Drug development hopefuls 'wish we could turn back time'

Print 29 April 2016
Marie Powers / BioWorld

We live in an aging world, according to a U.S. Census Bureau report of the same name issued last month. Based on 2015 data, researchers Wan He and Daniel Goodkind of the Census Bureau and Paul Kowal of the World Health Organization's Study on Global Aging and Adult Health amassed some startling statistics. Among them:

• Growth of world's older population will continue to outpace that of the younger population over the next 35 years, with the oldest population in some countries expected to quadruple by 2050.

• Although the world's oldest countries, in population terms, are mostly in Europe today, some Asian and Latin American countries are catching up, and Asia leads the world in the speed of aging and size of the older population.

• Some countries are experiencing simultaneous population aging and population decline.

• Life expectancy at birth exceeds 80 years in 24 countries and, in many of those countries, life expectancy over age 80 is growing rapidly.

A key question posed in the report is whether increasing life expectancy translates into healthier populations, using a measure called healthy life expectancy, or HALE, which takes into account both morbidity and mortality to determine "years lived in less than full health due to disease and/or injury." Results of that analysis were sobering, with life expectancy and HALE diverging – sometimes rapidly – for men and women in a 2012 analysis of 30 EU countries. Risk factors such as tobacco use, physical inactivity, obesity, midlife hypertension and household air pollution from solid fuels were cited by researchers as directly or indirectly influencing a large share of the global burden of disease.

But Felipe Sierra, director of the Division of Aging Biology at the NIH's National Institute on Aging, cited another key reason why life expectancy is generally increasing but HALE is not. The body of research that serves as the framework for drug development, he said, is "completely focused" on attacking diseases that kill people. While that seems like a noble objective, an unintended consequence is that people live longer but not necessarily better lives.

"The elderly rarely get only one disease," Sierra told BioWorld Insight. "They get multiple ones. So let's imagine a person gets four diseases. What happens if we cure the one that was supposed to be the killer? The person will live longer but with the other three diseases, so their health has not improved, really. All we did was to prevent their dying from the fourth disease."

'THE MAJOR RISK FACTOR FOR MANY DISEASES'

A biochemist, Sierra is a passionate advocate for the interdisciplinary field of geroscience, the study of the relationship between aging and age-related diseases. As founder and coordinator of the trans-NIH Geroscience Interest Group (GSIG), he was organizer of the 2013 NIH summit, Advances in Geroscience: Impact on Healthspan and Chronic Disease, which sought to establish a framework for the field of geroscience and to outline a roadmap to discover the connection between aging and disease.

That summit resulted in a white paper, published in 2014 in Cell, describing seven "pillars of aging": adaption to stress, epigenetics, inflammation, macromolecular damage, metabolism, proteostasis and stem cells and regeneration. The initial summit also led to multidisciplinary NIH initiatives on geroscience projects in areas such as epigenetic analysis and animal models of chronic disease.

Sierra also spearheaded and spoke at the follow-up summit, Disease Drivers of Aging: 2016 Advances in Geroscience, earlier this month in New York. The goal of the 2013 meeting was to introduce the concepts of geroscience to the community and to explain why aging is the major risk factor for chronic diseases. This year's summit took the opposite approach by exploring three chronic diseases – cancer, HIV/AIDS and diabetes – that are major risk factors for accelerated aging. The choice was driven by data documenting the effects of those diseases – and, sometimes, their treatments – on the pace and frequency of age-related physical decline and disease.

"We have a body of epidemiological evidence that indicates accelerated aging in disease survivors," Sierra pointed out. "At the same time, we have advanced enormously in our understanding of the basic biology of aging and its effect on disease etiology. It is imperative that we now intensify efforts into uncovering the molecular and cellular mechanisms by which these two observations are linked: How is it that early exposure to disease, or treatment, accelerates the processes typically seen during aging?"

In drug development, far less emphasis is placed on treating conditions such as osteoarthritis than on cancer, Sierra pointed out – an assertion borne out by Thomson Reuters Cortellis, which cited more than 9,500 active trials in cancer but fewer than 900 in osteoarthritis.

"But living with arthritis is not fun," Sierra maintained. "The approach we're taking with the geroscience initiative is to accept that aging is, by far, the major risk factor for many diseases. We need to address aging and not one disease at a time."

'I'VE BEEN THOROUGHLY SHOWN TO BE WRONG'

A primary driver to uncover clues about aging is the science of senescence, or biological aging, a process that occurs at the cellular level across living organisms. A growing number of researchers – mostly in academia but also in biopharma – are exploring how to mitigate the effects of aging-related disease by manipulating cellular senescence.

Studies of senescence began in earnest after the process was described in 1961 by Leonard Hayflick and Paul Moorhead in a seminal paper published in Experimental Cell Research. Their work described degenerative changes, especially regarding viability and nuclear morphology, that occurred as cell strains approached their in vitro lifespan in a phenomenon the scientists labeled as "replicative senescence."

For years, however, many scientists – including Sierra – concluded that senescence was an artifact of cells in culture.

"I was a big critic of it," he admitted. "I thought it had nothing to do with aging. I've been thoroughly shown to be wrong."

Current methods to detect senescent cells remain primitive, according to Sierra, limiting the ability of researchers to assess the extent to which they're present in humans. What's better accepted is that the senescence-associated secretory phenotype, or SASP – first described by Judy Campisi, professor at the Buck Institute for Research on Aging and at Lawrence Berkeley National Laboratory – isn't benign but secretes numerous growth factors, cytokines, proteases and other proteins, "most of which are bad for you," Sierra said. "Even if you don't have many of them, they're affecting their neighbors, and that may be a more important reason to target them."

In 2011, scientists from the Mayo Clinic and Groningen University in the Netherlands reported in Nature that they designed a transgene to induce the elimination of p16Ink4a-positive senescent cells in mice when they administered a drug. In adipose tissue, skeletal muscle and eye tissue, p16Ink4a tumor suppressor protein contributes to the acquisition of age-related pathologies. Removal of p16Ink4a-expressing cells delayed onset of those phenotypes, according to the scientists.

For their study, the researchers used "a genetic trick" to eliminate the senescent cells in the animals, Sierra said. But earlier this year, an expanded group of researchers from Mayo reported dramatic findings in Nature. Removing senescent cells from middle-aged mice by pushing them into apoptosis lengthened the life span of the animals by 25 to 35 percent. The work offered additional proof that the cells play a broad role in promoting aging and suggested that targeting them could mitigate the effects of a number of age-related diseases. (See BioWorld Today, Feb. 5, 2016.)

SENESCENT CELLS ACCUMULATE WITH AGE

Two scientists with major influence in studies of senescence – Campisi and Jan van Deursen, a professor of biochemistry and molecular biology and professor of pediatrics who is part of the Mayo team – became co-founders of Unity Biotechnology Inc., along with Daohong Zhou, professor of pharmaceutical sciences at the University of Arkansas for Medical Sciences, and Nathaniel David, a molecular and cellular biologist and serial entrepreneur who serves as the company's CEO. Keith Leonard, an Amgen C-suiter who became founding CEO of Kythera Biopharmaceuticals Inc. – sold last year to Allergan plc for $2.1 billion – is Unity's executive chairman. (See BioWorld Today, June 18, 2015.)

The company is designing "senolytic" medicines that target vulnerabilities unique to senescent cells – Unity abbreviates them as SnCs – allowing them to be cleared from the human body while leaving normal cells unaffected. In addition to van Deursen's work at Mayo, the company has demonstrated that removing SnCs reverses or prevents many aging-related conditions, including osteoarthritis, atherosclerosis, eye diseases and kidney diseases.

SnCs have an important job early in life, when they halt the rapid process of cell division that begins following conception, David pointed out. They also serve as a critical anticancer system, pulling the "emergency break" increasingly through the lifespan to forestall disease. The problem is that the cells don't leave after they finish their work. They hang around so that, by the time people reach old age, SnCs have accumulated in substantial numbers in numerous tissues.

Collaborations with Campisi's lab at the Buck Institute and van Deursen's lab at the Mayo Clinic – both spoke about their work at this month's Geroscience Summit – enabled Unity to examine what happened when its early stage drug candidates were used to clear SnCs from mice. Treatment with its agents – Unity has not disclosed the mechanisms or number of assets in its arsenal – enabled mice to avoid kidney dysfunction, cardiac dysfunction, cataracts and osteoporosis that developed in genetically identical siblings and to live, on average, 35 percent longer than those siblings.

Unity, of Novato, Calif., has observed 21 phenotypes when clearing SnCs from mice, demonstrating measurable improvements such as stabilization of atherosclerotic plaques, increased intervertebral disc spacing, reduced tissue calcification, preservation of youthful kidney function and prevention of age-associated cardiac hypertrophy.

'KIDS DON'T HAVE SENESCENT CELLS'

Probing diseases of aging is nothing new, David admitted, and he acknowledged that previous failures in the field have caused researchers, pharmas, investors and even the public to approach the topic with a jaundiced eye. If the science was so good, "where are the drugs?" he asked. "It has something to do with the difficulty of giving people drugs every single day for a process that's going on every single moment of your life."

Unity's approach to "treat" aging differs from those of previous biopharmas in four ways, David told BioWorld Insight. The first is druggability. The company eradicates SnCs in a one-and-done operation, eliminating the need for chronic therapy and concomitant toxicity risks. Its senolytic drugs are cleared from cells 24 hours after their delivery.

The company established a clear link between SnCs and specific disease. SnCs cluster at sites of disease, such as the vertebral discs and knee articular cartilage affected by osteoarthritis and the trabecular meshwork and retinal ganglia cells affected by glaucoma, simplifying indication selection, according to David.

The third difference is a focus on the mechanism of aging related to SnCs rather than to a particular disease state, or as David likes to say, "Kids don't have senescent cells." The goal of senolysis is to "reset" tissues to a youthful state.

Finally, with more than five years under its belt in stealth mode, Unity has the advantage of technical maturity, David maintained. Backed by a syndicate that includes Arch Venture Partners and Venrock and holding intellectual property from its founding inventors, the company is looking to move a lead candidate into the clinic in a few years. The long-term goal is to file five investigational new drug applications in five years, initially focusing its senolytic drugs on indications such as osteoarthritis to prove the company's thesis before moving into more intractable indications, such as cognitive decline, that offer greater commercial potential.

'MORE THAN A GLIMMER OF INTEREST'

Senex Biotechnology Inc. – the company's name is derived from the Latin word for growing old – is approaching the science of aging from a different perspective by targeting cyclin-dependent kinase inhibitor (CKI) proteins, which are implicated in cancer and other aging-associated diseases. Working methodically for more than a decade, the small Columbia, S.C.-based firm has amassed a portfolio of 12 issued patents, according to Cortellis. The company optimized its lead CDK8/19 inhibitor program and is completing preclinical studies in preparation to enter human trials "in weeks, if not days," said Igor Roninson, the company's founder and president.

"Our work in aging and aging-related diseases was never separate from the area of cancer because cancer is also an aging-related disease," explained Roninson, who also serves as director of the Center for Targeted Therapeutics and professor at the University of South Carolina.

In 2000, Roninson and colleagues at the University of Illinois published a discovery in Proceedings of the National Academy of Sciences showing that expression of the CDK inhibitor p21 selectively inhibited various genes implicated in age-related diseases as well as a series of genes implicated in cancer. The researchers concluded that inhibition of cell-cycle progression genes is a mechanism of p21-induced growth arrest and suggested the effects of p21 induction on gene expression in senescent cells may contribute to the pathogenesis of cancer and age-related diseases.

"From the beginning, we knew that when we set out to inhibit this damage response, we were likely to get compounds that would have multiple therapeutic implications," Roninson told BioWorld Insight. "After we obtained those compounds, we concentrated on cancer because cancer provides the most direct and immediate route to get a compound on pharmacy shelves."

Roninson has high expectations for the CDK8/19 class, noting that Senex was the first to develop selective inhibitors of the kinase twins, offering opportunities to target breast and prostate cancer as well as leukemia. He pointed out that a similar research effort in the lab of Harvard University's Matthew Shair, professor in the department of chemistry and chemical biology, last month attracted an exclusive licensing deal with Merck & Co. Inc., of Kenilworth, N.J., for $20 million up front plus development and commercial milestone payments.

Shair's small molecules "inhibit enzymes that regulate the transcription of key genetic programs that are altered" in acute myeloid leukemia and other cancers, according to a statement by Harvard.

"The group at Harvard published an excellent paper in Nature recently where they demonstrated that a natural compound, cortastatin A – a very powerful CDK8/19 inhibitor – has very strong activity against a subset of leukemias," Roninson explained. "They did a great job identifying the molecular mechanism of this activity."

And the Harvard-Merck deal has driven up traffic to Senex's front door.

"This represents the first big pharma deal for CDK8/19 inhibitors," Roninson said, "and it's more than a glimmer of interest." He described the target as "absolutely unique" in terms of the proteins involved in the transcriptional machinery, representing a promising approach to treat cancer without off-target effects.
"CDK8/19 functions primarily when cells undergo transcriptional reprogramming," he pointed out, "and cancer is the prime example of transcriptional reprogramming."

Once Senex moves its CDK8/19 inhibitors through the clinic in cancer, the company will turn to other aging-related indications if it doesn't attract partners in the meantime.

"We are negotiating a partnership in the cardiovascular area right now," Roninson said. "It's fascinating to be at the hub of so many different diseases and to be able to manipulate them with a very nontoxic type of therapy."

Senex also has CDK3 and coatomer inhibitors in its pipeline, and the company's intellectual property includes rights to its assets in all indications.

HELPING PEOPLE TO LIVE HEALTHIER LIVES LONGER

In all, nearly two dozen drug candidates probing some aspect of cellular senescence are being investigated by biopharmas, according to Cortellis. Twenty additional efforts evaluating senescence as a biomarker or predictor of disease – mostly cancer – have advanced into the clinic, though solely by academic investigators.

But pharma's interest is growing in a variety of ways. An attempt to stay on top of neuroscience and to bring medicines to individuals with aging-related conditions such as Alzheimer's and Parkinson's disease was at the heart of a global partnership forged last week between Glaxosmithkline plc, of London, and the Sanford Burnham Prebys Medical Discovery Institute of La Jolla, Calif. (See BioWorld Today, April 21, 2016.)

As such collaborations grow, the NIH's Sierra envisions the development of compounds that enable individuals to live healthier lives longer. Already, drugs are being tested in animal models that address each of the seven pillars of aging.

"Drugs that affect senescence, which is a pillar of aging, affect the rate of aging overall," he explained. "Because of that, a person's risk of developing disease is diminished."

Multiple studies have suggested that, on average, people who live to 100 remain relatively healthy during their last 20 years, and their end-of-life care is three times less expensive than those who die at 80, Sierra said. Centenarians are less likely to succumb to a disease that can be detected by a pathologist than to what he called "a generalized imbalance" that occurs in the very old. In animals treated with early stage drug candidates targeting cellular senescence, pathologists are similarly unable to detect the cause of death.

"They're not dying of disease, or at least the disease is not dramatic enough that a pathologist can identify it," he said.

THE STUDY OF AGING CAN'T BE RUSHED

Last week, researchers from the Scripps Translational Science Institute reported findings from an eight-year accrual and analysis of the whole genome sequences of healthy elderly people, revealing a higher-than-normal presence of genetic variants offering protection from cognitive decline. The results, reported in Cell, suggested a possible link between long-term cognitive health and protection from chronic diseases.

The ongoing project has enrolled more than 1,400 people from across the country ranging in age from 80 to 105 who have not developed any chronic medical diseases, including cancer, stroke, Alzheimer's, Parkinson's disease, diabetes and heart attack. The group had a significantly lower genetic risk for Alzheimer's and coronary artery disease, according to the researchers, but no difference was found between the two groups in genetic risk for cancer, stroke or type 2 diabetes, suggesting protective behaviors or other genetic characteristics might be at play.

While such findings help to confirm the importance of the pillars of aging, assessing how quickly some of those efforts might result in actual therapeutics is "a wild guess," Sierra admitted. "But it will happen."

As drug studies emerge, he cautioned against drawing too many conclusions from mouse models, which by design mimic artificially induced disease states. The study of aging can't be rushed, he said.

"We have some controversy in the aging field because some people want to use accelerated models of aging, such as progeria," he said. "My concern is that those are the same as mouse models of disease, which are terrible. In most disease models, researchers don't look to see if their drug works in naturally occurring disease. Instead, they induce the disease in a particular animal model and then they cure it – in that model. In aging, I don't think that's going to translate well."

Addressing regulatory issues is another hurdle. Although regulators are wary of approving drugs for otherwise healthy people, compounds that target aging could follow the model of preventive classes such as statins, with the premise that "a person who is 75 years old is at high risk of developing a whole bunch of diseases," Sierra said. "So can we give them a drug that will protect them against those diseases?"

Winning such an argument with the FDA represents a "major burden" that biopharmas will have to confront, he said. But he's optimistic on that front, as well.

"We are in conversation with the FDA about this subject already," Sierra confided.

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