Small Molecule Enzyme Mimetics In Age-Related Neurodegeneration
A conversation with Jack Scannell, D.Phil, CEO, Etheros Pharmaceuticals
Reactive oxygen species (ROS) can damage DNA, proteins, and cell membranes. They are produced by inflammation and respiration. ROS have a causal role in a wide range of diseases and may also contribute to aging itself.
Etheros Pharmaceuticals is developing fullerene derivatives that mimic the enzymes that evolved to protect tissues from ROS. The target of the enzymes, and of the Etheros drugs, is the superoxide radical, which lies at the start of the dangerous ROS cascade.
In this Q&A, Life Science Connect’s Morgan Kohler caught up with Jack Scannell, D.Phil., CEO of Etheros Pharmaceuticals, to discuss the company’s work to create small molecule enzyme mimetics to tackle age-related neurodegeneration, inflammation, and potentially slow human aging.
What diseases of aging does Etheros target?
Our technology has, we hope, broad applications. The lead compound has extended mouse lifespan by nearly as much as caloric restriction in head-to-head experiments. Caloric restriction is the “gold standard” in terms of things that extend mammalian lifespan. In terms of interventions that extend lifespan, caloric restriction works across a remarkably wide range of taxa (from yeast via nematodes to mammals), and it also tends to have a very big effect versus other interventions. However, the first-in-human uses are likely to be rare and serious age-related neurodegenerative diseases. If things look good there, we intend to move into common pathologies, like Parkinson’s and Alzheimer’s.
Why is there a lack of antioxidant drugs and how is Etheros addressing that?
There have been many clinical trials of diverse antioxidants, but their successes are few and far between — and even the successes are underwhelming. This is because conventional antioxidants have a major potency problem. Once an antioxidant molecule has been oxidized, often via a single reaction with a single ROS, it is exhausted. So, in practical terms, conventional antioxidants can’t be delivered in sufficient quantity to the site of action without, for example, toxic side effects.
In contrast, the superoxide dismutase enzymes, and our compounds, are catalysts. They get rid of superoxide radicals without being used up in the reaction themselves. They eliminate superoxide via a reaction called “dismutation” in which two superoxide radicals react with each other and with two protons that are abundant in the water in cells. Catalysts can therefore eliminate thousands of superoxide radicals per second under physiological conditions and can keep doing that hour after hour.
What models are being used in Etheros’ preclinical research?
We founded Etheros because the body of prior academic work across a wide variety of in vitro and animal models was incredibly impressive. In other words, we did not get into this primarily because we wanted to “solve aging.” We got into this because we found an impressive and robust phenomenon that had a wide range of important uses. The animal work, for example, has focused on inflammatory and neurodegenerative models. These range from genetically induced Alzheimer’s and amyotrophic lateral sclerosis (ALS) to chemically induced Parkinson’s (via neuroinflammation caused by other drugs or asphyxia) to neurodegeneration in normal aging. The animal models have included species whose evolution diverged 60 million years ago (rodents, primates, and pigs). This kind of pathological and species diversity is unusual, but it makes it much more likely that the results are relevant to human medicine. And, importantly, all the animal work was placebo controlled and double blind, which reduces the risk of biased results leading us astray. To give a sense of scale, the original academic work attracted roughly $40 million dollars of highly competitive grant funding, mainly from the NIH and Veterans Administration in the U.S.
What results have been achieved with these models?
I’ll highlight the primate Parkinson’s disease results and the mouse longevity results. Primates are the closest relatives of humans in which it is possible to run preclinical experiments. We used a stringent experimental design where we induced Parkinson’s before we started treating with our lead drug. We showed that we could reduce the movement abnormalities typical of Parkinson’s while preserving the neurons that are typically lost in Parkinson’s. Furthermore, the animals were treated for two months with no apparent abnormalities in blood biochemistry or EKG. The mouse lifespan study was well powered (i.e., big enough to get reliable results), with treatment starting at 12 months of age (middle age for mice). The drug was given orally in drinking water. The median lifespan extension was around 14% with our lead compound — very close to the 16% that we achieved with caloric restriction also starting at 12 months. The elderly treated mice (aged 23 to 26 months) performed more like young mice (aged 6 months) in water maze tasks, much better than their untreated peers. They also looked “young” on measures of brain oxidative stress and brain mitochondrial function. Importantly, you also can view this mouse study as providing information on safety, since the median mouse got the drug for roughly 15 months — more than half its lifespan. The treated mice lived longer than untreated mice and appeared “younger” and healthier on a range of measures (e.g., lower rates of neoplasm, maintenance of bodyweight, etc.).
Why is Etheros’ research built on fullerene chemistry, and what is the significance of that?
Fullerenes are a new form of carbon where (usually) 60 carbon atoms form a kind of soccer-ball structure. They were discovered in 1985. The important thing is that electrons can flow freely around the soccer ball, and this gives fullerenes remarkable chemical properties. They can act as catalysts, making other chemical reactions happen without themselves being chemically altered. Proteins (“enzymes”) are the main biological catalysts and manage most of the biochemistry of life. Laura Dugan — one of the Etheros’ founders — discovered that a subset of fullerene derivatives that are neuroprotective perform the same catalysis as a set of enzymes, the superoxide dismutases. These enzymes are present in all living things and protect against oxidative and inflammatory injury. So, the Etheros compounds depend on fullerene chemistry. This is an entirely new therapeutic approach, so there is no other drug like this currently.
How do you see Etheros’ research developing in this area moving forward?
One of Etheros’ founders, Marc Feldmann, discovered the best-selling drug class: anti-TNFs. They treat a wide range of inflammatory and auto-immune diseases. Marc is fond of saying that we are not really interested in rare diseases; we are interested in the most common diseases.
We also believe that the most important new kinds of drugs have three attributes:
- They have an entirely new therapeutic mechanism.
- They act on a critical biological bottleneck.
- The bottleneck is important for a wide range of pathologies.
We set up Etheros because Laura Dugan’s fullerene derivatives appear to have those three attributes. So, for reasons of risk and capital efficiency, we are going to start with serious rare neurodegenerative pathologies — diseases where you can show positive results in humans quickly and at relatively low cost. But our ambitions are much wider and include the most feared diseases of aging, such as Alzheimer’s and Parkinson’s.
What advice do you have for biotechs working on therapeutics in this area?
Two related pieces of advice: First, doing new things in biology and chemistry is unpredictable, so raise more money than you think you need. Second, find investors who really know the field you are working in. Immortal Dragons, one of our investors, has been great here because they understand the challenges and opportunities, and because their expertise means you get more than mere cash.
If you’d like to read about funding anti-aging research from a VC perspective, check out this article by Immortal Dragons CEO, Boyang Wang.
About The Expert
Jack Scannell, D.Phil., is best known for his work on the scientific, economic, and regulatory influences on R&D productivity in the biotech and pharmaceutical industries. He is the CEO of Etheros Pharmaceuticals. He led discovery biology at e-Therapeutics PLC, an Oxford-based tech-bio firm. He has experience in drug and biotech investment at UBS and Sanford Bernstein where he ran the European Healthcare teams. He is also an associate of the Department of Science, Technology, and Innovation Studies at Edinburgh University. He has a Ph.D. in physiology (neuroscience) from Oxford University and a degree in medical sciences from Cambridge University.