One-liner: Assessment of Etheros Pharma, a preclinical biotech, pioneering a new small-molecule drug class that extends mammalian lifespan and neural healthspan (based on fullerene chemistry)
This proposal is based on the supporting documents provided by Etheros Pharma, as well as questions and answers to their team, and senior reviews.
If this goes on-chain, the VITA token holders will ratify the WG’s assessment via a decentralized vote
Applicant (project lead): Dr. Jack Scannell
Etheros is pioneering a new class of small molecule drugs, based on Nobel Prize-winning fullerene chemistry. The lead compound extends mouse lifespan, improves cognition in elderly mice, and has already proven neuroprotective in a wide range of other double-blind, placebo-controlled animal studies; ranging from a Parkinson’s Disease model in primates, via a familial ALS model in mice, to an asphyxia-induced brain injury model in pigs.
The compounds mimic enzymes, superoxide dismutases, that play a key role in protecting cells from oxidative and inflammatory injury; a type of injury to which neuronal tissue is particularly sensitive. The lead compound has good brain penetrance, high oral bioavailability, and considerable (though not IND-enabling) safety data from long-term exposure in mice and primates.
The compounds’ novel catalytic activity makes them extremely potent versus older drug classes that have typically struggled in human neuroprotection trials.
The current raise, a few hundred thousand dollars, will help Etheros improve its IP portfolio. It will also allow us to plan and cost, in executable detail, the optimal route to prove of mechanism in humans. Fresh IP and a firm plan to get to the clinic will help Etheros raise more capital on good terms in 6 to 8 months’ time.
Oxygen-based metabolism is a double-edged sword. On one hand, it provides far more energy than the wide variety of other metabolic chemistries. Hence all complex multicellular organisms respire with oxygen. On the other hand, oxygen’s high-energy chemistry destroys biological molecules. Fats, for example, go rancid as they oxidize. Sometimes oxidative damage is inadvertent (e.g., free radical leakage from mitochondria, superoxide cation production from radiation). Sometimes it has evolved (e.g., our immune system uses superoxide, produced by the enzyme NADPH, to destroy the biological machinery of pathogens). Consequently, all living things have a wide range of mechanisms to protect themselves against oxidative damage, including the superoxide dismutase enzymes that our drugs mimic.
Neural tissue is particularly sensitive to oxidative injury. This follows from neurons’ high metabolic rate, their high lipid content, and from the fact that they do not regenerate. A wide range of initial injuries can activate a common set of oxidative pathways, which increase the concentration of superoxide, hydrogen peroxide, and other reactive oxygen species, which in turn compound inflammation and injury.
Our technology can play in a wide range of therapeutic settings, some with huge commercial potential. That is why we founded Etheros.
One of our founders, Marc Feldmann, was responsible for the discovery of the anti-TNFs, which became the World’s best selling drug class, which have use in a wide range of inflammatory and auto-immune indications, and which are still being tested in new indications nearly 25 years after their first approval. He partnered with Dugan to commercialise her technology because he recognized a similar opportunity. To quote Feldmann: “My discovery and development of the anti-TNFs taught me that the biggest and best new drugs share three features: First, an entirely new mechanism; second, they act on a critical mechanistic bottleneck; and third, the critical bottleneck is present in a wide range of tissues. Our enzyme mimetics have all three attributes.”
One of our SAB members also has experience of prior attempts in this general field and understands its potential. Chas Bountra was head of Biology at GlaxoSmithKline. To quote Bountra: “Let’s be clear on why we don’t have effective treatments for [reactive oxygen species-dependent] injuries. It is not because we got the biology wrong. It is because, despite years of trying, neither big pharma nor biotech found drugs that had enough potency at the site of injury. We never found the right kind of chemistry. Etheros, at long last, seems to have solved the chemistry problem.”
We have already generated efficacy data in a wide range of animal models with mechanistic relevance to both rare and common human diseases. We also see a tractable path to use in large markets; starting in niche indications that are mechanistically attractive, and where we can prove the therapeutic concept, before raising the large sums of capital necessary to fund trials in common diseases.
The bulk of the current raise will be invested to secure patent protection for new chemical technologies so we do not want to disclose any detail at this stage. Note that the Etheros has engaged experienced IP counsel and that the team has deep experience in IP creation. We are confident that we will secure robust IP. We are also confident that we have freedom to operate, unconstrained by competitors’ IP.
Relevance to longevity
We have relevant data from several placebo-controlled double-blind animal studies. For a non-exhaustive list:
- Our lead compound increased lifespan in wild-type mice. Treatment started at 12 months of age. There was an 11% increase in median lifespan (mortality HR 0.59, p<0.004). In the same experiment, treated mice had better cognitive performance when aged between 23 and 26 months (measured via Morris water maze). Treatment also prevented the typical age-related decline in brain mitochondrial function and reduced measures of brain oxidative stress.
- Parkinson’s disease is a common age-related neurodegenerative disorder which itself is associated with other forms of age-related neurodegeneration (e.g. Lewy body dementia). Our lead compound is protective in a primate model of Parkinson’s. C3 was initiated 7 days after unilateral MPTP-induced brain injury. After 2 months, treated monkeys had significantly better parkinsonian motor ratings and higher striatal dopamine levels. None of the treated animals developed any toxicity.
- ALS is a rare age-related neurodegenerative disorder. We have run two separate studies. In both studies, our lead compound was effective in a mouse model of familial ALS. In untreated mice with the genetic modification, the symptomatic period runs 2 to 3 weeks before death (which occurs around 4 months of age). Drug treatment started at 2 months. Motor symptoms and death were delayed by 10 and 8 days respectively. This is a reasonably large effect size in this particular model.
- The aged brain typically shows evidence of impaired proteostasis. Aggregates of the protein p62 are markers of impaired proteostasis and are also implicated in neuronal injury. C3, administered to mice from 12 to 17 months of age, reduced p62 aggregation in the brain.
Note that influential theories of aging have drawn directly on the idea of cumulative oxidative damage. These theories are now contested. Our mouse lifespan results may add to the debate.
Etheros is seeking its first round of pre-seed / seed capital and is aiming to raise around $350k. Etheros expects to raise around $100k from sources other than VitaDAO, so is looking for an additional $250k.
The use of the capital raised will be:
- $75k for general expenses plus specialist consulting advice on our IP strategy, medicinal chemistry strategy, drug formulation, regulatory strategy, IND-enabling toxicology and CMC work.
- $75k to synthesise, purify, and quality-test a stock of C3. The work will be done by two of our founders, Chakroborty and Dugan, in incubator lab space near their academic base at Vanderbilt University in Nashville. With some C3, we can progress a collaboration with a philanthropic organisation that intends to fund preclinical studies in what could become a large and lucrative indication. With a stock of C3, plus our existing contacts, we may be able to create similar opportunities in other indications that match our priorities. We also want some stock in hand to start the major preclinical development effort after our next raise.
- $200k to synthesise, purify, quality-test, and assay a range of novel chemistries to secure new IP. Again, this will be done by Chakroborty and Dugan in incubator lab space in Nashville.
Professor Laura Dugan: Dugan is the Abram C. Shmerling Professor of Alzheimer’s and Geriatric Medicine at Vanderbilt University. Dugan is a former Paul Beeson Physician Scholar in Aging Research through the American Federation of Aging Research, The Hartford Foundation, and National Institute of Aging. She was also a Dana Foundation Research Scholar in Aging. She trained at MIT and Stanford. Dugan pioneered the technology that Etheros will commercialise during her research on neurodegenerative and aging-related diseases. The technology was built on ~$40m of competitive academic grant funding.
Professor Sir Marc Feldmann: An immunologist who Invented and developed the first successful monoclonal antibody therapy, anti-TNF, in his pioneering work with Remicade in the early 1990s. Remicade went on to sell over $7bn per year and the anti-TNFs became the World’s best selling drug class. Has been closely involved in commercial R&D ever since, and has founded several biotech firms. Marc was Director of the Kennedy Institute at Oxford University and is a winner of the Lasker Award.
Dr Subhasish Chakraborty: Chakraborty is an organic chemist with decades of experience designing, synthesising, and testing novel compounds. He was a Senior Research Scientist at Carnegie Mellon University between 2004 and 2016. He has worked in Prof Dugan’s research group since 2016. Dr Chakraborty received his MSc in agricultural chemistry in 1987, and a PhD in the same subject in 1993.
Dr Jack Scannell (CEO): Scannell has experience in drug discovery and biopharma investment. He led Discovery Biology at E-Therapeutics PLC, an Oxford-based biotech firm. He was Co-Head of European Pharmaceuticals & Biotech at UBS Investment Bank and Head of European Healthcare at Sanford Bernstein. He worked for drug industry clients while a consultant at the Boston Consulting Group. He studied medical sciences at Cambridge and has a PhD in neuroscience from Oxford. He is best known for his work on R&D productivity.
Frank Kneutell (COO / CFO): Kneutell has 30 years of management experience, growing early-stage and small-cap public companies. He has spent most of his career as a Chief Financial or Chief Strategic Officer. Most recently, he was the CEO of Unrivaled Brands, an operator of cannabis assets, where he grew revenue from an annualised $10 million to $100 million in six quarters. He has raised more than $300 million via venture, public equity and debt offerings. He has managed more than 15 mergers and acquisitions and has handled large-scale licensing transactions with fortune 50 companies. He holds an MBA from The Wharton School.
Etheros scientific advisory board
Professor Chas Bountra: Bountra is the Pro-Vice Chancellor for Innovation and Professor of Translational Medicine at Oxford University. He is also the Director of the Centre for Medicines Discovery. From 2008 to 2020 he Directed the Structural Genomics Consortium at Oxford. Bountra was Head of Biology at GlaxoSmithKline where he was involved in the identification of more than 40 clinical candidates across a range of therapy areas. More than 20 candidates progressed into human trials and more than five moved into late stage development.
Professor Lawrence Steinman: Steinman is the George A. Zimmermann Chair in the Neurology Department of Stanford University. He has experience in medical businesses, founding Neurocrine Biosciences, Tolerion, Transparency Life Sciences and Atreca. He held a fellowship in chemical immunology at the Weizmann Institute. He received the Frederich Sasse Award in 1994, the John Dystel Prize in 2004, the Charcot Prize in 2011, and the Cerami Prize in 2015. Steinman studied at Dartmouth and Harvard.
Professor Denis Choi: Choi is a pioneer in nervous system injury. He is Professor of Neurology at Stony Brook. He sits on the scientific advisory boards of several organisations, including the Cure Alzheimer’s Fund. He was the EVP for Neuroscience at Merck Research Labs. He was President of the Society for Neuroscience and the Vice President of the American Neurological Association. Dr Choi received his MD from the Harvard-MIT Health Sciences and Technology Program, and subsequently went on to receive a PhD in pharmacology and neurology, also from Harvard.
Highest priority publications are marked with an asterisk.
*Quick KL, Ali SS, Arch R, Xiong C, Wozniak D, Dugan LL. A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice. Neurobiol Aging. 2008 Jan 1;29(1):117–28.
*Dugan LL, Tian L, Quick KL, Hardt JI, Karimi M, Brown C, et al. Carboxyfullerene neuroprotection postinjury in Parkinsonian nonhuman primates. Ann Neurol. 2014;76(3):393–402.
*Hardt, J.I., Perlmutter, J.S., Smith, C.J. et al. Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid [C3] in Mice and Primates. Eur J Drug Metab Pharmacokinet 43, 543–554 (2018).
*Ali SS, Hardt JI, Quick KL, Sook Kim-Han J, Erlanger BF, Huang T ting, et al. A biologically effective fullerene (C60) derivative with superoxide dismutase mimetic properties. Free Radic Biol Med. 2004 Oct 15;37(8):1191–202.
Dugan LL, Lovett EG, Quick KL, Lotharius J, Lin TT, O’Malley KL. Fullerene-based antioxidants and neurodegenerative disorders. Parkinsonism Relat Disord. 2001 Jul 1;7(3):243–6.
Ruden JB, Quick KL, Gonzales ER, Shah AR, Park TS, Kennedy N, et al. Reduction of Leukocyte Microvascular Adherence and Preservation of Blood-Brain Barrier Function by Superoxide-Lowering Therapies in a Piglet Model of Neonatal Asphyxia. Front Neurol. 2019;10:447.
Dugan LL, Turetsky DM, Du C, Lobner D, Wheeler M, Almli CR, et al. Carboxyfullerenes as neuroprotective agents. Proc Natl Acad Sci. 1997 Aug 19;94(17):9434–9.
Dugan LL, Lovett EG, Cuddihy S, Almli CR, Lin TS, Choi DW. Carboxyfullerenes as neuroprotective antioxidants. Pharmacol Cereb Ischemia. 1998;257–68.
Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, et al. Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase. Science. 2007 Dec 7;318(5856):1645–7.
Ali SS, Hardt JI, Dugan LL. SOD Activity of carboxyfullerenes predicts their neuroprotective efficacy: a structure-activity study. Nanomedicine Nanotechnol Biol Med. 2008 Dec 1;4(4):283–94.
- A new mechanism for lifespan and neural healthspan extension in a mammalian longevity model
- Efficacy data from a diverse range of in vivo animal neural injury and neurodegeneration models, all conducted as double blind placebo-controlled studies
- High head to head potency in vitro versus a range of compounds that have been tested in some of our target indications
- Prima-facie evidence of safety from mouse longevity study and from chronic dosing in primates
- Good pharmacokinetics, with high level of brain penetrance, oral bioavailability, and clearance via urine and bile with minimal metabolism
- [Your input here…]
- Failure of novel chemistry. We believe that we can commercialise our lead compound, C3, in niche indications despite the fact that there is no composition of matter patent protection. Method of use patents, orphan exclusivity, and other barriers to competition should be sufficient. However, to raise the capital necessary to exploit larger and more lucrative markets, we very likely require new patentable chemistry. It is possible that the new chemistries that we plan to explore will work much less well than we hope.
- The choice of first-in-man indications. Our best studied compound, C3, is old. That means that the first-in-man indications will likely lie in rare diseases where we can secure both orphan exclusivity and method of use patents. These diseases are not our historic therapeutic focus. There is much we can do to mitigate risk in indication selection (e.g., knowledge of pathological mechanism, the predictive validity of screening and disease models, diversification across a range of disease mechanisms, a mixture of acute and chronic indications, etc.) but we cannot eliminate it.
- CMC (chemistry, manufacturing, and controls) requirements for an entirely new drug class. There are regulatory hurdles around product manufacturing quality, analytic standards, etc., for any new drug. We have done some initial scoping work with a specialist manufacturer, we have extensive analytic experience with this compound class, and we believe that CMC hurdles can be met. However, the fact that no fullerene-based compounds have ever been brought into the clinic raises the CMC risk.
- There are also a range of important “macro” risks in biotechnology. The biotech venture industry is cyclical. There are booms and busts in funding; partly driven by interest rates. Major drug pricing reform in the US is a perennial risk given the role that the price-insensitive, fast adopting, US market has in biotech asset valuation. It is possible, for example, that the new pricing rules introduced under the Inflation Reduction Act of 2022 may have an influence on our indication choices or indication sequencing; particularly for very large indications that relate to elderly Medicare population.
- [Your input here…]
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