VDP-74 [Assessment]: Etheros Pharma - Jack Scannell

One-liner: Etheros Pharma is a preclinical biotech, pioneering a new small-molecule drug class that extends mammalian lifespan and neural healthspan (based on fullerene chemistry)

Applicant (project lead): Dr. Jack Scannell

Simple Summary

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.

Problem

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.

Opportunity

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.

Intellectual Property

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.

Financing

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.

Team

Founders

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.

Additional information

Selected publications

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.

Highlights

  • 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…]

Risks

  • 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…]
  • Agree
  • Agree with revisions (please comment)
  • Disagree

0 voters

Doesn’t this mean the lead is dead in the water? Or is the raise to complete the safety data? Why hasn’t this gotten IND-enabling safety data?

It sounds like this is two distinct proposals. One is to make more C3 to test in orphan indications in which the team lacks prior experience, and/or get a grant from some aging foundation to do preclinical trials. But if the philanthropic org has already decided to fund a preclinical trial, it’s unclear why money is requested for this approach, instead of being part of the grant from the philanthropic org. Not clear how much benefit will accrue to VitaDAO in this case. The philanthropic org will want a cut, too.

The other is to create and screen similar compounds and hope one of them works. This seems more relevant to VitaDAO, since it has the potential to produce new IP. Would this IP be amenable to IP-NFT? What QC and assays are planned for the $200k?

One general concern with the approach is the lack of recent publications on the subject. The latest ‘high priority’ publication is from a no-name journal in 2018. If this is an up-and-coming technology, especially if C3 can’t get a composition of matter patent, why aren’t there more recent publications on it?

4 Likes

For a preclinical asset of this stage, Etheros has a lot of positive evidence on the safety of C3. The longevity studies show a high degree of safety in mice (including various postmortem examinations). The primates that received C3 on a chronic basis were studied extensively on a range of safety parameters (bloods, ECG, etc). What we do not have is the standard package that is required by the FDA to allow human trials. FDA IND-enabling tox requires 28 or 90 day tox in 2 species, mutagenicity testing, Irwin test, hERG, etc., and costs in the order of $1.5m. This kind of regulatory tox typically requires commercial funding. It is not the kind of thing that is provided within the academic grants that have funded the Dugan lab. Nor it is really worth starting before one has a clear idea on the first-in-human indication(s). Funds for IND-enabling tox will be part of a future raise, to get C3 into the clinic. Of course, the safety data we already have makes it less likely that C3 will fail IND-enabling tox or prove toxic in the clinic.

There are indeed two strands of work. We think there is a commercial case for C3 in a range of diseases where there is a strong mechanistic rationale, where there are good preclinical models, where we can secure IP, sometimes where there may be patient or philanthropic pull, and where we can prove the general mechanism quickly and at at low cost. This kind of “rare disease first” approach is very common with new therapeutic mechanisms because you can pick a homogeneous and mechanistically attractive patient population, run short trials in a few tens of patients, and show human results quickly. It is a feature, and not a bug. Any quick hints of efficacy in rare disease trials will make it easier to raise additional capital, for novel chemistry applied to common diseases, on good terms. It might be hard to put put a new mechanism (C3 or allied compounds) into long and expensive trials for common diseases without some kind of prior demonstration of human efficacy.

The second strand is novel chemistry to create a suite of compounds that are optimized for a range of uses, often in more common diseases. Recall that the mechanism of action of C3 and associated compounds. C3 is a catalyst that dismutes superoxide and hydrogen peroxide. There is already a little data in the public domain that shows structure-activity relationships. One can, for example, alter lipophilicity and change cell penetrance or extend half-life while maintaining catalytic activity. Dugan and Chakraborty have a great deal of experience of fullerene chemistry and we believe we can make a range compounds that are patentable and which are tailored to a range applications.

We do have interest from 3rd parties (academic and philanthropic) that want to fund preclinical efficacy and/or PK/PD studies. At present, they cannot fund the studies because we cannot supply C3 (and there is, as far as we know, no other source of supply). The indications in question are close to our core area of interests. Were we to enter into collaboration agreements we would retain full control of the IP and would insist on attractive commercial terms (e.g., paying a small royalty). If the terms are not attractive to Etheros and its shareholders, we won’t collaborate.

Turning finally to high impact publications, there are many different ways of judging scientific quality. The Dugan lab has raised around $40m of competitive grant funding (mainly NIH) over the last 20 years. Dugan’s long-term collaborators are also an impressive bunch including, for example, Joel Perlmutter at Wash U. (who is known, among other things, for his resignation from an FDA advisory board over the approval of adacamumab in Alzheimer’s). Dugan and Perlmutter collaborate on the Parkinson’s work. Furthermore, Marc Feldmann was the initial driving force in trying to commercialize Dugan’s work. He came across Dugan’s work around 2016 and became involved precisely because he believed it could have a huge impact; like the anti-TNFs. Chas Bountra on the SAB is also a compelling advocate for our approach.

3 Likes

A few other comments on publications from the Dugan lab (after talking to Laura). The PK/PD/safety paper has huge practical importance in terms of creating a human treatment, but is not the kind of thing that excites nature or science. At least one paper was put into a “easy” journal because the graduate student needed rapid publication for their personal career prospects. But perhaps most importantly, Dugan’s mouse colony largely ceased to exist during COVID. Most of the animals had to be sacrificed because there was a lack of staff. The major studies that stopped, and which needed to restart, require 18 months to 24 months of treatment. Consequently, what we believe to be high impact work that should have been submitted and published around 2021 is only maturing now.

3 Likes

Speaking for myself, journal brand needs no justification. There’s many reasons people publish in various journals. Having published in the top journals for years, it’s really nothing to be lauded. It’s mainly a battle of attrition. It’s a luxury to have the time and money to waste on getting a paper in CNS.

I’m excited for the future where journal brand goes away. Preprinting and post publication peer review is sufficient for me.

The Etheros teams’ track record and data speaks for itself. Kudos @Jack_Scannell on putting together such an excellent venture. I’m excited for you all!

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Thanks for clarifying the IND plans. The initial summary sounded to me like it had fallen short of IND testing, but my interpretation was incorrect.

The approach sounds reasonable to me. What’s not clear from the proposal is the track record of the team in the rare diseases being pursued. Do you plan to collaborate with people who use these disease models all the time? Are the diesase models simple ones that are hard to screw up? Or are there 10 different models for the disease, each one models a different aspect of disease, and if you make the mistake of giving the mice sterile water instead of fresh water from one random spring in Missouri the model doesn’t work? This may be a place where someone in the WG can comment in general as well, since you want to keep rare disease in question under wraps until IP is filed.

This part I like the idea. I have no concerns about the team’s ability to attempt it. My question on this part is milestones and scope. What are the expected results w/$200k of funding?

This part remains concerning to me. Why are the 3rd parties unwilling to pay you to create more C3 if they’re interested in pursuing it further?

I’m unclear on what “interest” means. Is “interest” = talked to a Program Officer who said the idea is in scope, “interest” = foundation reached out to you and said ‘send us a proposal and we’ll fund it’, “interest” = grant was discussed at study section but missed payline, or what? It seems like this part is being overstated, and there is significant uncertainty that these 3rd parties will fund the work.

For $350k, this also seems like STTR/SBIR territory. Are those funding mechanisms being pursued? If not, why not?

When I checked Dugan on NIH reporter (1985-current), I found $7M in total costs. However, it looks like the P41 and P01 are reported weird, and the VA funding is not reported at all, so the $7M is underreporting.

People with impressive credentials can afford to take high risks that zero because it doesn’t hurt them. I count it as good for fundraising because VCs are impressed by stuff like that, and those people are expected to have the network to access more funds (though a failure to get $75k for more C3 is a little concerning)

However, I’ve seen too many people with impressive credentials have ideas that fail to count credentials as a factor contributing to success of the project. I’ve also seen people with impressive credentials in one field do terrible work in another field. So I judge by preliminary data, and my evaluation of the authors’ interpretation of those data.

Part of my concern is not just the publications from the team, but on the subject in general. COVID is a strong example of this. Everyone and their uncle is publishing on COVID because it’s a hot area. A Pubmed search for ‘carboxyfullerenes’ gets 66 hits. COVID gets 322,978. I wouldn’t expect 300k hits, but this area of work appears to be unknown even after 20+ years of work. If there aren’t many publications in mid- to high-impact journals, despite being known for 15-20+ years, why is that? All it takes is one exciting paper on a subject, and then you have tons of competition (and/or collaboration).

I used to believe that every paper should be peer reviewed. Then I served as an editor for a low-ranked journal, and realized that some gate-keeping is necessary to not waste reviewers’ time. Top journals can afford to gatekeep on priority, but the mid-tier journals gatekeep on technical correctness and ‘was there an advance?’. With the existence of PLoS One, Sci Rep, and MDPI which mostly gatekeep on the latter, why publish in a journal that fewer people are expected to cite?

One or two low-ranked pubs alone aren’t an issue because as stated, there are reasons why people may need to publish there. But of the top 10 most important citations listed, only 3 were published in the last decade, and the best journal out of these is the oldest. This is not a strong list of publications to support proposed work.

I think the opposite will occur with pre-prints due them conveying the luxury of time for authors, and the information overload (which is a problem I see The Longevist solving). But that’s a seperate topic.

3 Likes

When I first reviewed the project I also flagged the lack of recent high impact publications. However, when seeing the full story I think this is an excellent example of why Eroom’s law exists. We all have these biases that don’t allow us to see the potential in a project (another of my biases was that I couldn’t imagine buckyball could be safe). This is a great story with solid data, it just took someone with a passion to shape the project. Had Jack not coined the phrase Eroom’s law I probably wouldn’t have dug deeper. But I knew there must be more to the story. C3’s lifespan effects are almost on par with rapamycin’s. That’s what should matter. Regardless of what happens with C3, Rapalogs are investible, so I think C3alogs should be too.

4 Likes

Thanks for the follow up questions. Turning first to rare diseases, we have given a lot more detail to the working group; both of the long list of potential indications and of the process we will use to prune the list down to a small handful for further investment. You are right that I don’t want to provide all that detail here given that there is an outside chance it could compromise our ability to secure method of use patents.

I will, however, say that our indication selection process is very sensitive to the likely predictive validity of disease models (or other sources of information such as human genetics) and also considers a range of other criteria such as clinical developability, IP, etc.

I would add that the evaluation of screening and disease model quality has been a major part of my work since long before I got involved in Etheros. I have been publishing work in the area and have also been consulting to companies on the subject of model validity / model evaluation / model choice. See here for example for some of my work:

Scannell JW, Bosley J, Hickman JA, Dawson GR, Truebel H, Ferreira GS, Richards D, Treherne JM. Predictive validity in drug discovery: what it is, why it matters and how to improve it. Nat Rev Drug Discov. 2022 Dec;21(12):915-931.

Scannell JW, Bosley J (2016) When Quality Beats Quantity: Decision Theory, Drug Discovery, and the Reproducibility Crisis. PLoS ONE 11(2): e0147215.

Ewart, L., Apostolou, A., Briggs, S.A. et al. Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology. Commun Med 2 , 154 (2022).

Regarding 3rd party collaborations, I apologize that it is hard to be clear without providing detail. There are two parties who I believe would start work quickly should we be able to supply C3. One is an academic group. One is a philanthropic body, which hopes to fund both efficacy and PK/PD testing in their area of interest (an age-related neurodegenerative pathology). The philanthropic body has given us permission to disclose our potential collaboration. I would be happy to introduce their CEO to working group members if the working group wants to understand more.

Recall also that C3 is off patent (although we do not believe there is a practical source of supply at present other than the Dugan lab). It is important to us that we can control the use to which C3 and that we can secure the IP. We think it would be harder to be able to insist on these conditions if the 3rd party had paid for the C3 and pays for all the testing.

I should add that the 3rd party collaborations are not the central plank of our plans. We believe they could be a cost effective way of exploring therapeutic opportunities. But we have not yet signed any contracts. We want to synthesise a stock of C3 for three reasons. First, to allow us to enter into collaborations should the terms be favourable. Second, so we have a stock of C3 for our own preclinical testing when we raise more capital. And third, as a feedstock for novel chemistry.

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An additional follow up comment on Dugan lab funding.

We totalled the grant funding that supported direct testing of the fullerene-derivatives and/or model development. The total is around $40m. The NIH was the largest source and there was also VA, DoD funding and philanthropic support.

Not all the NIH funding will show up under Laura’s name as she was co-PI on some of the grants (mainly those with Joel Perlmutter for the primate work). When these grants were awarded there was no way to show them as multi-PI grants.

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I came across an interesting paper that adds to the literature suggesting that viral infection → neuroinflammation → large increase in the risk of Parkinson’s, Alzheimer’s, MS, etc. Recall that our lead compound, C3, is a brain penetrant anti-inflammatory / neuroprotectant that we already know is effective in a wide range of in vivo neural injury / inflammation models:

Levine et al. (2022) in Neuron. Virus exposure and neurodegenerative disease risk across national biobanks. [doi.org/10.1016/j.neuron.2022.12.029]

From the paper:

“Additional concerns regarding the potential short and long-term cognitive impact of the current coronavirus pandemic have raised the priority of investigating the potential connection between viral exposures and neuroinflammation and/or neurodegeneration”

“This suggests that these viruses may increase NDD risk by lowering cognitive reserve (resilience to neurodegeneration and the ability to carry out complex mental tasks) by contributing to inflammation in the brain.”

“…growing and robust evidence points toward the immune system response and neuroinflammation as major disease contributors.”

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