts to be old,” reveals David. Incidentally, David himself suffers from early degenerative spine disease that he got from his father. “However, there is hope, because what we show is if we are clearing the senescent cells, we preserve 41% more of the inter-rotatable disc,” points out David.
Given that the Food and Drug Administration authority does not recognise aging as a disease, developing anti-aging drugs are difficult. “I think it’s better to study disease first and then see if there are side effects that extend life span,” van Deursen was quoted as saying. The big reason behind playing it safe is that studies also suggest that senescent cells can also serve a protective purpose – against cancer – by preventing a cell with damaged DNA from dividing again and, in turn, forming tumors. “This is a super emergency brake and you don’t want to screw with it. We know that because in mice if you delete a gene which is required for the emergency brake to pull, they are born normally but end up with tumours even before they reach the reproductive age. So, it’s dangerous to mess with the brake,” cautions David.
Hence, for now, Unity is focusing on treating age-related diseases and disabilities even as it keeps an eye out for age reversal signs. “It’s an incredible aspiration to have drugs that could prevent or even cure arthritis, heart disease or weak eyesight,” says David. The company will initially develop small-molecule chemicals that can treat osteoarthritis, age-related eye diseases such as macular (central area of the retina) degeneration and glaucoma. By focusing on therapies, localised injections can be delivered and Unity will also get to know the efficacy of the drugs (also called as senolytic medicines). “For osteoarthritis of the knee, we are looking at a drug that will be injected straight into the knee. It will kill the senescent cells of the knee, and if our idea is correct, it will stop hurting pretty fast and create a new cartilage,” explains David. In fact, this October, Unity’s researchers published a paper in the journal, Science, stating that eliminating senescent cells also had the potential to alter the course of atherosclerosis — the build-up of plaque within arteries that could trigger a heart attack or a stroke. “Since we started the research, we’ve observed 21 findings that happen that are good and we have thus far revealed only 9,” says David.
Huge opportunity
An estimated 23 million American adults suffer from chronic kidney disease. Currently, the National Institutes of Health (NIH) spends $655 million on kidney disease research. The US’ Medicare program spends $24 billion a year to take care of over 525,000 patients suffering from end-stage kidney failure. This represents nearly 6% of the total Medicare budget and if one were to include the cost to other payers and out-of-pocket expenses, the total annual bill for treating kidney failure is estimated at over $35 billion. “In mice when we clear senescent cells they don’t get kidney disease. What this means is that the NIH budget for that never gets spent,” says David.
Similarly, Humira, the largest-selling drug in the world from Abbott Laboratories, is used for treating rheumatoid arthritis, which is a smaller disease compared with osteoarthritis, but clocks $15 billion in sales. There are other smaller drug brands for rheumatoid arthritis, which cumulatively sell $30 billion. “Now imagine a drug that is way bigger than the rheumatoid arthritis class. The cool thing about the drugs we are building is that there will be around 7 billion people who will suffer from these diseases. But you could be entering into an era of unprecedented inexpensive drugs because the fixed cost of building and developing a drug instead of being spread over million people is spread over billions,” opines David. Given that estimates predict the number of people above the age of 65 to nearly triple to 1.5 billion by 2050, David is not off the mark.
Mice to men
Initially, Unity managed to raise $11 million since the funding was restricted to only a couple of investors such as Arch Venture Partners, Mayo Clinic, Venrock, WuXi Healthcare Ventures and David putting in some of his own funds. “I put a little bit of my money in, and then a few others. We just did it super cheap,” mentions David.
But the next big step for Unity would be the shift towards human clinical trials and that is a couple of years away. However, the progress made by the company has got the attention of the biggies. In October, the company announced a whopping $116 million Series-B funding, with Amazon founder’s venture capital unit, Bezos Expeditions, joining a group of investors that included Fidelity, Partner Fund Management, Arch Venture Partners, RCH Venture Partners, Baillie Gifford, Venrock, WuXi PharmaTech and Mayo Clinic Ventures.
Trials for the first human doses are scheduled to take place over the next couple of years. “Basically, our plan is to have six drugs into the clinic within six years. Our first drug in humans should be somewhere in the next 12-18 months,” reveals David. With the first set of clinical data likely to be available around 2018-2019, the drug launch will still be a decade long wait. “It could take probably seven to eight years. My previous drug took nine years; Alogliptin took 13 years, Kybela took nine years. So, there’s no reason to think this one will be faster... drugs take a longer time. Our ideas could be wrong most of the time. For example, the cells involved in osteoarthritis may not exactly be the way we thought or the molecule may not work out. So, you need to have multiple clinical trials out of the gate,” cautions David.
The company has built a staff of 30, and is looking to more than double the count to 70 in the next two years as it heads for clinical trials. Though Unity is working on an ambitious project, challenges remain. In the past, the hunt for anti-aging drugs saw start-ups such as Sirtris and Elixir Pharmaceuticals eventually floundering. Bob Nelsen, managing director at Arch Venture Partners, also an investor in Elixir, mentioned in an interview with the MIT Technology Review that the science wasn’t ready 10 years ago but seeing van Deursen’s new data was a “holy crap” moment. “It looks too good to be true, which is always why you take these things forward in a scientific manner. But it reminds me of those very simple ideas that are usually the groundbreaking ones in biology,” Nelsen was quoted as saying.
For now, Unity believes the senolytic drugs can be consumed by individuals to clear senescent cells once every three years in the 30s, every two years in the 40s, once a year in the 50s, and twice a year in the 60s. “Imagine, if your parents announce they want a second career in mathematics or if they want to study anthropology, or play a professional sport? How awesome would that be? And when we look back on this day 50 years from now, we’ll say, oh, that was when you guys first figured out that senescence thing,” sums up David, as he heads home to join his son’s 8th birthday celebrations.
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